Max Dose Research Articles

Correlation of clinical outcome, radiobiological modeling of tumor control, normal tissue complication probability in lung cancer patients treated with SBRT using Monte Carlo calculation algorithm.

Purpose/BackgroundWe analyzed the predictive value of non‐x‐ray voxel Monte Carlo (XVMC)‐based modeling of tumor control probability (TCP) and normal tissue complication probability (NTCP) in patients treated with stereotactic body radiotherapy (SBRT) using the XVMC dose calculation algorithm.Materials/MethodsWe conducted an IRB‐approved retrospective analysis in patients with lung tumors treated with XVMC‐based lung SBRT. For TCP, we utilized tumor size‐adjusted biological effective dose (s‐BED) TCP modeling validated in non‐MC dose calculated SBRT to: (1) verify modeling as a function of s‐BED in patients treated with XVMC‐based SBRT; and (2) evaluate the predictive potential of different PTV dosimetric parameters (mean dose, minimum dose, max dose, prescription dose, D95, D98, and D99) for incorporation into the TCP model. Correlation between observed local control and TCPs was assessed by Pearson's correlation coefficient. For NTCP, Lyman NTCP Model was utilized to predict grade 2 pneumonitis and rib fracture.ResultsEighty‐four patients with 109 lung tumors were treated with XVMC‐based SBRT to total doses of 40 to 60 Gy in 3 to 5 fractions. Median follow‐up was 17 months. The 2‐year local and local‐regional control rates were 91% and and 78%, respectievly. All estimated TCPs correlated significantly with 2‐year actuarial local control rates (P < 0.05). Significant corelations between TCPs and tumor control rate according to PTV dosimetric parameters were observed. D99 parameterization demonstrated the most robust correlation between observed and predicted tumor control. The incidences of grade 2 pneumonitis and rib fracture vs. predicted were 1% vs. 3% and 10% vs. 13%, respectively.ConclusionOur TCP results using a XVMC‐based dose calculation algorithm are encouraging and yield validation to previously described TCP models using non‐XVMC dose methods. Furthermore, D99 as potential predictive parameter in the TCP model demonstrated better correlation with clinical outcome.

Ionizing Radiation Effect upon Er/Yb Co-Doped Fibre Made by In-Situ Nano Solution Doping

In order to assess the possible use in terrestrial and space applications, radiation effects by different ionizing radiation (gamma ray, electron beam, and mixed neutron / γ radiation) upon erbium and ytterbium co-doped fibre (EYDF) made by in-situ nano solution doping have been investigated. The spectral attenuation, unsaturable loss at 830 nm, emission and lifetime of irradiated (max dose is up to 140 kGy) and non-irradiated EYDF samples are measured, and the outcomes were analysed and compared. The results indicate that both the spectral attenuation and unsaturable loss at 830 nm are increased significantly and that the emission is reduced by radiation induced attenuation (RIA) and the decrease of the lifetime. The radiation effects produced by electron beam and gamma ray are almost comparable. The comparison between the radiation effects induced by pure gamma radiation and mix gamma and neutron radiation indicates that the neutron irradiation may have, to some degree, opposite effects as compared with pure γ ray.

Development and application of an elastic net logistic regression model to investigate the impact of cardiac substructure dose on radiation-induced pericardial effusion in patients with NSCLC

Background Typically, cardiac substructures are neither delineated nor analyzed during radiation treatment planning. Therefore, we developed a novel machine learning model to evaluate the impact of cardiac substructure dose for predicting radiation-induced pericardial effusion (PCE). Materials and methods One-hundred and forty-one stage III NSCLC patients, who received radiation therapy in a prospective clinical trial, were included in this analysis. The impact of dose-volume histogram (DVH) metrics (mean and max dose, V5Gy[%]–V70Gy[%]) for the whole heart, left and right atrium, and left and right ventricle, on pericardial effusion toxicity (≥grade 2, CTCAE v4.0 grading) were examined. Elastic net logistic regression, using repeat cross-validation (n = 100 iterations, 75%/25% training/test set data split), was conducted with cardiac-based DVH metrics as covariates. The following model types were constructed and analyzed: (i) standard model type, which only included whole-heart DVH metrics; and (ii) a model type trained with both whole-heart and substructure DVH metrics. Model performance was analyzed on the test set using area under the curve (AUC), accuracy, calibration slope and calibration intercept. A final fitted model, based on the optimal model type, was developed from the entire study population for future comparisons. Results Grade 2 PCE incidence was 49.6% (n = 70). Models using whole heart and substructure dose had the highest performance (median values: AUC = 0.820; calibration slope/intercept = 1.356/−0.235; accuracy = 0.743) and outperformed the standard whole-heart only model type (median values: AUC = 0.799; calibration slope/intercept = 2.456/−0.729; accuracy = 0.713). The final fitted elastic net model showed high performance in predicting PCE (median values: AUC = 0.879; calibration slope/intercept = 1.352/−0.174; accuracy = 0.801). Conclusions We developed and evaluated elastic net regression toxicity models of radiation-induced PCE. We found the model type that included cardiac substructure dose had superior predictive performance. A final toxicity model that included cardiac substructure dose metrics was developed and reported for comparison with external datasets.

The effect of radiotherapy on taste sensation in head and neck cancer patients \u2013 a prospective study

BackgroundOne of the main side effects of head and neck (H&N) radiation therapy (RT) is alteration in taste sensation. It causes significant morbidity and has a major effect on quality of life (QoL). The aim of this study was to prospectively define the effect of RT on taste sensation (general, and four basic tastes) and correlate these findings with changes in saliva secretion and QoL questionnaires.MethodsPatients with H&N cancer treated with RT, in which the oral cavity was expected to receive a mean dose of 30 Gray (Gy). Patients were evaluated by Whole-Saliva Sialometry, validated Taste Strips and European Organization for Research and Treatment of Cancer H&N QoL questionnaires prior to RT (T0), mid-point of radiotherapy dose (T1), at the end of radiotherapy (T2) and 1 (T3), 3 (T4) and 12 months (T5) after completion of treatment course.ResultsTwenty-eight patients were recruited, and 21 patients completed study procedures and were analyzed. Median age was 66 years (range 18–90). The most common tumor site was the oral cavity. The median prescribed radiation dose to the high dose volume was 66 (range 60–70). The median mean and max dose to the oral cavity were 25.1 (range 14–69) and 64.9 (range 30–70), respectively. There was a significant decrease in overall taste sensation between T0 and T1 and T2. With specific tastes, there were significant decreases in sensation of sweet and salty, a trend with bitter and no change with sour. All returned to baseline at T3 and onwards. There was no significant correlation between the max or mean dose to the oral cavity and overall taste sensation or between doses to different areas of the tongue and overall or specific tastes. At T0 there was a significant positive correlation between overall taste sensation and whole-saliva sialometry, and at T1 and T2 there were strong trends. There were significant declines in QoL scores during RT.ConclusionsWe found a significant immediate reduction in taste sensation due to RT in H&N cancer patients with taste recovery 1 month after treatment completion. There were strong trends to a correlation with saliva production that requires further exploration.

An Examination of Changes in Urinary Metabolites and Behaviors with the Use of Leucovorin Calcium in Children with Autism Spectrum Disorder (ASD)

Children with autism spectrum disorder (ASD) have been found to have a high prevalence of folate receptor auto-antibodies (FRAA), which may impair the normal transport of folate from blood into the cerebrospinal fluid (CSF). Leucovorin calcium (LC) is believed to bypass the folate transport system and restore function. We sought to examine changes in behavior and urinary metabolites in children and young adults with ASD being treated with LC. Students attending a K-12 school for ASD were recruited for an open-label, 12-week study of high-dose LC (2 mg/kg/day, max dose 50 mg/day). The primary outcome measures were the mean changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). We also examined changes in Pediatric Quality of Life (PedsQL) and urinary metabolites. Changes were assessed with paired sample t-tests. Twelve students aged 13 to 19 (2 girls, 10 boys) completed the study. The parent-reported SRS showed a non-significant decrease (improvement) of 7.8 points (95% CI − 1.6 to 17.3, p = 0.095), and the ABC showed a non-significant decrease of 2.4 points (95% CI − 6.4 to 11.3, p = 0.56). The teacher-reported ABC and the parent-reported PedsQL showed very little change. Urinary metabolites with the greatest changes were involved in folate, phosphatidylcholine, and tocopherol metabolism. In an open-label study of school-aged children with ASD, LC treatment did not lead to significant improvements. The parent-reported SRS showed a non-significant improvement of 7.8 points, which is clinically important and worthy of future study with larger samples. The potential benefits of LC may be limited to children with a specific physiological abnormality (e.g., FRAA status) and may require a targeted treatment approach. Urinary metabolites may be a useful tool to identify children who are likely to respond to treatment.

Half Beam Technique in Patient with Left Breast Cancer and Evaluate its Dosimetry Parameters from Dosevolume Histograms

Using of 3DCRT for the treatment of left breast cancer by a single isocenter with half beam in the junctionof tangential and supraclavicular fields is an important method. The purpose was to evaluate the outcome ofRadiation Treatment Plans (RTP) that includes planning target volume (PTV) dose, conformity index (CI),homogeneity index (HI), organs at risk (OAR), and compared with tolerance doses of left-sided whole breastirradiation by half beam technique. Thirteen patients with left breast cancer who had received radiotherapyby using 6, 10, and 18 MV photons. The clinical target volume [CTV] was contoured as a target volume, andleft lung, right lung, heart, and spinal cord tissues as OAR planning technique was analyzed at Zhianawacancer center (ZCC), Sulaimany-KR-Iraq. There was No risk for 12 patients CI (&lt;1), accept patient No.(6) CI&gt;1. the PTV was under coverage (4060±32.116 cGy), was close to 4005 Gy volume. The left lung,and right lung mean dose was (33.923, 1018.231cGy &lt; tolerance mean Dose (4000 cGy), and for Lt lungDose V20 &lt; 30 cGy. Heart Dose V35 (2.354) &lt;20Gy, and Heart mean Dose (cGy)Dose was (358.308 cGy)&lt; tolerance mean Dose (2600 cGy). Cord Max dose was (682.692cGy) &lt; 2000. the Dose mean value ofesophagus was (29,077)cGy was &lt;3400 (Esophagus Tolerance mean dose (cGy). The application of leftbreast cancer provides significant advantages especially in PTV and OAR dosages.

Efficacy and Safety of Tocilizumab in the Treatment of Acute Active Antibody-mediated Rejection in Kidney Transplant Recipients.

Background.Antibody-mediated rejection (AMR) continues to have a deleterious impact on kidney allograft survival. Recent evidence supports use of tocilizumab for treatment of chronic active AMR, but it has not been assessed for treatment of acute active AMR.Methods.We performed a single-center, observational study of kidney transplant recipients who received at least 1 dose of tocilizumab in addition to conventional therapies for acute active AMR between October 2016 and October 2018 with follow-up through August 2019.Results.Seven patients were included. All 7 patients received tocilizumab 8 mg/kg (max dose, 800 mg) monthly. We noted a 50% or greater reduction in immunodominant donor-specific antibodies in 4 of 6 patients. Renal function improved or stabilized in all patients throughout the duration of therapy. One patient developed cytomegalovirus esophagitis and 1 had a potential hypersensitivity reaction. In the extended follow-up, 1 patient had mixed rejection and 2 patients had T-cell–mediated rejection, which occurred 6 to 24 mo after completion of therapy.Conclusions.Tocilizumab may be considered as an addition to conventional therapies for treatment of acute active AMR. More studies are needed to determine which patients may benefit from therapy and to examine the appropriate duration of treatment.

Telomerase Reverse Transcriptase Mediates Restoration of Functional Vasodilation in Isolated Coronary Microvessels of Aged Female Rats

IntroductionReactive oxygen species (ROS) increase during aging, resulting in decreased NO signaling and the production of ROS damages cellular components including mitochondrial DNA. Telomerase Reverse Transcriptase (TERT) has ROS‐suppressing effects in the mitochondria and is decreased in coronary artery disease (CAD). Upregulation of Telomerase restores NO mediated vasodilation in CAD. We hypothesize that treatment of isolated coronary microvessels of aged female rats with peptide nucXTERT (shunts TERT to mitochondria) will increase functional vasodilation while treatment of isolated coronary microvessels from young female rats with mitoXTERT (shunts TERT away from mitochondria) will blunt functional vasodilation.MethodsIsolated coronary microvessels from young (4 months, n = 2) or old (24 months, n = 5) Fischer 344 female rats were assessed via pressure myography. Vessels were incubated for 12 hours with nucXTERT or mitoXTERT, AGS 499 (TERT activator), or a scramble peptide negative control. Vessel relaxation to dobutamine (10−5 – 10−10 M), isoproterenol (10−4 – 10−8 M), acetylcholine (10−4 – 10−9 M), and H2O2 (10−3 – 10−8 M) was assessed post‐incubation.ResultsnucXTERT and AGS 499 treated vessel percent relaxation in old rats for isoproterenol, acetylcholine, and dobutamine were increased compared to scramble treated vessels (Figure 1a–c). Compared to scramble, nucXTERT increase of percent relaxation was significant for isoproterenol at 10−4 – 10−6 M (p = .007, .003, and .013, respectively), dobutamine at 10−5 – 10−7 M (p = &lt; .001, .016, and .016, respectively) and near significant for acetylcholine at 10−4 and 10−6 M (p = .097 and .062, respectively). Following nucxTERT and AGS 499 treatment, the percent relaxation to H2O2 (7.3% and 3.8% at max dilation, respectively) was reduced compared to scramble‐treated vessels (34.5% at max dilation)(Figure 1d). As expected, mitoXTERT incubation of young rat microvessels abrogated vasodilation of vessels to isoproterenol, acetylcholine, and dobutamine compared to scramble and AGS 499 responses. Hydrogen peroxide percent relaxation was increased in mitoXTERT (83.9% at max dose) compared to AGS 499 and scramble (3.79% and 34.38%, respectively).ConclusionsThe data support a vasoprotective and restorative role of TERT in coronary microvessels from aged female rats as adrenergic and acetylcholine‐mediated vasodilation were increased in nucXTERT and AGS 499 relative to the scrambled peptide. With nucXTERT, TERT was being blocked from nuclear translocation, increasing extranuclear TERT available for mitochondrial protection from ROS. Shunting TERT away from the mitochondria via mitoXTERT blunted adrenergic and acetylcholine‐mediated vasodilation as less TERT was available for mitochondrial ROS protection. Considering oxidative stress is a driver of CAD and the concomitant importance of altering vessel patency to allow for adequate blood flow to match metabolic demand, the modulation of TERT may be a holistic and plausible future clinical direction.Support or Funding InformationFunding for this project was provided by NIH RO1 AG053585 and the Gheen’s Foundation to Amanda Jo LeBlanc.Old rat isolated coronary arteriole vasoreactivity with nucXTERT peptide, AGS 499, or scramble peptide incubation. Shown as percent relaxation to isoproterenol (a) dobutamine (b) acetylcholine (c) and hydrogen peroxide (d). p ≤ 0.05 for nucXTERT (*) vs scramble. Data are presented as means ± SE, analyzed with two‐way repeated measures ANOVA followed by post‐hoc Bonferroni test.Figure 1

Verification of dose distribution on the gamma knife perfexion radiosurgery using gafchromic EBT3 film: RANDO phantom study

Leksell gamma knife (LGK) is an advanced modality of radiation therapy sourced Co-60 radioactive for treating patient with intracranial lesion. Small field techniques with highly integrated radiation delivering to patients in single session must be calculated accurately and verified carefully. This study illustrates a procedure to verify the accuracy of dose distribution associated with Leksell Gamma Plan (LGP) using RANDO phantom and gafchromic EBT3 film dosimetry. First, we assessed the profile dose on LGK standard phantom with collimators size 4, 8 and 16 mm and compared the results with the profile dose based on RANDO to obtained Full Width Half Maximum (FWHM) and beam-symmetry. Absorbed-dose distributions on RANDO with various combinations of lesion volume, collimator size, location and number of shots assessed by EBT3 film using LGK Perfexion. Scanned images of the measured films were processed following standard EBT3 film-handling procedures. Dose distribution calculation were performed using ImageJ software and MATLAB in-house software. The study shows different FHWM and beam symmetry of collimator size of 16 mm on standard phantom between LGP and measurement is 1.83 % and 1.58 % respectively whereas the discrepancy in RANDO phantom is 2.15 %, and 1.64 % respectively. Verification of max dose shows the smallest discrepancy on collimator size 16 single shot is 1.9 % on 7.61 cc superior lesion volume, where 12.12 Gy obtained by measurement and 12.36 Gy from LGP. In conclusion, collimator size 16 mm have a highest accuracy of FWHM and beam-symmetry value. However, on smaller lesion volume, collimator 16 mm with single shot give higher deviation dose value.

Contour Variability in Thyroid Eye Disease with Compressive Optic Neuropathy Treated with Radiation Therapy

PurposeFew studies have evaluated the methodology by which radiation therapy (RT) for thyroid eye disease and compressive optic neuropathy is performed. The objective of this study was to retrospectively review our experience from a radiation planning standpoint and to determine whether current treatment methods provide adequate dose to target and collateral structures. MethodsA retrospective review of 52 patients (104 orbits) with bilateral thyroid eye disease and compressive optic neuropathy treated with RT (20 Gy in 10 fractions) at our institution. RT plans were analyzed for target volumes and doses. Visual fields, color plates, and visual acuity were assessed pretreatment and at last available follow-up post RT. A standardized, anatomic contour of the retro-orbital space was applied to these retrospective plans to determine dose to the entire space, rather than the self-selected target structure. ResultsCompared with the anatomic retro-orbital space, the original contour overlapped by only 68%. Maximum and mean dose was 2134 cGy and 1910 cGy to the anatomic retro-orbital space. Consequently, 39.8% of the orbits had a mean dose <19 Gy (<17 Gy 16.4%, <18 Gy 27.6% <19 Gy 37.8%, <20 Gy 59.2%, 20-21 Gy 35.8%, >21 Gy 5%). There was no significant association of improvement in color plates (P = .07), visual fields (P = .77), and visual acuity (P = .62), based on these dose differences. When beam placement was retrospectively adjusted to include a space of 0.5 cm between the lens and the anterior beam edge, there was a 39.4% and 20.3% decrease in max and mean dose to the lens. ConclusionsWithout a standardized protocol for contouring in thyroid eye disease, target delineation was found to be rather varied, even among the same practitioner. Differences in dose to the anatomic retro-orbital space did not affect outcomes in the follow-up period. Although precise contouring of the retro-orbital space may be of little clinical consequence overall, a >0.5 cm space from the lens may significantly reduce or delay cataractogenesis.

Radiation dose-painting with protons vs. photons for head-and-neck cancer

Background: Dose-painting has recently been investigated in early-phase trials in head-and-neck cancer (HNC) with the aim of improving local tumor control. At the same time proton therapy has been reported as potentially capable of decreasing toxicity. Here, we investigate whether protons could be applied in a dose-painting setting by comparing proton dose distributions with delivered photon plans from a phase-I trial of FDG-PET based dose-painting at our institution.Material and methods: Eleven oropharynx (5), hypopharynx (2) and larynx cancer (4) patients from the recently conducted phase I trial were used for comparison of proton and photon dose-painting techniques. Robust optimization (3.5%/3 mm) was used for proton plans. Plan robustness and difference in dose metrics to targets and organs at risk were evaluated.Results: The proton plans met target dose constraints, while having lower non-target dose than photon plans (body-minus-CTV, mean dose 3.9 Gy vs 7.2 Gy, p = .004). Despite the use of robust proton planning for plan max dose, photon plan max doses were more robust (p = .006). Max dose to medulla, brainstem and mandible were lower in the proton plans, while there was no significant difference in mean dose to submandibular- and parotid glands.Conclusion: Proton dose-painting for HNC seems feasible and can reduce the non-target dose overall, however not significantly to certain organs close to the target, such as the salivary glands. Max dose in proton plans had a lower robustness compared to photons, requiring caution to avoid unintended hot spots in consideration of the risk of mucosal toxicity.

Evaluation of a new GPU-enabled VMAT multi-criteria optimisation plan generation algorithm

To evaluate the new Varian, graphical processing unit (GPU)-enabled, volumetric-modulated arc therapy (VMAT) multi-criteria optimisation (MCO) tool for both its dosimetric accuracy and calculation time. This is a new capability within V16.0 and greater of the Varian Eclipse treatment planning system that allows VMAT optimisation and dose calculation using the GPU (termed GPU-VMAT). In versions prior to V16.0 VMAT multi-criteria optimisation calculations were only possible using central processing unit (CPU) (termed CPU-VMAT) and Hybrid-VMAT (H-VMAT). The H-VMAT method breaks down the VMAT plan into IMRT fields which utilised GPU calculations. The study consisted of a cohort of 50 patients representing a range of anatomical treatment sites; bladder (5), brain (5), gynae (5), head & neck (5), lung (7), mediastinum (7) prostate (4), oesophagus (7) and rectum (5). Each case was planned to that of a clinical standard (Base) which was compared to a CPU-VMAT, GPU-VMAT and H-VMAT approaches. The study analysed dose to organ at risk (OAR) and target coverage, plan calculation time data and plan complexity through monitor unit (MU) for each approach. Negligible dosimetric differences were found between the CPU-VMAT, GPU-VMAT and H-VMAT approaches for the cohort of patients evaluated. The largest dosimetric change were observed in the lacrimal gland for a head and neck case, where the GPU-VMAT and H-VMAT achieved a max dose of +2.8 ± 0.0 Gy and −4.6 ± 0.0 Gy, respectively, when compared to CPU-VMAT. The majority of organ at risk’s (OAR) provided indistinguishable dosimetric outcomes, namely: heart, kidneys, femur, lens, oral cavity and oesophagus. Large time savings were found using the GPU-VMAT technique compared to CPU-VMAT, a mean decrease in calculation time across all sites of 60.2% ± 15.6%. Negligible dosimetric change between the 2 techniques and large time saving were observed with the GPU-VMAT and H-VMAT approaches when compared to the CPU-VMAT. We have shown that the GPU-VMAT technique has been safely implemented with minimal differences from CPU-VMAT, but with significant optimisation and calculation times savings.

Pelvic insufficiency fractures –a late effect of radiotherapy

Keywords, late effects, pelvic radiotherapy Introduction: Pelvic insufficiency fractures are stress fractures caused by normal or physiological stress on weakened bone . Radiotherapy increases the risk of insufficiency fractures in patients(1). These fractures are underdiagnosed in younger women. Presenting symptoms include pelvic and back pain of which can substantially affect quality of life. Aim- To evaluate the characteristics of patients with pelvic insufficiency fractures following radiotherapy Methods: Four patients presented to pelvic late effects clinic between Jan-June 2019, with confirmed sacral insufficiency fractures on diagnostic magnetic resonance imaging (MRI). Radiotherapy technique 4 field brick 3D CRT (n=1), volumetric modulated arc therapy (VMAT) (n=3), 1 of these with a library of 3 adaptive plans. All patients had concurrent weekly cisplatin. Dose prescribed 50Gy/25# (n=2) and 45Gy/25# (n=2). All Ca Cervix patients had 4 Brachytherapy insertions (24Gy) and Ca Endometrium patient had no insertions. All patients presented with lower back pain. Retrospective planning CT dosimetric analysis, by delineation of the sacrum in Eclipse V15.5 (Varian Medical Systems,Palo Alto). A structure was created using boolean operator to define sacrum overlap with PTV. Dose volume histograms were exported for the sacrum structure and planning characteristics recorded. Results: Age range of patients was 32-73. Radiotherapy complete between Feb 2013-June 2018 for Ca Cervix (n=3) stages 2B (n=2), 11b2 (n=1) and Ca Endometrium grade 3 1B(n=1). 2 patients were pre-menopausal on hormone replacement therapy (HRT) with 2 remaining patients on no HRT. Time to confirmed diagnosis of insufficiency fractures from radiotherapy completion was mean 13 (4-26) months. The mean sacrum volume was 149.6cm3 (130.97-186.61). The mean sacrum overlap with PTV volume was 35.99 cm3 (30.73-40.75). The max dose to the sacrum was 53.27Gy and minimum 16.22Gy. The mean D50% of the sacrum was 40.24Gy (38.69-44.98) and mean D40% 42.91Gy (39.29-74.77). Conclusion/Discussion: The dose-effect relationship has been defined with a 22% risk of fracture at 35Gy and 45% at 40Gy for D50%(2). Our patients D50% were all above 35Gy. Dose received from Brachytherapy has not been accounted for. There is potential using dosimetric analysis to identify patients at high risk of fractures. Numerical

Incorporating human and learned domain knowledge into training deep neural networks: A differentiable dose-volume histogram and adversarial inspired framework for generating Pareto optimal dose distributions in radiation therapy.

We propose a novel domain-specific loss, which is a differentiable loss function based on the dose-volume histogram (DVH), and combine it with an adversarial loss for the training of deep neural networks. In this study, we trained a neural network for generating Pareto optimal dose distributions, and evaluate the effects of the domain-specific loss on the model performance. In this study, three loss functions - mean squared error (MSE) loss, DVH loss, and adversarial (ADV) loss - were used to train and compare four instances of the neural network model: (a) MSE, (b) MSE+ADV, (c) MSE+DVH, and (d) MSE+DVH+ADV. The data for 70 prostate patients, including the planning target volume (PTV), and the organs at risk (OAR) were acquired as 96×96×24 dimension arrays at 5mm3 voxel size. The dose influence arrays were calculated for 70 prostate patients, using a 7 equidistant coplanar beam setup. Using a scalarized multicriteria optimization for intensity-modulated radiation therapy, 1200 Pareto surface plans per patient were generated by pseudo-randomizing the PTV and OAR tradeoff weights. With 70 patients, the total number of plans generated was 84000 plans. We divided the data into 54 training, 6 validation, and 10 testing patients. Each model was trained for a total of 100,000 iterations, with a batch size of 2. All models used the Adam optimizer, with a learning rate of 1×10-3 . Training for 100000 iterations took 1.5days (MSE), 3.5days (MSE+ADV), 2.3days (MSE+DVH), and 3.8days (MSE+DVH+ADV). After training, the prediction time of each model is 0.052s. Quantitatively, the MSE+DVH+ADV model had the lowest prediction error of 0.038 (conformation), 0.026 (homogeneity), 0.298 (R50), 1.65% (D95), 2.14% (D98), and 2.43% (D99). The MSE model had the worst prediction error of 0.134 (conformation), 0.041 (homogeneity), 0.520 (R50), 3.91% (D95), 4.33% (D98), and 4.60% (D99). For both the mean dose PTV error and the max dose PTV, Body, Bladder and rectum error, the MSE+DVH+ADV outperformed all other models. Regardless of model, all predictions have an average mean and max dose error <2.8% and 4.2%, respectively. The MSE+DVH+ADV model performed the best in these categories, illustrating the importance of both human and learned domain knowledge. Expert human domain-specific knowledge can be the largest driver in the performance improvement, and adversarial learning can be used to further capture nuanced attributes in the data. The real-time prediction capabilities allow for a physician to quickly navigate the tradeoff space for a patient, and produce a dose distribution as a tangible endpoint for the dosimetrist to use for planning. This is expected to considerably reduce the treatment planning time, allowing for clinicians to focus their efforts on the difficult and demanding cases.

Inter-fraction robustness of intensity-modulated proton therapy in the post-operative treatment of oropharyngeal and oral cavity squamous cell carcinomas.

To evaluate dosimetric consequences of inter-fraction setup variation and anatomical changes in patients receiving multifield optimised (MFO) intensity modulated proton therapy for post-operative oropharyngeal (OPC) and oral cavity (OCC) cancers. Six patients receiving MFO for post-operative OPC and OCC were evaluated. Plans were robustly optimised to clinical target volumes (CTVs) using 3 mm setup and 3.5% range uncertainty. Weekly online cone beam CT (CBCT) were performed. Planning CT was deformed to the CBCT to create virtual CTs (vCTs) on which the planned dose was recalculated. vCT plan robustness was evaluated using a setup uncertainty of 1.5 mm and range uncertainty of 3.5%. Target coverage, D95%, and hotspots, D0.03cc, were evaluated for each uncertainty along with the vCT-calculated nominal plan. Mean dose to organs at risk (OARs) for the vCT-calculated nominal plan and relative % change in weight from baseline were evaluated. Robustly optimised plans in post-operative OPC and OCC patients are robust against inter-fraction setup variations and range uncertainty. D0.03cc in the vCT-calculated nominal plans were clinically acceptable across all plans. Across all patients D95% in the vCT-calculated nominal treatment plan was at least 100% of the prescribed dose. No patients lost ≥10% weight from baseline. Mean dose to the OARs and max dose to the spinal cord remained within tolerance. MFO plans in post-operative OPC and OCC patients are robust to inter-fraction uncertainties in setup and range when evaluated over multiple CT scans without compromising OAR mean dose. This is the first paper to evaluate inter-fraction MFO plan robustness in post-operative head and neck treatment.

Objective function based ranking method for selection of optimal beam angles in IMRT

We propose a novel method for the selection of optimal beam angles in Intensity Modulated Radiation Therapy (IMRT). The proposed approach uses an objective function based metric called “target-to-critical organ objective function ratio” to find out the optimal gantry angles. The beams are ranked based on this metric and are accordingly chosen for IMRT optimization. We have used the Pinnacle TPS (Philips Medical System V 16.2) for performing the IMRT optimization. In order to validate our approach, we have applied it in four clinical cases: Head and Neck, Lung, Abdomen and Prostate. Basically, for all clinical cases, two set of plans were created with same clinical objectives, namely Equal angle plan (EA Plan) and Suitable angle Plan (SA Plan). In the EA plans, the beam angles were placed in an equiangular manner starting from the gantry angle of 0°. In the corresponding SA plans, the beam angles were decided using the guidance provided by the algorithm. The reduction in OAR mean dose and max dose obtained in SA plans is about 3 to 16% and 3 to 15% respectively depending upon the treatment site while obtaining equal target coverage as compared to their EA counterparts. It takes approximately 15–25 min to find the optimal beam angles. The results obtained from the clinical cases indicate that the plan quality is considerably improved when the beam angles are optimized using the proposed method.

Association between the location of transposed ovary and ovarian dose in patients with cervical cancer treated with postoperative pelvic radiotherapy

Background and purposeHow to protect the ovarian function during radiotherapy is uncertain. The purpose of this study was to explore the association between the location of the transposed ovary and the ovarian dose in patients with cervical cancer received radical hysterectomy, ovarian transposition, and postoperative pelvic radiotherapy.MethodsA retrospective analysis was conducted of 150 young patients with cervical cancer who received radical hysterectomy, intraoperative ovarian transposition, and postoperative adjuvant radiotherapy in Zhejiang Cancer Hospital. Association between location of the transposed ovaries and ovarian dose was evaluated. The transposed position of ovaries with a satisfactory dose was explored using a receiver operator characteristic curve (ROC) analysis. Patients’ ovarian function was followed up 3 months and 1 year after radiotherapy.ResultsA total of 32/214 (15%) transposed ovaries were higher than the upper boundary of the planning target volume (PTV). The optimum cutoff value of > 1.12 cm above the iliac crest plane was significantly associated with ovaries above the upper PTV boundary. When the ovaries were below the upper boundary of PTV, the optimum cutoff value of transverse distance > 3.265 cm between the ovary and PTV was significantly associated with ovarian max dose (Dmax) ≤ 4Gy, and the optimum cutoff value of transverse distance > 2.391 cm was significantly associated with ovarian Dmax≤5Gy. A total of 77 patients had received complete follow-up, and 56 patients (72.7%) showed preserved ovarian function 1 year after radiotherapy, which was significantly increased compared with 3 months (44.2%) after radiotherapy.ConclusionsThe location of transposed ovaries in patients with cervical cancer is significantly correlated with ovarian dose in adjuvant radiotherapy. We recommend transposition of ovaries > 1.12 cm higher than the iliac crest plane to obtain ovarian location above PTV. When the transposed ovary is below the upper boundary of PTV, ovarian Dmax ≤4Gy may be obtained when the transverse distance between the ovary and PTV was > 3.265 cm, and the ovarian Dmax≤5Gy may be obtained when the transverse distance was > 2.391 cm.

Abstract 104: Metabolic Effect of Temperature Manipulation in Healthy Individuals

Introduction: Temperature manipulation to decrease metabolism is commonly after acute brain injury. Preclinical data suggest metabolism decreases 7-8% for each degree C drop in core temperature. We hypothesized similar results would be found in healthy individuals. Methods: Following informed consent and physical screening, we administered a 1mcg/kg bolus of dexmedetomidine followed by 20cc/kg of cold (4C) saline bolus. We cooled subjects using surface pads (emcools (Austria)). Dexmedetomidine infusion was titrated to effect (max dose &lt;1.5mcg/kg/hr). We recorded vital signs, Richmond Agitation Sedation Scale, Bedside Shivering Assessment Scale and sensation of cold every 15 minutes. We measured resting metabolism at baseline and after each 1 C decrease in temperature thereafter using indirect calorimetry and a ventilated canopy system. We analyzed data using analysis of variance. Results: Median age in the 9 enrolled subjects was 30 (SD 10) years and most (78%) were male. Median height was 173 (IQR 168, 180) cm and median weight was 77 (IQR 72, 83) kg. Baseline VO2 was 3.4 (IQR 3.0, 3.8) ml/kg/min and baseline energy expenditure was 1692 (IQR 1579, 1845) kcal/day. Both VO2 and energy expenditure decreased with core temperature (p=0.017 and p=0.027) (Table). Conclusion: Metabolic rate decreases with core temperature manipulation. The largest change occurs between 37C and 36C with smaller changes thereafter.

Bendamustine and Rituximab Plus Venetoclax in Untreated Mantle Cell Lymphoma over 60 Years of Age (PrE0405): A Phase II Study

Background: Mantle Cell Lymphoma (MCL) is an aggressive form of Non Hodgkin Lymphoma (NHL) and typically presents in patients over the age of 60 years. Bendamustine and rituximab (BR) combination is one of the standard treatments for MCL and is given to patients for whom high dose chemotherapy with autologous stem cell rescue is planned in the first remission. Progression free survival (PFS) with BR is approximately 36 months (Rummel M Lancet 2013; Flinn IW Blood 2014) and the regimen is overall well tolerated. Venetoclax (VEN) is an orally available inhibitor of BCL2, an anti-apoptotic protein highly expressed in several NHL. Single agent activity has mostly been studied in a Phase I study (in various NHL histologies) where 28 MCL patients were enrolled. Overall response rate was 75% (21 of 28) but complete response (CR) rate was only 21% (6 of 28). Tumor lysis syndrome (TLS) has been associated with VEN and initial dosing requires a ramp up period (Davids MS JCO 2018). VEN has also been combined with other agents in MCL with promising activity (Tam CS NEJM 2018) VEN has been studied as a chemotherapy sensitizer and has shown pre-clinical synergy with chemotherapy. In Follicular lymphoma, BR+VEN was studied at 800mg PO continuous daily dosing and showed an excessive Grade 3-4 adverse event (AE) rate of 78% compared to historical studies of 46% (Zinzani ASH 2016). We hypothesize that, in MCL, VEN can be safely combined with BR at a lower dose and intermittent dosing with improvements to the response rate based on historical controls and maintain a better safety profile. Study Design: This Phase II single arm, multicenter study evaluates VEN at a max dose of 400mg with BR (Bendamustine 90mg/m2 IV day 1 and 2; rituximab 375mg/m2 IV or SQ equivalent day 1) for six 28-day cycles in untreated patients with MCL over the age of 60 years (NCT03834688). Cycle 1 will include a VEN dose titration over the 4 week course (20mg D1-7, 50mg D8-14, 100mg D15-21, and 200mg D22-28). For Cycles 2-6, VEN will be given at 400mg daily x 10 days starting with day 1. Participants are followed for 6 cycles, though will be followed for progression and survival afterward. Participants may receive maintenance rituximab at investigator's discretion. Eligible participants, age 60 years or older, must have biopsy proven untreated MCL with t(11;14) or cyclin D1 expression, though a short course of steroids is allowed for symptomatic MCL. They must have adequate organ function and not require any prohibited concomitant medications. Primary outcome is CR rate as assessed by the Lugano criteria. We estimate a historical CR rate of BR after induction of about 70%. A 15% increase in this rate, to 85% CR, is considered promising for the combination. To achieve this goal, the study will enroll 56 participants (53 eligible) to achieve a 90% power to detect the difference with a 10% Type I error rate. We will also evaluate PFS and overall survival. TLS is an AE of interest and will be evaluated after 19 participants have been enrolled and treated during cycle 1. Minimal residual disease (MRD) will be assessed throughout the study. MRD from peripheral blood will be compared to bone marrow aspirates in all participants undergoing bone marrow aspirate at the end of treatment. Tumor samples at screening and progression will be collected for future study. This study is conducted through PrECOG and is funded by Genentech, a member of the Roche Group. Venetoclax is co-developed by Genentech and AbbVie. The study is slated to open in Fall of 2019 at 10 US sites. Figure Disclosures Portell: AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board. Naik:Celgene: Other: Advisory board. Parsons:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Kahl:BeiGene: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Venetoclax is not approved for use in MCL.

Results of a Phase III Double-Blind Study of the Addition of Tocilizumab Vs. Placebo to Cyclosporin/Methotrexate Gvhd Prophylaxis after HLA-Matched Allogeneic Stem Cell Transplantation

Results of a Phase III Double-Blind Study of the Addition of Tocilizumab Vs. Placebo to Cyclosporin/Methotrexate Gvhd Prophylaxis after HLA-Matched Allogeneic Stem Cell Transplantation