Citations

The objective of this study was to evaluate and understand the systematic error between the planned three‐dimensional (3D) dose and the delivered dose to patient in scanning beam proton therapy for lung tumors. Single‐field and multifield optimized scanning beam proton therapy plans were generated for ten patients with stage II‐III lung cancer with a mix of tumor motion and size. 3D doses in CT datasets for different respiratory phases and the time‐weighted average CT, as well as the four‐dimensional (4D) doses were computed for both plans. The 3D and 4D dose differences for the targets and different organs at risk were compared using dose‐volume histogram (DVH) and voxel‐based techniques, and correlated with the extent of tumor motion. The gross tumor volume (GTV) dose was maintained in all 3D and 4D doses, using the internal GTV override technique. The DVH and voxel‐based techniques are highly correlated. The mean dose error and the standard deviation of dose error for all target volumes were both less than 1.5% for all but one patient. However, the point dose difference between the 3D and 4D doses was up to 6% for the GTV and greater than 10% for the clinical and planning target volumes. Changes in the 4D and 3D doses were not correlated with tumor motion. The planning technique (single‐field or multifield optimized) did not affect the observed systematic error. In conclusion, the dose error in 3D dose calculation varies from patient to patient and does not correlate with lung tumor motion. Therefore, patient‐specific evaluation of the 4D dose is important for scanning beam proton therapy for lung tumors.PACS number: 87.55.D

616 Background: Polybromo-1 (PBRM1) and BRCA1 associated protein-1 (BAP1) are genes commonly mutated in clear cell RCC (ccRCC) and have been associated with clinical outcome. This work aims to evaluate the impact of PBRM1 and BAP1 expression by IHC in mRCC patients treated with VEGF-TT. Methods: PBRM1 and BAP1 expression was evaluated by IHC in a TMA including 146 mRCC patients. PBRM1 and BAP1 IHC scores were dichotomized as a binary variable: negative (-) or positive (+) (weak positivity was excluded). The associations of PBRM1 or BAP1 expression with baseline clinico-pathological characteristics were evaluated, as well as with overall survival (OS) and time to treatment failure (TTF) usingCox proportional hazards models. Results: Out of 146 patients, 116 and 109 samples had available results for PBRM1 and BAP1 staining, respectively. Overall, 90% (n = 131) patients had ccRCC. 70/116 samples (60%) were PBRM1- and 26/109 patients (24%) were BAP1-. Only 12% (n = 13) of patients had simultaneous negative PBRM1 and BAP1. While there was no association between PBRM1 expression status and clinical factors, BAP1- samples were associated with poor IMDC prognostic risk score (p = 0.004) and higher Fuhrman grade (p = 0.012). PBRM1+ patients showed a trend towards an increased risk of death and a shorter TTF compared to PBRM1- patients (OS: HR = 1.38, 95%CI: 0.92-2.07, p = 0.1; TTF: HR = 1.39, 95%CI: 0.94-2.06, p = 0.1). BAP1 expression was not independently associated with OS or TTF. Conclusions: Loss of PBRM1, but not BAP1 expression showed a trend towards longer TTF and OS in mRCC patients treated with VEGF-TT.

Abstract Ultrasound and magnetic resonance elastography techniques are used to assess mechanical properties of soft tissues. Tissue stiffness is related to various pathologies such as fibrosis, loss of compliance, and cancer. One way to perform elastography is measuring shear wave velocity of propagating waves in tissue induced by intrinsic motion or an external source of vibration, and relating the shear wave velocity to tissue elasticity. All tissues are inherently viscoelastic and ignoring viscosity biases the velocity-based estimates of elasticity and ignores a potentially important parameter of tissue health. We present attenuation measuring ultrasound shearwave elastography (AMUSE), a technique that independently measures both shear wave velocity and attenuation in tissue and therefore allows characterization of viscoelasticity without using a rheological model. The theoretical basis for AMUSE is first derived and validated in finite element simulations. AMUSE is validated against the traditional methods for assessing shear wave velocity (phase gradient) and attenuation (amplitude decay) in tissue mimicking phantoms and excised tissue. The results agreed within one standard deviation. AMUSE was used to measure shear wave velocity and attenuation in 15 transplanted livers in patients with potential acute rejection, and the results were compared with the biopsy findings in a preliminary study. The comparison showed excellent agreement and suggests that AMUSE can be used to separate transplanted livers with acute rejection from livers with no rejection.

The spine is the most common site for secondary bone metastases, and clinical management for fractures is based on size and geometry of the defect. About 75% of the bone needs to be damaged before lesions are detectable, so clinical tools should measure changes in both geometry and material properties. We have developed an automated, user-friendly, Spine Cancer Assessment (SCA) image-based analysis method that builds on a platform designed for clinical practice providing failure characteristics of vertebrae. The objectives of this study were to (1) validate SCA predictions with experimental failure load outcomes; (2) evaluate the planning capabilities for prophylactic vertebroplasty procedures; and (3) investigate the effect of computed tomography (CT) protocols on predicted failure loads. Twenty-one vertebrae were randomly divided into two groups: (1) simulated defect without treatment (negative control) [ n = 9] and (2) with treatment [ n = 12]. Defects were created and a polymeric biomaterial was injected into the vertebrae in the treated-defect group. Spines were scanned, reconstructed with two algorithms, and analyzed for fracture loads. To virtually plan for prophylactic intervention, vertebrae with empty lesions were simulated to be augmented with either poly(methyl methacrylate) (PMMA) or a novel bone replacement copolymer, poly(propylene fumarate-co-caprolactone) [P(PF-co-CL)]. Axial rigidities were calculated from the CT images. Failure loads, determined from the cross section with the lowest axial rigidity, were compared with experimental values. Predicted loads correlated well with experimental outcomes ( R 2 = 0.73, p < 0.0001). Predictions from negative control specimens highly correlated with measured values ( R 2 = 0.90, p < 0.0001). Although a similar correlation was obtained using both algorithms, the smooth reconstruction (B30) tended to underestimate predicted failure loads by ∼50% compared with the ∼10% underestimate of the sharp reconstruction (B70). Percent increase in failure loads after virtual vertebroplasty showed a higher increase in samples with PMMA compared with those with copolymer. The SCA method developed in this study calculated failure loads from quantitative computed tomography scans in vertebrae with simulated metastatic lytic defects, with or without treatment, facilitating clinical applicability and providing more reliable guidelines for physicians to select appropriate treatment options. Furthermore, the analysis could accommodate augmentation planning procedures that aimed to determine the optimum material that would increase vertebral body failure load.

Abstract Purpose: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC). Experimental Design: We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response. Results: Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response. Conclusions: In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445–52. ©2016 AACR. See related commentary by Voss and Hsieh, p. 2320

Calf muscles and Achilles tendon play important roles in functional activities. However, it is not clear how biomechanical properties of the uniarticular soleus (SOL) and biarticular gastrocnemius muscle and Achilles tendon, including the fascicle length, pennation angle, and stiffness, change concurrently post stroke. Biomechanical properties of the medial gastrocnemius (GM) and soleus muscles were evaluated bilaterally in 10 hemiparetic stroke survivors using combined ultrasonography-biomechanical measurements. Biomechanical properties of the Achilles tendon including the length, cross-sectional area (CSA), stiffness, and Young's modulus were evaluated, together with calf muscle biomechanical properties. Gastrocnemius and SOL contributions were separated using flexed and extended knee positions. The impaired side showed decreased fascicle length (GM: 6%, P = 0.002 and SOL: 9%, P = 0.03, at full knee extension and 0° ankle dorsiflexion) and increased fascicular stiffness (GM: 64%, P = 0.005 and SOL: 19%, P = 0.012, at a common 50 N force level). In contrast, Achilles tendon on the impaired side showed changes in the opposite direction as the muscle fascicles with increased tendon length (5%, P < 0.001), decreased tendon CSA (5%, P = 0.04), decreased tendon stiffness (42%, P < 0.001) and Young's modulus (30%, P < 0.001) compared with the unimpaired side. The fascicle and tendon stiffness changes were correlated negatively to the corresponding fascicle and tendon length changes, and decrease in Achilles tendon stiffness was correlated to the increases of SOL and GM fascicular stiffness ( P < 0.05). Characterizations of calf muscle fascicles and Achilles tendon biomechanical properties help us better understand concurrent changes of fascicles and tendon as part of the calf muscle-tendon unit and facilitate development of more effective treatments.

AbstractIn tissue engineering, development of an osteoconductive construct that integrates with host tissue remains a challenge. In this work, the effect of bone‐like minerals on maturation of pre‐osteoblast cells was investigated using polymer‐mineral scaffolds composed of poly(propylene fumarate)‐co‐poly(caprolactone) (PPF‐co‐PCL) and nano‐sized hydroxyapatite (HA). The HA of varying concentrations was added to an injectable formulation of PPF‐co‐PCL and the change in thermal and mechanical properties of the scaffolds was evaluated. No change in onset of degradation temperature was observed due to the addition of HA, however compressive and tensile moduli of copolymer changed significantly when HA amounts were increased in composite formulation. The change in mechanical properties of copolymer was found to correlate well to HA concentration in the constructs. Electron microscopy revealed mineral nucleation and a change in surface morphology and the presence of calcium and phosphate on surfaces was confirmed using energy dispersive X‐ray analysis. To characterize the effect of mineral on attachment and maturation of pre‐osteoblasts, W20‐17 cells were seeded on HA/copolymer composites. We demonstrated that cells attached more to the surface of HA containing copolymers and their proliferation rate was significantly increased. Thus, these findings suggest that HA/PPF‐co‐PCL composite scaffolds are capable of inducing maturation of pre‐osteoblasts and have the potential for use as scaffold in bone tissue engineering. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 2549–2557, 2015.

Key PointsIn this first ALL GWAS in AYAs, we determined that inherited GATA3 variants strongly influence ALL susceptibility in this age group. These findings revealed similarities and differences in the genetic basis of ALL susceptibility between young children and AYAs.