The tumor-stroma ratio (TSR) has been reported as a strong, independent prognostic parameter in colon cancer as well as in other epithelial cancer types, and may be implemented to routine pathology ...diagnostics. The TSR is an easy technique, based on routine hematoxylin and eosin stained histological sections, estimating the amount of stroma present in the primary tumor. It links tumors with high stromal content to poor prognosis. The analysis time is less than 2 min with a low inter-observer variation. Scoring of the TSR has been validated in a number of independent international studies. In this manuscript, we provide a detailed technical description of estimating the TSR in colon cancer, including examples, pitfalls, and recommendations.
An element test specimen with ply drops, intended to be representative of a composite structure of varying thickness such as the main laminate in a wind turbine rotor blade structure, is used to ...investigate the fatigue damage initiating from a ply drop under cyclic tension–tension loading. The focus is to measure the growth rate of delamination cracks propagating from a thin towards a thicker section. Several delaminations initiate from tunneling cracks - cracks between the ply drops and resin reach areas - after very few load cycles. All except one delamination crack propagate for a number of cycles but eventually stop growing. The only delamination crack that continued to grow has the characteristic that its growth rate increases as it propagates to thicker sections of the element specimen. The experimental findings are supported by finite element results.
This study investigated the predictive value of circulating microRNA-126 (cir-miRNA-126) in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy combined with ...bevacizumab.
The study included 68 patients. Blood samples (plasma) were collected before the treatment initiation, at the first clinical evaluation after 3 weeks and at progression. Levels of cir-miRNA-126 were determined by qRT-PCR after purification of total RNA from plasma. Primary clinical end points were response rates evaluated according to the Response Evaluation Criteria In Solid Tumours (RECIST) and progression-free survival (PFS).
Changes in circulating miRNA-126 during treatment were predictive of tumour response. Non-responding patients had a median increase in cir-miRNA-126 of 0.244 (95% confidence interval (CI), 0.050-0.565) compared with a median decrease of -0.374 (95% CI, -0.472 to -0.111) in the responding patients, P=0.002. A significant positive correlation was demonstrated by comparing the changes in tumour size with the changes in cir-miRNA-126, r=0.48, P=0.0001. Grouping the patients according to the changes in cir-miRNA-126 disclosed a borderline significant separation of the groups in the PFS analysis favouring patients with decreasing miRNA-126 levels, hazard ratio (HR) 0.60 (95% CI, 0.33-1.09), P=0.07.
The present results indicate that changes in cir-miRNA-126 during treatment are related to the response to chemotherapy and bevacizumab in patients with mCRC, thus representing a possible biomarker for the resistance to anti-angiogenic containing treatments.
This study investigated the clinical importance of linked angiogenetic biomarkers to chemotherapy, combined with the anti-vascular endothelial growth factor A (anti-VEGF-A), as a first-line treatment ...in patients with metastatic colorectal cancer (mCRC).
A total of 230 patients from a randomised phase III study were included. The primary microRNA-126 (pri-miRNA-126) A24G single-nucleotide polymorphism and the mature miRNA-126 were analysed by PCR using genomic DNA (full blood) and formalin-fixed paraffin-embedded tissue sections, respectively. The epidermal growth factor-like domain 7 (EGFL7) protein was visualised and quantified using immunohistochemistry.
High tumour expression of miRNA-126 was significantly related to a longer progression-free survival. The independent prognostic value of miRNA-126 was confirmed using a Cox regression analysis (hazard ratio=0.49, 95% confidence interval=0.29-0.84, P=0.009). Although not significant, a relationship between EGFL7 expression and response rates is suggested, with EGFL7 expression at the invasive front being lower in responding patients than in the non-responders (P=0.063).
The results validate the previous findings on the prognostic value of miRNA-126 in mCRC and may suggest a relationship between treatment efficacy and EGFL7 expression. As miRNA-126 may target VEGF-A as well as EGFL7, the results may provide predictive information in relation to next-generation anti-angiogenetics.
•Anticlastic bending affect the position of the crack front in delaminating beams.•Anticlastic bending needs to be taken into account when calculating a cohesive law.•A correct cohesive law can be ...found through an optimization procedure.•A cohesive law as implemented for optimisation in the FE-code LS-DYNA.•The optimised cohesive law was tested against separate delamination tests.
A user defined cohesive material model is implemented in the LS-DYNA finite element code. The model is based on interface properties characterised from DCB specimens loaded with unequal bending moments. Different mode mixities are obtained by applying different ratios of moments to the two beams in the cracked part of the specimen. The mixed mode cohesive law is fitted for large scale bridging delamination through inverse modelling. In this way, the variations in stress and crack opening across the width of the specimen are taken into account. The J integral approach is used to find a starting point for the fitting procedure. Three properties from five moment configurations are evaluated to find a first estimate of the shape of the cohesive law: crack tip fracture energy, steady-state fracture resistance and crack end-opening at steady-state fracture resistance. The parameters of the cohesive law are then further adjusted using the optimisation tool LS-OPT. The implemented cohesive model is assessed by comparing numerical to experimental test results from the standardised ASTM double cantilever beam test and the ASTM mixed mode bending test.
A novel method is proposed for extracting the mixed-mode cohesive laws of composite materials undergoing delamination with large-scale fibre bridging. In the approach, the mixed-mode cohesive laws ...are derived from a potential function expressed in cylindrical coordinates with the magnitude and phase angle between the normal and tangential end-openings. The potential function is mapped using experimental R-curves in terms of the J-integral and the end-openings. The mixed-mode cohesive laws describe both the crack tip (high tractions, small separations) and bridging region (small tractions, high separations). The extracted mixed-mode cohesive tractions are fully coupled, i.e., both the normal and shear traction depend on the normal and tangential openings. The peak normal and shear tractions were found to be at a mixed mode opening.
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Small-scale cohesive-zone models based on potential functions are expected to be consistent with the important features of linear-elastic fracture mechanics (LEFM). These include an ...inverse-square-root K-field ahead of a crack, with the normal and shear stresses being proportional to the mode-I and mode-II stress-intensity factors, KI and KII, the work done against crack-tip tractions being equal to KI2+KII2∕Ē, where Ē is the appropriate modulus, and failure being controlled by the toughness. The use of an LEFM model also implicitly implies that the partition of the crack-tip work into shear and normal components is given by a phase angle defined as ψK=tan−1KII∕KI. In this paper, we show that the partition of crack-tip work in a cohesive-zone model is consistent with LEFM if the normal and shear deformations across an interface are uncoupled. However, we also show that this is not the case for coupled cohesive laws, even if these are derived from a potential function. For coupled laws, LEFM cannot be used to predict the partition of work at the crack tip even when the small-scale requirements for LEFM conditions being met; furthermore, the partition of the work may depend on the loading path. This implies that LEFM cannot be used to predict mixed-mode fracture for interfaces that are described by coupled cohesive laws, and that have a phase-angle-dependent toughness.
•Uncoupled, potential-based laws reliably mimic LEFM.•For uncoupled laws, the work partition at the crack tip into the two orthogonal modes is in agreement with LEFM.•The total work at the crack tip for coupled, potential-based laws is path-independent and consistent with LEFM.•However, the partition of this work at the crack tip does not necessarily follow LEFM predictions for coupled laws.
About a half of all cancer patients receive radiotherapy as part of their oncological treatment. Because of the carcinogenic effect of ionising radiation, there is a rare, but definite, risk of ...developing secondary malignancies, including sarcomas. The aim of this retrospective study was to describe the prevalence, patient and tumour characteristics, as well as prognosis and outcome, of patients with radiation-induced sarcomas (RIS) in a cohort of patients treated in the Sarcoma Centre at Aarhus University Hospital over a period of 34 years.
All patients who fulfilled the criteria for RIS and were treated for RIS in the period 1979–2013 were included. Patient data were retrieved from the Aarhus Sarcoma Registry and the National Danish Sarcoma Database, crosschecked with the National Register of Pathology and validated using the patients' medical records. The primary end point was the effect of surgery and treatment intent on overall survival. Overall survival is reported using the Kaplan–Meier estimates and compared using the Log-rank test. Descriptive statistics are presented for patients, tumours and treatment characteristics.
Of 2845 patients diagnosed with sarcoma between 1979 and 2013, 64 (2%) were diagnosed with RIS. The median interval from the original malignancy was 11 years. The most common histological type was undifferentiated pleomorphic sarcoma (33%). Curative treatment was intended for 45 patients. Fifty patients underwent surgery, of whom 80% had microscopically radical resection (R0). The 5-year overall survival for the whole cohort was 32%. Patients who underwent surgery had a significantly better overall survival compared with patients who were not treated with surgery. In the univariate Cox proportional hazard analyses, no metastases at diagnosis, surgery and R0 resection were favourable prognostics factors of survival.
This study showed that RIS patients are unique in their epidemiology and tumour characteristics. They have a poor prognosis and need special research investigating new intensive treatment strategies to improve the outcome.
The cohesive law for Mode I delamination in glass fibre Non-Crimped Fabric reinforced vinylester is determined for use in finite element models. The cohesive law is derived from a delamination test ...based on DCB specimens loaded with pure bending moments taking into account the presence of large-scale bridging and the multi-axial state of stress in the test specimen. The fracture resistance is calculated from the applied moments, the elastic material properties and the geometry of the test specimen. The cohesive law is then determined in a three step procedure: 1) Obtain the bridging law by differentiating the fracture resistance with respect to opening displacement at the initial location of the crack tip, measured at the specimen edge. 2) Extend the bridging law to a cohesive law by accounting for crack tip fracture energy. 3) Fine-tune the cohesive law through an iterative modelling approach so that the changing state of stress and deformation across the width of the test specimen is taken into account. The changing state of stress and deformation across the specimen width is shown to be significant for small openings (small fracture process zone size). This will also be important for the initial part of the cohesive law with high stress variation for small openings (a few microns), but the effects are expected to be smaller for large-scale-bridging where the stress varies slowly over an increase in crack opening of several millimetres. The accuracy of the proposed approach is assessed by comparing the results of numerical simulation using the cohesive law derived by the above method, with those of physical testing for the standard DCB Mode I delamination test (ASTM D 5528).
A novel mixed-mode cohesive law derived from a potential function is presented. The potential function is formulated using physical parameters that can be extracted from any fracture mechanics test ...capable of providing R-curves in terms of the J-integral as a function of the normal and tangential end-openings. The proposed cohesive law is able to describe the fracture behaviour of composites with large fracture process zones, including fibre bridging. As such, it is capable of describing both the crack tip, as well as the bridging region. An important aspect of the formulation is that the shape of the mixed-mode cohesive laws are derived and not assumed. The mixed-mode cohesive law was tested using synthetic data emulating mixed-mode fracture mechanics tests. The cohesive tractions extracted from the method exhibited characteristics which were not seeded on the model such as negative normal tractions under pure mode shear loading and non-zero shear loading under pure normal mode loading.
•A novel procedure is proposed to extract mixed-mode cohesive laws from experimental R-curves.•Mixed-mode cohesive tractions are derived using a potential function defined in terms of the natural coordinate system of current fracture mechanics tests.•The derived mixed-mode cohesive laws accounts for both the crack tip and bridging tractions regions.•The derived cohesive laws are coupled in agreement with previous findings.
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