Preclinical prototype validation and characterization of a thermobrachytherapy system for interstitial hyperthermia and high-dose-rate brachytherapy.

Background and purpose: Integrating simultaneous interstitial hyperthermia in high-dose-rate brachytherapy treatments (HDR-BT) is expected to lead to enhanced therapeutic effect. However, there is currently no device available for such an integration. In this study, we presented and validated the thermobrachytherapy (TBT) preclinical prototype system that is able to seamlessly integrate into the HDR-BT workflow. Materials and methods: The TBT system consisted of an advanced radiofrequency power delivery and control system, dual-function interstitial applicators, and integrated connection and impedance matching system. The efficiency and minimum heating ability of the system was calculated performing calorimetric experiments. The effective-heating-length and heating pattern was evaluated using single-applicator split phantom experiments. The heating independence between applicators, the ability of the system to adaptable and predictable temperature steering was evaluated using multi-applicator split phantom experiments. Results: The system satisfied interstitial hyperthermia requirements. It demonstrated 50 % efficiency and ability to reach 6 °C temperature increase in 6 min. Effective-heating-length of the applicator was 43.7 mm, following the initial design. Heating pattern interference between applicators was lower than recommended. The system showed its ability to generate diverse heating patterns by adjusting the phase and amplitude settings of each electrode, aligning well with simulations (minimum agreement of 88 %). Conclusions: The TBT preclinical prototype system complied with IHT requirements, and agreed well with design criteria and simulations, hence performing as expected. The preclinical prototype TBT system can now be scaled to an in-vivo validation prototype, including an adaptable impedance matching solution, appropriate number of channels, and ensuring biocompatibility and regulatory compliance.

Magnetic resonance thermometry for hyperthermia in the oropharynx region.

Magnetic resonance thermometry (MRT) can measure in-vivo 3D-temperature changes in real-time and noninvasively. However, for the oropharynx region and the entire head and neck, motion potentially introduces large artifacts. Considering long treatment times of 60-90 min, this study aims to evaluate whether MRT around the oropharynx is clinically feasible for hyperthermia treatments and quantify the effects of breathing and swallowing on MRT performance. A 3D-ME-FGRE sequence was used in a phantom cooling down and around the oropharynx of five volunteers over ∼75 min. The imaging protocol consisted of imaging with acceleration (ARC = 2), number of image averages (NEX = 1,2 and 3). For volunteers, the acquisitions included a breath-hold scan and scans with deliberate swallowing. MRT performance was quantified in neck muscle, spinal cord and masseter muscle, using mean average error (MAE), mean error (ME) and spatial standard deviation (SD). In phantom, an increase in NEX leads to a significant decrease in SD, but MAE and ME were unchanged. No significant difference was found in volunteers between the different scans. There was a significant difference between the regions evaluated: neck muscle had the best MAE (=1.96 °C) and SD (=0.82 °C), followed by spinal cord (MAE = 3.17 °C, SD = 0.92 °C) and masseter muscle (MAE = 4.53 °C, SD = 1.16 °C). Concerning the ME, spinal cord did best, then neck muscle and masseter muscle, with values of -0.64 °C, 1.15 °C and -3.05 °C respectively. Breathing, swallowing, and different ways of imaging (acceleration and NEX) do not significantly influence the MRT performance in the oropharynx region. The ROI selected however, leads to significant differences.

Utility of carboplatin therapeutic drug monitoring for the treatment of neonate and infant retinoblastoma patients in the United Kingdom.

BACKGROUND: Retinoblastoma is the most common intra-ocular malignancy in children and frequently presents in very young patients who commonly require intravenous carboplatin. Delivering this is challenging due to a lack of uniform dosing recommendations, rapid changes in physiological function and the risk of side-effects. METHODS: We conducted a retrospective review of neonates and infants in the UK with retinoblastoma, who have undergone carboplatin therapeutic drug monitoring (TDM). We report on the pharmacokinetic, treatment efficacy and toxicity data. RESULTS: In total, 29 patients (median age 5 weeks at treatment onset) underwent a total of 74 TDM guided cycles of chemotherapy, involving real time sampling and dose adjustment. An additional 13 patients underwent TDM sampling to modify doses between cycles. Without the adoption of TDM guided dosing, carboplatin exposures would have been ≥20% outside the target AUC in 38/78 (49%) of treatment cycles. Excellent responses and a reassuringly low incidence of toxicities were observed following dose adjustment, despite the young patient age and the implementation of dose increases in the majority of cases. CONCLUSIONS: Real time TDM is safe, effective and deliverable for neonates and infants receiving carboplatin for retinoblastoma and should be considered standard of care up to the age of 6 months.

Adapting Temperature Predictions to MR Imaging in Treatment Position to Improve Simulation-Guided Hyperthermia for Cervical Cancer.

Hyperthermia treatment consists of elevating the temperature of the tumor to increase the effectiveness of radiotherapy and chemotherapy. Hyperthermia treatment planning (HTP) is an important tool to optimize treatment quality using pre-treatment temperature predictions. The accuracy of these predictions depends on modeling uncertainties such as tissue properties and positioning. In this study, we evaluated if HTP accuracy improves when the patient is imaged inside the applicator at the start of treatment. Because perfusion is a major uncertainty source, the importance of accurate treatment position and anatomy was evaluated using different perfusion values. Volunteers were scanned using MR imaging without ("planning setup") and with the MR-compatible hyperthermia device ("treatment setup"). Temperature-based quality indicators were used to assess the differences between the standard, apparent and the optimized hyperthermia dose. We conclude that pre-treatment imaging can improve HTP predictions accuracy but also, that tissue perfusion modelling is crucial if temperature-based optimization is applied.

Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes.

It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID-19), with amplified immune activation in diverse cell types, including cells without angiotensin-converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS-CoV-2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self-organization in the infected host environment. Interestingly, a machine learning analysis to SARS-CoV-2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL-37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS-CoV-2 relative to low-pathogenicity coronaviruses. Moreover, xenoAMPs from SARS-CoV-2 but not low-pathogenicity homologs assemble double-stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll-like receptor (TLR)-3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin's role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID-19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin-6 and CXCL1 levels as observed in COVID-19 patients.

Invasiveness of previous treatment for peripheral arterial disease and risk of adverse cardiac events after coronary stenting.

Patients with peripheral arterial disease (PADs), undergoing percutaneous coronary intervention (PCI), have higher adverse event risks. The effect of invasiveness of PADs treatment on PCI outcome is unknown. This study assessed the impact of the invasiveness of previous PADs treatment (invasive or non-invasive) on event risks after PCI with contemporary drug-eluting stents. This post-hoc analysis pooled 3-year patient-level data of PCI all-comer patients living in the eastern Netherlands, previously treated for PADs. PADs included symptomatic atherosclerotic lesion in the lower or upper extremities; carotid or vertebral arteries; mesenteric arteries or aorta. Invasive PADs treatment comprised endarterectomy, bypass surgery, percutaneous transluminal angioplasty, stenting or amputation; non-invasive treatment consisted of medication and participation in exercise programs. Primary endpoint was (coronary) target vessel failure: composite of cardiac mortality, target vessel-related myocardial infarction, or clinically indicated target vessel revascularization. Of 461 PCI patients with PADs, information on PADs treatment was available in 357 (77.4%) patients; 249 (69.7%) were treated invasively and 108 (30.3%) non-invasively. Baseline and PCI procedural characteristics showed no between-group difference. Invasiveness of PADs treatment was not associated with adverse event risks, including target vessel failure (20.5% vs. 16.0%; HR: 1.30, 95%-CI 0.75-2.26, p = 0.35), major adverse cardiac events (23.3% vs. 20.4%; HR: 1.16, 95%-CI 0.71-1.90, p = 0.55), and all-cause mortality (12.1% vs. 8.3%; HR: 1.48, 95%-CI 0.70-3.13, p = 0.30). In PADs patients participating in PCI trials, we found no significant relation between the invasiveness of previous PADs treatment and 3-year outcome after PCI. Consequently, high-risk PCI patients can be identified by consulting medical records, searching for PADs, irrespective of the invasiveness of PADs treatment.

Magnetic hybrid Pd/Fe-oxide nanoparticles meet the demands for ablative thermo-brachytherapy.

OBJECTIVE: To investigate the potential of hybrid Pd/Fe-oxide magnetic nanoparticles designed for thermo-brachytherapy of breast cancer, considering their specific loss power (SLP) and clinical constraints in the applied magnetic field. METHODS: Hybrid nanoparticles consisting of palladium-core and iron oxide shell of increasing thickness, were suspended in water and their SLPs were measured at varying magnetic fields (12-26 mT peak) and frequencies (50-730 kHz) with a commercial alternating magnetic field generator (magneTherm™ Digital, nanoTherics Ltd.). RESULTS: Validation of the heating device used in this study with commercial HyperMag-C nanoparticles showed a small deviation (±4%) over a period of 1 year, confirming the reliability of the method. The integration of dual thermometers, one in the center and one at the bottom of the sample vial, allowed monitoring of homogeneity of the sample suspensions. SLPs measurements on a series of nanoparticles of increasing sizes showed the highest heating for the diameter of 21 nm (SLP = 225 W/g) at the applied frequencies of 346 and 730 kHz. No heating was observed for the nanoparticles with the size <14 nm, confirming the importance of the size-parameter. The heating ability of the best performing Pd/Fe-oxide-21 was calculated to be sufficient to ablate tumors with a radius ±4 and 12 mm using 10 and 1 mg/mL nanoparticle concentration, respectively. CONCLUSIONS: Nanoparticles consisting of non-magnetic palladium-core and magnetic iron oxide shell are suitable for magnetic hyperthermia/thermal ablation under clinically safe conditions of 346 kHz and 19.1 mT, with minimal eddy current effects in combination with maximum SLP.

NRP1 interacts with endoglin and VEGFR2 to modulate VEGF signaling and endothelial cell sprouting.

Endothelial cells express neuropilin 1 (NRP1), endoglin (ENG) and vascular endothelial growth factor receptor 2 (VEGFR2), which regulate VEGF-A-mediated vascular development and angiogenesis. However, the link between complex formation among these receptors with VEGF-A-induced signaling and biology is yet unclear. Here, we quantify surface receptor interactions by IgG-mediated immobilization of one receptor, and fluorescence recovery after photobleaching (FRAP) measurements of the mobility of another coexpressed receptor. We observe stable ENG/NRP1, ENG/VEGFR2, and NRP1/VEGFR2 complexes, which are enhanced by VEGF-A. ENG augments NRP1/VEGFR2 interactions, suggesting formation of tripartite complexes bridged by ENG. Effects on signaling are measured in murine embryonic endothelial cells expressing (MEEC+/+) or lacking (MEEC-/-) ENG, along with NRP1 and/or ENG overexpression or knockdown. We find that optimal VEGF-A-mediated phosphorylation of VEGFR2 and Erk1/2 requires ENG and NRP1. ENG or NRP1 increase VEGF-A-induced sprouting, becoming optimal in cells expressing all three receptors, and both processes are inhibited by a MEK1/2 inhibitor. We propose a model where the maximal potency of VEGF-A involves a tripartite complex where ENG bridges VEGFR2 and NRP1, providing an attractive therapeutic target for modulation of VEGF-A signaling and biological responses.

Application of the ESHO-QA guidelines for determining the performance of the LCA superficial hyperthermia heating system.

PURPOSE: This study aimed to assess the quality of the lucite cone applicator (LCA), the standard applicator for superficial hyperthermia at the Erasmus MC Cancer Institute, using the most recent quality assurance guidelines, thus verifying their feasibility. MATERIALS AND METHODS: The assessment was conducted on each of the six LCAs available for clinical treatments. The temperature distribution was evaluated using an infrared camera across different layers of a fat-muscle mimicking phantom. The maximum temperature increase, thermal effective penetration depth (TEPD), and thermal effective field size (TEFS) were used as quality metrics. The experimental results were validated through comparison with simulated results, using a canonical phantom model and a realistic phantom model segmented from CT imaging. RESULTS: A maximum temperature increase above 6 °C at 2 cm depth in the fat-muscle phantom for all the experiments was found. A mean negative difference between simulated and experimental data was of 1.3 °C when using the canonical phantom model. This value decreased to a mean negative difference of 0.4 °C when using the realistic model. Simulated and measured TEPD showed good agreement for both in silico scenarios, while discrepancies were present for TEFS. CONCLUSIONS: The LCAs passed all QA guidelines requirements for superficial hyperthermia delivery when used singularly or in an array configuration. A further characterization of parameters such as antenna efficiency and heat transfer coefficients would be beneficial for translating experimental results to simulated values. Implementing the QA guidelines was time-consuming and demanding, requiring careful preparation and correct setup of antenna elements.

Impact of premature coronary artery disease on adverse event risk following first percutaneous coronary intervention.

Objectives: We assessed differences in risk profile and 3-year outcome between patients undergoing percutaneous coronary intervention (PCI) for premature and non-premature coronary artery disease (CAD). Background: The prevalence of CAD increases with age, yet some individuals develop obstructive CAD at younger age. Methods: Among participants in four randomized all-comers PCI trials, without previous coronary revascularization or myocardial infarction (MI), we compared patients with premature (men <50 years; women <55 years) and non-premature CAD. Various clinical endpoints were assessed, including multivariate analyses. Results: Of 6,171 patients, 887 (14.4%) suffered from premature CAD. These patients had fewer risk factors than patients with non-premature CAD, but were more often smokers (60.7% vs. 26.4%) and overweight (76.2% vs. 69.8%). In addition, premature CAD patients presented more often with ST-segment elevation MI and underwent less often treatment of multiple vessels, and calcified or bifurcated lesions. Furthermore, premature CAD patients had a lower all-cause mortality risk (adj.HR: 0.23, 95%-CI: 0.10-0.52; p < 0.001), but target vessel revascularization (adj.HR: 1.63, 95%-CI: 1.18-2.26; p = 0.003) and definite stent thrombosis risks (adj.HR: 2.24, 95%-CI: 1.06-4.72; p = 0.034) were higher. MACE rates showed no statistically significant difference (6.6% vs. 9.4%; adj.HR: 0.86, 95%-CI: 0.65-1.16; p = 0.33). Conclusions: About one out of seven PCI patients was treated for premature CAD. These patients had less complex risk profiles than patients with non-premature CAD; yet, their risk of repeated revascularization and stent thrombosis was higher. As lifetime event risk of patients with premature CAD is known to be particularly high, further efforts should be made to improve modifiable risk factors such as smoking and overweight. TWENTE trials: (TWENTE I, clinicaltrials.gov: NCT01066650), DUTCH PEERS (TWENTE II, NCT01331707), BIO-RESORT (TWENTE III, NCT01674803), and BIONYX (TWENTE IV, NCT02508714).

Assessing the utility of molecular diagnostic classification for cancers of unknown primary.

BACKGROUND: Roughly 5% of metastatic cancers present with uncertain origin, for which molecular classification could influence subsequent management; however, prior studies of molecular diagnostic classifiers have reported mixed results with regard to clinical impact. In this retrospective study, we evaluated the utility of a novel molecular diagnostic classifier by assessing theoretical changes in treatment and additional testing recommendations from oncologists before and after the review of classifier predictions. METHODS: We retrospectively analyzed de-identified records from 289 patients with a consensus diagnosis of cancer of uncertain/unknown primary (CUP). Two (or three, if adjudication was required) independent oncologists separately reviewed patient clinical information to determine the course of treatment before they reviewed results from the molecular diagnostic classifier and subsequently evaluated whether the predicted diagnosis would alter their treatment plan. RESULTS: Results from the molecular diagnostic classifier changed the consensus oncologist-reported treatment recommendations for 235 out of 289 patients (81.3%). At the level of individual oncologist reviews (n = 414), 64.7% (n = 268) of treatment recommendations were based on CUP guidelines prior to review of results from the molecular diagnostic classifier. After seeing classifier results, 98.1% (n = 207) of the reviews, where treatment was specified (n = 211), were guided by the tissue of origin-specific guidelines. Overall, 89.9% of the 414 total reviews either expressed strong agreement (n = 242) or agreement (n = 130) that the molecular diagnostic classifier result increased confidence in selecting the most appropriate treatment regimen. CONCLUSIONS: A retrospective review of CUP cases demonstrates that a novel molecular diagnostic classifier could affect treatment in the majority of patients, supporting its clinical utility. Further studies are needed to prospectively evaluate whether the use of molecular diagnostic classifiers improves clinical outcomes in CUP patients.

First myocardial infarction in patients with premature coronary artery disease: insights into patient characteristics and outcome after treatment with contemporary stents.

AIMS: Patients with premature coronary artery disease (CAD) have a higher incidence of myocardial infarction (MI) than patients with non-premature CAD. The aim of the present study is to asess differences in clinical outcome after a first acute MI, percutaneously treated with new-generation drug-eluting stents between patients with premature and non-premature CAD. METHODS AND RESULTS: We pooled and analysed the characteristics and clinical outcome of all patients with a first MI (and no previous coronary revascularization) at time of enrolment, in four large-scale drug-eluting stent trials. Coronary artery disease was classified premature in men aged <50 and women <55 years. Myocardial infarction patients with premature and non-premature CAD were compared. The main endpoint was major adverse cardiac events (MACE): all-cause mortality, any MI, emergent coronary artery bypass surgery, or clinically indicated target lesion revascularization. Of 3323 patients with a first MI, 582 (17.5%) had premature CAD. These patients had lower risk profiles and underwent less complex interventional procedures than patients with non-premature CAD. At 30-day follow-up, the rates of MACE [hazard ratio (HR): 0.22, 95% confidence interval (CI): 0.07-0.71; P = 0.005), MI (HR: 0.22, 95% CI: 0.05-0.89; P = 0.020), and target vessel failure (HR: 0.30, 95% CI: 0.11-0.82; P = 0.012) were lower in patients with premature CAD. At 1 year, premature CAD was independently associated with lower rates of MACE (adjusted HR: 0.50, 95% CI: 0.26-0.96; P = 0.037) and all-cause mortality (adjusted HR: 0.24, 95% CI: 0.06-0.98; P = 0.046). At 2 years, premature CAD was independently associated with lower mortality (adjusted HR: 0.16, 95% CI: 0.05-0.50; P = 0.002). CONCLUSIONS: First MI patients with premature CAD, treated with contemporary stents, showed lower rates of MACE and all-cause mortality than patients with non-premature CAD, which is most likely related to differences in cardiovascular risk profile. TWENTE trials: TWENTE I, clinicaltrials.gov: NCT01066650), DUTCH PEERS (TWENTE II, NCT01331707), BIO-RESORT (TWENTE III, NCT01674803), and BIONYX (TWENTE IV, NCT02508714).

IgA antibody immunotherapy targeting GD2 is effective in preclinical neuroblastoma models.

BACKGROUND: Immunotherapy targeting GD2 is very effective against high-risk neuroblastoma, though administration of anti-GD2 antibodies induces severe and dose-limiting neuropathic pain by binding GD2-expressing sensory neurons. Previously, the IgG1 ch14.18 (dinutuximab) antibody was reformatted into the IgA1 isotype, which abolishes neuropathic pain and induces efficient neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) via activation of the Fc alpha receptor (FcαRI/CD89). METHODS: To generate an antibody suitable for clinical application, we engineered an IgA molecule (named IgA3.0 ch14.18) with increased stability, mutated glycosylation sites and substituted free (reactive) cysteines. The following mutations were introduced: N45.2G and P124R (CH1 domain), C92S, N120T, I121L and T122S (CH2 domain) and a deletion of the tail piece P131-Y148 (CH3 domain). IgA3.0 ch14.18 was evaluated in binding assays and in ADCC and antibody-dependent cellular phagocytosis (ADCP) assays with human, neuroblastoma patient and non-human primate effector cells. We performed mass spectrometry analysis of N-glycans and evaluated the impact of altered glycosylation in IgA3.0 ch14.18 on antibody half-life by performing pharmacokinetic (PK) studies in mice injected intravenously with 5 mg/kg antibody solution. A dose escalation study was performed to determine in vivo efficacy of IgA3.0 ch14.18 in an intraperitoneal mouse model using 9464D-GD2 neuroblastoma cells as well as in a subcutaneous human xenograft model using IMR32 neuroblastoma cells. Binding assays and PK studies were compared with one-way analysis of variance (ANOVA), ADCC and ADCP assays and in vivo tumor outgrowth with two-way ANOVA followed by Tukey's post-hoc test. RESULTS: ADCC and ADCP assays showed that particularly neutrophils and macrophages from healthy donors, non-human primates and patients with neuroblastoma are able to kill neuroblastoma tumor cells efficiently with IgA3.0 ch14.18. IgA3.0 ch14.18 contains a more favorable glycosylation pattern, corresponding to an increased antibody half-life in mice compared with IgA1 and IgA2. Furthermore, IgA3.0 ch14.18 penetrates neuroblastoma tumors in vivo and halts tumor outgrowth in both 9464D-GD2 and IMR32 long-term tumor models. CONCLUSIONS: IgA3.0 ch14.18 is a promising new therapy for neuroblastoma, showing (1) increased half-life compared to natural IgA antibodies, (2) increased protein stability enabling effortless production and purification, (3) potent CD89-mediated tumor killing in vitro by healthy subjects and patients with neuroblastoma and (4) antitumor efficacy in long-term mouse neuroblastoma models.

Immuno-oncology approaches in uveal melanoma: tebentafusp and beyond.

Uveal melanoma (UM) is the most common ocular malignancy in adults, associated with the poorest prognosis, with metastatic disease occurring in up to 50% of patients. In contrast to metastatic cutaneous melanoma, the use of immune checkpoint inhibitors is associated with poor outcomes in metastatic uveal melanoma (mUM). Tebentafusp, a bispecific molecule, has recently become the first treatment in decades to improve overall survival for mUM. This review summarises the existing and emerging immuno-oncology approaches for the treatment of mUM, and biomarkers of response and resistance to the same. Finally, we propose future research directions that could maximise treatment benefit to a wider pool of patients with UM.

Design and Validation of Experimental Setup for Cell Spheroid Radiofrequency-Induced Heating.

While hyperthermia has been shown to induce a variety of cytotoxic and sensitizing effects on cancer tissues, the thermal dose-effect relationship is still not well quantified, and it is still unclear how it can be optimally combined with other treatment modalities. Additionally, it is speculated that different methods of applying hyperthermia, such as water bath heating or electromagnetic energy, may have an effect on the resulting biological mechanisms involved in cell death or in sensitizing tumor cells to other oncological treatments. In order to further quantify and characterize hyperthermia treatments on a cellular level, in vitro experiments shifted towards the use of 3D cell spheroids. These are in fact considered a more representative model of the cell environment when compared to 2D cell cultures. In order to perform radiofrequency (RF)-induced heating in vitro, we have recently developed a dedicated electromagnetic field applicator. In this study, using this applicator, we designed and validated an experimental setup which can heat 3D cell spheroids in a conical polypropylene vial, thus providing a reliable instrument for investigating hyperthermia effects at the cellular scale.

Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial.

PURPOSE: To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer. METHODS: Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful. RESULTS: For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores. CONCLUSION: Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

Multi-echo gradient echo pulse sequences: which is best for PRFS MR thermometry guided hyperthermia?

PURPOSE: MR thermometry (MRT) enables noninvasive temperature monitoring during hyperthermia treatments. MRT is already clinically applied for hyperthermia treatments in the abdomen and extremities, and devices for the head are under development. In order to optimally exploit MRT in all anatomical regions, the best sequence setup and post-processing must be selected, and the accuracy needs to be demonstrated. METHODS: MRT performance of the traditionally used double-echo gradient-echo sequence (DE-GRE, 2 echoes, 2D) was compared to multi-echo sequences: a 2D fast gradient-echo (ME-FGRE, 11 echoes) and a 3D fast gradient-echo sequence (3D-ME-FGRE, 11 echoes). The different methods were assessed on a 1.5 T MR scanner (GE Healthcare) using a phantom cooling down from 59 °C to 34 °C and unheated brains of 10 volunteers. In-plane motion of volunteers was compensated by rigid body image registration. For the ME sequences, the off-resonance frequency was calculated using a multi-peak fitting tool. To correct for B0 drift, the internal body fat was selected automatically using water/fat density maps. RESULTS: The accuracy of the best performing 3D-ME-FGRE sequence was 0.20 °C in phantom (in the clinical temperature range) and 0.75 °C in volunteers, compared to DE-GRE values of 0.37 °C and 1.96 °C, respectively. CONCLUSION: For hyperthermia applications, where accuracy is more important than resolution or scan-time, the 3D-ME-FGRE sequence is deemed the most promising candidate. Beyond its convincing MRT performance, the ME nature enables automatic selection of internal body fat for B0 drift correction, an important feature for clinical application.

Using MRI to measure position and anatomy changes and assess their impact on the accuracy of hyperthermia treatment planning for cervical cancer.

PURPOSE: We studied the differences between planning and treatment position, their impact on the accuracy of hyperthermia treatment planning (HTP) predictions, and the relevance of including true treatment anatomy and position in HTP based on magnetic resonance (MR) images. MATERIALS AND METHODS: All volunteers were scanned with an MR-compatible hyperthermia device, including a filled waterbolus, to replicate the treatment setup. In the planning setup, the volunteers were scanned without the device to reproduce the imaging in the current HTP. First, we used rigid registration to investigate the patient position displacements between the planning and treatment setup. Second, we performed HTP for the planning anatomy at both positions and the treatment mimicking anatomy to study the effects of positioning and anatomy on the quality of the simulated hyperthermia treatment. Treatment quality was evaluated using SAR-based parameters. RESULTS: We found an average displacement of 2 cm between planning and treatment positions. These displacements caused average absolute differences of ∼12% for TC25 and 10.4%-15.9% in THQ. Furthermore, we found that including the accurate treatment position and anatomy in treatment planning led to an improvement of 2% in TC25 and 4.6%-10.6% in THQ. CONCLUSIONS: This study showed that precise patient position and anatomy are relevant since these affect the accuracy of HTP predictions. The major part of improved accuracy is related to implementing the correct position of the patient in the applicator. Hence, our study shows a clear incentive to accurately match the patient position in HTP with the actual treatment.

Risk of bleeding after percutaneous coronary intervention and its impact on further adverse events in clinical trial participants with comorbid peripheral arterial disease.

BACKGROUND: Both patients with obstructive coronary artery disease (CAD) and patients with peripheral arterial disease (PADs) have an increased bleeding risk. Information is scarce on bleeding in CAD patients, treated with percutaneous coronary intervention (PCI), who have comorbid PADs. We assessed whether PCI patients with PADs have a higher bleeding risk than PCI patients without PADs. Furthermore, in PCI patients with PADs we evaluated the extent by which bleeding increased the risk of further adverse events. METHODS: Three-year pooled patient-level data of two randomized PCI trials (BIO-RESORT, BIONYX) with drug-eluting stents were analyzed to assess mortality and the composite endpoint major adverse cardiac events (MACE: all-cause mortality, any myocardial infarction, emergent coronary artery bypass surgery, or target lesion revascularization). RESULTS: Among 5989 all-comer patients, followed for 3 years, bleeding occurred in 7.7% (34/440) with comorbid PADs and 5.0% (279/5549) without PADs (HR: 1.59, 95%CI: 1.11-2.23, p = 0.010). Of all PADs patients, those with a bleeding had significantly higher rates of all-cause mortality (HR: 4.70, 95%CI: 2.37-9.33, p < 0.001) and MACE (HR: 2.39, 95%CI: 1.23-4.31, p = 0.003). Furthermore, PADs patients with a bleeding were older (74.4 ± 6.9 vs. 67.4 ± 9.5, p < 0.001). After correction for age and other potential confounders, bleeding remained independently associated with all-cause mortality (adj.HR: 2.97, 95%CI: 1.37-6.43, p = 0.006) while the relation of bleeding with MACE became borderline non-significant (adj.HR: 1.85, 95%CI: 0.97-3.55, p = 0.06). CONCLUSION: PCI patients with PADs had a higher bleeding risk than PCI patients without PADs. In PADs patients, bleeding was associated with all-cause mortality, even after adjustment for potential confounders.

Feasibility Study on the Radiation Dose by Radioactive Magnetic Core-Shell Nanoparticles for Open-Source Brachytherapy.

BACKGROUND: Treatment of early-stage breast cancer currently includes surgical removal of the tumor and (partial) breast irradiation of the tumor site performed at fractionated dose. Although highly effective, this treatment is exhaustive for both patient and clinic. In this study, the theoretical potential of an alternative treatment combining thermal ablation with low dose rate (LDR) brachytherapy using radioactive magnetic nanoparticles (RMNPs) containing 103-palladium was researched. METHODS: The radiation dose characteristics and emission spectra of a single RMNP were calculated, and dose distributions of a commercial brachytherapy seed and an RMNP brachytherapy seed were simulated using Geant4 Monte Carlo toolkit. RESULTS: It was found that the RMNP seeds deliver a therapeutic dose similar to currently used commercial seed, while the dose distribution shows a spherical fall off compared to the more inhomogeneous dose distribution of the commercial seed. Changes in shell thickness only changed the dose profile between 2 × 10-4 mm and 3 × 10-4 mm radial distance to the RMNP, not effecting long-range dose. CONCLUSION: The dose distribution of the RMNP seed is comparable with current commercial brachytherapy seeds, while anisotropy of the dose distribution is reduced. Because this reduces the dependency of the dose distribution on the orientation of the seed, their surgical placement is easier. This supports the feasibility of the clinical application of the proposed novel treatment modality.