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Purpose: Adaptive antitumor immunity following ablative radiotherapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T-cell (Treg) infiltrates. We hypothesized treatment with ART and a secondary mitochondrial-derived activators of caspase (SMAC) mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity., Experimental Design: To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8 + T cells and TNFα, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30 Gy) with or without anti-CD8, anti-TNFα, or anti-IFNγ antibodies. Tumor-infiltrating OVA-specific CD8 + T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNFα, IFNγ, and IL1β and the immunosuppressive IL10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA., Results: ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8 + cells, TNFα, and IFNγ with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs., Conclusions: Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNFα, IFNγ, and CD8 + T-cell-dependent manner. This provides a novel strategy to enhance the immunogenicity of ART., (©2018 American Association for Cancer Research.)

Simple Summary: Proton beam therapy delivered via pencil beam scanning is an advanced method for treating cancer. Two types of scanning modes are available for this method: discrete spot scanning (DSS) and continuous scanning. Continuous scanning has some advantages over DSS including improved proton beam delivery efficiency and reduced delivery time. However, continuous scanning delivers a dose between consecutive spots, and currently commercially available treatment planning systems do not account for this. Consequently, the continuous scanning delivered dose is inherently different from the planned one, which is discrete spot based. We conducted a proof-of-concept study of the ability of a prediction model to reduce the dose discrepancy between continuous scanning and discrete spot plan. Our findings suggest that selecting planning parameters with the prediction model reduces the dose discrepancy and therefore may permit relaxed dose delivery constraint, which further improves the benefits of continuous scanning. Pencil beam scanning delivered with continuous scanning has several advantages over conventional discrete spot scanning. Such advantages include improved beam delivery efficiency and reduced beam delivery time. However, a move dose is delivered between consecutive spots with continuous scanning, and current treatment planning systems do not take this into account. Therefore, continuous scanning and discrete spot plans have an inherent dose discrepancy. Using the operating parameters of the state-of-the-art particle therapy system, we conducted a proof-of-concept study in which we systematically generated 28 plans for cubic targets with different combinations of plan parameters and simulated the dose discrepancies between continuous scanning and a planned one. A nomograph to guide the selection of plan parameters was developed to reduce the dose discrepancy. The effectiveness of the nomograph was evaluated with two clinical cases (one prostate and one liver). Plans with parameters guided by the nomograph decreased dose discrepancy than those used standard plan parameters. Specifically, the 2%/2 mm gamma passing rate increased from 96.3% to 100% for the prostate case and from 97.8% to 99.7% for the liver case. The CTV DVH root mean square error decreased from 2.2% to 0.2% for the prostate case and from 1.8% to 0.9% for the liver case. The decreased dose discrepancy may allow the relaxing of the delivery constraint for some cases, leading to greater benefits in continuous scanning. Further investigation is warranted. [ABSTRACT FROM AUTHOR]

Flattening filter free (FFF) linear accelerators produce a fluence distribution that is forward peaked. Various dosimetric benefits, such as increased dose rate, reduced leakage and out of field dose has led to the growth of FFF technology in the clinic. The literature has suggested the idea of vendors offering dedicated FFF units where the flattening filter (FF) is removed completely and manipulating the beam to deliver conventional flat radiotherapy treatments. This work aims to develop an effective way to deliver modulated flat beam treatments, rather than utilizing a physical FF. This novel optimization model is an extension of the direct leaf trajectory optimization (DLTO) previously developed for volumetric modulated radiation therapy (VMAT) and is capable of accounting for all machine and multileaf collimator (MLC) dynamic delivery constraints, using a combination of linear constraints and a convex objective function. Furthermore, the tongue and groove (T&G) effect was also incorporated directly into our model without introducing nonlinearity to the constraints, nor nonconvexity to the objective function. The overall beam flatness, machine deliverability, and treatment time efficiency were assessed. Regular square fields, including field sizes of 10 × 10 cm2 to 40 × 40 cm2 were analyzed, as well as three clinical fields, and three arbitrary contours with "concave" features. Quantitative flatness was measured for all modulated FFF fields, and the results were comparable or better than their open FF counterparts, with the majority having a quantitative flatness of less than 3.0%. The modulated FFF beams, due to the included efficiency constraint, were able to achieve acceptable delivery time compared to their open FF counterpart. The results indicated that the dose uniformity and flatness for the modulated FFF beams optimized with the DLTO model can successfully match the uniformity and flatness of their conventional FF counterparts, and may even provide further benefit by taking advantage of the unique FFF beam characteristics. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide. Current treatment options, even though potentially curative, have many limitations including a high rate of complications. Over the past few years immune checkpoint inhibitors (ICI) targeting cytotoxic lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have changed treatment paradigms in many malignancies and are currently under investigation in HNSCC as well. Despite improvements in treatment outcomes and the implementation of combined modality approaches long-term survival rates in patients with locally advanced HNSCC remain suboptimal. Accumulating evidence suggests that under certain conditions, radiation may be delivered in conjunction with ICI to augment efficacy. In this review, we will discuss the immune modulating mechanisms of ICI and radiation, how changing the dose, fractionation, and field of radiation may alter the tumor microenvironment (TME), and how these two treatment modalities may work in concert to generate durable treatment responses against HNSCC. [ABSTRACT FROM AUTHOR]

Purpose To propose a universal, parameterized gradient-based method (PGM) for radiation field size determination. Methods The PGM locates the beam profile's edge by parameterizing its penumbra region with a modified sigmoid function where the inflection point can be determined in a closed form. The parametrization was validated with filter-flattened (FF), flattening-filter-free (FFF) and wedged profiles measured on two Elekta linac models (Synergy and Versa HD). Gamma analysis with the delta dose function set to zero was used to quantitatively assess the parameterization accuracy. Field sizes of FF beams were calculated with the PGM and the full width at half maximum (FWHM) methods for comparison. To assess the consistency of the PGM and the FWHM method with geometric scaling across different depths, the calculated field size at a reference depth was scaled to other depths and compared with the field sizes calculated from the measured profiles. The method was also validated against a maximum-slope method (MSM) with wedge and FFF profiles. We also evaluated the robustness of the three methods with respect to measurement noise, varying scanning step sizes, detector characteristics, and beam energy/modality. Results Small distance-to-agreement (0.02 ± 0.02 mm) between the measured and parameterized penumbra region was observed for all profiles. The differences between the field sizes calculated with the FWHM method and the PGM were consistent (0.9 ± 0.3 mm), with the FWHM method yielding larger values. With geometrical scaling, the PGM and the FWHM method produced maximum differences of 0.26 and 1.16 mm, respectively. For wedge and FFF beams, the mean differences relative to FF fields were 0.15 ± 0.09 mm and 0.57 ± 0.91 mm for the PGM and the MSM, respectively. The PGM was also found to produce more consistent results than the FWHM method and the MSM when measurement noise, scanning step size, detector characteristics, and beam energy/modality changed. Conclusion The proposed PGM is universally applicable to all beam modalities (FF, wedge and FFF) for accurate field size determination. Compared to the FWHM and the MSM, it is more robust to variations in measurement condition and detection system. [ABSTRACT FROM AUTHOR]

Purpose: In radiation therapy, accurate data acquisition of photon beam dosimetric quantities is important for (1) beam modeling data input into a treatment planning system (TPS), (2) comparing measured and TPS modeled data, (3) the quality assurance process of a linear accelerator's (Linac) beam characteristics, (4) the establishment of a standard data set for comparison with other data, etcetera. Parameterization of the photon beam dosimetry creates a data set that is portable and easy to implement for different applications such as those previously mentioned. The aim of this study is to develop methods to parameterize photon beam dosimetric quantities, including percentage depth doses (PDDs), profiles, and total scatter output factors (Scp). Methods: Scp, PDDs, and profiles for different field sizes, depths, and energies were measured for a Linac using a cylindrical 3D water scanning system. All data were smoothed for the analysis and profile data were also centered, symmetrized, and geometrically scaled. The Scp data were analyzed using an exponential function. The inverse square factor was removed from the PDD data before modeling and the data were subsequently analyzed using exponential functions. For profile modeling, one halfside of the profile was divided into three regions described by exponential, sigmoid, and Gaussian equations. All of the analytical functions are field size, energy, depth, and, in the case of profiles, scan direction specific. The model's parameters were determined using the minimal amount of measured data necessary. The model's accuracy was evaluated via the calculation of absolute differences between the measured (processed) and calculated data in low gradient regions and distance-to-agreement analysis in high gradient regions. Finally, the results of dosimetric quantities obtained by the fitted models for a different machine were also assessed. Results: All of the differences in the PDDs' buildup and the profiles' penumbra regions were less than 2 and 0.5 mm, respectively. The differences in the low gradient regions were 0.20% ± 0.20% (<1% for all) and 0.50% ± 0.35% (<1% for all) for PDDs and profiles, respectively. For Scp data, all of the absolute differences were less than 0.5%. Conclusions: This novel analytical model with minimum measurement requirements was proved to accurately calculate PDDs, profiles, and Scp for different field sizes, depths, and energies. [ABSTRACT FROM AUTHOR]

Purpose: The use of sophisticated dose calculation procedure in modern radiation therapy treatment planning is inevitable in order to account for complex treatment fields created by multileaf collimators (MLCs). As a consequence, independent volumetric dose verification is time consuming, which affects the efficiency of clinical workflow. In this study, the authors present an efficient adaptive beamlet-based finite-size pencil beam (AB-FSPB) dose calculation algorithm that minimizes the computational procedure while preserving the accuracy. Methods: The computational time of finite-size pencil beam (FSPB) algorithm is proportional to the number of infinitesimal and identical beamlets that constitute an arbitrary field shape. In AB-FSPB, dose distribution from each beamlet is mathematically modeled such that the sizes of beamlets to represent an arbitrary field shape no longer need to be infinitesimal nor identical. As a result, it is possible to represent an arbitrary field shape with combinations of different sized and minimal number of beamlets. In addition, the authors included the model parameters to consider MLC for its rounded edge and transmission. Results: Root mean square error (RMSE) between treatment planning system and conventional FSPB on a 10 × 10 cm² square field using 10 × 10, 2.5 × 2.5, and 0.5 × 0.5 cm² beamlet sizes were 4.90%, 3.19%, and 2.87%, respectively, compared with RMSE of 1.10%, 1.11%, and 1.14% for AB-FSPB. This finding holds true for a larger square field size of 25 × 25 cm², where RMSE for 25 × 25, 2.5 × 2.5, and 0.5 × 0.5 cm² beamlet sizes were 5.41%, 4.76%, and 3.54% in FSPB, respectively, compared with RMSE of 0.86%, 0.83%, and 0.88% for AB-FSPB. It was found that AB-FSPB could successfully account for the MLC transmissions without major discrepancy. The algorithm was also graphical processing unit (GPU) compatible to maximize its computational speed. For an intensity modulated radiation therapy (~12 segments) and a volumetric modulated arc therapy fields (~90 control points) with a 3D grid size of 2.0 × 2.0 × 2.0 mm³, dose was computed within 3-5 and 10-15 s timeframe, respectively. Conclusions: The authors have developed an efficient adaptive beamlet-based pencil beam dose calculation algorithm. The fast computation nature along with GPU compatibility has shown better performance than conventional FSPB. This enables the implementation of AB-FSPB in the clinical environment for independent volumetric dose verification. [ABSTRACT FROM AUTHOR]

Purpose: Recent knowledge on the effects of cardiac toxicity warrants greater precision for left-sided breast radiotherapy. Different breath-hold (BH) maneuvers (abdominal vs thoracic breathing) can lead to chest wall positional variations, even though the patient's tidal volume remains consistent. This study aims to investigate the feasibility of using optical tracking for real-time quality control of active breathing coordinator (ABC)-assisted deep inspiration BH (DIBH). Methods: An in-house optical tracking system (OTS) was used to monitor ABC-assisted DIBH. The stability and localization accuracy of the OTS were assessed with a ball-bearing phantom. Seven patients with left-sided breast cancer were included. A free-breathing (FB) computed tomography (CT) scan and an ABC-assisted BH CT scan were acquired for each patient. The OTS tracked an infrared (IR) marker affixed over the patient's xiphoid process to measure the positional variation of each individual BH. Using the BH within which the CT scan was performed as the reference, the authors quantified intra- and interfraction BH variations for each patient. To estimate the dosimetric impact of BH variations, the authors studied the positional correlation between the marker and the left breast using the FB CT and BH CT scans. The positional variations of 860 BHs as measured by the OTS were retrospectively incorporated into the original treatment plans to evaluate their dosimetric impact on breast and cardiac organs [heart and left anterior descending (LAD) artery]. Results: The stability and localization accuracy of the OTS was within 0.2 mm along each direction. The mean intrafraction variation among treatment BHs was less than 2.8 mm in all directions. Up to 12.6 mm anteroposterior undershoot, where the patient's chest wall displacement of a BH is less than that of a reference BH, was observed with averages of 4.4, 3.6, and 0.1 mm in the anteroposterior, craniocaudal, and mediolateral directions, respectively. A high positional correlation between the marker and the breast was found in the anteroposterior and craniocaudal directions with respective Pearson correlation values of 0.95 and 0.93, but no mediolateral correlation was found. Dosimetric impact of BH variations on breast coverage was negligible. However, the mean heart dose, mean LAD dose, and max LAD dose were estimated to increase from 1.4/7.4/18.6 Gy (planned) to 2.1/15.7/31.0 Gy (delivered), respectively. Conclusions: In ABC-assisted DIBH, large positional variation can occur in some patients, due to their different BH maneuvers. The authors' study has shown that OTS can be a valuable tool for real-time quality control of ABC-assisted DIBH. [ABSTRACT FROM AUTHOR]

Purpose: To propose a simple model to explain the origin of ghost markers in marker-based optical tracking systems (OTS) and to develop retrospective strategies to detect and eliminate ghost markers. Methods: In marker-based OTS, ghost markers are virtual markers created due to the cross-talk between the two camera sensors, which can lead to system execution failure or inaccuracy in patient tracking. As a result, the users have to limit the number of markers and avoid certain marker configurations to reduce the chances of ghost markers. In this work, the authors propose retrospective strategies to detect and eliminate ghost markers. The two camera sensors were treated as mathematical points in space. The authors identified the coplanar within limit (CWL) condition as the necessary condition for ghost marker occurrence. A simple ghost marker detection method was proposed based on the model. Ghost marker elimination was achieved through pattern matching: a ghost marker-free reference set was matched with the optical marker set observed by the OTS; unmatched optical markers were eliminated as either ghost markers or misplaced markers. The pattern matching problem was formulated as a constraint satisfaction problem (using pairwise distances as constraints) and solved with an iterative backtracking algorithm. Wildcard markers were introduced to address missing or misplaced markers. An experiment was designed to measure the sensor positions and the limit for the CWL condition. The ghost marker detection and elimination algorithms were verified with samples collected from a five-marker jig and a nine-marker anthropomorphic phantom, rotated with the treatment couch from -60° to +60°. The accuracy of the pattern matching algorithm was further validated with marker patterns from 40 patients who underwent stereotactic body radiotherapy (SBRT). For this purpose, a synthetic optical marker pattern was created for each patient by introducing ghost markers, marker position uncertainties, and marker displacement. Results: The sensor positions and the limit for the CWL condition were measured with excellent reproducibility (standard deviation ≤ 0.39 mm). The ghost marker detection algorithm had perfect detection accuracy for both the jig (1544 samples) and the anthropomorphic phantom (2045 samples). Pattern matching was successful for all samples from both phantoms as well as the 40 patient marker patterns. Conclusions: The authors proposed a simple model to explain the origin of ghost markers and identified the CWL condition as the necessary condition for ghost marker occurrence. The retrospective ghost marker detection and elimination algorithms guarantee complete ghost marker elimination while providing the users with maximum flexibility in selecting the number of markers and their configuration to meet their clinic needs. [ABSTRACT FROM AUTHOR]

Understanding the mutations that confer radiation resistance is crucial to developing mechanisms to subvert this resistance. Here we describe the creation of a radiation resistant cell line and characterization of a novel p53 mutation. Treatment with 20 Gy radiation was used to induce mutations in the H460 lung cancer cell line; radiation resistance was confirmed by clonogenic assay. Limited sequencing was performed on the resistant cells created and compared to the parent cell line, leading to the identification of a novel mutation (del) at the end of the DNA binding domain of p53. Levels of p53, phospho-p53, p21, total caspase 3 and cleaved caspase 3 in radiation resistant cells and the radiation susceptible (parent) line were compared, all of which were found to be similar. These patterns held true after analysis of p53 overexpression in H460 cells; however, H1299 cells transfected with mutant p53 did not express p21, whereas those given WT p53 produced a significant amount, as expected. A luciferase assay demonstrated the inability of mutant p53 to bind its consensus elements. An MTS assay using H460 and H1299 cells transfected with WT or mutant p53 showed that the novel mutation did not improve cell survival. In summary, functional characterization of a radiation-induced p53 mutation in the H460 lung cancer cell line does not implicate it in the development of radiation resistance. [ABSTRACT FROM AUTHOR]

Purpose: In this work, the authors propose a novel registration strategy for translation-only correction scenarios of lung stereotactic body radiation therapy setups, which can achieve optimal dose coverage for tumors as well as preserve the consistency of registrations with minimal human interference. Methods: The proposed solution (centroid-to-centroidor CTC solution) uses the average four-dimensional CT (A4DCT) as the reference CT. The cone-beam CT (CBCT) is deformed to acquire a new centroid for the internal target volume (ITV) on the CBCT. The registration is then accomplished by simply aligning the centroids of the ITVs between the A4DCT and the CBCT. Sixty-seven cases using 64 patients (each case is associated with separate isocenters) have been investigated with the CTC method and compared with the conventional gray-value (G) mode and bone (B) mode registration methods. Dosimetric effects among the tree methods were demonstrated by 18 selected cases. The uncertainty of the CTC method has also been studied. Results: The registration results demonstrate the superiority of the CTC method over the other two methods. The differences in the D99 and D95 ITV dose coverage between the CTC method and the original plan is small (within 5%) for all of the selected cases except for one for which the tumor presented significant growth during the period between the CT scan and the treatment. Meanwhile, the dose coverage differences between the original plan and the registration results using either the B or G method are significant, as tumor positions varied dramatically, relative to the rib cage, from their positions on the original CT. The largest differences between the D99 and D95 dose coverage of the ITV using the B or G method versus the original plan are as high as 50%. The D20 differences between any of the methods versus the original plan are all less than 2%. Conclusions: The CTC method can generate optimal dose coverage to tumors with much better consistency compared with either the G or B method, and it is especially useful when the tumor position varies greatly from its position on the original CT, relative to the rib cage. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this work is to investigate the impact of small rotational errors on the magnitudes and distributions of spatial dose variations for intracranial stereotactic radiotherapy (SRT) treatment setups, and to assess the feasibility of using the original dose map overlaid with rotated contours (ODMORC) method as a fast, online evaluation tool to estimate dose changes (using DVHs) to clinical target volumes (CTVs) and organs-at-risks (OARs) caused by small rotational setup errors. Methods: Fifteen intracranial SRT cases treated with either three-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) techniques were chosen for the study. Selected cases have a variety of anatomical dimensions and pathologies. Angles of ±3° and ±5° in all directions were selected to simulate the rotational errors. Dose variations in different regions of the brain, CTVs, and OARs were evaluated to illustrate the various spatial effects of dose differences before and after rotations. DVHs accounting for rotations that were recomputed by the treatment planning system (TPS) and those generated by the ODMORC method were compared. A framework of a fast algorithm for multicontour rotation implemented by ODMORC is introduced as well. Results: The average values of relative dose variations between original dose and recomputed dose accounting for rotations were greater than 4.0% and 10.0% in absolute mean and in standard deviation, respectively, at the skull and adjacent regions for all cases. They were less than 1.0% and 2.5% in absolute mean and in standard deviation, respectively, for dose points 3 mm away from the skull. The results indicated that spatial dose to any part of the brain organs or tumors separated from the skull or head surface would be relatively stable before and after rotations. Statistical data of CTVs and OARs indicate the lens and cochleas have the large dose variations before and after rotations, whereas the remaining ROIs have insignificant dose differences. DVH comparisons suggest that the ODMORC method is able to estimate the DVH of CTVs fairly accurately (within 1.5% of relative dose differences for evaluation volumes). The results also show that most of the OARs including the brain stem, spinal cord, chiasm, hippocampuses, optic nerves, and retinas, which were relatively distal from the skull and surface, had good agreement (within 2.0% of relative dose differences for 0.1 cc of the volumes ) between the ODMORC method and the recomputation, whereas OARs more proximate to the bone-tissue interface or surface, such as the lenses and cochlea, had larger dose variations (greater than 5.0%) for some cases due to the incapability of the ODMORC to account for scatter contribution variations proximate to interfaces and intrinsic dose calculation uncertainties for ROIs with small volumes. Conclusions: The ODMORC method can be implemented as an online evaluation system for rotation-induced dose changes of CTVs and most OARs and for other related dose consequence analyses. [ABSTRACT FROM AUTHOR]

: PurposeRecent studies have demonstrated radiosensitization by inhibiting receptor tyrosine kinases (RTKs). Irradiation activates RTKs and their downstream prosurvival molecule, Akt. In this study, we investigated the mechanism by which SU6668, an inhibitor of RTKs involved in angiogenic pathways, enhances effects of irradiation.: Methods and materialsWestern blots were used to determine Akt phosphorylation. Clonogenic assays were performed to determine endothelial survival after combination of SU6668 and irradiation. This combination therapy was also tested in mouse models with Lewis lung carcinoma or glioblastoma multiforme (GL261) for inhibition of tumor growth and tumor vasculature by examining tumor volume, tumor vascular window, and blood flow.: ResultsWe found that SU6668 inhibited the Akt activation inducible by irradiation. Clonogenic survival of endothelial cells was decreased after the combined therapy compared with radiotherapy alone. In vivo studies demonstrated reduction of tumor vasculature and blood flow. In addition, 21 Gy in 7 fractions given concurrently with SU6668 resulted in tumor growth delay compared to either treatment alone.: ConclusionThese data suggest that the combination therapy was more effective in destroying tumor vasculature than either treatment alone. SU6668 augments tumor-suppressive effects of radiotherapy in Lewis lung carcinoma and GL261 xenographs, possibly through reducing the survival of tumor endothelium. [Copyright &y& Elsevier]

Background Purpose Methods Results Conclusions Intensity Modulated Proton Therapy (IMPT) is a sophisticated radiation treatment allowing for precise dose distributions. However, conventional spot selection strategies in IMPT face challenges, particularly with minimum monitor unit (MU) constraints, affecting planning quality and efficiency.This study introduces an innovative Two‐Stage Mixed Integer Linear Programming (MILP) method to optimize spot intensity in IMPT with Lower Bound (LB) constraints. This method seeks to improve treatment planning efficiency and precision, overcoming limitations of existing strategies.Our approach evaluates prevalent IMPT spot selection strategies, identifying their limitations, especially concerning MU constraints. We integrated LB constraints into a MILP framework, using a novel three‐phase strategy for spot pool selection, to enhance performance over traditional heuristic methods and L1 + L∞ strategies. The method's efficacy was tested in eight study cases, using Dose‐Volume Histograms (DVHs), spot selection efficiency, and computation time analysis for benchmarking against established methods.The proposed method showed superior performance in DVH quality, adhering to LB constraints while maintaining high‐quality treatment plans. It outperformed existing techniques in spot selection, reducing unnecessary spots and balancing precision with efficiency. Cases studies confirmed the method's effectiveness in producing clinically feasible plans with enhanced dose distributions and reduced hotspots, especially in cases with elevated LB constraints.Our Two‐Stage MILP strategy signifies a significant advancement in IMPT treatment planning. By incorporating LB constraints directly into the optimization process, it achieves superior plan quality and deliverability compared to current methods. This approach is particularly advantageous in clinical settings requiring minimum spot number and high MU LB constraints, offering the potential for improved patient outcomes through more precise and efficient radiation therapy plans. [ABSTRACT FROM AUTHOR]

Background. Unresectable stage III non-small cell lung cancer (NSCLC) has a 5-year survival rate of 20%, and concurrent chemoradiotherapy results in significant toxicity with the use of current chemotherapeutic agents. nab-Paclitaxel was approved by the U.S. Food and Drug Administration in October 2012 for use along with carboplatin in advanced NSCLC. This study was undertaken to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of weekly nab-paclitaxel given in combination with carboplatin and concurrent radiotherapy in patients with unresectable stage III NSCLC. Methods. Escalating doses of once-weekly nab-paclitaxel were given along with once-weekly carboplatin area under the plasma concentration time curve (AUC) of 2 and concurrent radiotherapy 66 Gy in 33 fractions, followed by 2 cycles of carboplatin and nab-paclitaxel consolidation chemotherapy. Results. Eleven patients were enrolled and received treatment per protocol, with 10 evaluable for efficacy and toxicity. At dose level 1 (nab-paclitaxel 60 mg/m²), 2 DLTs were observed: esoph-agitis and radiation dermatitis. Six patients were enrolled at dose level 0 (nab-paclitaxel 40 mg/m2) with no DLTs. Nine of 10 evaluable patients had a partial response. Conclusion. Concurrent chemoradiotherapy with nab-paclitaxel 40 mg/m² and carboplatin AUC 2 is a safe and well-tolerated therapeutic regimen in patients with stage III NSCLC. A separate phase I/II study to evaluate the efficacy of this regimen is under way. [ABSTRACT FROM AUTHOR]

Abstract: We are developing a Monte-Carlo based method for spectral stripping of a low-voltage X-ray detector spectrum for calibrating and performing quality assurance with orthovoltage (X-ray) radiation therapy systems. The technique involves a tungsten-based X-ray generator with limited energy spectral information of at the most two half value layers of shielding available from the manufacturer. The goal is to generate a complete energy spectrum of the source from a measured detector spectrum, by correcting for radiation losses and misplaced counts due to Compton scattering and the photoelectric effect. In this work, energy spectra were measured at generator voltages of 150–300kVp with HPGe and Si detectors, with several optional shielding configurations. The source to detector geometry were modeled in MCNP, and the reaction rates and spatial locations of Compton scattering and photoelectric events in the detectors have been investigated as a function of source energy to gain information on where interactions occur for the given beam collimation and geometry. Photon leakage and energy flux out of the detector were also simulated, and initial spectral stripping has been performed on the HPGe and Si detector spectra. [Copyright &y& Elsevier]

Purpose: Ablative hypofractionated radiation therapy (AHFRT) presents a therapeutic advantage compared with conventional fractionated radiation therapy (CFRT) for primary and oligometastatic cancers. However, the underlying mechanisms remain largely unknown. In the present study, we compared the immune alterations in response to AHFRT versus CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT.Methods and Materials: We established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biologically equivalent dose.Results: Compared with CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not immunocompromised, mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8+ T cells. Through the downregulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGF receptor signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented with greater efficacy in controlling tumor growth and improving mouse survival. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field.Conclusions: Targeting MDSC recruitment and enhancing antitumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT was more potent for cancer treatment. [ABSTRACT FROM AUTHOR]

Purpose: To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer.Methods and Materials: A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOG protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry.Results: The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules.Conclusions: It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics. [ABSTRACT FROM AUTHOR]

Summary: We report our initial experience with deep-inspiration breath-hold (DIBH) cone-beam CT (CBCT) on the treatment table, using the kilovoltage imager integrated into our linear accelerator, for setting up patients for DIBH stereotactic body radiation therapy (SBRT) for lung tumors. Nine patients with non-small cell lung cancer (seven stage I), were given 60Gy in three fractions. All nine patients could perform a DIBH for 35s. For each patient we used a diagnostic reference CT volume image acquired during a DIBH to design an SBRT plan consisting of 7–10 noncoplanar conformal beams. Four patients were setup by registering DIBH kilovoltage projection radiographs or megavoltage portal images on the treatment table to digitally reconstructed radiographs from the reference CT. Each of the last 14 fractions out of a total of 27 was setup by acquiring a CBCT volume image on the treatment table in three breath-holds. The CBCT and reference CT volume images were directly registered and the shift was calculated from the registration. The CBCT volume images contained excellent detail on soft tissue and bony anatomy for matching to the reference CT. Most importantly, the tumor was always clearly visible in the CBCT images, even when it was difficult or impossible to see in the radiographs or portal images. The accuracy of the CBCT method was confirmed by DIBH megavoltage portal imaging and each treatment beam was delivered during a DIBH. CBCT acquisition typically required five more minutes than radiograph acquisition but the overall setup time was often shorter using CBCT because repeat imaging was minimized. We conclude that for setting up SBRT treatments of lung tumors, DIBH CBCT is feasible, fast and may result in less variation among observers than using bony anatomy in orthogonal radiographs. [Copyright &y& Elsevier]

Purpose: Clusterin plays important roles in cell survival and death. Inactivation of clusterin enhances the therapeutic efficacy of chemotherapy in lung cancer models. The purpose of this study was to determine whether inhibition of clusterin by an antisense-based investigative drug enhances radiation sensitization in a lung cancer model. Methods and Materials: Cells were transfected with an antisense oligonucleotide (ASO) against clusterin (OGX-011). Apoptosis was determined by 7-aminoactinomycin D staining. Cell survival was examined by 3-(4, 5-methylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) and clonogenic assay. Xenograft model was used to demonstrate tumor growth and tumor blood flow. Results: OGX-011 specifically attenuated the expression of secreted clusterin (prosurvival), with no apparent effect on the expression of nuclear clusterin (proapoptotic). Apoptosis was significantly increased when H460 lung cancer cells were treated with OGX-011 plus radiation. Inhibition of clusterin followed by radiation greatly decreased cell survival. H460 xenografts that were treated with OGX-011 plus radiotherapy demonstrated growth delay beyond 17 days. Doppler studies showed that tumor blood flow was compromised when mice bearing H460 xenografts were treated with OGX-011 and radiation. Conclusion: A combination of radiotherapy and OGX-011 improved control of tumor growth and vascular regression in the H460 lung cancer model. [Copyright &y& Elsevier]

The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non–small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment. [ABSTRACT FROM AUTHOR]