New observations in tumor cell plasticity: mutational profiling in a case of metastatic melanoma with biphasic sarcomatoid transdifferentiation.

We describe a highly unusual case of metastatic melanoma in a 61-year-old female that manifested as a single groin lymph node metastasis accompanied by two distinct, subcutaneous sarcomatoid tumors on the same leg, without evidence of a primary tumor. Characterization encompassed extensive immunohistochemical staining as well as next-generation sequencing (NGS). The lymph node metastasis showed obvious features of melanoma.

Baseline staging of melanoma with unknown primary site: the value of serum s100 protein and positron emission tomography.

Background: Baseline staging is important in all melanoma types, including melanoma with unknown primary site (MUP). Staging includes different examination strategies, each with different accuracy.

Objective: To determine the value of serum S100 protein levels and positron emission tomography (PET) in the baseline staging of MUP.

Green tea extract reduces induction of p53 and apoptosis in UVB-irradiated human skin independent of transcriptional controls.

Ultraviolet (UV) irradiation plays a pivotal role in human skin carcinongenesis. Preclinically, systemically and topically applied green tea extract (GTE) has shown reduction of UV-induced (i) erythema, (ii) DNA damage, (iii) formation of radical oxygen species and (iv) downregulation of numerous factors related to apoptosis, inflammation, differentiation and carcinogenesis. In humans, topical GTE has so far only been tested in limited studies, with usually very high GTE concentrations and over short periods of time.

Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma.

Numerous preclinical and clinical studies have shown that interleukin-2 (IL-2) induces regression of metastatic tumors. We have conducted a phase I/II, multicenter, open-label, dose-escalating study to evaluate the safety, efficacy, and biological effects of repeated intratumoral injections of adenovirus-IL-2 (TG1024) in patients with advanced solid tumors and melanoma. Thirty five patients (twenty-five with metastatic melanoma and ten with other solid tumors) were treated in eight successive cohorts at dose levels ranging from 3 x 10(8) to 3 x 10(11) viral particles (vp).

An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma.

Purpose: A topical Toll-like receptor 7 (TLR7) agonist induces regression of cutaneous melanocytic neoplasms. We explored antitumor activity of a systemically administered TLR7 agonist, 852A, in patients with metastatic melanoma.

Experimental Design: We undertook a phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma.

Human leukocyte antigen-G and cancer immunoediting.

Immunosurveillance is an extrinsic mechanism of cancer suppression that eliminates nascent tumors. However, the selection imposed by immunosurveillance can drive tumor evolution and the emergence of clinically apparent neoplasms. Mechanisms of immune escape acquired by less immunogenic variants during this process, termed immunoediting, may contribute significantly to malignant progression.

HLA-G in the skin--friend or foe?

Skin is the largest organ of the human body that harbors a robust and versatile immune surveillance system. Whereas impaired immune function of the skin enables tumor growth, excessive immune activation results in different inflammatory diseases of the skin. HLA-G is a non-classical MHC class I molecule that was initially described to provide immunotolerogenic signals.

Recent advances in cutaneous lymphomas.

Cutaneous lymphomas are a heterogeneous group of extranodal lymphomas that are characterized by an initial accumulation of mononuclear, mostly lymphocytic cells in the skin. Recent discoveries of changes in molecular biology and immunology of these tumors have paved the way to a better understanding of the processes that govern lymphomagenesis in the skin and more importantly, they have contributed to the development of the new WHO-EORTC classification system. Only now has the field of cutaneous lymphomas gained a novel, long-awaited basis that may act as a new starting point in the collection of clinical as well molecular and immunological data on comparative basis.

Induction of the members of Notch pathway in superficial basal cell carcinomas treated with imiquimod.

Basal cell carcinoma of the skin (BCC) is the most common skin tumor in Caucasians worldwide. Different therapeutic options are available to treat BCC, including topical immunotherapy. Imiquimod is topical Toll-like receptor 7 agonist that activates anti-tumor immune response and has been recently approved for the treatment of superficial BCC (sBCC).

Type I IFN innate immune response to adenovirus-mediated IFN-gamma gene transfer contributes to the regression of cutaneous lymphomas.

The fact that adenoviral vectors activate innate immunity and induce type I IFNs has not been fully appreciated in the context of cancer gene therapy. Type I IFNs influence different aspects of human immune response and are believed to be crucial for efficient tumor rejection. We performed transcriptional profiling to characterize the response of cutaneous lymphomas to intralesional adenovirus-mediated IFN-gamma (Ad-IFN-gamma) gene transfer.

Drug evaluation: TG-1042, an adenovirus-mediated IFNgamma gene delivery for the intratumoral therapy of primary cutaneous lymphomas.

Transgene SA is developing TG-1042, a replication-deficient adenovirus type 5 that carries the IFNgamma gene, for the potential treatment of cutaneous T-cell and B-cell lymphoma (CTCL and CBCL, respectively). A phase I/II clinical trial in CTCL and CBCL was recently completed, and in November 2006 Transgene initiated a phase II clinical trial in CBCL.

Spontaneous CD8 T cell responses against the melanocyte differentiation antigen RAB38/NY-MEL-1 in melanoma patients.

The melanocyte differentiation Ag RAB38/NY-MEL-1 was identified by serological expression cloning (SEREX) and is expressed in the vast majority of melanoma lesions. The immunogenicity of RAB38/NY-MEL-1 has been corroborated previously by the frequent occurrence of specific Ab responses in melanoma patients. To elucidate potential CD8 T cell responses, we applied in vitro sensitization with overlapping peptides spanning the RAB38/NY-MEL-1 protein sequence and the reverse immunology approach.

Anti-HIV state but not apoptosis depends on IFN signature in CD4+ T cells.

To gain insights into the molecular mechanisms underlying early host responses to HIV in the CD4(+) T cell target population, we examined gene expression in CD4(+) T cells isolated 24 h after ex vivo HIV infection of lymphocyte aggregate cultures derived from human tonsils. Gene profiling showed a distinct up-regulation of genes related to immune response and response to virus, notably of IFN-stimulated genes (ISGs), irrespective of the coreceptor tropism of the virus. This mostly IFN-alpha-dependent gene signature suggested the involvement of plasmacytoid dendritic cells, a principal component of the antiviral immune response.

[Perspective of cutaneous lymphoma reserach].

Primary cutaneous lymphomas are characterized by an expansion of hematopoietic cells in the special microenvironment of the skin. They represent a special challenge both for researches and for clinicians who treat patients with these disorders. New research data concerning the biology of lymphocytes and the cutaneous microenvironment have increased our knowledge of these diseases in the last decades.

Melanocyte differentiation antigen RAB38/NY-MEL-1 induces frequent antibody responses exclusively in melanoma patients.

Expression pattern and immunogenicity are critical issues that define tumor antigens as diagnostic markers and potential targets for immunotherapy. The development of SEREX (serological analysis of recombinant expression libraries) has provided substantial progress in the identification of tumor antigens eliciting both cellular and humoral immune responses in cancer patients. By SEREX, we have previously identified RAB38/NY-MEL-1 as a melanocyte differentiation antigen that is highly expressed in normal melanocytes and melanoma tissues but not in other normal tissues or cancer types.

Pathogenesis and therapy of cutaneous lymphomas--progress or impasse?

The cutaneous environment hosts a number of hematopoietic neoplasms that are dominated by primary cutaneous (PC) T-cell lymphomas. Recent progress in molecular biology and immunology has provided tools to investigate the pathogenesis and the biology of these neoplasms. This review highlights newest findings concerning the immune biology of CD4+ CD56+ hematodermic neoplasms, and PC T-cell and B-cell lymphomas, speculating how these can be translated into more sophisticated, biology-based treatment approaches in the near future.

Standard and experimental therapy in cutaneous T-cell lymphomas.

Cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative disorders, characterized by the accumulation of clonal lymphocytes in the skin. Skin-directed therapies are the preferred first-line modalities. There are interesting new developments in topical therapy using retinoids and gene-therapy products such as adenovirus- interferon (IFN)-gamma.

CD4+CD56+ hematodermic neoplasms bear a plasmacytoid dendritic cell phenotype.

CD4+CD56+ hematodermic neoplasms (HNs) with initial presentation in the skin are characterized by highly aggressive behavior and poor prognosis. Recent studies indicate that malignant cells, which are devoid of common T-, B-, NK-, and myeloid lineage markers, may be of plasmacytoid dendritic cell (pDC) origin. We undertook a study to assess the expression of several pDC-associated molecules on a series of 5 CD4+CD56+ HN cases.

Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment.

Background: Imiquimod, an immune response modifier that is used topically to treat different types of skin cancer, induces the production of proinflammatory cytokines that stimulate an antitumor immune response. We assessed characteristics of the imiquimod-induced immune activation in epithelial and lymphoproliferative neoplasias of human skin. We focused on plasmacytoid predendritic cells (PDCs), the primary producer of interferon alpha (IFN-alpha) after imiquimod activation in vitro.

Expression of melanoma-associated antigens in melanoma cell cultures.

The efficiency of melanoma immunotherapy appears to depend on both melanoma- and immune system-specific factors. Melanoma-specific factors include melanoma-associated antigen (MAA) expression as well as HLA class I molecule expression. We investigated the expression of five MAA - Melan-A/MART-1, tyrosinase, gp100, MAGE-1 and MAGE-3 - by means of FACS analysis in 50 melanoma cell cultures and compared them to the cultures of human foreskin-derived melanocytes and melanoma cell line UKRV-Mel2.

Successful imiquimod treatment of multiple basal cell carcinomas after radiation therapy for Hodgkin's disease.

We present a case of a 55-year-old male patient who developed five basal cell carcinomas 23 years after radiation therapy of Hodgkin's disease. In 1980 he received radiation therapy twice. Due to relapses, he was treated with aggressive polychemotherapy and underwent autologous stem cell transplantation, which then led to complete remission.

Role of imiquimod in skin cancer treatment.

Cancer of the skin is by far the most common form of all cancers. Given the increasing incidence of skin cancer worldwide, it seems feasible to reconsider the treatment options available for dealing with this growing problem. Despite the lower costs associated with classical methods such as surgery and radiotherapy, immune response modifiers such as imiquimod appear to be good candidates for the future given their good cosmetic effects, the possibility of treating large areas, and the simpleness of patient-applied treatment with a cream formulation.

Expression of Melan-A/MART-1 in primary melanoma cell cultures has prognostic implication in metastatic melanoma patients.

The lack of melanoma-associated antigen (MAA) expression has been associated with the reduced overall survival in melanoma patients. In order to investigate whether the MAA expression detected on cell cultures established from melanoma patients might relate to the overall survival in these patients, we screened primary cell cultures derived from 37 melanoma metastases for the expression of five known MAA: Melan-A, tyrosinase, gp-100, MAGE-1 and MAGE-3 by polymerase chain reaction (PCR) and fluorescence-activated cell sorting (FACS). MAA expression detected by PCR was found at a high percentage in evaluated melanoma cell lines: 25 of 28 (89%) were positive for Melan-A, 22 of 28 (79%) were positive for tyrosinase, 26 of 28 (93%) were positive for gp-100, and 18 of 28 (64%) were positive for MAGE-3 expression.

Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation.

Interferons (IFNs) are cytokines that possess potent anti-viral and immunoregulatory activities. In contrast, their potential role(s) in anti-bacterial defense and neutrophil activation mechanisms is less well explored. By comparing gene expression patterns between immature and mature human neutrophils, we obtained evidence that intracellular proteases and other anti-bacterial proteins are produced at earlier stages of maturation, whereas the genes for receptors and signaling molecules required for the release of these effector molecules are preferentially induced during terminal differentiation.

Imiquimod treatment induces expression of opioid growth factor receptor: a novel tumor antigen induced by interferon-alpha?

Purpose: Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-alpha.

Experimental Design: To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays.