Effect of Paget's disease on survival in breast cancer: an exploratory study.

OBJECTIVE: To explore whether Paget's disease (PD) has an effect on outcome in patients with breast cancer. DESIGN: Retrospective analysis of comprehensive pathology database, medical records, and slides of samples showing pathologic features. SETTING: UMass Memorial Health Care. PATIENTS: All patients with breast cancer and PD with records in a prospectively maintained database between January 1, 1990, and December 31, 2008, were identified. Each participant was matched (criteria: age within 5 years, year of treatment, and stage of breast cancer) with 2 controls (1:2 ratio). MAIN OUTCOME MEASURES: Overall and disease-free survival were analyzed using Kaplan-Meier statistics and Cox proportional hazards modeling, accounting for matching in the latter analyses by using robust standard error estimates. RESULTS: Mean (SD) follow-up was 47 (33) months. Treatment involved mastectomy in 29 (91%) PD vs 16 (25%) non-PD patients (P < .001), radiotherapy in 14 (44%) PD vs 53 (83%) non-PD patients (P < .001), and hormonal therapy in 14 (44%) PD vs 33 (52%) non-PD patients (P = .004). Biological markers were not significantly different except for ERBB2 (formerly HER2 or HER2/neu) overexpression in 14 (44%) PD vs 16 (25%) non-PD patients (P = .008). The PD group had an overall 5-year survival of 81.2% vs 93.8% of the non-PD group (Kaplan-Meier log-rank, P = .03). The unadjusted hazard ratio for the PD vs non-PD group was 5.31 (95% CI, 1.74-16.27; P = .003). The corresponding hazard ratio after adjusting for local and systemic treatment was 2.26 (95% CI, 0.46-11.06; P = .32). CONCLUSIONS: These exploratory data show that PD may have a negative effect on breast cancer survival. This finding needs to be substantiated in larger data sets.

Multiple inflammatory nodules: a differential diagnosis of new pulmonary nodules in oncology patients.

New pulmonary nodules in an oncology patient are often considered metastatic unless proven otherwise. However, the possibility of an inflammatory cause needs to be considered in this setting. Clinicopathologic correlation is always needed in such cases to establish a diagnosis, especially before initiating a new treatment. The multiplicity of inflammatory nodules in this case, in the form of multiple pulmonary nodules and a spinal soft tissue mass, can be a considerable diagnostic challenge. The potential ramifications of not being familiar with inflammatory pseudotumors and not knowing when to suggest it involve unnecessary and incorrect patient treatment including chemotherapy, and may have medicolegal implications for the radiologist. Therefore all radiologists, especially those involved in oncologic imaging, need to be aware of this entity.

A mimic of tumor rejection antigen-associated carbohydrates mediates an antitumor cellular response.

Tumor-associated carbohydrate antigens are typically perceived as inadequate targets for generating tumor-specific cellular responses. Lectin profile reactivity and crystallographic studies demonstrate that MHC class I molecules can present to the immune system posttranslationally modified cytosolic peptides carrying O-beta-linked N-acetylglucosamine (GlcNAc). Here we report that a peptide surrogate of GlcNAc can facilitate an in vivo tumor-specific cellular response to established Meth A tumors that display native O-GlcNAc glycoproteins on the tumor cell surface. Peptide immunization of tumor-bearing mice had a moderate effect on tumor regression. Inclusion of interleukin 12 in the immunization regimen stimulated complete elimination of tumor cells in all of the mice tested, whereas interleukin 12 administration alone afforded no tumor growth inhibition. Adoptive transfer of immune T cells into tumor-bearing nude mice indicates a role for CD8+ T cells in tumor regression. This work postulates that peptide mimetics of glycosylated tumor rejection antigens might be further developed for immune therapy of cancer.

Strategies in cancer vaccines development.

The recent definition of tumour-specific immunity in cancer patients and the identification of tumour-associated antigens have generated renewed enthusiasm for the application of immune-based therapies for the treatment of malignancies. Recent developments in cancer vaccines have also been based on an improved understanding of the cellular interactions required to induce a specific anti-tumour immune response. Consequently, a number of cancer vaccines have entered clinical trials. Targeting broad-spectrum tumour-associated antigens has emerged as a strategy to lower the risk of tumour escape due to the loss of specific nominal antigen. Amongst the most challenging of tumour-associated antigens to which to target in active specific immunotherapy applications are carbohydrate antigens. As carbohydrates are intrinsically T-cell-independent antigens, more novel approaches are perhaps needed to drive specific-T-cell-dependent immune responses to carbohydrate antigens. In this context peptide mimetics of core structures of tumour-associated carbohydrate antigens might be developed to augment immune responses to these broad-spectrum antigens.

Priming characteristics of peptide mimotopes of carbohydrate antigens.

Immunization with peptide mimetics of carbohydrate antigens can induce functional carbohydrate-reactive antibodies. Here, we examine the immune characteristics of alternative approaches in prime and boost strategies using glycosylated HIV-1 envelope protein and model tumor associated carbohydrate antigens. Our results indicate that peptide mimotopes either in a DNA or carrier-conjugated format can induce comparable levels of IgM and IgG. Carbohydrate boosting of peptide-primed animals does not affect end-point titer, however, boosting mediates a stable long lasting carbohydrate reactive IgM response, not achievable by carbohydrate immunization alone. Boosting with carbohydrate in animals primed with DNA- or peptide-conjugate, facilitates the induction of detectable IgG with a dominant IgG2a isotype. Immunization with HIV-1 envelope glycoprotein of peptide-primed animals induces different IgG isotype profiles with a dominant IgG1 antibody. We observed that HIV-1 envelope glycoprotein immunization of peptide primed mice induces a cross-reactive cellular response, as detected by cytokine secretion, which lends to IFN-gamma production upon splenocyte stimulation and CTL activity against recombinant vaccinia virus infected cells after in vitro stimulation. DNA immunization with mimotope, inclusion of a T-cell epitope from the HIV-1 envelope protein in the expression cassette and co-administration with IL-12 or GM-CSF encoding plasmids activate a cellular response to the HIV-1 envelope protein.

Use of surrogate antigens as vaccines against cancer.

Tumor cells may evade immune surveillance by possessing polysaccharides or carbohydrates on their surface. This evasive strategy is effective because glycans are poorly immunogenic and fail to elicit immunological memory responses due to an absence of T-cell processing. Induction of an immune response to cell surface carbohydrate antigens is considered as an important strategy to fight cancer. As carbohydrates per se are poor immunogens, alternative approaches are being evaluated to induce functional cross-reactive responses. We are focusing on the use of peptide mimotopes of tumor-associated carbohydrate antigens to challenge cancer, as we would manipulate the immune system to establish protective immunity based on carbohydrate cross-reactive humoral and cellular responses.

Peptide mimotopes as surrogate antigens of carbohydrates in vaccine discovery.

Carbohydrate antigens are immune targets associated with a variety of pathogens and tumor cells. Unfortunately, most carbohydrates are intrinsically T cell-independent antigens, which diminishes their efficacy as immunogens. The conversion of carbohydrate epitopes to peptide mimotopes is one means to overcome the T cell-independent nature of carbohydrate antigens because peptides have an absolute requirement for T cells. Although such conversion has great potential for the development of veterinarian and human vaccines, there are issues related to the use of peptide-based immunogens as functional surrogates. Some of these issues are fundamental, pertaining to how mimicry comes about at the molecular level, and some are application oriented, directed at elucidating important immunological mechanisms. In this article the potential and caveats of this technology regarding its application in vaccine discovery are analyzed.