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1.
Pharmaceutics ; 13(4)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808416

RESUMO

Sirolimus is widely used in transplantation, where its therapeutic drug monitoring (TDM) is well established. Evidence of a crucial role for sirolimus in the PI3K/AkT/mTor pathway has stimulated interest in its involvement in neoplasia, either as monotherapy or in combination with other antineoplastic agents. However, in cancer, there is no consensus on sirolimus TDM. In the RAPIRI phase I trial, the combination sirolimus + irinotecan was evaluated as a new treatment for refractory pediatric cancers. Blood sampling at first sirolimus intake (D1) and at steady state (D8), followed by LC/MS2 analysis, was used to develop a population pharmacokinetic model (Monolix® software). A mono-compartmental model with first-order absorption and elimination best fit the data. The only covariate retained for the final model was "body surface area" (D1 and D8). The model also demonstrated that 1.5 mg/m2 would be the recommended sirolimus dose for further studies and that steady-state TDM is necessary to adjust the dosing regimen in atypical profiles (36.4% of the population). No correlation was found between sirolimus trough concentrations and efficacy and/or observed toxicities. The study reveals the relevance of sirolimus TDM in pediatric oncology as it is needed in organ transplantation.

2.
Neuro Oncol ; 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33377141

RESUMO

BACKGROUND: High-risk medulloblastoma are defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5 to 19 years with newly diagnosed high-risk medulloblastoma treated according to the phase 2 trial PNET HR+5. METHODS: All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m 2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1-3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy). RESULTS: Fifty-one patients (median age, 8 years; range, 5-19) were enrolled. The median follow-up was 7.1 years (range: 3.4-9.0). The 3 and 5-year PFS with their 95% confidence intervals (95%CI) were 78% (65-88) and 76% (63-86), and the 3 and 5-year OS were 84% (72-92) and 76% (63-86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (p-value=0.039) with large-cell/anaplastic being of worse prognosis, as well as molecular subgroup (p-value=0.012) with SHH and group 3 being of worse prognosis than WNT and group 4. Therapy was well tolerated. CONCLUSIONS: This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.

3.
Chembiochem ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33140906

RESUMO

Integrins are heterodimeric transmembrane proteins able to connect cells with the micro-environment. They represent a family of receptors involved in almost all the hallmarks of cancer. Integrins recognizing the Arg-Gly-Asp (RGD) peptide in their natural extracellular matrix ligands have been particularly investigated as tumoral therapeutic targets. In the last 30 years, intense research has been dedicated to designing specific RGD-like ligands able to discriminate selectively the different RGD-recognizing integrins. Chemists' efforts have led to the proposition of modified peptide or peptidomimetic libraries to be used for tumor targeting and/or tumor imaging. Here we review, from the biological point of view, the rationale underlying the need to clearly delineate each RGD-integrin subtype by selective tools. We describe the complex roles of RGD-integrins (mainly the most studied αvß3 and α5ß1 integrins) in tumors, the steps towards selective ligands and the current usefulness of such ligands. Although the impact of integrins in cancer is well acknowledged, the biological characteristics of each integrin subtype in a specific tumor are far from being completely resolved. Selective ligands might help us to reconsider integrins as therapeutic targets in specific clinical settings.

4.
Cancers (Basel) ; 12(10)2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33092063

RESUMO

Hypoxic environment is a prognostic factor linked in pediatric cancers to a worse outcome, favoring tumor progression and resistance to treatments. The activation of mechanistic Target Of Rapamycin (mTor)/hypoxia inducible factor (HIF)-1 pathway can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a phase I trial associating both drugs in pediatric refractory/relapsing solid tumors. Patients were enrolled according to a 3 + 3 escalation design with ten levels, aiming to determine the MTD (maximum tolerated dose) of rapamycin plus irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day), associating biweekly intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics, efficacy analyses, and pharmacodynamics were evaluated. Forty-two patients, aged from 2 to 18 years, were included. No MTD was reached. Adverse events were mild to moderate. Only rapamycin doses of 1.5 mg/m2/day reached over time clinically active plasma concentrations. Tumor responses and prolonged stable disease were associated with a mean irinotecan area under the curve of more than 400 min.mg/L. Fourteen out of 31 (45.1%) patients had a non-progressive disease at 8 weeks. Most of them were sarcomas and brain tumors. For the phase II trial, we can then propose biweekly 125 mg/m2 irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m2/day, reaching a blood concentration above 10 g/L.

5.
Cells ; 9(9)2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32878021

RESUMO

Osteosarcoma is the most frequent primary bone tumor diagnosed during adolescence and young adulthood. It is associated with the worst outcomes in the case of poor response to chemotherapy and in metastatic disease. While no molecular biomarkers are clearly and currently associated with those worse situations, the study of pathways involved in the high level of tumor necrosis and in the immune/metabolic intra-tumor environment seems to be a way to understand these resistant and progressive osteosarcomas. In this review, we provide an updated overview of the role of hypoxia in osteosarcoma oncogenesis, progression and during treatment. We describe the role of normoxic/hypoxic environment in normal tissues, bones and osteosarcomas to understand their role and to estimate their druggability. We focus particularly on the role of intra-tumor hypoxia in osteosarcoma cell resistance to treatments and its impact in its endogenous immune component. Together, these previously published observations conduct us to present potential perspectives on the use of therapies targeting hypoxia pathways. These therapies could afford new treatment approaches in this bone cancer. Nevertheless, to study the osteosarcoma cell druggability, we now need specific in vitro models closely mimicking the tumor, its intra-tumor hypoxia and the immune microenvironment to more accurately predict treatment efficacy and be complementary to mouse models.

6.
Br J Haematol ; 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32700439

RESUMO

The nucleoside analogue, 2-chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO-) involvement. However, we lack data on long-term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long-term tolerance. This study included 44 children from the French LCH registry, treated for a RO- LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3-19·7 years) and the median follow-up after was 5·4 years (range, 0·6-15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five-year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five-year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long-term therapy for treating patients with RO- LCH. Appropriate management of induced immune deficiency is mandatory.

7.
J Endocr Soc ; 4(5): bvaa039, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432211

RESUMO

Purpose: The purpose of this work is to assess the clinical outcome of pediatric patients diagnosed with pheochromocytoma and paraganglioma (PPGL) detected in France since 2000. Methods: A retrospective multicenter study was conducted that included all patients younger than 18 years with PPGL diagnosed in France between 2000 and 2016. Patients were identified from 4 different sources: the National Registry of Childhood Solid Tumors, the French Pediatric Rare Tumors Database, the French registry of succinate dehydrogenase (SDH)-related hereditary paraganglioma, and the nationwide TenGen network. Results: Among 113 eligible patients, 81 children with available data were enrolled (41 with adrenal and 40 with extra-adrenal PPGL). At diagnosis, 11 had synchronous metastases. After a median follow-up of 53 months, 27 patients experienced a new event (n = 7 second PPGL, n = 1 second paraganglioma [PGL], n = 8 local recurrences, n = 10 metastatic relapses, n = 1 new tumor) and 2 patients died of their disease. The 3- and 10-year event-free survival rates were 80% (71%-90%) and 39% (20%-57%),respectively, whereas the overall survival rate was 97% (93%-100%)at 3 and 10 years. A germline mutation in one PPGL-susceptibility gene was identified in 53 of the 68 (77%) patients who underwent genetic testing (SDHB [n = 25], VHL [n = 21], RET [n = 2], HIF2A [n = 2], SDHC [n = 1], SDHD [n = 1], NF1 [n = 1]). Incomplete resection and synchronous metastases were associated with higher risk of events (P = .011, P = .004), but presence of a germline mutation was not (P = .11). Conclusions: Most pediatric PPGLs are associated with germline mutations and require specific follow-up because of the high risk of tumor recurrence.

8.
Cancers (Basel) ; 12(4)2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32326644

RESUMO

The brain tumor microenvironment has recently become a major challenge in all pediatric cancers, but especially in brain tumors like high-grade gliomas. Hypoxia is one of the extrinsic tumor features that interacts with tumor cells, but also with the blood-brain barrier and all normal brain cells. It is the result of a dramatic proliferation and expansion of tumor cells that deprive the tissues of oxygen inflow. However, cancer cells, especially tumor stem cells, can endure extreme hypoxic conditions by rescheduling various genes' expression involved in cell proliferation, metabolism and angiogenesis and thus, promote tumor expansion, therapeutic resistance and metabolic adaptation. This cellular adaptation implies Hypoxia-Inducible Factors (HIF), namely HIF-1α and HIF-2α. In pediatric high-grade gliomas (pHGGs), several questions remained open on hypoxia-specific role in normal brain during gliomagenesis and pHGG progression, as well how to model it in preclinical studies and how it might be counteracted with targeted therapies. Therefore, this review aims to gather various data about this key extrinsic tumor factor in pHGGs.

9.
Lancet Oncol ; 21(3): 446-455, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32078813

RESUMO

BACKGROUND: Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma. METHODS: We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m2) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605. FINDINGS: Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects. INTERPRETATION: Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation. FUNDING: Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.


Assuntos
Anilidas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Sarcoma de Ewing/tratamento farmacológico , Adulto , Neoplasias Ósseas/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Osteossarcoma/patologia , Prognóstico , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Sarcoma de Ewing/patologia , Taxa de Sobrevida , Adulto Jovem
10.
Pediatr Blood Cancer ; 67(1): e28022, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31571386

RESUMO

BACKGROUND: Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT. METHODS: Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3). RESULTS: Median observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation. CONCLUSIONS: Long-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.


Assuntos
Biomarcadores Tumorais/genética , Tumor Rabdoide/mortalidade , Neoplasias da Medula Espinal/mortalidade , Teratoma/mortalidade , Criança , Pré-Escolar , Terapia Combinada , DNA Helicases/genética , Feminino , Seguimentos , Humanos , Lactente , Masculino , Proteínas Nucleares/genética , Prognóstico , Estudos Retrospectivos , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Tumor Rabdoide/terapia , Proteína SMARCB1/genética , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/patologia , Neoplasias da Medula Espinal/terapia , Taxa de Sobrevida , Teratoma/genética , Teratoma/patologia , Teratoma/terapia , Fatores de Transcrição/genética
11.
Cancers (Basel) ; 11(12)2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31779235

RESUMO

BACKGROUND: Pediatric high-grade gliomas (pHGGs) are facing a very dismal prognosis and representative pre-clinical models are needed for new treatment strategies. Here, we examined the relevance of collecting functional, genomic, and metabolomics data to validate patient-derived models in a hypoxic microenvironment. METHODS: From our biobank of pediatric brain tumor-derived models, we selected 11 pHGGs driven by the histone H3.3K28M mutation. We compared the features of four patient tumors to their paired cell lines and mouse xenografts using NGS (next generation sequencing), aCGH (array comparative genomic hybridization), RNA sequencing, WES (whole exome sequencing), immunocytochemistry, and HRMAS (high resolution magic angle spinning) spectroscopy. We developed a multicellular in vitro model of cell migration to mimic the brain hypoxic microenvironment. The live cell technology Incucyte© was used to assess drug responsiveness in variable oxygen conditions. RESULTS: The concurrent 2D and 3D cultures generated from the same tumor sample exhibited divergent but complementary features, recreating the patient intra-tumor complexity. Genomic and metabolomic data described the metabolic changes during pHGG progression and supported hypoxia as an important key to preserve the tumor metabolism in vitro and cell dissemination present in patients. The neurosphere features preserved tumor development and sensitivity to treatment. CONCLUSION: We proposed a novel multistep work for the development and validation of patient-derived models, considering the immature and differentiated content and the tumor microenvironment of pHGGs.

12.
J Neurooncol ; 145(1): 177-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522324

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/diagnóstico , Glioma Pontino Intrínseco Difuso/terapia , Biópsia , Terapia Combinada , Progressão da Doença , Humanos , Prognóstico
13.
Orthop Traumatol Surg Res ; 105(6): 1181-1185, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31358461

RESUMO

BACKGROUND: Aneurysmal bone cyst (ABC) is a benign tumour whose progression involves the RANK/RANKL signalling pathway. Surgery is the reference standard treatment but carries risks that vary with the site of the tumour. Denosumab is a human monoclonal IgG2 antibody that targets the RANK/RANKL pathway and may therefore hold promise for inhibiting ABC progression. The objective of this study was to evaluate denosumab use in paediatric patients (younger than 18 years) with ABC and to describe the clinical and radiological outcomes, as well as the side effect profile. HYPOTHESIS: Denosumab is a viable option in children with ABC refractory to standard treatments. MATERIAL AND METHODS: We retrospectively reviewed the medical files of paediatric patients given denosumab to treat ABC in any of 32 centres affiliated with the French Paediatric Cancer Society (Société Française du Cancer de l'Enfant, SFCE) and French Sarcoma Group (Groupe Sarcome Français, GSF-GETO). We identified 5 patients treated between March 2015 and June 2018. Median age was 8 years (range, 7-17 years). Pain was a symptom in all 5 patients and neurological deficits were present in 3 patients. Surgery was performed in 4 patients, either before (n=3) or after (n=1) denosumab therapy; the remaining patient had no surgery. Denosumab was given as monthly injections in a dosage of 70mg/m2 for a median of 12 months (range, 4-23 months). The clinical outcomes and changes in computed tomography and/or magnetic resonance imaging findings were evaluated. RESULTS: Abnormalities in calcium and phosphate levels secondary to the ABC occurred in 2 patients. At median of 24 months (range, 0-28 months) after denosumab initiation, all 5 patients were free of pain, and the neurological deficits in 3 patients had improved. Central remineralisation and cortical reconstitution were demonstrated consistently by the imaging studies. DISCUSSION: Denosumab is a viable treatment option in selected paediatric patients with inoperable ABC. The immediate adverse effect profile is acceptable. A larger study with a longer follow-up would be welcome to further assess the contribution of denosumab to the treatment of ABC. LEVEL OF EVIDENCE: IV.


Assuntos
Cistos Ósseos Aneurismáticos/tratamento farmacológico , Denosumab/administração & dosagem , Adolescente , Cistos Ósseos Aneurismáticos/diagnóstico , Conservadores da Densidade Óssea/administração & dosagem , Criança , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Imagem por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios X
14.
Metabolomics ; 15(5): 69, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31037432

RESUMO

INTRODUCTION: The identification of frequent acquired mutations shows that patients with oligodendrogliomas have divergent biology with differing prognoses regardless of histological classification. A better understanding of molecular features as well as their metabolic pathways is essential. OBJECTIVES: The aim of this study was to examine the relationship between the tumor metabolome, six genomic aberrations (isocitrate dehydrogenase1 [IDH1] mutation, 1p/19q codeletion, tumor protein p53 [TP53] mutation, O6-methylguanin-DNA methyltransferase [MGMT] promoter methylation, epidermal growth factor receptor [EGFR] amplification, phosphate and tensin homolog [PTEN] methylation), and the patients' survival time. METHODS: We applied 1H high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy to 72 resected oligodendrogliomas. RESULTS: The presence of IDH1, TP53, 1p19q codeletion, MGMT promoter methylation reduced the relative risk of death, whereas PTEN methylation and EGFR amplification were associated with poor prognosis. Increased concentration of 2-hydroxyglutarate (2HG), N-acetyl-aspartate (NAA), myo-inositol and the glycerophosphocholine/phosphocholine (GPC/PC) ratio were good prognostic factors. Increasing the concentration of serine, glycine, glutamate and alanine led to an increased relative risk of death. CONCLUSION: HRMAS NMR spectroscopy provides accurate information on the metabolomics of oligodendrogliomas, making it possible to find new biomarkers indicative of survival. It enables rapid characterization of intact tissue and could be used as an intraoperative method.


Assuntos
Metabolômica , Oligodendroglioma/genética , Oligodendroglioma/metabolismo , Adulto , Humanos , Espectroscopia de Ressonância Magnética , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de Tempo
15.
Oncotarget ; 9(56): 30883-30893, 2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-30112115

RESUMO

Platinum is extensively used in the treatment of several childhood cancers. However, ototoxicity is one of the most notable adverse effects, especially in children. Several studies suggest that genetics may predict its occurrence. Here, polymorphisms associated with platinum-induced ototoxicity were selected from the literature and were investigated in a pediatric population treated with platinum-based agents. In this retrospective study, patients treated with cisplatin and/or carboplatin were screened. The patients with pre- and post-treatment audiogram (Brock criteria) available were included. We selected polymorphisms that have previously been associated with cisplatin ototoxicity with a minor allele frequency ≥30%. Deletion of GSTM1 and GSTT1, rs1799735 (GSTM3), rs1695 (GSTP1), rs4880 (SOD2), rs2228001 (XPC), rs1799793 (XPD) and rs4788863 (SLC16A5) were investigated. Data of one hundred and six children matching the eligible criteria were analyzed. Thirty-three patients (31%) developed ototoxicity (with a Brock grade ≥2). The probability of hearing loss increased significantly in patients carrying the null genotype for GSTT1 (P = 0.03), A/A genotype at rs1695 (P = 0.01), and C/C genotype at rs1799793 (P = 0.008). We also showed an association of the cumulative doses of carboplatin with cisplatin ototoxicity (P <0.05). To conclude, deletion of GSTT1, rs1695 and rs1799793 may constitute potential predictors of platinum-induced ototoxicity.

16.
Nat Med ; 24(8): 1204-1215, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29967352

RESUMO

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Glioblastoma/patologia , Animais , Neoplasias do Tronco Encefálico/genética , Carcinogênese/patologia , Separação Celular , Criança , Células Clonais , Genótipo , Glioblastoma/genética , Humanos , Camundongos Nus , Fenótipo , Células Tumorais Cultivadas
17.
J Clin Pharmacol ; 58(12): 1541-1549, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29791011

RESUMO

Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK-pharmacogenetic model to evaluate the part of between-subject variability due to single-nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma-09 trial (a multicenter, open-label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed-effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK-pharmacogenetic analysis. A 2-compartment model adequately described the data. Although high-dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between-subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P < .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Ósseas/tratamento farmacológico , Proteínas de Transporte/metabolismo , Metotrexato/farmacocinética , Osteossarcoma/tratamento farmacológico , Adolescente , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/metabolismo , Proteínas de Transporte/genética , Criança , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Metotrexato/sangue , Metotrexato/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
18.
Eur J Cancer ; 88: 57-66, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29190507

RESUMO

BACKGROUND: In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014. METHODS: Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate. RESULTS: 409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7-24.5), with 55 patients aged 18-25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51-62%) and overall survival 71% (66-76%). CONCLUSION: M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/cirurgia , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Terapia Combinada , Difosfonatos/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , França , Humanos , Ifosfamida/administração & dosagem , Imidazóis/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Neutropenia/induzido quimicamente , Osteossarcoma/cirurgia , Adulto Jovem , Ácido Zoledrônico
19.
Oncotarget ; 8(42): 71597-71617, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-29069732

RESUMO

Pediatric high grade glioma (pHGGs), including sus-tentorial and diffuse intrinsic pontine gliomas, are known to have a very dismal prognosis. For instance, even an increased knowledge on molecular biology driving this brain tumor entity, there is no treatment able to cure those patients. Therefore, we were focusing on a translational pathway able to increase the cell resistance to treatment and to reprogram metabolically tumor cells, which are, then, adapting easily to a hypoxic microenvironment. To establish, the crucial role of the hypoxic pathways in pHGGs, we, first, assessed their protein and transcriptomic deregulations in a pediatric cohort of pHGGs and in pHGG's cell lines, cultured in both normoxic and hypoxic conditions. Secondly, based on the concept of a bi-therapy targeting in pHGGs mTORC1 (rapamycin) and HIF-1α (irinotecan), we hypothesized that the balanced expressions between RAS/ERK, PI3K/AKT and HIF-1α/HIF-2α/MYC proteins or genes may provide a modulation of the cell response to this double targeting. Finally, we could evidence three protein, genomic and metabolomic profiles of response to rapamycin combined with irinotecan. The pattern of highly sensitive cells to mTOR/HIF-1α targeting was linked to a MYC/ERK/HIF-1α over-expression and the cell resistance to a major hyper-expression of HIF-2α.

20.
Cancer Cell ; 32(4): 520-537.e5, 2017 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-28966033

RESUMO

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.


Assuntos
Neoplasias do Tronco Encefálico/genética , Glioma/genética , Histonas/genética , Mutação , Adolescente , Neoplasias do Tronco Encefálico/patologia , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , DNA Topoisomerases Tipo I/genética , Exoma , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Feminino , Dosagem de Genes , Glioma/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Ubiquitina-Proteína Ligases/genética , Adulto Jovem
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