Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific ...and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.
Conventional anticancer treatments are often impaired by the presence of hypoxia. TH-302 selectively targets hypoxic tumor regions, where it is converted into a cytotoxic agent. This study assessed ...the efficacy of the combination treatment of TH-302 and radiotherapy in two preclinical tumor models. The effect of oxygen modification on the combination treatment was evaluated and the effect of TH-302 on the hypoxic fraction (HF) was monitored using (18)FHX4-PET imaging and pimonidazole IHC stainings.
Rhabdomyosarcoma R1 and H460 NSCLC tumor-bearing animals were treated with TH-302 and radiotherapy (8 Gy, single dose). The tumor oxygenation status was altered by exposing animals to carbogen (95% oxygen) and nicotinamide, 21% or 7% oxygen breathing during the course of the treatment. Tumor growth and treatment toxicity were monitored until the tumor reached four times its start volume (T4×SV).
Both tumor models showed a growth delay after TH-302 treatment, which further increased when combined with radiotherapy (enhancement ratio rhabdomyosarcoma 1.23; H460 1.49). TH-302 decreases the HF in both models, consistent with its hypoxia-targeting mechanism of action. Treatment efficacy was dependent on tumor oxygenation; increasing the tumor oxygen status abolished the effect of TH-302, whereas enhancing the HF enlarged TH-302's therapeutic effect. An association was observed in rhabdomyosarcoma tumors between the pretreatment HF as measured by (18)FHX4-PET imaging and the T4×SV.
The combination of TH-302 and radiotherapy is promising and warrants clinical testing, preferably guided by the companion biomarker (18)FHX4 hypoxia PET imaging for patient selection.
The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients ...with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment.
Al-matrix material composites were produced from pure Al and 40 vol% Ti3AlC2 powders using hot isostatic pressing. The nanocrystallised-Ti3AlC2 agglomerates were uniformly distributed in the Al ...matrix and formed a hard continuous skeleton. The mechanical properties of the composites were evaluated over the temperature range 20-500 C by performing compression tests at a constant strain rate. The monotonic temperature dependence of the proof stress at 0.2% plastic strain suggests that the same thermally activated mechanism controlled the composite plastic deformation over the entire temperature range. The yield stress of the composite was about twice as high as that of the Al matrix in the investigated temperature range. This proves that Ti3AlC2 particles constitute efficient reinforcement particles for the Al matrix. SEM observations showed that plastic deformation of 40Ti3AlC2/60Al composite takes place in the Al matrix while Ti3AlC2 particle agglomerates undergo substantial fracture.
The HIPing of Ti–Al–1.9TiC and Ti–Al–0.2Sn–1.8TiC reactant mixtures yields Ti3AlC2 and Ti3Al0.8Sn0.2C2 solid solutions, respectively. Rietveld refinement gives a = 3.0786 ± 0.0001 Å and ...c = 18.589 ± 0.001 Å lattice parameters for Ti3AlC2 and a = 3.0837 ± 0.0001 Å and c = 18.621 ± 0.002 Å for Ti3Al0.8Sn0.2C2. Furthermore, about 2–3 vol% of TixAly intermetallics is detected in Ti3Al0.8Sn0.2C2 solid solution. The intrinsic hardness, measured by nanoindention tests, is 11.4 ± 0.7 GPa for Ti3AlC2 and 10.2 ± 0.6 GPa for Ti3Al0.8Sn0.2C2. Furthermore, hardness values, measured by microindentation tests, are compared with the ones measured by nanoindentation. It is shown that microindentation and nanoindentation performed with large loads lead to underestimated hardness values as several grains are involved in the deformation process. Finally, Young's modulus of Ti3AlC2 and Ti3Al0.8Sn0.2C2 is 260 ± 10 and 250 ± 10 GPa, respectively.
We present an analysis of high energy (HE; 0.1-300 GeV) γ-ray observations of 1FGL J1227.9−4852 with the Fermi Gamma-ray Space Telescope, follow-up radio observations with the Australia Telescope ...Compact Array, Giant Metrewave Radio Telescope and Parkes radio telescopes of the same field and follow-up optical observations with the ESO VLT. We also examine archival XMM-Newton and INTEGRAL X-ray observations of the region around this source. The γ-ray spectrum of 1FGL J1227.9−4852 is best fitted with an exponentially cut-off power law, reminiscent of the population of pulsars observed by Fermi. A previously unknown, compact radio source within the 99.7 per cent error circle of 1FGL J1227.9−4852 is discovered and has a morphology consistent either with an AGN core/jet structure or with two roughly symmetric lobes of a distant radio galaxy. A single bright X-ray source XSS J12270−4859, a low-mass X-ray binary, also lies within the 1FGL J1227.9−4852 error circle and we report the first detection of radio emission from this source. The potential association of 1FGL J1227.9−4852 with each of these counterparts is discussed. Based upon the available data we find the association of the γ-ray source to the compact double radio source unlikely and suggest that XSS J12270−4859 is a more likely counterpart to the new HE source. We propose that XSS J12270−4859 may be a millisecond binary pulsar and draw comparisons with PSR J1023+0038.
To determine the impact of chemoradiation therapy (CRT) on overall survival (OS) after resection of pancreatic adenocarcinoma.
A multicenter retrospective review of 955 consecutive patients who ...underwent complete resection with macroscopically negative margins (R0-1) for invasive carcinoma (T1-4; N0-1; M0) of the pancreas was performed. Exclusion criteria included metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiation therapy (IORT), and a histological diagnosis of no ductal carcinoma, or postoperative death (within 60 days of surgery). In all, 623 patients received postoperative radiation therapy (RT), 575 patients received concurrent chemotherapy (CT), and 462 patients received adjuvant CT.
Median follow-up was 21.0 months. Median OS after adjuvant CRT was 39.9 versus 24.8 months after no adjuvant CRT (P<.001) and 27.8 months after CT alone (P<.001). Five-year OS was 41.2% versus 24.8% with and without postoperative CRT, respectively. The positive impact of CRT was confirmed by multivariate analysis (hazard ratio HR = 0.72; confidence interval CI, 0.60-0.87; P=.001). Adverse prognostic factors identified by multivariate analysis included the following: R1 resection (HR = 1.17; CI = 1.07-1.28; P<.001), higher pT stage (HR = 1.23; CI = 1.11-1.37; P<.001), positive lymph nodes (HR = 1.27; CI = 1.15-1.41; P<.001), and tumor diameter >20 mm (HR = 1.14; CI = 1.05-1.23; P=.002). Multivariate analysis also showed a better prognosis in patients treated in centers with >10 pancreatic resections per year (HR = 0.87; CI = 0.78-0.97; P=.014) CONCLUSION: This study represents the largest comparative study on adjuvant therapy in patients after resection of carcinoma of the pancreas. Overall survival was better in patients who received adjuvant CRT.
In this study, we report on the compressive behavior of Ti3AlC2 and Ti3Al0.8Sn0.2C2 MAX phases at room temperature. We found that these two phases could be classified as Kinking Nonlinear Elastic ...(KNE) solids. The cyclic compressive stress–strain loops for Ti3AlC2 and Ti3Al0.8Sn0.2C2 are typical hysteretic and fully reversible. At failure, both compositions fracture in shear with maximum stresses of 545 MPa for Ti3AlC2 and 839 MPa for Ti3Al0.8Sn0.2C2. Consequently, the macroshear stresses for failure, τc, are 185 MPa and 242 MPa for Ti3AlC2 and Ti3Al0.8Sn0.2C2, respectively. In addition to the grain size effects, the presence of a ductile TixAly intermetallic distributed in the grain boundaries plays an important role in the enhancement of the ultimate compressive and macroshear stresses for Ti3Al0.8Sn0.2C2. SEM observations reveal that these two MAX phases exhibit crack deflections, intragranular fractures, kink band formation and delaminations, grain push‐in and pull‐out.
The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like ...receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.
PDF
