Use of an ultrasound imaging device within the applicator to evaluate placement and support treatment planning for breast brachytherapy and intraoperative radiation therapy.

PURPOSE: We evaluated the use of ultrasound imaging within a brachytherapy applicator as a method for applicator positioning, evaluation, and treatment planning in a series of in vitro, cadaver, and human studies. METHODS AND MATERIALS: We evaluated the performance of a prototype system comprising a small ultrasound imaging catheter inserted within the lumen of a balloon brachytherapy catheter. We tested the device in an ultrasound phantom, in human breast tissue, and in an endoscopic ultrasound catheter in cadaveric breast tissue. We evaluated the visualization of adjacent tissue to consider future development of a similar system for use in brachytherapy and intraoperative radiation therapy. RESULTS: Based on the ultrasound images obtained in an ultrasound phantom, cadaveric breast, and human participants, we observed that an ultrasound imaging catheter placed within the lumen of a brachytherapy applicator can effectively image adjacent tissue, ribs, and air voids, with appropriate quality to support clinical use. We observed high correlation in clinically useful information detected on ultrasound and comparative CT, with ultrasound spatial resolution near 1 mm (spatially variant). CONCLUSIONS: The findings from our pilot work suggest that real-time ultrasound imaging, operated from within the applicator, is a promising technique for image guidance and treatment planning during brachytherapy and intraoperative radiation therapy. Further expansion of this technology for clinical use will require development of a cohesive system of components to suit specific clinical applications.

Transition from LDR to HDR brachytherapy for cervical cancer: Evaluation of tumor control, survival, and toxicity.

PURPOSE: In 2012, our institution transitioned from low-dose-rate (LDR) brachytherapy to high dose-rate (HDR) brachytherapy. We report clinical outcomes after brachytherapy for cervical cancer at our institution over a continuous 10-year period. METHODS AND MATERIALS: From 2004 to 2014, 258 women (184 LDR and 74 HDR) were treated with tandem and ovoid brachytherapy in the multidisciplinary management of International Federation of Gynecology and Obstetrics Stages IA-IVB cervical cancer. Clinical and treatment-related prognostic factors including age, stage, smoking status, relevant doses, and toxicity data were recorded. RESULTS: Median followup for the LDR and HDR groups was 46 months and 12 months, respectively. The majority of patients (92%) received external beam radiotherapy as well as concurrent chemotherapy (83%) before the start of brachytherapy. For all stages, the 1-year local control and overall survival (OS) rates were comparable between the LDR and HDR groups (87% vs. 81%, p = 0.12; and 75% vs. 85%, p = 0.16), respectively. Factors associated with OS on multivariate analysis include age, stage, and nodal involvement. On multivariate analysis, severe toxicity (acute or chronic) was higher with HDR than LDR (24% vs. 10%, p = 0.04). Additional prognostic factors associated with increased severe toxicity include former/current smokers and total dose to lymph nodes. CONCLUSIONS: This comparative retrospective analysis of a large cohort of women treated with brachytherapy demonstrates no significant difference in OS or local control between the LDR and HDR. Acute and chronic toxicity increased shortly after the implementation of HDR, highlighting the importance of continued refinement of HDR methods, including integrating advanced imaging.

SU-E-J-192: Static Breath-Hold MRI Based Measurement of Change in Pulmonary Function Following a Course of Radiation Therapy.

PURPOSE: Radiation Therapy (RT) induced pulmonary function change may depend on the location, underlying function of that lung prior to radiations, radiation dose/fractionation and other factors. We propose to evaluate the radiation induced pulmonary function change using static breath-hold MRI scans with vascular information and 3D deformable image registration which can provide pulmonary function relative to RT dose on a regional basis. METHODS: A MRI scan pair near the end of inhale and near the end of exhale with breath hold were acquired for one lung cancer patient before RT and 6 months after RT. The patient was treated with SBRT with 55 Gy to PTVs in the right and the left lung respectively. B-spline based vesselness preserving image registration algorithm was applied to register the MRI pair for the calculation of local lung expansion as a measurement of regional pulmonary function (PF). The PF maps before RT and after RT were then mapped to the planning CT using the same algorithm tuned for MRI-CT registration. The pulmonary function change was calculated via the PF ratio between two MRI pairs. RESULTS: Strong spatial correlation was found between the irradiated lung region and the region with greatly decreased PF. Based on dose and PFC distribution, no strong determinant factor was found for PF lost in the left lung while the right lung shows that all the lung tissue receiving dose larger than 28 Gy will have a decreased PF. CONCLUSIONS: We demonstrated a method that uses static breath-hold MRI based lung imaging to evaluate radiation induced pulmonary function change which can be applied to study the dose and the pulmonary function change in a regional basis. This work is supported by NIH grant support 1R21CA144063.

SU-E-T-427: Effect of Contrast in Radiadyne Alatus Balloon Packing System on Bladder and Rectal Doses in Gynecological Brachytherapy.

PURPOSE: Vaginal packing for gynecological brachytherapy is used to immobilize the applicator and reduce doses to the bladder and rectum by increasing the separation from the applicator. With the introduction of theRadiadyne Alatus™ balloon packing system, we evaluate further reductions in dose to these structures by increasing the concentration of contrast in the balloon, increasing its attenuation. This evaluation has been performed using the Acuros™ dose calculation algorithm. METHODS: A patient with cervical cancer was treated with HDR Ir-192 by insertion of a tandem and ovoid applicator, with the Alatus™ balloon system used for vaginal packing instead of wet gauze. The balloons were filled with distilled water containing 10% Omnipaque contrast. Retrospectively, the balloons were contoured in the BrachyVision™ planning system, and the CT number of the structure set was adjusted to determine the effect of the concentration of the contrast in the balloons on bladder and rectal doses after heterogeneity correction using the Acuros™ algorithm. RESULTS: Use of 10% Omnipaque solution reduced the bladder and rectal point doses by 6% and 9.5%, respectively, with similar reductions in the D2cc and D1cc for each structure. Overriding the density of the balloon showed that a 50% solution would reduce the doses by 8% and 30%, respectively, due to the positions of the balloons with respect to the applicator dwell positions. CONCLUSIONS: Use of the Alatus™ balloon packing system allows reduction of the bladder and rectal doses both by increasing the distance between the bladder and rectum and the applicators and by increased attenuation of the dose by the use of contrast solution. Optimal dilution of the contrast should take into account both the positive protective effect of the solution as well as any negative artifact that the solution causes in the CT scan, which might obscure the patient's anatomy patient.

SU-D-BRB-05: Small Animal Lung Compliance Imaging: Assessment System for Tissue Sensitivity to Radiation Induced Lung Injury.

PURPOSE: Recent clinical trials and animal studies have indicated that the tissue sensitivity to radiation induced lung injury (RILI) may be region- specific. In this study, we propose a new 4D cone beam CT (CBCT) basedcompliance imaging method to measure regional pulmonary function change in precisely irradiated small animal under CBCT guidance on small animal radiation research platform (SARRP) to facilitate our understanding of region-specific tissue sensitivity to RILI. METHODS: Four Sprague-Dawley rats underwent prospective pressure gated 4D CBCT on SARRP. Three animals were selected as control group which underwent a second 4D CBCT scan. The fourth animal was irradiated in the central lung (24 Gy) using 3 × 3 mm collimating cone 2 months prior to the scan. The specific compliance (Csp) was calculated via the real time pressure measurement from the ventilator and displacement field from 3D B-spline image registration between the end of inhale and end of exhale phases from the 4D CBCT scan. The 3D Csp maps from the control animal group were mapped to the irradiated animal as a Csp functional atlas for statistical analysis. We alsoevaluated the repeatability of the Csp measurement on a voxel-by-voxel basis. RESULTS: No significant Csp difference is found after two month of radiation between the irradiated rat (0.22±0.05) and the functional atlas (0.21±0.07). The observation is consistent with previous publications. The averaged linear correlation coefficient between the voxel-by-voxel Csp measurements from initial and repeat scans in control group is 0.98. CONCLUSIONS: We proposed a method that uses 4D CBCT based compliance imaging to measure region-specific tissue sensitivity of RILI. We compared the irradiated animal two months after radiation with the control group. Our study shows an excellent robustness of the proposed method for regional lung tissue specific compliance measurement. This work was supported in part by UVa George Amorino Pilot Grant.

Altered amino acid excretion in children with autism.

Autism is a complex and life-long behavioural disorder of unknown aetiology. Recent reports have indicated the involvement of digestive tract dysfunction and possible complications from inadequate nutrition. In this study, 34 autistic children (12 untreated and 22 receiving therapeutic treatments related to digestive function and nutritional uptake) and 29 control subjects (all 5-15 years of age) were investigated to determine whether there were any anomalies in the urinary excretion of amino acids, glucose, sucrose, arabinose and tartaric acid using GC/FID and GC/MS analysis techniques. Significantly lower relative urinary levels of essential amino acids were revealed for both the untreated (mean +/- SEM, 32.53 +/- 3.09%) and treated (31.98 +/- 2.87%) autistic children compared with the controls (37.87 +/- 1.50%). There were no significant differences in measured excretions of sugars or tartaric acid. It was concluded that the untreated autistic children had evidence of altered metabolic homeostasis.

Adsorption/desorption hysteresis in inkbottle pores: a density functional theory and Monte Carlo simulation study.

The mechanisms of adsorption and desorption in inkbottle-shaped pores are considered for lattice models using grand canonical mean field density functional theory and Monte Carlo simulation. We find that they depend significantly on the particular pore geometry, the nature of the fluid-solid interaction, and the temperature. We find two mechanisms for desorption. One mechanism involves the emptying of the main cavity even as the density of fluid in the necks remains high, a mechanism observed recently in studies of an off-lattice model of an inkbottle. The other is a simultaneous desorption from the entire pore space, behavior that is more closely related to the traditional picture of pore blocking in the inkbottle system.

Motivational interviewing to enhance treatment initiation in substance abusers: an effectiveness study.

Sixty individuals referred for a substance abuse evaluation by a child welfare worker were randomly assigned to either a standard evaluation or an evaluation enhanced by Motivational Interviewing techniques, each delivered in a single session. Participants who received the enhanced evaluation were significantly more likely to attend at least one additional treatment session after the initial evaluation (59% versus 29%). This finding suggests that comparatively inexpensive modifications of "standard" initial evaluations with substance-using parents may increase engagement of substance-abusing parents in treatment. Moreover, this study adds to an overwhelmingly positive literature supporting Motivational Interviewing with alcohol-using populations and extends prior findings to non-research community settings.

Antideuteron yield at the AGS and coalescence implications

We present Experiment 864's measurement of invariant antideuteron yields in 11.5A GeV/c Au+Pt collisions. The analysis includes 250x10(6) triggers representing 14x10(9) 10% central interactions sampled for events with high mass candidates. We find (1/2pip(t))d(2)N/dydp(t) = 3.5+/-1.5(stat)+0.9-0.5(syst)x10(-8) GeV-2 c(2) for 1.8 = 0.35 GeV/c ( y(c.m.) = 1.6) and 3.7+/-2.7(stat)+1.4-1.5(syst)x10(-8) GeV-2 c(2) for 1.4 = 0.26 GeV/c, and a coalescence parameter B2; of 4.1+/-2. 9(stat)+2.3-2.4(syst)x10(-3) GeV2 c(-3). Implications for coalescence and antimatter annihilation are discussed.

Interdigitated deletion complexes on mouse chromosome 5 induced by irradiation of embryonic stem cells.

Chromosome deletions have several applications in the genetic analysis of complex organisms. They can be used as reagents in region-directed mutagenesis, for mapping of simple or complex traits, or to identify biological consequences of segmental haploidy, the latter being relevant to human contiguous gene syndromes and imprinting. We have generated three deletion complexes in ES (Embryonic Stem) cells that collectively span approximately 40 cM of proximal mouse chromosome 5. The deletion complexes were produced by irradiation of F(1) hybrid ES cells containing herpes simplex virus thymidine kinase genes (tk) integrated at the Dpp6, Hdh (Huntington disease locus), or Gabrb1 loci, followed by selection for tk-deficient clones. Deletions centered at the adjacent Hdh and Dpp6 loci ranged up to approximately 20 cM or more in length and overlapped in an interdigitated fashion. However, the interval between Hdh and Gabrb1 appeared to contain a locus haploinsufficient for ES cell viability, thereby preventing deletions of either complex from overlapping. In some cases, the deletions resolved the order of markers that were previously genetically inseparable. A subset of the ES cell-bearing deletions was injected into blastocysts to generate germline chimeras and establish lines of mice segregating the deletion chromosomes. At least 11 of the 26 lines injected were capable of producing germline chimeras. In general, those that failed to undergo germline transmission bore deletions larger than the germline-competent clones, suggesting that certain regions of chromosome 5 contain haploinsufficient developmental genes, and/or that overall embryonic viability is cumulatively decreased as more genes are rendered hemizygous. Mice bearing deletions presumably spanning the semidominant hammertoe locus (Hm) had no phenotype, suggesting that the classic allele is a dominant, gain-of-function mutation. Overlapping deletion complexes generated in the fashion described in this report will be useful as multipurpose genetic tools and in systematic functional mapping of the mouse genome.

Mouse mutants from chemically mutagenized embryonic stem cells.

The drive to characterize functions of human genes on a global scale has stimulated interest in large-scale generation of mouse mutants. Conventional germ-cell mutagenesis with N-ethyl-N-nitrosourea (ENU) is compromised by an inability to monitor mutation efficiency, strain and interlocus variation in mutation induction, and extensive husbandry requirements. To overcome these obstacles and develop new methods for generating mouse mutants, we devised protocols to generate germline chimaeric mice from embryonic stem (ES) cells heavily mutagenized with ethylmethanesulphonate (EMS). Germline chimaeras were derived from cultures that underwent a mutation rate of up to 1 in 1,200 at the Hprt locus (encoding hypoxanthine guanine phosphoribosyl transferase). The spectrum of mutations induced by EMS and the frameshift mutagen ICR191 was consistent with that observed in other mammalian cells. Chimaeras derived from ES cells treated with EMS transmitted mutations affecting several processes, including limb development, hair growth, hearing and gametogenesis. This technology affords several advantages over traditional mutagenesis, including the ability to conduct shortened breeding schemes and to screen for mutant phenotypes directly in ES cells or their differentiated derivatives.

Validation of Monte Carlo generated phase-space descriptions of medical linear accelerators.

The accuracy of Monte Carlo codes in dose calculation systems relies on the correctness of the input data. Monte Carlo calculations are performed to generate phase-space descriptions of the Varian 2100C accelerator at 6 and 18 MeV. Before these data can be reliably used as the input for dose calculations in patients, they must be properly validated. This validation consists of three different stages: validation of the coding of the geometry, validation of the user code for the Monte Carlo code, and validation of calculated results. Geometric validation is performed by isolating and testing treatment head components independently. The user code is checked by testing for energy conservation and the variance reduction schemes incorporated into the user code are checked by comparison of results calculated with and without their employment. Validation of the phase-space description is performed by calculation of depth dose curves and lateral profiles for dose deposition in phantom, with difference plots used to illustrate any discrepancies. Calculated and experimental in-phantom output is also determined. After complete validation, the calculated data can then be reliably used as the input for dose calculations.

Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase.

Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.

Comparison of EGS4 and MCNP4b Monte Carlo codes for generation of photon phase space distributions for a Varian 2100C.

Monte Carlo based dose calculation algorithms require input data or distributions describing the phase space of the photons and secondary electrons prior to the patient-dependent part of the beam-line geometry. The accuracy of the treatment plan itself is dependent upon the accuracy of this distribution. The purpose of this work is to compare phase space distributions (PSDs) generated with the MCNP4b and EGS4 Monte Carlo codes for the 6 and 18 MV photon modes of the Varian 2100C and determine if differences relevant to Monte Carlo based patient dose calculations exist. Calculations are performed with the same energy transport cut-off values. At 6 MV, target bremsstrahlung production for MCNP4b is approximately 10% less than for EGS4, while at 18 MV the difference is about 5%. These differences are due to the different bremsstrahlung cross sections used in the codes. Although the absolute bremsstrahlung production differs between MCNP4b and EGS4, normalized PSDs agree at the end of the patient-independent geometry (prior to the jaws), resulting in similar dose distributions in a homogeneous phantom. EGS4 and MCNP4b are equally suitable for the generation of PSDs for Monte Carlo based dose computations.

Molecular basis for p38 protein kinase inhibitor specificity.

p38 is a member of the mitogen-activated protein (MAP) kinase family and is a critical enzyme in the proinflammatory cytokine pathway. Other MAP kinase group members that share both structural and functional homology to p38 include the c-Jun NH2-terminal kinases (JNKs or SAPKs) and the extracellular-regulated protein kinases (ERKs). In this study, we determined the molecular basis for p38alpha inhibitor specificity exhibited by five compounds in the diarylimidazole, triarylimidazole, and triarylpyrrole classes of protein kinase inhibitors. These compounds are significantly more potent inhibitors of p38 compared to the JNKs and ERKs. Three active site ATP-binding domain residues in p38, T106, M109, and A157, selected based on primary sequence alignment, molecular modeling, and X-ray crystal structure data, were mutated to assess their role in inhibitor binding and enzymatic catalysis. All mutants, with the exception of T106M, had kinase activity within 3-fold of wild-type p38. Mutation of T106 to glutamine, the residue present at the corresponding position in ERK-2, or methionine, the corresponding residue in p38gamma, p38delta, and the JNKs, rendered all five inhibitors ineffective. The diarylimidazoles had approximately a 6-fold decrease in potency toward M109A p38. For the mutant A157V, all diarylimidazoles and triarylimidazoles tested were 5-10-fold more potent compared with wild-type p38. In contrast, two triarylpyrroles were 15-40-fold less potent versus A157V p38. These results showed that the molecular basis for the specificity of the p38 inhibitors was attributed largely to threonine 106 in p38 and that methionine 109 contributes to increased binding affinity for imidazole based inhibitors.