Influence of growth modulation on the effective permeability of the vertebral end plate. A porcine experimental scoliosis model

Background: Abnormal mechanical loading occurs in scoliosis as compared to normal spines. Intervertebral disc degeneration has been correlated with alteration of bone density in adjacent vertebral bodies. How vertebral end plate remodels in scoliosis and the consequences on disc homeostasis are not well understood. Permeability is a relevant physical measure to quantify mass transport in porous media. We hypothesized that effective permeability of the vertebral end plate was modified by growth modulation in a scoliosis animal model. Methods: Flexible asymmetric posterior instrumentation was undertaken on six healthy four-week-old pigs. Two sets of left pedicle screws were inserted and connected with a stainless steel cable. After two months, the apical intervertebral unit and three units located cranially and caudally, were harvested. One central and two lateral specimens were investigated using a previously validated method for measuring permeability. Findings: A three-dimensional deformity was obtained in all six animals with an average of 42 degrees right thoracic curve. 44 degrees lordosis and 21 degrees rotation. Permeability was significantly greater in the center of the end plates than in the periphery and it was decreased by -45% towards the apex of the deformity. Fluid flow direction did not play a significant role. No significant difference was found between the convex side and the concave side. Interpretation: The end plate is a crucial zone for diffusive and convective transport and we showed in a scoliosis animal model that a growth modulation may decrease its effective permeability. The proposed methodology and associated results could help to understand degenerative changes in human spine

Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations

BACKGROUND: Whole-genome sequencing studies have recently shown that osteosarcomas (OSs) display high rates of structural variation, i.e. they contain many somatic mutations and copy number alterations. TP53 and RB1 show recurrent somatic alterations in concordant studies, suggesting that they could be key players in bone oncogenesis. PATIENTS AND METHODS: we carried out whole-genome sequencing of DNA from seven high-grade OS samples matched with normal tissue from the same patients. RESULTS: We confirmed the presence of genetic alterations of the TP53 (including novel unreported mutations) and RB1 genes. Most interestingly, we identified a total of 84 point mutations and 4 deletions related to 82 different genes in OS samples, of which only 15 have been previously reported. Interestingly, the number of mutated genes (ranging from 4 to 8) was lower in TP53mut cases compared with TP53wt cases (ranging from 14 to 45). This was also true for the mutated RB1 case. We also observed that a dedifferentiated OS harboring MDM2 amplification did not carry any other mutations. CONCLUSION: This study suggests that bone oncogenesis driven by TP53 or RB1 mutations occurs on a background of relative genetic stability and that the dedifferentiated OS subtype represents a clinico-pathological entity with distinct oncogenic mechanisms and thus requires different therapeutic managemen

Analyse des délais de prise en charge des cancers thoraciques : étude prospective

RésuméIntroductionLe cancer broncho-pulmonaire est la première cause de décès par cancer en France. Son diagnostic est le plus souvent tardif, alors que le délai entre le début des symptômes et la prise en charge est considéré comme un facteur aggravant.Matériel et méthodesNotre étude prospective a recueilli les différentes dates de prise en charge de 139 patients consécutifs bénéficiant d’un traitement primaire pour un cancer thoracique dans notre hôpital entre novembre 2008 et mai 2009. L’objectif de cette étude était d’évaluer différents délais de prise en charge des patients porteurs d’un cancer thoracique quelle que soit sa prise en charge thérapeutique (médicale ou chirurgicale) et de déterminer la cause de ces délais.RésultatsLe délai médian entre la première imagerie pathologique et le traitement est de 9,6 semaines. Les délais étaient significativement plus courts dans les stades tardifs et les carcinomes à petites cellules (p=0,001). Il existait une tendance à des délais plus courts pour les femmes et des délais plus longs pour les classes d’âge les plus élevées.ConclusionL’évaluation des délais de prise en charge, en particulier pour les stades précoces, s’intègre dans le contrôle de la qualité de prise en charge de ces pathologies.SummaryIntroductionLung cancer is the main cause of cancer death in France. The diagnosis is often late and the delay between the onset of symptoms and management is considered an aggravating factor.Material and methodsOur prospective study collected the dates of the start of management of 139 consecutive patients receiving first line treatment for thoracic cancer in our hospital between November 2008 and May 2009. The aim of this study was to evaluate the delays in medical or surgical treatments in patients with thoracic cancer and to determine the cause of these delays.ResultsThe median delay between the first abnormal chest X-ray and treatment was 9.6 weeks. The delays were significantly shorter in the late stages and in small cell cancer (P=0.001). There was a tendency for shorter delays in women and for longer delays in older patients.ConclusionEvaluation of the delays in treatment, particularly in the early stages, is part of the quality control of management of these diseases

Planning for Bone Excision in Ewing Sarcoma: Post-Chemotherapy MRI More Accurate Than Pre-Chemotherapy MRI Assessment

International audienceBACKGROUND: In determining the level of bone resection in Ewing sarcoma, the most suitable time at which to perform magnetic resonance imaging (MRI) remains controversial. Current guidelines recommend that surgical planning be based on MRI performed prior to neoadjuvant chemotherapy. The goal of this study was to determine whether pre-chemotherapy or post-chemotherapy MRI provides greater accuracy of tumor limits for planning bone excision in the management of Ewing sarcoma.METHODS: This was a single-center, retrospective study. MRI was performed using 3 sequences: T1-weighted, T1-weighted with contrast enhancement by gadolinium injection, and a fluid-sensitive sequence (STIR [short tau inversion recovery] or proton-density-weighted with fat saturation). The tumor extent as assessed on pre-chemotherapy and post-chemotherapy MRI was compared with histological measurement of the resected specimen.RESULTS: Twenty patients with Ewing sarcoma of a long bone were included. In 6 cases, the tumor was located on the femur, in 5, the tibia; in 5, the fibula; and in 4, the humerus. The median patient age at diagnosis was 9.7 years. We found greater accuracy of measurements from MRI scans acquired after chemotherapy than from those acquired before chemotherapy. For both pre-chemotherapy and post-chemotherapy MRI, the greatest accuracy was achieved with the nonenhanced T1 sequence. There was no benefit to gadolinium enhancement. The median difference between T1 MRI and histological measurements was 19.0 mm (interquartile range [IQR], 4.3 to 32.8 mm) before chemotherapy and 5.0 mm (IQR, 2.0 to 13.0 mm) after chemotherapy. Adding a minimum margin of 20 mm to the limit of the tumor on post-chemotherapy T1 MRI always led to safe histological margin.CONCLUSIONS: Post-chemotherapy MRI provided a more accurate assessment of the limits of Ewing sarcoma. Surgical planning can therefore be based on post-chemotherapy MRI. Surgical cuts can be, at minimum, 20 mm from the limits as seen on MRI

Quantification of bone tissue heterogeneity and cell distributionpatterns from digital histology: application to osteosarcoma

Like most sarcomas with complex genomics,or more generally bone tissues, osteosarcoma isa type of tumors exhibiting a strong spatialheterogeneity of the micro-environment. Thisheterogeneity makes the diagnostic complex andcan induce strong spatial variability in theresponse to treatments. New researchstrategies are consequently needed tounderstand the impact of spatial heterogeneity onthe diagnostic accuracy and on the treatmentefficiency, and more generally to understand thelinks between tissue scale bone matrix structuresand underlying biology occurring at the cell scale.The aim of this interdisciplinary work is to obtain the quantification of correlations between clinicaldata, heterogeneity of bone tissues and mechanobiological parameters. To this purpose, original numerical developments were initiated in our group to study the intratumoral and healthy bone tissue heterogeneity from histological and immunohistological sections. The code aimed at obtaining quantitative metrics of the cell population distribution, of the bone matrix micro-architecture (porosity) and of the transport properties (such as effective diffusivity). Because tissues exhibit naturally a complex spatial scales cascade, it can be modeled, at the tissue scale, as a three phases porous medium (fluid, solid, cell populations). Using methodologies related to porous media analysis, characteristic lengths were extracted and correlations of phenomena occurring cell and tissue scale examined. Further developments permitted the calculation of effective mechanical properties. The methodology used successive algorithms of machine learning for the histological image segmentation and a combination of iterative algorithms and filters for the correlation calculations. Results put forward the strength of this approach for the identification of new markers in the study of pathological bone tissues

Upscaling of fluid flow in spatially heterogeneous bone tumors

Osteosarcoma is a malignant bone tumor that preferentially arises in adolescents and young adults. Like many sarcomas with complex genomics, this type of tumors exhibits strong spatial heterogeneities in terms of micro-architecture or differentiated response to treatments due to localized effect of chemotherapy. Clinical images at a tissue scale such as histological and immunohistological sections, exhibit three phases: fluid, solid, cells populations. Therefore the tumor can be considered as a porous medium. The objective of this work was to develop a mechanical approach based on upscaling methods to study the interstitial flow within the tumor at the tissue scale. The statistical study of the micro-architecture of the media shows that the identification of characteristic lengths is complex and that a separation of spatial scales is not necessarily identified. We therefore chose a special sequential upscaling technique, named Grid-Block approach to solve this problem

An unusual intracardiac foreign body following penetrating thoracic injury

Foreign bodies in the heart after thoracic trauma may result in fatal outcome. We report a pendant inside the pericardium after penetrating injury that did not cause major cardiac injury with a favorable outcome

Cardiovascular roles of estrogen receptors: insights gained from knockout models

The effects of estrogen are mediated through two functionally distinct receptors, estrogen receptor α (ER- α ), and estrogen receptor β (ER- β ), both of which are expressed in the cardiovascular system. The etiology of cardiovascular disease is believed to result in part from the loss of endogenous estrogen, indicating that estrogen and its receptors may play important roles in the prevention of cardiovascular disease in women

Hypoxia Induces VEGF-C Expression in Metastatic Tumor Cells via a HIF-1α-Independent Translation-Mediated Mechanism

SummaryVarious tumors metastasize via lymph vessels and lymph nodes to distant organs. Even though tumors are hypoxic, the mechanisms of how hypoxia regulates lymphangiogenesis remain poorly characterized. Here, we show that hypoxia reduced vascular endothelial growth factor C (VEGF-C) transcription and cap-dependent translation via the upregulation of hypophosphorylated 4E-binding protein 1 (4E-BP1). However, initiation of VEGF-C translation was induced by hypoxia through an internal ribosome entry site (IRES)-dependent mechanism. IRES-dependent VEGF-C translation was independent of hypoxia-inducible factor 1α (HIF-1α) signaling. Notably, the VEGF-C IRES activity was higher in metastasizing tumor cells in lymph nodes than in primary tumors, most likely because lymph vessels in these lymph nodes were severely hypoxic. Overall, this transcription-independent but translation-dependent upregulation of VEGF-C in hypoxia stimulates lymphangiogenesis in tumors and lymph nodes and may contribute to lymphatic metastasis