Death education interventions for people with advanced diseases and/or their family caregivers: A scoping review.

BACKGROUND: People with life-threatening diseases and their family caregivers confront psychosocial and spiritual issues caused by the persons' impending death. Reviews of death education interventions in the context of life-threatening diseases are scarce and limited to certain intervention types. AIMS: This study aims to ascertain existing evidence on death education interventions for the population of adults with advanced diseases and/or their family caregivers and identify gaps for future research. DESIGN: A scoping review guided by Arksey and O'Malley's framework. DATA SOURCES: Thirteen electronic databases were searched for experimental and qualitative studies on death education interventions for the advanced disease population and/or their family caregivers between 1 January 1960 and 25 October 2023. RESULTS: Nine types of interventions were identified in 47 studies, which included 5 qualitative and 42 experimental designs, half of which were pilot and feasibility trials. Most of the studies focused on people with advanced cancer, and only seven investigated caregivers or families/couples. Death-related outcomes were less likely to be assessed relative to psychological outcomes, spiritual well-being, and quality of life. Life review interventions, cognitive-behavior therapy, narrative therapy, and general psychosocial interventions decreased depression and anxiety, but evidence was limited. Factors contributing to the interventions' success included intervention content, which enabled the disclosure of personal experience and death concerns comfortably, trained professionals, and connection to family caregivers. CONCLUSIONS: This work identified a few potentially effective death education interventions for psychological outcomes for people with advanced cancer or their caregivers. Additional trials are needed to confirm the effectiveness of these interventions.

A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia.

ABSTRACT: FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and, unlike other inhibitors, is minimally vulnerable to resistance induced by FLT3 ligand. We conducted a phase 1 dose escalation study of oral FF-10101 in patients with relapsed and/or refractory AML, the majority of whom harbored FLT3-activating mutations and/or had prior exposure to FLT3 inhibitors. Fifty-four participants enrolled in cohorts receiving doses ranging from 10 to 225 mg per day and 50 to 100 mg twice daily (BID). The dose limiting toxicities were diarrhea and QT prolongation. Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. Overall, 56% of participants had prior exposure to FLT3 inhibitors. The recommended phase 2 dose was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03194685.

Community Engagement in Vaccination Promotion: Systematic Review and Meta-Analysis.

BACKGROUND: Community engagement plays a vital role in global immunization strategies, offering the potential to overcome vaccination hesitancy and enhance vaccination confidence. Although there is significant backing for community engagement in health promotion, the evidence supporting its effectiveness in vaccination promotion is fragmented and of uncertain quality. OBJECTIVE: This review aims to systematically examine the effectiveness of different contents and extent of community engagement for promoting vaccination rates. METHODS: This study was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive and exhaustive literature search was performed in 4 English databases (PubMed, Embase, Web of Science, and Cochrane Library) and 2 Chinese databases (CNKI and Wan Fang) to identify all possible articles. Original research articles applying an experimental study design that investigated the effectiveness of community engagement in vaccination promotion were eligible for inclusion. Two reviewers independently performed the literature search, study selection, quality assessment, and data extraction. Discrepancies were resolved through discussion, with the arbitration of a third reviewer where necessary. RESULTS: A total of 20 articles out of 11,404 records from 2006 to 2021 were retrieved. The studies used various designs: 12 applied single-group pre-post study designs, 5 were cluster randomized controlled trials (RCTs), and 3 were non-RCTs. These studies targeted multiple vaccines, with 8 focusing on children's immunization, 8 on human papillomavirus vaccine, 3 on hepatitis B virus vaccine, and 1 on COVID-19 vaccine. The meta-analysis revealed significant increases in vaccination rates both in pre-post comparison (rate difference [RD] 0.34, 95% CI 0.21-0.47, I2=99.9%, P<.001) and between-group comparison (RD 0.18, 95% CI 0.07-0.29, I2=98.4%, P<.001). The meta-analysis revealed that participant recruitment had the largest effect size (RD 0.51, 95% CI 0.36-0.67, I2=99.9%, P<.001), followed by intervention development (RD 0.36, 95% CI 0.23-0.50, I2=100.0%, P<.001), intervention implementation (RD 0.35, 95% CI 0.22-0.47, I2=99.8%, P<.001), and data collection (RD 0.34, 95% CI 0.19-0.50, I2=99.8%, P<.001). The meta-analysis indicated that high community engagement extent yielded the largest effect size (RD 0.49, 95% CI 0.17-0.82, I2=100.0%, P<.001), followed by moderate community engagement extent (RD 0.45, 95% CI 0.33-0.58, I2=99.6%, P<.001) and low community engagement extent (RD 0.15, 95% CI 0.05-0.25, I2=99.2%, P<.001). The meta-analysis revealed that "health service support" demonstrated the largest effect sizes (RD 0.45, 95% CI 0.25-0.65, I2=99.9%, P<.001), followed by "health education and discussion" (RD 0.39, 95% CI 0.20-0.58, I2=99.7%, P<.001), "follow-up and reminder" (RD 0.33, 95% CI 0.23-0.42, I2=99.3%, P<.001), and "social marketing campaigns and community mobilization" (RD 0.24, 95% CI 0.06-0.41, I2=99.9%, P<.001). CONCLUSIONS: The results of this meta-analysis supported the effectiveness of community engagement in vaccination promotion with variations in terms of engagement contents and extent. Community engagement required a "fit-for-purpose" approach rather than a "one-size-fits-all" approach to maximize the effectiveness of vaccine promotion. TRIAL REGISTRATION: PROSPERO CRD42022339081; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=339081.

Prostate diffusion-weighted imaging (DWI) in MR-guided radiotherapy: Reproducibility assessment on 1.5 T MR-Linac and 1.5 T MR-simulator.

PURPOSE: Diffusion-weighted imaging (DWI) holds promise for image-guided radiotherapy (MRgRT) in prostate cancer. However, challenges persist due to image distortion, artifacts, and apparent diffusion coefficient (ADC) reproducibility issues. This study aimed to assess DWI image quality and ADC reproducibility on both a 1.5 T MR-simulator and a 1.5 T MR-Linac, employing measurements from both an ACR MRI phantom and prostate cancer patients undergoing MRgRT. METHODS: DW-MRI scans were conducted on 19 patients (mean age = 69 ± 8 years, with 23 MR-visible intra-prostatic lesions) and an ACR MRI phantom using a 1.5 T MR-simulator (b-values = 0, 800, 1400s/mm2) and a 1.5 T MR-Linac (b-values = 50, 500, 800 s/mm2). ADC homogeneity in the phantom was evaluated via 1D profile flatness (FL) in three directions. Image quality was assessed through qualitative 5-point Likert scale ratings and quantitative ADC and signal-to-noise ratio (SNR) measurements. Intra-observer reproducibility of image quality scores was evaluated using ICC(1, 2). Geometric distortion was measured by comparing landmark sizes on the ACR phantom against the ground truth. Mean ADC and reproducibility were assessed using Bland-Altman plots. RESULTS: Both MR-simulator and MR-Linac demonstrated high ADC homogeneity (FL > 87.5% - MR-simulator: 97.23 ± 0.62%, MR-Linac: 94.75 ± 0.62%, p < 0.05) in the phantom. Image quality scores revealed acceptable ratings (≥3) for capsule demarcation, image artifacts, and geometric distortion in patients. However, intra-prostatic lesions were barely discernible in b800 images for both MR-simulator (average score = 2.37 ± 1.33) and MR-Linac (average score = 2.16 ± 1.28). While MR-Linac DWI scans exhibited significantly more severe geometric distortion than MR-simulator scans (p < 0.01), most phantom measurements fell within the image in-plane resolution of 3 mm. Significant differences were noted in MR-simulator ADC (CTV: 1.20 ± 0.14 × 10-3 mm2/s (MR-simulator) vs 1.06 ± 0.10 × 10-3 mm2/s (MR-Linac); GTV: 1.05 ± 0.21 × 10-3 mm2/s vs 0.91 ± 0.16 × 10 mm2/s, all p < 0.05), with a small non-zero bias observed in the Bland-Altman analysis (CTV: 12.3%; GTV: 14.5%). CONCLUSION: The significantly larger MR-simulator ADC and the small non-zero bias hint at potential systematic differences in ADC values acquired from an MR-simulator and an MR-Linac, both at 1.5 T. Although acceptable ADC homogeneity was noted, caution is warranted in interpreting MR-Linac DWI images due to occasional severe artifacts. Further studies are essential to validate DWI and ADC as reliable imaging markers in prostate cancer MRgRT.

One-year clinical outcomes of MR-guided stereotactic body radiation therapy with rectal spacer for patients with localized prostate cancer.

BACKGROUND AND PURPOSE: This prospective study aimed to investigate adaptive magnetic resonance (MR)-guided stereotactic body radiation therapy (MRgSBRT) with rectal spacer for localized prostate cancer (PC) and report 1-year clinical outcomes. MATERIALS AND METHODS: Thirty-four consecutive patients with low- to high-risk localized PC that underwent 5-fraction adaptive MRgSBRT with rectal spacer were enrolled. The dosimetric comparison was performed on a risk- and age-matched cohort treated with MRgSBRT but without a spacer at a similar timepoint. Clinician-reported outcomes were based on Common Terminology Criteria for Adverse Events. Patient-reported outcomes were based on the Expanded Prostate Cancer Index Composite (EPIC) questionnaire at baseline, acute (1-3 months), subacute (4-12 months), and late (> 12 months) phases. RESULTS: The median follow-up was 390 days (range 28-823) and the median age was 70 years (range 58-82). One patient experienced rectal bleeding soon after spacer insertion that subsided before MRgSBRT. The median distance between the midline of the prostate midgland and the rectum after spacer insertion measured 7.8 mm (range 2.6-15.3), and the median length of the spacer was 45.9 mm (range 16.8-62.9) based on T2-weighted MR imaging. The use of spacer resulted in significant improvements in target coverage (V100% > 95% = 98.6% [range 93.4-99.8] for spacer vs. 97.8% [range 69.6-99.7] for non-spacer) and rectal sparing (V95% < 3 cc = 0.7 cc [range 0-4.6] for spacer vs. 4.9 cc [range 0-12.5] for non-spacer). Nine patients (26.5%) experienced grade 1 gastrointestinal toxicities, and no grade ≥ 2 toxicities were observed. During the 1-year follow-up period, EPIC scores for the bowel domain remained stable and were the highest among all other domains. CONCLUSIONS: MRgSBRT with rectal spacer for localized PC showed exceptional tolerability with minimal gastrointestinal toxicities and satisfactory patient-reported outcomes. Improvements in dosimetry, rectal sparing, and target coverage were achieved with a rectal spacer. Randomized trials are warranted for further validation.

A study of Bayesian deep network uncertainty and its application to synthetic CT generation for MR-only radiotherapy treatment planning.

BACKGROUND: The use of synthetic computed tomography (CT) for radiotherapy treatment planning has received considerable attention because of the absence of ionizing radiation and close spatial correspondence to source magnetic resonance (MR) images, which have excellent tissue contrast. However, in an MR-only environment, little effort has been made to examine the quality of synthetic CT images without using the original CT images. PURPOSE: To estimate synthetic CT quality without referring to original CT images, this study established the relationship between synthetic CT uncertainty and Bayesian uncertainty, and proposed a new Bayesian deep network for generating synthetic CT images and estimating synthetic CT uncertainty for MR-only radiotherapy treatment planning. METHODS AND MATERIALS: A novel deep Bayesian network was formulated using probabilistic network weights. Two mathematical expressions were proposed to quantify the Bayesian uncertainty of the network and synthetic CT uncertainty, which was closely related to the mean absolute error (MAE) in Hounsfield Unit (HU) of synthetic CT. These uncertainties were examined to demonstrate the accuracy of representing the synthetic CT uncertainty using a Bayesian counterpart. We developed a hybrid Bayesian architecture and a new data normalization scheme, enabling the Bayesian network to generate both accurate synthetic CT and reliable uncertainty information when probabilistic weights were applied. The proposed method was evaluated in 59 patients (13/12/32/2 for training/validation/testing/uncertainty visualization) diagnosed with prostate cancer, who underwent same-day pelvic CT- and MR-acquisitions. To assess the relationship between Bayesian and synthetic CT uncertainties, linear and non-linear correlation coefficients were calculated on per-voxel, per-tissue, and per-patient bases. For accessing the accuracy of the CT number and dosimetric accuracy, the proposed method was compared with a commercially available atlas-based method (MRCAT) and a U-Net conditional-generative adversarial network (UcGAN). RESULTS: The proposed model exhibited 44.33 MAE, outperforming UcGAN 52.51 and MRCAT 54.87. The gamma rate (2%/2 mm dose difference/distance to agreement) of the proposed model was 98.68%, comparable to that of UcGAN (98.60%) and MRCAT (98.56%). The per-patient and per-tissue linear correlation coefficients between the Bayesian and synthetic CT uncertainties ranged from 0.53 to 0.83, implying a moderate to strong linear correlation. Per-voxel correlation coefficients varied from -0.13 to 0.67 depending on the regions-of-interest evaluated, indicating tissue-dependent correlation. The R2 value for estimating MAE solely using Bayesian uncertainty was 0.98, suggesting that the uncertainty of the proposed model was an ideal candidate for predicting synthetic CT error, without referring to the original CT. CONCLUSION: This study established a relationship between the Bayesian model uncertainty and synthetic CT uncertainty. A novel Bayesian deep network was proposed to generate a synthetic CT and estimate its uncertainty. Various metrics were used to thoroughly examine the relationship between the uncertainties of the proposed Bayesian model and the generated synthetic CT. Compared with existing approaches, the proposed model showed comparable CT number and dosimetric accuracies. The experiments showed that the proposed Bayesian model was capable of producing accurate synthetic CT, and was an effective indicator of the uncertainty and error associated with synthetic CT in MR-only workflows.

Effects of Bis(imino)acenaphthene (Bian)-Derived Ligands on the Cytotoxicity, DNA Interactions, and Redox Activity of Palladium(II) Bipyridine Complexes.

A series of heteroleptic bipyridine Pd(II) complexes based on 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene (dpp-Bian) or 1,2-bis[(2,4,6-trimethylphenyl)imino]acenaphthene (tmp-Bian) were prepared. All complexes were fully characterized by spectrochemical methods, and their crystal structures were confirmed by X-ray diffraction analysis. The 72 h stability of heteroleptic bipyridine Pd(II) complexes with Bian ligands under physiological conditions was investigated using 1H NMR spectroscopy. The anticancer activity of all complexes was assessed in a panel of cancer cell lines in comparison with uncoordinated ligands and clinically used drugs cisplatin and doxorubicin. The ability of the complexes to bind DNA was investigated using several methods, including EtBr replacement assay, density functional theory calculations, circular dichroism spectroscopy, DNA gel electrophoresis, and TUNEL assay. The electrochemical activity of all complexes and the uncoordinated ligands was studied using cyclic voltammetry, and reactive oxygen species production in cancer cells was investigated using confocal microscopy. Heteroleptic bipyridine PdII-Bian complexes were cytotoxic in a low micromolar concentration range and showed some selectivity toward cancer cells in comparison with noncancerous MRC-5 lung fibroblasts.

Magnetic field induced dose effects in radiation therapy using MR-linacs.

MR-guided radiotherapy (MRgRT) is one of the most significant advances in radiotherapy in recent years. The hybrid systems were designed to visualize patient anatomical and physiological changes during the course of radiotherapy, enabling more precise treatment. However, before MR-linacs reach their full potential in delivering safe and accurate treatments to patients, the radiotherapy team must understand how a magnetic field alters the dosimetric properties of the radiation beam and its potential impact on treatment quality and clinical outcomes. This review aims to provide an in-depth description of the magnetic field induced dose effects for the two widely available systems, the 0.35 T and the 1.5 T MR-linacs. In MR-linac treatments, the primary photon beam passes through MR components that never exist in conventional linacs, which alter both in-field and out-of-field doses. More importantly, the interplay between the always-on magnetic field and the secondary electrons is not negligible. This interplay affects dose deposition in the patient, resulting in reduced in-field skin dose due to purged-out contaminant electrons, shortened build-up distance and a shifted crossline profile owing to asymmetric dose kernel. Especially two effects, namely, electron return effect (ERE) and electron stream effect (ESE), are not seen in conventional radiotherapy. This review also summarizes the clinical observations on the site-specific treatments influenced mostly by the magnetic field. In MR-linac treatment, the head and neck region is one of the most challenging sites as ERE occurs at low and high density tissue interfaces and around air cavities, generating hot and cold spots. In breast cancer treatment, consideration should be given to the increased in-field skin dose induced by ERE and the increased out-of-field dose caused by ESE for regions such as the ears, chin, and neck. In lung cancer treatments, tissue inhomogeneity combined with ERE will exacerbate target dose heterogeneity and increase or decrease interface dose. Lastly, treatment in the abdomen and pelvic region will be affected by the presence of gas pockets near the target. The review provides practical recommendations to mitigate these effects.

A phase 1/2a safety, pharmacokinetics, and efficacy study of the novel nucleoside analog FF-10502-01 for the treatment of advanced solid tumors.

BACKGROUND: The nucleoside FF-10502-01, structurally similar to but with different biologic effects than gemcitabine, shows promising activity both alone and combined with cisplatin in preclinical gemcitabine-resistant tumor models. We conducted an open-label, single-arm, 3 + 3 first-in-human trial to explore the safety, tolerability, and antitumor activity of FF-10502-01 in patients with solid tumors. METHODS: Patients with inoperable metastatic tumors refractory to standard therapies were enrolled. Escalating intravenous FF-10502-01 doses (8-135 mg/m2 ) were administered weekly for 3 weeks in 28-day cycles until progressive disease or unacceptable toxicity was observed. Three expansion cohorts were subsequently evaluated. RESULTS: A phase 2 dose of 90 mg/m2 was determined after evaluating 40 patients. Dose-limiting toxicities included hypotension and nausea. Phase 2a enrolled patients with cholangiocarcinoma (36), gallbladder cancer (10), and pancreatic/other tumors (20). Common adverse events were grade 1-2 rash, pruritus, fever, and fatigue. Grade 3 or 4 hematologic toxicities were observed at low incidences, including thrombocytopenia (5.1%) and neutropenia (2%). Confirmed partial responses (PRs) occurred in five patients with gemcitabine-refractory tumors, including three with cholangiocarcinoma and one each with gallbladder and urothelial cancer. Median progression-free and overall survival rates in patients with cholangiocarcinoma were 24.7 and 39.1 weeks, respectively. Prolonged progression-free survival in patients with cholangiocarcinoma was associated with BAP1 and PBRM1 mutations. CONCLUSION: FF-10502-01 was well tolerated with manageable side effects and limited hematologic toxicity. Durable PRs and disease stabilizations were observed in heavily pretreated biliary tract patients who had received prior gemcitabine. FF-10502-01 is distinct from gemcitabine and may represent an effective therapy.

A pilot study of MRI radiomics for high-risk prostate cancer stratification in 1.5 T MR-guided radiotherapy.

PURPOSE: To investigate the potential value of MRI radiomics obtained from a 1.5 T MRI-guided linear accelerator (MR-LINAC) for D'Amico high-risk prostate cancer (PC) classification in MR-guided radiotherapy (MRgRT). METHODS: One hundred seventy-six consecutive PC patients underwent 1.5 T MRgRT treatment were retrospectively enrolled. Each patient received one or two pretreatment T2 -weighted MRI scans on a 1.5 T MR-LINAC. The endpoint was to differentiate high-risk from low/intermediate-risk PC based on D'Amico criteria using MRI-radiomics. Totally 1023 features were extracted from clinical target volume (CTV) and planning target volume (PTV). Intraclass correlation coefficient of scan-rescan repeatability, feature correlation, and recursive feature elimination were used for feature dimension reduction. Least absolute shrinkage and selection operator regression was employed for model construction. Receiver operating characteristic area under the curve (AUC) analysis was used for model performance assessment in both training and testing data. RESULTS: One hundred and eleven patients fulfilled all criteria were finally included: 76 for training and 35 for testing. The constructed MRI-radiomics models extracted from CTV and PTV achieved the AUC of 0.812 and 0.867 in the training data, without significant difference (P = 0.083). The model performances remained in the testing. The sensitivity, specificity, and accuracy were 85.71%, 64.29%, and 77.14% for the PTV-based model; and 71.43%, 71.43%, and 71.43% for the CTV-based model. The corresponding AUCs were 0.718 and 0.750 (P = 0.091) for CTV- and PTV-based models. CONCLUSION: MRI-radiomics obtained from a 1.5 T MR-LINAC showed promising results in D'Amico high-risk PC stratification, potentially helpful for the future PC MRgRT. Prospective studies with larger sample sizes and external validation are warranted for further verification.

Empiric vs Preemptive Antifungal Strategy in High-Risk Neutropenic Patients on Fluconazole Prophylaxis: A Randomized Trial of the European Organization for Research and Treatment of Cancer.

BACKGROUND: Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown. METHODS: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization. RESULTS: Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001). CONCLUSIONS: The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27.

Analysis of online plan adaptation for 1.5T magnetic resonance-guided stereotactic body radiotherapy (MRgSBRT) of prostate cancer.

PURPOSE: To analyze and characterize the online plan adaptation of 1.5T magnetic resonance-guided stereotactic body radiotherapy (MRgSBRT) of prostate cancer (PC). METHODS: PC patients (n = 107) who received adaptive 1.5 Tesla MRgSBRT were included. Online plan adaptation was implemented by either the adapt-to-position (ATP) or adapt-to-shape (ATS) methods. Patients were assigned to the ATS group if they underwent ≥ 1 ATS fraction (n = 51); the remainder were assigned to the ATP group (n = 56). The online plan adaptation records of 535 (107 × 5) fractions were retrospectively reviewed. Rationales for ATS decision-making were determined and analyzed using predefined criteria. Statistics of ATS fractions were summarized. Associations of patient characteristics and clinical factors with ATS utilization were investigated. RESULTS: There were 87 (16.3%) ATS fractions and 448 ATP fractions (83.7%). The numbers of ATS adoptions in fractions 1-5 were 29 (29/107, 27.1%), 18 (16.8%), 15 (14.0%), 16 (15.0%), and 9 (8.4%), respectively, with significant differences in adoption frequency between fractions (p = 0.007). Other baseline patient characteristics and clinical factors were not significantly associated with ATS classification (all p > 0.05). Underlying criteria for the determination of ATS implementation comprised anatomical changes (77 fractions in 50 patients) and discrete multiple targets (15 fractions in 3 patients). No ATS utilization was determined using dosimetric or online quality assurance criteria. CONCLUSIONS: This study contributes to facilitating the establishment of a standardized protocol for online MR-guided adaptive radiotherapy in PC.

Determining the reliable feature change in longitudinal radiomics studies: A methodological approach using the reliable change index.

PURPOSE: Determination of reliable change of radiomics feature over time is essential and vital in delta-radiomics, but has not yet been rigorously examined. This study attempts to propose a methodological approach using reliable change index (RCI), a statistical metric to determine the reliability of quantitative biomarker changes by accounting for the baseline measurement standard error, in delta-radiomics. The use of RCI was demonstrated with the MRI data acquired from a group of prostate cancer (PCa) patients treated by 1.5 T MRI-guided radiotherapy (MRgRT). METHODS: Fifty consecutive PCa patients who underwent five-fractionated MRgRT were retrospectively included, and 1023 radiomics features were extracted from the clinical target volume (CTV) and planning target volume (PTV). The two MRI datasets acquired at the first fraction (MRI11 and MRI21) were used to calculate the baseline feature reliability against image acquisition using intraclass correlation coefficient (ICC). The RCI was constructed based on the baseline feature measurement standard deviation, ICC, and feature value differences at two time points between the fifth (MRI51) and the first fraction MRI (MRI11). The reliable change of features was determined in each patient only if the calculated RCI was over 1.96 or smaller than -1.96. The feature changes between MRI51 and MRI11 were correlated to two patient-reported quality-of-life clinical endpoints of urinary domain summary score (UDSS) and bowel domain summary score (BDSS) in 35 patients using the Spearman correlation test. Only the significant correlations between a feature that was reliably changed in ≥7 patients (20%) by RCI and an endpoint were considered as true significant correlations. RESULTS: The 352 (34.4%) and 386 (37.7%) features among all 1023 features were determined by RCI to be reliably changed in more than five (10%) patients in the CTV and PTV, respectively. Nineteen features were found reliably changed in the CTV and 31 features in the PTV, respectively, in 10 (20%) or more patients. These features were not necessarily associated with significantly different longitudinal feature values (group p-value < 0.05). Most reliably changed features in more than 10 patients had excellent or good baseline test-retest reliability ICC, while none showed poor reliability. The RCI method ruled out the features to be reliably changed when substantial feature measurement bias was presented. After applying the RCI criterion, only four and five true significant correlations were confirmed with UDSS and BDSS in the CTV, respectively, with low true significance correlation rates of 10.8% (4/37) and 17.9% (5/28). No true significant correlations were found in the PTV. CONCLUSIONS: The RCI method was proposed for delta-radiomics and demonstrated using PCa MRgRT data. The RCI has advantages over some other statistical metrics commonly used in the previous delta-radiomics studies, and is useful to reliably identify the longitudinal radiomics feature change on an individual basis. This proposed RCI method should be helpful for the development of essential feature selection methodology in delta-radiomics.

Diminished muscle integrity in patients with fibrodysplasia ossificans progressiva assessed with at-home electrical impedance myography.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder involving skeletal dysplasia and heterotopic ossification (HO) of muscle and connective tissue. We aimed to define a novel biomarker in FOP that enables reliable assessment of musculoskeletal tissue integrity. Considering logistical difficulties that FOP patients often face, our goal was to identify an at-home biomarker technique. Electrical impedance myography (EIM) is a non-invasive, portable method that can inform on muscle health. 15 FOP patients (age 10-52) and 13 healthy controls were assessed. Using EIM, multiple muscle groups were characterized per participant in a 45-min period. The Cumulative Analogue Joint Involvement Scale (CAJIS) was implemented to determine mobility burden severity. We additionally evaluated physical activity levels via a Patient-Reported Outcomes Measurement Information System (PROMIS)-based questionnaire. Relative to controls, FOP patients demonstrated significantly lower regional and whole-body phase values at 50 kHz and 100 kHz, indicating more diseased muscle tissue. Lower whole-body phase and reactance values, and higher resistance values, were associated with greater FOP burden (CAJIS score range: 4-30) and lower physical activity levels at 50 kHz and 100 kHz. This study points to the potential utility of EIM as a clinical biomarker tool capable of characterizing muscle integrity in FOP.

Clinical implementation of kVCT-guided tomotherapy with ClearRT.

A helical fan-beam kilovoltage computed tomography (kVCT) was recently introduced into Tomotherapy units. This study aims to share the initial experience of kVCT in clinical workflow, compare its performance with that of the existing megavoltage computed tomography (MVCT), and explore its potential in adaptive planning. We retrospectively enrolled 23 patients who underwent both MVCT and kVCT scans. The clinical performance data regarding image acquisition time, nominal dose length product (DLP), registration time and registration corrections were extracted and compared. Image quality was scored by six experienced radiation therapists and quantified based on phantom measurements. CT number stability and the implementation of adaptive radiotherapy were dosimetrically evaluated by performing the dose recalculation on kVCT. Compared to MVCT, kVCT significantly reduced DLP (except the highest kVp protocol), image acquisition and registration time. KVCT obtained higher scores than MVCT on all criteria except artifacts. Phantom measurements also revealed a better image performance characterization of kVCT except for image uniformity. The CT number variation could lead to a dose difference of 0.5% for D95% of target and Dmean of organ-at-risk. For the treatment planning with kVCT, a systematic dose difference (> 1%) in PTV dose metrics was observed at regions with large longitudinal density discontinuities compared to the reference plans. The new kVCT imaging provides enhanced soft-tissue visualization. The improved efficiency with kVCT-guided treatment will allow more patients to be treated each day. In most cases, the dose calculation accuracy of kVCT images is acceptable except for regions with severe artifacts.

A Prospective Study of Stereotactic Body Radiotherapy (SBRT) with Concomitant Whole-Pelvic Radiotherapy (WPRT) for High-Risk Localized Prostate Cancer Patients Using 1.5 Tesla Magnetic Resonance Guidance: The Preliminary Clinical Outcome.

Background: Conventionally fractionated whole-pelvic nodal radiotherapy (WPRT) improves clinical outcome compared to prostate-only RT in high-risk prostate cancer (HR-PC). MR-guided stereotactic body radiotherapy (MRgSBRT) with concomitant WPRT represents a novel radiotherapy (RT) paradigm for HR-PC, potentially improving online image guidance and clinical outcomes. This study aims to report the preliminary clinical experiences and treatment outcome of 1.5 Tesla adaptive MRgSBRT with concomitant WPRT in HR-PC patients. Materials and methods: Forty-two consecutive HR-PC patients (72.5 ± 6.8 years) were prospectively enrolled, treated by online adaptive MRgSBRT (8 Gy(prostate)/5 Gy(WPRT) × 5 fractions) combined with androgen deprivation therapy (ADT) and followed up (median: 251 days, range: 20−609 days). Clinical outcomes were measured by gastrointestinal (GI) and genitourinary (GU) toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) Scale v. 5.0, patient-reported quality of life (QoL) with EPIC (Expanded Prostate Cancer Index Composite) questionnaire, and prostate-specific antigen (PSA) responses. Results: All MRgSBRT fractions achieved planning objectives and dose specifications of the targets and organs at risk, and they were successfully delivered. The maximum cumulative acute GI/GU grade 1 and 2 toxicity rates were 19.0%/81.0% and 2.4%/7.1%, respectively. The subacute (>30 days) GI/GU grade 1 and 2 toxicity rates were 21.4%/64.3% and 2.4%/2.4%, respectively. No grade 3 toxicities were reported. QoL showed insignificant changes in urinary, bowel, sexual, and hormonal domain scores during the follow-up period. All patients had early post-MRgSBRT biochemical responses, while biochemical recurrence (PSA nadir + 2 ng/mL) occurred in one patient at month 18. Conclusions: To our knowledge, this is the first prospective study that showed the clinical outcomes of MRgSBRT with concomitant WPRT in HR-PC patients. The early results suggested favorable treatment-related toxicities and encouraging patient-reported QoLs, but long-term follow-up is needed to confirm our early results.

Acquisition repeatability of MRI radiomics features in the head and neck: a dual-3D-sequence multi-scan study.

Radiomics has increasingly been investigated as a potential biomarker in quantitative imaging to facilitate personalized diagnosis and treatment of head and neck cancer (HNC), a group of malignancies associated with high heterogeneity. However, the feature reliability of radiomics is a major obstacle to its broad validity and generality in application to the highly heterogeneous head and neck (HN) tissues. In particular, feature repeatability of radiomics in magnetic resonance imaging (MRI) acquisition, which is considered a crucial confounding factor of radiomics feature reliability, is still sparsely investigated. This study prospectively investigated the acquisition repeatability of 93 MRI radiomics features in ten HN tissues of 15 healthy volunteers, aiming for potential magnetic resonance-guided radiotherapy (MRgRT) treatment of HNC. Each subject underwent four MRI acquisitions with MRgRT treatment position and immobilization using two pulse sequences of 3D T1-weighed turbo spin-echo and 3D T2-weighed turbo spin-echo on a 1.5 T MRI simulator. The repeatability of radiomics feature acquisition was evaluated in terms of the intraclass correlation coefficient (ICC), whereas within-subject acquisition variability was evaluated in terms of the coefficient of variation (CV). The results showed that MRI radiomics features exhibited heterogeneous acquisition variability and uncertainty dependent on feature types, tissues, and pulse sequences. Only a small fraction of features showed excellent acquisition repeatability (ICC > 0.9) and low within-subject variability. Multiple MRI scans improved the accuracy and confidence of the identification of reliable features concerning MRI acquisition compared to simple test-retest repeated scans. This study contributes to the literature on the reliability of radiomics features with respect to MRI acquisition and the selection of reliable radiomics features for use in modeling in future HNC MRgRT applications.

Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, IDH-wildtype: Post Hoc Analysis of the EORTC Randomized Phase III CATNON Trial.

PURPOSE: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase-wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. PATIENTS AND METHODS: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. RESULTS: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82-1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61-1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. CONCLUSIONS: In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.

A narrative review of MRI acquisition for MR-guided-radiotherapy in prostate cancer.

Magnetic resonance guided radiotherapy (MRgRT), enabled by the clinical introduction of the integrated MRI and linear accelerator (MR-LINAC), is a novel technique for prostate cancer (PCa) treatment, promising to further improve clinical outcome and reduce toxicity. The role of prostate MRI has been greatly expanded from the traditional PCa diagnosis to also PCa screening, treatment and surveillance. Diagnostic prostate MRI has been relatively familiar in the community, particularly with the development of Prostate Imaging - Reporting and Data System (PI-RADS). But, on the other hand, the use of MRI in the emerging clinical practice of PCa MRgRT, which is substantially different from that in PCa diagnosis, has been so far sparsely presented in the medical literature. This review attempts to give a comprehensive overview of MRI acquisition techniques currently used in the clinical workflows of PCa MRgRT, from treatment planning to online treatment guidance, in order to promote MRI practice and research for PCa MRgRT. In particular, the major differences in the MRI acquisition of PCa MRgRT from that of diagnostic prostate MRI are demonstrated and explained. Limitations in the current MRI acquisition for PCa MRgRT are analyzed. The future developments of MRI in the PCa MRgRT are also discussed.