Ewing's Sarcoma.

In 1920, during a meeting of the New York Pathological Society, James Ewing described an unusual tumor in a 14-year-old girl as a “diffuse endothelioma of bone.”1 The tumor had initially been diagnosed as an osteosarcoma, but its architecture, the morphologic features of its cells, and its marked sensitivity to radiation therapy led Ewing to consider it as a distinct entity, going so far as to hypothesize an endothelial-cell origin.1 He later reported similar tumors in other adolescents, which pathologists variously referred to as Ewing’s sarcoma, Askin’s tumor, and peripheral primitive neuroectodermal tumor, on the basis of their shared morphologic and immunohistochemical features. The first landmark discovery toward unequivocally diagnosing Ewing’s sarcoma was made more than 70 years later, when the most frequent of the chromosomal translocations that define the tumor was identified.2 A century after Ewing’s seminal observation, the cancer that bears his name has become a paradigm for solid-tumor development after a single genetic rearrangement. In this review, we discuss the clinical features and pathogenesis of Ewing’s sarcoma, along with current and experimental therapeutic approaches. From the mechanistic point of view, we review the way in which a unique chromosomal translocation harnesses the epigenetic machinery of permissive cells to rewire their transcriptome and initiate a heterogeneous cancer that can elude even the most intensive conventional therapy available

IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer.

IMPs, also known as insulin-like growth factor 2 (IGF2) messenger RNA (mRNA)-binding proteins (IGF2BPs), are highly conserved oncofetal RNA-binding proteins (RBPs) that regulate RNA processing at several levels, including localization, translation, and stability. Three mammalian IMP paralogs (IMP1-3) have been identified that are expressed in most organs during embryogenesis, where they are believed to play an important role in cell migration, metabolism, and stem cell renewal. Whereas some IMP2 expression is retained in several adult mouse organs, IMP1 and IMP3 are either absent or expressed at very low levels in most tissues after birth. However, all three paralogs can be re-expressed upon malignant transformation and are found in a broad range of cancer types where their expression often correlates with poor prognosis. IMPs appear to resume their physiological functions in malignant cells, which not only contribute to tumor progression but participate in the establishment and maintenance of tumor cell hierarchies. This review summarizes our current understanding of the functions of IMPs during normal development and focuses on a series of recent observations that have provided new insight into how their physiological functions enable IMPs to play a potentially key role in cancer stem cell maintenance and tumor growth

Antibiotic Prophylaxis During Dental Procedures in Patients with Prosthetic Joints.

In patients with artificial joints, the need for antimicrobial prophylaxis during dental procedures is often raised. The present document describes the pathogenic mechanisms and epidemiological data on the subject of periprosthetic joint infections (PJI) after dental procedures. The document reflects the opinion and recommendations of the expert group 'Infection' of Swiss Orthopaedics. Microorganisms belonging to oral flora can seed haematogenously to an artificial joint. The proof of a causative relation with dental procedures is not possible, because the responsible bacteraemia can originate from the oral cavity at any time, irrespective of when the dental procedure occurs. Good oral hygiene is associated with a lower risk for PJI. Transient bacteraemia occurs during daily oral hygiene activity (e.g., tooth brushing) and thus the cumulative risk for a haematogenous PJI from tooth brushing is higher than that from a dental procedure. PJI after a dental procedure are rarely reported. On the basis of an epidemiological model, several thousand patients with artificial joints must receive antimicrobial prophylaxis to prevent a single PJI. Considering this ratio, the number of adverse events due to the antimicrobial compound exceeds the benefit of administering it by a large magnitude. Therefore, as a rule for the vast majority of cases, antimicrobial prophylaxis during dental procedures is not recommended. It is important that a patient has a good oral health status before joint implantation and that good oral hygiene is continuously maintained in patients with artificial joints

Environmental reduplicative paramnesia in a case of atypical Alzheimer's disease.

A 79-year-old patient with neuropathologically confirmed Alzheimer's disease (AD) presented with a selective environmental reduplicative paramnesia (RP), the belief that one or more environments exist simultaneously in two or more physical locations. Clinical presentation and neuropathological examination revealed an atypical form of AD. High neurofibrillary tangle densities were observed in the frontal and temporal association cortex, whereas the parietal and entorhinal cortex, as well as the hippocampus, were nearly spared. These findings are compared to those reported in frontal and frontotemporal variants of AD and discussed in the light of current anatomoclinical models for environmental RP

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood–brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity. Keywords: siRNA; lipopolymeric nanoparticle; glioblastoma transcription factor; brain tumor-initiating; cells; convection-enhanced deliver

Are there clinical variables determining antibiotic prophylaxis-susceptible versus resistant infection in open fractures?

Purpose: In Gustilo grade III open fractures, it remains unknown which demographic or clinical features may be associated with an infection resistant to the administered prophylactic agent, compared to one that is susceptible. Methods: This was a retrospective case-control study on patients hospitalized from 2004 to 2009. Results: We identified 310 patients with Gustilo-III open fractures, 36 (12%) of which became infected after a median of tendays. In 26 (72%) of the episodes the pathogen was susceptible to the prophylactic antibiotic agent prescribed upon admission, while in the other ten it was resistant. All antibiotic prophylaxis was intravenous; the median duration of treatment was threedays and the median delay between trauma and surgery was oneday. In multivariate analysis adjusting for case-mix, only Gustilo-grade-IIIc fractures (vascular lesions) showed tendency to be infected with resistant pathogens (odds ratio 10; 95% confidence interval 1.0-10; p = 0.058). There were no significant differences between cases caused by antibiotic resistant and susceptible pathogen cases in patient's sex, presence of immune suppression, duration and choice of antibiotic prophylaxis, choice of surgical technique or materials, time delay until surgery, use of bone reaming, fracture localization, or presence of compartment syndrome. Conclusion: We were unable to identify any specific clinical parameters associated with infection with antibiotic resistant pathogens in Gustilo-grade III open fractures, other than the severity of the fracture itself. More research is needed to identify patients who might benefit from a broader-spectrum antibiotic prophylaxis

Remission rate of implant-related infections following revision surgery after fractures

Purpose: In contrast to a large amount of epidemiological data regarding the incidence of implant infections after fracture management, surprisingly few have been published concerning the success of their treatment. Methods: This was a single-centre cohort study at Geneva University Hospitals from 2000 to 2012 investigating the remission rates of orthopaedic implant infections after fracture repair and associated variables. Results: A total of 139 episodes were included: There were 51 women (37%) and 28 immunosuppressed (20%) patients with a median age and American Society of Anaesthesiologists (ASA) score of 51years and 2 points, respectively. The infected implants were plates (n = 75, 54%), nails (24, 17%), wires (20), screws (10), cerclage cables or wires (3), hip screws (4) or material for spondylodesis (3). A pathogen was identified in 135 (97%) cases, including Staphylococcus aureus (73, 52%), coagulase-negative staphylococci (20), streptococci (7) and 19 Gram-negative rods. All patients underwent antibiotic treatment, and 128 (92%) remained in remission at a median follow-up time of 2.6years (range one to 13years). In multivariate logistic regression analysis, the plate infections were significantly associated with lower remission rates [65/75, 87%, odds ratio (OR) 0.1, 95% confidence interval (CI) 0.01-0.90]. No associations were found for gender, age, immune status, ASA score, additional surgical interventions (OR 0.4, 95% CI 0.1-4.1) or duration of antibiotic treatment (OR 1.0, 95% CI 0.98-1.01). Conclusions: Among all infected and removed orthopaedic implants, plates were associated with slightly lower remission rates, while the overall treatment success exceeded 90%. The duration of antibiotic therapy did not alter the outcom

<i>TP53</i> drives invasion through expression of its ∆133p53β variant

International audienceTP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform D133p53b promotes cancer cell invasion, regardless of TP53 mutation status. D133p53b increases risk of cancer recurrence and death in breast cancer patients. Furthermore D133p53b is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant D133p53b depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant D133p53b induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression