3 research outputs found

    Osteosarcoma en la infancia y adolescencia: factores pronósticos e identificación de nuevas dianas terapéuticas

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    Introduction Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Current management of high-grade osteosarcoma consists of administration of neoadjuvant/adjuvant chemotherapy and complete surgical removal of all tumour sites. The most important prognostic factors for long-term survival are: disease extension (localized/metastatic), primary tumour location (extremity/axial), histologic response to first-line induction chemotherapy and surgical removal of all detectable lesions. The addition of chemotherapy to surgery in the 1970s and 80s increased substantially long-term survival of osteosarcoma patients. However, no further improvement of survival has been observed since then, with currently 5-year overall survival of 60-70% for localized and 20-30% for metastatic osteosarcoma. Therefore, there is an urgent need for new therapeutic agents to improve prognosis for osteosarcoma patients. General objective: - To identify prognostic factors, at diagnosis and relapse, for children and adolescents with high-grade osteosarcoma and identify new therapeutic targets. Specific objectives: - To identify prognostic factors and survival of children and adolescents with highgrade osteosarcoma at diagnosis and relapse. - To determine the incidence and cancer distribution, treatment setting and provider specialty of children and adolescents in the Comunidad Valenciana. - To identify new therapeutic targets in paediatric and adolescent osteosarcoma Methods: This PhD thesis consists of four papers of which the candidate is the first author: 1. Pablo Berlanga, Adela Cañete, Roberto Díaz, Marta Salom, Francisco Baixauli, Jacinto Gómez, Margarita Llavador, Victoria Castel. Presentation and Long-term Outcome of High-grade Osteosarcoma: A Single-institution Experience. J Pediatric Hematol Oncol 2015; 37: e272-e277. 2. Pablo Berlanga, Adela Cañete, Marta Salom, Joaquin Montalar, María Guasp, Alfredo Marco, Victoria Castel. Postrelapse Prognostic Factors in Nonmetastatic Osteosarcoma: A Single-Institution Experience. J Pediatric Hematol Oncol 2016; 38: 176-181. 3. Pablo Berlanga, María Luisa Vicente, Adela Cañete, Carmen Alberich, Victoria Castel. Cancer in cancer in children and adolescents in Spain: incidence, treatment setting and provider specialty. Clin Transl Oncol 2016; 18: 27-32. 4. Pablo Berlanga, Lisandra Muñoz, Marta Piqueras, Antoni Sirerol, María Dolors Sánchez-Izquierdo, David Hervás, Miguel Hernández, Margarita Llavador, Isidro Machado, Antonio Llombart-Bosch, Adela Cañete, Victoria Castel, Jaime Font de Mora. miR-200c and Akt predict osteosarcoma progression and lung metastasis. Mol Oncol. 2016; 10: 1043-53. This work was supported by a Predoctoral Research Fellowship from the Instituto de Investigación Sanitaria La Fe (2011/0319) Results and conclusions: Five-year overall survival (OS), event-free survival (EFS) and main prognostic factors for high-grade osteosarcoma patients in our cohort are similar to those previously described: A) At diagnosis: metastatic disease, poor histologic response to first-line induction chemotherapy and incomplete surgical removal of all detectable lesions are the main negative prognostic factors. B) At first relapse: good histologic response to neoadjuvant first-line chemotherapy and complete surgical removal of all lesions at relapse are the main favourable prognostic factors. Chemotherapy and surgery are the cornerstone of osteosarcoma treatment. Despite the important role of chemotherapy in the treatment of metastatic disease,surgical removal of all tumour lesions at first-line treatment and relapse is necessary for long-term survival. The improvement of imaging techniques, such as the computed tomography (TC) scan, has increased its sensitivity while decreasing its specificity in the identification of pulmonary metastases and a new definition of “pulmonary metastases” at diagnosis with current imaging techniques is needed. In order to maintain chemotherapy intensity, a delay in the resumption of chemotherapy after primary tumour surgery needs to be avoided. Osteosarcoma incidence is higher during adolescence. Adolescents are a unique group, with patterns of disease and healthcare challenges distinctly different than those faced by younger children and adults. In our region, childhood and adolescent cancer incidence is similar to other European countries, with higher overall incidence of malignancy in adolescents than children. Of importance, our results show an important dispersion of treatment of adolescents compared to children in the Comunidad Valenciana. We suggest the centralization of care of adolescents with cancer with the creation of specific teenager and young adult cancer centres in which these patients can benefit from the shared expertise of medical and paediatric specialists. There is an urgent need for new therapeutic agents to improve prognosis for osteosarcoma patients. PI3K/AKT/mTOR activation, determined by phopho-AKT immunostaining, is associated with lower overall survival in osteosarcoma primary tumours. MiR-200 is overexpressed in lung metastases and plays a role in the molecular processes of lung metastasis. Therefore, PI3k/AKT/mTOR and miR-200c inhibitors are potential therapeutic targets to prevent progression and metastasis of paediatric osteosarcomas.Introduction Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Current management of high-grade osteosarcoma consists of administration of neoadjuvant/adjuvant chemotherapy and complete surgical removal of all tumour sites. The most important prognostic factors for long-term survival are: disease extension (localized/metastatic), primary tumour location (extremity/axial), histologic response to first-line induction chemotherapy and surgical removal of all detectable lesions. The addition of chemotherapy to surgery in the 1970s and 80s increased substantially long-term survival of osteosarcoma patients. However, no further improvement of survival has been observed since then, with currently 5-year overall survival of 60-70% for localized and 20-30% for metastatic osteosarcoma. Therefore, there is an urgent need for new therapeutic agents to improve prognosis for osteosarcoma patients. General objective: - To identify prognostic factors, at diagnosis and relapse, for children and adolescents with high-grade osteosarcoma and identify new therapeutic targets. Specific objectives: - To identify prognostic factors and survival of children and adolescents with highgrade osteosarcoma at diagnosis and relapse. - To determine the incidence and cancer distribution, treatment setting and provider specialty of children and adolescents in the Comunidad Valenciana. - To identify new therapeutic targets in paediatric and adolescent osteosarcoma Methods: This PhD thesis consists of four papers of which the candidate is the first author: 1. Pablo Berlanga, Adela Cañete, Roberto Díaz, Marta Salom, Francisco Baixauli, Jacinto Gómez, Margarita Llavador, Victoria Castel. Presentation and Long-term Outcome of High-grade Osteosarcoma: A Single-institution Experience. J Pediatric Hematol Oncol 2015; 37: e272-e277. 2. Pablo Berlanga, Adela Cañete, Marta Salom, Joaquin Montalar, María Guasp, Alfredo Marco, Victoria Castel. Postrelapse Prognostic Factors in Nonmetastatic Osteosarcoma: A Single-Institution Experience. J Pediatric Hematol Oncol 2016; 38: 176-181. 3. Pablo Berlanga, María Luisa Vicente, Adela Cañete, Carmen Alberich, Victoria Castel. Cancer in cancer in children and adolescents in Spain: incidence, treatment setting and provider specialty. Clin Transl Oncol 2016; 18: 27-32. 4. Pablo Berlanga, Lisandra Muñoz, Marta Piqueras, Antoni Sirerol, María Dolors Sánchez-Izquierdo, David Hervás, Miguel Hernández, Margarita Llavador, Isidro Machado, Antonio Llombart-Bosch, Adela Cañete, Victoria Castel, Jaime Font de Mora. miR-200c and Akt predict osteosarcoma progression and lung metastasis. Mol Oncol. 2016; 10: 1043-53. This work was supported by a Predoctoral Research Fellowship from the Instituto de Investigación Sanitaria La Fe (2011/0319) Results and conclusions: Five-year overall survival (OS), event-free survival (EFS) and main prognostic factors for high-grade osteosarcoma patients in our cohort are similar to those previously described: A) At diagnosis: metastatic disease, poor histologic response to first-line induction chemotherapy and incomplete surgical removal of all detectable lesions are the main negative prognostic factors. B) At first relapse: good histologic response to neoadjuvant first-line chemotherapy and complete surgical removal of all lesions at relapse are the main favourable prognostic factors. Chemotherapy and surgery are the cornerstone of osteosarcoma treatment. Despite the important role of chemotherapy in the treatment of metastatic disease,surgical removal of all tumour lesions at first-line treatment and relapse is necessary for long-term survival. The improvement of imaging techniques, such as the computed tomography (TC) scan, has increased its sensitivity while decreasing its specificity in the identification of pulmonary metastases and a new definition of “pulmonary metastases” at diagnosis with current imaging techniques is needed. In order to maintain chemotherapy intensity, a delay in the resumption of chemotherapy after primary tumour surgery needs to be avoided. Osteosarcoma incidence is higher during adolescence. Adolescents are a unique group, with patterns of disease and healthcare challenges distinctly different than those faced by younger children and adults. In our region, childhood and adolescent cancer incidence is similar to other European countries, with higher overall incidence of malignancy in adolescents than children. Of importance, our results show an important dispersion of treatment of adolescents compared to children in the Comunidad Valenciana. We suggest the centralization of care of adolescents with cancer with the creation of specific teenager and young adult cancer centres in which these patients can benefit from the shared expertise of medical and paediatric specialists. There is an urgent need for new therapeutic agents to improve prognosis for osteosarcoma patients. PI3K/AKT/mTOR activation, determined by phopho-AKT immunostaining, is associated with lower overall survival in osteosarcoma primary tumours. MiR-200 is overexpressed in lung metastases and plays a role in the molecular processes of lung metastasis. Therefore, PI3k/AKT/mTOR and miR-200c inhibitors are potential therapeutic targets to prevent progression and metastasis of paediatric osteosarcomas

    Pharmacogenetics in Neuroblastoma: What Can Already Be Clinically Implemented and What Is Coming Next?

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    Pharmacogenetics is one of the cornerstones of Personalized Precision Medicine that needs to be implemented in the routine of our patients' clinical management in order to tailor their therapies as much as possible, with the aim of maximizing efficacy and minimizing toxicity. This is of great importance, especially in pediatric cancer and even more in complex malignancies such as neuroblastoma, where the rates of therapeutic success are still below those of many other types of tumors. The studies are mainly focused on germline genetic variants and in the present review, state of the art is presented: which are the variants that have a level of evidence high enough to be implemented in the clinic, and how to distinguish them from the ones that still need validation to confirm their utility. Further aspects as relevant characteristics regarding ontogeny and future directions in the research will also be discussed

    Next-Generation Sequencing Identifies Potential Actionable Targets in Paediatric Sarcomas

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    Background: Bone and soft-tissue sarcomas represent 13% of all paediatric malignancies. International contributions to introduce next-generation sequencing (NGS) approaches into clinical application are currently developing. We present the results from the Precision Medicine program for children with sarcomas at a reference centre. Results: Samples of 70 paediatric sarcomas were processed for histopathological analysis, reverse transcriptase polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) with a consensus gene panel. Pathogenic alterations were reported and, if existing, targeted recommendations were translated to the clinic. Seventy paediatric patients with sarcomas from 10 centres were studied. Median age was 11.5 years (range 1-18). Twenty-two (31%) had at least one pathogenic alteration by NGS. Thirty pathogenic mutations in 18 different genes were detected amongst the 22 patients. The most frequent alterations were found in TP53, followed by FGFR4 and CTNNB1. Combining all biological studies, 18 actionable variants were detected and six patients received targeted treatment observing a disease control rate of 78%. Extrapolating the results to the whole cohort, 23% of the patients would obtain clinical benefit from this approach. Conclusions: Paediatric sarcomas have a different genomic landscape when compared to adult cohorts. Incorporating NGS targets into paediatric sarcomas' therapy is feasible and allows personalized treatments with clinical benefit in the relapse setting
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