CD8+ NKs as a potential biomarker of complete response and survival with lenalidomide plus R-GDP in the R2-GDP-GOTEL trial in recurrent/refractory diffuse large B cell lymphoma.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.

Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis.

PURPOSE: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. PATIENTS AND METHODS: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1-14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1-3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1-21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). RESULTS: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3-4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

Immunometabolism Modulation in Therapy.

The study of cancer biology should be based around a comprehensive vision of the entire tumor ecosystem, considering the functional, bioenergetic and metabolic state of tumor cells and those of their microenvironment, and placing particular importance on immune system cells. Enhanced understanding of the molecular bases that give rise to alterations of pathways related to tumor development can open up new therapeutic intervention opportunities, such as metabolic regulation applied to immunotherapy. This review outlines the role of various oncometabolites and immunometabolites, such as TCA intermediates, in shaping pro/anti-inflammatory activity of immune cells such as MDSCs, T lymphocytes, TAMs and DCs in cancer. We also discuss the extraordinary plasticity of the immune response and its implication in immunotherapy efficacy, and highlight different therapeutic intervention possibilities based on controlling the balanced systems of specific metabolites with antagonistic functions.

Metabolic Classification and Intervention Opportunities for Tumor Energy Dysfunction.

A comprehensive view of cell metabolism provides a new vision of cancer, conceptualized as tissue with cellular-altered metabolism and energetic dysfunction, which can shed light on pathophysiological mechanisms. Cancer is now considered a heterogeneous ecosystem, formed by tumor cells and the microenvironment, which is molecularly, phenotypically, and metabolically reprogrammable. A wealth of evidence confirms metabolic reprogramming activity as the minimum common denominator of cancer, grouping together a wide variety of aberrations that can affect any of the different metabolic pathways involved in cell physiology. This forms the basis for a new proposed classification of cancer according to the altered metabolic pathway(s) and degree of energy dysfunction. Enhanced understanding of the metabolic reprogramming pathways of fatty acids, amino acids, carbohydrates, hypoxia, and acidosis can bring about new therapeutic intervention possibilities from a metabolic perspective of cancer.

Integrating the Tumor Microenvironment into Cancer Therapy.

Tumor progression is mediated by reciprocal interaction between tumor cells and their surrounding tumor microenvironment (TME), which among other factors encompasses the extracellular milieu, immune cells, fibroblasts, and the vascular system. However, the complexity of cancer goes beyond the local interaction of tumor cells with their microenvironment. We are on the path to understanding cancer from a systemic viewpoint where the host macroenvironment also plays a crucial role in determining tumor progression. Indeed, growing evidence is emerging on the impact of the gut microbiota, metabolism, biomechanics, and the neuroimmunological axis on cancer. Thus, external factors capable of influencing the entire body system, such as emotional stress, surgery, or psychosocial factors, must be taken into consideration for enhanced management and treatment of cancer patients. In this article, we review prognostic and predictive biomarkers, as well as their potential evaluation and quantitative analysis. Our overarching aim is to open up new fields of study and intervention possibilities, within the framework of an integral vision of cancer as a functional tissue with the capacity to respond to different non-cytotoxic factors, hormonal, immunological, and mechanical forces, and others inducing stroma and tumor reprogramming.

[An integral view of cancer (III). Evaluation of new biomarkers and treatment strategies]. / Una visión integral del cáncer (III). Evaluación de nuevos biomarcadores y posibilidades de intervención.

We propose a comprehensive approach to oncological disease, based on a systemic consideration of biology, health and disease. Our two previous review articles focused on tumour microenvironment and the discovery of new biomarkers; here we discuss the practical application of these principles to pathology, through the identification, evaluation and quantitative analysis of new prognostic and predictive factors (Immunoscore, TIME). We also consider the clinical use of promising, better tolerated treatments, such as immunotherapy. The integrative pathologist now has access to the latest improved oncology stratification tools designed to identify effective treatment strategies, based on the natural evolution of clinical and scientific knowledge that transcend the gene-centric theory of cancer.

Una visión integral del cáncer (II). Campos de estudio y biomarcadores emergentes / An integral view of cancer (II). Fields of investigation and emerging biomarkers

El mundo de la Patología cobra sentido de la mano de la Oncología Clínica, donde técnicas y tratamientos, biomarcadores y anticuerpos, comparten el objetivo de hallar nuevas posibilidades de intervención, más eficaces, menos agresivas y más integrales. En esta búsqueda, la evidencia muestra como la mecánica tisular afecta la carcinogénesis y como la heterogeneidad tumoral depende de la alteración metabólica del estroma y del efecto Warburg de las células malignas, regulado directamente por PD-1 y diana del tratamiento inmunoterápico. Proliferación y apoptosis dependen de la disfunción mitocondrial de la célula tumoral que determina el grado de quimio- y radiorresistencia. El estado de la microbiota intestinal determina la respuesta inmune, la estructura del microambiente del tumor y la respuesta al tratamiento oncológico, y el receptor de la vitamina D permite la reprogramación del estroma tumoral. En la actualidad, la colaboración entre los mundos de la investigación básica y clínica establece como zonas de desarrollo próximo el estudio del microambiente tumoral y la mecanoterapia molecular, el metabolismo y la inmunoterapia, la mitocondria y la oncogénesis, la microbiota y la quimioterapia, el eje psiconeuroendocrino y el desequilibrio homeostático, la epigenética y las posibilidades de reprogramación del fenotipo tumoral. De todos estos campos de conocimiento surgen nuevos biomarcadores, pronósticos y predictivos, que revisamos en este artículo al servicio de nuevas posibilidades de intervención terapéutica

Pathology and clinical oncology work hand in hand so that techniques and treatments, biomarkers and antibodies share the common goal of identifying integral new treatment regimens that are more effective and less aggressive. Evidence shows how tissue mechanics affect carcinogenesis and that tumor heterogeneity depends on metabolic stromal alteration and the Warburg effect of malignant cells, regulated directly by PD-1, becoming a target for immunotherapy. Proliferation and apoptosis depend on mitochondrial dysfunction in tumor cells, determining the grade of chemo/radio-resistance. The status of intestinal microbiota regulates immune response, tumor microenvironment structure and oncologic treatment response, whilst the Vitamin D receptor allows reprogramming of tumor stroma. Current collaboration between basic and clinical research paves the way for future investigation into areas such as tumor microenvironment and molecular mechanotherapy, metabolism and immunotherapy, mitochondria and oncogenesis, microbiota and chemotherapy, psychoneuroendocrine axis and homeostatic imbalance, epigenetics and reprogramming possibilities of the tumor phenotype. We review new prognostic and predictive biomarkers emerging from these fields of knowledge, opening up new therapeutic possibilities

[An integral view of cancer (II). Fields of investigation and emerging biomarkers]. / Una visión integral del cáncer (II). Campos de estudio y biomarcadores emergentes.

Pathology and clinical oncology work hand in hand so that techniques and treatments, biomarkers and antibodies share the common goal of identifying integral new treatment regimens that are more effective and less aggressive. Evidence shows how tissue mechanics affect carcinogenesis and that tumor heterogeneity depends on metabolic stromal alteration and the Warburg effect of malignant cells, regulated directly by PD-1, becoming a target for immunotherapy. Proliferation and apoptosis depend on mitochondrial dysfunction in tumor cells, determining the grade of chemo/radio-resistance. The status of intestinal microbiota regulates immune response, tumor microenvironment structure and oncologic treatment response, whilst the Vitamin D receptor allows reprogramming of tumor stroma. Current collaboration between basic and clinical research paves the way for future investigation into areas such as tumor microenvironment and molecular mechanotherapy, metabolism and immunotherapy, mitochondria and oncogenesis, microbiota and chemotherapy, psychoneuroendocrine axis and homeostatic imbalance, epigenetics and reprogramming possibilities of the tumor phenotype. We review new prognostic and predictive biomarkers emerging from these fields of knowledge, opening up new therapeutic possibilities.

Una visión integral del cáncer (I). Microambiente tumoral: estudio, clasificación y reprogramación / An integral view of cancer (I). The study, classification and reprogramming of the tumoral microclimate

El grupo de enfermedades al que nos referimos como «cáncer» comparte una estructura biológica conformada por un ecosistema complejo, donde se han alterado las relaciones intercelulares, los campos de información, el desarrollo y la función tisular. Más allá de las alteraciones genéticas de la célula tumoral, la demostración de un ecosistema alterado, con sus interconexiones a nivel sistémico, abre una nueva perspectiva de la biología y del comportamiento del cáncer. Diversas facetas del tumor, su morfología, clasificación, agresividad clínica, pronóstico y respuesta al tratamiento aparecen ahora bajo una visión integral que ofrece un nuevo horizonte de estudio, investigación y manejo clínico. La Teoría de la Mutación Somática en cáncer, vigente desde hace más de 100 años, se ve hoy completada por el estudio del microambiente tumoral, la matriz extracelular, las células estromales, la respuesta inmune, la inervación, la nutrición, la mitocondria, el metabolismo, el fluido intersticial, las propiedades mecánicas y electromagnéticas del tejido, y muchas otras áreas de conocimiento emergente, que abren la puerta a un ejercicio de reprogramación del fenotipo tumoral a través de la modificación de las claves ofrecidas por este nuevo paradigma. Su reconocimiento permite pasar de considerar el proceso oncológico como un problema celular a una alteración supracelular basada en la desorganización de los tejidos, inmersos en las relaciones del sistema complejo que conforma un ser vivo

The group of diseases that we call cancer share a biological structure formed by a complex ecosystem, with altered intercellular communication, information fields, development and tissue function. Beyond the genetic alterations of the tumor cell, the demonstration of an altered ecosystem, with interconnections at systemic levels, opens up a new perspective on cancer biology and behavior. Different tumor facets, such as morphology, classification, clinical aggressiveness, prognosis and response to treatment now appear under a comprehensive vision that offers a new horizon of study, research and clinical management. The Somatic Mutation Theory in cancer, in force for more than one hundred years, is now completed by the study of the tumor microenvironment, the extracellular matrix, the stromal cells, the immune response, the innervation, the nutrition, the mitochondria, the metabolism, the interstitial fluid, the mechanical and electromagnetic properties of the tissue and many other areas of emerging knowledge; thus opening the door to a reprogramming exercise of the tumor phenotype through the modification of the keys offered by this new paradigm. Its recognition makes it possible to go from considering the oncological process as a cellular problem to a supracellular alteration based on the disorganization of tissues, immersed in the relationships of the complex system of the living being

[An integral view of cancer (I). The study, classification and reprogramming of the tumoral microclimate]. / Una visión integral del cáncer (I). Microambiente tumoral: estudio, clasificación y reprogramación.

The group of diseases that we call cancer share a biological structure formed by a complex ecosystem, with altered intercellular communication, information fields, development and tissue function. Beyond the genetic alterations of the tumor cell, the demonstration of an altered ecosystem, with interconnections at systemic levels, opens up a new perspective on cancer biology and behavior. Different tumor facets, such as morphology, classification, clinical aggressiveness, prognosis and response to treatment now appear under a comprehensive vision that offers a new horizon of study, research and clinical management. The Somatic Mutation Theory in cancer, in force for more than one hundred years, is now completed by the study of the tumor microenvironment, the extracellular matrix, the stromal cells, the immune response, the innervation, the nutrition, the mitochondria, the metabolism, the interstitial fluid, the mechanical and electromagnetic properties of the tissue and many other areas of emerging knowledge; thus opening the door to a reprogramming exercise of the tumor phenotype through the modification of the keys offered by this new paradigm. Its recognition makes it possible to go from considering the oncological process as a cellular problem to a supracellular alteration based on the disorganization of tissues, immersed in the relationships of the complex system of the living being.

Uso de técnicas complementarias en el tratamiento de la fibromalgia / No disponible

No disponible

Tumor-infiltrating cells as a prognostic factor in Hodgkin's lymphoma: a quantitative tissue microarray study in a large retrospective cohort of 267 patients.

The present study aimed to describe the general tissular composition of the immune infiltrate observed in Hodgkin's lymphoma (HL) and its possible relationship with clinical and survival prognostic factors. In this retrospective study of 267 HL patients, the relative proportions of infiltrating T lymphocytes (CD4+, CD8+), natural killer cells (CD 56+, CD 57+), cytotoxic cells (Granzyme B+, TIA-1+) and dendritic cells (CD 21+, S-100+) were quantified immunohistochemically with tissue microarray technology. Our results confirm the predominance of CD4 + T lymphocytes in the background of tumoral cells, in addition to a high number of cytotoxic lymphocytes (CD8, CD 57 and TIA-1). Patients with low numbers of infiltrating CD8, CD 56, CD 57+cells and high numbers of Granzyme B and TIA-1+cells presented a significantly unfavourable clinical course (presence of leukocytosis, B symptoms, advanced clinical stage (III/IV), non-responding patients). A reduced infiltration of CD4+T lymphocytes was related with the presence of Epstein - Barr virus. Significantly longer survival times were observed in patients with a high level of infiltrating CD 57, as well as a low level of Granzyme B and TIA-1+cells (log-rank test). When evaluated in a multivariate model, high levels of infiltrating TIA-1 and Granzyme B+cells were shown to be independent prognostic factors that negatively influenced overall survival. The presence of TIA-1+cells was found to be the only unfavorable prognostic factor of event-free survival and disease-free survival. The overall detection of tumor-infiltrating cells in HL confirms the importance of cytotoxic T lymphocyte infiltration (Granzyme B and TIA-1+cells) in these patients. Independently of the classical clinical and pathological features, these cells appear to be an unfavourable prognostic factor in HL and, more particularly, the presence of cytotoxic TIA-1+cells.

Decreased number of granzyme B+ activated CD8+ cytotoxic T lymphocytes in the inflammatory background of HIV-associated Hodgkin's lymphoma.

This study aimed to assess the differences in the cellular composition of the inflammatory reactive background around tumoral cells of classical Hodgkin's lymphomas (cHL) inside and outside the HIV settings. This retrospective study evaluates the infiltrating T lymphocytes (CD4 and CD8), natural killer cells (CD57+ cells), and more especially cytotoxic cells [granzyme B (GrB) and TIA-1+ cells] in the background of 99 EBV+ cHL. Sections from paraffin-embedded tumor samples from nine HIV-infected cHL patients were immunostained, using standard immunohistochemical protocols and were compared to a control group of 90 HIV-noninfected cHL patients. Our clinical and histological data indicate that HIV-infected cHL patients present a higher frequency of mixed cellularity (MC) histological subtypes, more advanced disease stages, a poor response to treatment, and a poor overall survival compared to control patients. In controls, CD4/CD8 and GrB/TIA-1 ratios were determined as 2:1 and 1:2, respectively. The inflammatory infiltrate of HIV-infected patients had a significant reduction of CD4+ T lymphocytes (CD4/CD8 ratio 1:23), a decrease in infiltrating GrB+ cells (activated cytotoxic cells) and an increase in infiltrating TIA+ T cells (mainly nonactivated cytotoxic cells) in these patients (GrB/TIA-1 ratio 1:12). In conclusion, this study highlights an important intratumoral loss of CD4+ T cells (striking inversion in the CD4/CD8 ratio) and a decrease in intratumoral activated cytotoxic T lymphocytes in HIV-associated cHL patients. Further studies are required to confirm these results and to determine the role of these findings on the antitumoral immune response observed in HIV-associated cHL.

Enfermedad de Hodgkin. Papel etiopatogénico del virus de Epstein-Barr en las comarcas de Tarragona / Hodgkin's disease. Etiopathogenic role of EBV in Tarragona (Spain)

Fundamento: Se pretende determinar la proporción de enfermedad de Hodgkin (EH) que expresa el virus de Epstein-Barr (VEB) en nuestro medio. Pacientes y métodos: Se ha realizado un estudio retrospectivo sobre 49 casos de EH usando la técnica inmunohistoquímica LMP-1 y la técnica de hibridación in situ para EBER-1. Resultados: Un 40,8 por ciento (20/49) de los casos expresaba VEB (EBER-1 y/o LMP-1 positivos). Este porcentaje fue significativamente mayor en EH diagnosticadas a pacientes mayores de 55 años y no hubo diferencias por sexo, aunque fue mayor, pero no de forma significativa, en el subtipo histológico de EH de celularidad mixta. Conclusiones: El VEB se asocia a un 40,8 por ciento de las EH en las comarcas de Tarragona (AU)