Supplementary Figures S1-S4; Supplementary Table S1.

El tumor fibroso solitario (TFS) es una neoplasia de celulas fusadas, de muy baja frecuencia, encontrada mayormente en la pleura pero tambien descrita en sitios extrapleurales. En la literatura se han reportado 24 casos de TFS originados en el tiroides, todos con caracteristicas patologicas e inmunohistoquimicas (IHQ) similares. Reportamos el caso de un tumor tiroideo en un hombre de 30 anos. El tumor se caracterizo por ser una proliferacion de celulas fusadas dispuestas en un patron estoriforme y hemangiopericitoide, sin necrosis ni atipias, con baja actividad mitotica. El estudio IHQ presento positividad para CD34 y bcl-2 y negatividad para Desmina, Pancitokeratina y S-100, caracteristicas concordantes con un TFS. Es importante saber que esta entidad puede surgir en el tiroides y asi poder orientar el estudio para su diagnostico correcto.

Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm mostly found in the pleural tissue but also described in other parenchymas. There are twenty four cases of thyroid SFT, all of them with similar histological appearance and immunohistochemical reaction pattern. We report the case of a thyroid tumor in a thirty year old man. The tumor was characterized by a proliferation of spindle cells arranged in a storiform and hemangiopericitoid pattern, without cell atypia and necrosis, and with low mitotic rate. The tumor showed a strong positive immunohistochemical reaction for CD-34 and bcl-2. There were no reactions for Desmin, Pancytokeratin and S-100. All of these features confirm the diagnosis of a thyroid SFT. It is important to know that this entity can arise in the thyroid gland to direct the analysis in a correct way.

Abstract Purpose: This study characterizes, biologically and clinically, a novel type of dendritic cells (DC) produced in the short term and called tumor antigen–presenting cells (TAPCells). In particular, we identified factors present in a lysate derived from heat-shocked allogeneic melanoma cells (TRIMEL) that are associated with TAPCells' enhanced capability to induce CD8+ T-cell responses in vitro and in vaccinated melanoma patients. Experimental Design: First, extensive phenotypic and functional characterization of TAPCells was performed, followed by vaccination of 45 melanoma patients with four doses of TAPCells over a period of 2 months. Specific delayed-type hypersensitivity (DTH) reaction was analyzed posttreatment and correlated with overall survival rates. Furthermore, heat-shock (HS)-induced factors present in TRIMEL and their effects on DC activation were identified and studied. Results: TRIMEL induced a committed, mature, DC-like phenotype in TAPCells and effectively activated melanoma-specific CD4+ and CD8+ T cells. Clinically, 64% of vaccinated patients showed positive DTH reaction against TRIMEL, and this was associated with improved overall survival. HS treatment of tumor cells increased calreticulin (CRT) plasma membrane translocation and induced the release of high-mobility group box 1 proteins (HMGB1). Both CRT and HMGB1 mobilization were associated with enhanced TAPCells' maturation and antigen (Ag) cross-presentation, respectively. DTH infiltration analysis revealed the presence of CD8+/CD45RO+ T cells, thus confirming TAPCells' ability to cross-present Ags in vivo. Conclusions: Our results indicate that lysates derived from heat-shocked tumor cells are an optimal source of tumor-associated Ags, which are crucial for the generation of DCs with improved Ag cross-presentation capacity and clinically effective immunogenicity. Clin Cancer Res; 17(8); 2474–83. ©2011 AACR.

Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that initiate a cell-mediated antitumor immune response. Recently, we showed that monocyte-derived DCs loaded with a heat-shocked melanoma cell lysate (TRIMEL®) induce melanoma-specific immune responses, thus prolonging patient survival. Here, we describe the rapid effect of TRIMEL on human monocytes differentiation to tumor-antigen presenting cells (TAPCells®). TAPCells showed a mature DC-like phenotype and effectively activated melanoma associated antigen (MAA)-specific CD4+ and CD8+ T lymphocytes. Moreover, heat shock (HS) pre-conditioning of TRIMEL composing cells increased calreticulin (CRT) cell surface translocation and released high-mobility group box 1 protein (HMGB1), which was closely associated to the induction of APC maturation and efficient MAAs cross-presentation. Finally, 26 out of 43 patients vaccinated with TAPCells showed a TRIMEL-specific delayed type hypersensitivity reaction (DTH) associated to anti-melanoma T cell recognition, reduced rates of progression and prolonged patient survival. Our results suggest that heat-shocked tumor cell lysates are optimal source of MAAs, inducing activated APCs with improved MAAs cross-presentation capacity and clinically effective immunogenicity. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B17

PURPOSE:The aim of this work was to assess immunologic response, disease progression, and post-treatment survival of melanoma patients vaccinated with autologous dendritic cells (DCs) pulsed with a novel allogeneic cell lysate (TRIMEL) derived from three melanoma cell lines.PATIENTS AND METHODS:Forty-three stage IV and seven stage III patients were vaccinated four times with TRIMEL/DC vaccine. Specific delayed type IV hypersensitivity (DTH) reaction, ex vivo cytokine production, and regulatory T-cell populations were determined. Overall survival and disease progression rates were analyzed using Kaplan-Meier curves and compared with historical records.RESULTS:The overall survival for stage IV patients was 15 months. More than 60% of patients showed DTH-positive reaction against the TRIMEL. Stage IV/DTH-positive patients displayed a median survival of 33 months compared with 11 months observed for DTH-negative patients (P = .0014). All stage III treated patients were DTH positive and remained alive and tumor free for a median follow-up period of 48 months (range, 33 to 64 months). DTH-positive patients showed a marked reduction in the proportion of CD4+ transforming growth factor (TGF) beta+ regulatory T cells compared to DTH-negative patients (1.54% v 5.78%; P < .0001).CONCLUSION:Our findings strongly suggest that TRIMEL-pulsed DCs provide a standardized and widely applicable source of melanoma antigens, very effective in evoking antimelanoma immune response. To our knowledge, this is the first report describing a correlation between vaccine-induced reduction of CD4+TGFbeta+ regulatory T cells and in vivo antimelanoma immune response associated to improved patient survival and disease stability.

L’infection du tractus digestif par le cytomégalovirus (CMV) survient le plus souvent chez des malades immunodéprimés. Nous rapportons un cas de rectite pseudo-tumorale à CMV chez une femme immunocompétente de 76 ans, révélé par une diarrhée hémorragique et d’évolution favorable sous traitement anti-viral. En l’absence d’essais thérapeutique dans le domaine des infections intestinales à CMV chez l’immunocompétent, nous discutons l’intérêt d’un traitement anti-viral dans les formes sévères ne régressant pas spontanément.Cytomegalovirus (CMV) infection of the gastrointestinal tract occurs mainly in immunosuppressed patients. We report here the case of a 76-year-old woman, without obvious cause of immunosuppression, who developed severe proctitis. The clinical course was favourable with ganciclovir therapy. In the absence of controlled data in the field of CMV intestinal infections in immunocompetents, we discuss the potential benefit of an antiviral therapy in those patients who do not recover rapidly and spontaneously.

Immunotherapy has become a novel therapeutic alternative for various kinds of tumours. Recently, we have finalized the first phase I clinical study in Chile for the treatment of advanced malignant melanoma, using dendritic cells (DCs) loaded with allogeneic melanoma cell lysate. This study included 20 patients and the obtained results, pioneer in Latin America, showed that DC-based immunotherapy is innocuous, even provided in combination with IL-2. In addition, immunological responses were detected in 50% of the treated patients, establishing a positive correlation between the delayed type hypersensitivity (DTH) reaction, which indicates induction of in vivo immunological memory, and patients surviving. Nevertheless, objective clinical responses in vaccinated patients are still insufficient. Only sporadic objective metastasis regressions have been registered and an important proportion of the treated patients did not respond, or their responses were weak. Several strategies have been described to be used by tumours to escape from the immune response. Actually, we have demonstrated that IL-10 inhibits antigen presentation in melanoma, reducing tumour sensitivity to melanoma-specific cytotoxic T lymphocytes (CTLs). Regulation of the immunological response by inhibitory cells could be another possible cause of clinical unresponsiveness. Lately, the existence of subpopulations of regulatory T lymphocytes (RTL) able to limit the immune response in a specific form has been established, specially inhibiting the proliferation and activity of CD4+ and CD8+ effector T lymphocytes. These cellular subpopulations, mostly CD4+/CD25+/Foxp3+ T lymphocytes (Treg) of thymic origin, or TR1 lymphocytes able to release IL-10, and tumour growth factor β (TGF-β) producing TH3 lymphocytes, would be accumulated in the body during tumour growth, inhibiting the immune response. In relation to RTL and cancer, evidence indicates that Treg cell numbers are increased in blood and other tissues in different types of cancer. Additionally, it has been demonstrated that in patients with refractory metastatic melanoma, the adoptive transference of anti-tumour CD8+ T lymphocytes after non-myeloablative chemotherapy was able to induce important tumour regressions that would be due to elimination of RTL populations. Additionally, chemotherapeutical drugs like decarbazine, besides their effect on tumour proliferation, also have an immunosuppressive effect on T lymphocyte populations, as well as on accumulated RTL. In this article, a novel strategy for the study of RTL is proposed, including potential therapeutic innovations, which is being pioneered in current clinical trials.

Dendritic cell (DC)-based therapy has proved to be effective in patients with a variety of malignancies. However, an optimal immunization protocol using DCs and the best means for delivering antigens has not yet been described. In this study, 20 patients with malignant melanoma in stages III or IV were vaccinated with autologous DCs pulsed with a melanoma cell lysate, alone (n = 13) or in combination with low doses of subcutaneous (s.c.)interleukin (IL)-2 injections (n = 7), to assess toxicity, immunological and clinical responses. Monocyte-derived DCs were morphological, phenotypic and functionally characterized in vitro. Peripheral blood mononuclear cells (PBMC), harvested from patients either prior to and after the treatment, were analysed using enzyme-linked immunosorbent spot (ELISPOT). After vaccination, 50% of the patients tested (seven of 13) from the first group and (three of seven) from the second, showed an increase in interferon (IFN)-gamma production in response to allogeneic melanoma cell lines but not to controls. Four of five tested human leucocyte antigen (HLA)-A2(+) patients with anti-melanoma activity also showed specific T cell responses against peptides derived from melanoma-associated antigens. Delayed type IV hypersensitivity reaction (DTH) against melanoma cell lysate was observed in six of 13 patients from the group treated with DC vaccines only and four of seven from the group treated with the combination of DCs and IL-2. Significant correlations were found between DTH-positive responses against tumour lysate and both disease stability and post-vaccination survival on the stage IV patients. There were no toxicities associated with the vaccines or evidence of autoimmunity including vitiligo. Furthermore, no significant enhancement was observed as a result of combining DC vaccination with IL-2. Our data suggest that autologous DCs pulsed with tumour lysate may provide a standardized and widely applicable source of melanoma specific antigens for clinical use. It is safe and causes no significant side effects and has been demonstrated to be partially efficient at triggering effective anti-melanoma immunity.

Resumen es: La clasificacion y gradacion histologica de los tumores de glandulas salivales ha cambiado en los ultimos anos. La variedad y grado histologico son actua...

Resumen es: Introduccion: Los tumores de la glandula submandibular son poco frecuentes. El diagnostico diferen- cial entre tumores benignos y malignos no siempre es ...

An alternative strategy for cancer treatment is the manipulation of the immune system, denominated cancer immunotherapy. The immunotherapeutical use of cells of the immune system, like dendritic cells (DC), is being explored in different clinical protocols. Recently, we finalized a clinical phase I protocol, for the treatment of malignant melanoma, using DCs loaded with tumor lysates. Our results indicate that the subcutaneous application of DCs do not produce adverse effects. We also observed an increase of tumor specific T lymphocytes precursors in the blood, associated to hypersensitivity reactions (DTH) in 60% of the treated patients. In most cases, an stability in the disease was observed, although without a significant association between vaccination and survival. Additionally, therapies based on Interleukin-2 (IL-2) have been used with relative success in the treatment of some kind of tumors since 1985. However, problems associated to the toxicity of IL-2 still restrict its massive use. Our direct experience with the use of IL-2, indicates that low doses and its subcutaneous application, maintains the beneficial effects for patients, eliminating the adverse effects. Based on the accumulated evidence during last the five years, we decided to implement an optimized clinical protocol, which alternatively combines dendritic cells vaccines with the use of low doses of IL-2 for the reinforcement of the immunological system.

A theoretical study is made of the reduction of NO by CO on Rh(111) in terms of the variation of the parameters of the system within an adsorption-desorption quasi-equilibrium regime.

A study of the activity of bimetallic Pd-Rh catalysts supported on silica in the reduction of NO by CO is presented. The catalysts were prepared by three different methods: (1) Pd and Rh were coimpregnated on the support, (2) Rh was impregnated first and, after calcining, the sample was impregnated with Pd, (3) the monometallic Pd and Rh catalysts were physically mixed. The results showed that the activity of the catalysts prepared by coimpregnation was much lower than that of the other two catalysts.