Development and validation of a nomogram incorporating gene expression profiling and clinical factors for accurate prediction of metastasis in patients with cutaneous melanoma following Mohs micrographic surgery.

Background: There is a need to improve prognostic accuracy for patients with cutaneous melanoma. A 31-gene expression profile (31-GEP) test uses the molecular biology of primary tumors to identify individual patient metastatic risk.

Objective: Develop a nomogram incorporating 31-GEP with relevant clinical factors to improve prognostic accuracy.

Long-term clinical outcomes of patients with invasive cutaneous squamous cell carcinoma treated with Mohs micrographic surgery: A 5-year, multicenter, prospective cohort study.

Background: Outcomes for patients with cutaneous squamous cell carcinoma (CSCC) treated with Mohs micrographic surgery (MS) in the United States have never been prospectively defined. Risk factors as they relate to outcomes are primarily derived from single-institution, retrospective data without regard for treatment modality. The American Joint Committee on Cancer Staging Manual, Eighth Edition, and the Brigham and Women's Hospital T staging systems have not been prospectively validated.

A prospective evaluation of the clinical, histologic, and therapeutic variables associated with incidental perineural invasion in cutaneous squamous cell carcinoma.

Background: The prognosis and management of incidental perineural invasion (PNI) in patients with cutaneous squamous cell carcinoma (CSCC) has not been well defined.

Objective: We sought to investigate the clinical, histologic, and treatment characteristics associated with incidental PNI, histologic PNI extending beyond the tumor bulk, in patients with CSCC.

Methods: We conducted a multicenter prospective analysis of patients with CSCC undergoing Mohs micrographic surgery.

HLA antigen expression in melanocytic lesions: is acquisition of HLA antigen expression a biomarker of atypical (dysplastic) melanocytes?

Background: Although criteria are established for the histologic diagnosis of atypical nevi (AN), consensus about the criteria in the diagnosis of and in the definition of AN is limited. Moreover, intraobserver and interobserver differences in the application of these criteria for the diagnosis of AN have been observed.

Objective: We sought to determine the usefulness of HLA antigen expression as a biomarker of AN.

HLA antigen and NK cell activating ligand expression in malignant cells: a story of loss or acquisition.

Malignant transformation of cells is often associated with changes in classical and non-classical HLA class I antigen, HLA class II antigen as well as NK cell activating ligand (NKCAL) expression. These changes are believed to play a role in the clinical course of the disease since these molecules are critical to the interactions between tumor cells and components of both innate and adaptive immune system. For some time, it has been assumed that alterations in the expression profile of HLA antigens and NKCAL on malignant cells represented loss of classical HLA class I antigen and induction of HLA class II antigen, non-classical HLA class I antigen and/or NKCAL expression.

Functional and clinical relevance of chondroitin sulfate proteoglycan 4.

The lack of effective conventional therapies for the treatment of advanced stage melanoma has stimulated interest in the development of novel strategies for the management of patients with malignant melanoma. Among them, immunotherapy has attracted much attention because of the potential role played by immunological events in the clinical course of melanoma. For many years, T cell-based immunotherapy has been emphasized in part because of the disappointing results of the monoclonal antibody (mAb)-based clinical trials conducted in the early 1980s and in part because of the postulated major role played by T cells in tumor growth control.

Immunotherapy of malignant disease with tumor antigen-specific monoclonal antibodies.

A few tumor antigen (TA)-specific monoclonal antibodies (mAb) have been approved by the Food and Drug Administration for the treatment of several major malignant diseases and are commercially available. Once in the clinic, mAbs have an average success rate of approximately 30% and are well tolerated. These results have changed the face of cancer therapy, bringing us closer to more specific and more effective biological therapy of cancer.

Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumors.

Purpose: To determine the frequency of abnormalities in human leukocyte antigen (HLA) and antigen processing machinery (APM) component expression in malignant brain tumors. This information may contribute to our understanding of the immune escape mechanisms used by malignant brain tumors because HLA antigens mediate interactions of tumor cells with the host's immune system.

Experimental Design: Eighty-eight surgically removed malignant astrocytic tumors, classified according to the WHO criteria, were stained in immunoperoxidase reactions with monoclonal antibody recognizing monomorphic, locus-specific, and allospecific determinants of HLA class I antigens, beta2-microglobulin, APM components (LMP2, LMP7, TAP1, TAP2, calnexin, calreticulin, and tapasin), and HLA class II antigens.

Mechanisms of tumor evasion.

The results from in vitro immunological experiments, murine tumor models and patients with cancer clearly demonstrate that tumors have multiple mechanisms to evade the immune response. During the early stages of tumor development malignant cells can be poor stimulators, present poor targets or become resistant to the innate immune response, while at later stages, progressively growing tumors impair the adaptive immune response by blocking the maturation and function of antigen presenting cells and causing alterations in T cell signal transduction and function. Preliminary results also suggest a correlation between some of these changes and an increased metastatic potential of the tumor cells, a diminished response to immunotherapy, and poor prognosis.

A method to generate antigen-specific mAb capable of staining formalin-fixed, paraffin-embedded tissue sections.

Abnormalities in HLA class I antigen expression are frequently found in malignant tumors. Their potential role in the clinical course of the disease and in the outcome of T cell-based immunotherapy has stimulated interest in the characterization of the molecular mechanisms underlying HLA class I antigen abnormalities in malignant cells. Multiple mechanisms have been identified.

Classical and nonclassical HLA class I antigen and NK Cell-activating ligand changes in malignant cells: current challenges and future directions.

Changes in classical and nonclassical HLA class I antigen and NK cell-activating ligand expression have been identified in malignant lesions. These changes, which are described in this chapter, are believed to play a major role in the clinical course of the disease since both HLA class I antigens and NK cell-activating ligands are critical to the interaction between tumor cells and components of both innate and adaptive immune systems. Nevertheless, there is still debate in the literature about the biologic and functional significance of HLA class I antigen and NK cell-activating ligand abnormalities in malignant lesions.

Immune selection of hot-spot beta 2-microglobulin gene mutations, HLA-A2 allospecificity loss, and antigen-processing machinery component down-regulation in melanoma cells derived from recurrent metastases following immunotherapy.

Scanty information is available about the mechanisms underlying HLA class I Ag abnormalities in malignant cells exposed to strong T cell-mediated selective pressure. In this study, we have characterized the molecular defects underlying HLA class I Ag loss in five melanoma cell lines derived from recurrent metastases following initial clinical responses to T cell-based immunotherapy. Point mutations in the translation initiation codon (ATG-->ATA) and in codon 31 (TCA-->TGA) of the beta(2)-microglobulin (beta(2)m) gene were identified in the melanoma cell lines 1074MEL and 1174MEL, respectively.

Immunotherapy of melanoma targeting human high molecular weight melanoma-associated antigen: potential role of nonimmunological mechanisms.

Induction of humoral anti-human high molecular weight melanoma-associated antigen (anti-HMW-MAA) immunity following active specific immunotherapy is associated with a statistically significant prolongation of survival in patients with melanoma. This association does not appear to be mediated by immunological mechanisms because anti-HMW-MAA antibodies are poor mediators of complement- and cell-mediated cytotoxicity of melanoma cells. Therefore, we have been investigating nonimmunological mechanisms by which anti-HMW-MAA antibodies (Abs) affect the biology of melanoma cells.

Enhancement of scFv fragment reactivity with target antigens in binding assays following mixing with anti-tag monoclonal antibodies.

The phage display Ab library technology has been found to be a useful method to isolate antigen-specific Ab fragments, since the repertoire of antibody specificities is broad and since it bypasses the need of immunization. However, when screening clones isolated from a phage display Ab library, the yield of isolating antigen-specific Ab fragments is low and the rate of false negative results is high. This limitation reflects the low affinity/avidity of Ab fragments and/or the low density of the target antigen.

Human high molecular weight-melanoma-associated antigen (HMW-MAA): a melanoma cell surface chondroitin sulfate proteoglycan (MSCP) with biological and clinical significance.

The lack of effective conventional therapies for the treatment of advanced stage melanoma has stimulated interest in the application of novel strategies for the treatment of patients with malignant melanoma. Because of its expression in a large percentage of melanoma lesions and its restricted distribution in normal tissues, the high molecular weight-melanoma-associated antigen (HMW-MAA), also known as the melanoma chondroitin sulfate proteoglycan (MCSP), has been used to implement immunotherapy of melanoma. The potential clinical relevance of HMW-MAA/MCSP has stimulated investigations to characterize its structural properties and biological function in melanoma cells.

HLA class I antigen expression in malignant cells: why does it not always correlate with CTL-mediated lysis?

HLA class I antigen defects are frequently found in malignant cells. They appear to play a role in the clinical course of the disease, probably because they provide tumor cells with a mechanism to escape cytotoxic T lymphocyte (CTL) recognition and destruction. Expression of HLA class I antigens, however, is not always associated with the susceptibility of tumor cells to CTL lysis.

T-cell-based immunotherapy of melanoma: what have we learned and how can we improve?

The lack of effective treatment for advanced stage melanoma by conventional therapies, such as radiation and chemotherapy, has highlighted the need to develop alternative therapeutic strategies. Among them, immunotherapy has attracted much attention because of the potential role played by immunological events in the clinical course of melanoma and the availability of well-characterized melanoma antigens to target melanoma lesions with immunological effector mechanisms. In recent years, T-cell-based immunotherapy has been emphasized, in part because of the disappointing results of the antibody-based trials conducted in the early 1980s, and in part because of the postulated major role played by T-cells in tumor growth control.

HLA class I defects in malignant lesions: what have we learned?

Depending on the tumor types, HLA class I antigen downregulation or loss has been found in 16% to 50% of malignant lesions in many malignancies with a clinical association with histopathological markers of poor prognosis of the disease and with reduced free interval and survival. These findings may reflect the escape of tumor cells with HLA class I abnormalities from recognition and destruction by HLA class I-restricted, tumor-associated antigen-specific cytotoxic T lymphocytes. This possibility has stimulated investigations on the mechanisms underlying HLA class I antigen abnormalities in malignant cells.

HLA class I antigen loss, tumor immune escape and immune selection.

Poor clinical response rates have been observed in the majority of the T cell-based immunotherapy clinical trials conducted to date. One reason might be the presence of abnormalities in HLA class I antigen presentation in malignant lesions. An increased frequency of HLA class I abnormalities has been observed in malignant lesions from patients treated with T cell-based immunotherapy and in lesions which have recurred in patients who had experienced clinical responses following T cell-based immunotherapy.