Polarized fluorescence depletion reports orientation distribution and rotational dynamics of muscle cross-bridges

The method of polarized fluorescence depletion (PFD) has been applied to enhance the resolution of orientational distributions and dynamics obtained from fluorescence polarization (FP) experiments on ordered systems, particularly in muscle fibers. Previous FP data from single fluorescent probes were limited to the 2nd- and 4th-rank order parameters, and , of the probe angular distribution (ß) relative to the fiber axis and , a coefficient describing the extent of rapid probe motions. We applied intense 12-µs polarized photoselection pulses to transiently populate the triplet state of rhodamine probes and measured the polarization of the ground-state depletion using a weak interrogation beam. PFD provides dynamic information describing the extent of motions on the time scale between the fluorescence lifetime (e.g., 4 ns) and the duration of the photoselection pulse and it potentially supplies information about the probe angular distribution corresponding to order parameters above rank 4. Gizzard myosin regulatory light chain (RLC) was labeled with the 6-isomer of iodoacetamidotetramethylrhodamine and exchanged into rabbit psoas muscle fibers. In active contraction, dynamic motions of the RLC on the PFD time scale were intermediate between those observed in relaxation and rigor. The results indicate that previously observed disorder of the light chain region in contraction can be ascribed principally to dynamic motions on the microsecond time scale

High-dose intensity-modulated radiotherapy for prostate cancer using daily fiducial marker-based position verification: acute and late toxicity in 331 patients

We evaluated the acute and late toxicity after high-dose intensity-modulated radiotherapy (IMRT) with fiducial marker-based position verification for prostate cancer. Between 2001 and 2004, 331 patients with prostate cancer received 76 Gy in 35 fractions using IMRT combined with fiducial marker-based position verification. The symptoms before treatment (pre-treatment) and weekly during treatment (acute toxicity) were scored using the Common Toxicity Criteria (CTC). The goal was to score late toxicity according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale with a follow-up time of at least three years. Twenty-two percent of the patients experienced pre-treatment grade ≥ 2 genitourinary (GU) complaints and 2% experienced grade 2 gastrointestinal (GI) complaints. Acute grade 2 GU and GI toxicity occurred in 47% and 30%, respectively. Only 3% of the patients developed acute grade 3 GU and no grade ≥ 3 GI toxicity occurred. After a mean follow-up time of 47 months with a minimum of 31 months for all patients, the incidence of late grade 2 GU and GI toxicity was 21% and 9%, respectively. Grade ≥ 3 GU and GI toxicity rates were 4% and 1%, respectively, including one patient with a rectal fistula and one patient with a severe hemorrhagic cystitis (both grade 4). In conclusion, high-dose intensity-modulated radiotherapy with fiducial marker-based position verification is well tolerated. The low grade ≥ 3 toxicity allows further dose escalation if the same dose constraints for the organs at risk will be used

A multi-institutional analysis of a general pelvis continuous Hounsfield unit synthetic CT software for radiotherapy

Purpose To validate a synthetic computed tomography (sCT) software with continuous HUs and large field-of-view (FOV) coverage for magnetic resonance imaging (MRI)-only workflow of general pelvis anatomy in radiotherapy (RT).Methods An sCT software for general pelvis anatomy (prostate, rectum, and female pelvis) has been developed by Philips Healthcare and includes continuous HUs assignment along with large FOV coverage. General pelvis sCTs were generated using a two-stack T1-weighted mDixon fast-field echo (FFE) sequence with a superior-inferior coverage of 36 cm. Seventy-seven prostate, 43 rectum, and 27 gynecological cases were scanned by three different institutions. mDixon image quality and sCTs were evaluated for soft tissue contrast by using a confidence level scale from 1 to 5 for bladder, prostate/rectum interface, mesorectum, and fiducial maker visibility. Dosimetric comparison was performed by recalculating the RT plans on the sCT after rigid registration. For 12 randomly selected cases, the mean absolute error (MAE) between sCT and CT was calculated to evaluate HU similarity, and the Pearson correlation coefficients (PCC) between the CT- and sCT-generated digitally reconstructed radiographs (DRRs) were obtained for quantitative comparison. To examine geometric accuracy of sCT as a reference for cone beam CT (CBCT), the difference between bone-based alignment of CBCT to CT and CBCT to sCT was obtained for 19 online-acquired CBCTs from three patients.Results Two-stack mDixon scans with large FOV did not show any image inhomogeneity or fat-water swap artifact. Fiducials, Foley catheter, and even rectal spacer were visible as dark signal on the sCT. Average visibility confidence level (average +/- standard deviation) on the sCT was 5.0 +/- 0.0, 4.6 +/- 0.5, 3.8 +/- 0.4, and 4.0 +/- 1.1 for bladder, prostate/rectum interface, mesorectum and fiducial markers. Dosimetric accuracy showed on average < 1% difference with the CT-based plans for target and normal structures. The MAE of bone and soft tissue between the sCT and CT are 120.9 +/- 15.4 HU, 33.4 +/- 4.1 HU, respectively. Average PCC of all evaluated DRR pairs was 0.975. The average offset between CT and sCT as reference was (LR, AP, SI) = (0.19 +/- 0.35, 0.14 +/- 0.60, 0.44 +/- 0.54) mm.Conclusions The continuous HU sCT software-generated realistic sCTs and DRRs to enable MRI-only planning for general pelvis anatomy

Urethral and bladder dose-effect relations for late genitourinary toxicity following external beam radiotherapy for prostate cancer in the FLAME trial

Purpose or objectives: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort. Material and methods: The dose–effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated. Results: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm 3 and urethra D0.1 cm 3, with adjusted odds ratios of 1.14 (95% CI 1.12–1.16, p < 0.0001) and 1.12 (95% CI 1.11–1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed. Conclusion: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer

Single blind randomized Phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial

Background: The treatment results of external beam radiotherapy for intermediate and high risk prostate cancer patients are insufficient with five-year biochemical relapse rates of approximately 35%. Several randomized trials have shown that dose escalation to the entire prostate improves biochemical disease free survival. However, further dose escalation to the whole gland is limited due to an unacceptable high risk of acute and late toxicity. Moreover, local recurrences often originate at the location of the macroscopic tumor, so boosting the radiation dose at the macroscopic tumor within the prostate might increase local control. A reduction of distant metastases and improved survival can be expected by reducing local failure. The aim of this study is to investigate the benefit of an ablative microboost to the macroscopic tumor within the prostate in patients treated with external beam radiotherapy for prostate cancer.Methods/Design: The FLAME-trial (Focal Lesion Ablative Microboost in prostatE cancer) is a single blind randomized controlled phase III trial. We aim to include 566 patients (283 per treatment arm) with intermediate or high risk adenocarcinoma of the prostate who are scheduled for external beam radiotherapy using fiducial markers for position verification. With this number of patients, the expected increase in five-year freedom from biochemical failure rate of 10% can be detected with a power of 80%. Patients allocated to the standard arm receive a dose of 77 Gy in 35 fractions to the entire prostate and patients in the experimental arm receive 77 Gy to the entire prostate and an additional integrated microboost to the macroscopic tumor of 95 Gy in 35 fractions. The secondary outcome measures include treatment-related toxicity, quality of life and disease-specific survival. Furthermore, by localizing the recurrent tumors within the prostate during follow-up and correlating this with the delivered dose, we can obtain accurate dose-effect information for both the macroscopic tumor and subclinical disease in prostate cancer. The rationale, study design and the first 50 patients included are described.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Recommendations for improved reproducibility of ADC derivation on behalf of the Elekta MRI-linac consortium image analysis working group

Background and purpose: The apparent diffusion coefficient (ADC), a potential imaging biomarker for radiotherapy response, needs to be reproducible before translation into clinical use. The aim of this study was to evaluate the multi-centre delineation- and calculation-related ADC variation and give recommendations to minimize it. Materials and methods: Nine centres received identical diffusion-weighted and anatomical magnetic resonance images of different cancerous tumours (adrenal gland, pelvic oligo metastasis, pancreas, and prostate). All centres delineated the gross tumour volume (GTV), clinical target volume (CTV), and viable tumour volume (VTV), and calculated ADCs using both their local calculation methods and each of the following calculation conditions: b-values 0–500 vs. 150–500 s/mm 2, region-of-interest (ROI)-based vs. voxel-based calculation, and mean vs. median. ADC variation was assessed using the mean coefficient of variation across delineations (CV D) and calculation methods (CV C). Absolute ADC differences between calculation conditions were evaluated using Friedman's test. Recommendations for ADC calculation were formulated based on observations and discussions within the Elekta MRI-linac consortium image analysis working group. Results: The median (range) CV D and CV C were 0.06 (0.02–0.32) and 0.17 (0.08–0.26), respectively. The ADC estimates differed 18% between b-value sets and 4% between ROI/voxel-based calculation (p-values < 0.01). No significant difference was observed between mean and median (p = 0.64). Aligning calculation conditions between centres reduced CV C to 0.04 (0.01–0.16). CV D was comparable between ROI types. Conclusion: Overall, calculation methods had a larger impact on ADC reproducibility compared to delineation. Based on the results, significant sources of variation were identified, which should be considered when initiating new studies, in particular multi-centre investigations

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial

INTRODUCTION: Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT. METHODS AND ANALYSIS: The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction. ETHICS AND DISSEMINATION: The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int)

Recommendations for implementing stereotactic radiotherapy in peripheral stage IA non-small cell lung cancer: report from the Quality Assurance Working Party of the randomised phase III ROSEL study

<p>Abstract</p> <p>Background</p> <p>A phase III multi-centre randomised trial (ROSEL) has been initiated to establish the role of stereotactic radiotherapy in patients with operable stage IA lung cancer. Due to rapid changes in radiotherapy technology and evolving techniques for image-guided delivery, guidelines had to be developed in order to ensure uniformity in implementation of stereotactic radiotherapy in this multi-centre study.</p> <p>Methods/Design</p> <p>A Quality Assurance Working Party was formed by radiation oncologists and clinical physicists from both academic as well as non-academic hospitals that had already implemented stereotactic radiotherapy for lung cancer. A literature survey was conducted and consensus meetings were held in which both the knowledge from the literature and clinical experience were pooled. In addition, a planning study was performed in 26 stage I patients, of which 22 were stage 1A, in order to develop and evaluate the planning guidelines. Plans were optimised according to parameters adopted from RTOG trials using both an algorithm with a simple homogeneity correction (Type A) and a more advanced algorithm (Type B). Dose conformity requirements were then formulated based on these results.</p> <p>Conclusion</p> <p>Based on current literature and expert experience, guidelines were formulated for this phase III study of stereotactic radiotherapy versus surgery. These guidelines can serve to facilitate the design of future multi-centre clinical trials of stereotactic radiotherapy in other patient groups and aid a more uniform implementation of this technique outside clinical trials.</p

A computer simulation study of the relation between lipid and probe behaviour in bilayer systems

NRC publication: Ye