Despite advances in cancer genomics, radiotherapy is still prescribed on the basis of an empirical one-size-fits-all paradigm. Previously, we proposed a novel algorithm using the genomic-adjusted ...radiation dose (GARD) model to personalise prescription of radiation dose on the basis of the biological effect of a given physical dose of radiation, calculated using individual tumour genomics. We hypothesise that GARD will reveal interpatient heterogeneity associated with opportunities to improve outcomes compared with physical dose of radiotherapy alone. We aimed to test this hypothesis and investigate the GARD-based radiotherapy dosing paradigm.
We did a pooled, pan-cancer analysis of 11 previously published clinical cohorts of unique patients with seven different types of cancer, which are all available cohorts with the data required to calculate GARD, together with clinical outcome. The included cancers were breast cancer, head and neck cancer, non-small-cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. Our dataset comprised 1615 unique patients, of whom 1298 (982 with radiotherapy, 316 without radiotherapy) were assessed for time to first recurrence and 677 patients (424 with radiotherapy and 253 without radiotherapy) were assessed for overall survival. We analysed two clinical outcomes of interest: time to first recurrence and overall survival. We used Cox regression, stratified by cohort, to test the association between GARD and outcome with separate models using dose of radiation and sham-GARD (ie, patients treated without radiotherapy, but modelled as having a standard-of-care dose of radiotherapy) for comparison. We did interaction tests between GARD and treatment (with or without radiotherapy) using the Wald statistic.
Pooled analysis of all available data showed that GARD as a continuous variable is associated with time to first recurrence (hazard ratio HR 0·98 95% CI 0·97–0·99; p=0·0017) and overall survival (0·97 0·95–0·99; p=0·0007). The interaction test showed the effect of GARD on overall survival depends on whether or not that patient received radiotherapy (Wald statistic p=0·011). The interaction test for GARD and radiotherapy was not significant for time to first recurrence (Wald statistic p=0·22). The HR for physical dose of radiation was 0·99 (95% CI 0·97–1·01; p=0·53) for time to first recurrence and 1·00 (0·96–1·04; p=0·95) for overall survival. The HR for sham-GARD was 1·00 (0·97–1·03; p=1·00) for time to first recurrence and 1·00 (0·98–1·02; p=0·87) for overall survival.
The biological effect of radiotherapy, as quantified by GARD, is significantly associated with time to first recurrence and overall survival for patients with cancer treated with radiation. It is predictive of radiotherapy benefit, and physical dose of radiation is not. We propose integration of genomics into radiation dosing decisions, using a GARD-based framework, as the new paradigm for personalising radiotherapy prescription dose.
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•Design and development of novel cellular materials based on triply periodic minimal surfaces (TPMS).•Study the conductivity of TPMS-foams using finite element analysis.•Investigate the elasticity of ...TPMS-foams using finite element analysis.•Study the anisotropy of TPMS-foams.
Triply periodic minimal surfaces (TPMS) are employed to create novel cellular materials. They include Schwarz Primitive, Schoen IWP, Neovius, Schoen Gyroid, Fischer-Koch S, and Schwarz CLP geometries. Unit cells are studied using a finite element method with periodic boundary conditions in order to predict effective electrical/thermal conductivities and elastic moduli of these TPMS-based foams. The conductivities vary linearly with relative density. The conductivities of the Primitive-, IWP-, Neovius-, Gyroid-, and S-foams are very close to each other. The conductivity of the CLP-foam needs to be described by two values because of its geometrical asymmetry while the other foams are found to be isotropic when their conductivities are studied. The uniaxial, shear and bulk moduli, Poisson ratio and elastic anisotropy of these TPMS-foams are also computed and compared. When the mechanical properties are investigated, the CLP-foam is found to have highest anisotropy among the considered TPMS-foams. In addition, the Primitive-foam possesses highest shear modulus while the Neovius, IWP-, and Primitive-foams possess highest bulk moduli among the TPMS-foams.
Stereotactic body radiation therapy in spinal metastases Ahmed, Kamran A; Stauder, Michael C; Miller, Robert C ...
International journal of radiation oncology, biology, physics,
04/2012, Letnik:
82, Številka:
5
Journal Article
Recenzirano
Based on reports of safety and efficacy, stereotactic body radiotherapy (SBRT) for treatment of malignant spinal tumors was initiated at our institution. We report prospective results of this ...population at Mayo Clinic.
Between April 2008 and December 2010, 85 lesions in 66 patients were treated with SBRT for spinal metastases. Twenty-two lesions (25.8%) were treated for recurrence after prior radiotherapy (RT). The mean age of patients was 56.8 ± 13.4 years. Patients were treated to a median dose of 24 Gy (range, 10-40 Gy) in a median of three fractions (range, 1-5). Radiation was delivered with intensity-modulated radiotherapy (IMRT) and prescribed to cover 80% of the planning target volume (PTV) with organs at risk such as the spinal cord taking priority over PTV coverage.
Tumor sites included 48, 22, 12, and 3 in the thoracic, lumbar, cervical, and sacral spine, respectively. The mean actuarial survival at 12 months was 52.2%. A total of 7 patients had both local and marginal failure, 1 patient experienced marginal but not local failure, and 1 patient had local failure only. Actuarial local control at 1 year was 83.3% and 91.2% in patients with and without prior RT. The median dose delivered to patients who experienced local/marginal failure was 24 Gy (range, 18-30 Gy) in a median of three fractions (range, 1-5). No cases of Grade 4 toxicity were reported. In 1 of 2 patients experiencing Grade 3 toxicity, SBRT was given after previous radiation.
The results indicate SBRT to be an effective measure to achieve local control in spinal metastases. Toxicity of treatment was rare, including those previously irradiated. Our results appear comparable to previous reports analyzing spine SBRT. Further research is needed to determine optimum dose and fractionation to further improve local control and prevent toxicity.
Three-dimensional printed polymeric lattice structures have recently gained interests in several engineering applications owing to their excellent properties such as low-density, energy absorption, ...strength-to-weight ratio, and damping performance. Three-dimensional (3D) lattice structure properties are governed by the topology of the microstructure and the base material that can be tailored to meet the application requirement. In this study, the effect of architected structural member geometry and base material on the viscoelastic response of 3D printed lattice structure has been investigated. The simple cubic lattice structures based on plate-, truss-, and shell-type structural members were used to describe the topology of the cellular solid. The proposed lattice structures were fabricated with two materials, i.e., PLA and ABS using the material extrusion (MEX) process. The quasi-static compression response of lattice structures was investigated, and mechanical properties were obtained. Then, the creep, relaxation and cyclic viscoelastic response of the lattice structure were characterized. Both material and topologies were observed to affect the mechanical properties and time-dependent behavior of lattice structure. Plate-based lattices were found to possess highest stiffness, while the highest viscoelastic behavior belongs to shell-based lattices. Among the studied lattice structures, we found that the plate-lattice is the best candidate to use as a creep-resistant LS and shell-based lattice is ideal for damping applications under quasi-static loading conditions. The proposed analysis approach is a step forward toward understanding the viscoelastic tolerance design of lattice structures.
Although breast cancer brain metastasis is an increasingly common occurrence, relatively little is known about miliary brain metastases, a rare subtype that presents unique diagnostic and management ...challenges. The present study from Bashour et al. proposes the first objective diagnostic imaging criteria, enabling improved future study.
We assessed the radiosensitivity of lung metastases on the basis of primary histologic type by using a validated gene signature and model lung metastases for the gnomically adjusted radiation dose ...(GARD).
Tissue samples were identified from our prospective observational protocol. The radiosensitivity index (RSI) 10-gene assay was run on samples and calculated alongside the GARD by using the previously published algorithms. A cohort of 105 patients with 137 lung metastases treated with stereotactic body radiation therapy (SBRT) at our institution was used for clinical correlation.
A total of 138 unique metastatic lung lesions from our institution’s tissue biorepository were identified for inclusion. There were significant differences in the RSI of lung metastases on the basis of histology. In order of decreasing radioresistance, the median RSIs for the various histologic types of cancer were endometrial adenocarcinoma (0.49), soft-tissue sarcoma (0.47), melanoma (0.44), rectal adenocarcinoma (0.43), renal cell carcinoma (0.33), head and neck squamous cell cancer (0.33), colon adenocarcinoma (0.32), and breast adenocarcinoma (0.29) (p = 0.002). We modeled the GARD for these samples and identified the biologically effective dose necessary to optimize local control. The 12- and 24-month Kaplan-Meier rates of local control for radioresistant versus radiosensitive histologic types from our clinical correlation cohort after lung SBRT were 92%/87% and 100%, respectively (p = 0.02).
In this analysis, we have noted significant differences in radiosensitivity on the basis of primary histologic type of lung metastases and have modeled the biologically effective dose necessary to optimize local control. This study suggests that primary histologic type may be an additional factor to consider in selection of SBRT dose to the lung and that dose personalization may be feasible.
We previously developed a multigene expression model of tumor radiation sensitivity index (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck ...patients). The purpose of this study was to assess differences between RSI scores in primary colon cancer and metastases.
Patients were identified from our institutional review board-approved prospective observational protocol. A total of 704 metastatic and 1362 primary lesions were obtained from a de-identified metadata pool. RSI was calculated using the previously published rank-based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiation therapy (SBRT) was used for validation.
The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors, compared with 54% of primaries, were in the RSI radiation-resistant peak, suggesting metastatic tumors may be slightly more radiation resistant than primaries (P=.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radiation resistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31) (P<.0001). These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control rate compared to that in patients with liver metastases (2-year local control rate of 100% vs 73.0%, respectively; P=.026).
Assessment of radiation sensitivity between primary and metastatic tissues of colon cancer histology revealed significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort.
Triple negative breast cancer (TNBC) is an aggressive disease, but recent studies have identified heterogeneity in patient outcomes. However, the utility of histologic subtyping in TNBC has not yet ...been well-characterised. This study utilises data from the National Cancer Center Database (NCDB) to complete the largest series to date investigating the prognostic importance of histology within TNBC.
A total of 729,920 patients (pts) with invasive ductal carcinoma (IDC), metaplastic breast carcinoma (MBC), medullary breast carcinoma (MedBC), adenoid cystic carcinoma (ACC), invasive lobular carcinoma (ILC) or apocrine breast carcinoma (ABC) treated between 2004 and 2012 were identified in the NCDB. Of these, 89,222 pts with TNBC that received surgery were analysed. Kaplan–Meier analysis, log-rank testing and multivariate Cox proportional hazards regression were utilised with overall survival (OS) as the primary outcome.
MBC (74.1%), MedBC (60.6%), ACC (75.7%), ABC (50.1%) and ILC (1.8%) had significantly different proportions of triple negativity when compared to IDC (14.0%, p < 0.001). TNBC predicted an inferior OS in IDC (p < 0.001) and ILC (p < 0.001). Lumpectomy and radiation (RT) were more common in MedBC (51.7%) and ACC (51.5%) and less common in MBC (33.1%) and ILC (25.4%), when compared to IDC (42.5%, p < 0.001). TNBC patients with MBC (HR 1.39, p < 0.001), MedBC (HR 0.42, p < 0.001) and ACC (HR 0.32, p = 0.003) differed significantly in OS when compared to IDC.
Our results indicate that histologic heterogeneity in TNBC significantly informs patient outcomes and thus, has the potential to aid in the development of optimum personalised treatments.
•Proportion and prognostic value of triple negativity varies by histology.•Treatment trends vary significantly by histology within triple negative breast cancer (TNBC).•Within TNBC, histology informs overall survival.•Prognostic factors associated with overall survival vary by histology within TNBC.
This paper investigates the interdependencies of crack depth and crack location on the dynamic response of a cantilever beam under thermo-mechanical loads. Temperature can influence the stiffness of ...the structure, thus, the change in stiffness can lead to variation in frequency, damping and amplitude response. These variations are used as key parameters to quantify damage of Aluminum 2024 specimen under thermo-mechanical loads. Experiments are performed on cantilever beams at non-heating (room temperature) and elevated temperature, i.e., 50 °C, 100 °C, 150 °C and 200 °C. This study considers a cantilever beam having various initially seeded crack depth and locations. The analytical, numerical and experimental results for all configurations are found in good agreement. Dynamic response formulation is presented experimentally on beam for the first time under thermo-mechanical loads. Using available experimental data, a novel tool is formulated for in-situ damage assessment in the metallic structures. This tool can quantify and locate damage using the dynamic response and temperature including the diagnosis of subsurface cracking. The obtained results demonstrate the possibility to diagnose the crack growth at any instant within the operational condition under thermo-mechanical loads.
Friction stir lap welding (FSLW) remains a pioneering technique for creating hybrid joints between AA5052 aluminium alloy and polypropylene (PP), particularly with the metal-on-top configuration. ...Building upon previous research, this study introduces a tapered fluted pin tool design and investigates its effectiveness in the welding process. Our results, supported by ANOVA, chemical, and microstructural analyses, reiterate that the optimal welding parameters stand at a rotational speed of 1400 RPM and a traverse speed of 20 mm/min. This combination produces a joint tensile strength of 3.8 MPa, signifying 16.54% of the weaker material's inherent strength. Microstructural evaluations revealed a unique composite of aluminium chips intermeshed with PP, strengthened further by aluminium hooks. Crucially, mechanical interlocking plays a predominant role over chemical bonding in achieving this joint strength. The study underscores the absence of significant C-O-Al bonds, hinting at the PP degradation without the thermo-oxidation process. Additionally, joint strength was found to inversely correlate with the interaction layer's thickness. The findings fortify the promise of FSLW with the novel fluted pin design for enhancing joints between AA5052 and PP, emphasising the potential of mechanical interlocking as a principal factor in achieving high-quality welds.
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