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Criado-Otero M, Navedo-de las Heras M, Samaniego-González E. Topical and Intralesional Treatments for Skin Metastases and Locoregionally Advanced Melanoma. Cancers (Basel) 2024; 17:67. [PMID: 39796696 PMCID: PMC11718870 DOI: 10.3390/cancers17010067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/22/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Cutaneous melanoma is a malignant neoplasm with local and distant metastatic potential. When feasible, surgery is the first line of treatment in locoregionally advanced disease. Topical and intralesional treatments can be an alternative second-line treatment. The aim of this article was to perform a narrative review of the most widely used topical and intralesional treatments for locoregionally advanced melanoma. Diphenciprone, imiquimod and 5-florouracil were included as topical treatments and bacillus Calmette-Guerin, interleukin 2, rose bengal, talimogene laherparepvec and electrochemotherapy were included as intralesional treatments. Brief comments on other alternatives in development such as interferon-alpha, interleukin-12, ipilimumab and intralesional daromun are presented. Topical treatments generally have higher response rates in epidermal metastases than in deeper metastases. In addition, the larger the lesions, the worse they tend to respond to local treatments. Some reports show that combining certain systemic treatments and topical or intralesional therapies can improve response rates. It has also been described in a few papers that non-injected lesions may respond after the application of a local therapy in distant skin-metastases. Many of these intralesional treatments are being combined in different investigations with systemic immunotherapies, with the aim of obtaining synergic responses in those patients with refractory disease.
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Affiliation(s)
- María Criado-Otero
- Dermatology Department, Complejo Asistencial Universitario de León, 24008 León, Spain; (M.N.-d.l.H.); (E.S.-G.)
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Fay CJ, Jakuboski S, Mclellan B, Allais BS, Semenov Y, Larocca CA, LeBoeuf NR. Diagnosis and Management of Dermatologic Adverse Events from Systemic Melanoma Therapies. Am J Clin Dermatol 2023; 24:765-785. [PMID: 37395930 PMCID: PMC10796164 DOI: 10.1007/s40257-023-00790-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2023] [Indexed: 07/04/2023]
Abstract
The advent of protein kinase inhibitors and immunotherapy has profoundly improved the management of advanced melanoma. However, with these therapeutic advancements also come drug-related toxicities that have the potential to affect various organ systems. We review dermatologic adverse events from targeted (including BRAF and MEK inhibitor-related) and less commonly used melanoma treatments, with a focus on diagnosis and management. As immunotherapy-related toxicities have been extensively reviewed, herein, we discuss injectable talimogene laherparepvec and touch on recent breakthroughs in the immunotherapy space. Dermatologic adverse events may severely impact quality of life and are associated with response and survival. It is therefore essential that clinicians are aware of their diverse presentations and management strategies.
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Affiliation(s)
- Christopher J Fay
- Department of Dermatology, Brigham and Women's Hospital, and the Center for Cutaneous Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA
| | | | - Beth Mclellan
- Department of Dermatology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Blair S Allais
- Department of Dermatology, Brigham and Women's Hospital, and the Center for Cutaneous Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Yevgeniy Semenov
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cecilia A Larocca
- Department of Dermatology, Brigham and Women's Hospital, and the Center for Cutaneous Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Nicole R LeBoeuf
- Department of Dermatology, Brigham and Women's Hospital, and the Center for Cutaneous Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.
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Prajapat VM, Mahajan S, Paul PG, Aalhate M, Mehandole A, Madan J, Dua K, Chellappan DK, Singh SK, Singh PK. Nanomedicine: A pragmatic approach for tackling melanoma skin cancer. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
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Tran CA, Lynch KT, Meneveau MO, Katyal P, Olson WC, Slingluff CL. Intratumoral IFN-γ or topical TLR7 agonist promotes infiltration of melanoma metastases by T lymphocytes expanded in the blood after cancer vaccine. J Immunother Cancer 2023; 11:e005952. [PMID: 36746511 PMCID: PMC9906378 DOI: 10.1136/jitc-2022-005952] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Immune-mediated melanoma regression relies on melanoma-reactive T cells infiltrating tumor. Cancer vaccines increase circulating melanoma-reactive T cells, but little is known about vaccine-induced circulating lymphocytes (viCLs) homing to tumor or whether interventions are needed to enhance infiltration. We hypothesized that viCLs infiltrate melanoma metastases, and intratumoral interferon (IFN)-γ or Toll-like receptor 7 (TLR7) agonism enhances infiltration. METHODS Patients on two clinical trials (Mel51 (NCT00977145), Mel53 (NCT01264731)) received vaccines containing 12 class I major histocompatibility complex-restricted melanoma peptides (12MP). In Mel51, tumor was injected with IFN-γ on day 22, and biopsied on days 1, 22, and 24. In Mel53, dermal metastases were treated with topical imiquimod, a TLR7 agonist, for 12 weeks, and biopsied on days 1, 22, and 43. For patients with circulating T-cell responses to 12MP by IFN-γ ELISpot assays, DNA was extracted from peripheral blood mononuclear cells (PBMCs) pre-vaccination and at peak T-cell response, and from tumor biopsies, which underwent T-cell receptor sequencing. This enabled identification of clonotypes induced in PBMCs post-vaccination (viCLs) and present in tumor post-vaccination, but not pre-vaccination. RESULTS Six patients with T-cell responses post-vaccination (Mel51 n = 4, Mel53 n = 2) were evaluated for viCLs and vaccine-induced tumor infiltrating lymphocytes (viTILs). All six patients had viCLs, five of whom were evaluable for viTILs in tumor post-vaccination alone. Mel51 patients had viTILs identified in day 22 tumors, post-vaccination and before IFN-γ (median = 2, range = 0-24). This increased in day 24 tumors after IFN-γ (median = 30, range = 4-74). Mel53 patients had viTILs identified in day 22 tumors, post-vaccination plus imiquimod (median = 33, range = 2-64). Three of five evaluable patients across both trials had viTILs with vaccination alone. All five had enhancement of viTILs with tumor-directed therapy. viTILs represented 0.0-2.9% of total T cells after vaccination alone, which increased to 0.6-8.7% after tumor-directed therapy. CONCLUSION Cancer vaccines induce expansion of new viCLs, which infiltrate melanoma metastases in some patients. Our findings identify opportunities to combine vaccines with tumor-directed therapies to enhance T-cell infiltration and T cell-mediated tumor control. These combinations hold promise in improving the therapeutic efficacy of antigen-specific therapies for solid malignancies.
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Affiliation(s)
- Christine A Tran
- Department of Surgery, University of Virginia Health, Charlottesville, Virginia, USA
| | - Kevin T Lynch
- Department of Surgery, University of Virginia Health, Charlottesville, Virginia, USA
| | - Max O Meneveau
- Department of Surgery, University of Virginia Health, Charlottesville, Virginia, USA
| | - Priya Katyal
- University of Virginia College and Graduate School of Arts and Sciences, Charlottesville, Virginia, USA
| | - Walter C Olson
- Department of Surgery, University of Virginia Health, Charlottesville, Virginia, USA
| | - Craig L Slingluff
- Department of Surgery, University of Virginia Health, Charlottesville, Virginia, USA
- Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA
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Skudalski L, Waldman R, Kerr PE, Grant-Kels JM. Melanoma: An update on systemic therapies. J Am Acad Dermatol 2022; 86:515-524. [PMID: 34915056 DOI: 10.1016/j.jaad.2021.09.075] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/10/2021] [Accepted: 09/11/2021] [Indexed: 10/19/2022]
Abstract
Despite advances in early detection as described in part 1 of this continuing medical education series, melanoma continues to be a large contributor to cutaneous cancer-related mortality. In a subset of patients with unresectable or metastatic disease, surgical clearance is often not possible; therefore, systemic and local therapies are considered. The second article in this series provides dermatologists with an up-to-date working knowledge of the treatment options that may be prescribed by oncologists for patients with unresectable stage III, stage IV, and recurrent melanoma.
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Affiliation(s)
- Lauren Skudalski
- Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut
| | - Reid Waldman
- Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut
| | - Philip E Kerr
- Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut
| | - Jane M Grant-Kels
- Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut; Department of Dermatology, University of Florida College of Medicine, Gainesville, Florida.
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Knackstedt R, Smile T, Yu J, Gastman BR. Non-Operative Options for Loco-regional Melanoma. Clin Plast Surg 2021; 48:631-642. [PMID: 34503723 DOI: 10.1016/j.cps.2021.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Malignant melanoma is the 5th most common cancer and stage IV melanoma accounts for approximately 4% of new melanoma diagnoses in the United States. The prognosis for regionally advanced disease is poor, but there have been numerous recent advances in the medical management of melanoma in-transit metastases. The goal of this paper is to review currently accepted treatment options for in-transit metastases and introduce emerging therapies. Therapies to be discussed include limb perfusion and infusion, immunotherapy, checkpoint inhibitors, and radiation therapy.
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Affiliation(s)
- Rebecca Knackstedt
- Department of Plastic Surgery, Cleveland Clinic, 2049 East 100th Street, Desk A60, Cleveland, OH 44195, USA
| | - Timothy Smile
- Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Center, 10201 Carnegie Avenue, Cleveland, OH 44195, USA
| | - Jennifer Yu
- Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Center, 10201 Carnegie Avenue, Cleveland, OH 44195, USA
| | - Brian R Gastman
- Department of Plastic Surgery, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, 2049 East 100th Street, Desk A60, Cleveland, OH 44195, USA.
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Chanda M, Cohen MS. Advances in the discovery and development of melanoma drug therapies. Expert Opin Drug Discov 2021; 16:1319-1347. [PMID: 34157926 DOI: 10.1080/17460441.2021.1942834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Therapeutic strategies for melanoma have evolved significantly over the last decade shifting from cytotoxic chemotherapies like dacarbazine to targeted therapies and immunotherapies including immune checkpoint inhibitors. These new drug therapies have improved overall as well as progression-free survival, lowering the mortality of this cancer for melanoma patients with advanced disease. Newer strategies incorporate combination therapies that harness synergies between mechanisms of anticancer efficacy as well as help overcome resistance issues of monotherapies, which remain a challenge. AREAS COVERED This review looks at each class of drug therapy for melanoma and provides an overview of the preclinical mechanism of action, the clinical efficacy data, and their applications in combination therapy regimens. NCCN treatment guidelines, safety, toxicity, and immune-related adverse events are also described as well as a note on cost. EXPERT OPINION Numerous ongoing trials continue to evaluate the role of novel therapies and combinations for this challenging disease and understanding their mechanism of action, risks, benefits, and treatment guidelines can help care providers and patients have a more comprehensive and tailored discussion of treatment options and expectations.
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Affiliation(s)
- Monica Chanda
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
| | - Mark S Cohen
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.,Department of Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
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Zhao R, Cao J, Yang X, Zhang Q, Iqbal MZ, Lu J, Kong X. Inorganic material based macrophage regulation for cancer therapy: basic concepts and recent advances. Biomater Sci 2021; 9:4568-4590. [PMID: 34113942 DOI: 10.1039/d1bm00508a] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Macrophages with the M1 phenotype are a type of immune cell with exciting prospects for cancer therapy; however, when these macrophages infiltrate into tumours, many of them are induced by the tumour microenvironment to transform into the M2 type, which can enable tumour defence against external therapeutic strategies, assisting in tumour development. Macrophages have strong plasticity and functional heterogeneity, and their phenotypic transformation is complex and still poorly understood in relation to cancer therapy. Recent material advances in inorganic nanomaterials, especially inorganic elements in vivo, have accelerated the development of macrophage regulation-based cancer treatments. This review summarizes the basics of recent research on macrophage phenotype transformation and discusses the current challenges in macrophage type regulation. Then, the current achievements involving inorganic material-based macrophage regulation and the related anticancer effects of induced macrophages and their extracellular secretions are reviewed systematically. Importantly, inorganic nanomaterial-based macrophage phenotype regulation is flexible and can be adapted for different types of cancer therapies, presenting a possible novel approach for the generation of immune materials for cancer therapy.
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Affiliation(s)
- Ruibo Zhao
- Institute of Smart Biomaterials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China. and Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China
| | - Jinping Cao
- Institute of Smart Biomaterials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China. and Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China
| | - Xinyan Yang
- School of Bioengineering, Hangzhou Medical College, Hangzhou 310013, Zhejiang, China
| | - Quan Zhang
- Institute of Smart Biomaterials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China. and Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China
| | - Muhammad Zubair Iqbal
- Institute of Smart Biomaterials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China. and Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China
| | - Jiaju Lu
- Institute of Smart Biomaterials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China. and Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China
| | - Xiangdong Kong
- Institute of Smart Biomaterials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China. and Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China
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Eddy K, Chen S. Overcoming Immune Evasion in Melanoma. Int J Mol Sci 2020; 21:E8984. [PMID: 33256089 PMCID: PMC7730443 DOI: 10.3390/ijms21238984] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/17/2020] [Accepted: 11/25/2020] [Indexed: 02/06/2023] Open
Abstract
Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in situ, as it is "curable" at this stage. However, after metastasis, it is difficult to treat and the five-year survival is only 25%. In recent years, a better understanding of the etiology of melanoma and its progression has made it possible for the development of targeted therapeutics, such as vemurafenib and immunotherapies, to treat advanced melanomas. In this review, we focus on the molecular mechanisms that mediate melanoma development and progression, with a special focus on the immune evasion strategies utilized by melanomas, to evade host immune surveillances. The proposed mechanism of action and the roles of immunotherapeutic agents, ipilimumab, nivolumab, pembrolizumab, and atezolizumab, adoptive T- cell therapy plus T-VEC in the treatment of advanced melanoma are discussed. In this review, we implore that a better understanding of the steps that mediate melanoma onset and progression, immune evasion strategies exploited by these tumor cells, and the identification of biomarkers to predict treatment response are critical in the design of improved strategies to improve clinical outcomes for patients with this deadly disease.
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Affiliation(s)
- Kevinn Eddy
- Graduate Program in Cellular and Molecular Pharmacology, School of Graduate Studies Rutgers University, Piscataway, NJ 08854, USA;
- Susan Lehman Cullman Laboratory for Cancer Research, Rutgers University, Piscataway, NJ 08854, USA
| | - Suzie Chen
- Graduate Program in Cellular and Molecular Pharmacology, School of Graduate Studies Rutgers University, Piscataway, NJ 08854, USA;
- Susan Lehman Cullman Laboratory for Cancer Research, Rutgers University, Piscataway, NJ 08854, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
- Environmental & Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA
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Scarfì F, Patrizi A, Veronesi G, Lambertini M, Tartari F, Mussi M, Melotti B, Dika E. The role of topical imiquimod in melanoma cutaneous metastases: A critical review of the literature. Dermatol Ther 2020; 33:e14165. [PMID: 32772481 DOI: 10.1111/dth.14165] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/29/2020] [Accepted: 07/31/2020] [Indexed: 02/06/2023]
Abstract
Despite of the emerging new systemic and local oncologic treatments (immunotherapy and checkpoint inhibitors, oncolytic viral treatments and injected immunostimulants) the management of skin melanoma metastasis can be still challenging. The main aim of this review was to assess the efficacy and the role of imiquimod in local metastatic melanoma disease. An extensive literature review was performed from September 2000 to March 2020 using PubMed, MEDLINE, Embase, and Cochrane Library databases. Selected articles regarded topical imiquimod, its mode of action as an antitumoral agent and its applications in melanoma metastases treatment. We analyzed a total of 18 published article of clinical cases and small case series and five studies: two retrospective large case series, two Phase I and II clinical trials and one cohort non randomized study. Generally, the treatment is safe and well tolerated. Imiquimod lead to an unstable locoregional control. The use of topical imiquimod for the treatment of MM cutaneous metastases should be considered in selected cases and in palliative settings.
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Affiliation(s)
- Federica Scarfì
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Annalisa Patrizi
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Giulia Veronesi
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Martina Lambertini
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Federico Tartari
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Martina Mussi
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Barbara Melotti
- Oncology Unit, Department of Diagnostic Medicine and Prevention, Sant'Orsola Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Emi Dika
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
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11
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Vrielink OM, Kruijff S, van Leeuwen BL, Roodenburg JL. Application of CO 2 laser evaporation in locally advanced melanoma. Melanoma Manag 2019; 6:MMT14. [PMID: 31236206 PMCID: PMC6582456 DOI: 10.2217/mmt-2018-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 02/18/2019] [Indexed: 11/21/2022] Open
Abstract
Aim This study aims to investigate the role of CO2 laser evaporation in the treatment of melanoma patients with satellite or in-transit metastases. Materials & methods Patients who underwent CO2 laser evaporation were retrospectively included between November 2002 and August 2018. The Sharplan 40C CO2 laser was used with a high pulse wave mode. Data concerning patient and tumor characteristics, CO2 laser evaporation and subsequent therapies were collected. Results A total of 26 patients were included. Median duration of local control was 5.5 months. The median number of lesions evaporated per treatment was three (1-16); patients received a median of three (1-19) treatments. Conclusion In a selected group of melanoma patients with satellite or in-transit metastases, CO2 laser evaporation should be considered as treatment for local control.
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Affiliation(s)
- Otis M Vrielink
- Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Schelto Kruijff
- Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Barbara L van Leeuwen
- Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan Ln Roodenburg
- Department of Oral & Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Oral & Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Mishra H, Mishra PK, Ekielski A, Jaggi M, Iqbal Z, Talegaonkar S. Melanoma treatment: from conventional to nanotechnology. J Cancer Res Clin Oncol 2018; 144:2283-2302. [PMID: 30094536 DOI: 10.1007/s00432-018-2726-1] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 07/30/2018] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Melanoma is the most serious form of skin cancer causing most of the skin cancer-related deaths. The incidence of melanoma has risen so dramatically over past few years that no other solid or blood malignancy comes close to it in terms of increased incidence. The main problem associated with the treatment of melanoma is low response rate to the existing treatment modalities, which in turn is due to the incomplete response by chemotherapeutic agents and inherent resistance of melanoma cells. MATERIALS AND METHODS Conventional therapeutic strategies, as well as, recent literature on melanoma have been thoroughly studied. This review summarizes the base of anti-melanoma treatment with conventional chemotherapeutic drugs, followed by an account of recent studies which explored the potential of nanotechnology and newer strategies and agents in melanoma treatment. CONCLUSION Although melanoma is curable if detected in its early localized form, metastatic melanoma continues to be a therapeutic challenge. Metastatic melanoma has a very poor prognosis and conventional therapies have not improved the outcomes of the treatment so far. For this reason, newer combinations of anti-melanoma drugs and newer strategies utilizing nanotechnology have been constantly explored.
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Affiliation(s)
- Harshita Mishra
- School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Pawan K Mishra
- Department of Wood Processing Technologies, Mendel University in Brno, Brno, Czech Republic
| | - Adam Ekielski
- Department of Production Management and Engineering, Faculty of Production Engineering, Warsaw University of Life Sciences, Warsaw, Poland
| | - Manu Jaggi
- Dabur Research Foundation, Ghaziabad, India
| | - Zeenat Iqbal
- School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Sushama Talegaonkar
- School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
- Department of Pharmaceutics, Delhi Pharmaceutical Sciences and Research University, Government of NCT of Delhi, New Delhi, India.
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Chiang CLL, Kandalaft LE. In vivo cancer vaccination: Which dendritic cells to target and how? Cancer Treat Rev 2018; 71:88-101. [PMID: 30390423 DOI: 10.1016/j.ctrv.2018.10.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/20/2018] [Accepted: 10/22/2018] [Indexed: 12/24/2022]
Abstract
The field of cancer immunotherapy has been revolutionized with the use of immune checkpoint blockade antibodies such as anti-programmed cell death 1 protein (PD-1) and chimeric antigen receptor T cells. Significant clinical benefits are observed in different cancer types with these treatments. While considerable efforts are made in augmenting tumor-specific T cell responses with these therapies, other immunotherapies that actively stimulate endogenous anti-tumor T cells and generating long-term memory have received less attention. Given the high cost of cancer immunotherapies especially with chimeric antigen receptor T cells, not many patients will have access to such treatments. The next-generation of cancer immunotherapy could entail in vivo cancer vaccination to activate both the innate and adaptive anti-tumor responses. This could potentially be achieved via in vivo targeting of dendritic cells which are an indispensable link between the innate and adaptive immunities. Dendritic cells highly expressed toll-like receptors for recognizing and eliminating pathogens. Synthetic toll-like receptors agonists could be synthesized at a low cost and have shown promise in preclinical and clinical trials. As different subsets of human dendritic cells exist in the immune system, activation with different toll-like receptor agonists could exert profound effects on the quality and magnitude of anti-tumor T cell responses. Here, we reviewed the different subsets of human dendritic cells. Using published preclinical and clinical cancers studies available on PubMed, we discussed the use of clinically approved and emerging toll-like receptor agonists to activate dendritic cells in vivo for cancer immunotherapy. Finally, we searched www.clinicaltrials.gov and summarized the active cancer trials evaluating toll-like receptor agonists as an adjuvant.
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Affiliation(s)
- Cheryl Lai-Lai Chiang
- Ludwig Institute for Cancer Research, and Department of Oncology, University Hospital of Lausanne (CHUV), Lausanne CH-1066, Switzerland
| | - Lana E Kandalaft
- Ludwig Institute for Cancer Research, and Department of Oncology, University Hospital of Lausanne (CHUV), Lausanne CH-1066, Switzerland; Ovarian Cancer Research Center, University of Pennsylvania Medical Center, Smilow Translational Research Center 8th Floor, 186B, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
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14
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Manome Y, Suzuki D, Mochizuki A, Saito E, Sasa K, Yoshimura K, Inoue T, Takami M, Inagaki K, Funatsu T, Kamijo R. The inhibition of malignant melanoma cell invasion of bone by the TLR7 agonist R848 is dependent upon pro-inflammatory cytokines produced by bone marrow macrophages. Oncotarget 2018; 9:29934-29943. [PMID: 30042824 PMCID: PMC6057452 DOI: 10.18632/oncotarget.25711] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 06/12/2018] [Indexed: 12/22/2022] Open
Abstract
Distant metastasis remarkably worsens the prognoses of malignant melanoma patients. Toll-like receptors (TLRs) recognize molecules derived from many types of pathogens and activate the innate intravital immune system. In this study, we examined the effects of R848, a TLR7 ligand, on bone invasion by malignant melanoma cells. Mice underwent transplantation with cells of a malignant melanoma cell line B16F10, and were also administered R848 every three days. Hindlimbs were obtained 13 days after transplantation and invasion of bone marrow by B16F10 cells was evaluated. ELISA was used to determine the concentrations of cytokines in mouse serum and in the culture medium from bone marrow macrophages (BMMs) in the presence or absence of R848. In addition, MTS assays were used to examine the effects of media from BMM cultures on the proliferation of B16F10 cells. The rate of infiltration by B16F10 cells and the area of invasion were significantly reduced with R848 administration. Furthermore, serum levels of IL-6, IL-12, and IFN-γ were significantly increased in mice administered R848, with the same trend observed in the culture medium of BMMs treated with R848. In addition, B16F10 cell proliferation was suppressed by the addition of medium from cultured BMMs treated with R848. Neutralization by antibodies against IL-6, IL-12, and IFN-γ abrogated the suppression of proliferation of B16F10 cells by culture medium from BMMs treated with R848. Our results suggest that R848 drives the production of IL-6, IL-12, and IFN-γ in BMMs, which reduces proliferation and bone invasion by B16F10 cells.
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Affiliation(s)
- Yoko Manome
- Departments of Biochemistry School of Dentistry, Showa University, Shinagawa, Tokyo, Japan.,Department of Special Needs Dentistry, Division of Dentistry for Persons with Disabilities, Showa University Dental Hospital, Shinagawa, Tokyo, Japan
| | - Dai Suzuki
- Departments of Biochemistry School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
| | - Ayako Mochizuki
- Departments of Oral Physiology School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
| | - Emi Saito
- Departments of Biochemistry School of Dentistry, Showa University, Shinagawa, Tokyo, Japan.,Department of Orthopedic Surgery School of Medicine, Showa University, Shinagawa, Tokyo, Japan
| | - Kiyohito Sasa
- Departments of Biochemistry School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
| | - Kentaro Yoshimura
- Departments of Biochemistry School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
| | - Tomio Inoue
- Departments of Oral Physiology School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
| | - Masamichi Takami
- Departments of Pharmacology School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
| | - Katsunori Inagaki
- Department of Orthopedic Surgery School of Medicine, Showa University, Shinagawa, Tokyo, Japan
| | - Takahiro Funatsu
- Department of Special Needs Dentistry, Division of Dentistry for Persons with Disabilities, Showa University Dental Hospital, Shinagawa, Tokyo, Japan
| | - Ryutaro Kamijo
- Departments of Biochemistry School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
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15
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Vola M, Mónaco A, Bascuas T, Rimsky G, Agorio CI, Chabalgoity JA, Moreno M. TLR7 agonist in combination with Salmonella as an effective antimelanoma immunotherapy. Immunotherapy 2018; 10:665-679. [PMID: 29562809 DOI: 10.2217/imt-2017-0188] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM We evaluated a novel approach combining the use of attenuated Salmonella immunotherapy with a Toll-like receptor agonist, imiquimod, in B16F1 melanoma-bearing mice. MATERIALS & METHODS B16F1 melanoma-bearing mice were daily treated with topical imiquimod in combination with one intratumoral injection of attenuated Salmonella enterica serovar Typhimurium LVR01. RESULTS The combined therapy resulted in retarded tumor growth and prolonged survival. Combination treatment led to an enhancement in the expression of pro-inflammatory cytokines and chemokines in the tumor microenvironment, with a Th1-skewed profile, resulting in a broad antitumor response. The induced immunity was effective in controlling the occurrence of metastasis. CONCLUSION Salmonella LVR01 immunotherapy in combination with imiquimod is a novel approach that could be considered as an effective antimelanoma therapy.
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Affiliation(s)
- Magdalena Vola
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene. Facultad de Medicina, Universidad de la República. Av. A. Navarro 3051, Montevideo, CP 11600, Uruguay.,Cátedra de Dermatología, Hospital de Clínicas 'Dr. Manuel Quintela'. Facultad de Medicina, Universidad de la República. Av. Italia s/n, Montevideo, Uruguay
| | - Amy Mónaco
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene. Facultad de Medicina, Universidad de la República. Av. A. Navarro 3051, Montevideo, CP 11600, Uruguay
| | - Thais Bascuas
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene. Facultad de Medicina, Universidad de la República. Av. A. Navarro 3051, Montevideo, CP 11600, Uruguay
| | - Geraldine Rimsky
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene. Facultad de Medicina, Universidad de la República. Av. A. Navarro 3051, Montevideo, CP 11600, Uruguay
| | - Caroline Isabel Agorio
- Cátedra de Dermatología, Hospital de Clínicas 'Dr. Manuel Quintela'. Facultad de Medicina, Universidad de la República. Av. Italia s/n, Montevideo, Uruguay
| | - José Alejandro Chabalgoity
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene. Facultad de Medicina, Universidad de la República. Av. A. Navarro 3051, Montevideo, CP 11600, Uruguay
| | - María Moreno
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene. Facultad de Medicina, Universidad de la República. Av. A. Navarro 3051, Montevideo, CP 11600, Uruguay
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16
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Hanna E, Abadi R, Abbas O. Imiquimod in dermatology: an overview. Int J Dermatol 2017; 55:831-44. [PMID: 27387373 DOI: 10.1111/ijd.13235] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 07/28/2015] [Accepted: 11/04/2015] [Indexed: 11/28/2022]
Abstract
Imiquimod is an immune response modifier commercially available as a 3.75 and 5% cream. Topical imiquimod stimulates the innate and adaptive immune responses and induces cytokine production. This allows its use for the treatment of a wide variety of benign and malignant skin conditions due to its potential antiviral, antitumor, and immunoregulatory effects. Currently, topical imiquimod is US Food and Drug Administration (FDA)-approved for the treatment of anogenital warts, actinic keratosis, and superficial basal cell carcinomas. However, it has also shown a beneficial effect in the treatment of many other skin disorders. In this review, we describe existing evidence on the mechanism of action of topical imiquimod, its FDA-approved indications, off-label uses, and side effects.
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Affiliation(s)
- Edith Hanna
- American University of Beirut-Medical Center, Beirut, Lebanon
| | - Rami Abadi
- American University of Beirut-Medical Center, Beirut, Lebanon
| | - Ossama Abbas
- American University of Beirut-Medical Center, Beirut, Lebanon
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17
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Ibrahim S, Al-Turk B, Harris C, Al-Saffar F, Said S, Farsi M, Winder J, Landa C. Melanoma Masquerading as a Zosteriform Rash. AMERICAN JOURNAL OF CASE REPORTS 2017; 18:537-540. [PMID: 28507284 PMCID: PMC5441273 DOI: 10.12659/ajcr.902377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Primary care physicians and internal medicine specialists frequently encounter a variety of rashes. Many of these cases look and feel typical of common entities, resulting in the potential for misdiagnosis. CASE REPORT This is a case of a zosteriform rash where the surprising true diagnosis of metastatic melanoma was confirmed with bedside skin punch biopsy. Possible mechanisms involve direct cutaneous injury, neuronal, and dorsal root ganglia involvement in metastases. CONCLUSIONS Skin biopsy is indispensable especially when there is a lack of clinical response or deterioration in the clinical condition. The pathophysiology of zosteriform metastasis is unclear.
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Affiliation(s)
- Saif Ibrahim
- Department of Cardiology, University of Florida, Jacksonville, FL, USA
| | - Bashar Al-Turk
- Department of Medicine, University of Florida, Jacksonville, FL, USA
| | - Ciel Harris
- Department of Medicine, University of Florida, Jacksonville, FL, USA
| | | | - Sayf Said
- Department of Medicine, Providence Hospital, Washington, DC, USA
| | - Maheera Farsi
- Department of Dermatology, Largo Medical Center, Largo, FL, USA
| | - Jeffrey Winder
- Department of Medicine, University of Florida, Jacksonville, FL, USA
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18
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Tio D, van der Woude J, Prinsen CAC, Jansma EP, Hoekzema R, van Montfrans C. A systematic review on the role of imiquimod in lentigo maligna and lentigo maligna melanoma: need for standardization of treatment schedule and outcome measures. J Eur Acad Dermatol Venereol 2017; 31:616-624. [PMID: 27987308 DOI: 10.1111/jdv.14085] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 12/02/2016] [Indexed: 12/12/2022]
Abstract
Lentigo maligna (LM) is an in situ variant of melanoma. Our objective was to systematically review clinical and histological clearance and recurrence rates of imiquimod treatment of LM with emphasis on progression to lentigo maligna melanoma (LMM). PubMed, EMBASE and the Cochrane library were searched from inception to May 2015. Articles were included if they described histologically proven LM treated with imiquimod 5% monotherapy or combined with another topical therapy. Analysed outcomes were clinical and histological clearance, recurrence rates and number of LMM. The quality was assessed using the GRADE-like checklist, and results were reported according to the PRISMA Statement. Twenty-six case reports, 11 retrospective studies, three prospective studies and one randomized controlled trial were included. One case report of poor quality was excluded. Complete clinical clearance was seen in 369 of 471 patients (78.3%). Histological clearance was present in 285 of 370 (77%) patients. LMM was diagnosed in nine (1.8%) patients 3.9 months (range 0-11 months) post-treatment. Univariate multinominal logistic regression showed that 6-7 applications/week had a 6.47 greater odds (P = 0.017) of resulting in complete clinical clearance compared to 1-4 applications/week. An intensity of 6-7 applications/week showed a 8.85 greater odds (P = 0.003) of resulting in histological clearance compared to 1-4 applications. Applying imiquimod >60 times during a treatment period of 12 weeks (range 4-36) showed a 7.75 greater odds (P = 0.001) of resulting in histological clearance compared to <60 total applications. In conclusion, a treatment schedule using imiquimod 6-7 applications per week, with at least 60 applications, shows the greatest odds of complete clinical and histological clearance of LM. Imiquimod is an option for patients unfit for or not willing to undergo surgery or radiotherapy. Nine cases of LM progressed to LMM shortly after treatment. Our hypothesis is that these LMM may have been present before starting imiquimod.
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Affiliation(s)
- D Tio
- Department of Dermatology, VUmc Amsterdam, Amsterdam, The Netherlands
| | | | - C A C Prinsen
- Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VUmc Amsterdam, Amsterdam, The Netherlands
| | - E P Jansma
- VU University Amsterdam, Amsterdam, The Netherlands
| | - R Hoekzema
- Department of Dermatology, VUmc Amsterdam, Amsterdam, The Netherlands
| | - C van Montfrans
- Department of Dermatology, Erasmus Medical Center, Rotterdam, The Netherlands
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19
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Testori A, Ribero S, Bataille V. Diagnosis and treatment of in-transit melanoma metastases. Eur J Surg Oncol 2016; 43:544-560. [PMID: 27923593 DOI: 10.1016/j.ejso.2016.10.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 10/10/2016] [Accepted: 10/12/2016] [Indexed: 01/09/2023] Open
Abstract
In transit metastases (ITM) from extremity or trunk melanomas are subcutaneous or cutaneous lymphatic deposits of melanoma cells, distant from the primary site but not reaching the draining nodal basin. Superficial ITM metastases develop in 5-10% of melanoma patients and are thought to be caused by cells spreading along lymphatics; ITM appear biologically different from distant cutaneous metastases, these probably due to a haematogenous dissemination. The diagnosis is usually clinical and by patients, but patients need to be adequately educated in the recognition of this clinical situation. Ultrasound or more sophisticated instrumental devices may be required if the disease develops more deeply in the soft tissues. According to AJCC 2009 staging classification, ITM are included in stages IIIb and IIIc, which are considered local advanced disease with quite poor 5-year survival rates and outcomes of 24-54% at 5 years.2 Loco-regional recurrence is in fact an important risk factor for distant metastatic disease, either synchronous or metachronous. Therapy for this pattern of recurrence is less standardised then in most other clinical situations and options vary based on the volume and site of the disease. Definitive surgical resection remains the preferred therapeutic approach. However, when surgery cannot be performed with a reasonable cosmetic and functional outcome, other options must be utilized.3-6 Treatment options are classified as local, regional or systemic. The choice of therapy depends on the number of lesions, their anatomic location, whether or not these are dermal or subcutaneous, the size and the presence or absence of extra-regional disease.
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Affiliation(s)
- A Testori
- Divisione di Chirurgia Dermatoncologica, Istituto Europeo di Oncologia, Milano, Italy.
| | - S Ribero
- Dermatologia, Dipartimentto di Scienze mediche, Università di Torino, Italy
| | - V Bataille
- West Herts NHS Trust, London, UK; Mount Vernon Cancer Centre, Northwood, UK
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20
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Coati I, Miotto S, Zanetti I, Alaibac M. Toll-like receptors and cutaneous melanoma. Oncol Lett 2016; 12:3655-3661. [PMID: 27900049 DOI: 10.3892/ol.2016.5166] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 06/07/2016] [Indexed: 12/31/2022] Open
Abstract
Innate immune cells recognize highly conserved pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). Previous studies have demonstrated that PRRs also recognize endogenous molecules, termed damage-associated molecular patterns (DAMPs) that are derived from damaged cells. PRRs include Toll-like receptors (TLRs), scavenger receptors, C-type lectin receptors and nucleotide oligomerization domain-like receptors. To date, 10 TLRs have been identified in humans and each receptor responds to a different ligand. The recognition of PAMPS or DAMPs by TLRs leads to the activation of signaling pathways and cellular responses with subsequent pro-inflammatory cytokine release, phagocytosis and antigen presentation. In the human skin, TLRs are expressed by keratinocytes and melanocytes: The main cells from which skin cancers arise. TLRs 1-6 and 9 are expressed in keratinocytes, while TLRs 2-5, 7, 9 and 10 have been identified in melanocytes. It is hypothesized that TLRs may present a target for melanoma therapies. In this review, the involvement of TLRs in the pathogenesis and treatment of melanoma was discussed.
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Affiliation(s)
- Ilaria Coati
- Department of Medicine, Unit of Dermatology, University of Padua, Padua 35128, Italy
| | - Serena Miotto
- Department of Medicine, Unit of Dermatology, University of Padua, Padua 35128, Italy
| | - Irene Zanetti
- Department of Medicine, Unit of Dermatology, University of Padua, Padua 35128, Italy
| | - Mauro Alaibac
- Department of Medicine, Unit of Dermatology, University of Padua, Padua 35128, Italy
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21
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Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases. Cancer Immunol Immunother 2016; 65:1201-12. [PMID: 27522582 DOI: 10.1007/s00262-016-1880-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 08/02/2016] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases. PATIENTS AND METHODS Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression. RESULTS AND CONCLUSIONS Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.
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22
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Chaney J, Gauthier J, Dipanda M, Da Silva S, Lévêque L, Manckoundia P. A Case of Eyelid Melanoma in a 99-Year-Old Woman. J Am Geriatr Soc 2016; 64:234-5. [DOI: 10.1111/jgs.13902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Jonathan Chaney
- Department of Geriatrics and Internal Medicine; Hospital of Champmaillot; University Hospital; Dijon France
| | - Julien Gauthier
- Department of Geriatrics and Internal Medicine; Hospital of Champmaillot; University Hospital; Dijon France
| | - Mélanie Dipanda
- Department of Geriatrics and Internal Medicine; Hospital of Champmaillot; University Hospital; Dijon France
| | - Sofia Da Silva
- Department of Geriatrics and Internal Medicine; Hospital of Champmaillot; University Hospital; Dijon France
| | - Laurent Lévêque
- Department of Geriatrics and Internal Medicine; Hospital of Champmaillot; University Hospital; Dijon France
| | - Patrick Manckoundia
- Department of Geriatrics and Internal Medicine; Hospital of Champmaillot; University Hospital; Dijon France
- Institut National de la Santé et de la Recherche Médicale U1093 Motricity-Plasticity; University of Burgundy; Dijon France
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23
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Abstract
Treatment strategies for metastatic melanoma have changed markedly in recent times due to the advent of targeted systemic therapies. In addition to these developments, surgery remains a useful adjunct that can confer survival benefits in selected patients. In this review, we examine the current literature to highlight the role of surgical intervention in metastatic melanoma in the era of targeted systemic therapies.
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24
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Savarese I, Papi F, D'Errico A, Gori A, Grazzini M, Vannucchi M, Massi D, De Giorgi V. Acral lentiginous melanoma treated with topical imiquimod cream: possible cooperation between drug and tumour cells. Clin Exp Dermatol 2014; 40:27-30. [DOI: 10.1111/ced.12469] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2014] [Indexed: 11/30/2022]
Affiliation(s)
- I. Savarese
- Department of Dermatology; University of Florence; Florence Italy
| | - F. Papi
- Department of Dermatology; University of Florence; Florence Italy
| | - A. D'Errico
- Department of Dermatology; University of Florence; Florence Italy
| | - A. Gori
- Department of Dermatology; University of Florence; Florence Italy
| | - M. Grazzini
- Department of Dermatology; University of Florence; Florence Italy
| | - M. Vannucchi
- Division of Pathological Anatomy; Department of Surgery and Translational Medicine; University of Florence; Florence Italy
| | - D. Massi
- Division of Pathological Anatomy; Department of Surgery and Translational Medicine; University of Florence; Florence Italy
| | - V. De Giorgi
- Division of Pathological Anatomy; Department of Surgery and Translational Medicine; University of Florence; Florence Italy
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25
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Rutkowski P, Zdzienicki M, Kozak K. Subcutaneous metastases from melanoma: a discussion of clinical experience. Melanoma Manag 2014; 1:31-40. [DOI: 10.2217/mmt.14.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
SUMMARY The majority of locoregional relapses of cutaneous melanoma occur as subcutaneous local recurrences/in-transit metastases; subcutaneous metastases (SMs) are also common in distant metastases. SM therapy is challenging and depends on the number, site, depth, size, clinical behavior and presence of other metastases. Isolated, resectable SMs should be treated surgically. In multiple/unresectable lesions, several local modalities are used: carbon dioxide laser ablation, radiotherapy, cryotherapy, intralesional injections and electrochemotherapy. Hyperthermic isolated limb perfusion is the preferred method of treating multiple, bulky in-transit metastases in extremities, allowing for high response rates and long-lasting remission. Electrochemotherapy is a simple method for the fast ablation of SMs that are not feasible for hyperthermic isolated limb perfusion. Recent advances in systemic therapy of melanoma, including immunotherapy (anti-CTLA4/anti-PD-1) and targeted therapy (BRAF/MEK inhibitors), have significantly impacted on SM treatment. We present our own SM cases treated with different modalities. The future of SM therapy will rely on a combination of different local, locoregional and systemic modalities, and we can expect major improvements in long-term outcomes.
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Affiliation(s)
- Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma & Melanoma, Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
| | - Marcin Zdzienicki
- Department of Soft Tissue/Bone Sarcoma & Melanoma, Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
| | - Katarzyna Kozak
- Department of Soft Tissue/Bone Sarcoma & Melanoma, Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
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26
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Micali G, Lacarrubba F, Nasca MR, Ferraro S, Schwartz RA. Topical pharmacotherapy for skin cancer: part II. Clinical applications. J Am Acad Dermatol 2014; 70:979.e1-12; quiz 9912. [PMID: 24831325 DOI: 10.1016/j.jaad.2013.12.037] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Revised: 12/15/2013] [Accepted: 12/20/2013] [Indexed: 01/11/2023]
Abstract
The purpose of the paper is to provide an in-depth, evidence-based analysis of the clinical use of topical treatments for skin cancer. A comprehensive review of topical drugs has been performed, including 5-fluorouracil, imiquimod, diclofenac, ingenol mebutate, retinoids, resiquimod, piroxicam, dobesilate, and betulinic acid. The evaluated studies were rated according to their level of evidence level (I-V), as indicated by recent guidelines for evidence-based medicine, The Oxford 2011 Levels of Evidence. Therapeutic response is generally related to tumor type, extent, and localization, and also to patient compliance. Careful patient selection is required in order to achieve the desired goal of complete tumor clearance.
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Affiliation(s)
| | | | | | | | - Robert A Schwartz
- Department of Dermatology, Rutgers University, New Jersey Medical School, Newark, New Jersey
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27
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Wong CYB, Helm MA, Kalb RE, Helm TN, Zeitouni NC. The presentation, pathology, and current management strategies of cutaneous metastasis. NORTH AMERICAN JOURNAL OF MEDICAL SCIENCES 2014; 5:499-504. [PMID: 24251266 PMCID: PMC3818821 DOI: 10.4103/1947-2714.118918] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Skin metastases are rare in the routine clinical practice of dermatology, but are of major clinical significance because they usually indicate advanced disease. We reviewed the literature on skin metastasis regarding recent trends in clinical presentation and diagnosis of the most common cutaneous lesions. An extensive literature review was conducted using PubMed from May 26, 2011 to July 16, 2013 relating cutaneous metastases. Articles chosen for reference were queried with the following prompts: “Cutaneous metastases”, “clinical presentation”, “histological features”, and “immunohistochemistry”. Further searches included “treatment” and “management” options for “metastatic breast”, “metastatic colorectal”, “metastatic melanoma”, “metastatic lung”, and “hematologic cancers.” We also reviewed the literature on the current management of melanoma as a model for all cutaneous metastatic disease. Our own clinical findings are presented and compared to the literature. Additionally, we highlight the most useful immunohistochemical studies that aid in diagnoses. Several novel therapies and combination therapies such as electrochemotherapy, vemurafenib, and imiquimod will be discussed for palliative treatment of cancers that have been found to improve cutaneous lesions. We review these notable findings and developments regarding skin metastases for the general dermatologist.
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Affiliation(s)
- Christina Yin Bin Wong
- Department of Dermatology, Roswell Park Cancer Institute, University at Buffalo, Buffalo, New York, USA
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28
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Elfatoiki FZ, Longvert C, Clerici T, Bourgault-Villada I, Roudier-Pujol C, Vasseur E, Saiag P. Métastases en transit du mélanome : efficacité de l’imiquimod topique combiné au laser CO2 ou à l’électrocoagulation. Ann Dermatol Venereol 2014; 141:106-10. [DOI: 10.1016/j.annder.2013.10.058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 05/12/2013] [Accepted: 10/30/2013] [Indexed: 10/25/2022]
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29
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Abstract
Better understanding of the underlying principles of tumor biology and immunology, enhanced by recent insights into the mechanisms of immune recognition, regulation, and tumor escape has provided new approaches for cancer immunotherapy. This article reviews the current status and future directions of cancer immunotherapy, with a focus on the recent encouraging results from immune-modulating antibodies and adoptive cell therapy.
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Affiliation(s)
- Fumito Ito
- Department of Surgery, University of Michigan Health System, 3410 Cancer Center/5932, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5932, USA
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30
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Abstract
Surgical excision is the treatment of choice for primary melanomas and radiation therapy is the accepted alternative for the subset of lesions not amenable to surgery. With the recent rise in melanoma incidence, especially in the elderly, there are a growing number of cases that are neither amenable to surgery nor radiation therapy. In this article, we review pharmacotherapeutic approaches to microinvasive melanoma (invasive radial growth phase melanoma) that might be considered in such circumstances. There are no approved drugs for the treatment of primary melanoma and randomized controlled trials with 5 or more years of follow-up have not been performed. The limited studies and numerous case series in the literature on pharmacologic treatment of primary melanoma have focused on topical therapies. Accordingly, we provide a review of the potential pharmacotherapeutic agents in the treatment of microinvasive melanoma by extrapolating from the available limited literature on the use of fluorouracil, azelaic acid, retinoic acid derivatives, interferon (IFN)-α, imiquimod, and other agents for melanoma in situ, invasive melanoma, and epidermotropic melanoma metastases. Our review indicates that topical fluorouracil and tretinoin are not effective as single agents. The efficacy of azelaic acid, tazarotene, cidofovir, and intralesional IFN-α, interleukin-2, and IFN-β is undefined. Imiquimod is the most studied and promising agent; however, optimal dosage, therapeutic regimen, and survival rates are unknown. In the face of a growing demand for non-surgical treatments, formal clinical trials are needed to ascertain the role of pharmacotherapeutic agents in the treatment of microinvasive melanoma.
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Affiliation(s)
- Elizabeth A Quigley
- Dermatology Service, Memorial Sloan Kettering Cancer Center, 136 Mountain View Blvd, Basking Ridge, NJ, USA.
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31
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Combined intralesional Bacille Calmette-Guérin (BCG) and topical imiquimod for in-transit melanoma. J Immunother 2013; 35:716-20. [PMID: 23090081 DOI: 10.1097/cji.0b013e31827457bd] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The introduction of numerous immunotherapeutic agents into the clinical arena has allowed the long-time promise of immunotherapy to begin to become reality. Intralesional immunotherapy has demonstrated activity in multiple tumor types, and as the number of locally applicable agents has increased, so has the opportunity for therapeutic combinations. Both intralesional Bacille Calmette-Guérin (ILBCG) and topical 5% imiquimod cream have been used as single agents for the treatment of dermal/subcutaneous lymphatic metastases or in-transit melanoma, but the combination has not previously been reported. We used this combination regimen in 9 patients during the period from 2004 to 2011 and report their outcomes here. All patients were initially treated with ILBCG, followed by topical imiquimod after development of an inflammatory response to BCG. In this retrospective study, we examined their demographics, tumor characteristics, clinical and pathologic response to treatment, associated morbidities, local and distant recurrence, and overall survival. The 9 patients (8 male) had a mean age of 72 years (range, 56-95 y). Mild, primarily local toxicities were noted. Five patients (56%) had complete regression of their in-transit disease and 1 had a partial response. The 3 others had "surgical" complete responses with resection of solitary resistant lesions. The mean interval between the first treatment and complete resolution of in-transit disease was of 6.5 months (range, 2-12 mo). With a mean follow-up of 35 months (range 12-58 mo), 7 patients (78%) had not developed recurrent in-transit disease. Two patients (22%) have died of nonmelanoma causes, and none have died due to melanoma.
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Fox MC, Lao CD, Schwartz JL, Frohm ML, Bichakjian CK, Johnson TM. Management options for metastatic melanoma in the era of novel therapies: A primer for the practicing dermatologist. J Am Acad Dermatol 2013; 68:1.e1-9; quiz 10-12. [DOI: 10.1016/j.jaad.2012.09.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Revised: 09/10/2012] [Accepted: 09/18/2012] [Indexed: 11/30/2022]
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Arbiser JL, Bips M, Seidler A, Bonner MY, Kovach C. Combination therapy of imiquimod and gentian violet for cutaneous melanoma metastases. J Am Acad Dermatol 2012; 67:e81-3. [PMID: 22794825 DOI: 10.1016/j.jaad.2011.10.028] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 10/18/2011] [Accepted: 10/24/2011] [Indexed: 11/16/2022]
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34
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Hui AM, Jacobson M, Markowitz O, Brooks NA, Siegel DM. Mohs Micrographic Surgery for the Treatment of Melanoma. Dermatol Clin 2012; 30:503-15. [DOI: 10.1016/j.det.2012.04.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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35
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Ulrich M, Lange-Asschenfeldt S, Gonzalez S. The use of reflectance confocal microscopy for monitoring response to therapy of skin malignancies. Dermatol Pract Concept 2012; 2:202a10. [PMID: 23785598 PMCID: PMC3663336 DOI: 10.5826/dpc.0202a10] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2012] [Accepted: 02/25/2012] [Indexed: 01/12/2023] Open
Abstract
SUMMARY Reflectance confocal microscopy (RCM) is a new non-invasive imaging technique that enables visualizing cells and structures in living skin in real-time with resolution close to that of histological analysis. RCM has been successfully implemented in the assessment of benign and malignant lesions. Most importantly, it also enables monitoring dynamic changes in the skin over time and in response to different therapies, e.g., imiquimod, photodynamic therapy, and others. Given the often traumatic nature of skin cancer that affects both the physiology and the psychology of the patients, it is crucial to have methods that enable monitoring the response to treatment but that minimize the distress and discomfort associated with such process. This article provides a very brief overview of the fundamentals of RCM and then focuses on its recent employment as a monitoring tool in skin cancer and other pathologies that may require frequent follow-up.
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Affiliation(s)
- Martina Ulrich
- Department of Dermatology, Skin Cancer Center, Charité Universitätsmedizin, Berlin, Germany
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36
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Mimeault M, Batra SK. Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World J Clin Oncol 2012; 3:32-42. [PMID: 22442756 PMCID: PMC3309891 DOI: 10.5306/wjco.v3.i3.32] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 02/12/2012] [Accepted: 03/05/2012] [Indexed: 02/06/2023] Open
Abstract
Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cell-based therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transformation of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-RafV600E and N-RasQ61R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor (EGFR), stem cell-like factor (SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition (EMT)-associated molecules, including phosphatidylinositol 3’-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.
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Affiliation(s)
- Murielle Mimeault
- Murielle Mimeault, Surinder K Batra, Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, United States
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Goutagny N, Estornes Y, Hasan U, Lebecque S, Caux C. Targeting pattern recognition receptors in cancer immunotherapy. Target Oncol 2012; 7:29-54. [PMID: 22399234 DOI: 10.1007/s11523-012-0213-1] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Accepted: 01/13/2012] [Indexed: 12/20/2022]
Abstract
Pattern recognition receptors (PRRs) are known for many years for their role in the recognition of microbial products and the subsequent activation of the immune system. The 2011 Nobel Prize for medicine indeed rewarded J. Hoffmann/B. Beutler and R. Steinman for their revolutionary findings concerning the activation of the immune system, thus stressing the significance of understanding the mechanisms of activation of the innate immunity. Such immunostimulatory activities are of major interest in the context of cancer to induce long-term antitumoral responses. Ligands for the toll-like receptors (TLRs), a well-known family of PRR, have been shown to have antitumoral activities in several cancers. Those ligands are now undergoing extensive clinical investigations both as immunostimulant molecules and as adjuvant along with vaccines. However, when considering the use of these ligands in tumor therapy, one shall consider the potential effect on the tumor cells themselves as well as on the entire organism. Recent data indeed demonstrate that TLR activation in tumor cells could trigger both pro- or antitumoral effect depending on the context. This review discusses this balance between the intrinsic activation of PRR in tumor cells and the extrinsic microenvironment activation in term of overall effect of PRR ligands on tumor development. We review recent advances in the field and underline appealing prospects for clinical development of PRR agonists in the light of our current knowledge on their expression and activation.
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Affiliation(s)
- Nadège Goutagny
- Université de Lyon, Université Lyon I, UMR INSERM 1052 CNRS 5286, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France.
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38
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39
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Ellis LZ, Cohen JL, High W, Stewart L. Melanoma in situ treated successfully using imiquimod after nonclearance with surgery: review of the literature. Dermatol Surg 2012; 38:937-46. [PMID: 22338583 DOI: 10.1111/j.1524-4725.2012.02362.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND The standard of care for melanoma in situ (MIS) is surgical removal by surgical excision with a 5-mm margin or Mohs micrographic surgery, but as more and more MIS is diagnosed in the head and neck region, surgeries may not be an option for patients when the lesions are large or less well defined. In addition, when negative margins cannot be achieved without grossly disfiguring the patient or when patients have medical comorbidities that preclude a surgical option, other treatment modalities may be considered. Recently, topical treatment with an immunomodulator, imiquimod, has been proposed as an alternative treatment for MIS. OBJECTIVE We report a case of MIS successfully treated with topical imiquimod cream. In addition, because there has not been any comprehensive review of the use of topical imiquimod on melanoma and MIS, we conducted an extensive literature search and reviewed the topic in detail. MATERIALS AND METHODS Using the keywords "imiquimod," "melanoma," "melanoma-in-situ," and "lentigo maligna," we searched the literature using PubMed in an attempt to find all relevant articles on the use of imiquimod on MIS or melanoma. RESULTS There were 46 reports involving 264 patients on the use of imiquimod on MIS or lentigo maligna. Twenty-three reports were published on the use of imiquimod on metastatic melanoma involving 55 patients, and two articles were on melanoma, with two patients in total. In addition, there were two articles on the use of imiquimod on dysplastic or atypical nevi with a total of 13 subjects. CONCLUSION Imiquimod appears to be beneficial in the treatment of MIS and melanoma metastases when surgical options are not feasible. Imiquimod should not be used for removal of dysplastic or atypical nevi. The treatment regimens varied from study to study, and there are no randomized controlled trials in the literature. More studies are needed to develop a reliable and reproducible treatment regimen, to fully elucidate the role of imiquimod in the treatment of MIS and melanoma, and to determine the prognostic predictors for favorable responses to imiquimod.
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Affiliation(s)
- Lixia Z Ellis
- Department of Dermatology, University of Colorado, Aurora, Colorado 80045, USA.
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40
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Messeguer F, Agustí-Mejías A, Traves V, Requena C, Alegre V, Guillén C, Oliver V, Nagore E. Mitotic rate and subcutaneous involvement are prognostic factors for survival after recurrence in patients with only locoregional skin metastasis as the first site of recurrence from cutaneous melanoma. J Eur Acad Dermatol Venereol 2012; 27:436-41. [DOI: 10.1111/j.1468-3083.2012.04454.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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41
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Triozzi PL, Tuthill RJ, Borden E. Re-inventing intratumoral immunotherapy for melanoma. Immunotherapy 2011; 3:653-71. [DOI: 10.2217/imt.11.46] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Immunotherapeutics have been applied intratumorally to manage accessible lesions and to induce systemic immunity in malignant melanoma. Intratumoral bacillus Calmette-Guérin (BCG) has been used for 40 years, and intratumoral BCG, IL-2, IFN-α and imiquimod are recommended as treatment options for patients with in-transit melanoma metastases. Regression of cutaneous metastases can be achieved. Subcutaneous metastases are more refractory, and regression of uninjected, visceral metastases is infrequent. Other microbial products, cytokines, chemicals, immune cells, antibody and viral and plasmid vectors expressing immunologically active molecules have been tested. Antitumor activity has not been demonstrated to be superior to that of intratumoral BCG. There are few controlled trials, and whether survival is impacted with any approach has not yet been established. The immunotherapeutics applied and the intratumoral administration procedure itself can activate responses that are immune inhibitory. More rigorous clinical testing and improved understanding and modulation of regulatory immune responses are necessary.
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Affiliation(s)
- Pierre L Triozzi
- Taussig Cancer Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue/R40, Cleveland, OH 44195, USA
| | - Ralph J Tuthill
- Melanoma Program, The Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA
| | - Ernest Borden
- Melanoma Program, The Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA
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42
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Engel AL, Holt GE, Lu H. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system. Expert Rev Clin Pharmacol 2011; 4:275-89. [PMID: 21643519 PMCID: PMC3105468 DOI: 10.1586/ecp.11.5] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Toll-like receptor (TLR) ligation activates both the innate and adaptive immune systems, and plays an important role in antiviral and anti-tumor immunity. Therefore, a significant amount of effort has been devoted to exploit the therapeutic potential of TLR agonists. Depending on the therapeutic purpose, either as adjuvants to vaccine, chemotherapy or standalone therapy, TLR agonists have been administered via different routes. Both preclinical and clinical studies have suggested that the route of administration has significant effects on pharmacokinetics, and that understanding these effects is critical to the success of TLR agonist drug development. This article will summarize the pharmacokinetics of TLR agonists with different administration routes, with an emphasis on clinical studies of TLR ligands in oncologic applications.
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Affiliation(s)
| | - Gregory E Holt
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Miami, Miami, FL, USA
| | - Hailing Lu
- Tumor Vaccine Group, University of Washington, Box 358050, Seattle, WA 98109, USA
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43
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Abstract
Food and Drug Administration-approved treatment for metastatic melanoma, including interferon alpha and interleukin-2, offer a modest benefit. Immunotherapy, although has not enjoyed high overall response rates, is capable of providing durable responses in a subset of patients. In recent years, new molecular-targeted therapies have become available and offer promise of clinical benefit, although low durability of response. It is not yet clear how best to integrate these 2 novel modalities that target the immune response to melanoma (immune therapy) or that target molecular signaling pathways in the melanoma cells (targeted therapy). Many signal transduction pathways are important in both tumor cell and T-cell proliferation and survival, which generate risk in combining targeted therapy and immunotherapy. This review focuses on the role of targeted therapy and immunotherapy in melanoma, and discusses how to combine the 2 modalities rationally for increased duration and response.
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Affiliation(s)
- Amber L Shada
- Department of Surgery, Division of Surgical Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908-0709, USA
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44
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Lu H, Wagner WM, Gad E, Yang Y, Duan H, Amon LM, Van Denend N, Larson ER, Chang A, Tufvesson H, Disis ML. Treatment failure of a TLR-7 agonist occurs due to self-regulation of acute inflammation and can be overcome by IL-10 blockade. THE JOURNAL OF IMMUNOLOGY 2010; 184:5360-7. [PMID: 20308630 DOI: 10.4049/jimmunol.0902997] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Multiple TLR agonists have been shown to have antitumor effects in animal models. However, the therapeutic efficacy of TLR agonist monotherapy in cancer treatment has been limited, and the mechanisms of failure remain unknown. We demonstrate that topical treatment with a TLR-7 agonist, imiquimod, can elicit significant regression of spontaneous breast cancers in neu transgenic mice, a model of human HER-2/neu(+) breast cancer. However, tumor growth progressed once imiquimod therapy was ended. Gene expression analysis using tumor-derived RNA demonstrated that imiquimod induced high levels of IL-10 in addition to TNF-alpha and IFN-gamma. Elevated levels of circulating IL-10 were also detected in sera from imiquimod-treated mice. Elevated serum IL-10 appeared to be derived from IL-10 and dual cytokine secreting (IFN-gamma(+) and IL-10(+)) CD4(+) T cells rather than CD4(+)CD25(+)Foxp3(+) T regulatory cells, which were also induced by imiquimod treatment. Blockade of IL-10, but not TGF-beta, enhanced the antitumor effect of imiquimod by significantly prolonging survival in treated mice. These data suggest that the excessive inflammation induced by TLR agonists may result in a self-regulatory immunosuppression via IL-10 induction and that blocking IL-10 could enhance the therapeutic efficacy of these agents.
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Affiliation(s)
- Hailing Lu
- Tumor Vaccine Group, Center for Translational Medicine in Women's Health, 815 Mercer Street, Room 220, Box 358050, University of Washington, Seattle, WA 98195, USA.
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