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Aim: To evaluate acute toxicity at 6 months after stereotactic body radiotherapy (SBRT) in patients with oligometastatic cancer within the OligoCare cohort., Material and Methods: OligoCare is a prospective, registry-based, single-arm, observational study that aims to report prospective real-world data of patients with oligometastases from solid cancer treated with SBRT (NCT03818503). Primary tumor included non-small cell lung cancer (NSCLC), breast cancer (BC), colorectal cancer (CRC), and prostate cancer (PC). This analysis addresses a secondary endpoint of the trial, acute toxicity within 6 months after SBRT., Results: Out of 1,597registered patients, 1'468 patients were evaluated for acute toxicity. Globally, 290 (20 %) had NSCLC primary disease, 227 (16 %) had BC, 293 (20 %) had CRC, and 658 (45 %) had PC. Concomitant systemic treatment was administered in 527 (35.9 %) patients. According to the EORTC/ESTRO oligometastatic disease (OMD) classification, 828 (56 %) patients had de novo OMD, 464 (32 %) repeat OMD, and 176 (12 %) induced OMD. Acute grade ≥ 3 SBRT related adverse events were reported in 8 (0.5 %) patients, including 2 (0.1 %) fatal AEs. In particular, 6 (0.4 %) grade 3 events were: 1 empyema, 1 pneumonia, 1 radiation pneumonitis, 1 radiation skin injury, 1 decreased appetite, and 1 bone pain. Among those 2 occurred in NSCLC patients, 2 in BC patients, and 1 in CRC and PC patients each. The two (0.1 %) grade 5 toxicity were represented by: pneumonitis and cerebral hemorrhage., Conclusion: OligoCare is the largest prospective registry cohort on oligometastatic disease. Acute toxicity within 6 months was low, confirming the safety of SBRT in the treatment of oligometastases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neo-adjuvant chemoradiotherapy (CRT) and perioperative chemotherapy are different strategies for treating non-metastatic esophageal cancer (EC). The advantages of neo-adjuvant therapies are primarily seen in patients who achieve a pathologic complete response (pCR) and therefore show higher survival rates and better prognosis. In general, less than one-third of patients with EC experience pCR after neo-adjuvant therapies; however, patients with esophageal adenocarcinoma (AC) demonstrate lower rates of pCR compared to those with esophageal squamous cell carcinoma (SCC), respectively. Herein, we describe two cases of locally advanced esophageal AC treated with cone-beam computed tomography (CBCT)-based online adaptive radiotherapy (ART) on the ETHOS platform. Both patients received CRT with 50.4 Gy in 28 fractions, combined with weekly carboplatin and paclitaxel. For each fraction, we evaluated scheduled and adapted plans using dose-volume histogram (DVH) data, and patients were treated with the superior plan. We prioritized ensuring optimal coverage of the planning target volume (PTV) over limiting the dose to organs at risk (OARs) when selecting the superior treatment plan. In this instance, we present the translation of superior dosimetric data into clinical benefits, as evidenced by an excellent pathologic response., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: We have planned a prospective trial as an investigator-initiated study with Varian. This study will include patients with esophageal cancer who are treated with online adaptive radiotherapy. In this submission, we report on two cases that are not related to the planned prospective trial., (Copyright © 2024, Bachmann et al.)

Background: The purpose of this randomised study was to determine whether dose-intensified stereotactic body radiotherapy (SBRT) for painful vertebral metastases results in increased rates of pain improvement compared with conventional external beam radiotherapy (cEBRT) (control) 6 months after treatment., Methods: This randomized, controlled phase 3 trial was conducted between November 2016 and January 2023, when it was stopped early. Patients were eligible if they were aged 18 years or older; had one or two painful, stable, or potentially unstable vertebral metastases; and had a life expectancy of 1 year or longer according to the investigator's estimates. Patients received 48.5 grays (Gy) in 10 fractions (with epidural involvement) or 40 Gy in five fractions (without epidural involvement) in the SBRT group and 30 Gy in 10 fractions or 20 Gy in five fractions in the cEBRT group, respectively. The primary end point was an improvement in the pain score at the treated site by at least 2 points (on a visual analog scale from 0 to 10 points) at 6-month follow-up. Data were analyzed on an intention-to-treat and per-protocol basis., Results: Of 214 patients who were screened for eligibility, 63 were randomized 1:1 between SBRT (33 patients with 36 metastases) and cEBRT (30 patients with 31 metastases). The median age of all patients was 66 years, and 40 patients were men (63.5%). In the intention-to-treat analysis, the 6-month proportion of patients who had metastases with pain reduction by 2 or more points was significantly higher in the SBRT group versus the control group (69.4% vs. 41.9%, respectively; two-sided p = .02). Changes in opioid medication intake relative to baseline were nonsignificant between the groups. No differences were observed in vertebral compression fracture or adverse event rates between the groups., Conclusions: Dose-intensified SBRT improved pain score more effectively than cEBRT at 6 months., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background and Introduction: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation., Materials and Methods: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/β of 10 Gy for all primaries, and cancer-specific α/β of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC)., Results: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions., Conclusion: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BAJF received grants from Accuray, AIRC, IBA and Fondazione IEO-CCM, lecture payments/honoraria from Bayer, Accuray, Astellas, IBA, IPSEN, Astra Zeneca, Tecnologie Avanzate, Recordati, and Novartis, and has board appointments at Astra Zeneca, Bayer, and Seagen. MG and PO are PIs of the ESTRO-EORTC 1811-E²-RADIatE OligoCare trial. MG is president-elect of ESTRO., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the impact of metastases-directed stereotactic body radiotherapy (SBRT) on health-related quality of life (HRQoL) in men with oligometastatic prostate cancer (PCa) using real-world data from the OligoCare cohort., Materials and Methods: OligoCare is a pragmatic, observational cohort designed to assess the impact of metastases-directed SBRT on patients with oligometastatic disease (OMD). We report an interim analyses of the secondary endpoint HRQoL, assessed using the EORTC QLQ-C30, within six months of metastases-directed SBRT for oligometastatic disease in men with PCa among the first 1600 registered patients. HRQoL data collection was optional within the OligoCare cohort. To compare HRQoL between baseline and first follow-up assessment, a Wilcoxon signed-rank test was used. A multiple linear regression model was used to explore the HRQoL associations with predefined factors., Results: Out of the 1600 registered patients, 658 were treated for oligometastatic PCa, of which 233 had baseline QoL data and 132 patients had both baseline and follow-up HRQoL data. At baseline, most patients had a WHO performance status of 0 or 1 (87 %), were de-novo oligometastatic (79 %), had one metastasis (90 %), and had a good overall global health status (mean 80.81, SD16.11, IQR 75-92). 51 % received hormonal therapy as concomitant systemic treatment. Patients with comorbidities as assessed by the Charlson Comorbidity index had a worse global health status at baseline (-4.88, 95 % CI:-9.35, -0.42). No clinically meaningful significant difference in global health status was observed at first assessment following SBRT (median 3.0 months) compared with baseline (mean difference 2.27, 95 % CI:-1.54, 6.08). Upon evaluating the proportions, meaningful clinically important differences (a 10-point or more difference) was observed in, 17 % and 11 % of the patients reporting deterioration and improvement of global health status, respectively., Conclusion: Metastases-directed stereotactic body radiotherapy had no negative impact on global HRQoL within the first six months after treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. -Matthias Guckenberger and Piet Ost are PIs of the ESTRO-EORTC 1811-E2-RADIatE OligoCare trial.-Matthias Guckenberger is president-elect of ESTRO.-Mieke Van Hemelrijck is board member of the EORTC.-Piet Ost reports a relationship with Janssen, Advanced Accelerator Applications, Curium, Bayer and MSD that includes: consulting or advisory. Piet Ost reports a relationship with Bayer and Varian that includes: funding grants, (© 2023 The Author(s).)

Glioblastoma is a highly heterogeneous primary malignant brain tumor with marked inter-/intratumoral diversity and a poor prognosis. It may contain a population of neural stem cells (NSC) and glioblastoma stem cells that have the capacity for migration, self-renewal and differentiation. While both may contribute to resistance to therapy, NSCs may also play a role in brain tissue repair. The subventricular zone (SVZ) is the main reservoir of NSCs. This study investigated the impact of bilateral SVZ radiation doses on patient outcomes. We included 147 patients. SVZs were delineated and the dose administered was extracted from dose-volume histograms. Tumors were classified based on their spatial relationship to the SVZ. The dose and outcome correlations were analyzed using the Kaplan-Meier and Cox proportional hazards regression methods. Median progression-free survival (PFS) was 7 months (range: 4-11 months) and median overall survival (OS) was 14 months (range: 9-23 months). Patients with an ipsilateral SVZ who received ≥50 Gy showed significantly better PFS (8 versus 6 months; p < 0.001) and OS (16 versus 11 months; p < 0.001). Furthermore, lower doses (<32 Gy) to the contralateral SVZ were associated with improved PFS (8 versus 6 months; p = 0.030) and OS (15 versus 11 months; p = 0.001). Targeting the potential tumorigenic cells in the ipsilateral SVZ while sparing contralateral NSCs correlated with an improved outcome. Further studies should address the optimization of dose distribution with modern radiotherapy techniques for the areas surrounding infiltrated and healthy SVZs.

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and fractionation. Results of this systematic review and consensus process compile the best available evidence for safe combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or oligometastatic cancer and aim to guide today's clinical practice and the design of future clinical trials., Competing Interests: Declaration of interests FA declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Varian, Elekta, Brainlabs, outside of this Policy Review. CBe declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis. CBe also declares support for attending meetings and travel from Pfizer and Eli Lilly, unrelated to this Policy Review. CBi declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from SPCC congress, unrelated to this Policy Review. BdB declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Debiopharma, Ipsen, and Astellas; support for attending meetings and travel from Debiopharma and Micropos medical; and leadership or fiduciary role in the board, society, committee, or advocacy group of ESTRO, SAKK, and SASRO, unrelated to this Policy Review. BAJ-F declares grants or contracts from Italian Association for Cancer Research, FIEO-CCM and FUV, Accuray, and IBA Dosimetry; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Bayer, Roche, Astellas, Ipsen, and Accuray; and participation on a data safety monitoring board or advisory board for Bayer, unrelated to this Policy Review. XG declares a grant from Varian paid to their institution; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Congress Care and Sanofi; and a leadership or fiduciary role in the board, society, committee, or advocacy group for RIZIV–INAMI and FANC–AFCN. YL declares grants or contracts from ImmunoSABR, EU Project, and HERO–VBHC; consulting fees paid to the institution by AstraZeneca; and a leadership or fiduciary role in the board, society, committee, or advocacy group of ESTRO, Belgian College of Oncology, and EORTC–ESTRO Radiation Infrastructure for Europe project, unrelated to this Policy Review. PO declares grants or contracts from Varian and Bayer; consulting fees from Bayer, AAA, Curium, Janssen, Telix, MSD, and Ferring; and support for attending meetings and travel from Ferring, unrelated to this Policy Review. SP declares personal fees from Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational event from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Sereno, Roche, Takeda, and Pfizer; payment for expert testimony from Roche and Merck Sereno; support for attending meetings and travel from Janssen and Roche; participation on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, and Seattle Genetics; and leadership or fiduciary role in the board, society, committee, or advocacy group of British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP–IBCSG Partners Foundation Board, unrelated to this Policy Review. SR declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD Italia, Genetec, and Istituto Gentili Amgen; and participation on a data safety monitoring board or advisory board for Roche and AstraZeneca, unrelated to this Policy Review. UR declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Elekta and Accuray, unrelated to this Policy Review. MS declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Roche, and Merck; participation on a data safety monitoring board or advisory board for Janssen, Ipsen, and Merck; and a leadership or fiduciary role in the board, society, committee, or advocacy group for ESMO, unrelated to this Policy Review. TZ declares grants or contracts from Varian Medical Systems and Debiopharm; consulting fees from Janssen and Astellas; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Astellas, Debiopharm, Bayer, and Ferring; support for attending meetings and travel from Debiopharm; and participation on a data safety monitoring board or advisory board for SAKK scientific board and GFRU, unrelated to this Policy Review. All other authors report no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Purpose: To assess the feasibility of postoperative stereotactic body radiation therapy (SBRT) for patients with hybrid implants consisting of carbon fiber reinforced polyetheretherketone and titanium (CFP-T) using CyberKnife., Materials and Methods: All essential steps within a radiation therapy (RT) workflow were evaluated. First, the contouring process of target volumes and organs at risk (OAR) was done for patients with CFP-T implants. Second, after RT-planning, the accuracy of the calculated dose distributions was tested in a slab phantom and an anthropomorphic phantom using film dosimetry. As a third step, the accuracy of the mandatory image guided radiation therapy (IGRT) including automatic matching was assessed using the anthropomorphic phantom. For this goal, a standard quality assurance (QA) test was modified to carry out its IGRT part in presence of CFP-T implants., Results: Using CFP-T implants, target volumes could precisely delineated. There was no need for compromising the contours to overcome artifact obstacles. Differences between measured and calculated dose values were below 11% for the slab phantom, and at least 95% of the voxels were within 5% dose difference. The comparisons for the anthropomorphic phantom showed a gamma-passing rate (5%, 1 mm) of at least 97%. Additionally the test results with and without CFP-T implants were comparable. No issues concerning the IGRT were detected. The modified machine QA test resulted in a targeting error of 0.71 mm, which corresponds to the results of the unmodified standard tests., Conclusion: Dose calculation and delivery of postoperative spine SBRT is feasible in proximity of CFP-T implants using a CyberKnife system., (© 2022. The Author(s).)

Background: The use of stereotactic body radiation therapy (SBRT) for tumor and pain control in patients with bone metastases is increasing. We report response assessment after bone SBRT using radiological changes through time and clinical examination of patients., Methods: We analyzed retrospectively oligo-metastatic/progressive patients with bony lesions treated with SBRT between 12/2008 and 10/2018, without in-field re-irradiation, in our institution. Radiological data were obtained from imaging modalities used for SBRT planning and follow-up purposes in picture archiving and communication system and assessed by two independent radiologists blind to the time of treatment. Several radiological changes were described. Radiographic response assessment was classified according to University of Texas MD Anderson Cancer Center criteria. Pain response and the neurological deficit were captured before and at least 6 months after SBRT., Results: A total of 35 of the 74 reviewed patients were eligible, presenting 43 bone metastases, with 51.2% (n = 22) located in the vertebral column. Median age at the time of SBRT was 66 years (range 38-84) and 77.1% (n = 27) were male. Histology was mainly prostate (51.4%, n = 18) and breast cancer (14.3%, n = 5). Median total radiation dose delivered was 24 Gy (range 24-42), in three fractions (range 2-7), prescribed to 70-90% isodose-line. After a median follow-up of 1.8 years (range < 1-8.2) for survivors, complete or partial response, stable, and progressive disease occurred in 0%, 11.4% (n = 4), 68.6% (n = 24), and 20.0% (n = 7) of the patients, respectively. Twenty patients (57.1%) died during the follow-up time, all from disease progression, yet 70% (n = 14) from this population with local stable disease after SBRT. From patients who were symptomatic and available for follow-up, almost half (44.4%) reported pain reduction after SBRT., Conclusions: Eighty percent of the patients showed local control after SBRT for bone metastases. Pain response was favorable. For more accurate response assessment, comparing current imaging modalities with advanced imaging techniques such as functional MRI and PET/CT, in a prospective and standardized way is warranted. Trial registration Retrospectively registered., (© 2022. The Author(s).)

Introduction: Chemokines and their cognate receptors play a major role in modulating inflammatory responses. Depending on their ligand binding, chemokine receptors can stimulate both immune activating and inhibitory signaling pathways. The CC chemokine receptor 5 (CCR5) promotes immune responses by recruiting immune cells to the sites of inflammation/tumor, and is involved in stimulating tumor cell proliferation, invasion and migration through various mechanisms. Moreover, CCR5 also contributes to an immune-suppressive tumor microenvironment by recruiting regulatory T cells and myeloid-derived suppressor cells facilitating tumor development and progression. In summary, cells expressing CCR5 modulate immune response and tumor progression. Expression of CCR5 is increased in various malignancies and associated with poor outcome. Experimental data show promising efficacy signals with CCR5 antagonists in preclinical tumor models. Therefore, CCR5 has been recognized as a potential therapeutic target for cancer., Areas Covered: In this review, we focus on the role of CCR5 in cancer progression and discuss its impact and potential as a therapeutic target for cancer., Expert Opinion: Beyond immune-checkpoint inhibitors, potentially synergistic immune-modulatory drugs such as CCR5 antagonists are a promising approach to enlarge our treatment armamentarium against cancer.

Background: In order to locate an arteriovenous malformation, typically, a digital subtraction angiography (DSA) is carried out. To use the DSA for target definition an accurate image registration between CT and DSA is required. Carrying out a non-invasive, frameless procedure, registration of the 2D-DSA images with the CT is critical. A new software prototype is enabling this frameless procedure. The aim of this work was to evaluate the prototype in terms of targeting accuracy and reliability based on phantom measurements as well as with the aid of patient data. In addition, the user's ability to recognize registration mismatches and quality was assessed., Methods: Targeting accuracy was measured with a simple cubic, as well as with an anthropomorphic head phantom. Clearly defined academic targets within the phantoms were contoured on the CT. These reference structures were compared with the structures generated within the prototype. A similar approach was used with patient data, where the clinically contoured target served as the reference structure. An important error source decreasing the target accuracy comes from registration errors between CT and 2D-DSA. For that reason, the tools in BC provided to the user to check these registrations are very important. In order to check if the user is able to recognize registration errors, a set of different registration errors was introduced to the correctly registered CT and 2D-DSA image data sets of three different patients. Each of six different users rated the whole set of registrations within the prototype., Results: The target accuracy of the prototype was found to be below 0.04 cm for the cubic phantom and below 0.05 cm for the anthropomorphic head phantom. The mean target accuracy for the 15 patient cases was found to be below 0.3 cm. In the registration verification part, almost all introduced registration errors above 1° or 0.1 cm were detected by the six users. Nevertheless, in order to quantify and categorize the possibility to detect mismatches in the registration process more data needs to be evaluated., Conclusion: Our study shows, that the prototype is a useful tool that has the potential to fill the gap towards a frameless procedure when treating AVMs with the aid of 2D-DSA images in radiosurgery. The target accuracy of the prototype is similar to other systems already established in clinical routine.

Purpose: Although volumetric modulated arc therapy (VMAT) is a well-accepted treatment technique in radiotherapy using a coplanar delivery approach, VMAT might be further improved by including dynamic table and collimator rotations leading to dynamic trajectory radiotherapy (DTRT). In this work, an optimization procedure for DTRT was developed and the potential benefit of DTRT was investigated for different treatment sites., Methods: For this purpose, a dedicated optimization framework for DTRT was developed using the Eclipse Scripting Research Application Programming Interface (ESRAPI). The contours of the target and organs at risk (OARs) structures were exported by applying the ESRAPI and were used to determine the fractional volume-overlap of the OARs with the target from several potential beam directions. Thereby, an additional weighting was applied taking into account the relative position of the OAR with respect to the target and radiation beam, that is, penalizing directions where the OAR is proximal to the target. The resulting two-dimensional gantry-table map was used as input for an A* path finding algorithm returning an optimized gantry-table path. Thereby, the process is also taking into account CT scan length and collision restrictions. The A* algorithm was used again to determine the dynamic collimator angle path by optimizing the area between the MLC leaves and the target contour for each gantry-table path leading to gantry-collimator paths. The resulting gantry-table and gantry-collimator paths are combined and serve as input for the intensity modulation optimization using a research VMAT optimizer and the ESRAPI resulting in dynamic trajectories. This procedure was evaluated for five clinically motivated cases: two head and neck, one lung, one esophagus, and one prostate. Final dose calculations were performed using the Swiss Monte Carlo Plan (SMCP). Resulting dose distributions for the DTRT treatment plans and for the standard VMAT plans were compared based on dose distributions and dose volume histogram (DVH) parameters. For this comparison, the dose distribution for the VMAT plans were recalculated using the SMCP. In addition, the suitability of the delivery of a DTRT treatment plan was demonstrated by means of gafchromic film measurements on a TrueBeam linear accelerator., Results: DVHs for the target volumes showed similar or improved coverage and dose homogeneity for DTRT compared with VMAT using equal or less number of dynamic trajectories for DTRT than arcs for VMAT for all cases studied. Depending on the case, improvements in mean and maximum dose for the DTRT plans were achieved for almost all OARs compared with the VMAT plans. Improvements in DTRT treatment plans for mean and maximum dose compared to VMAT plans were up to 16% and 38% relative to the prescribed dose, respectively. The measured and calculated dose values resulted in a passing rate of more than 99.5% for the two-dimensional gamma analysis using 2% and 2 mm criteria and a threshold of 10%., Conclusions: DTRT plans for different treatment sites were generated and compared with VMAT plans. The delivery is suitable and dose comparisons demonstrate a high potential of DTRT to reduce dose to OARs using less dynamic trajectories than arcs, while target coverage is preserved., (© 2018 American Association of Physicists in Medicine.)

Background and Purpose: This study investigated whether tumor perfusion, FDG uptake and their correlation depend on tumor stage, site and HPV in head and neck cancer., Material and Methods: 41/55 eligible patients with integrated FDG-PET/perfusion CT from 2 prospective studies were assessed. A GTV(CT) and GTV(PET) were created. Perfusion maps were calculated using singular value decomposition method. Blood volume (BV), blood flow (BF), mean transit time (MTT) and standardized uptake value (SUV) in the tumor were compared to the surrounding tissue using Wilcoxon test and Spearman correlation of perfusion and SUVmean in the tumor was studied (p=0.05)., Results: Perfusion parameters were significantly increased in the GTV(CT) of advanced tumors in comparison to the surrounding soft tissue (p<0.01). Oral cavity and oropharyngeal cancer showed a higher BF than laryngeal cancer (p<0.04). No correlation between perfusion and SUVmean was found, however SUVmean correlated significantly with BF for the HPV-positive tumors (r=0.86, p=0.04) and with BV for the oropharyngeal cancer (r=0.63, p=0.05)., Conclusion: Tumor stage, site and HPV are associated with different perfusion or combined perfusion/SUV signatures. Further studies are needed to investigate if these signatures co-determine clinical outcome., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing protein 2 (NOD-2), have been shown to contribute to the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to analyze the expression, regulation, and function of the PRR NOD-1 in RA synovial fibroblasts (RASFs), and to examine its interaction with other PRRs., Methods: Expression of NOD-1 was analyzed by immunohistochemistry in synovial tissue from RA patients, psoriatic arthritis patients, gout patients, and osteoarthritis (OA) patients. RASFs and human monocyte-derived macrophages (HMDMs) were stimulated with L-alanyl-γ-D-glutamyl-meso-diaminopimelic acid, palmitoyl-3-cysteine-serine-lysine-4, poly(I-C), lipopolysaccharide, heat-inactivated bacteria, tumor necrosis factor α (TNFα), or interleukin-1β (IL-1β). Expression levels of IL-6, CCL5, matrix metalloproteinases (MMPs), NODs, and TLRs were measured by real-time reverse transcription-polymerase chain reaction and/or enzyme-linked immunosorbent assay. NOD-1 and NOD-2 were silenced with target-specific small interfering RNA. Phosphorylation of IL-1 receptor-associated kinase 1 (IRAK-1) was measured by Western blotting., Results: Expression of NOD-1 protein was significantly increased in RA synovium compared to OA synovium. The basal expression of NOD-1 was similar in RASFs, OASFs, healthy control peripheral blood mononuclear cells, and healthy control HMDMs. Stimulation of RASFs with TLR-3 up-regulated the expression of NOD-1. Expression of IL-6, CCL5, MMPs, TLR-2, and NOD-2 was significantly up-regulated in RASFs by stimulation with the NOD-1 ligand. A synergistic effect on IL-6 production was observed in cells stimulated with NOD-1 and TLR-2 ligands or NOD-1 and TLR-4 ligands. Silencing of NOD-1, but not NOD-2, decreased the levels of IL-6 in RASFs after stimulation with TLR-2 and IL-1β, and blocked the phosphorylation of IRAK-1., Conclusion: NOD-1 is strongly expressed in different cell types in the synovial tissue of patients with RA. These results indicate that NOD-1, either alone or interacting with other inflammatory mediators, can play an important role in the chronic and destructive inflammation of the joints in RA., (Copyright © 2012 by the American College of Rheumatology.)

The aggressive phenotype of RA synovial fibroblasts (RASF) is characterised by the increased expression of matrix metalloproteinase (MMP)-1 as well as the small ubiquitin like modifier (SUMO)-1 and decreased expression of SUMO-specific protease SENP1. Since we showed an increased activity of acetyltransferases in this autoimmune disease, we wanted to analyze whether this affects the expression of MMP-1 and can be reversed by the reconstitution of SENP1. In RASF, the acetylation of histone H4 was significantly increased in the distal region of the MMP-1 promoter by 274 +/- 36% compared to OASF. Most interestingly, overexpression of SENP1 in RASF decreased acetylation specifically in this region by 51 +/- 0.5% and globally by 73 +/- 11%. Furthermore, the overexpression of SENP1 resulted in a downregulation of MMP-1 at both the mRNA (58 +/- 7%) and protein levels (28 +/- 6%), significantly reduced the invasiveness of RASF (from 34 +/- 9% to 2 +/- 2%) and led to an accumulation of histone deacetylase 4 (HDAC4) on the MMP-1 promoter (197 +/- 36%). Interestingly, SENP1 failed to modulate the expression of MMP-1 in the cells silenced for HDAC4. This is the first study linking the SUMOylation pathway and the production of MMP-1 to an epigenetic control mechanism mediated through histone acetylation which has a functional consequence for the invasiveness of RASF.

Objective: Since fibroblasts in the synovium of patients with rheumatoid arthritis (RA) express the serine proteases fibroblast activation protein (FAP) and dipeptidylpeptidase 4 (DPP-4)/CD26, we undertook the current study to determine the functional role of both enzymes in the invasion of RA synovial fibroblasts (RASFs) into articular cartilage., Methods: Expression of FAP and DPP-4/CD26 by RASFs was analyzed using fluorescence-activated cell sorting and immunocytochemistry. Serine protease activity was measured by cleavage of fluorogenic substrates and inhibited upon treatment with L-glutamyl L-boroproline. The induction and expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in RASFs were detected using real-time polymerase chain reaction. Densitometric measurements of MMPs using immunoblotting confirmed our findings on the messenger RNA level. Stromal cell-derived factor 1 (SDF-1 [CXCL12]), MMP-1, and MMP-3 protein levels were measured using enzyme-linked immunosorbent assay. The impact of FAP and DPP-4/CD26 inhibition on the invasiveness of RASFs was analyzed in the SCID mouse coimplantation model of RA using immunohistochemistry., Results: Inhibition of serine protease activity of FAP and DPP-4/CD26 in vitro led to increased levels of SDF-1 in concert with MMP-1 and MMP-3, which are downstream effectors of SDF-1 signaling. Using the SCID mouse coimplantation model, inhibition of enzymatic activity in vivo significantly promoted invasion of xenotransplanted RASFs into cotransplanted human cartilage. Zones of cartilage resorption were infiltrated by FAP-expressing RASFs and marked by a significantly higher accumulation of MMP-1 and MMP-3, when compared with controls., Conclusion: Our results indicate a central role for the serine protease activity of FAP and DPP-4/CD26 in protecting articular cartilage against invasion by synovial fibroblasts in RA.

Objective: We have recently shown a significant reduction in cytokine-induced transcription of type I collagen and fibronectin in systemic sclerosis (SSc) skin fibroblasts upon treatment with trichostatin A (TSA). Moreover, in a mouse model of fibrosis, TSA prevented the dermal accumulation of extracellular matrix. The purpose of this study was to analyze the silencing of histone deacetylase 7 (HDAC-7) as a possible mechanism by which TSA exerts its antifibrotic function., Methods: Skin fibroblasts from patients with SSc were treated with TSA and/or transforming growth factor beta. Expression of HDACs 1-11, extracellular matrix proteins, connective tissue growth factor (CTGF), and intercellular adhesion molecule 1 (ICAM-1) was analyzed by real-time polymerase chain reaction, Western blotting, and the Sircol collagen assay. HDAC-7 was silenced using small interfering RNA., Results: SSc fibroblasts did not show a specific pattern of expression of HDACs. TSA significantly inhibited the expression of HDAC-7, whereas HDAC-3 was up-regulated. Silencing of HDAC-7 decreased the constitutive and cytokine-induced production of type I and type III collagen, but not fibronectin, as TSA had done. Most interestingly, TSA induced the expression of CTGF and ICAM-1, while silencing of HDAC-7 had no effect on their expression., Conclusion: Silencing of HDAC-7 appears to be not only as effective as TSA, but also a more specific target for the treatment of SSc, because it does not up-regulate the expression of profibrotic molecules such as ICAM-1 and CTGF. This observation may lead to the development of more specific and less toxic targeted therapies for SSc.

Objective: Tissue fibrosis is a hallmark compromising feature of many disorders. In this study, we investigated the antifibrogenic effects of the histone deacetylase inhibitor trichostatin A (TSA) on cytokine-driven fibrotic responses in vitro and in vivo., Methods: Skin fibroblasts from patients with systemic sclerosis (SSc) and normal healthy control subjects were stimulated with profibrotic cytokines in combination with TSA. Human Colalpha1(I) and fibronectin were measured using real-time polymerase chain reaction, and levels of soluble collagen were estimated using the SirCol collagen assay. Electromobility shift assay and confocal fluorescence microscopy were used to investigate the intracellular distribution of Smad transcription factors. For in vivo analysis, skin fibrosis was quantified by histologic assessment of mouse skin tissue in a model of bleomycin-induced fibrosis., Results: Reductions in the cytokine-induced transcription of Colalpha1(I) and fibronectin were observed in both normal and SSc skin fibroblasts following the addition of TSA. Similarly, the expression of total collagen protein in TSA-stimulated SSc skin fibroblasts was reduced to basal levels. The mechanism of action of TSA included inhibition of the nuclear translocation and DNA binding of profibrotic Smad transcription factors. Western blot analysis revealed an up-regulation of the cell cycle inhibitor p21 by TSA, leading to reduced proliferation of fibroblasts. In addition, in bleomycin-induced fibrosis in mice, TSA prevented dermal accumulation of extracellular matrix in vivo., Conclusion: These findings provide novel insights into the epigenetic regulation of fibrosis. TSA and similar inhibitory compounds appear to represent early therapeutic strategies for achieving reversal of the cytokine-driven induction of matrix synthesis that leads to fibrosis.

Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown origin. Histone deacetylase (HDA) activity is considered to play a major role in the transcriptional regulation of proinflammatory genes. We undertook this study to investigate the balance of histone acetylase and HDA activity in synovial tissue from RA patients compared with that from patients with osteoarthritis (OA) and normal controls., Methods: Activity of histone acetylases and HDAs was measured in nuclear extracts of total synovial tissue samples, which were obtained from RA and OA patients undergoing surgical joint replacement, and compared with the activity in synovial tissues from patients without arthritis. Tissue expression of HDAs 1 and 2 was quantified by Western blotting. In addition, immunohistochemistry was performed for HDA-2., Results: Mean+/-SEM HDA activity in synovial tissue samples derived from patients with RA was measured as 1.5+/-0.3 micromoles/microg, whereas the activity levels in OA (3.2+/-0.7 micromoles/microg) and normal (7.1+/-4.2 micromoles/microg) synovial tissue samples were significantly higher. Histone acetylase activity reached similar levels in RA and OA tissues and in normal tissues. The ratio of HDA activity to histone acetylase activity in RA synovial tissue was significantly reduced (12+/-2%) compared with that in OA synovial tissue (26+/-3%). The activity ratio in normal control samples was arbitrarily set at 100+/-40%. In addition, the tissue expression of HDA-1 and HDA-2 proteins was clearly lower in RA samples than in OA samples., Conclusion: The balance of histone acetylase/HDA activities is strongly shifted toward histone hyperacetylation in patients with RA. These results offer novel molecular insights into the pathogenesis of the disease that might be relevant to the development of future therapeutic approaches.