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Objectives Tumor angiogenesis is an essential and complex process necessary for the growth of all tumors which represents a potential therapeutic target. Angiogenesis inhibitors targeting vascular endothelial growth factor (VEGF) or their receptor tyrosine kinases have been approved by the FDA. In thymic epithelial tumors (TET), targeted therapies have been sporadically applied due to their rarity. To ascertain the presence of potential therapeutic targets, we analyzed by immunohistochemistry the expression of angiogenesis-related biomarkers in a large series of TET arranged in Tissue Micro Arrays (TMA). Materials and methods We assessed by immunohistochemistry the expression of the possible molecular target of anti-angiogenic therapy, i.e. VEGFA, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, and PDGFRβ, in a TMA series of 200 TET collected in the framework of a multi-institutional collaborative project for Rare Diseases. Results When compared to the low-risk tumors, high-risk TET (B2, B3, carcinomas) contained higher proportion of cancer cells expressing VEGFA, VEGFC and VEGFD (P<0.001, P<0.001, and P<0.001) growth factors, and their receptors VEGFR1 (P=0.002), VEGFR2 (P=0.013), and VEGFR3 (P=0.041). No differences were observed in terms of PDGFRβ expression. Conclusions According to our data, it is possible to hypothesize the existence of multiple paracrine and/or autocrine loops in TET, particularly in the high-risk ones, involved in TET growth and progression. Anti-angiogenic agents, directed to inhibit these loops, are therefore to be considered as potential tools in advanced TET therapy. [ABSTRACT FROM AUTHOR]

Abstract: Despite advances in surgery and radiotherapy of uveal melanoma (UM), many patients develop distant metastases that poorly respond to therapy. Improved therapies for the metastatic disease are therefore urgently needed. Expression of the epidermal growth factor receptor (EGFR), a target of kinase inhibitors and humanised antibodies in use for several cancers, had been reported. Forty-eight human UMs were analysed by expression profiling. Signalling was tested in three EGFR expressing UM cell lines by Western blotting using phosphorylation specific antibodies for EGFR and the downstream mediators AKT (v-akt murine thymoma viral oncogene homolog) and extracellular signal-regulated kinase (ERK). Evidence for signalling in tumours was obtained through the application of a UM-specific EGF-signature. The EGFR specific kinase inhibitor, Gefitinib and the humanised monoclonal antibody, Cetuximab, were tested for their effect on EGFR signalling. Natural killer cell mediated antibody-dependent cellular cytotoxicity (ADCC) and tumour necrosis factor α (TNF-α) release was analysed for Cetuximab. Fourteen of 48 UMs and three of 14 cell lines (over-)express EGFR, at least in part due to trisomy of the EGFR locus on chromosome 7p12. EGFR and the downstream mediator, AKT, are phosphorylated upon stimulation with EGF in EGFR expressing cell lines. EGFR over-expressing tumours but not EGFR negative tumours show an activated EGF-signature. Gefitinib inhibits EGFR and AKT phosphorylation and Cetuximab induces EGFR phosphorylation but inhibits signalling to AKT induced with EGF. Cetuximab triggers natural killer (NK) cells to lyse EGFR+ cell lines and to release TNF-α. EGFR appears suited as a novel molecular drug target for therapy of uveal melanoma. [Copyright &y& Elsevier]

Objective: Interleukin (IL)-21, a member of the IL-2 family, has antitumor activity and is now being tested in non-Hodgkin''s lymphoma in combination with anti-CD20 antibodies. IL-21 may either induce apoptosis or promote growth in different lymphoid malignancies. We therefore investigated the IL-21/IL-21R system in follicular lymphoma (FL) cells. Materials and Methods: IL-21R expression was studied by reverse transcription polymerase chain reaction, immunofluorescence, and Western blot analyses. Apoptosis was measured by Annexin-V−propidium iodide staining. Signaling via IL-21R was studied using antibodies specific for phosphorylated Janus-activating kinase and signal transducers and activators of transcription proteins by Western Blot. Results: IL-21R was found on primary FL cells in 15 of 15 cases at diagnosis and IL-21 increased apoptosis in 10 of 10 FL samples. However, cells from areas of diffuse growth in FL and from two diffuse lymphomas evolved from previous FL, showed low IL-21R expression. The latter were also resistant to IL-21−mediated apoptosis. Among lymphoma cell lines bearing the t(14;18) translocation, only 1 of 7 showed increased apoptosis in response to IL-21 stimulation. This cell line was IL-21R−positive, whereas five of six nonresponsive cell lines showed very low IL-21R expression. Intriguingly, one of the IL-21-resistant cell lines (DOHH2) expressed high levels of IL-21R. Treatment with IL-21 or IL-4 upregulated suppressor of cytokine signaling 3 gene expression in the IL-21−responsive cell line, but not in DOHH2 cells, which showed defective Janus-activating kinase/signal transducers and activators of transcription signaling in response to IL-21, in relationship to the lack of Janus-activating kinase 3 gene expression. Conclusion: These data indicate that low IL-21R expression or defective signal transduction downstream IL-21R may cause refractoriness to IL-21−mediated effects in some FL cells. [Copyright &y& Elsevier]

Abstract: Investigation is lacking regarding the clinical impact of human leukocyte antigen (HLA) class I downregulation in breast cancer and results are inconsistent. In this study, we investigated the expression of HLA class I, the heavy chain, and β2-microglobulin (β2-m) by immunohistochemistry in 67 breast carcinomas (BC) and correlated results with clinical–pathologic parameters and patient outcomes. Seventy-six percent of BC were downregulated for HLA class I, whereas downregulation of heavy chain and β2-m was observed in 57 and 46% of BC, respectively. A significant association existed between the absence of tumor necrosis and downregulation of class I and β2-m and between the absence of lymphovascular invasion and patient''s age and downregulated class I and heavy chain, respectively. Among the lymph node-positive BC patients, a significantly improved overall survival was observed in those showing β2-m downregulation compared with patients with normal β2-m. This result may correlate with the role of β2-m in regulating cancer cell growth. [Copyright &y& Elsevier]

Objectives: To obtain accurate spatial information on cancer distribution with a novel prostate biopsy regimen. Methods: From 2003 to 2005, 265 patients underwent a three fan-shaped biopsy (3FSB) technique of 12 to 14 cores and sextant biopsy (SB) simultaneously. When both techniques had positive findings, and radical prostatectomy was performed, the concordance among the positive biopsy locations of the SB, 3FSB, and the combination of both (the reference standard biopsy [RSB]), the proven locations of cancer, and the presence of extracapsular extension and positive surgical margins was calculated. Results: A total of 41 patients were selected, and 74 locations (left and right apex, left and right lobe) had cancer. Of these, 61 were confirmed by RSB, 58 by 3FSB, and 43 by SB with a sensitivity of 95%, 78%, and 58%, respectively. The sensitivity at the apical location was consistently greater for the 3FSB at 68% (19 of 28) compared with 40% (11 of 28) for all proven apical positive localizations and 100% (19 of 19) compared with 58% (11 of 19) for the RSB. The receiver operating characteristic analysis showed 78% accuracy for 3FSB and 68% accuracy for SB compared with the RSB. At the apex, the 3FSB and SB revealed positive surgical margins with a sensitivity of 1 and 0.4, specificity of 0.067 and 0.4, positive predictive value of 0.263 and 0.182, and negative predictive value of 1 and 0.667, respectively. Conclusions: The 3FSB had a great ability to find cancer in the gland, especially at the apex. [ABSTRACT FROM AUTHOR]