Dose Matrices Research Articles

Comparison of two biologically effective dose calculation models applied to single fraction stereotactic radiosurgery

BackgroundRecent studies suggest strong correlations between Biologically Effective Doses (BED) and single fraction stereotactic radiosurgery treatment outcomes, as demonstrated for vestibular schwannomas (VS), arterio-venous malformations and pituitary adenomas. The BEDs calculated in these studies consider an uniform dose delivery where the spatio-temporal aspects of dose delivery were neglected. PurposeThe aim of the study is to quantify the discrepancies between the BED values calculated with a simplified model of uniform dose delivery against the more complex model that incorporates the temporo-spatial incrementation of dose delivery and the bi-exponential effect of the sub-lethal damage repair. MethodsA software tool that computes the BED distributions based on individual isocenter dose matrices extracted from the GammaPlan (Elekta) treatment planning was developed. Two cohorts 5 VS and 5 jugular foramen schwannoma cases of various tumor volumes and isocenter number were utilized to benchmark the method. Their BEDs covering 98% of tumor volumes were compared against those determined with the uniform delivery model. ResultsThe BEDs covering 98% of the tumor volumes as calculated with both models show an approximately linear dependency with the treatment time. For all studied cases, the uniform delivery model overestimates the BEDs calculated with the full spatio-temporal delivery model. This discrepancy seems to accentuate with the tumor volume and treatment complexity. ConclusionsDespite their resemblance, the BED distributions provide a plethora of BED measures more suitable to characterize clinical outcomes than the unique peripheral BED value calculated with the simplified model of uniform dose delivery.

Predictors of radiation-induced late rectal toxicity in prostate cancer treatment: a volumetric and dosimetric analysis.

Prostate cancer (PCa) is a prevalent malignancy in European men, often treated with radiotherapy (RT) for localized disease. While modern RT achieves high success rates, concerns about late gastrointestinal (GI) toxicities persist. This retrospective study aims to identify predictors for late GI toxicities following definitive conventionally fractionated external beam RT (EBRT) for PCa, specifically exploring the dose to the rectal wall. A cohort of 96 intermediate- to high-risk PCa patients underwent EBRT between 2008 and 2016. Rectum and rectum wall contours were delineated, and 3D dose matrices were extracted. Volumetric and dosimetric indices were computed, and statistical analyses were performed to identify predictors using the Mann-Whitney U-rank test, logistic regression, and recursive feature elimination. In our cohort, 15 out of 96 patients experienced grade II late proctitis. Our analysis reveals distinct optimal predictors for rectum and rectum wall (RW) structures varying with α/β values (3.0 and 2.3 Gy) across prescribed doses of 68 to 76 Gy. Despite variability, RW predictors demonstrate greater consistency, notably V68Gy[%] to V74Gy[%] for α/β 3.0 Gy, and V68Gy[%] to V70Gy[%] for α/β 2.3 Gy. The model with α/β 2.3 Gy, featuring RW volume receiving 70 Gy (V70Gy[%]), stands out with a BIC value of 62.92, indicating its superior predictive effectiveness. Finally, focusing solely on the rectum structure, the V74Gy[%] emerges the best predictor for α/β 3.0 Gy, with a BIC value of 66.73. This investigation highlights the critical role of V70Gy[%] in the rectum wall as a robust predictor for grade II late gastrointestinal (GI) toxicity following external beam radiation therapy (EBRT) for prostate cancer (PCa). Furthermore, our findings suggest that focusing on the rectum wall specifically, rather than the entire rectum, may offer improved accuracy in assessing proctitis development. A V70Gy (in EQD2 with α/β 2.3 Gy) of ≤5% and if possible ≤1% for the rectal wall should be achieved to minimize the risk of late grade II proctitis.

Impact of radiation dose distribution on nutritional supplementation needs in head and neck cancer radiotherapy: a voxel-based machine learning approach.

To investigate the relationship between nutritional supplementation and radiation dose to the pharyngeal constrictor muscles and larynx for head and neck (HN) cancer patients undergoing radiotherapy. We retrospectively analyzed radiotherapy (RT) dose for 231 HN cancer patients, focusing on the pharyngeal constrictors and larynx. We defined nutritional supplementation as feeding tube utilization or >10% weight loss from baseline within 90 days after radiotherapy completion. Using deformable image registration (DIR), we mapped each patient's anatomical structures to a reference coordinate system, and corresponding deformations were applied to dose matrices. Voxel doses were utilized as features for ridge logistic regression models, optimized through 5-fold cross-validation. Model performance was assessed with area under the curve of a receiver operating curve (AUC) and F1 score. We built and compared models using 1) pharyngeal constrictor voxels, 2) larynx voxels, 3) clinical factors and mean regional dose metrics, and 4) clinical factors and dose-volume histogram metrics. Test set AUCs were compared among the models, and feature importance was evaluated. DIR of the pharyngeal constrictors and larynx yielded mean Dice coefficients of 0.80 and 0.84, respectively. Pharyngeal constrictors voxels and larynx voxel models had AUC of 0.88 and 0.82, respectively. Voxel-based dose modeling identified the superior to middle regions of the pharyngeal constrictors and the superior region of larynx as most predictive of feeding tube use/weight loss. Univariate analysis found treatment setting, treatment laterality, chemotherapy, baseline dysphagia, weight, and socioeconomic status predictive of outcome. An aggregated model using mean doses of pharyngeal constrictors and larynx subregions had an AUC of 0.87 and the model using conventional DVH metrics had an AUC of 0.85 with p-value of 0.04. Feature importance calculations from the regional dose model indicated that mean doses to the superior-middle pharyngeal constrictor muscles followed by mean dose to the superior larynx were most predictive of nutritional supplementation. Machine learning modeling of voxel-level doses enables identification of subregions within organs that correlate with toxicity. For HN radiotherapy, doses to the superior-middle pharyngeal constrictors are most predictive of feeding tube use/weight loss followed by the doses to superior portion of the larynx.

RADT-04. DOSE PAINTING WITH THE GAMMA KNIFE LIGHTNING OPTIMIZER TO ESCALATE RADIATION DOSE TO RESIDUAL TUMOR WITHIN BRAIN METASTASIS RESECTION CAVITIES

Abstract BACKGROUND The novel Gamma Knife (GK) Lightning optimizer allows simultaneous automated optimization of multiple intracranial radiotherapy targets. We used this optimizer to create a dose-painting treatment plan where an escalated dose was prescribed to residual disease within a brain metastasis resection cavity. We validated this method by measuring dose-delivery accuracy using radiochromic film in an anthropomorphic phantom. METHODS A 15.7cc irregular contour was drawn to represent a brain metastasis resection cavity, a 2mm expansion contour created, and a 1.6cc contour drawn representing a nodule of residual disease. In GammaPlan v11.3.1, three targets were created with overlapping dose matrices. Targets were prescribed 3Gy (2mm expansion), 4Gy (resection cavity), and 5Gy (residual disease) in one fraction. On the GK Icon system, an occipital mold was made, an unexposed film placed in the phantom’s cranium, cone-beam coregistration conducted, and treatment delivered. The film was scanned and calibrated for absolute dosimetry. To evaluate dose-painting accuracy, global gamma index (GI) analyses were performed at various dose and distance tolerances, excluding points below 30% of the maximum dose. RESULTS An 18-minute treatment plan with 40 shots was created and delivered. Prescription isodose lines were 3Gy at 55% (2mm expansion, mean 4.8Gy), 4Gy at 69% (resection cavity, mean 5.2Gy), and 5Gy at 75% (residual disease, mean 6.1Gy). All target volumes had ≥ 99% prescription dose coverage and the maximum dose was 6.9Gy. Paddick conformality indices were 0.79 (2mm expansion), 0.74 (resection cavity), and 0.15 (residual disease). Gamma index pass rate/mean GI/median GI were 73%/0.68/0.55 at 1%/1mm tolerance, 85%/0.58/0.48 at 2%/1mm tolerance, and 97%/0.34/0.28 at 2%/2mm tolerance. An average of 17,883 points were evaluated per analysis. CONCLUSIONS We successfully performed GK dose painting with the Lightning optimizer, verifying dose delivery within clinically acceptable tolerances. Future work is needed to determine optimal dose levels for use in clinical practice.

Catechin-enhanced sulfamethoxazole degradation in Fe(II) activated peracetic acid process: Efficiency, mechanism and affecting factors

Peracetic acid (PAA), a commonly used environmentally friendly disinfectant, has recently gained attention on its potential for degrading organic pollutants in water due to its high oxidation potential. A potential approach for enhancing the Fe(II)/PAA process was proposed in this study. The effect of catechin (CAT), a polyphenolic antioxidant, on Fe(II)/PAA system for the degradation of sulfamethoxazole (SMX) in water was investigated. The results showed that CAT significantly enhanced the degradation efficiency of Fe(II)/PAA against SMX. The SMX degradation rate improved from 39.2 % to 88.2 % in 60 min in the presence of CAT. CAT might serve as an effective reducing agent to quantitatively reduce Fe(III) to Fe(II) with a molar ratio of about 1:2.4 between CAT and Fe(III). Reactive species were fully identified. Hydroxyl radicals, organic radicals and FeIVO2+ might involve in the degradation of SMX. Affecting factors including reagent dose, pH and water matrices were investigated. Three possible degradation pathways of SMX were proposed based on the identified reaction products, underscoring its potential applicability in water treatment.

Dysphagia at 1 Year is Associated With Mean Dose to the Inferior Section of the Brain Stem

Dysphagia is a common toxicity after head and neck (HN) radiation therapy that negatively affects quality of life. We explored the relationship between radiation therapy dose to normal HN structures and dysphagia 1 year after treatment using image-based datamining (IBDM), a voxel-based analysis technique. We used data from 104 patients with oropharyngeal cancer treated with definitive (chemo)radiation therapy. Swallow function was assessed pretreatment and 1 year posttreatment using 3 validated measures: MD Anderson Dysphagia Inventory (MDADI), performance status scale for normalcy of diet (PSS-HN), and water swallowing test (WST). For IBDM, we spatially normalized all patients' planning dose matrices to 3 reference anatomies. Regions where the dose was associated with dysphagia measures at 1 year were found by performing voxel-wise statistics and permutation testing. Clinical factors, treatment variables, and pretreatment measures were used in multivariable analysis to predict each dysphagia measure at 1 year. Clinical baseline models were found using backward stepwise selection. Improvement in model discrimination after adding the mean dose to the identified region was quantified using the Akaike information criterion. We also compared the prediction performance of the identified region with a well-established association: mean doses to the pharyngeal constrictor muscles. IBDM revealed highly significant associations between dose to distinct regions and the 3 outcomes. These regions overlapped around the inferior section of the brain stem. All clinical models were significantly improved by including mean dose to the overlap region (P ≤ .006). Including pharyngeal dosimetry significantly improved WST (P=.04) but not PSS-HN or MDADI (P ≥ .06). In this hypothesis-generating study, we found that mean dose to the inferior section of the brain stem is strongly associated with dysphagia 1 year posttreatment. The identified region includes the swallowing centers in the medulla oblongata, providing a possible mechanistic explanation. Further work including validation in an independent cohort is required.

The delivered dose assessment in pancreas SBRT with the target position determined using an in-house position monitoring system.

This study assessed the delivered dose accuracy in pancreas SBRT by incorporating the real-time target position determined using an in-house position monitoring system. An online image-based position monitoring system, SeedTracker, was developed to monitor radiopaque marker positions using monoscopic x-ray images, available from the Elekta XVI imaging system. This system was applied to patients receiving SBRT for pancreatic cancer on the MASTERPLAN Pilot trial (ACTRN 12617001642370). All patients were implanted pre-treatment with at least three peri-tumoral radiopaque markers for target localisation. During treatment delivery, marker positions were compared to expected positions delineated from the planning CT. The position tolerance of ±3mm from the expected position of the markers was set to trigger a gating event (GE) during treatment. The dosimetric impact of position deviations and actual dose delivered with position corrections was assessed by convolving the plan control point dose matrices with temporal target positions determined during treatment. Eight patients were treated within this study. At least one GE was observed in 38% of the treatment fractions and more than one GE was observed in 10% of the fractions. The position deviations resulted in the mean(range) difference of -0.1(-1.1 - 0.4)Gy in minimum dose to tumour and 1.9(-0.1- 4.6)Gy increase to Dmax to duodenum compared to planned dose. In actual treatment delivery with the patient realignment, the mean difference of tumour min dose and duodenal Dmax was reduced to 0.1(-1.0 - 1.1)Gy and 1.1 (-0.7 - 3.3)Gy respectively compared to the planned dose. The in-house real-time position monitoring system improved the treatment accuracy of pancreatic SBRT in a general-purpose linac and enabled assessment of delivered dose by incorporating the temporal target position during delivery. The intrafraction motion impacts the dose to tumour even if target position is maintained within a 3mm position tolerance.

Evaluation of the Impact of Defacing Head-and-Neck Datasets on Radiomics Features and Dosimetry

<h3>Purpose/Objective(s)</h3> Sharing head-and-neck (HN) CT data through public medical image repositories helps research institutions worldwide to evaluate and validate novel image processing and artificial intelligence approaches. However, public sharing of such data raises concerns about facial recognition compromising patient privacy. While existing defacing techniques can address this issue by eliminating identifiable facial features, these algorithms may also result in the obliteration of some critical information. The goal of this study is to evaluate the impact of three different publicly and commercially available defacing tools on radiomics features and dosimetry in HN datasets. <h3>Materials/Methods</h3> Radiotherapy (RT) planning HN CT images of 31 patients who had their whole brain scanned were selected from RTOG 0522 datasets. Four primary RT structures including brainstem, clinical target volume (CTV), gross tumor volume (GTV) and spinal cord were studied. HN CT data were defaced using a commercial solution, Carina Medical LLC's deidentifier (Carina), as well as two publicly available methods, quickshear (QS) and CT_biometric_mask (CTBIO). Open-source software was used to extract a total of 93 radiomics features from each structure, including first-, second-, and higher-order texture features. The Wilcoxon signed-rank test was performed for paired comparisons of each radiomics feature and each RT structure between the original and defaced CT. A P value of 0.05 or less was considered statistically significant. <h3>Results</h3> All 3 defacing methods successfully deidentified patients, making visual recognition from 3D volume rendering impossible. Carina's deidentifier preserved the original values of all 93 radiomics features across all 4 structures because it created a face mask leaving the head intact. Although QS and CTBIO defacing methods maintained the original values of all 93 radiomics features from brainstem and spinal cord, those from CTV and GTV were not completely preserved for some cases because the process partially erased sections within both structures. Only 19.35% and 13.98% of the radiomics features on CTV and GTV were not statistically significantly different for CTBIO, whereas for QS the ratio is only 30.11% and 62.36% for the two structures respectively. Such failure occurred because CTV and GTV were in different locations for each patient. With QS defacing, 7 cases had GTV, and 21 cases had CTV altered, whereas with CTBIO defacing, the numbers are 23 and 27. When it is determined that it is required to delete a portion that may be reconstructed for re-identification, the dose matrices are altered similarly to the associated image. <h3>Conclusion</h3> Defacing HN CT data is feasible for safeguarding patients' privacy while keeping most of the quantitative information of CT radiomics and dosimetry. Carina's deidentifier which uses a mask to completely cover a patient's face while leaving the head intact was found to be an effective way for retaining more quantitative information in target RT structures.

Evaluation of MIM ProtegeAI Prostate: Time Gain, Accuracy and Dosimetric Consequences

<h3>Purpose/Objective(s)</h3> To compare and measure the potential benefit of time-saving, accuracy and dosimetric impact, the MIM ProtegeAI Prostate 2.0 auto-segmentation™ was compared to the manual delineation of the radiation oncologist. Furthermore, the intra-observer variability and familiarization bias were also assessed. <h3>Materials/Methods</h3> Forty-eight consecutive prostate cancer cases have been retrospectively investigated. The planning CT scan (3mm slice thickness, from vertebrae L1/2 to 3cm below the ischial tuberosity, without contrast) was used for auto-contouring (<i>AI</i>) and manual delineation by a single observer (<i>Manual</i>). Femur_L/_R, PenileBulb, Rectum, SeminalVes and Bladder were evaluated; while another five AI-generated OARs were discarded. Time (minute: second; [Q1-Q3]) of <i>AI</i> delineation scoring (<i>AIscor</i>: major/minor/no correction needed), AI correction (<i>AIcor</i>), total <i>AI</i> (=AIscor+AIcor) and manual delineation were measured. The potential gain was assessed per individual OARs. To access familiarization half of the cohort started with <i>AIscor</i> and <i>AIcor</i> followed by <i>Manual</i>, while the other half started with <i>Manual</i>, followed by <i>AIscor</i> and <i>AIcor</i>. T-test at p<0.05 significance level was used for comparisons. Dice Similarity Coefficient (DSC), 95% Hausdorff and median surface distance (HD95, MSD) were also determined. Given that both contours were found to be clinically acceptable by the same radiation oncologist, the <i>AIcor</i>/<i>Manual</i> was used to define intra-observer variability. Original dose matrices were used to access median dose differences for each evaluated organ. <h3>Results</h3> A total of 473 contours were generated by <i>AI</i><b>,</b> with a fixed of 5 minutes per patient. For 36 patients (75%), AI failed to generate Kidney_L/_R. Major, minor, or no correction was considered in 14%, 72% and 14% of delineations, respectively. <i>Manual</i> delineation took on average 12:52 [7:51-24:19], <i>AIscor</i> and <i>AIcor</i> 2:45 [1:52-5:00] and 6:18 [2:49-14:14], respectively. AI gave up to 16:16 time gain with an average of 5:37 (p<0.001). Per OARs, the average time gain was 0:47 [0:11-1:44]. The familiarization bias, observed for <i>Manual</i> (p=0.09), was on average 1:27 faster when AI workflow started first, while for <i>AIcor</i> no significant bias was observed (p=0.168). Good DSC (>0.8) was observed for <i>AI/AIcor</i>, while HD95 and MSD showed a larger discrepancy. Intra-observer (<i>AIcor</i>/<i>Manual</i>) variability was worse for DSC and better for HD95 and MSD compared to <i>AI</i> vs. <i>AIcor</i>. Relevant (>5%) median dose (Gray) differences were observed for only two OARs: rectum and penile bulb. <h3>Conclusion</h3> ProtegeAI Prostate 2.0 auto-segmentation™ provides on average more than 4 minutes of gain per patient and requires only minor corrections. The realistic time saving is likely higher, as <i>AIscor+AIcor</i> prior manual delineation significantly reduced manual delineation time. Intra-observer variability remains a substantial source of differences, especially when relying on the DSC. Dose differences may be as high as 5% when using the corrected AI.

Dexamethasone degradation in aqueous medium by a thermally activated persulfate system: Kinetics and transformation products

Dexamethasone (DEX) is a synthetic steroid hormone that, owing to its endocrine disruptive effects, has the potential to be detrimental. DEX must be successfully removed during drinking water treatment to preserve human and aquatic animals' health. This study investigates the thermally activated persulfate (TAP) process for the efficient decomposition of DEX. The effectiveness of several variables such as pH, persulfate dose, DEX concentration, reaction temperature, and water matrices was studied. Removal of 500 μg/L DEX reached 100 % by using 100 mg/L of persulfate in ultrapure water (pH = 7) at 50 °C, within 45 min of reaction time. DEX removal usually followed exponential decay. The removal efficiency of DEX in the TAP process was pH-dependent, as 61 % of DEX was removed at a pH value of 9. In contrast, complete degradation was achieved under acidic and near neutral conditions.Moreover, environmentally relevant degradation experiments showed that, in principle, the presence of bicarbonate ions and humic acid had a negative effect on DEX decomposition by reducing the percentage removal of the target compound by >50 %. Six transformation products derived from DEX oxidation were identified using high-resolution LC-MS. TAP system could be proposed as a promising application for removing steroid hormones n real water matrices after process optimization in real conditions.

Abstract 1105: MET or SHP2 inhibition enhances targeted therapies and delays the emergence of resistance in oncogene-driven NSCLC

Abstract Background: Although advancements have been made in available targeted therapies for non-small cell lung cancer (NSCLC), most patients have an incomplete response and eventually acquire resistance. It is well known that MET signaling is a key pathway that mediates osimertinib resistance. Concurrently targeting multiple proteins in critical signaling pathways, including the MET receptor or SHP2, a key node downstream of receptor tyrosine kinases, may prevent or delay resistance. Here, we explore the promising concept of combining upfront targeted therapies with a selective MET inhibitor or SHP2 inhibitor as promising therapeutic strategies for oncogene-driven NSCLC. Methods: All cell lines were obtained from commercial vendors. Drugs were synthesized at Merck KGaA or purchased from commercial vendors. Cell viability upon inhibitor treatment was investigated by Resazurin Cell Viability Assay (R&amp;D Systems), and the effect of the inhibitors on colony forming ability was assessed using colony formation assays. Western blot was conducted to analyze pathway activity. The emergence of resistance was investigated by measuring the cell surface confluence using the IncuCyte S3 system (Essen Bioscience). Results: The lung cancer cell lines used were NCI-H358 (KRAS G12C), HCC-827 (EGFR L858R), NCI-H2228 (ALK fusion), HCC-78 (ROS1 fusion), and NCI-H1781 (HER2 exon 20 insertion), with their respective targeted therapies sotorasib, osimertinib, alectinib, entrectinib, and poziotinib. The antiproliferative effects of targeted therapies combined with a MET or SHP2 inhibitor were assessed using combination dose matrices in 6-day viability assays. While MET inhibition did not further sensitize the already sensitive cells to the targeted therapies, synergism occurred when the drugs were combined with the SHP2 inhibitor. Similar results were obtained by colony formation assays lasting 2 weeks. Furthermore, the combination of the targeted therapies with the SHP2 inhibitor led to stronger ERK signaling abrogation than with single therapies. In a long-term proliferation assay, the combined inhibition of EGFR and MET receptor delayed the emergence of osimertinib resistance in the EGFR mutant HCC827 cells, which have MET protein overexpression and phosphorylation. Conclusions: Our data show that combining targeted therapies with a SHP2 inhibitor synergistically decreases the viability of oncogene-driven NSCLC cell lines, indicating that initial combination therapy may be an appealing approach to improve patient outcomes. The observed delay in the emergence of osimertinib resistance, from combining a MET inhibitor with osimertinib, provides preclinical evidence to support further investigating MET inhibition upfront to improve the long-term therapeutic efficacy of EGFR inhibitors. Citation Format: Nadine Reischmann, Lorenz Pudelko, Christopher Stroh, Nina Linde, Doreen Musch, Marina Keil, Linda Pudelko, Christina Esdar, Andree Blaukat, Karl M. Schumacher, Niki Karachaliou. MET or SHP2 inhibition enhances targeted therapies and delays the emergence of resistance in oncogene-driven NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1105.

Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in combination with MEK inhibition in preclinical models of human NRAS mutant melanoma.

e15099 Background: NRAS mutations which activate MAPK signaling represent oncogenic driver alterations in approximately 20% melanoma cases in the US. NRAS mutant melanomas are uniquely dependent upon CRAF rather than BRAF for activation of downstream MEK/ERK signaling. In BRAF mutant melanoma, approved RAF-targeted therapies are commonly used in combination with a MEK inhibitor which provides clinical benefit by inhibition of two targets within the oncogenic MAPK signaling pathway. Emerging data with pan-RAF inhibitors in early clinical development suggests benefit with and without combined MEK inhibition, yet no approved targeted therapy exists for NRAS mutant melanoma patients. KIN-2787 is a novel, orally available pan-RAF inhibitor designed to be effective in RAF-dependent cancers, regardless of isoform. Methods: Kinome profiling was evaluated by radiometric enzyme assay at Reaction Biology across 688 kinases (including wild type, atypical, and mutant). Cellular activity was assessed by suppression of downstream MAPK pathway signaling and cell growth inhibition in human tumor cell lines. Combination cell growth inhibition studies were performed in 9x5 dose matrices with KIN-2787 and binimetinib, respectively. Extended cell growth inhibition effects were assessed by Incucyte imaging. In vivo KIN-2787 and combination efficacy was evaluated in NRAS mutant xenograft models. Results: Kinome profiling of KIN-2787 revealed exquisite selectivity with only 2 of 669 non-RAF family kinases inhibited &gt; 75% at 1 M KIN-2787 and retained ̃10x and 70x selectivity window against those two kinases, DDR1 and p38b, respectively, relative to RAF kinases. We previously reported KIN-2787 activity across BRAF, NRAS, and KRAS mutant tumor cell lines with greatest sensitivity in Class II and III dimer-driven BRAF models. Here, we evaluated NRAS mutant, BRAF WT melanoma for combination potential with binimetinib. Melanoma tumor cell lines bearing NRAS hotspot mutations demonstrated synergistic benefit with KIN-2787 combined with binimetinib. Daily KIN-2787 plus binimetinib treatment in NRAS mutant melanoma xenograft models resulted in significant tumor growth inhibition benefit relative to either agent alone and was associated with added MAPK pathway biomarker suppression. Conclusions: KIN-2787 is a highly selective, potent, next-generation, pan-RAF inhibitor with activity across BRAF and RAS mutant human tumor cell models. Preclinical in vitro and in vivo studies using KIN-2787 in combination with binimetinib demonstrated significant combination benefit in NRAS mutant melanoma models. Taken together with its unique selectively, these data support use of KIN-2787 in combination therapy in this patient segment. A Phase 1/1b dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 is ongoing (NCT04913285).

Anatomical Association of Dose Distribution With Radiotherapy-Related Lymphopenia in Oropharynx Cancer

<h3>Purpose/Objective(s)</h3> Lymphopenia during radiotherapy (RT) may be related to adverse outcome for head and neck cancer and is a theoretical concern for effectiveness of adjuvant immunotherapy. Prevention may be possible via plan adaptation if the relationship between RT dose distribution and incidence of lymphopenia is known. This work utilized image-based data mining to identify anatomical regions associated with development of lymphopenia during RT. <h3>Materials/Methods</h3> 639 oropharyngeal cancer patients treated from 2005-2016 at a single institution with curative intent RT and baseline lymphocytes ≥ 0.5 × 10⁹/L were studied. To control for co-founders and improve data mining sensitivity, two matched groups were defined - patients with and without lymphopenia (defined as Grade 3 or higher based on lymphocytes at nadir during RT < 0.5 × 10⁹/L according to CTCAE v5.0) - matched on target volume, baseline lymphocytes, and prescribed dose (propensity score matching, M = 1:1, caliper = 0.2). Following matching, 309 patients remained, and image-based data mining was used to identify regions where dose correlates with lymphopenia. EQD2 dose matrices (α/β = 10) were mapped onto a reference patient using deformable registration of the planning CT images. L-R mirrored images were included in the cohort to compensate for potential laterality bias. Mean dose distributions for the groups with/without lymphopenia were calculated and regions with significant differences between the mean dose of the two groups detected using permutation testing with 1000 permutations. Multivariable logistic analysis was conducted for the full cohort including mean dose to the identified region, along with age, gender, smoking, performance status, HPV status, stage, histology, target volume, prescribed dose, RT modality, RT duration, baseline lymphocytes, and chemotherapy delivery to generate a predictive model for development of lymphopenia. <h3>Results</h3> 74% of the patients developed lymphopenia ≥ G3 during RT. An association with dose to a discrete anatomical region was found. Of interest, this location corresponds to dense lymphoid tissue, bone marrow reserve, and numerous blood vessels. Following elastic-net least absolute shrinkage and selection operator regression, bootstrapped 100 times, a model including baseline lymphocytes (HR = 0.43, <i>P</i> < 0.001) and mean dose to the identified region (HR = 1.02 Gy⁻¹, <i>P</i> = 0.006) adjusted for age (HR = 0.98, <i>P</i> = 0.09) and target volume (HR = 1.83, <i>P</i> = 0.07) was proposed. The Hosmer-Lemeshow test indicated that the model was a good fit, C-statistics 94%. <h3>Conclusion</h3> In this large oropharynx cohort, RT related lymphopenia ≥ G3 was associated with dose to a discrete anatomical region including structures containing blood, lymphoid tissue, and bone marrow that may offer a mechanistic explanation. While hypothesis generating, this suggests the possibility that treatment related lymphopenia may be mitigated by prioritizing dose reduction to this region. Further confirmatory studies are indicated.

A method using 4D dose accumulation to quantify the interplay effect in lung stereotactic body radiation therapy

The purpose of this study was to devise and evaluate a method to quantify the dosimetric uncertainty produced by the interplay between the movement of multileaf collimator and respiratory motion in lung stereotactic body radiation therapy. The method calculates the dose distribution for all control points from a dynamic treatment in all respiratory phases. The methodology includes some characteristics of a patient’s irregular breathing patterns. It selects, for each control point, the phases with maximum and minimum mean dose over the tumor and their corresponding adjacent phases, whenever necessary. According to this selection, the dose matrices from each control point are summed up to obtain two dose distributions in each phase, which are accumulated in the reference phase subsequently by deformable image registration (DIR). D 95 and were calculated over those accumulated dose distributions for Gross Tumor Volume (GTV), Planning Target Volume—based on Internal Target Volume approach—and Evaluation Target Volume (ETV), a novel concept that applies to 4D dose accumulation. With the ETV, DIR and interplay uncertainties are separated. The methodology also evaluated how variations in the breathing rate and field size affects the mean dose received by the GTV. The method was applied retrospectively in five patients treated with intensity modulated radiotherapy—minimum area defined by the leaves configuration at any control point was at least 4 cm2. Uncertainties in tumor coverage were small (in most patients, changes on D 95 and were below 2% for GTV and ETV) but significant over- and under-dosages near ETV, which can be accentuated by highly irregular breathing. Uncertainties in mean dose for GTV tended to decrease exponentially with increasing field size and were reduced by an increase of breathing rate. The implementation of this method would be helpful to assess treatment quality in patients with irregular breathing. Furthermore, it could be used to study interplay uncertainties when small field sizes are used.

Enhanced optimization of volumetric modulated arc therapy plans using Monte Carlo generated beamlets.

A treatment planning system (TPS) produces volumetric modulated arc therapy (VMAT) plans by applying an optimization process to an objective function, followed by an accurate calculation of the final, deliverable dose. However, during the optimization step, a rapid dose calculation algorithm is required, which reduces its accuracy and its representation of the objective function space. Monte Carlo (MC) routines, considered the gold standard in accuracy, are currently too slow for practical comprehensive VMAT optimization. Therefore, we propose a novel approach called enhanced optimization (EO), which employs the TPS VMAT plan as a starting point, and applies small perturbations to nudge the solution closer to a true objective minimum. The perturbations consist of beamlet dose matrices, calculated using MC routines on a distributed-computing framework. DICOM files for clinical VMAT plans files are exported from the TPS and used to generate input files for the EGSnrc MC toolkit. Beamlet doses are calculated using the MC routines, each corresponding to a single multileaf collimator leaf from a single control point traveling 0.5cm in or out of the field. A typical VMAT plan requires 5000 to 10000 beamlets, which may be calculated overnight. This results in a ternary-valued objective function, which may use the same clinical objectives as the original VMAT plan. A simple greedy search algorithm is applied to minimize this function and determine the optimal set of ternary variables. The resulting modified control point parameters are imported into the TPS to calculate the final, deliverable dose, and to compare the EO plan with the original. EO was evaluated retrospectively on seven VMAT plans (two adult brain, one pediatric brain, two head and neck, and two prostate). Additionally, the use of stricter objectives was investigated for two of the cases: the left cochlea planning organ at risk (OAR) volume objective for the pediatric brain case, and the rectum objective for a prostate case. EO produced improved objective scores (by 6% to 60%) and dose-volume histograms (DVH) for the brain plans and the head and neck plans. For each of these plans, the target dose minimum and homogeneity were preserved, while one or more of the OAR DVH's was reduced. Although EO also reduced the objective scores for the prostate plans (by 46% and 79%), their absolute score and DVH improvements were not substantial. The stricter objective on the pediatric brain case resulted in lower dose to the OAR without compromising the target dose. However, the rectum dose in the prostate case could not be improved without reducing dose homogeneity to the planning target volume, suggesting that VMAT prostate cases may already be highly optimized by the TPS. We have developed a novel approach to improving the dose distribution of VMAT plans, which relies on MC calculations to provide small modifications to the control points. This method may be particularly useful for complex treatments in which a certain OAR is of concern and it is difficult for the treatment planner to obtain an acceptable solution with the TPS. Further development will reduce the beamlet computation time and result in more sophisticated EO treatment planning methods.

KMnO4-mediated reactions for hexachlorophene in aqueous solutions: Direct oxidation, self-coupling, and cross-coupling

Hexachlorophene (HCP) is used in a range of general cleaning and disinfecting products and has received increased attention due to its damaging effect to the central nervous system in animals and its toxicity in humans. The chemical oxidation of HCP by KMnO4 was performed to systematically evaluate the effects of oxidant dose, pH, temperature, typical anions, humic acid (HA), and various matrices on HCP removal. The second-order rate constant for HCP was determined to be 4.83 × 104 M−1 s−1 at pH 7.0 and 25 °C. The presence of HA can inhibit the removal of HCP by KMnO4, while Cl−, NO3−, SO42−, PO43−, and CO32− have negligible effects. Degradation products analysis of the reaction, as well as theoretical calculations of HCP molecule and its phenoxy radical species, indicated that KMnO4 oxidation for HCP included a C–C bridge bond cleavage, hydroxylation, direct oxidation and self-coupling, and cross-coupling reactions. This study revealed that KMnO4 oxidation is an effective technique for eliminating HCP in real water and wastewater.

Radiotherapy-Related Lymphopenia Affects Overall Survival in Patients With Lung Cancer.

Lymphopenia after radiotherapy has an adverse effect on the patient's outcome. However, the relationship between radiotherapy dose delivery and lymphopenia is not fully understood. This work used image-based data mining to identify anatomical regions where the received dose is correlated with severe lymphopenia. A total of 901 patients with lung cancer were analyzed. A Cox model was used to assess prognostic factors of overall survival (OS). Two matched groups were defined-patients with lymphopenia of grade 3 or higher and patients without lymphopenia of grade 3-based on tumor volume, baseline lymphocytes, and prescribed dose. Then, data mining was used to identify regions where dose correlates significantly with lymphopenia of grade 3 or higher. For this, dose matrices were aligned using registration of the computed tomography images to one reference patient. Mean dose distributions were obtained for the two groups, and organs of significance were detected. Dosimetric parameters from the identified organs that had the highest correlation with lymphocytes at nadir were selected. Multivariable analysis was conducted for lymphopenia of grade 3 or higher on the full lung cohort, and the model was tested on 305 patients with esophageal cancer. Adjusted Cox regression revealed that lymphopenia of grade 3 or higher is an independent factor of OS. The anatomical regions identified were the heart, lung, and thoracic vertebrae. Dosimetric parameters for lymphopenia included thoracic vertebrae V20, mean lung dose, and mean heart dose, which were further validated in the esophageal cancer cohort. We report that severe lymphopenia during radiotherapy is a poor prognostic factor for OS in patients with lung cancer and could be mitigated by minimizing thoracic vertebrae V20, mean lung dose, and mean heart dose to limit the irradiation of stem cells and blood pool.

Erectile Dysfunction and Absorbed Dose to Penile Base Structures in a Randomized Trial Comparing Ultrahypofractionated and Conventionally Fractionated Radiation Therapy for Prostate Cancer

To study the relationships between absorbed dose to penile base structures and erectile dysfunction (ED) in patients treated with ultrahypofractionated (UHF) radiation therapy (RT) or conventionally fractionated (CF) RT for prostate cancer. This dose-response study comprises 673 patients (57%) of the 1180 per-protocol patients included in the HYPO-RT-PC trial (median follow-up 5, years), where patients were randomized to CF (39 × 2.0 Gy, 8 weeks) or UHF (7 × 6.1 Gy, 2.5 weeks). No androgen deprivation therapy was allowed. Only patients with erectile function sufficient for intercourse at baseline and complete RT data were included in this study. Erectile function was assessed by physician at regular follow-ups. The main endpoint was severe ED (EDs). The penile bulb (PB) and crus were retrospectively delineated on the treatment planning computed tomography scans. Dose-volume descriptors were derived from EQD2 converted dose matrices (α/β = 3 Gy). Univariable and multivariable Cox proportional hazard regression and logistic regression were used to find predictors for EDS. No significant difference in EDs was found between CF and UHF. During the follow-up period, EDs occurred in 27% of the patients in both treatment groups. Average (median) PB mean dose, Dmean, was 24.5 (20.2) in CF and 18.7 (13.1) Gy3 in UHF. Age was the only significant predictor for EDs in Cox analyses. All dose-volume variables contributed significantly in univariable logistic regression at 2-year follow-up. Age and near maximum dose (D2%) were significant predictors for EDs in multivariable logistic regression analyses at both 1 and 2 years. The frequency of EDS was similar in the CF and UHF treatment groups. Age at radiation therapy was the strongest predictor for EDs, followed by dose to PB, and was most evident for younger patients. We propose D2 % <50 Gy3 and Dmean <20 Gy3 to the PB as the primary objectives to be applied in the treatment planning process.

OAR sparing 3D radiotherapy planning supported by fMRI brain mapping investigations

The human brain as an organ has numerous functions; some of them can be visualized by functional imaging techniques (e.g., functional MRI [fMRI] or positron emission tomography). The localization of the appropriate activity clusters requires sophisticated instrumentation and complex measuring protocol. As the inclusion of the activation pattern in modern self-tailored 3D based radiotherapy has notable advantages, this method is applied frequently. Unfortunately, no standardized method has been published yet for the integration of the fMRI data into the planning process and the detailed description of the individual applications is usually missing. Thirteen patients with brain tumors, receiving fMRI based RT planning were enrolled in this study. The delivered dose maps were exported from the treatment planning system and processed for further statistical analysis. Two parameters were introduced to measure the geometrical distance Hausdorff Distance (HD), and volumetric overlap Dice Similarity Coefficient (DSC) of fMRI corrected and not corrected dose matrices as calculated by 3D planning to characterize similarity and/or dissimilarity of these dose matrices. Statistical analysis of bootstrapped HD and DSC data was performed to determine confidence intervals of these parameters. The calculated confidence intervals for HD and DSC were (5.04, 7.09), (0.79, 0.86), respectively for the 40 Gy and (5.2, 7.85), (0.74, 0.83), respectively for the 60 Gy dose volumes. These data indicate that in the case of HD < 5.04 and/or DSC > 0.86, the 40 Gy dose volumes obtained with and without fMRI activation pattern do not show a significant difference (5% significance level). The same conditions for the 60 Gy dose volumes were HD < 5.2 and/or DSC > 0.83. At the same time, with HD > 7.09 and/or DSC < 0.79 for 40 Gy and HD > 7.85 and/or DSC < 0.74 for 60 Gy the impact of fMRI utilization in RT planning is excessive. The fMRI activation clusters can be used in daily RT planning routine to spare activation clusters as critical areas in the brain and avoid their high dose irradiation. Parameters HD (as distance) and DSC (as overlap) can be used to characterize the difference and similarity between the radiotherapy planning target volumes and indicate whether the fMRI delivered activation patterns and consequent fMRI corrected planning volumes are reliable or not.

Impact of intrafraction prostate motion on clinical target coverage in proton therapy: A simulation study of dosimetric differences in two delivery techniques.

PurposeTo investigate the dosimetric impact of prostate intrafraction motion on proton double‐scattering (DS) and uniform scanning (US) treatments using electromagnetic transponder‐based prostate tracking data in simulated treatment deliveries.MethodsIn proton DS delivery, the spread‐out Bragg peak (SOBP) is created almost instantaneously by the constant rotation of the range modulator. US, however, delivers each entire energy layer of the SOBP sequentially from distal to proximal direction in time, which can interplay with prostate intrafraction motion. This spatiotemporal interplay during proton treatment was simulated to evaluate its dosimetric impact. Prostate clinical target volume (CTV) dose was obtained by moving CTV through dose matrices of the energy layers according to prostate‐motion traces. Fourteen prostate intrafraction motion traces of each of 17 prostate patients were used in the simulated treatment deliveries. Both single fraction dose‐volume histograms (DVHs) and fraction‐cumulative DVHs were obtained for both 2 Gy per fraction and 7.25 Gy per fraction stereotactic body radiotherapy (SBRT).ResultsThe simulation results indicated that CTV dose degradation depends on the magnitude and direction of prostate intrafraction motion and is patient specific. For some individual fractions, prescription dose coverage decreased in both US and DS treatments, and hot and cold spots inside the CTV were observed in the US results. However, fraction‐cumulative CTV dose coverage showed much reduced dose degradation for both DS and US treatments for both 2 Gy per fraction and SBRT simulations.ConclusionsThis study indicated that CTV dose inhomogeneity may exist for some patients with severe prostate intrafraction motion during US treatments. However, there are no statistically significant dose differences between DS and US treatment simulations. Cumulative dose of multiple‐fractions significantly reduced dose uncertainties.