Target Coverage Research Articles

Distributed dynamic scheduling algorithm of target coverage for wireless sensor networks with hybrid energy harvesting system

Distributed dynamic scheduling algorithm of target coverage for wireless sensor networks with hybrid energy harvesting system

Assessing yellow fever outbreak potential and implications for vaccine strategy

Yellow fever (YF), a vector-borne viral hemorrhagic fever, is endemic in tropical regions of Africa and South America, with large vaccination programmes being used for control. However, significant outbreaks have occurred in recent years. Data on infection rates and seroprevalence is often sparse, requiring robust mathematical models to estimate the burden of yellow fever. In particular, modelling is required to estimate the risk of outbreaks and inform policy decisions regarding the targeting of vaccination. We present a dynamic, stochastic model of YF transmission which uses environmental covariates to estimate the force of infection due to spillover from the sylvatic (non-human primate) reservoir and the basic reproduction number for human-to-human transmission. We examine the potential for targets identified by the World Health Organization EYE Strategy (50%, 60% or 80% vaccination coverage in 1-60 year olds) to achieve different threshold values for the effective reproduction number. Threshold values are chosen to reflect the potential for seasonal and/or climatic variation in YF transmission even in a scenario where vaccination lowers the median reproduction number below 1. Based on parameter estimates derived from epidemiological data, it is found that the 2022 EYE Strategy target coverage is sufficient to reduce the static averaged annual effective reproduction number R below 1 across most or all regions in Africa depending on the effectiveness of reported vaccinations, but insufficient to reduce it below 0.5 and thereby eliminate outbreaks in areas with high seasonal range. Coverage levels aligned with the 2026 targets are found to significantly decrease the proportion of regions where R is greater than 0.5.

Abstract 4148070: Clonal Hematopoeisis of Indeterminate Potential and Risk of Autopsy-defined Sudden Cardiac Death

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of coronary artery disease (CAD) and cardiovascular (CV) mortality. Whether CHIP may affect myocardium beyond promoting CAD, or its potential association with sudden cardiac death (SCD), the most feared manifestation of CV disease, is unknown. Research Questions/Hypothesis: We hypothesize that CHIP-mutant macrophages infiltrate the myocardium and are associated with autopsy-defined arrhythmic death. Goals/Aims: (1) determine rate of CHIP at time of death in an unselected, countywide study of all incident sudden deaths; (2) evaluate whether CHIP-mutant macrophages infiltrate into myocardium; and (3) evaluate potential association of CHIP with autopsy-confirmed arrhythmic causes among countywide sudden deaths Methods/Approach: We used autopsy to adjudicate arrhythmic from non-arrhythmic (PE, stroke, overdose, tamponade) causes in 1,148 sudden deaths and 141 trauma control deaths in San Francisco County from 2011-23. DNA was extracted from frozen blood samples collected at time of death from 399 consented cases. Sequencing of 22 CHIP-associated genes was performed to ~2000x mean target coverage. All pathogenic/likely pathogenic CHIP variants at >2% variant allele frequency (VAF) were considered CHIP+. DNA was then isolated from left ventricular (LV) tissue sampled at autopsy in all CHIP+ blood cases and sequenced as above. Results: Of 399 consented cases, 70 blood samples (17.5%) were CHIP+ (range 2%-39.6%; mean age 70.6 years vs. 58.1 years for CHIP-). The most frequent mutant genes were DNMT3A, TET2, and ASXL1. Proportion of arrhythmic causes among sudden deaths was similar for CHIP+ vs. CHIP- cases (36 of 70 [52%] vs. 171 of 329 [51%]). Sequencing of available LV tissue from 61 CHIP+ blood cases revealed 67% (n=41) harbored the same CHIP mutation identified in blood at >0.2% VAF (range 0.2%-4.3%). Proportion of arrhythmic causes among sudden deaths was significantly higher in cases where both blood and LV were CHIP+ (24 of 41 [58.5%] vs. 5 of 19 [26.3%] CHIP+ blood/CHIP- LV, p=0.02). Conclusions: Prevalence of CHIP positivity at sudden death is similar to published studies and correlated with age. CHIP+ status in myocardial tissue but not peripheral blood was associated with arrhythmic causes of sudden death, suggesting a direct tissue effect of CHIP-mutant macrophages.

RADT-45. INTEGRATION OF FUNCTIONAL MAGNETIC RESONANCE IMAGING INTO STEREOTACTIC RADIOSURGERY PLANNING TO REDUCE SYMPTOMATIC RADIATION NECROSIS

Abstract BACKGROUND Radiation necrosis (RN) is a common complication of stereotactic radiosurgery (SRS). Functional magnetic resonance imaging (fMRI) localizes eloquent cortical areas for neurosurgical planning but is seldom applied to SRS. We explored the relationship between symptomatic RN and functional neuroanatomy on fMRI. We evaluated the potential benefit of reducing radiation dose to functional areas. METHODS From 2011 to 2022, patients with an fMRI within 3 months of SRS for resected or unresected brain metastases (BM) were included. The BM nearest to the primary motor, language, or visual cortices was designated as the index BM. The functional area on fMRI nearest to the index BM was designated as the fOAR. Focally symptomatic RN (FSRN) was defined as radiographic RN alongside new or worsening focal neurologic symptoms consistent with the fOAR. Patients treated with 5-fraction SRS and modern planning techniques after 2013 were included in the dosimetric analysis. Associations between fOAR dose and FSRN were evaluated with logistic regression. SRS replanning was performed to determine if fOAR dose could be reduced without sacrificing target coverage. RESULTS Among 94 patients, 82% received SRS postoperatively, and 71% received 5-fraction SRS. fOARs included the primary motor (77%), language (19%), and visual (2%) cortices. Of 20 patients with radiographic RN, 20% were neurologically asymptomatic, 20% had anatomically unrelated neurologic symptoms, and 60% had FSRN. The dosimetric analysis included 39 patients. The fOAR volume receiving a single-fraction equivalent dose ≥14 Gy (V14Gy) was associated with FSRN at 18 months post-SRS (OR=6.8/mL, p=0.05). Replanning reduced fOAR V14Gy in all cases. The mean reduction was 28%. CONCLUSION Neurologic symptoms of SRS-induced RN reflect nearby functional neuroanatomy on fMRI. Dose reduction to functional areas while maintaining target coverage is consistently achievable and may mitigate symptomatic RN. Integrated fMRI-based SRS planning may protect neurologic function when treating tumors near eloquent areas.

Multicriteria optimization achieves superior normal tissue sparing in volumetric modulated arc therapy for gastric cancer

Abstract Objective To evaluate the benefits of volumetric modulated arc therapy (VMAT) based on multicriteria optimization (MCO) for gastric cancer patients, particularly the protection of serial organs at risk (OARs) that overlap with the target volume. Methods MCO and single-criterion optimization (SCO) VMAT plans were conducted among 30 gastric cancer patients, with a prescription dose of 50.4 Gy delivered in 28 fractions. All treatment plans underwent review, and a comparison was made between the active planning time and different dose-volume parameters. Results Both the MCO and SCO VMAT plans achieved the target dose coverage, with no significant difference in the conformity index (CI) for the planning target volume (PTV), at median CI values of 0.887 and 0.891, respectively (P = 0.417). The MCO plans showed a slight but significant increase in the homogeneity index of the PTV, with a median increase of 0.029 (P < 0.001). Additionally, the MCO plans resulted in a lower D2% to the small intestine and duodenum, with reductions of 3.43 Gy and 0.3 Gy, respectively (P < 0.05). Furthermore, the Dmax to the small intestine correlated moderately with the overlapping volume between the small intestine and the target volume (ρ = 0.42, P = 0.023). Except for the mean dose to the liver, the MCO plans performed better in terms of dose indicators for other OARs. Moreover, compared to the SCO plans, the median active planning time in the MCO plans was significantly reduced by 53.2 min (P < 0.0001). Conclusions MCO can effectively help the physicians to quickly select an optimal treatment plan for patients with gastric cancer. It has been shown that MCO VMAT plans can significantly reduce the dose to OARs and shorten the active planning time, with acceptable target coverage. In addition, these plans take less dosimetric time, thereby streamlining the treatment planning process.

Effects of spot size errors in DynamicARC pencil beam scanning proton therapy planning.

Spot size stability is crucial in pencil beam scanning (PBS) proton therapy, and variations in spot size can disrupt dose distributions. Recently, a novel proton beam delivery method known as DynamicARC PBS scanning has been introduced. The current study investigates the dosimetric impact of spot size errors in DynamicARC proton therapy for head and neck (HNC), prostate, and lung cancers.
Approach: Robustly optimized DynamicARC proton therapy plans were created for HNC (n=4), prostate (n=4), and lung (n=4) cancer patients. Spot size errors of ±10%, ±15%, and ±20% were introduced, and their effects on target coverage (D95% and D99%), homogeneity index (HI), and organ-at-risk (OAR) doses were analyzed across different cancer sites.
Main Results: HNC and lung cancer plans showed greater vulnerability to spot size errors, with reductions in target coverage of up to 4.8% under -20% spot size errors. Dose homogeneity was also more affected in these cases, with HI degrading by 0.12 in lung cancer. Prostate cancer demonstrated greater resilience to spot size variations, even under errors of ±20%. For spot size errors ±10%, the oral cavity, parotid glands, and constrictor muscles experienced Dmean deviations within ±1.2%, while deviations were limited to ±0.5% for D10% of the bladder and rectum and ±0.3% for V20Gy(RBE) of the lungs. The robustness analysis indicated that lung cancer plans were most susceptible to robustness reductions caused by spot size errors, while HNC plans demonstrated moderate sensitivity. Conversely, prostate cancer plans demonstrated high robustness, experiencing only minimal reductions in target coverage.
Significance: While the ±10% spot size tolerance is appropriate in the majority of the cases, lung cancer plans may require more stringent criteria. As DynamicARC becomes clinically available, measuring spot size errors in practice will be essential to validate these findings and refine tolerance thresholds for clinical use.

Controlling titanium incorporation in hydrogenated amorphous carbon films via closed-loop feedback in reactive high power impulse magnetron sputtering

A closed-loop feedback approach has been developed to control titanium incorporation in hydrogenated amorphous carbon (a-C:H) films during reactive high-power impulse magnetron sputtering (R-HiPIMS). The average discharge current measured at the magnetron target is used as the primary feedback signal to regulate the target coverage state. Hence, the titanium concentration in the films can be controlled. Significant changes were observed in the film microstructure and properties as the target state evolved with increasing target coverage. This causes the film transition from metallic titanium to a-C:H films with decreasing titanium concentration. For example, the XRD and Raman analyses indicated a microstructural change from hexagonal titanium to cubic titanium carbide and finally to amorphous carbon. The change in microstructure aligned with the density decreasing from 4.7 g∙cm‒3 to 1.6 g∙cm‒3 measured by XRR technique. In addition, a decrease in the Ti/C atomic ratio, from 1.53 to 0.03, clearly demonstrates that the titanium content can precisely be controlled. A simplified model was proposed to explain the relationship between the average HiPIMS current and the carbon coverage fraction on the target surface. The suggested relationship clarifies how adjusting the average discharge current effectively regulates the target coverage state and the consequent titanium concentration. The approach not only enhances process stability, but also offers an alternative to traditional control techniques during the deposition process.

Improvement of plan quality in whole-breast radiation following BCS using feasibility DVH by less-experienced planners.

Variability in plan quality of radiotherapy is commonly attributed to the planner's skill rather than technological parameters. While experienced planners can set reasonable parameters before optimization, less experienced planners face challenges. This study aimed to assess the quality of volumetric-modulated arc therapy (VMAT) in patients with left-sided breast cancer following breast-conserving surgery. Twenty-eight patients requiring whole-breast irradiation were randomly selected for inclusion. Each patient underwent two VMAT treatment plans: one optimized by an experienced planner (VMAT-EXP group) and the other designed by a less experienced planner using feasibility dose-volume histogram (FDVH) parameters from PlanIQ (VMAT-FDVH group). Both plans aimed to deliver a prescription dose of 50Gy in 25 fractions to the planning target volume (PTV). Dosimetry parameters for the PTV and organs at risk (OARs) were compared between the two groups. Both the VMAT-EXP and VMAT-FDVH groups met the clinical plan goals for PTV and OARs. VMAT-FDVH demonstrated a PTV coverage and homogeneity comparable to those of VMAT-EXP. Compared to VMAT-EXP plans, VMAT-FDVH plans resulted in a significant reduction in the mean ipsilateral lung dose, with an average decrease of 0.9Gy (8.5Gy vs. 7.6Gy, P < 0.001). The V5Gy and V20Gy of the ipsilateral lung were also reduced by 3.2% and 1.8%, respectively. Minor differences were observed in the heart, contralateral lung, breast, and liver. Personalized objectives derived from the feasibility DVH tool facilitated the generation of acceptable VMAT plans. Less experienced planners achieved lower doses to the ipsilateral lung while maintaining adequate target coverage and homogeneity. These findings suggest the potential for the effective use of VMAT in in patients with left-sided breast cancer following breast-conserving surgery, especially when guided by feasibility DVH parameters.

CBCT-based online adaptive radiotherapy of the prostate bed: first clinical experience and comparison to nonadaptive conventional IGRT.

Conventional image-guided radiotherapy (IGRT) of the prostate bed is challenged by the varying anatomy due to dynamic changes of surrounding organs such as the bladder and rectum. This leads to changed dose coverage of target and surrounding tissue. The novel online adaptive radiotherapy (oART) aims to improve target coverage as well as reduce dose exposure to surrounding healthy tissues by daily reoptimization of treatment plans. Here we set out to quantify the resulting changes of this adaptation for patients and treatment team. Atotal of 198 fractions of radiotherapy of the prostate bed (6patients) were treated using oART with the Ethos accelerator (Varian Medical Systems, Palo Alto, CA, USA). For each fraction, volumes and several dose-volume parameters of target volumes and organs at risk were recorded for the scheduled plan (initial plan, recalculated based on daily cone beam computed tomography [CBCT]), the adapted plan, and the verification plan, which is the dose distribution of the applied plan recalculated on the closing CBCT after the adaptation process. Clinical acceptability for all plans was determined using given dose-volume parameters of target volumes. Additionally, the time needed for the adaptation process was registered and compared to the time required for the daily treatment of five conventional IGRT patients. Volumes of target and organs at risk (OAR) exhibited broad variation from day to day. The differences in dose coverage D98% of the clinical target volume (CTV) were significant through adaptation (p < 0.0001; median D98% 97.1-98.0%) and further after verification CBCT (p < 0.001; median D98% 98.1%). Similarly, differences in D98% of the planning target volume (PTV) were significant with adaptation (p < 0.0001; median D98% 91.8-96.5%) and after verification CBCT (p < 0.001; median D98% 96.4%) with decreasing interquartile ranges (IQR). Dose to OAR varied extensively and did not show aconsistent benefit from oART but decreased in IQR. Clinical acceptability increased significantly from 19.2% for scheduled plans to 76.8% for adapted plans and decreased to 70.7% for verification plans. The scheduled plan was never chosen for treatment. The median time needed for oART was 25 min compared to 8 min for IGRT. Target dose coverage was significantly improved using oART. IQR decreased for target coverage as well as OAR doses indicating higher repeatability of dose delivery using oART. Differences in doses after verification CBCT for targets as well as OAR were significant compared to adapted plans but did not offset the overall dosimetric gain of oART. The median time required is three times higher for oART compared to IGRT.

Development of a Tumor Growth-responsive Robust Planning Method for Head and Neck Cancer in Carbon-ion Radiotherapy.

The current study aimed to evaluate a treatment planning method that is robust against tumor growth and to assess its effectiveness in particle therapy for head and neck cancer. The proposed method optimizes dose distribution by replacing the relative stopping power ratio (rSPR) of the clinical target volume (CTV) cavity region with a tumor-equivalent rSPR (Condition 1). The optimized initial treatment plan template was then recalculated using in-room CT images acquired in the same treatment position, and the doses to the tumor and organs at risk were compared with those in the initial treatment plan. We evaluated this method in 10 patients with head and neck cancer treated with carbon ion radiotherapy. To evaluate the effectiveness of the proposed method, we compared it to the initial treatment plan without the replacement (Condition 2). CTV V95% reduction relative to that of the initial treatment plan at the end of treatment was 1.3%±2.9% and 2.6%±3.7% for Condition 1 and Condition 2, respectively, with Condition 1 (Replacement condition) providing better CTV coverage. Subgroup analysis showed a higher change in target coverage in the mucosal melanoma than in the adenoid cystic carcinoma, suggesting that this was influenced by the rate of tumor growth. The proposed treatment planning method, which adjusts for tumor growth by modifying the rSPR in the cavity region, improved robustness in carbon ion radiotherapy for head and neck cancer. Condition 1 (with replacement) achieved better CTV coverage than Condition 2 (without replacement), particularly in fast-growing tumors like mucosal melanoma. This method ensures consistent dose delivery to tumors while maintaining safe doses to organs at risk, offering potential for improved treatment outcomes.

The effect of intra- and inter-fractional motion on target coverage and margins in proton therapy for uveal melanoma

Introduction.This study aims to assess the effective lateral margin requirements for target coverage in ocular proton therapy (OPT), considering the unique challenges posed by eye motion and hypofractionation. It specifically addresses the previously unaccounted-for uncertainty contribution of intra-fractional motion, in conjunction with setup uncertainties, on dosimetric determination of lateral margin requirements.Method.The methodology integrates dose calculations from the in-house developed treatment planning system OCULARIS with measured intra-fractional motion, patient models from EyePlan and Monte Carlo (MC) sampling of setup uncertainties. The study is conducted on 16 uveal melanoma patients previously treated in the OPTIS2 treatment room at the Paul Scherrer Institute (PSI).Result.The retrospective simulation analysis highlights a significant impact of non-systematic factors on lateral margin requirements in OPT. Simulations indicate that reducing the 2.5 mm clinical lateral margin, represented by a 2.1 mm margin in this work, would have resulted in inadequate target coverage for two patients, revealing a greater impact of non-systematic factors on lateral margin requirements.Conclusions.This work characterizes intra-fractional motion in 16 OPT patients and identifies limitations of clinical margin selection protocols for OPT applications. A novel framework was introduced to assess margin sufficiency for target coverage. The findings suggest that prior research underestimated non-systematic factors and overestimated systematic contributions to lateral margin components. This re-evaluation highlights the critical need to prioritize the management of non-systematic uncertainty contributions in OPT.

Effect of breathing phase number on the 4D robust optimization for pancreatic cancer intensity modulated proton therapy

PurposeRespiratory movement, as one of the main challenges in proton therapy for pancreatic cancer patients, could not only lead to harm to normal tissues but also lead to failure of the tumor control, resulting in irreversible consequences. Including respiratory movements into the plan optimization, i.e. 4D robust optimization, may mitigate the interplay effect. However, 4D robust optimization considering images of all breathing phases is time-consuming and less efficient. This work aims to investigate the effect of the breathing phase number on the 4D robust optimization for pancreatic cancer intensity modulated proton therapy (IMPT) by examining plan quality and computational efficiency.MethodsA total of 15 pancreatic cancer patients were retrospectively analyzed. In this study, both anterior-fields and posterior-fields plans were created for each patient. For each plan, six four-dimensional (4D) robust treatment planning strategies with different numbers of respiratory phases and one three-dimensional (3D) treatment plan were created. Optimization of the plans were performed on all ten phases (10phase plan), two extreme phases (2phase plan), two extreme phases plus an intermediate state (3phase plan), two extreme phases plus the 3D CT (3Aphase plan), six phases during the exhalation stage (6Exphase plan), six phases during the inhalation stage (6Inphase plan) and 3D Computed Tomography (CT) scan image (3D plan), respectively. 4D dynamic dose (4DDD) was then calculated to access the interplay effect by considering respiratory motion and dynamic beam delivery. Plan quality and dosimetric parameters for the target and organs at risk (OARs) were then analyzed.ResultsCompared to the 4D plans, 3D plan performed terribly in terms of target coverage and organs at risk. Target dose in anterior-fields plan varied slightly among all six 4D treatment planning strategies. Both the 6Exphase and 6Inphase plans demonstrated performance that was comparable to the 10phase plan in target coverage, outperforming the other five plans for anterior-fields plan. It’s basically the same for the posterior-fields plan. The six strategies showed similar OARs sparing effect for both anterior-fields and posterior-fields plan. Compared with the 10phase plan, the average decline rates of the optimization time of the six plans of 2phase, 3phase, 3Aphase, 6Exphase, 6Inphase, and 3D were 73.26 ± 6.54% vs. 74.48 ± 6.63%, 65.80 ± 7.89% vs. 65.81 ± 9.58%, 54.67 ± 11.52% vs. 65.75 ± 9.58%, 42.14 ± 13.57% vs. 39.63 ± 16.93%, 37.72 ± 11.70% vs. 40.79 ± 13.62% and 75.52 ± 8.21% vs. 80.67 ± 5.62%, respectively (anterior vs. posterior). With the decrease of the number of phases selected for optimization, the decline rates increased, while the other dosimetry parameters generally showed a deterioration trend.ConclusionIn this study, a comprehensive evaluation of six 4D robust treatment planning strategies and one 3D treatment planning strategy for pancreatic cancer patients receiving IMPT was performed. The results showed that six 4D robust optimization strategies were comparable in common posterior field therapy. 2phase and 3phase (including 3Aphase) treatment planning strategies could replace the 10phase treatment planning strategy. It should be noted that patients with large motion amplitudes should receive special attention. The dosimetric performance of the 6Exphase and 6Inphase plans closely aligned with that of the 10phase plan in anterior fields. These plans offered a feasible alternative to 10phase treatment planning strategy by reducing optimization time while maintaining dose coverage of the target and protection of OARs. This research provides guidelines to reduce optimization time and improve clinical efficiency for pancreatic cancer IMPT.

A dosimetric and robustness analysis of proton arc therapy with early energy layer and spot assignment for lung cancer versus conventional intensity modulated proton therapy.

Intensity Modulated Proton Therapy (IMPT) faces challenges in lung cancer treatment, like maintaining plan robustness for moving tumors against setup, range errors, and interplay effects. Proton Arc Therapy (PAT) is an alternative to maintain target coverage, potentially improving organ at risk (OAR) sparing, reducing beam delivery time (BDT), and enhancing patient experience. We aim to perform a systematic plan comparison study between IMPT and energy layer (EL) and spot assignment algorithm - Proton Arc Therapy (ELSA-PAT) to assess its potential for lung cancer treatment. A total of 14 Lung ELSA-PAT plans were compared retrospectively with IMPT plans. 4D worst-case minimax robust optimization was performed, including 84 scenarios (3%, 3 mm). Dosimetry assessment included target (clinical tumor volume [CTV]) and important OARs, on nominal and worst-case scenarios. Most relevant normal tissue complication probabilities (NTCP), target coverage robustness against interplay effect, and BDT were evaluated. CTV D95% and D98% showed no significant difference in comparison. PAT demonstrated better conformality by 66% (p = 0.00012) but delivered a higher heart mean dose (HMD, 23%). There was a 2% increase in NTCP 2-year mortality risk with PAT. Total BDT was comparable among techniques. IMPT was more robust than PAT against interplay effect, considering both D1% (1.0 ± 0.8 Gy vs 1.1 ± 1.4 Gy) and D98% bandwidths (0.9 ± 0.9 Gy vs 1.1 ± 1.3 Gy). Both techniques provide a similar level of dose coverage to the target volume. Although PAT improved dose conformality, higher HMD translated into increased heart toxicity, presumably due to chosen planning methodology and OAR proximity to target. Increased ELs and spots raised PAT BDT, although it could improve daily treatment workflow.

Dosimetric Evaluation of Beam-specific PTV and Worst-case Optimization Methods for Liver Proton Therapy.

In spot-scanning proton therapy, intra-fractional anatomical changes by organ movement can lead to deterioration in dose distribution due to beam range variation. To explore a more robust treatment planning method, this study evaluated the dosimetric characteristics and robustness of two proton therapy planning methods for liver cancer. Two- or three-field treatment plans were created for 11 patients with hepatocellular carcinoma or metastatic liver cancer using a single-field uniform dose (SFUD) technique. The plans were optimized using either beam-specific planning target volume (BSPTV) or worst-case optimization (WCO). The target coverage for the gross tumor volume (GTV), planning target volume (PTV), and organs at risk (OAR) parameters related to toxicity were calculated from the perturbed dose distributions, considering setup and range uncertainties. Statistical analyses of the BSPTV and WCO plans were performed using the Wilcoxon signed-rank sum test (p<0.05). The calculation times for a single optimization process were also recorded and compared. The robustness of the WCO plans in the worst-case scenario was significantly higher than that of the BSPTV plan in terms of GTV target coverage, prevention of maximum dose increase to the gastrointestinal tract, and the dose received by normal liver regions. However, there were no significant differences in PTV, and the calculation time required to create the WCO plan was considerably longer. In SFUD proton therapy for liver cancer, the WCO plans required a longer optimization time but exhibited superior robustness in GTV coverage and sparing of OARs.

Preliminary results of the non-invasive cardiac radioablation for ventricular tachycardia study; an in silico dosimetric comparison of photon vs proton radiotherapy for ventricular arrhythmias

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has been proposed as an alternative treatment for refractory ventricular arrhythmias (VA) in patients who are unsuitable or refractory to standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. Most of the STAR treatments performed so far used photon radiotherapy. As compared to photons, particle therapy with protons, based on its finite penetration depth in tissue, might have the potential to reduce the dose to surrounding healthy tissues thus lowering the risk of side effects. Purpose The purpose of this in silico simulation study was to evaluate the feasibility of STAR with protons in patients with VA and to compare the doses of the organs at risk (OARs) in photon and proton treatment plans. Methods 14 patients (11 males) candidates to standard CA for VA were enrolled. ECG gated CT scans in expiratory breath-hold, and standard electroanatomical mapping were performed in each patients to reconstruct a 3D bipolar voltage map and identify the ablation target. Based on the information obtained by the contouring of the ablation target three treatment plans were simulated: one with photons, and two with protons - with and without cardiac gating- to assess the doses at the OARs. Results The median age was 68.5 (63.25-71.5), all patients had a history of recurrent VA and the indication for treatment with CA. 7 patients had an ischemic cardiomyopathy, 4 an idiopathic cardiomyopathy and 3 ventricular ectopic beats without structural heart disease. The mean left ventricular ejection fraction was 40±11% and 8 out of 14 patients were ICD carriers. Both photons and protons treatment plans reached the goals for target coverage (25 Gy on 98% of the target volume). A statistically significant reduction in the mean maximum dose (Dmax) to some OARs was observed in proton compared to photon plans (see table 1). Specifically, the Dmax delivered to the mitral valve, vena cava, descending aorta, esophagus and to the lungs have been largely reduced with the proton plans. However, in some specific cases, a higher maximum dose was observed for protons in structures close or overlapping with the target, mainly due to the need of an additional margin in the treatment plan to account for proton range uncertainty. The use of cardiac gating did not show a significant dose reduction to OARs compared to the non-gated proton plan. Conclusion The preliminary results of our in silico simulation study suggest that STAR therapy with the use of protons might be associated with a significant dose reduction to the surrounding organs. Nevertheless, the choice of the best treatment should be evaluated on a case by-case strategy since some specific cases may be better suitable for photon treatment.Table 1

Preoperative chemo-CIRT in Re/BRe pancreatic cancer: Insights from a multicenter prospective phase II clinical study (NCT03822936).

There is debate about the optimal management of borderline resectable (bRe) and resectable (Re) pancreatic ductal adenocarcinoma (PDAC). Both preclinical and clinical evidence showed that carbon ion radiotherapy (CIRT) produces superior control on radioresistant histologies compared to conventional photon beam radiotherapy (RT). However, so far there is a lack of data concerning the integration of CIRT in a multimodal approach with chemotherapy and surgery for bRe/Re. We recently presented the first analysis of a multicenter prospective phase II clinical study aimed at assessing the feasibility and effectiveness of a neoadjuvant chemotherapy + short course of CIRT followed by surgery and adjuvant chemotherapy in the management of bRe/Re PDAC. The study was terminated early due to low patient enrollment.Herein, we reported a post-hoc analysis focusing on toxicity, dosimetry and translational assessment. In our experience, CIRT can be integrated into a multimodal treatment strategy for bRe/Re PDAC, alongside chemotherapy and surgery. A case of fatal liver failure occurring three months post-surgery has been documented, likely related to the combination approach. Although the treatment plans were satisfactory according to the Local Effect Model (LEM) model, recalculations using the modified Microdosimetric Kinetic Model (mMKM) revealed suboptimal target coverage. Additionally, we observed an increased expression of PD-L1 following CIRT. This multimodal approach was well tolerated; however, clinicians should carefully monitor for vascular disorders during follow-up and further investigate surgical techniques after CIRT. The increased PD-L1 expression supports the immunogenic effects of particle therapy and lays the groundwork for future studies. To enhance the therapeutic ratio of CIRT treatments, integrating dose-averaged LETd (LETd-based objectives into the plan optimization process should be considered. ClinicalTrials.gov Identifier: NCT03822936.

Dosimetric optimization for dynamic mixed beam arc therapy (DYMBARC).

Non-coplanarity and mixed beam modality could be combined to further enhance dosimetric treatment plan quality. We introduce dynamic mixed beam arc therapy (DYMBARC) as an innovative technique that combines non-coplanar photon and electron arcs, dynamic gantry and collimator rotations, and intensity modulation with photon multileaf collimator (MLC). However, finding favorable beam directions for DYMBARC is challenging due to the large solution space, machine component constraints, and optimization parameters, posing a highly non-convex optimization problem. To establish DYMBARC and solve the pathfinding challenge by employing direct aperture optimization (DAO) to determine the table angles and gantry angle ranges of photon and electron arcs for different clinically motivated cases. The method starts by generating a grid of beam directions based on user-defined resolutions along the gantry and table angle axes for each beam quality considered. Beam directions causing collisions or entering through the end of CT are excluded. For electrons, a fixed source-to-surface distance of 80cm is used to reduce in-air scatter. Electron beam energies with insufficient range to reach the target or beam directions impinging on the table before reaching the patient are excluded. The remaining beam directions form the pathfinding solution space. Promising photon and electron MLC-defined apertures, with associated monitor unit (MU) weights, are iteratively added using a hybrid-DAO algorithm. This algorithm combines column generation to add apertures and simulated annealing to further refine aperture shapes and weights. Apertures are added until the requested number of paths are formed and the user-defined maximum total gantry angle range is reached. Paths are resampled to a finer gantry angle resolution and subject to DAO for simultaneous optimization of beam intensities along the photon/electron arcs. Subsequent final dose calculation and MU weight reoptimization result in a deliverable DYMBARC plan. DYMBARC plans are created for three clinically motivated cases (brain, breast, and pelvis) and compared to DYMBARC variants: colli-DTRT (dynamic collimator trajectory radiotherapy) using non-coplanar photon arcs; and Arc-MBRT (mixed beam radiotherapy) using photons and electrons but restricted to coplanar setup. Additionally, a manually defined volumetric modulated arc therapy (VMAT) setup serves as a reference clinical technique. Dose distributions, dose-volume histograms, and dosimetric endpoints are evaluated. Dosimetric validation with radiochromic film measurements (gamma evaluation, 3% / 2mm (global), 10% dose threshold) is performed on a TrueBeam system in developer mode for one case. While maintaining similar target coverage and homogeneity, DYMBARC reduced mean doses to organs-at-risk compared to VMAT by an average of 3.2, 0.5, and 2.9Gy for the brain, breast, and pelvis cases, respectively. Similar or smaller mean dose reductions were observed for Arc-MBRT or colli-DTRT, compared to VMAT. Electron contributions to the mean planning target volume dose ranged from 2% to 34% for DYMBARC and from 11% to 40% for Arc-MBRT. Measurement validation showed>99.7% gamma passing rate. DYMBARC was successfully established using a dosimetrically optimized pathfinding approach, combining non-coplanarity with mixed beam modality. DYMBARC facilitated the determination of photon and electron contributions on a case-by-case basis, enhancing more personalized treatment modalities.

Proton ARC based LATTICE radiation therapy: feasibility study, energy layer optimization and LET optimization

Objective.LATTICE, a spatially fractionated radiation therapy (SFRT) modality, is a 3D generalization of GRID and delivers highly modulated peak-valley spatial dose distribution to tumor targets, characterized by peak-to-valley dose ratio (PVDR). Proton LATTICE is highly desirable, because of the potential synergy of the benefit from protons compared to photons, and the benefit from LATTICE compared to GRID. Proton LATTICE using standard proton RT via intensity modulated proton therapy (IMPT) (with a few beam angles) can be problematic with poor target dose coverage and high dose spill to organs-at-risk (OAR). This work will develop novel proton LATTICE method via proton ARC (with many beam angles) to overcome these challenges in target coverage and OAR sparing, with optimized delivery efficiency via energy layer optimization and optimized biological dose distribution via linear energy transfer (LET) optimization, to enable the clinical use of proton LATTICE.Approach.ARC based proton LATTICE is formulated and solved with energy layer optimization, during which plan quality and delivery efficiency are jointly optimized. In particular, the number of energy jumps (NEJ) is explicitly modelled and minimized during plan optimization for improving delivery efficiency, while target dose conformality and OAR dose objectives are optimized. The plan deliverability is ensured by considering the minimum-monitor-unit (MMU) constraint, and the plan robustness is accounted for using robust optimization. The biological dose is optimized via LET optimization. The optimization solution algorithm utilizes iterative convex relaxation method to handle the dose-volume constraint and the MMU constraint, with spot-weight optimization subproblems solved by proximal descent method.Main results.ARC based proton LATTCE substantially improved plan quality from IMPT based proton LATTICE, such as (1) improved conformity index (CI) from 0.47 to 0.81 for the valley target dose and from 0.62 to 0.97 for the peak target dose, (2) reduced esophagus dose from 0.68 Gy to 0.44 Gy (a 12% reduction with respect to 2 Gy valley prescription dose) and (3) improved PVDR from 4.15 to 4.28 in the lung case. Moreover, energy layer optimization improved plan delivery efficiency for ARC based proton LATTICE, such as (1) reduced NEJ from 71 to 56 and (2) reduction of energy layer switching time by 65% and plan delivery time by 52% in the lung case. The biological target and OAR dose distributions were further enhanced via LET optimization. On the other hand, proton ARC LATTCE also substantially improved plan quality from VMAT LATTICE, such as (1) improved CI from 0.45 to 0.81 for the valley target dose and from 0.63 to 0.97 for the peak target dose, (2) reduced esophagus dose from 0.59 Gy to 0.38 Gy (a 10.5% reduction with respect to 2 Gy valley prescription dose) and (3) improved PVDR from 3.88 to 4.28 in the lung case.Significance.The feasibility of high-plan-quality proton LATTICE is demonstrated via proton ARC with substantially improved target dose coverage and OAR sparing compared to IMPT, while the plan delivery efficiency for ARC based proton LATTICE can be optimized using energy layer optimization.

Mechanism of Action and Pharmacokinetics of Approved Bispecific Antibodies.

Bispecific antibodies represent a significant advancement in therapeutic antibody engineering, offering the ability to simultaneously target two distinct antigens. This dual-targeting capability enhances therapeutic efficacy, especially in complex diseases, such as cancer and autoimmune disorders, where drug resistance and incomplete target coverage are prevalent challenges. Bispecific antibodies facilitate immune cell engagement and disrupt multiple signaling pathways, providing a more comprehensive treatment approach than traditional monoclonal antibodies. However, the intricate structure of bispecific antibodies introduces unique pharmacokinetic challenges, including issues related to their absorption, distribution, metabolism, and excretion, which can significantly affect their efficacy and safety. This review provides an in-depth analysis of the structural design, mechanisms of action, and pharmacokinetics of the currently approved bispecific antibodies. It also highlights the engineering innovations that have been implemented to overcome these challenges, such as Fc modifications and advanced dimerization techniques, which enhance the stability and half-life of bispecific antibodies. Significant progress has been made in bispecific antibody technology; however, further research is necessary to broaden their clinical applications, enhance their safety profiles, and optimize their incorporation into combination therapies. Continuous advancements in this field are expected to enable bispecific antibodies to provide more precise and effective therapeutic strategies for a range of complex diseases, ultimately improving patient outcomes and advancing precision medicine.

Assessing the robustness of dose distributions in carbon ion prostate radiotherapy using a fast dose evaluation system.

We developed a software program for swiftly calculating dose distributions for carbon ion beams. This study aims to evaluate the accuracy of dose calculations using this software and assess the robustness of dose distribution in treating prostate cancer. At the Osaka Heavy Ion Therapy Center, markers are inserted into the prostate gland and used for position verification. To account for geometric changes along the beam path due to marker translation, a beam-specific planning target volume (bsPTV) is set for each beam. To validate the accuracy of the dose calculations using the developed software, dose distributions for prostate and sarcoma cases were calculated and compared with the treatment planning system. To assess the robustness of the dose distribution, position verification data from 346 cases were utilized to reproduce dose distributions for three matching methods: bone matching, widely adopted in most particle therapy centers; marker translation, which involves direct translation to markers without bone matching; and marker translation after bone matching. The coverage of the target (D99 of clinical target volume (CTV)) was assessed to evaluate the robustness of the dose distribution. Additionally, statistical analyses were conducted for the dose distributions of each matching method. The dose calculation for a single condition can be completed very quickly. Statistical analysis revealed significant differences among dose distributions considering the three matching methods. When irradiation was performed with bone matching only, the D99 was reduced by more than 10% in approximately 7.5% of cases, making it as the poorest among the three matching methods. However, there was no significant reduction in target coverage with the other two methods. We have demonstrated the accuracy of the developed software for rapidly calculating dose distributions for carbon ion beams and confirmed the robustness of the dose distributions based on the bsPTV.