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Mitchell, M

Publications and source records attributed to Mitchell, M.

9 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

WE-H-BRA-02: Radiobiological Modeling of Tumor Control Probability (TCP) and Radiation-Induced Pneumonitis (RP) for Lung Cancer Patients Treated with Monte Carlo-Based Lung SBRT

Purpose: To present radiobiological modeling of TCP using tumor size-adjusted BED(s-BED)and PTV(D99) to lung SBRT patients treated with X-ray Voxel Monte Carlo(XVMC) algorithm, apply parameterized Lyman-NTCP model to predict grade-2 RP and subsequently, compare with clinical outcomes/observations. Methods: Dosimetric parameters and clinical follow-up for XVMC-based lung-SBRT patients were retrospectively evaluated. Patients were treated at Novalis-TX with hybrid(2 non-coplanar partial-arcs plus 3–6 static-beams)plan using HD-MLC/6MV-SRS-beam.For TCP,s-BED modelling was utilized: TCP=EXP[sBED-TCD50]/k/(1.0+EXP[sBED-TCD50]/k), where k=31Gy corresponding to TCD50=0Gy and s-BED was defined as BED10 minus 10 times the tumor diameter(in centimeters)by Ohri et al.(IJROBP,2012). For 2-yr local-control, we used more-realistic MC-computed PTVD99 as a predictive parameter, s-BED(D99).Due to relatively shorter median follow-up interval(12-months),Kaplan-Meier curves were generated to estimate 2-yr observed local-control and compared to predicted-rate by TCP modeling. For NTCP, we employed parameterized Lyman-NTCP model utilizing normal-lung DVH and α/β=3Gy fitted to predict grade-2 RP after lung-SBRT. Results: Total 108 patients (137 tumors) treated for 35–70Gy in 3–5 fractions, either primary-lung(n=74)or metastatic-lung(n=53)tumors were included.F or the given prescription dose with MC-computed MUs, 2-yr local-control rates with s-BED(D99) was 87±8%. Kaplan-Meier generated observed local-control rate at 2-yr was 87.5%,suggesting that PTV(D99) could be a potential predictor (p-value=0.38). Observed vs predicted TCP for primary-lung tumors and metastatic tumors were 97% vs 88±7% and 94% vs 86±9%.NTCP model predicted well for symptomatic-RP with predicted vs observed (3±5% vs 2%). Radiographic and clinically significant RP was observed in 13% and 2% of patients. Higher rates of radiographic change were observed in patients who received >50Gy compared to ≤50Gy(24% vs 10%). Conclusion: Utilizing MC-computed PTVD99, our TCP results were well correlated with clinical outcome. The predicted grade-2 RP rate was comparable to clinical observations. Clinical application of these radiobiological models may potentially allow for target dose escalation and/or lung-toxicity reduction. Further validation of these radiobiological models with longer follow up interval for large cohorts of lung-SBRT patients is anticipated.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-T-95: An Alternative Option for Reducing Lung Dose for Electron Scar Boost Irradiation in Post-Mastectomy Breast Cancer Patients with a Thin Chest Wall

Purpose: Breast cancer patients who undergo a mastectomy often require post-mastectomy radiation therapy (PMRT) due to high risk disease characteristics. PMRT usually accompanies scar boost irradiation (10–16Gy in 5–8 fractions) using en face electrons, which often results in increased dose to the underlying lungs, thereby potentially increasing the risk of radiation pneumonitis. Hence, this study evaluated water-equivalent phantoms as energy degraders and as an alternative to a bolus to reduce radiation dose to the underlying lungs for electron scar boost irradiation. Methods: Percent depth dose (PDD) profiles of 6 MeV (the lowest electron energy available in most clinics) were obtained without and with commercial solid water phantoms (1 to 5mm by 1mm increments) placed on top of electron cones. Phantom attenuation was measured by taking a ratio of outputs with to without the phantoms in 10×10cm2 cone size for monitor unit (MU) calculation. In addition, scatter dose to contralateral breast was measured on a human-like phantom using two selected scar (short and long) boost patient setups. Results: The PDD plots showed that the solid water phantoms and the bolus had similar dosimetric effects for the same thickness. Lower skin dose (up to 3%) to ipsilateral breast was observed with a 5mm phantom compared with a 5mm bolus (up to 10%) for all electron cones. Phantom attenuation was increased by 50% with about a 4.5mm phantom. Also, the energy degraders caused scatter dose to contralateral breast by a factor of 3 with a 5mm phantom. Conclusion: Our results demonstrate the feasibility of using water-equivalent phantoms to reduce lung dose using en face electrons in patients with a thin chest wall undergoing PMRT. The disadvantages of this treatment approach (i.e., the increase in MUs and treatment time, and clinically insignificant scatter dose to the contralateral breast given usually 10Gy) are outweighed by its above clinical benefits.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

SU-E-T-525: Dose Volume Histograms (DVH) Analysis and Comparison with ICRU Point Doses in MRI Guided HDR Brachytherapy for Cervical Cancer

Purpose: Brachytherapy plays a crucial role in management of cervix cancer. MRI compatible applicators have made it possible to accurately delineate gross-target-volume(GTV) and organs-at-risk(OAR) volumes, as well as directly plan, optimize and adapt dose-distribution for each insertion. We sought to compare DVH of tumor-coverage and OARs to traditional Point-A, ICRU-38 bladder and rectum point-doses for four different planning-techniques. Methods: MRI based 3D-planning was performed on Nucletron-Oncentra-TPS for 3 selected patients with varying tumor-sizes and anatomy. GTV,high-risk-clinical-target-volume(HR-CTV), intermediate-risk-clinical-target-volume(IR-CTV) and OARs: rectum, bladder, sigmoid-colon, vaginal-mucosa were delineated. Three conventionally used techniques: mg-Radium-equivalent(RaEq),equal-dwell-weights(EDW), Medical-College-of-Wisconsin proposed points-optimization (MCWO) and a manual-graphical-optimization(MGO) volume-coverage based technique were applied for each patient. Prescription was 6Gy delivered to point-A in Conventional techniques (RaEq, EDW, MCWO). For MGO, goal was to achieve 90%-coverage (D90) to HR-CTV with prescription-dose. ICRU point doses for rectum and bladder, point-A doses, DVH-doses for HR-CTV-D90,0.1cc-volume(D0.1),1ccvolume( D1),2cc-volume(D2) were collected for all plans and analyzed . Results: Mean D90 for HR-CTV normalized to MGO were 0.89,0.84,0.9,1.0 for EDW, RaEq, MCWO, MGO respectively. Mean point-A doses were 21.7% higher for MGO. Conventional techniques with Point-A prescriptions under covered HR-CTV-D90 by average of 12% as compared to MGO. Rectum, bladder and sigmoid doses were highest in MGO-plans for ICRU points as well as D0.1,D1 and D2 doses. Among conventional-techniques, rectum and bladder ICRU and DVH doses(0.1,1,2cc) were not significantly different (within 7%).Rectum D0.1 provided good estimation of ICRU-rectum-point doses (within 3.9%),rectum D0.1 were higher from 0.8 to 3.9% while bladder D0.1 overestimated the bladder ICRU point dose up to 43% for conventional-techniques.Bladder-D2 provided a good estimation of ICRU bladder point-doses(within 3.6%) for conventional-techniques. This correlation is not observed for MGO plans perhaps due to steering of isodose line, leading to unpredictable dwell-weighting. Conclusion: MRI based HDR-planning provides accurate delineation of tumor volumes and normal structures, and optimized tumor-coverage can be achieved with acceptable normal-tissue doses. This study showed that for conventional techniques D0.1 rectum dose and D2 bladder dose are good representation of ICRU-reference-point doses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

Cdc13 N-Terminal Dimerization DNA Binding and Telomere Length Regulation

The essential yeast protein Cdc13 facilitates chromosome end replication by recruiting telomerase to telomeres, and together with its interacting partners Stn1 and Ten1, it protects chromosome ends from nucleolytic attack, thus contributing to genome integrity. Although Cdc13 has been studied extensively, the precise role of its N-terminal domain (Cdc13N) in telomere length regulation remains unclear. Here we present a structural, biochemical, and functional characterization of Cdc13N. The structure reveals that this domain comprises an oligonucleotide/oligosaccharide binding (OB) fold and is involved in Cdc13 dimerization. Biochemical data show that Cdc13N weakly binds long, single-stranded, telomeric DNA in a fashion that is directly dependent on domain oligomerization. When introduced into full-length Cdc13 in vivo, point mutations that prevented Cdc13N dimerization or DNA binding caused telomere shortening or lengthening, respectively. The multiple DNA binding domains and dimeric nature of Cdc13 offer unique insights into how it coordinates the recruitment and regulation of telomerase access to the telomeres.

59 BASIC BIOLOGICAL SCIENCES↗