Staging of newly diagnosed Ewing sarcoma: Results of bone marrow aspiration and biopsy versus (18)FDG-PET/CT imaging for bone marrow involvement.

BACKGROUND: Ewing sarcoma (ES) is an aggressive bone or extraosseous tumour with an unfavourable prognosis when bone marrow metastases are present at diagnosis. The gold standard diagnosis for bone marrow (BM) involvement is cytological and pathological analysis through bone marrow aspiration and biopsy (BMAB). Several recent studies suggest that these invasive and painful procedures could be replaced by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography ((18)FDG-PET/CT), as this nuclear imaging technique is highly sensitive at detecting bone and extraosseous metastases of ES. METHODS: In order to study the precision of (18)FDG-PET/CT in the evaluation of bone marrow metastases at diagnosis, we compared the imaging results with cytological/histological analyses performed on BM samples. We retrospectively studied 180 patients with ES recorded at the Léon Bérard Centre over the past 10 years, who were evaluated by (18)FDG-PET/CT and BMAB at diagnosis. RESULTS: Of the 180 patients, 13 displayed marrow metastases by cytological/histological examination, and only one of these did not have (18)FDG-PET/CT signs of bone marrow involvement, whereas the 167 remaining patients without marrow metastasis all had a negative (18)FDG-PET/CT, except for one. Hence, the sensitivity and specificity of (18)FDG-PET/CT in these patients was 92.3% and 99.4%, respectively. The overall survival at five years of all patients was 67.4% but decrease to 38.5% in the group with bone marrow metastases. CONCLUSION: Given the results presented herein the bone sarcoma group of the French Sarcoma Group suggests that invasive BMAB no longer be systematically performed for the staging at the diagnosis of ES.

Identification of genetic variants in pharmacokinetic genes associated with Ewing Sarcoma treatment outcome.

BACKGROUND: Despite the effectiveness of current treatment protocols for Ewing sarcoma (ES), many patients still experience relapse, and survival following recurrence is <15%. We aimed to identify genetic variants that predict treatment outcome in children diagnosed with ES. PATIENTS AND METHODS: We carried out a pharmacogenetic study of 384 single-nucleotide polymorphisms (SNPs) in 24 key transport or metabolism genes relevant to drugs used to treat in pediatric patients (<30 years) with histologically confirmed ES. We studied the association of genotypes with tumor response and overall survival (OS) in a discovery cohort of 106 Spanish children, with replication in a second cohort of 389 pediatric patients from across Europe. RESULTS: We identified associations with OS (P < 0.05) for three SNPs in the Spanish cohort that were replicated in the European cohort. The strongest association observed was with rs7190447, located in the ATP-binding cassette subfamily C member 6 (ABCC6) gene [discovery: hazard ratio (HR) = 14.30, 95% confidence interval (CI) = 1.53-134, P = 0.020; replication: HR = 9.28, 95% CI = 2.20-39.2, P = 0.0024] and its correlated SNP rs7192303, which was predicted to have a plausible regulatory function. We also replicated associations with rs4148737 in the ATP-binding cassette subfamily B member 1 (ABCB1) gene (discovery: HR = 2.96, 95% CI = 1.08-8.10, P = 0.034; replication: HR = 1.60, 95% CI = 1.05-2.44, P = 0.029), which we have previously found to be associated with poorer OS in pediatric osteosarcoma patients, and rs11188147 in cytochrome P450 family 2 subfamily C member 8 gene (CYP2C8) (discovery : HR = 2.49, 95% CI = 1.06-5.87, P = 0.037; replication: HR = 1.77, 95% CI = 1.06-2.96, P = 0.030), an enzyme involved in the oxidative metabolism of the ES chemotherapeutic agents cyclophosphamide and ifosfamide. None of the associations with tumor response were replicated. CONCLUSION: Using an integrated pathway-based approach, we identified polymorphisms in ABCC6, ABCB1 and CYP2C8 associated with OS. These associations were replicated in a large independent cohort, highlighting the importance of pharmacokinetic genes as prognostic markers in ES.

The pig model in brain imaging and neurosurgery.

The pig model is increasingly used in the field of neuroscience because of the similarities of its brain with human. This review presents the peculiarities of the anatomy and functions of the pig brain with specific reference to its human counterpart. We propose an approximate mapping of the pig's cortical areas since a comprehensive description of the equivalent of Brodmann's areas is lacking. On the contrary, deep brain structures are received more consideration but a true three-dimensional (3D) atlas is still eagerly required. In the second section, we present an overview of former works describing the use of functional imaging and neuronavigation in the pig model. Recently, the pig has been increasingly used for molecular imaging studies using positron emission tomography (PET). Indeed, the large size of its brain is compatible with the limited spatial resolution of the PET scanner built to accommodate a human being. Similarly, neuronavigation is an absolute requirement to target deep brain areas in human and in pig since the surgeon cannot rely on external skull structures for zeroing the 3D reference frame. Therefore, a large body of methodological refinements has been dedicated to image guided surgery in the pig model. These refinements allow now a millimetre precision: an absolute requirement for basal nuclei targeting. In the third section, several examples of ongoing studies in our laboratory were presented to illustrate the intricacies of using the pig model. For both examples, after a brief description of the scientific context of the experiment, we present, in detail, the methodological steps required to achieve the experimental goals, which are specific to the porcine model. Finally, in the fourth section, the anatomical variations depending on the breed and age are discussed in relation with neuronavigation and brain surgery. The need for a digitized multimodality brain atlas is also highlighted.

Correlation between brain glycogen and convulsive state in mice submitted to methionine sulfoximine.

It is now well established that in epileptic patients, hypometabolic foci appear during interictal periods. The meaning and the mechanism of such an hypometabolism are as yet unclear. The aim of the present investigation was to look for a putative relationship between glucose metabolism in the brain and the genesis of seizures in mice using administration of the convulsant, methionine sulfoximine. Besides its epileptic action, methionine sulfoximine is a powerful glycogenic agent. We analyzed the epileptogenic and glycogenic effects of methionine sulfoximine in two inbred mouse strains with different susceptibility towards the convulsant. CBA/J mice displayed high response to methionine sulfoximine. The tonic convulsions appeared 5-6 h after MSO administration, without brain glycogen content variations during the preconvulsive period. These mice died of status epilepticus during the first seizure(s). Conversely, C57BL/6J mice displayed low response to MSO. The tonic and clonic seizures appeared 8 to 14 h after MSO administration with only 2% mortality. The seizures were preceded by an increase in brain glycogen content during the preconvulsive period. Moreover, during seizures, C57BL/6J mice were able to mobilize this accumulated brain glycogen, that returned to high value after seizures. The epileptic and glycogenic responses of the parental strains were also observed in mice of the F2 generation. The F2 mice that convulsed early (16%) did not utilize their small increase in brain glycogen content, and resembled CBA/J mice; while the F2 mice that seized tardily (24%) increased their brain glycogen content before convulsion, utilized it during convulsions, and resembled C57BL/6J mice. Sixty percent of the F2 mice presented an intermediate pattern in epileptogenic responses to the convulsant. These data suggest a possible genetic link between the two MSO effects, epileptiform seizures and increase in brain glycogen content. The increase in brain glycogen content and the capability of its mobilization during seizures could delay the seizure's onset and could be considered a "resistance factor" against the seizures.