Inmunopatología del cáncer de próstata

Sistema inmunológico/inflamatorio y cáncer de próstata ¿Participa el sistema inmunológico/ inflamatorio en la etiopatogenia de la enfermedad? ¿Existen alteraciones del sistema inmunológico/inflamatorio en los pacientes? ¿son reversibles? Se puede modular terapéuticamente el sistema inmunológico/ inflamatorio?

Etiopatogenia del cáncer de próstata Factores de riesgo Historia familiar Edad avanzada La dieta, de forma emergente

As men in South East Asian countries have a low incidence of prostate cancer that increases rapidly after immigration to the West, this disease is not an intrinsic feature of ageing. The pathogenesis of prostate cancer reflects both hereditary and environmental components. What are the environmental factors and genetic variations that have produced such an epidemic of prostate cancer? Approximately 20% of all human cancers in adults result from chronic inflammatory states and/or chronic inflammation2–4 (

La etiología (el por qué) La patogenia (el como) Etiopatogenia del cáncer de próstata Implicaciones del sistema inmune/inflamatorio La etiología (el por qué) La patogenia (el como) Alteraciones intrínsecas de lás células tumorales (acumulación de alteraciones genéticas y epigenéticas) Interacciones con el huésped

Enigmas de la etiopatogenia del cáncer de próstata Etiología desconocida Alta incidencia en países occidentales y baja en los del extremo oriente Incidencia nivelada tras la primera generación en emigrantes asiáticos Marcada alta incidencia con respecto a otros tumores genitourinarios (vesículas seminales) Localización preferente en área periférica de la glándula A third key unsolved problem is the zonal predilection of prostate cancer. Most cancer lesions occur in the peripheral zone of the gland, fewer occur in the transition zone, and almost none arise in the central zone15 (

Enigmas de la etiopatogenia del cáncer de próstata En las autopsias la incidencia de prostatitis es los hombres caucasianos y afroamericanos es alta y muy baja o inexistente en asiáticos en la primera generación Borowsky A Neoplasia 8,709-715, 2006

Sistema inmunológico/inflamatorio y patogenia del cáncer de próstata En la patogenia de un 20% de los tumores de los adultos se implica un entorno inflamatorio crónico (estómago, intestino grueso, hígado, árbol biliar, vejiga urinaria )

Inflamación y cáncer de próstata Inflamación crónica Alteración epitelial Atrofia focal o difusa del epitelio Áreas de proliferación epitelial “Proliferative inflammatory atrophy” (PIA) Lesiones transicionales entre epitelio atrófico y adenocarcinoma McNeal J in Histology for Pathologists Lippincott-Raven, Philadelphia, 1997 De Marzo, A Am J Pathol. 155, 1985, 1999 McNeal, J Am J Surg Pathol 12, 619, 1998 Nakayama, M Am J Pathol 163, 923, 2003

Inflamación y cáncer de próstata Las lesiones del epitelio atrófico proliferante (PIA) comparten alteraciones moleculares con el cáncer de próstata Disminución de la expresión de genes supresores NKX3.1 CDKN1B (p27) PTEN Bethel, Cancer Res. 66, 10683, 2006 Several key molecular pathways involved in prostate cancer have also been shown to be altered in PIA lesions (BOX 3). For example, the protein products of three prostate tumour-suppressor genes: NKX3.1 (REF. 27), CDKN1B, which encodes p27 (REFS 18,23), and phosphatase and tensin homologue (PTEN) (A.M.D. and D. Faith, unpublished observations) are all downregulated in focal atrophy lesions. These genes are highly expressed in normal prostate epithelium, and frequently decreased or absent in PIN and prostate cancer. In addition, one allele of their corresponding genetic loci is frequently deleted in carcinomas (TABLE 1), and forced overexpression of each of these genes causes decreased growth of prostate cancer cells in culture. Finally, animal models with targeted disruption of either one or two alleles of the corresponding mouse genes develop prostate hyperplasia, PIN and/or invasive carcinoma28

Atypical proliferations arise in an inflamed prostate Segmental area of inflammation (Infl) and another area of atrophy (Atr) Epithelial proliferation with cellular loss of polarity and cytologic atypia

Inflammation and Atrophy Precede Prostatic Neoplasia in a 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP)-Induced Rat Model A Borowsky et al 2006

La etiología (el por qué) La patogenia (el como) Etiopatogenia del cáncer de próstata Implicaciones del sistema inmune/inflamatorio La etiología (el por qué) La patogenia (el como) Alteraciones intrínsecas de lás células tumorales (acumulación de alteraciones genéticas y epigenéticas) Interacciones con el huésped

The molecular mechanisms that underlie the pathogenesis of inflammation-associated cancer are complex, and involve both the innate and adaptive immune systems Highly reactive chemical compounds, including superoxide, hydrogen peroxide, singlet oxygen and nitric oxide are released from activated phagocytic inflammatory cells of the innate immune system These molcelules can cause oxidative or nitrosative damage to DNA in the epithelial cells, or react with other cellular components such as phospholipids, initiating a free-radical chain reaction Condeelis Cell 124, 263–266 (2006) Lewis Cancer Res. 66, 605–612 (2006) de Visser Nature Rev. Cancer 6, 24–37 (2006)

Monocitos proinflamatorios CD14+low CD16+hi CD14+hi CD16+hi CD14+hi CD16+low CD14+hi CD16- Monocitos clásicos

Respuesta inflamatoria conlleva activación de las células Macrófago TNF- IL-1 IL-2 IFN- TH IL-13 IL-4 IL-8, gro IFN-  PMN TNF Linfocitos T citotóxicos y NK Células Plasmáticas IgG1 IgE Célula Troncal PAF LTC4 Respuesta inflamatoria conlleva activación de las células sistema inmune y secreción de citoquinas y factores de crecimiento O2- proteasa PGE2

Infiltración de células inmunológicas/ inflamatorias Participación patogénica del sistema inmunitario/inflamatorio en el cáncer de próstata Infiltración de células inmunológicas/ inflamatorias Secretan citoquinas y quimioquinas que promueven: el crecimiento epitelial angiogénesis Secretan enzimas proteolíticas de la matriz extracelular que favorecen: Invasión tumoral del estroma Invasión vascular

CÁNCER DE PROSTATA. INFLAMACIÓN CITOQUINAS Y FACTORES DE CRECIMIENTO MULTIPLES RELACIONES AUTOCRINAS Y PARACRINAS ESTROMA, EPITELIO / LINFOCITOS Y MONOCITOS

Interleukin-6 It is implicated in the development and progression of prostate cancer (Keller et al., 1996; Trikha et al., 2003, Cavarretta et al., 2007) Correlation between IL-6 protein levels and more advanced stages of the disease and poor prognosis is now well established (Siegall et al., 1990; Siegsmund et al., 1994; Adler et al., 1999; Drachenberg et al., 1999; Nakashima et al., 2000; Giri et al., 2001; Hobisch et al., 2001)

IL-17RC Protein Isoforms Were Differentially Expressed in Prostate Cancers Four of 54 (7%) androgen-dependent prostate cancers were positively stained by anti-ICD, whereas 12 of 55 (22%) androgen-independent prostate cancers were positively stained

La doble cara del sistema inmune y el cáncer JANO INDUCE Y/O FAVORECE DEFIENDE

Entorno inflamatorio tisular inductor de: Participación patogénica del sistema inmunitario/inflamatorio en el cáncer de próstata Entorno inflamatorio tisular inductor de: Supresión de la respuesta efectora inmunológica Apoptosis de las células efectoras Inmunodeficiencia

Participación patogénica del sistema inmunitario/inflamatorio en el cáncer de próstata Entorno tisular inductor de: Supresión de la respuesta efectora inmunológica Monocitos inflamatorios Células dendríticas inmaduras Predomino de subpoblaciones Treg Th17 Th1 Miller, J. Immunol. 177, 7398–7405 (2006) Weaver Immunity 24, 677–688 (2006)

Participación patogénica del sistema inmunitario/inflamatorio en el cáncer de próstata Entorno tisular inductor de: Supresión de la respuesta efectora inmunológica Monocitos inflamatorios Células dendríticas inmaduras Predomino de subpoblaciones Treg Th17 Th1 Miller, J. Immunol. 177, 7398–7405 (2006) Weaver Immunity 24, 677–688 (2006)

Prevalence and function of CD4CD25high T cells is elevated in peripheral blood and tissue samples from PC patients HC BPH PC

FOXP3 expression in prostate tissue Representative sections of prostate tissue, showing benign or malignant gland from the same prostate Arrows indicate FOXP3-positive cells (brown nuclear staining; original magnification, 40) Miller et al The Journal of Immunology, 2006, 177: 7398 –7405.

Participación patogénica del sistema inmunitario/inflamatorio en el cáncer de próstata Entorno tisular inductor de: Supresión de la respuesta efectora inmunológica Monocitos inflamatorios Células dendríticas inmaduras Predomino de subpoblaciones Treg Th17 Th1 Miller, J. Immunol. 177, 7398–7405 (2006) Weaver Immunity 24, 677–688 (2006)

In prostate cancer IL-10 prevents the CD40-induced CTL and TNF- and IL-12 production, Th1 skewing, and tumor regression The Journal of Immunology, 2006, 177: 6642–6649

Participación patogénica del sistema inmunitario/inflamatorio en el cáncer de próstata Genes implicados en susceptibilidad a cáncer de próstata Pertenecientes a la respuesta inmunológica innata Respuesta a virus, RNASEL Respuesta a patrones microbiológicos, TLR Respuesta a mediadores inflamatorios, MSR1 Vías inflamatorias Il-1R, MIC1 RNASEL and MSR1. Following up genomic regions of interest identified by linkage studies of prostate cancer families, two genes involved in innate immunity unexpectedly emerged as candidate prostate cancer susceptibility genes. Inactivating mutations (E265X and M1I) in ribonuclease L (RNASEL) segregate with prostate cancer in two prostate

La doble cara del sistema inmune y el cáncer JANO INDUCE Y/O FAVORECE DEFIENDE

1 2 DC New Paradigm – 2 Hit Model - - Chronic inflammation DC T/NK Tumor Necrosis [↓Apoptosis] ↓ Release of Factors [HMGB1, others?] Tumor Growth 1 2 - - Immunosuppression mediated by PDC, tumor, other cells T/NK CELL TUMOR TUMOR DC DC Perforin FasL IFNγ TNFα HMGB1, HSP, Uric Acid HSP, Adenine, ATP Chronic inflammation

Causas de la inflamación crónica prostática Cáncer de próstata Causas de la inflamación crónica prostática

Possible causes of prostate inflammation a | Infection Chronic bacterial, viruses, fungi, mycobacteria and parasites b | Hormones Hormonal alterations such as oestrogen exposure at crucial developmental junctures can result in architectural alterations in the prostate that produce an inflammatory response c | Physical trauma Corpora amylacea can traumatize the prostate on a microscopic level De Marzo Nature Reviews Cancer 7. 256-269, 2007

Possible causes of prostate inflammation d | Urine reflux Urine that travels up back towards the bladder can penetrate the ducts and acini of the prostate Some compounds, such as crystalline uric acid, can directly activate innate inflammatory cells Although these compounds would not be expected to traverse the prostate epithelium, if the epithelium was already damaged this would facilitate the leakage of these compounds into the stromal space where they would readily activate inflammatory cells e | Dietary habits Ingested carcinogens (for example 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which derives from charred meat) can reach the prostate through the bloodstream or by urine reflux and cause DNA damage and mutations, and result in an influx of inflammatory cells De Marzo Nature Reviews Cancer 7. 256-269, 2007

Sistema inmunológico/inflamatorio y cáncer de próstata ¿Participa el sistema inmunológico/ inflamatorio en la etiopatogenia de la enfermedad? ¿Existen alteraciones del sistema inmunológico/inflamatorio en los pacientes? ¿son reversibles? Se puede modular terapéuticamente el sistema inmunológico/ inflamatorio?

DEFECTIVE T LYMPHOCYTE ACTIVATION IN PATIENTS WITH PROSTATE CANCER *Peripheral blood mononuclear cells (PBMC) were cultured in the presence of the indicated stimuli and pulsed for 18 h with Ci/well 3H-TdR. The mean ct/min of triplicate samples was determined by liquid scintillation on day 3. Results are indicated as mean ± s.d. in ct/min X 1000. Anti-CD28 and anti-CD2 (CD2.1 + CD2.9) are not mitogenic (data not shown). &.-The degree of statistical significance was calculated by Student´s t test. NS, not significant. Con A, concanavalin A; PHA, phytohaemagglutinin; PMA, phorbol myristate acetate.

DEFECTIVE T LYMPHOCYTE ACTIVATION IN PATIENTS WITH PROSTATE CANCER *Peripheral blood mononuclear cells (PBMC) were cultured in the presence of the indicated stimuli and pulsed for 18 h with Ci/well 3H-TdR. The mean ct/min of triplicate samples was determined by liquid scintillation on day 3. Results are indicated as mean ± s.d. in ct/min X 1000. Anti-CD28 and anti-CD2 (CD2.1 + CD2.9) are not mitogenic (data not shown). &.-The degree of statistical significance was calculated by Student´s t test. NS, not significant. Con A, concanavalin A; PHA, phytohaemagglutinin; PMA, phorbol myristate acetate.

VIABILIDAD CELULAR TRAS ESTIMULAR CON anti-CD3 + PMA 300 CD4 200 CD8 CONTROL CaP 100 CD4 CD8 1000 24 48 72 96 600 750 450 CD45RO 300 CÉLULAS VIVAS X 1000 500 CÉLULAS VIVAS X 1000 150 CD45RA 250 24 48 72 96 300 24 48 72 96 CD8 + CD45RO + 200 CD4 + CD45RO + CD4 + CD45RO + 100 CD8 + CD45RO + CD4 + CD45RA + CD8 + CD45RA + 24 48 72 96

DEFECTIVE T LYMPHOCYTE ACTIVATION IN PATIENTS WITH PROSTATE CANCER *Peripheral blood mononuclear cells (PBMC) were cultured in the presence of the indicated stimuli and pulsed for 18 h with Ci/well 3H-TdR. The mean ct/min of triplicate samples was determined by liquid scintillation on day 3. Results are indicated as mean ± s.d. in ct/min X 1000. Anti-CD28 and anti-CD2 (CD2.1 + CD2.9) are not mitogenic (data not shown). &.-The degree of statistical significance was calculated by Student´s t test. NS, not significant. Con A, concanavalin A; PHA, phytohaemagglutinin; PMA, phorbol myristate acetate.

DEFECTIVE T LYMPHOCYTE ACTIVATION IN PATIENTS WITH PROSTATE CANCER *Cells were cultured for 3 days with the indicated stimuli and stained with anti-CD25-FITC and an irrelevant MoAb of the same subclass (IgG1). , Anti-. &The results are shown as percentage of positive cells for CD25 expression (mean ±s.d.). The degree of statistical significance was calculated with Mann-Whiyney U-test. NS, Not significant. PMA, Phorbol myristate acetate; PCaD, prostate cancer patients; PHA, phytohaemagglutinin.

LAS ALTERACIONES DEL SISTEMA INMUNE....COMO FACTOR DE RIESGO

MURPHY´S LAW FRIENDS COME AND GO BUT ENEMIES ACCUMULATE M U R P H Y W

Sistema inmunológico/inflamatorio y cáncer de próstata ¿Participa el sistema inmunológico/ inflamatorio en la etiopatogenia de la enfermedad? ¿Existen alteraciones del sistema inmunológico/inflamatorio en los pacientes? ¿son reversibles? Se puede modular terapéuticamente el sistema inmunológico/ inflamatorio?

DC vaccination induces tumor-specific T cells with potent effector function TCR-I T cells primed with a DC vaccine were protected from tolerance and acquired cytolytic function Twelve-week-old male TRAMP mice or WT mice received 3 106 CD8 and Thy1.1 TCR-I T cells Eighteen hours later, mice received peptide-pulsed DCs as previously described. Prostates were harvested on the indicated day postvaccine, and TCR-I cells were isolated by magnetic beads A, T cells were directly used as responder cells in an IFN-ELISPOT assay. B, T cells were directly used as responder cells in a granzyme B ELISPOT assay C, T cells were assayed for their ability to Degranulate in response to the cognate TAg epitope, based on CD107a expression Anderson J Immunology, 2007, 178: 1268–1276.

Priming with a DC vaccine results in upregulation of activation markers and IFN-g production Twelve-week-old male TRAMP or nontransgenic, WT mice received 3 106 CFSE, CD8, and Thy1.1 TCR-I T cells. Eighteen hours later, mice received peptide-pulsed DCs Vaccine DLN were harvested 3 days after DC vaccine Anderson J Immunology, 2007, 178: 1268–1276.

Autoantibody responses in patients undergoing Standard Treatments Induce Antigen-Specific Immune Responses in Prostate Cancer Clin Cancer Res 13,1493 2007 Autoantibody responses in patients undergoing Neoadjuvant hormone therapy (7 of 24, 29.2%) External beam radiation therapy (4 of 29, 13.8%) Brachytherapy (5 of 20, 25%) 0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%)

Standard Treatments Induce Antigen-Specific Immune Responses in Prostate Cancer Clin Cancer Res 13,1493 2007

Standard Treatments Induce Antigen-Specific Immune Responses in Prostate Cancer Clin Cancer Res 13,1493 2007 Several antigens recognized by treatment associated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2 Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups.

PSA values over time for patients who showed a hormone therapy associated autorreactivity Clin Cancer Res 13,1493 2007

Sistema inmunológico/inflamatorio y cáncer de próstata ¿Participa el sistema inmunológico/ inflamatorio en la etiopatogenia de la enfermedad? ¿Existen alteraciones del sistema inmunológico/inflamatorio en los pacientes? ¿son reversibles? Se puede modular terapéuticamente el sistema inmunológico/ inflamatorio?

Immunotherapy for prostate cancer Dendritic cell-based immunotherapeutics GM-CSF-based approaches Systemic GM-CSF Cellular delivery of GM-CSF Antigen-pulsed dendritic cells T Lymphocyte-based immunotherapeutics Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy B Lymphocyte-based immunotherapeutics Antibody-based therapy Antibody to vascular endothelial growth factor Antibody to PSMA Radiolabelled antibody therapy PSA vaccines Prostate-specific membrane antigen Glycoprotein vaccines

Immunotherapy for prostate cancer Dendritic cell-based immunotherapeutics GM-CSF-based approaches Systemic GM-CSF Cellular delivery of GM-CSF Antigen-pulsed dendritic cells T Lymphocyte-based immunotherapeutics Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy B Lymphocyte-based immunotherapeutics Antibody-based therapy Antibody to vascular endothelial growth factor Antibody to PSMA Radiolabelled antibody therapy PSA vaccines Prostate-specific membrane antigen Glycoprotein vaccines

DC vaccination trials Of the about 17 DC vaccination trials reported on in peerreviewed journals All trials have demonstrated negligible toxicity Clinical responses or favorable changes in PSA-kinetics in about 45% of the patients In the first randomized, placebo-controlled vaccination trial, a survival benefit of several months for vaccinated patients could be shown

Immunotherapy for prostate cancer using prostatic acid phosphatase loaded antigen presenting cells Loaded dendritic cell therapy using prostatic acid phosphatase (APC8015; Provenge®, Dendreon Corp., Seattle, WA) as an immunogen has shown a survival benefit in patients with metastatic hormone-refractory prostate cancer in a randomized phase III trial In the intent-to-treat analysis, which included all 127 patients, there was a survival advantage with APC8015, with a median overall survival of 25.9 months versus 21.4 months (representing a 4.5-month difference), hazard ratio 1.43 (P 0.01) Urologic Oncology, 24 (2006) 434–441

DC vaccination trials Although from the other (Phase I/II) trials, a clinical efficacy cannot formally be concluded, their results are encouraging and provide a proof of principle for the immunogenicity of DC-based immunotherapy in prostate cancer patients

CD14+ or CD34+ DC precursors in blood Antigen-loaded DC Which subset ? Dose and frequency ? Which route of injection ? Which maturation stimulus ? Which method of antigen preparation and delivery ? Combination with other therapies ? How to determine efficacy ? Induce CTL and Th1 Critical parameters for DC-based immunotherapy

DC vaccination trials To further improve patients’ outcome, several strategies involving choice of antigen, optimization of DC maturation, combination with conventional treatment or immune modulation such as removal of Treg are being evaluated. Furthermore, patients with low tumor burden and better immune competence might profit more from vaccination therapy than heavily pre-treated, advanced-stage cancer patients Standardization of DC preparation, clinical and immune monitoring are warranted.

Immunotherapy for prostate cancer Dendritic cell-based immunotherapeutics GM-CSF-based approaches Systemic GM-CSF Cellular delivery of GM-CSF Antigen-pulsed dendritic cells T Lymphocyte-based immunotherapeutics Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy B Lymphocyte-based immunotherapeutics Antibody-based therapy Antibody to vascular endothelial growth factor Antibody to PSMA Radiolabelled antibody therapy PSA vaccines Prostate-specific membrane antigen Glycoprotein vaccines

PSA-modulating effects observed warrant further investigation A PilotTrial of CTLA-4 Blockade with Human Anti CTLA-4 in Patients with Hormone-Refractory Prostate Cancer A single dose of 3 mg/kg Ipilimumab, an anti-CTLA-4a ntibody, given to patients with prostate cancer is safe and does not result in significant clinical autoimmunity PSA-modulating effects observed warrant further investigation Eric J. Small et al Clin Cancer Res 13, 15, 2007

Immunotherapy for prostate cancer Dendritic cell-based immunotherapeutics GM-CSF-based approaches Systemic GM-CSF Cellular delivery of GM-CSF Antigen-pulsed dendritic cells T Lymphocyte-based immunotherapeutics Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy B Lymphocyte-based immunotherapeutics Antibody-based therapy Antibody to vascular endothelial growth factor Antibody to PSMA Radiolabelled antibody therapy PSA vaccines Prostate-specific membrane antigen Glycoprotein vaccines

Anticuerpos monoclonales Dirigidos frente an antígenos tumorales o específicos de la próstata: PSA, PSCA Conjugados a tóxina o agenets radiactivos o no conjugados Lampe MI, et al. Development of new prostate specific monoclonal antibodies. Prostate 58, 225, 2004 Nanus DM, et al. Clinical use of monoclonal antibody HuJ591 therapy: targeting prostate specific membrane antigen. J Urol 170, 84, 2004 Milowsky MI, et al. Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer J Clin Oncol 22, 2522, 2004 Bander NH, et al. Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate specific membrane antigen, in patients with androgen-independent prostate cancer. J Clin Oncol 23, 4591, 2005

Immunotherapy for prostate cancer Dendritic cell-based immunotherapeutics GM-CSF-based approaches Systemic GM-CSF Cellular delivery of GM-CSF Antigen-pulsed dendritic cells T Lymphocyte-based immunotherapeutics Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy B Lymphocyte-based immunotherapeutics Antibody-based therapy Antibody to vascular endothelial growth factor Antibody to PSMA Radiolabelled antibody therapy PSA vaccines Prostate-specific membrane antigen Glycoprotein vaccines

Vaccines Recently, immunotherapy with tumor vaccines has emerged as an alternative therapeutic approach However, despite evidence for the induction of tumor-specific T cell responses, significant objective clinical response rates are low The reasons behind the limited success of these approaches in PC patients are still largely unknown

Sistema inmunológico/inflamatorio y cáncer de próstata ¿Participa el sistema inmunológico/ inflamatorio en la etiopatogenia de la enfermedad? ¿Existen alteraciones del sistema inmunológico/inflamatorio en los pacientes? ¿son reversibles? Se puede modular terapéuticamente el sistema inmunológico/ inflamatorio?

Investigación etiopatogénica, diagnóstica, terapéutica y reparativa SUPERAR LIMITACIONES EN: LA REALIZACIÓN DE ENSAYOS CLÍNICOS LA OPTIMIZACIÓN Y EL DESARROLLO TERAPÉUTICO Y REPARATIVO SIMILITUD CLÍNICA DIAGNÓSTICO DE ENFERMEDAD ÚNICA HETEROGENEIDAD EN LOS MECANISMOS ETIOPATOGÉNICOS CELULARES Y MOLECULARES EN LAS ENFERMEDADES CONSIDERADAS ÚNICAS Medicina traslacional Medicina individualizada No existen enfermedades sino enfermos

El mal de quien la causa no se sabe, milagro es acertar la medicina Cervantes, 1605

Hospital Universitario Puerta de Hierro Medicina clínica de calidad fundamentada en hacer investigación biomédica mutidisciplinaria y traslacional hacia la enfermedad y el paciente Belen Martínez Jorge Monserrat Joaquín Carballido Hospital Universitario Puerta de Hierro

Gracias por su atención 15-11-2007 AM3 State of the Arts