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Although significant progress has been made in understanding the cortical correlates underlying balance control, these studies focused on a single task, limiting the ability to generalize the findings. Different balance tasks may elicit cortical activations in the same regions but show different levels of activation because of distinct underlying mechanisms. In this study, twenty young, neurotypical adults were instructed to maintain standing balance while the standing support surface was either translated or rotated. The differences in cortical activations in the frontocentral region between these two widely used tasks were examined using electroencephalography (EEG). Additionally, the study investigated whether transcranial magnetic stimulation could modulate these cortical activations during the platform translation task. Higher delta and lower alpha relative power were found over the frontocentral region during the platform translation task when compared to the platform rotation task, suggesting greater engagement of attentional and sensory integration resources for the former. Continuous theta burst stimulation over the supplementary motor area significantly reduced delta activity in the frontocentral region but did not alter alpha activity during the platform translation task. The results provide a direct comparison of neural activations between two commonly used balance tasks and are expected to lay a strong foundation for designing neurointerventions for balance improvements with effects generalizable across multiple balance scenarios.

The implementation and early adoption of online adaptive radiotherapy (oART) has required the presence of clinicians, physicists and radiation therapists (RTT) at the treatment console. The impact on each of them is unique to their profession and must be considered for safe and efficient implementation. In the short term future, widespread adoption will depend on the development of innovative workflows, and rethinking of traditional roles and responsibilities may be required. For the future, technologies such as artificial intelligence promise to change the workflow significantly in terms of speed, automation and decision-making. However, overall communication within the team will persist in being one of the most important aspects., (Copyright © 2024. Published by Elsevier Inc.)

Balance control is an important indicator of mobility and independence in activities of daily living. How the functional coupling between the cortex and the muscle for balance control is affected following stroke remains to be known. We investigated the changes in coupling between the cortex and leg muscles during a challenging balance task over multiple frequency bands in chronic stroke survivors. Fourteen participants with stroke and ten healthy controls performed a challenging balance task. They stood on a computerized support surface that was either fixed (low difficulty condition) or sway-referenced with varying gain (medium and high difficulty conditions). We computed corticomuscular coherence between electrodes placed over the sensorimotor area (electroencephalography) and leg muscles (electromyography) and assessed balance performance using clinical and laboratory-based tests. We found significantly lower delta frequency band coherence in stroke participants when compared with healthy controls under medium difficulty condition, but not during low and high difficulty conditions. These differences were found for most of the distal but not for proximal leg muscle groups. No differences were found at other frequency bands. Participants with stroke showed poor balance clinical scores when compared with healthy controls, but no differences were found for laboratory-based tests. The observation of effects at distal but not at proximal muscle groups suggests differences in the (re)organization of the descending connections across two muscle groups for balance control. We argue that the observed group difference in delta band coherence indicates balance context-dependent alteration in mechanisms for the detection of somatosensory modulation resulting from sway-referencing of the support surface for balance maintenance following stroke., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: There is a need for a pediatric hand function test that can be used to objectively assess movement quality. We have developed a toy-based test, the Bead Maze Hand Function (BMHF) test, to quantify how well a child performs an activity. This is achieved by assessing the control of forces applied while drawing a bead over wires of different complexity., Objective: To study the psychometric properties of the BMHF test and understand the influence of age and task complexity on test measures., Design: A cross-sectional, observational study performed in a single visit., Setting: Clinical research laboratory., Participants: Twenty-three participants (ages 4-15 yr) were recruited locally. They were typically developing children with no illness or conditions that affected their movement. Interventions/Assessments: Participants performed the BMHF test and the Box and Block test with both hands., Outcomes and Measures: Total force and completion time were examined according to age and task complexity using a linear mixed-effects model. We calculated intraclass correlation coefficients to measure interrater reliability of the method and estimated concurrent validity using the Box and Block test., Results: Total force and completion time decreased with age and depended on task complexity. The total force was more sensitive to task complexity. The Box and Block score was associated with BMHF completion time but not with total force. We found excellent interrater reliability., Conclusions and Relevance: A familiar toy equipped with hidden sensors provides a sensitive tool to assess a child's typical hand function. Plain-Language Summary: We developed the Bead Maze Hand Function (BMHF) test to determine how well a child performs an activity with their hands. The BMHF test is a toy equipped with hidden sensors. Twenty-three typically developing children with no illnesses or conditions that affected their hand movement participated in the study. We asked the children to perform the BMHF test with both hands. Our study found that occupational therapists can reliably use the BMHF test to assess a child's hand function., (Copyright © 2024 by the American Occupational Therapy Association, Inc.)

A patient fall is one of the adverse events in an inpatient unit of a hospital that can lead to disability and/or mortality. The medical literature suggests that increased visibility of patients by unit nurses is essential to improve patient monitoring and, in turn, reduce falls. However, such research has been descriptive in nature and does not provide an understanding of the characteristics of an optimal inpatient unit layout from a visibility-standpoint. To fill this gap, we adopt an interdisciplinary approach that combines the human field of view with facility layout design approaches. Specifically, we propose a bi-objective optimization model that jointly determines the optimal (i) location of a nurse in a nursing station and (ii) orientation of a patient's bed in a room for a given layout. The two objectives are maximizing the total visibility of all patients across patient rooms and minimizing inequity in visibility among those patients. We consider three different layout types, L-shaped, I-shaped, and Radial; these shapes exhibit the section of an inpatient unit that a nurse oversees. To estimate visibility, we employ the ray casting algorithm to quantify the visible target in a room when viewed by the nurse from the nursing station. The algorithm considers nurses' horizontal visual field and their depth of vision. Owing to the difficulty in solving the bi-objective model, we also propose a Multi-Objective Particle Swarm Optimization (MOPSO) heuristic to find (near) optimal solutions. Our findings suggest that the Radial layout appears to outperform the other two layouts in terms of the visibility-based objectives. We found that with a Radial layout, there can be an improvement of up to 50% in equity measure compared to an I-shaped layout. Similar improvements were observed when compared to the L-shaped layout as well. Further, the position of the patient's bed plays a role in maximizing the visibility of the patient's room. Insights from our work will enable understanding and quantifying the relationship between a physical layout and the corresponding provider-to-patient visibility to reduce adverse events., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Interruptions during dental treatment are frequent, and often impact provider satisfaction and processing times We investigate the source and duration of such interruptions at a German dental clinic., Methods: A pre-post approach was adopted at this dental clinic. This included direct observations of 3 dentists and 3 dental hygienists, and a survey of providers. Following that, an intervention (switchable 'Do Not Enter' sign) was chosen, and a pilot study was conducted to evaluate if the chosen intervention can reduce processing time and improve provider satisfaction. Additional observations and surveys were performed afterwards., Results: Pre-intervention data indicated that interruptions have the highest negative impact on provider satisfaction at this clinic as well as on processing time during longer and more complex treatments, where a minor error due to an interruption could lead to rework of 30 minutes and more. The total number of interruptions dropped by 72.5% after the intervention, short interruptions (< 1min) by 86%. Provider survey indicated improvement due to the intervention in perceived workload, provider work satisfaction, patient safety and stress., Conclusions: This study demonstrates that a switchable sign can substantially reduce the number of interruptions in this dental clinic. It also shows the potential of improving the work environment by reducing interruptions to the dental providers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ziegler, Parikh. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Purpose: The SOFT trial is a prospective, multicenter, phase 2 trial investigating magnetic resonance (MR)-guided stereotactic ablative radiotherapy (SABR) for abdominal, soft tissue metastases in patients with oligometastatic disease (OMD) (clinicaltrials.gov ID NCT04407897). We present the primary endpoint analysis of 1-year treatment-related toxicity (TRAE)., Materials and Methods: Patients with up to five oligometastases from non-hematological cancers were eligible for inclusion. A risk-adapted strategy prioritized fixed organs at risk (OAR) constraints over target coverage. Fractionation schemes were 45-67.5 Gy in 3-8 fractions. The primary endpoint was grade ≥ 4 TRAE within 12 months post-SABR. The association between the risk of gastrointestinal (GI) toxicity and clinical and dosimetric parameters was tested using a normal tissue complication probability model., Results: We included 121 patients with 147 oligometastatic targets, mainly located in the liver (41 %), lymph nodes (35 %), or adrenal glands (14 %). Nearly half of all targets (48 %, n = 71) were within 10 mm of a radiosensitive OAR. No grade 4 or 5 TRAEs, 3.5 % grade 3 TRAEs, and 43.7 % grade 2 TRAEs were reported within the first year of follow-up. We found a significant association between grade ≥ 2 GI toxicity and the parameters GI OAR D 0.1cc, D 1cc, and D 20cc ., Conclusion: In this phase II study of MR-guided SABR of oligometastases in the infra-diaphragmatic region, we found a low incidence of toxicity despite half of the lesions being within 10 mm of a radiosensitive OAR. GI OAR D 0.1cc, D 1cc, and D 20cc were associated with grade ≥ 2 GI toxicity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MF has received research grant from Varian Medical Systems and support from The Danish National Research Centre for Radiotherapy and the Danish Cancer Society. CPB reports institutional research contracts with Brainlab, Varian Medical Systems, Siemens, and ViewRay and teaching contracts with Varian Medical Systems. Research funding from Danish Comprehensive Cancer Center National Thematic Center on radiotherapy (DCCC-RT). UB reports institutional research contracts with Elekta. IVR reports institutional research contracts with Brainlab, Varian Medical Systems, and ViewRay and teaching contracts with Varian Medical Systems. GP has received research grants from Varian Medical Systems, The Danish National Research Centre for Radiotherapy, and the Danish Cancer Society, Herlev & Gentofte Hospitals Internal Research Council, Villadsens Family Foundation. Conference participance from MSD, Daiichi Sankyo, and Pfizer, Pierre Fabre and honoraria for consultancies and lectures from Astra Zeneca. PP has received research grant from Viewray; not relevant to this article; Stock ownership of Nuvaira (COPD device company). MJ have received research support from The Danish National Research Centre for Radiotherapy and the Danish Cancer Society. MP have received honoraria for lectures from Astra Zeneca, BMS, MSD, Pfizer, Roche, Amgen. TS have received honoraria for lectures and travel expenses from Elekta and declares travel assistance from ELEKTA and is member of the MR-L consortium. SB have received research support from The Danish National Research Centre for Radiotherapy. PG reports institutional research contracts with Viewray. PK, ESH, and KJ has nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.

The ability to hold objects relies on neural processes underlying grip force control during grasping. Brain activity lateralized to contralateral hemisphere averaged over trials is associated with grip force applied on an object. However, the involvement of neural variability within-trial during grip force control remains unclear. We examined dependence of neural variability over frontal, central, and parietal regions of interest (ROI) on grip force magnitude using noninvasive electroencephalography (EEG). We utilized our existing EEG dataset comprised of healthy young adults performing an isometric force control task, cued to exert 5, 10, or 15% of their maximum voluntary contraction (MVC) across trials and received visual feedback of their grip force. We quantified variability in EEG signal via sample entropy (sequence-dependent) and standard deviation (sequence-independent measure) over ROI. We found lateralized modulation in EEG sample entropy with force magnitude over central electrodes but not over frontal or parietal electrodes. However, modulation was not observed for standard deviation in the EEG activity. These findings highlight lateralized and spatially constrained modulation in sequence-dependent, but not sequence-independent component of EEG variability. We contextualize these findings in applications requiring finer precision (e.g., prosthesis), and propose directions for future studies investigating role of neural entropy in behavior.

The introduction of online adaptive magnetic resonance (MR)-guided radiation therapy (RT) has enabled safe treatment of pancreatic cancer with ablative doses. The aim of this review is to provide a comprehensive overview of the current literature on the use and clinical outcomes of MR-guided RT for treatment of pancreatic cancer. Relevant outcomes included toxicity, tumor response, survival and quality of life. The results of these studies support further investigation of the effectiveness of ablative MR-guided SBRT as a low-toxic, minimally-invasive therapy for localized pancreatic cancer in prospective clinical trials., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: The total time of radiation treatment delivery for pancreatic cancer patients with daily online adaptive radiation therapy (ART) on an MR-Linac can range from 50 to 90 min. During this period, the target and normal tissues undergo changes due to respiration and physiologic organ motion. We evaluated the dosimetric impact of the intrafraction physiological organ changes., Methods: Ten locally advanced pancreatic cancer patients were treated with 50 Gy in five fractions with intensity-modulated respiratory-gated radiation therapy on a 0.35-T MR-Linac. Patients received both pre- and post-treatment volumetric MRIs for each fraction. Gastrointestinal organs at risk (GI-OARs) were delineated on the pre-treatment MRI during the online ART process and retrospectively on the post-treatment MRI. The treated dose distribution for each adaptive plan was assessed on the post-treatment anatomy. Prescribed dose volume histogram metrics for the scheduled plan on the pre-treatment anatomy, the adapted plan on the pre-treatment anatomy, and the adapted plan on post-treatment anatomy were compared to the OAR-defined criteria for adaptation: the volume of the GI-OAR receiving greater than 33 Gy (V33Gy) should be ≤1 cubic centimeter., Results: Across the 50 adapted plans for the 10 patients studied, 70% were adapted to meet the duodenum constraint, 74% for the stomach, 12% for the colon, and 48% for the small bowel. Owing to intrafraction organ motion, at the time of post-treatment imaging, the adaptive criteria were exceeded for the duodenum in 62% of fractions, the stomach in 36%, the colon in 10%, and the small bowel in 48%. Compared to the scheduled plan, the post-treatment plans showed a decrease in the V33Gy, demonstrating the benefit of plan adaptation for 66% of the fractions for the duodenum, 95% for the stomach, 100% for the colon, and 79% for the small bowel., Conclusion: Post-treatment images demonstrated that over the course of the adaptive plan generation and delivery, the GI-OARs moved from their isotoxic low-dose region and nearer to the dose-escalated high-dose region, exceeding dose-volume constraints. Intrafraction motion can have a significant dosimetric impact; therefore, measures to mitigate this motion are needed. Despite consistent intrafraction motion, plan adaptation still provides a dosimetric benefit., Competing Interests: JC and JA report travel expenses from ViewRay outside of this work. PP and JD report grants, honoraria and travel expenses from ViewRay outside of this work. PP has clinical research funding from Speakers Board, ViewRay and ownership interest in Nuvaira, neither are related to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rusu, Cunningham, Arch, Chetty, Parikh and Dolan.)

Purpose: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC)., Methods and Materials: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART., Results: One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%., Conclusions: The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: This study investigated kinematic and EMG changes in gait across simulated gravitational unloading levels between 100% and 20% of normal body weight. This study sought to identify if each level of unloading elicited consistent changes-particular to that percentage of normal body weight-or if the changes seen with unloading could be influenced by the previous level(s) of unloading. Methods: 15 healthy adult participants (26.3 ± 2.5 years; 53% female) walked in an Alter-G anti-gravity treadmill unloading system (mean speed: 1.49 ± 0.37 mph) for 1 min each at 100%, 80%, 60%, 40% and 20% of normal body weight, before loading back to 100% in reverse order. Lower-body kinematic data were captured by inertial measurement units, and EMG data were collected from the rectus femoris, biceps femoris, medial gastrocnemius, and anterior tibialis. Data were compared across like levels of load using repeated measures ANOVA and statistical parametric mapping. Difference waveforms for adjacent levels were created to examine the rate of change between different unloading levels. Results: This study found hip, knee, and ankle kinematics as well as activity in the rectus femoris, and medial gastrocnemius were significantly different at the same level of unloading, having arrived from a higher, or lower level of unloading. There were no significant changes in the kinematic difference waveforms, however the waveform representing the change in EMG between 100% and 80% load was significantly different from all other levels. Discussion: This study found that body weight unloading from 100% to 20% elicited distinct responses in the medial gastrocnemius, as well as partly in the rectus femoris. Hip, knee, and ankle kinematics were also affected differentially by loading and unloading, especially at 40% of normal body weight. These findings suggest the previous level of gravitational load is an important factor to consider in determining kinematic and EMG responses to the current level during loading and unloading below standard g. Similarly, the rate of change in kinematics from 100% to 20% appears to be linear, while the rate of change in EMG was non-linear. This is of particular interest, as it suggests that kinematic and EMG measures decouple with unloading and may react to unloading uniquely., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Malaya, Parikh, Smith, Riaz, Chandrasekaran and Layne.)

Purpose: Magnetic resonance-guided stereotactic body radiation therapy (MRgSBRT) with optional online adaptation has shown promise in delivering ablative doses to unresectable primary liver cancer. However, there remain limited data on the indications for online adaptation as well as dosimetric and longer-term clinical outcomes following MRgSBRT., Methods and Materials: Patients with unresectable hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and combined biphenotypic hepatocellular-cholangiocarcinoma (cHCC-CCA) who completed MRgSBRT to 50 Gy in 5 fractions between June of 2015 and December of 2021 were analyzed. The necessity of adaptive techniques was evaluated. The cumulative incidence of local progression was evaluated and survival and competing risk analyses were performed., Results: Ninety-nine analyzable patients completed MRgSBRT during the study period and 54 % had planning target volumes (PTVs) within 1 cm of the duodenum, small bowel, or stomach at the time of simulation. Online adaptive RT was used in 53 % of patients to correct organ-at-risk constraint violation and/or to improve target coverage. In patients who underwent adaptive RT planning, online replanning resulted in superior target coverage when compared to projected, non-adaptive plans (median coverage ≥ 95 % at 47.5 Gy: 91 % [IQR: 82-96] before adaptation vs 95 % [IQR: 87-99] after adaptation, p < 0.01). The median follow-up for surviving patients was 34.2 months for patients with HCC and 10.1 months for patients with CCA/cHCC-CCA. For all patients, the 2-year cumulative incidence of local progression was 9.8 % (95 % CI: 1.5-18 %) for patients with HCC and 9.0 % (95 % CI: 0.1-18) for patients with CCA/cHCC-CCA. Grade 3 through 5 acute and late clinical gastrointestinal toxicities were observed in < 10 % of the patients., Conclusions: MRgSBRT, with the option for online adaptive planning when merited, allows delivery of ablative doses to primary liver tumors with excellent local control with acceptable toxicities. Additional studies evaluating the efficacy and safety of MRgSBRT in the treatment of primary liver cancer are warranted., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Purpose: Ablative radiation therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) may limit concurrent chemotherapy dosing and usually is only safely deliverable to tumors distant from gastrointestinal organs. Magnetic resonance guided radiation therapy may safely permit radiation and chemotherapy dose escalation., Methods and Materials: We conducted a single-arm phase I study to determine the maximum tolerated dose of ablative hypofractionated radiation with full-dose gemcitabine/nab-paclitaxel in patients with BR/LA-PDAC. Patients were treated with gemcitabine/nab-paclitaxel (1000/125 mg/m 2 ) x 1c then concurrent gemcitabine/nab-paclitaxel and radiation. Gemcitabine/nab-paclitaxel and radiation doses were escalated per time-to-event continual reassessment method from 40 to 45 Gy 25 fxs with chemotherapy (600-800/75 mg/m 2 ) to 60 to 67.5 Gy/15 fractions and concurrent gemcitabine/nab-paclitaxel (1000/100 mg/m 2 ). The primary endpoint was maximum tolerated dose of radiation as defined by 60-day dose limiting toxicity (DLT). DLT was treatment-related G5, G4 hematologic, or G3 gastrointestinal requiring hospitalization >3 days. Secondary endpoints included resection rates, local progression free survival (LPFS), distant metastasis free survival (DMFS), and overall survival (OS)., Results: Thirty patients enrolled (March 2015-February 2019), with 26 evaluable patients (2 progressed before radiation, 1 was determined ineligible for radiation during planning, 1 withdrew consent). One DLT was observed. The DLT rate was 14.1% (3.3%-24.9%) with a maximum tolerated dose of gemcitabine/nab-paclitaxel (1000/100 mg/m 2 ) and 67.5 Gy/15 fractions. At a median follow-up of 40.6 months for living patients the median OS was 14.5 months (95% confidence interval [CI], 10.9-28.2 months). The median OS for patients with Eastern Collaborative Oncology Group 0 and carbohydrate antigen 19-9 <90 were 34.1 (95% CI, 13.6-54.1) and 43.0 (95% CI, 8.0-not reached) months, respectively. Two-year LPFS and DMFS were 85% (95% CI, 63%-94%) and 57% (95% CI, 34%-73%), respectively., Conclusions: Full-dose gemcitabine/nab-paclitaxel with ablative magnetic resonance guided radiation therapy dosing is safe in patients with BR/LA-PDAC, with promising LPFS and DMFS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Early clinical results on the application of magnetic resonance imaging (MRI) coupled with a linear accelerator to deliver Magnetic Resonance-guided Radiation Therapy (MRgRT) have demonstrated feasibility for safe delivery of stereotactic body radiation therapy in treatment of oligometastatic disease. Here, we set out to review the clinical evidence and challenges associated with MRgRT in this setting., Methods and Materials: We performed a systematic review of the literature pertaining to clinical experiences and trials on the use of MRgRT primarily for the treatment of oligometastatic cancers. We reviewed the opportunities and challenges associated with the use of MRgRT., Results: Benefits of MRgRT pertaining to superior soft-tissue contrast, real-time imaging and gating, and online adaptive radiation therapy facilitate safe and effective dose escalation to oligometastatic tumors while simultaneously sparing surrounding healthy tissues. Challenges concerning further need for clinical evidence and technical considerations related to planning, delivery, quality assurance of hypofractionated doses, and safety in the MRI environment must be considered., Conclusions: The promising early indications of safety and effectiveness of MRgRT for stereotactic body radiation therapy-based treatment of oligometastatic disease in multiple treatment locations should lead to further clinical evidence to demonstrate the benefit of this technology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose/objective: Magnetic resonance-guided radiation therapy (MRgRT) utilization is rapidly expanding worldwide, driven by advanced capabilities including continuous intrafraction visualization, automatic triggered beam delivery, and on-table adaptive replanning (oART). Our objective was to describe patterns of 0.35Tesla(T)-MRgRT (MRIdian) utilization in the United States (US) among early adopters of this novel technology., Materials/methods: Anonymized administrative data from all US MRIdian treatment systems were extracted for patients completing treatment from 2014 to 2020. Detailed treatment information was available for all MRIdian linear accelerator (linac) systems and some cobalt systems., Results: Seventeen systems at 16 centers delivered 5736 courses and 36,389 fractions (fraction details unavailable for 1223 cobalt courses), of which 21.1% were adapted. Ultra-hypofractionation (UHfx) (1-5 fractions) was used in 70.3% of all courses. At least one adaptive fraction was used for 38.5% of courses (average 1.7 adapted fractions/course), with higher oART use in UHfx dose schedules (47.7% of courses, average 1.9 adapted fractions per course). The most commonly treated organ sites were pancreas (20.7%), liver (16.5%), prostate (12.5%), breast (11.5%), and lung (9.4%). Temporal trends show a compounded annual growth rate (CAGR) of 59.6% in treatment courses delivered, with a dramatic increase in use of UHfx to 84.9% of courses in 2020 and similar increase in use of oART to 51.0% of courses., Conclusions: This is the first comprehensive study reporting patterns of utilization among early adopters of MRIdian in the US. Intrafraction MR image-guidance, advanced motion management, and increasing adoption of adaptive radiation therapy has led to a substantial transition to ultra-hypofractionated regimens. 0.35  T -MRgRT has been predominantly used to treat abdominal and pelvic tumors with increasing use of on-table adaptive replanning, which represents a paradigm shift in radiation therapy., Competing Interests: Michael Chuong reports grants and personal fees from ViewRay; personal fees and non-financial support from Accuray and Sirtex; participates on an advisory board for ViewRay. Mary Ann Clark and Martin Fuss are employees and shareholders of ViewRay, Inc. Lauren E. Henke reports consulting fees from ViewRay, Inc. and Radialogica and grants and other from Varian Medical Systems. Amar Kishan has a grant with ASTRO-PCF, consulting fees and honoraria paid by Varian Medical Systems, Inc. and ViewRay, Inc., shareholder of ViewRay, Inc. Lorraine Portelance has a consulting contract with ViewRay, Inc.Parag J. Parikh reports stock and other ownership of Nuvaira, honoraria, speakers’ bureau from ViewRay, and research funding from ViewRay. Michael F. Bassetti has a research grant from Astra Zeneca and royalties or licenses from National Jewish Hospital (Bcl3 antibody and Spi2A antibody). Himanshu Nagar participates on advisory boards for Bristol Meyers Squibb and ViewRay, Inc. Stephen A. Rosenberg participates on ViewRay medical advisory boards, Lung Research Consortium (both non-compensated), and has research grants from ViewRay; consulting fees paid by Novocure. Minesh Mehta has consulting fees from Karyopharm, Sapience, Zap, Mevion, Xoft, Tocagen; he is on the Board of Directors of Oncoceutics and owns stock in Oncoceutics and Chimerix. Bassem I. Zaki received manuscript support from ViewRay, Inc. and is a member of the ASTRO guideline subcommittee. Tamer Refaat reports nothing to disclose. Justin Rineer reports nothing to disclose. Adam Smith reports nothing to disclose. Steven Seung reports nothing to disclose. Bassem I. Zaki reports leadership role on ASTRO’s Guidelines Committee. Raymond H. Mak reports grants from ViewRay; consulting fees from ViewRay and Astra Zeneca., (© 2022 The Author(s).)

Trauma continues to be the leading cause of death and disability in the U.S. for those under the age of 44, making it a prominent public health problem. Recent literature suggests that geographical maldistribution of Trauma Centers (TCs), and the resultant increase of the access time to the nearest TC, could impact patient safety and increase disability or mortality. To address this issue, we introduce the Trauma Center Location Problem (TCLP) that determines the optimal number and location of TCs in order to improve patient safety. We model patient safety through a surrogate measure of mistriages, which refers to a mismatch in the injury severity of a trauma patient and the destination hospital. Our proposed bi-objective optimization model directly accounts for the two types of mistriages, system-related under-triage (srUT) and over-triage (srOT), both of which are estimated using a notional tasking algorithm. We propose a heuristic based on the Particle Swarm Optimization framework to efficiently derive a near-optimal solution to the TCLP for realistic problem sizes. Based on 2012 data from the state of Ohio, we observe that the solutions are sensitive to the choice of weights for srUT and srOT, volume requirements at a TC, and the two thresholds used to mimic EMS decisions. Using our approach to optimize that network resulted in over 31.5% reduction in the objective with only 1 additional TC; redistribution of the existing 21 TCs led to 30.4% reduction., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Short-course radiation followed by chemotherapy as total neoadjuvant therapy has been investigated primarily in Europe and Australia with increasing global acceptance. There are limited data on this regimen's use in the United States, however, potentially delaying implementation., Objective: This study aimed to compare clinical performance and oncologic outcomes of 2 rectal cancer neoadjuvant treatment modalities: short-course total neoadjuvant therapy versus standard chemoradiation., Design: This is a retrospective cohort study., Setting: This study was performed at a National Cancer Institute-designated cancer center., Patients: A total of 413 patients had locally advanced rectal cancers diagnosed from June 2009 to May 2018 and received either short-course total neoadjuvant therapy or standard chemoradiation., Interventions: There were 187 patients treated with short-course total neoadjuvant therapy (5 × 5 Gy radiation followed by consolidation oxaliplatin-based chemotherapy) compared with 226 chemoradiation recipients (approximately 50.4 Gy radiation in 28 fractions with concurrent fluorouracil equivalent)., Main Outcome Measures: Primary end points were tumor downstaging, measured by complete response and "low" neoadjuvant rectal score rates, and progression-free survival. Secondary analyses included treatment characteristics and completion, sphincter preservation, and recurrence rates., Results: Short-course total neoadjuvant therapy was associated with higher rates of complete response (26.2% vs 17.3%; p = 0.03) and "low" neoadjuvant rectal scores (40.1% vs 25.7%; p < 0.01) despite a higher burden of node-positive disease (78.6% vs 68.9%; p = 0.03). Short-course recipients also completed trimodal treatment more frequently (88.4% vs 50.4%; p < 0.01) and had fewer months with temporary stomas (4.8 vs 7.0; p < 0.01). Both regimens achieved comparable local control (local recurrence: 2.7% short-course total neoadjuvant therapy vs 2.2% chemoradiation, p = 0.76) and 2-year progression-free survival (88.2% short-course total neoadjuvant therapy (95% CI, 82.9-93.5) vs 85.6% chemoradiation (95% CI, 80.5-90.7))., Limitations: Retrospective design, unbalanced disease severity, and variable dosing of neoadjuvant consolidation chemotherapy were limitations of this study., Conclusions: Short-course total neoadjuvant therapy was associated with improved downstaging and similar progression-free survival compared with chemoradiation. These results were achieved with shortened radiation courses, improved treatment completion, and less time with diverting ostomies. Short-course total neoadjuvant therapy is an optimal regimen for locally advanced rectal cancer. See Video Abstract at http://links.lww.com/DCR/B724.TERAPIA NEOADYUVANTE TOTAL CON RADIACIÓN DE CORTA DURACIÓN: EXPERIENCIA ESTADOUNIDENSE DE UNA TERAPIA NEOADYUVANTE CONTRA EL CÁNCER DE RECTO., Antecedentes: La radiación de corta duración seguida de quimioterapia como terapia neoadyuvante total se ha investigado principalmente en Europa y Australia con una aceptación mundial cada vez mayor. Sin embargo, datos limitados sobre el uso de este régimen en los Estados Unidos, han potencialmente retrasando su implementación., Objetivo: Comparar el desempeño clínico y los resultados oncológicos de dos modalidades de tratamiento neoadyuvante del cáncer de recto: terapia neoadyuvante total de corta duración versus quimioradiación. estándar., Diseo: Cohorte retrospectivo., Ajuste: Centro oncológico designado por el NCI., Pacientes: Un total de 413 cánceres rectales localmente avanzados diagnosticados entre junio de 2009 y mayo de 2018 que recibieron cualquiera de los regímenes neoadyuvantes., Intervenciones: Hubo 187 pacientes tratados con terapia neoadyuvante total de ciclo corto (radiación 5 × 5 Gy seguida de quimioterapia de consolidación basada en oxaliplatino) en comparación con 226 pacientes de quimiorradiación (aproximadamente 50,4 Gy de radiación en 28 fracciones con equivalente de fluorouracilo concurrente)., Principales Medidas De Resultado: Los criterios primarios de valoración fueron la disminución del estadio del tumor, medido por la respuesta completa y las tasas de puntuación rectal neoadyuvante "baja", y la supervivencia libre de progresión. Los análisis secundarios incluyeron las características del tratamiento y las tasas de finalización, conservación del esfínter y recurrencia., Resultados: La terapia neoadyuvante total de corta duración, se asoció con tasas más altas de respuesta completa (26,2% versus 17,3%, p = 0,03) y puntuaciones rectales neoadyuvantes "bajas" (40,1% versus 25,7%, p < 0,01) a pesar de una mayor carga de enfermedad con ganglios positivos (78,6% versus 68,9%, p = 0,03). Los pacientes de ciclo corto también completaron el tratamiento trimodal con mayor frecuencia (88,4% versus 50,4%, p < 0,01) y tuvieron menos meses con estomas temporales (4,8 versus 7,0, p < 0,01). Ambos regímenes lograron un control local comparable (recidiva local: 2,7% de SC-TNT versus 2,2% de TRC, p = 0,76) y supervivencia libre de progresión a 2 años (88,2% de SC-TNT [IC: 82,9 - 93,5] versus 85,6% CRT [CI: 80,5 - 90,7])., Limitaciones: Diseño retrospectivo, gravedad de la enfermedad desequilibrada y dosificación variable de quimioterapia neoadyuvante de consolidación., Conclusiones: La terapia neoadyuvante total de ciclo corto se asoció con una mejora en la reducción del estadio y una supervivencia libre de progresión similar en comparación con la quimioradiación. Estos resultados se lograron con ciclos de radiación más cortos, tratamientos mejor finalizados y menos tiempo en ostomías de derivación. La terapia neoadyuvante total de corta duración es un régimen óptimo para el cáncer de recto localmente avanzado. Consulte Video Resumen en http://links.lww.com/DCR/B724. (Traducción- Dr. Fidel Ruiz Healy)., (Copyright © The ASCRS 2021.)

Naturally occurring postural instabilities that occur while standing and walking elicit specific cortical responses in the fronto-central regions (N1 potentials) followed by corrective balance responses to prevent falling. However, no framework could simultaneously track different biomechanical parameters preceding N1s, predict N1s, and assess their predictive power. Here, we propose a framework and show its utility by examining cortical activity (through electroencephalography [EEG]), ground reaction forces, and head acceleration in the anterior-posterior (AP) direction. Ten healthy young adults carried out a balance task of standing on a support surface with or without sway referencing in the AP direction, amplifying, or dampening natural body sway. Using independent components from the fronto-central cortical region obtained from subject-specific head models, we first robustly validated a prior approach on identifying low-amplitude N1 potentials before early signs of balance corrections. Then, a machine learning algorithm was used to evaluate different biomechanical parameters obtained before N1 potentials, to predict the occurrence of N1s. When different biomechanical parameters were directly compared, the time to boundary (TTB) was found to be the best predictor of the occurrence of upcoming low-amplitude N1 potentials during a balance task. Based on these findings, we confirm that the spatio-temporal characteristics of the center of pressure (COP) might serve as an essential parameter that can facilitate the early detection of postural instability in a balance task. Extending our framework to identify such biomarkers in dynamic situations like walking might improve the implementation of corrective balance responses through brain-machine-interfaces to reduce falls in the elderly.

Importance: Predicting outcomes in patients receiving neoadjuvant therapy for rectal cancer is challenging because of tumor downstaging. Validated clinical calculators that can estimate recurrence-free survival (RFS) and overall survival (OS) among patients with rectal cancer who have received multimodal therapy are needed., Objective: To develop and validate clinical calculators providing estimates of rectal cancer recurrence and survival that are better for individualized decision-making than the American Joint Committee on Cancer (AJCC) staging system or the neoadjuvant rectal (NAR) score., Design, Setting, and Participants: This prognostic study developed risk models, graphically represented as nomograms, for patients with incomplete pathological response using Cox proportional hazards and multivariable regression analyses with restricted cubic splines. Because patients with complete pathological response to neoadjuvant therapy had uniformly favorable outcomes, their predictions were obtained separately. The study included 1400 patients with stage II or III rectal cancer who received treatment with chemotherapy, radiotherapy, and surgery at 2 comprehensive cancer centers (Memorial Sloan Kettering [MSK] Cancer Center and Siteman Cancer Center [SCC]) between January 1, 1998, and December 31, 2017. Patients from the MSK cohort received chemoradiation, surgery, and adjuvant chemotherapy from January 1, 1998, to December 31, 2014; these patients were randomly assigned to either a model training group or an internal validation group. Models were externally validated using data from the SCC cohort, who received either chemoradiation, surgery, and adjuvant chemotherapy (chemoradiotherapy group) or short-course radiotherapy, consolidation chemotherapy, and surgery (total neoadjuvant therapy with short-course radiotherapy group) from January 1, 2009, to December 31, 2017. Data were analyzed from March 1, 2020, to January 10, 2021., Exposures: Chemotherapy, radiotherapy, chemoradiotherapy, and surgery., Main Outcomes and Measures: Recurrence-free survival and OS were the outcome measures, and the discriminatory performance of the clinical calculators was measured with concordance index and calibration plots. The ability of the clinical calculators to predict RFS and OS was compared with that of the AJCC staging system and the NAR score. The models for RFS and OS among patients with incomplete pathological response included postoperative pathological tumor category, number of positive lymph nodes, tumor distance from anal verge, and large- and small-vessel venous and perineural invasion; age was included in the risk model for OS. The final clinical calculators provided RFS and OS estimates derived from Kaplan-Meier curves for patients with complete pathological response and from risk models for patients with incomplete pathological response., Results: Among 1400 total patients with locally advanced rectal cancer, the median age was 57.8 years (range, 18.0-91.9 years), and 863 patients (61.6%) were male, with tumors at a median distance of 6.7 cm (range, 0-15.0 cm) from the anal verge. The MSK cohort comprised 1069 patients; of those, 710 were assigned to the model training group and 359 were assigned to the internal validation group. The SCC cohort comprised 331 patients; of those, 200 were assigned to the chemoradiotherapy group and 131 were assigned to the total neoadjuvant therapy with short-course radiotherapy group. The concordance indices in the MSK validation data set were 0.70 (95% CI, 0.65-0.76) for RFS and 0.73 (95% CI, 0.65-0.80) for OS. In the external SCC data set, the concordance indices in the chemoradiotherapy group were 0.71 (95% CI, 0.62-0.81) for RFS and 0.72 (95% CI, 0.59-0.85) for OS; the concordance indices in the total neoadjuvant therapy with short-course radiotherapy group were 0.62 (95% CI, 0.49-0.75) for RFS and 0.67 (95% CI, 0.46-0.84) for OS. Calibration plots confirmed good agreement between predicted and observed events. These results compared favorably with predictions based on the AJCC staging system (concordance indices for MSK validation: RFS = 0.69 [95% CI, 0.64-0.74]; OS = 0.67 [95% CI, 0.58-0.75]) and the NAR score (concordance indices for MSK validation: RFS = 0.56 [95% CI, 0.50-0.63]; OS = 0.56 [95% CI, 0.46-0.66]). Furthermore, the clinical calculators provided more individualized outcome estimates compared with the categorical schemas (eg, estimated RFS for patients with AJCC stage IIIB disease ranged from 7% to 68%)., Conclusions and Relevance: In this prognostic study, clinical calculators were developed and validated; these calculators provided more individualized estimates of the likelihood of RFS and OS than the AJCC staging system or the NAR score among patients with rectal cancer who received multimodal treatment. The calculators were easy to use and applicable to both short- and long-course radiotherapy regimens, and they may be used to inform surveillance strategies and facilitate future clinical trials and statistical power calculations.

Purpose: Short-course radiation therapy (SCRT) and nonoperative management are emerging paradigms for rectal cancer treatment. This clinical trial is the first to evaluate SCRT followed by chemotherapy as a nonoperative treatment modality., Methods: Patients with nonmetastatic rectal adenocarcinoma were treated on the single-arm, Nonoperative Radiation Management of Adenocarcinoma of the Lower Rectum study of SCRT followed by chemotherapy. Patients received 25 Gy in 5 fractions to the pelvis followed by FOLFOX ×8 or CAPOX ×5 cycles. Patients with clinical complete response (cCR) underwent nonoperative surveillance. The primary end point was cCR at 1 year. Secondary end points included safety profile and anorectal function., Results: From June 2016 to March 2019, 19 patients were treated (21% stage I, 32% stage II, and 47% stage III disease). At a median follow-up of 27.7 months for living patients, the 1-year cCR rate was 68%. Eighteen of 19 patients are alive without evidence of disease. Patients with cCR versus without had improved 2-year disease-free survival (93% vs 67%; P = .006), distant metastasis-free survival (100% vs 67%; P = .03), and overall survival (100% vs 67%; P = .03). Involved versus uninvolved circumferential resection margin on magnetic resonance imaging was associated with less initial cCR (40% vs 93%; P = .04). Anorectal function by Functional Assessment of Cancer Therapy-Colorectal cancer score at 1 year was not different than baseline. There were no severe late effects., Conclusions: Treatment with SCRT and chemotherapy resulted in high cCR rate, intact anorectal function, and no severe late effects. NCT02641691., (Copyright © 2021. Published by Elsevier Inc.)

Explicit knowledge of object center of mass or CM location fails to guide anticipatory scaling of digit forces necessary for dexterous manipulation. We previously showed that allowing young adults to choose where to grasp the object entailed an ability to use arbitrary color cues about object CM location to gradually minimize object tilt across several trials. This conditional learning was achieved through accurate anticipatory modulation of digit position using the color cues. However, it remains unknown how aging affects the ability to use explicit color cues about object CM location to modulate digit placement for dexterous manipulation. We instructed healthy older and young adults to learn a manipulation task using arbitrary color cues about object CM location. Subjects were required to exert clockwise, counterclockwise, or no torque on the object according to the color cue and lift the object while minimizing its tilt. Older adults produced larger torque error during conditional learning trials, resulting in a slower rate of learning than young adults. Importantly, older adults showed impaired anticipatory modulation of digit position when information of the CM location was available via explicit color cues. The older adults also did not modulate their digit forces to compensate for this impairment. Interestingly, however, anticipatory modulation of digit position was intact in the same individuals when information of object CM location was implicitly conveyed from trial-to-trial. We discuss our findings in relation to age-dependent changes in processes and neural network essential for learning dexterous manipulation using arbitrary color cue about object property. NEW & NOTEWORTHY We studied whether older adults are able to predictively modulate digit position using arbitrary color cues indicating object center of mass location for dexterous manipulation. Older adults showed an impaired ability to modulate digit position using the color cues when compared with young adults. Interestingly, similar impairments were not found when same older individuals learned the task using implicit knowledge. Our findings suggest an age-related impairment specifically in the conditional learning mechanisms for dexterous manipulation.

Introduction: Pancreatic adenocarcinoma (PAC) has some of the worst treatment outcomes for any solid tumor. PAC creates substantial difficulty for effective treatment with traditional RT delivery strategies primarily secondary to its location and limited visualization using CT. Several of these challenges are uniquely addressed with MR-guided RT. We sought to summarize and place into context the currently available literature on MR-guided RT specifically for PAC., Methods: A literature search was conducted to identify manuscript publications since September 2014 that specifically used MR-guided RT for the treatment of PAC. Clinical outcomes of these series are summarized, discussed, and placed into the context of the existing pancreatic literature. Multiple international experts were involved to optimally contextualize these publications., Results: Over 300 manuscripts were reviewed. A total of 6 clinical outcomes publications were identified that have treated patients with PAC using MR guidance. Successes, challenges, and future directions for this technology are evident in these publications. MR-guided RT holds theoretical promise for the treatment of patients with PAC. As with any new technology, immediate or dramatic clinical improvements associated with its use will take time and experience. There remain no prospective trials, currently publications are limited to small retrospective experiences. The current level of evidence for MR guidance in PAC is low and requires significant expansion. Future directions and ongoing studies that are currently open and accruing are identified and reviewed., Conclusions: The potential promise of MR-guided RT for PAC is highlighted, the challenges associated with this novel therapeutic intervention are also reviewed. Outcomes are very early, and will require continued and long term follow up. MR-guided RT should not be viewed in the same fashion as a novel chemotherapeutic agent for which dosing, administration, and toxicity has been established in earlier phase studies. Instead, it should be viewed as a novel procedural intervention which must be robustly tested, refined and practiced before definitive conclusions on the potential benefits or detriments can be determined. The future of MR-guided RT for PAC is highly promising and the potential implications on PAC are substantial., Competing Interests: LaD: Licensing agreement with Research, funds paid to institution. SR: Consults for Novocure Gani: University Hospital Tübingen receives financial and technical support including costs for travels and symposia from Elekta AB (Stockholm, Sweden) under a research agreement. The department of radiation oncology at the Medical College of Wisconsin receives research funding from Elekta AB. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hall, Small, Paulson, Koay, Crane, Intven, Daamen, Meijer, Heerkens, Bassetti, Rosenberg, Aitken, Myrehaug, Dawson, Lee, Gani, Chuong, Parikh and Erickson.)

The era of real-time radiotherapy is upon us. Robotic and gimbaled linac tracking are clinically established technologies with the clinical realization of couch tracking in development. Multileaf collimators (MLCs) are a standard equipment for most cancer radiotherapy systems, and therefore MLC tracking is a potentially widely available technology. MLC tracking has been the subject of theoretical and experimental research for decades and was first implemented for patient treatments in 2013. The AAPM Task Group 264 Safe Clinical Implementation of MLC Tracking in Radiotherapy Report was charged to proactively provide the broader radiation oncology community with (a) clinical implementation guidelines including hardware, software, and clinical indications for use, (b) commissioning and quality assurance recommendations based on early user experience, as well as guidelines on Failure Mode and Effects Analysis, and (c) a discussion of potential future developments. The deliverables from this report include: an explanation of MLC tracking and its historical development; terms and definitions relevant to MLC tracking; the clinical benefit of, clinical experience with and clinical implementation guidelines for MLC tracking; quality assurance guidelines, including example quality assurance worksheets; a clinical decision pathway, future outlook and overall recommendations., (© 2020 American Association of Physicists in Medicine.)

Gait is one of the fundamental behaviors we use to interact with the world. The functionality of the locomotor system is thus related to enriching interactions with our environment. The posterior parietal cortex (PPC) has been found to contribute to motor adaptation during both visuomotor and postural adaptation tasks. Additionally, structural or functional deficits of the PPC lead to impairments in gaits such as shortened steps and increased step width. Based on the aforementioned roles of the PPC, and the importance of gait adaptability, the current investigation sought to identify the role of the PPC in gait adaptation. To achieve this, we performed transcranial direct current stimulation (tDCS) over the bilateral PPC before performing a split-belt treadmill gait adaptation paradigm. We used three stimulation conditions in a within-subject design. tDCS was administered in a randomized and double-blinded order. Following each stimulation session, subjects first performed baseline walking with both belts running at the same speed. Then, subjects walked for 15 min on an uncoupled treadmill, with the belts being driven at a 3:1 speed ratio. Last, they returned to normal (i.e., tied-belt) walking for 5 min. Results from 15 young and healthy subjects identified that subjects required more steps to adapt to split-belt walking following the suppression of the left hemisphere PPC, contralateral to the fast belt. Furthermore, while suppression of the left hemisphere PPC did not increase the number of steps required to re-adapt to tied-belt walking, this condition did lead to increased magnitude of after-effects. Together, these findings indicate that the PPC is involved in locomotor adaptation. These results support previous literature regarding the upper body or postural adaptation and extend these findings to the realm of gait. Results highlight the PPC as a potential target for neurorehabilitation designed to improve gait adaptability., (Copyright © 2020 Young, Parikh and Layne.)

Comprehensive analysis of daily, online adaptive plan quality and safety in magnetic resonance imaging (MRI) guided radiation therapy is critical to its widespread use. Artificial neural network models developed with offline plans created after simulation were used to analyze and compare online plans that were adapted and reoptimized in real time prior to treatment. Roughly one third of 60 Co adapted plans were of inferior quality relative to fully optimized, offline plans, but MRI-linac adapted plans were essentially equivalent to offline plans. The models also enabled clear justification that MRI-linac plans are superior to 60 Co in an overwhelming majority of cases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Effective central sensory integration of visual, vestibular, and proprioceptive information is required to promote adaptability in response to changes in the environment during postural control. Patients with a lesion in the posterior parietal cortex (PPC) have an impaired ability to form an internal representation of body position, an important factor for postural control and adaptation. Suppression of PPC excitability has also been shown to decrease postural stability in some contexts. As of yet, it is unknown whether stimulation of the PPC may influence postural adaptation. This investigation aimed to identify whether transcranial direct current stimulation (tDCS) of the bilateral PPC could modulate postural adaptation in response to a bipedal incline postural adaptation task. Using young, healthy subjects, we delivered tDCS over bilateral PPC followed by bouts of inclined stance (incline-interventions). Analysis of postural after-effects identified differences between stimulation conditions for maximum lean after-effect (LAE; p = 0.005) as well as a significant interaction between condition and measurement period for the average position ( p = 0.03). We identified impaired postural adaptability following both active stimulation conditions. Results reinforce the notion that the PPC is involved in motor adaptation and extend this line of research to the realm of standing posture. The results further highlight the role of the bilateral PPC in utilizing sensory feedback to update one's internal representation of verticality and demonstrates the diffuse regions of the brain that are involved in postural control and adaptation. This information improves our understanding of the role of the cortex in postural control, highlighting the potential for the PPC as a target for sensorimotor rehabilitation., (Copyright © 2020 Young, Parikh and Layne.)

Dexterous object manipulation is a hallmark of human evolution and a critical skill for everyday activities. A previous work has used a grasping context that predominantly elicits memory-based control of digit forces by constraining where the object should be grasped. For this "constrained" grasping context, the primary motor cortex (M1) is involved in storage and retrieval of digit forces used in previous manipulations. In contrast, when choice of digit contact points is allowed ("unconstrained" grasping), behavioral studies revealed that forces are adjusted, on a trial-to-trial basis, as a function of digit position. This suggests a role of online feedback of digit position for force control. However, despite the ubiquitous nature of unconstrained hand-object interactions in activities of daily living, the underlying neural mechanisms are unknown. Using noninvasive brain stimulation, we found the role of primary motor cortex (M1) and somatosensory cortex (S1) to be sensitive to grasping context. In constrained grasping, M1 but not S1 is involved in storing and retrieving learned digit forces and position. In contrast, in unconstrained grasping, M1 and S1 are involved in modulating digit forces to position. Our findings suggest that the relative contribution of memory and online feedback modulates sensorimotor cortical interactions for dexterous manipulation., (© The Author(s) 2019. Published by Oxford University Press.)

Colorectal cancer is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiotherapy in colorectal cancer. We used human and mouse colorectal cancer cell lines, organoids, mouse syngeneic colorectal cancer tumor graft models, and colorectal cancer tissues from patients who received radiotherapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation induced IDO1 overexpression in colorectal cancer through type I and II IFN signaling. IDO1 enzymatic activity directly influenced colorectal cancer radiation sensitivity. IDO1 inhibition sensitized colorectal cancer to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side effects. These data demonstrated that IDO1 inhibition potentiates radiotherapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer., (©2020 American Association for Cancer Research.)

Primary somatosensory cortex (S1) is involved in pain processing and thus its suppression using neuromodulatory techniques such as continuous theta burst stimulation (cTBS) might be a potential pain management strategy in patients with neuropathic pain. cTBS over S1 is known to elevate pain threshold in young adults. However, the time course of this after-effect is unknown. Furthermore, the effect of cTBS over S1 on pain threshold might be confounded by changes in the excitability of primary motor cortex (M1), an area known to be involved in pain processing, due to spread of current. Therefore, whether S1 plays a role in pain processing independent of M1 also remains unknown. The corticospinal excitability (CSE) can provide a measure of M1 excitability because cTBS over M1 is known to reduce CSE. Here, we studied the time-course of the effects of MRI-guided cTBS over S1 on electrical pain threshold (EPT) and CSE. Ten healthy young adults received cTBS over S1 and sham stimulation in counterbalanced sessions at least 5 days apart. EPT and CSE were recorded before and following cTBS over S1. We assessed each measure once before stimulation and then every 10 min starting immediately after stimulation until 40 min. cTBS over S1 elevated EPT compared to sham stimulation with the after-effect lasting for 40 min. We observed no change in CSE following cTBS and sham stimulation. Our findings suggest that cTBS over S1 can elevate EPT for 40 min without altering M1 excitability., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The Calypso Beacon transponder has been modified by the addition of a nitinol anchor feature to allow for positional stability when implanted bronchoscopically into the lung. The purpose of this study was to confirm the feasibility and safety of anchored transponder placement and feasibility of lung target localization and tracking., Methods and Materials: This study enrolled patients with histologically confirmed cancer in the lung (primary or metastatic) who were scheduled to receive external beam radiation therapy. Three anchored transponders were implanted via flexible bronchoscopy into small (approximately 2- to 2.5-mm diameter) airways. Patient alignment at each radiation fraction was performed with the Calypso system, and anchored transponder position was tracked during radiation delivery. The primary endpoint was defined as the ability to localize at least 85% of the patients during the first week of treatment. Four follow-up visits were specified including a posttreatment assessment and every 3 months up to 1 year., Results: A total of 69 patients underwent anchored transponder placement, and all 207 implanted anchored transponders were visible on the treatment-planning simulation computed tomography scan. Sixty-seven patients underwent radiation therapy, and localization was successful in 66 cases (98.5%). With 1 failure in 67 cases, the P value for rejecting the null hypothesis was <.001 and the primary objective of the study met. Five adverse events in 5 patients were potentially attributed to the study device or implantation procedure, consisting of pneumonia (2 cases), pleural abscess (1 case), and pneumothorax (2 cases). Two serious events (cardiac arrest and acute hypotension) were attributed to anesthesia during the implantation procedure., Conclusions: This study strongly supports that anchored transponders are safe, positionally stable, and useful for lung tumor localization and monitoring., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Neuronal firing rate variability prior to movement onset contributes to trial-to-trial variability in primate behavior. However, in humans, whether similar mechanisms contribute to trial-to-trial behavioral variability remains unknown. We investigated the time-course of trial-to-trial variability in corticospinal excitability (CSE) using transcranial magnetic stimulation (TMS) during a self-paced reach-to-grasp task. We hypothesized that CSE variability will be modulated prior to the initiation of reach and that such a modulation would explain trial-to-trial behavioral variability. Able-bodied individuals were visually cued to plan their grip force before exertion of either 30% or 5% of their maximum pinch force capacity on an object. TMS was delivered at six time points (0.5, 0.75, 1, 1.1, 1.2, and 1.3 s) following a visual cue that instructed the force level. We first modeled the relation between CSE magnitude and its variability at rest ( n = 12) to study the component of CSE variability pertaining to the task but not related to changes in CSE magnitude ( n = 12). We found an increase in CSE variability from 1.2 to 1.3 s following the visual cue at 30% but not at 5% of force. This effect was temporally dissociated from the decrease in CSE magnitude that was observed from 0.5 to 0.75 s following the cue. Importantly, the increase in CSE variability explained at least ∼40% of inter-individual differences in trial-to-trial variability in time to peak force rate. These results were found to be repeatable across studies and robust to different analysis methods. Our findings suggest that the neural mechanisms underlying modulation in CSE variability and CSE magnitude are distinct. Notably, the extent of modulation in variability in corticospinal system prior to grasp within individuals may explain their trial-to-trial behavioral variability., (Copyright © 2019 Rao and Parikh.)

Objective: Robotic devices show promise in restoring motor abilities to individuals with upper limb paresis or amputations. However, these systems are still limited in obtaining reliable signals from the human body to effectively control them. We propose that these robotic devices can be controlled through scalp electroencephalography (EEG), a neuroimaging technique that can capture motor commands through brain rhythms. In this work, we studied if EEG can be used to predict an individual's grip forces produced by the hand., Approach: Brain rhythms and grip forces were recorded from able-bodied human subjects while they performed an isometric force production task and a grasp-and-lift task. Grip force trajectories were reconstructed with a linear model that incorporated delta band (0.1-1 Hz) voltage potentials and spectral power in the theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), low gamma (30-50 Hz), mid gamma (70-110 Hz), and high gamma (130-200 Hz) bands. Trajectory reconstruction models were trained and tested through 10-fold cross validation., Main Results: Modest accuracies were attained in reconstructing grip forces during isometric force production (median r  =  0.42), and the grasp-and-lift task (median r  =  0.51). Predicted trajectories were also analyzed further to assess the linear models' performance based on task requirements. For the isometric force production task, we found that predicted grip trajectories did not yield static grip forces that were distinguishable in magnitude across three task conditions. For the grasp-and-lift task, we estimate there would be an approximate 25% error in distinguishing when a user wants to hold or release an object., Significance: These findings indicate that EEG, a noninvasive neuroimaging modality, has predictive information in neural features associated with finger force control and can potentially contribute to the development of brain machine interfaces (BMI) for performing activities of daily living.

Radiation therapy (RT) is an essential component of effective cancer care and is used across nearly all cancer types. The delivery of RT is becoming more precise through rapid advances in both computing and imaging. The direct integration of magnetic resonance imaging (MRI) with linear accelerators represents an exciting development with the potential to dramatically impact cancer research and treatment. These impacts extend beyond improved imaging and dose deposition. Real-time MRI-guided RT is actively transforming the work flows and capabilities of virtually every aspect of RT. It has the opportunity to change entirely the delivery methods and response assessments of numerous malignancies. This review intends to approach the topic of MRI-based RT guidance from a vendor neutral and international perspective. It also aims to provide an introduction to this topic targeted towards oncologists without a speciality focus in RT. Speciality implications, areas for physician education and research opportunities are identified as they are associated with MRI-guided RT. The uniquely disruptive implications of MRI-guided RT are discussed and placed in context. We further aim to describe and outline important future changes to the speciality of radiation oncology that will occur with MRI-guided RT. The impacts on RT caused by MRI guidance include target identification, RT planning, quality assurance, treatment delivery, training, clinical workflow, tumour response assessment and treatment scheduling. In addition, entirely novel research areas that may be enabled by MRI guidance are identified for future investigation., (Published by Elsevier Ltd.)

Neuroimaging studies have provided evidence for the involvement of frontal and parietal cortices in postural control. However, the specific role of these brain areas for postural control remains to be known. Here, we investigated the effects of disruptive transcranial magnetic stimulation (TMS) over supplementary motor areas (SMA) during challenging continuous balance task in healthy young adults. We hypothesized that a virtual lesion of SMA will alter activation within the brain network identified using electroencephalography (EEG) and impair performance of the postural task. Twenty healthy young adults received either continuous theta burst stimulation (cTBS) or sham stimulation over SMA followed by the performance of a continuous balance task with or without somatosensory input distortion created by sway-referencing the support surface. cTBS over SMA compared to sham stimulation showed a smaller increase in root mean square of center of pressure as the difficulty of continuous balance task increased suggestive of altered postural control mechanisms to find a stable solution under challenging sensory conditions. Consistent with earlier studies, we found sources of EEG activation within anterior cingulate (AC), cingulate gyrus (CG), bilateral posterior parietal regions (PPC) during the balance task. Importantly, cTBS over SMA compared to sham stimulation altered EEG power within the identified fronto-parietal regions. These findings suggest that the changes in activation within distant fronto-parietal brain areas following cTBS over SMA contributed to the altered postural behavior. Our study confirms a critical role of AC, CG, and both PPC regions in calibrating online postural responses during a challenging continuous balance task., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated., Methods: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method., Results: We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III-IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX., Conclusions: This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Adaptive magnetic resonance imaging-guided radiation therapy (MRgRT) can escalate dose to tumors while minimizing dose to normal tissue. We evaluated outcomes of inoperable pancreatic cancer patients treated using MRgRT with and without dose escalation., Methods: We reviewed 44 patients with inoperable pancreatic cancer treated with MRgRT. Treatments included conventional fractionation, hypofractionation, and stereotactic body radiation therapy. Patients were stratified into high-dose (biologically effective dose [BED 10 ] >70) and standard-dose groups (BED 10 ≤70). Overall survival (OS), freedom from local failure (FFLF) and freedom from distant failure (FFDF) were evaluated using Kaplan-Meier method. Cox regression was performed to identify predictors of OS. Acute gastrointestinal (GI) toxicity was assessed for 6 weeks after completion of RT., Results: Median follow-up was 17 months. High-dose patients (n = 24, 55%) had statistically significant improvement in 2-year OS (49% vs 30%, P = 0.03) and trended towards significance for 2-year FFLF (77% vs 57%, P = 0.15) compared to standard-dose patients (n = 20, 45%). FFDF at 18 months in high-dose vs standard-dose groups was 24% vs 48%, respectively (P = 0.92). High-dose radiation (HR: 0.44; 95% confidence interval [CI]: 0.21-0.94; P = 0.03) and duration of induction chemotherapy (HR: 0.84; 95% CI: 0.72-0.98; P = 0.03) were significantly correlated with OS on univariate analysis but neither factor was independently predictive on multivariate analysis. Grade 3+ GI toxicity occurred in three patients in the standard-dose group and did not occur in the high-dose group., Conclusions: Patients treated with dose-escalated MRgRT demonstrated improved OS. Prospective evaluation of high-dose RT regimens with standardized treatment parameters in inoperable pancreatic cancer patients is warranted., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Yttrium-90 ( 90 Y) microsphere radioembolization enables selective internal radiotherapy for hepatic malignancies. Currently, there is no standard postdelivery imaging and dosimetry of the microsphere distribution to verify treatment. Recent studies have reported utilizing the small positron yield of 90 Y (32 ppm) with positron emission tomography (PET) to perform treatment verification and dosimetry analysis. In this study, we validated a commercial dosimetry software, MIM SurePlan™ LiverY90 (MIM Software Inc., Cleveland, OH), for clinical use., Methods: A MATLAB-based algorithm for 90 Y PET-based dosimetry was developed in-house and validated for the purpose of commissioning the commercial software. The algorithm is based on voxel S values and dosimetry formalism reported in MIRD Pamphlet 17. We validated the in-house algorithm to establish it as the ground truth by comparing results from a digital point phantom and a digital uniform cylinder to manual calculations. Once we validated our in-house MATLAB-based algorithm, we used it to perform acceptance testing and commissioning of the commercial dosimetry software, MIM SurePlan, which uses the same dosimetry formalism. A 0.4 cm/5% gamma test was performed on PET-derived dose maps from each algorithm of uniform digital and nonuniform physical phantoms filled with 90 Y chloride solution. Average dose (D avg ) and minimum dose to 70% (D 70 ) of a given volume of interest (VOI) were compared for the digital phantom, the physical phantom, and five patient cases (27 tumor VOIs), representing different clinical scenarios., Results: The gamma-pass rates were 97.26% and 97.66% for the digital and physical phantoms, respectively. The differences between D avg and D 70 were 0.076% and 0.10% for the digital phantom, respectively, and <5.2% for various VOIs in the physical phantom. In the clinical cases, 96.3% of the VOIs had a difference <5% for D avg , and 88.9% of the VOIs had a difference <5% for D 70 ., Conclusions: Dose calculation results from MIM SurePlan were found to be in good agreement with our in-house algorithm. This indicates that MIM SurePlan performs as it should and, hence, can be deemed accepted and commissioned for clinical use for post-implant PET-based dosimetry of 90 Y radioembolization., (© 2019 American Association of Physicists in Medicine.)

Sensorimotor memory built through previous hand-object interactions allows subjects to plan grasp forces. The memory-based mechanism is particularly effective when contact points on the object do not change across multiple manipulations, thus allowing subjects to generate the same forces in a feedforward fashion. However, allowing subjects to choose where to grasp an object causes trial-to-trial variability in fingertip positioning, suggesting a decreased ability to predict where the object will be grasped. In this scenario, subjects modulate forces on a trial-to-trial basis as a function of fingertip positioning. We suggested that this fingertip force-to-position modulation could be implemented by transforming feedback of digit placement into an accurate distribution of fingertip forces. Thus, decreasing certainty of fingertip position on an object would cause a shift from predominantly memory- to feedback-based force control mechanisms. To gain further insight into these sensorimotor transformation mechanisms, we asked subjects to grasp and lift an object with an asymmetrical center of mass while preventing it from tilting. To isolate the effect of digit placement uncertainty, we designed two experimental conditions that differed in terms of predictability of fingertip position but had similar average fingertip positioning and force distribution. We measured corticospinal excitability to probe possible changes in sensorimotor processing associated with digit placement uncertainty. We found a differential effect of sensorimotor uncertainty after but not before object contact. Our results suggest that sensorimotor integration is rapidly tuned after object contact based on different processing demands for memory versus feedback mechanisms underlying the control of manipulative forces. NEW & NOTEWORTHY The relative contribution of predictive and feedback mechanisms for scaling digit forces to position during dexterous manipulation depends on the predictability of where the object will be grasped. We found that corticospinal excitability shortly after contact was sensitive to digit position predictability. This supports the proposition that distinct sensorimotor integration processes are engaged, depending on the role of feedback about digit placement versus sensorimotor memory in controlling manipulative forces.

Interruptions experienced by nurses may lead to errors as their focus and attention to multiple patient needs are disrupted. As quantitative models to understand the dynamics of interruptions are lacking, the objective of this study is a model of a nurse's work with interruptions, generating insights into the onset of interruptions and evaluating suggested interventions. We observed nurses in a US Level I trauma center for 47.3 h, including 259 interruptions (9.1% of total time) across 580 nursing activities. A stochastic, non-stationary, model of a nurse's work was developed considering source and activity-dependent interruptions, with parameters clustered across similar periods of day. Two interventions emulating 'do not disturb' strategies were evaluated, along with a more focused intervention from suggestions that nurses' phone calls be 'triaged'. Modeled outcomes included the increase in interruptions in other activities due to deferment and changes to the beneficial/detrimental interruption (B/D) ratio. Across-the-board sequestering of nurses by deferring interruptions during medication increased the B/D ratio 17% (1.35 vs. 1.58), but resulted in an unforeseen 73% (1.04/h vs. 1.80/h) increase in interruptions during direct care. In contrast, the focused intervention (deferring only those interruptions arriving via cell phone during medication and direct care), netted a 31% improvement in the B/D ratio (1.29 vs. 1.69) and with moderated (< 0.13/h) impact on interruptions during other activities. Modeling the dynamics of the onset of interruptions reveals the potentially negative impact of across-the-board interventions, and the advantage of focused interventions anticipating unmet needs before they present as interruptions.

Background: The prognosis of patients with hepatic metastases from neuroendocrine tumors (NET) is generally good, and radioembolization with Yttrium-90 microspheres is a locoregional therapy that is used in efforts to improve hepatic disease control and survival. This study aims to describe the survival outcomes and toxicities associated with radioembolization for hepatic-predominant metastatic NET in a large single-institution cohort., Methods: A total of 59 patients underwent radioembolization for metastatic NET with hepatic predominant disease at a single academic center. Patient outcomes were analyzed by Kaplan-Meier survival analysis and toxicities were detailed and described. Ten patients within the cohort underwent post-treatment dosimetric analysis using PET-MRI and normal liver dosimetry was correlated with hepatic fibrosis and toxicity., Results: Median overall survival from time of radioembolization in the patient cohort was 31 months, and the 1- and 2-year overall survival was 80.4% and 65.6% respectively. Median hepatic progression-free survival and overall progression-free survival were 18 and 13 months, respectively. Three patients died of hepatic failure that was possibly therapy-related. Ten patients underwent evaluation of post-treatment dosimetry following radioembolization. In patients who did not develop hepatotoxicity or hepatic fibrosis, mean dose to normal liver was 25.4 Gy, while the mean liver dose in patients who experienced toxicity (hepatic fibrosis in n=2 and death from hepatic failure in n=1) was 59.1 Gy., Conclusions: Overall survival following radioembolization for hepatic metastases from NET is excellent; however, deaths that are potentially treatment-related have been observed. Preliminary data regarding dose to normal liver is suggestive of a relation between dosimetry and toxicity, however further work is required to further elucidate the mechanism, correlation with dosimetry, as well as additional patient and tumor factors that may predispose these patients to toxicity., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.