Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer.

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â†’ T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â†’ T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â†’ T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.

Cytokines and angiogenic factors in patients with metastatic renal cell carcinoma treated with interferon-alpha: association of pretreatment serum levels with survival.

BACKGROUND: To correlate serum cytokine and angiogenic factor (CAF) levels with overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with interferon-alpha (IFN-alpha). PATIENTS AND METHODS: Serum CAF levels were measured in 103 patients treated on a randomized trial with IFN-alpha 0.5 million units (MU) twice daily or 5 MU daily. Concentrations of 17 analytes were determined by multiplex bead immunoassays [vascular endothelial growth factor A (VEGF(A)) and several cytokines] or enzyme-linked immunosorbent assay (basic fibroblast growth factor). We used proportional hazards models to evaluate the effect of CAF levels and clinical factors on OS. RESULTS: Pretreatment serum interleukin (IL) 5, IL-12 p40, VEGF(A), and IL-6 levels and Memorial Sloan-Kettering Cancer Center risk grouping independently correlated with OS, with hazard ratios of 2.33, 2.00, 2.07, 1.82, and 0.39, respectively (concordance index = 0.69 for the combined model versus 0.60 for the CAF model versus 0.52 for the clinical model). Based on an index derived from these five risk factors (RFs), patients with 0-2 RF had a median OS time of 32 months versus 9 months for patients with 3-5 RF (P < 0.0001). CONCLUSIONS: Serum CAF profiling contributes to prognostic evaluation in mRCC and helps to identify a subset of patients with 20% 5-year OS.

Acquisition of anoikis resistance in human osteosarcoma cells.

Under normal circumstances, adhered cells die of anoikis when detached from their extracellular matrix (ECM). Resistance to anoikis has been implicated in the progression of many human malignancies by affording an increased survival time in the absence of matrix attachment, facilitating the migration and eventual colonisation of distant sites. In this study, an anoikis-resistant variant of the human osteosarcoma cell line, SAOS-2 (SAOSar), was generated by sequential cycles of culturing under adhered and suspended conditions. It was also shown that although parental SAOS (SAOSp) cells are a heterogeneous population with varying levels of sensitivity to anoikis, the establishment of anoikis-resistant clones was not necessarily the result of mere selection of a previously resistant subpopulation. Anoikis-resistant cells were also derived from anoikis-sensitive SAOS clones by exposure to anoikis-inducing culture conditions. This suggests that lack of the normal signalling generated by attachment to the ECM could represent a driving force towards anoikis resistance. Resistance to anoikis could not be attributed to a general defect in the apoptotic pathway since apoptosis in both sensitive and resistant populations was induced after treatment with staurosporine, cycloheximide and hydrogen peroxide. This suggests that the apoptotic machinery is intact in both anoikis-sensitive and -resistant SAOS cells and that the death signal in anoikis-sensitive cells is generated by the lack of attachment, most probably by unligated integrins. Anoikis-resistant cells have circumvented this death signal and remain viable despite suspended conditions.

Identification of protective components of two major outer membrane proteins of spotted fever group Rickettsiae.

Fragments representing the genes of the two major outer membrane proteins of spotted fever group rickettsiae (rOmpA and rOmpB) were tested as DNA vaccines. Immunizations with each of three fragments (rompA4999-6710, rompB1550-2738, and rompB2459-4123) conferred a degree of protection on vaccinated mice against virulent rickettsial challenge. Protection was achieved when DNA immunizations were followed by booster immunizations with the homologous recombinant protein. Proliferation and gamma-interferon secretion were detected after in vitro stimulation of lymphocytes from immunized animals with whole Rickettsia conorii antigen. The data validate particular segments of rOmpA and rOmpB as potent immunogens and hence as sources of immunostimulatory elements with specificity for T lymphocytes, which are the key effectors of protective immunity against rickettsial infections.

Langerhans cell histiocytosis of the female genital tract: a literature review.

Langerhans cell histiocytosis (LCH) is a rare malignant disease involving the accumulation of a monoclonal proliferation of cells in various organs, that phenotypically resemble Langerhans cells (LC). LCH is not merely a hyperplasia of LC, as it typically affects organs that are outside of their normal physiologic distribution. Normal Langerhans cells are bone marrow-derived dendritic cells that populate the epidermis and are distinguished by the presence of Birbeck granules and cell surface protein CD1a. LC act as sentinels; they recognize, internalize, and process antigens encountered in the skin. Upon encountering an antigen, LC become activated with subsequent maturation and induction of their migratory capacity. Langerhans cells in patients with LCH are aberrant and profoundly differ from normal LC. The clinical spectrum of LCH is quite diverse; multiple organs can be affected. "Pure" genital Langerhans cell histiocytosis is a rare presentation, with only 12 previously reported cases. Due to the rarity of this disease, treatment of genital LCH is still very diverse. No modality is proven to be superior in improving patient outcome, and relapses frequently occur after surgery. Dramatic responses of cutaneous and ano-genital lesions to thalidomide and interferons have been reported. We advocate the use of immuno-modulating agents in LCH of the female genital tract first, rather than surgery.

Immunization with a portion of rickettsial outer membrane protein A stimulates protective immunity against spotted fever rickettsiosis.

Two approaches for presentation of a part of the rickettsial outer membrane protein A (OmpA) of Rickettsia rickettsii, namely (1) recombinant Mycobacterium vaccae (rMV) or (2) recombinant DNA vaccine, stimulated protective immunity against a lethal challenge with the closely related bacterium, R. conorii, in mice. After primary immunization with rMV and booster immunization with homologous recombinant protein, 67 and 55% of mice were protected against challenge in two experiments. DNA vaccination with booster recombinant protein immunization protected six out of eight animals from a lethal challenge. Production of IFN-gamma by antigen-exposed T-lymphocytes of DNA vaccine recipients indicated that cellular immunity had been stimulated.