One of our main research lines focuses on Histiocytosis. Histiocytic disorders are a heterogeneous group of rare diseases with unknown origin such as neoplasia, immunodeficiency or malignancy. They are characterized by an over-production of white blood cells (monocytes, macrophages or dendritic cells) which affect several organs and tissues. The most common types during childhood are Langerhans cell histiocytosis (LCH) and hemophagocytic lymphohistiocytosis (HLH).
Our research on Langerhans cell histiocytosis focuses on epidemiological studies, for example, the Spanish registry and database of paediatric which was created in collaboration with Asociación Española contra la Histiocitosis (ACHE) and Sociedad Española de Hematología y Oncología Pediátricas (SEHOP). It should be highlighted our participation, since 2003, in several treatment-based clinical trials conducted by the Histiocyte Society (LCH-III, LCH-IV). From 2008 to 2011, our group has led one part of the EuroHistioNet Project, which aimed to generate a reference network for Langerhans cell histiocytosis and histiocytic syndromes, and to design a website in several languages (including Spanish) with information about these diseases, clinical practice guidelines and their treatment for healthcare provider professionals and the general public. In order to continue this line of research, in 2011 a proposal to the EU 7th Framework Programme entitled "Improve clinical practice in the management of histiocytosis patients" (TREAT HISTIO) was submitted. Recent evidence of the origin of pathological Langerhans cells, clonal proliferation and cytokines synthesis mechanisms may be useful for gaining knowledge of histiocytosis pathogenesis and for searching novel therapeutic alternatives. These findings could be applied to other diseases, such as malignant tumours, which are characterized by alterations in the regulation of dendritic and myeloid cells.
Our research on hemophagocytic lymphohistiocytosis (HLH) started as collaboration with the Histiocyte Society for the development of a novel worldwide treatment protocol (HLH-2004) and the implementation of these international recommendations in Spain. After that, a Spanish network of hospitals was created in order to improve the detection of hereditary or familial cases and secondary types in Spain (Rare Disease Project funded by BIOEF in 2008). The HLH studies were initially epidemiological; but since 2009 our projects also include the search of novel diagnostic tools and biomarkers for hemophagocytic syndromes.
This disease, considered to be a primary immunodeficiency, is characterized by an excessive inflammatory response due to an over-proliferation of activated lymphocytes and hystiocytes which secrete high amount of cytokines. Therefore, identification of defective regulatory mechanisms of immune and inflammatory response and control of cellular proliferation and death may be used in others severe diseases, such as multiorgan failure sepsis and other hyper-inflammatory syndromes. These alterations in HLH and severe sepsis in paediatric and adult patients have been investigated in several ongoing projects (2011 and 2012).
Most patients with HLH display alterations in the function of natural killer cells (NK) and increased levels of several pro-inflammatory cytokines. These changes can also be observed in some cancer patients who suffered from defects in linfocitotoxicity mechanisms. In order to further investigate the role of immunotherapy with NK cells in child cancer, a project has been submitted to the Asociación Española Contra el Cáncer in collaboration with Hospital Niño Jesús and other Spanish Paediatric Oncology Units.
Histiocytosis displays a variable natural history and reactivations are common. Some disease outcomes include hormonal deficits and neurological problems. There is a general concern with patients' quality of life. In this regard, we collaborate with Deusto University in the development of a psycho-emotional support programme for patients with rare diseases (BIZKAIALAB project, funded by Diputación de Bizkaia). Moreover, we participate in an international project BURQOL, funded by DG Sanco (2010-2013), which aims to measure the socio-economic impact and health-related quality of life in ten rare diseases, including histiocytosis.
Since 1992, the Haematology and Paediatric Oncology Unit at Cruces University Hospital has been working on childhood leukaemia and tumours (mainly brain tumours), because the Head of the Unit was appointed as National Coordinator in the Brain Tumour Workgroup at Sociedad Española de Hematología y Oncología Pediátricas (SEHOP). Moreover, the group took part in international multicentre clinical trials conducted by Sociedad Internacional de Oncología Pediátrica (SIOP); and therefore the appropriate infrastructure for translation of research from basic and applied to clinical was created. Molecular biology techniques for medulloblastoma and gliomas were set up and optimized. Since Cruces University Hospital was designated as the centralized laboratory for molecular and immune-histochemical studies (a compulsory requirement for patients' enrolment in future clinical trials), the protocols for sample collection and shipment were forwarded to national collaborative hospitals. In this regard, and according to the SIOP Brain Tumour Group's regulatory legislation, the investigator team (both oncologists and biologists) has attended several meetings and teleconferences. Genetic biomarker assessment in paediatric solid tumours (Ewing sarcoma and Wilms' tumour) is performed in collaboration with the Pathological Anatomy Department.
Optimization of TP53 expression in the analysis of familial aggregation of cancer is performed in all requested cases and molecular markers analysis is expanded to other paediatric syndromes with higher risk of solid tumours and leukaemia development.
A serum bank, tumour biobank and cerebrospinal fluid (CSF) samples obtained from patients diagnosed with cancer have been created.
Pharmacogenetics studies on childhood leukaemia and lymphomas are performed in collaboration with the Genetics, Physical Anthropology and Animal Physiology Department at the University of the Basque Country (UPV/EHU). The results have been published in several scientific journals.
Analysis of other risk genetic biomarkers in leukaemia and bone tumours is performed in collaboration with the CNIO and the University of Navarra.
Our group also collaborates with Centro Superior del Instituto del Cáncer (Universidad Autónoma de Madrid) in molecular studies of Ewing Sarcoma and retinoblastoma; with Universidad de Valencia in molecular studies of neuroblastoma; and with Universidad Autónoma de Barcelona in studies of soft tissue sarcoma.
Our research projects are funded by several public institutions such as Carlos III Health Institute (ISCIII), Ministry of Health and Consumer Affairs (Redes Temáticas del Ministerio de Sanidad y Consumo), University of the Basque Country (the Principal Investigator is an Associate Professor at the Paediatrics Department in the Faculty of Medicine), Health Department of the Basque Government (the PI is the Clinical Head of the Paediatrics Department at Cruces University Hospital).
Moreover, the group participates in several lines of research on solid tumours and leukaemia as an external collaborator in several national and international projects, as part of the committee work and providing clinical data of patients. These projects have public and private funding.
- Histiocytosis. Langerhans Cell Histiocytosis – Hemophagocytic lymphohistiocytosis – Hemophagocytic Syndromes – Rare diseases
- Immune Response. Inflammatory response – dendritic cells – Natural Killer cells – immunodeficiency – cancer immunotherapy – severe sepsis – multiorgan failure sepsis
- Brain tumours. PNET/Medulloblastoma and Gliomas
- Familial aggregation of cancer
- Wilms' tumour and adjacent genes
- Generation of serum bank and tumour biobank
- Acute lymphoblastic leukaemia (Pharmacogenetics)