The Bone Niche of Chondrosarcoma: A Sanctuary for Drug Resistance, Tumour Growth and also a Source of New Therapeutic Targets

Chondrosarcomas are malignant cartilage-forming tumours representing around 20% of malignant primary tumours of bone and affect mainly adults in the third to sixth decade of life. Unfortunately, the molecular pathways controlling the genesis and the growth of chondrosarcoma cells are still not fully defined. It is well admitted that the invasion of bone by tumour cells affects the balance between early bone resorption and formation and induces an “inflammatory-like” environment which establishes a dialogue between tumour cells and their environment. The bone tumour microenvironment is then described as a sanctuary that contributes to the drug resistance patterns and may control at least in part the tumour growth. The concept of “niche” defined as a specialized microenvironment that can promote the emergence of tumour stem cells and provide all the required factors for their development recently emerges in the literature. The present paper aims to summarize the main evidence sustaining the existence of a specific bone niche in the pathogenesis of chondrosarcomas

Multicentre prospective evaluation of histological and molecular criterion for diagnosis of prosthetic-joint infection

Objectives: This multicenter prospective study was performed to assess the contribution of broad range PCR diagnosis in prosthetic-joint infection (PJI). Methods: Adult patients treated for PJI at 7 centers were included between December 2010 and March 2012. Six per-operative samples were obtained for each patient, 5 for conventional cultures and 16S rRNA gene real-time PCR followed by sequencing, and 1 for histopathological classification according to Morawietz. Cultures and PCR were performed in a highly standardized manner, with 3 quality controls of PCR analyses. An infection was considered as proved (3 criteria: per-operative, bacteriological and histological), probable (clinical or bacteriological criterium), or excluded (no criterium). Molecular criterium for predicting PJI was determined using the bacteriological one as reference (>=1 positive sample for virulent organism, and >=3 positive samples for coagulase-negative staphylococci (CoNS) and P. acnes). Results: 299 patients were included, 264 with suspicion of sepsis (S) and 35 as controls (C). The 264 S presented with acute (19%), or chronic suspicion of PJI (81%). Infection was proved or probable in 212/264 S (80%), with the bacteriological criterium in 189/212 S (89%). Out of these, 156 (83%) had monomicrobial and 33 (17%) polymicrobial infections. The isolated pathogens were S. aureus (40%), CoNS (25%), streptococci (14%), Gram-Negative rods (10%), and anaerobes 8%. Histology results were not available for 55 patients, leaving 244 patients available for analysis. Histological findings of infection (Morawietz types II or III) were present in 128/169 (76%) proved or probable infections, in 3 patients without any other criterium, and were absent in excluded infections (n=42) and controls (n=29). PCR results were not analysable for 32 patients (S=28, C=4), leaving 267 patients (S=236, C=31) available for analysis. Molecular criterium of infection was present in 63/68 (93%) proved infections, 83/124 (67%) probable infections, 3/42 excluded infections, 0/2 histological criterium alone and 2/31 controls. Molecular criterium of infection was absent in 34/189 (18%) culture-positive S, and present in 8/23 culture-negative S (8 patients treated with antibiotics). Conclusions: According to this multicenter prospective study, 16S rRNA gene real-time PCR is less susceptible than culture for diagnosis of PJI. Molecular analysis could be recommended in culture-negative patients who were receiving antibiotics

Assessing HER2 gene amplification as a potential target for therapy in invasive urothelial bladder cancer with a standardized methodology: results in 1005 patients

Background: This study assessed the human epidermal growth factor receptor-2 (HER2) protein expression and its relationship with gene amplification in invasive bladder carcinoma, using the same criteria than for breast cancer

Evaluation of 16S rRNA gene PCR sensitivity and specificity for diagnosis of prosthetic joint infection: a prospective multicenter cross-sectional study

There is no standard method for the diagnosis of prosthetic joint infection (PJI). The contribution of 16S rRNA gene PCR sequencing on a routine basis remains to be defined. We performed a prospective multicenter study to assess the contributions of 16S rRNA gene assays in PJI diagnosis. Over a 2-year period, all patients suspected to have PJIs and a few uninfected patients undergoing primary arthroplasty (control group) were included. Five perioperative samples per patient were collected for culture and 16S rRNA gene PCR sequencing and one for histological examination. Three multicenter quality control assays were performed with both DNA extracts and crushed samples. The diagnosis of PJI was based on clinical, bacteriological, and histological criteria, according to Infectious Diseases Society of America guidelines. A molecular diagnosis was modeled on the bacteriological criterion (≥ 1 positive sample for strict pathogens and ≥ 2 for commensal skin flora). Molecular data were analyzed according to the diagnosis of PJI. Between December 2010 and March 2012, 264 suspected cases of PJI and 35 control cases were included. PJI was confirmed in 215/264 suspected cases, 192 (89%) with a bacteriological criterion. The PJIs were monomicrobial (163 cases [85%]; staphylococci, n = 108; streptococci, n = 22; Gram-negative bacilli, n = 16; anaerobes, n = 13; others, n = 4) or polymicrobial (29 cases [15%]). The molecular diagnosis was positive in 151/215 confirmed cases of PJI (143 cases with bacteriological PJI documentation and 8 treated cases without bacteriological documentation) and in 2/49 cases without confirmed PJI (sensitivity, 73.3%; specificity, 95.5%). The 16S rRNA gene PCR assay showed a lack of sensitivity in the diagnosis of PJI on a multicenter routine basis

Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells

Animal science

Low-grade extraskeletal osteosarcoma of the chest wall: case report and review of literature

<p>Abstract</p> <p>Background</p> <p>Low-grade extraskeletal osteosarcomas (ESOS) are extremely rare.</p> <p>Case presentation</p> <p>We present the first case of low-grade ESOS of the chest wall, which occurred in a 30-year-old man. Because of initial misdiagnosis and patient's refusal of surgery, the diagnosis was done after a 4-year history of a slowly growing mass in soft tissues, leading to a huge (30-cm diameter) calcified mass locally extended over the left chest wall. Final diagnosis was helped by molecular analysis of <it>MDM2 </it>and <it>CDK4 </it>oncogenes. Unfortunately, at this time, no surgical treatment was possible due to loco-regional extension, and despite chemotherapy, the patient died one year after diagnosis, five years after the first symptoms.</p> <p>Conclusion</p> <p>We describe the clinical, radiological and bio-pathological features of this unique case, and review the literature concerning low-grade ESOS. Our case highlights the diagnostic difficulties for such very rare tumours and the interest of molecular analysis in ambiguous cases.</p

CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts

CD44 is a marker of tumour-initiating cells and is upregulated in invasive breast carcinoma; however, its role in the cancer progression is unknown. Here, we show that antibody-mediated CD44-targeting in human breast cancer xenografts (HBCx) significantly reduces tumour growth and that this effect is associated to induction of growth-inhibiting factors. Moreover, treatment with this antibody prevents tumour relapse after chemotherapy-induced remission in a basal-like HBCx

Polymorphisms in the Mitochondrial Ribosome Recycling Factor EF-G2mt/MEF2 Compromise Cell Respiratory Function and Increase Atorvastatin Toxicity

Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans