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      Treatment of In-Transit Melanoma With Intralesional Bacillus Calmette-Guérin (BCG) and Topical Imiquimod 5% Cream: A Report of 3 Cases

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          Abstract

          Local therapy for in-transit melanoma (ITM) is a treatment alternative for patients who are not good candidates for systemic therapy, regional therapy, or surgical management. In this case report, we describe 3 patients with ITM who were treated with intralesional Bacillus Calmette-Guérin (ILBCG) and/or topical imiquimod. Treatment course was dictated by the clinical response. Patient 1’s response to ILBCG monotherapy was not sufficient to cause disease regression; however, transition to topical imiquimod therapy resulted in complete and sustained response. Although patient 2 responded to ILBCG and imiquimod, she developed a hypersensitivity reaction to ILBCG; when topical imiquimod was continued as monotherapy, her clinical response was complete. Patient 3 responded completely to ILBCG monotherapy in injected lesions, but expired shortly thereafter from unrelated disease. Reports like this one are needed to define the success measures of local therapy in the treatment of ITM.

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          Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guérin: involvement of toll-like receptors.

          The constituents of mycobacteria are an effective immune adjuvant, as observed with complete Freund's adjuvant. In this study, we demonstrated that the cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guérin (BCG-CWS), a purified noninfectious material consisting of peptidoglycan, arabinogalactan, and mycolic acids, induces maturation of human dendritic cells (DC). Surface expression of CD40, CD80, CD83, and CD86 was increased by BCG-CWS on human immature DC, and the effect was similar to those of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), heat-killed BCG, and viable BCG. BCG-CWS induced the secretion of TNF-alpha, IL-6, and IL-12 p40. CD83 expression was increased by a soluble factor secreted from BCG-CWS-treated DC and was completely inhibited by monoclonal antibodies against TNF-alpha. BCG-CWS-treated DC stimulated extensive allogeneic mixed lymphocyte reactions. The level of TNF-alpha secreted through BCG-CWS was partially suppressed in murine macrophages with no Toll-like receptor 2 (TLR 2) or TLR4 and was completely lost in TLR2 and TLR4 double-deficient macrophages. These results suggest that the BCG-CWS induces TNF-alpha secretion from DC via TLR2 and TLR4 and that the secreted TNF-alpha induces the maturation of DC per se.
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            BCG immunotherapy of malignant melanoma: summary of a seven-year experience.

            Over the past 7 years, 151 patients with malignant melanoma have been treated with BCG immunotherapy alone or as an adjunct to surgical therapy. Direct injection of metastatic melanoma lesions limited to skin resulted in 90% regression of injected lesions and 17% regression of uninjected lesions in immunocompetent patients. Approximately 25% of these patients remained free of disease for 1 to 6 years. Direct injections of BCG into nodules of patients with subcutaneous or visceral metastases resulted in a lower incidence of local control and no long term survivors. Attempts to improve the results of immunotherapy in these patients by palliative surgical resection of large metastatic lesions to lower tumor burden followed by BCG immunotherapy significantly improved the results although many patients still developed recurrent disease. Early results of a clinical trial combining BCG immunotherapy with regional lymphadenectomy in patients with melanoma metastatic to lymph nodes have been encouraging and promising. Further controlled clinical trials are necessary to elucidate the role of BCG in immunotherapy. However, since BCG is but one of a number of potential immunologic adjuvants, even more effective immunotherapy will be possible as further knowledge of the interactions of cellular and humoral immunity is acquired.
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              Combined intralesional Bacille Calmette-Guérin (BCG) and topical imiquimod for in-transit melanoma.

              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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                Author and article information

                Journal
                J Immunother
                J. Immunother
                CJI
                Journal of Immunotherapy (Hagerstown, Md. : 1997)
                Lippincott Williams & Wilkins
                1524-9557
                1537-4513
                November 2015
                22 October 2015
                : 38
                : 9
                : 371-375
                Affiliations
                Departments of [* ]Dermatology
                []Surgery, Yale University School of Medicine, New Haven, CT
                []John Wayne Cancer Institute, Santa Monica, CA
                Author notes
                Reprints: Jennifer N. Choi, Department of Dermatology, Yale University, 333 Cedar Street, LMP 5040, New Haven, CT 06510 (e-mail: jennifer.choi@ 123456yale.edu ).
                Article
                10.1097/CJI.0000000000000098
                4661048
                26448581
                f8c1bbb9-1b0c-4eb3-8757-957fe0ad1ecc
                Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
                History
                : 16 May 2015
                : 29 July 2015
                Categories
                Clinical Study

                in-transit melanoma,local therapy,intralesional bacillus calmette-guérin,ilbcg,topical imiquimod

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