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Purpose: Our purpose was to develop a clinically intuitive and easily understandable scoring method using statistical metrics to visually determine the quality of a radiation treatment plan., Methods and Materials: Data from 111 patients with head and neck cancer were used to establish a percentile-based scoring system for treatment plan quality evaluation on both a plan-by-plan and objective-by-objective basis. The percentile scores for each clinical objective and the overall treatment plan score were then visualized using a daisy plot. To validate our scoring method, 6 physicians were recruited to assess 60 plans, each using a scoring table consisting of a 5-point Likert scale (with scores ≥3 considered passing). Spearman correlation analysis was conducted to assess the association between increasing treatment plan percentile rank and physician rating, with Likert scores of 1 and 2 representing clinically unacceptable plans, scores of 3 and 4 representing plans needing minor edits, and a score of 5 representing clinically acceptable plans. Receiver operating characteristic curve analysis was used to assess the scoring system's ability to quantify plan quality., Results: Of the 60 plans scored by the physicians, 8 were deemed as clinically acceptable; these plans had an 89.0th ± 14.5 percentile value using our scoring system. The plans needing minor edits or deemed unacceptable had more variation, with scores falling in the 62.6nd ± 25.1 percentile and 35.6th ± 25.7 percentile, respectively. The estimated Spearman correlation coefficient between the physician score and treatment plan percentile was 0.53 ( P < .001), indicating a moderate but statistically significant correlation. Receiver operating characteristic curve analysis demonstrated discernment between acceptable and unacceptable plan quality, with an area under the curve of 0.76., Conclusions: Our scoring system correlates with physician ratings while providing intuitive visual feedback for identifying good treatment plan quality, thereby indicating its utility in the quality assurance process., Competing Interests: This project was performed by the radiation planning team at MD Anderson, which receives funding from the NCI, the Cancer Prevention & Research Institute of Texas, the Wellcome Trust, and Varian Medical Systems. A premarket notification 510(k) for the Radiation Planning Assistant has been cleared for commercial distribution by the U.S. Food and Drug Administration; however, it is yet to be marketed. Authors of this work also receive funds in whole or in part from the NIH, Elekta AB, Oncospace Inc, and Phillips Medical Systems., (© 2024 The Authors.)

Competing Interests: K.A.W. serves as an Editorial Board Member for Physics and Imaging in Radiation Oncology. C.D.F. has received travel, speaker honoraria, and/or registration fee waivers unrelated to this project from The American Association for Physicists in Medicine, the University of Alabama-Birmingham, The American Society for Clinical Oncology, The Royal Australian and New Zealand College of Radiologists, The American Society for Radiation Oncology, The Radiologic Society of North America, and The European Society for Radiation Oncology. The other authors have no interests to disclose. During the preparation of this work, the authors used ChatGPT (GPT-4 architecture; ChatGPT September 25 Version) to improve the grammatical accuracy and semantic structure of portions of the text. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Purpose: MR-guided radiotherapy (MRgRT) has the advantage of utilizing high soft tissue contrast imaging to track daily changes in target and critical organs throughout the entire radiation treatment course. Head and neck (HN) stereotactic body radiation therapy (SBRT) has been increasingly used to treat localized lesions within a shorter timeframe. The purpose of this study is to examine the dosimetric difference between the step-and-shot intensity modulated radiation therapy (IMRT) plans on Elekta Unity and our clinical volumetric modulated arc therapy (VMAT) plans on Varian TrueBeam for HN SBRT., Method: Fourteen patients treated on TrueBeam sTx with VMAT treatment plans were re-planned in the Monaco treatment planning system for Elekta Unity MR-Linac (MRL). The plan qualities, including target coverage, conformity, homogeneity, nearby critical organ doses, gradient index and low dose bath volume, were compared between VMAT and Monaco IMRT plans. Additionally, we evaluated the Unity adaptive plans of adapt-to-position (ATP) and adapt-to-shape (ATS) workflows using simulated setup errors for five patients and assessed the outcomes of our treated patients., Results: Monaco IMRT plans achieved comparable results to VMAT plans in terms of target coverage, uniformity and homogeneity, with slightly higher target maximum and mean doses. The critical organ doses in Monaco IMRT plans all met clinical goals; however, the mean doses and low dose bath volumes were higher than in VMAT plans. The adaptive plans demonstrated that the ATP workflow may result in degraded target coverage and OAR doses for HN SBRT, while the ATS workflow can maintain the plan quality., Conclusion: The use of Monaco treatment planning and online adaptation can achieve dosimetric results comparable to VMAT plans, with the additional benefits of real-time tracking of target volume and nearby critical structures. This offers the potential to treat aggressive and variable tumors in HN SBRT and improve local control and treatment toxicity., 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., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background and Objective: There has been an increase in the study and use of stated-preference methods to inform medicine development decisions. The objective of this study was to identify prioritized topics and questions relating to health preferences based on the perspective of members of the preference research community., Methods: Preference research stakeholders from industry, academia, consultancy, health technology assessment/regulatory, and patient organizations were recruited using professional networks and preference-targeted e-mail listservs and surveyed about their perspectives on 19 topics and questions for future studies that would increase acceptance of preference methods and their results by decision makers. The online survey consisted of an initial importance prioritization task, a best-worst scaling case 1 instrument, and open-ended questions. Rating counts were used for analysis. The best-worst scaling used a balanced incomplete block design., Results: One hundred and one participants responded to the survey invitation with 66 completing the best-worst scaling. The most important research topics related to the synthesis of preferences across studies, transferability across populations or related diseases, and method topics including comparison of methods and non-discrete choice experiment methods. Prioritization differences were found between respondents whose primary affiliation was academia versus other stakeholders. Academic researchers prioritized methodological/less studied topics; other stakeholders prioritized applied research topics relating to consistency of practice., Conclusions: As the field of health preference research grows, there is a need to revisit and communicate previous work on preference selection and study design to ensure that new stakeholders are aware of this work and to update these works where necessary. These findings might encourage discussion and alignment among different stakeholders who might hold different research priorities. Research on the application of previous preference research to new contexts will also help increase the acceptance of health preference information by decision makers., (© 2023. The Author(s).)

Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs) are ubiquitous environmental contaminants. They were produced in relatively large volumes in the last century and are now subject to long-term monitoring and regulated under the United Nations Stockholm Convention (SC) on persistent organic pollutants (POPs). Though restricted, human exposure is still a concern and in some regions of the globe the information on the health risk is limited. Sixty breast milk samples from nursing mothers were collected between 2014 and 2015, residing in Bogota, Cartagena, and Medellin, which are industrialized cities in Colombia. This is the first comprehensive study to determine the concentrations in breast milk of PBDEs (n = 7), PCBs (n = 29), and OCPs (n = 28) in Colombia. The detection frequency of POPs, including BDE-47, CB-138, CB-153, CB-156, and CB-180, as well as several OCPs such as chloroneb, aldrins, HCHs, DDTs, and heptachlor, was found to be 100% in all samples tested. The mean concentrations of the analyzed legacy POPs were ∑3DDTs (423 ng/g lw) > chloroneb (50.1 ng/g lw) > ∑2permetrins (17.5 ng/g lw) > ∑2aldrins (16.7 ng/g lw) > 29 PCBs (15.04 ng/g lw) > ∑2chlordanes (CHLs) (11.2 ng/g lw) ≈ ∑3endosulfans (11.1 ng/g lw) > ∑2heptachlors (2.43 ng/g lw) > 7PBDEs (2.1 ng/g lw) > ∑4HCHs (0.58 ng/g lw). The results of this study suggest that the concentrations of DDTs were present in breast milk samples from Colombia at levels comparable to those found in previous studies conducted in other countries such as Brazil, Uruguay, Chile, and various Asian countries. The concentrations of PBDE and PCB congeners, as well as many pesticides, were found to be significantly correlated with each other. This suggests that these substances may have similar sources of exposure. The strength of the pair correlation among concentrations of POPs was assessed using Spearman's correlation coefficients, which varied from r = 0.62 for the association between BDE-47 and CB-153, to a high correlation of 0.99 for the correlation between γ-Chlordane and heptachlor. This suggests that these POPs may share similar sources, such as diet. An exposure assessment model obtained by Monte Carlo simulation showed that infants were exposed to low concentrations of POPs with exception of p,p'-DDE and Aldrin, in which 25 th , 50 th and 95 th percentiles were greater than the threshold reference values of non-carcinogenic effects suggested by US-EPA regulations while the 90 th percentile of pg TEQ/Kg-bw/day for dl-PCBs was above of the tolerable daily intake (TDI) proposed by the World Health Organization (WHO). Therefore, the health risk of infants exposed to OCPs and dl-PCBs should be exanimated continually through biomonitoring programs in the Colombian population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Pain during Radiation Therapy (RT) for oral cavity/oropharyngeal cancer (OC/OPC) is a clinical challenge due to its multifactorial etiology and variable management. The objective of this study was to define complex pain profiles through temporal characterization of pain descriptors, physiologic state, and RT-induced toxicities for pain trajectories understanding., Materials and Methods: Using an electronic health record registry, 351 OC/OPC patients treated with RT from 2013 to 2021 were included. Weekly numeric scale pain scores, pain descriptors, vital signs, physician-reported toxicities, and analgesics were analyzed using linear mixed effect models and Spearman's correlation. Area under the pain curve (AUC pain ) was calculated to measure pain burden over time., Results: Median pain scores increased from 0 during the weekly visit (WSV)-1 to 5 during WSV-7. By WSV-7, 60% and 74% of patients reported mouth and throat pain, respectively, with a median pain score of 5. Soreness and burning pain peaked during WSV-6/7 (51%). Median AUC pain was 16% (IQR (9.3-23)), and AUC pain significantly varied based on gender, tumor site, surgery, drug use history, and pre-RT pain. A temporal increase in mucositis and dermatitis, declining mean bodyweight (-7.1%; P < 0.001) and mean arterial pressure (MAP) 6.8 mmHg; P < 0.001 were detected. Pulse rate was positively associated while weight and MAP were negatively associated with pain over time ( P < 0.001)., Conclusion: This study provides insight on in-depth characterization and associations between dynamic pain, physiologic, and toxicity kinetics. Our findings support further needs of optimized pain control through temporal data-driven clinical decision support systems for acute pain management.

(1) Background: Radiotherapy (RT) is a central component for the treatment of many head and neck cancers. In this systematic review of the literature, we aimed to characterize and quantify the published evidence on RT-related hypothyroidism, including estimated incidence, clinical risk factors, and dosimetric parameters that may be used to guide clinical decision making. Furthermore, we aimed to identify potential areas of improvement in the prevention and clinical management of RT-induced hypothyroidism, including the role of modern advanced therapeutic techniques. (2) Methods: We conducted a systemic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed and Google Scholar were searched to identify original research articles describing the incidence, mechanism, dosimetry, treatment, or prevention of radiation-related hypothyroidism for adults receiving RT for the treatment of head and neck cancers. The snowball method was used to identify additional articles. For identified articles, we tabulated several datapoints, including publication date, patient sample size, estimated hypothyroidism incidence, cancer site/type, follow-up period, radiation modality and technique, use of multimodality therapy, method of thyroid function evaluation, and proposed dosimetric predictors of hypothyroidism. (3) Results: One hundred and eleven articles met inclusion criteria, reflecting a range of head and neck cancer subtypes. There was a large variation in the estimated incidence of RT-related hypothyroidism, with a median estimate of 36% (range 3% to 79%). Reported incidence increased in later publication dates, which was likely related to improved screening and longer follow up. There were a wide variety of predictive metrics used to identify patients at high risk of hypothyroidism, the most common of which were volumetric and mean dosimetrics related to the thyroid gland (Vxx%, Dmean). More recently, there has been increasing evidence to suggest that the thyroid gland volume itself and the volume of the thyroid gland spared from high-dose radiation (VSxx) may better predict thyroid function after RT. There were no identified studies investigating the role of advanced radiotherapeutic techniques such as MRI-guided RT or particle therapy to decrease RT-related hypothyroidism. Conclusions: Hypothyroidism is a common toxicity resulting from therapeutic radiation for head and neck cancer with recent estimates suggesting 40-50% of patients may experience hypothyroidism after treatment. Dosimetric predictive models are increasingly able to accurately identify patients at risk of hypothyroidism, especially those utilizing thyroid VS metrics. Further investigation regarding the potential for advanced radiotherapeutic therapies to decrease RT-induced thyroid dysfunction is needed.

Background/objective: Pain is the most common acute symptom following radiation therapy (RT) for head and neck cancer (HNC). The multifactorial origin of RT-induced pain makes it highly challenging to manage. Multiple studies were conducted to identify genetic variants associated with cancer pain, however few of them focused on RT-induced acute pain. In this review, we summarize the potential mechanisms of acute pain after RT in HNC and identify genetic variants associated with RT-induced acute pain and relevant acute toxicities., Methods: A comprehensive search of Ovid Medline, EMBASE and Web of Science databases using terms including "Variants", "Polymorphisms", "Radiotherapy", "Acute pain", "Acute toxicity" published up to February 28, 2022, was performed by two reviewers. Review articles and citations were reviewed manually. The identified SNPs associated with RT-induced acute pain and toxicities were reported, and the molecular functions of the associated genes were described based on genetic annotation using The Human Gene Database; GeneCards., Results: A total of 386 articles were identified electronically and 8 more articles were included after manual search. 21 articles were finally included. 32 variants in 27 genes, of which 25% in inflammatory/immune response, 20% had function in DNA damage response and repair, 20% in cell death or cell cycle, were associated with RT-inflammatory pain and acute oral mucositis or dermatitis. 4 variants in 4 genes were associated with neuropathy and neuropathic pain. 5 variants in 4 genes were associated with RT-induced mixed types of post-RT-throat/neck pain., Conclusion: Different types of pain develop after RT in HNC, including inflammatory pain; neuropathic pain; nociceptive pain; and mixed oral pain. Genetic variants involved in DNA damage response and repair, cell death, inflammation and neuropathic pathways may affect pain presentation post-RT. These variants could be used for personalized pain management in HNC patients receiving RT., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CF has received direct industry grant support, speaking honoraria, and travel funding from Elekta AB. The remaining authors declare that they have no known competing commercial, financial interests or personal relationships that could be constructed as potential conflict of interest., (© 2023 The Author(s).)

Ba 0.92 Ca 0.08 Ti 0.95 Zr 0.05 O 3 (BCZT8-5) ceramic materials have been scarcely studied as lead-free piezo/ferroelectrics despite their enhanced Curie temperature (>100 °C) with respect to most studied BCZT compositions. In this work, homogeneous dense BCZT8-5 ceramics with grain size in the range of 20 μm, and optimum ferroelectric, dielectric, and electromechanical performance, were prepared by the mixed oxides route using moderate synthesis (1250 °C-2 h) and sintering (1400 °C-2 h) conditions. Thickness-poled thin disks and monomodal shear plate resonators were used for the determination of piezoelectric coefficients, coupling factors, elastic, and dielectric permittivity coefficients, including all losses, by iterative analysis of impedance curves at resonance. Furthermore, the thermal evolution of the piezoelectric characteristics at resonance was determined to assess the enhanced working range of the ceramics (≈100 °C). Ferroelectric hysteresis loops and strains vs. electric-field butterfly loops were also measured and showed soft behavior with E c = 2 kV/cm, P r = 12 μC/cm 2 after a maximum applied field of 3 kV was used. The ceramics showed a high endurance of P-E cycles to electrical fatigue up to 10 7 cycles. Moreover, dielectric properties as a function of temperature were also accomplished and showed nearly normal ferroelectric behavior, characteristic of samples with low crystallographic disorder. Overall, these ceramics showed high sensitivity and higher stability than other currently studied BCZT compositions.

Background: A primary goal in transoral robotic surgery (TORS) for oropharyngeal squamous cell cancer (OPSCC) survivors is to optimize swallowing function. However, the uncertainty in the outcomes of TORS including postoperative residual positive margin (PM) and extranodal extension (ENE), may necessitate adjuvant therapy, which may cause significant swallowing toxicity to survivors., Methods: A secondary analysis was performed on a prospective registry data with low- to intermediate-risk human papillomavirus-related OPSCC possibly resectable by TORS. Decision trees were developed to model the uncertainties in TORS compared with definitive radiation therapy (RT) and chemoradiation therapy (CRT). Swallowing toxicities were measured by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST), MD Anderson Dysphagia Inventory (MDADI), and the MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) instruments. The likelihoods of PM/ENE were varied to determine the thresholds within which each therapy remains optimal., Results: Compared with RT, TORS resulted in inferior swallowing function for moderate likelihoods of PM/ENE (>60% in short term for all instruments, >75% in long term for DIGEST and MDASI) leaving RT as the optimal treatment. Compared with CRT, TORS remained the optimal therapy based on MDADI and MDASI but showed inferior swallowing outcomes based on DIGEST for moderate-to-high likelihoods of PM/ENE (>75% for short-term and >40% for long-term outcomes)., Conclusion: In the absence of reliable estimation of postoperative PM/ENE concurrent with significant postoperative PM, the overall toxicity level in OPSCC patients undergoing TORS with adjuvant therapy may become more severe compared with patients receiving nonsurgical treatments thus advocating definitive (C)RT protocols., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Clinical efficiency is a key component of the value-based care model and a driver of patient satisfaction. The purpose of this study was to identify and address inefficiencies at a high-volume radiation oncology clinic., Methods and Materials: Patient flow analysis (PFA) was used to create process maps and optimize the workflow of consultation visits in a gastrointestinal radiation oncology clinic at a large academic cancer center. Metrics such as cycle times, waiting times, and rooming times were assessed by using a real-time patient status function in the electronic medical record for 556 consults and compared between before vs after implementation of the PFA recommendations., Results: The initial PFA revealed four inefficiencies: (1) protracted rooming time, (2) inefficient communications, (3) duplicated tasks, and (4) ambiguous clinical roles. We analyzed 485 consult-visits before the PFA and 71 after the PFA. The PFA recommendations led to reductions in overall median cycle time by 21% (91 min vs 72 min, p < 0.001), in cumulative waiting times by 64% (45 min vs 16 min; p < 0.001), which included waiting room time (14 min vs 5 min; p < 0.001) and wait for physician (20 min vs. 6 min; p < 0.001). Slightly less than one-quarter (22%) of consult visits before the PFA lasted > 2 h vs. 0% after implementation of the recommendations (p < 0.001). Similarly, the proportion of visits requiring < 1 h was 16% before PFA vs 34% afterward (p < 0.001)., Conclusions: PFA can be used to identify clinical inefficiencies and optimize workflows in radiation oncology consultation clinics, and implementing their findings can significantly improve cycle times and waiting times. Potential downstream effects of these interventions include improved patient experience, decreased staff burnout, financial savings, and opportunities for expanding clinical capacity., (© 2022. The Author(s).)

Introduction: Coronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term., Methods: This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions., Results: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe., Discussion: The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection., Key Points: The following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility.The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease.We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic.The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations., Competing Interests: All authors state that they have no relationships/activities/interests to disclose related to the content of this submission. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy. Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman’s correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time. Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that can be assessed on MRI, and 31 patients had nodal disease with 46 nodes assessed. Median primary GTV (GTVp) size was 14.1cc. The rate of GTVp shrinkage was highest between pre-treatment and week 4. Patients with T3-T4 tumours had a 3.8-fold decrease in GTVp compared to T1-T2 tumours. The ADC values correlated with residual GTVp. The median nodal volume (GTVn) was 12.4cc. No clinical features were found to correlate with GTVn reduction. The overall change in ADC for GTVn from pre-treatment was significant for 35th−95th percentiles in weeks 1−4 (p < 0.001). Conclusion: A discrepancy in the trajectory of ADC between primary and nodal sites suggested that they exhibit different treatment responses and should be analysed separately in future studies.

Purpose: The COVID-19 pandemic posed unprecedented demands on health care. This study aimed to characterize COVID-19 inpatients and examine trends and risk factors associated with hospitalization duration, intensive care unit (ICU) admission, and in-hospital mortality., Methods: This retrospective study analyzed patients with SARS-CoV-2 infection hospitalized at an integrated health system between February 2, 2020, and December 12, 2020. Patient characteristics and clinical outcomes were obtained from medical records. Backward stepwise logistic regression analyses were used to identify independent risk factors of ICU admission and in-hospital mortality. Cox proportional hazards models were used to evaluate relationships between ICU admission and in-hospital mortality., Results: Overall, 9647 patients were analyzed. Mean age was 64.6 ± 18 years. A linear decrease was observed for hospitalization duration (0.13 days/week, R 2 =0.71; P<0.0001), ICU admissions (0.35%/week, R 2 =0.44; P<0.001), and hospital mortality (0.16%/week, R 2 =0.31; P<0.01). Bacterial co-infections, male sex, history of chronic lung and heart disease, diabetes, and Hispanic ethnicity were identified as independent predictors of ICU admission (P<0.001). ICU admission and age of ≥65 years were the strongest independent risk factors associated with in-hospital mortality (P<0.001). The in-hospital mortality rate was 8.3% (27.4% in ICU patients, 2.6% in non-ICU patients; P<0.001)., Conclusions: Results indicate that, over the pandemic's first 10 months, COVID-19 carried a heavy burden of morbidity and mortality in older patients (>65 years), males, Hispanics, and those with bacterial co-infections and chronic comorbidities. Although disease severity has steadily declined following administration of COVID-19 vaccines along with improved understanding of effective COVID-19 interventions, these study findings reflect a "natural history" for this novel infectious disease in the U.S. Midwest., Competing Interests: Conflicts of Interest None., (© 2022 Aurora Health Care, Inc.)

Aim: To investigate the effect of resistance training (RT) on hepatocardiovascular and muscle mitochondrial parameters in rats that were fed a high-calorie diet for 12 weeks., Main Methods: The animals were divided into four groups: control (C), exercise (E), obese (O), and obese plus exercise (OE). Group E and OE rats performed resistance training by climbing on a vertical ladder with load attached to the end of the tail (1×/day, 3×/week, for 12 weeks). Group O and OE rats were fed a high-calorie diet containing chow and a cafeteria diet for 12 weeks. Under anesthesia, the heart and liver were removed for histopathological analysis, and the gastrocnemius muscle was removed for Western blotting., Key Findings: Group O rats were heavier, with increased fat mass, elevated fasting glycemia, and total triglycerides, and exhibited a significant number of Kupffer cells and diffuse steatosis in the liver. Group O rats also showed increased thickness of the right ventricle, septum, and pulmonary artery. All of these parameters were attenuated by RT. PGC1-α protein levels were increased in both exercise groups. The protein levels of OXPHOS complexes III, IV, and V were reduced in Group O, while RT prevented this alteration., Significance: RT exerts a protective effect against hepato-cardiac alterations and prevents changes in the muscle mitochondrial protein profile induced by a high-calorie diet., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Introduction: Radiation dose-escalation for head and neck cancer (HNC) patients aiming to improve cure rates is challenging due to the increased risk of unacceptable treatment-induced toxicities. With "Proton Image-guided Radiation Assignment for Therapeutic Escalation via Selection of locally advanced head and neck cancer patients" (PIRATES), we present a novel treatment approach that is designed to facilitate dose-escalation while minimizing the risk of dose-limiting toxicities for locally advanced HPV-negative HNC patients. The aim of this Phase I trial is to assess the safety & feasibility of PIRATES approach., Methods: The PIRATES protocol employs a multi-faceted dose-escalation approach to minimize the risk of dose-limiting toxicities (DLTs): 1) sparing surrounding normal tissue from extraneous dose with intensity-modulated proton therapy, 2) mid-treatment hybrid hyper-fractionation for radiobiologic normal tissue sparing; 3) Magnetic Resonance Imaging (MRI) guided mid-treatment boost volume adaptation, and 4) iso-effective restricted organ-at-risk dosing to mucosa and bone tissues.The time-to-event Bayesian optimal interval (TITE-BOIN) design is employed to address the challenge of the long DLT window of 6 months and find the maximum tolerated dose. The primary endpoint is unacceptable radiation-induced toxicities (Grade 4, mucositis, dermatitis, or Grade 3 myelopathy, osteoradionecrosis) occurring within 6 months following radiotherapy. The second endpoint is any grade 3 toxicity occurring in 3-6 months after radiation., Discussion: The PIRATES dose-escalation approach is designed to provide a safe avenue to intensify local treatment for HNC patients for whom therapy with conventional radiation dose levels is likely to fail. PIRATES aims to minimize the radiation damage to the tissue surrounding the tumor volume with the combination of proton therapy and adaptive radiotherapy and within the high dose tumor volume with hybrid hyper-fractionation and not boosting mucosal and bone tissues. Ultimately, if successful, PIRATES has the potential to safety increase local control rates in HNC patients with high loco-regional failure risk.Trial registration: ClinicalTrials.gov ID: NCT04870840; Registration date: May 4, 2021.Netherlands Trial Register ID: NL9603; Registration date: July 15, 2021., (© 2021 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Introduction: It has become increasingly important to include patient preference information in decision-making processes for drug development. As neuromuscular disorders represent multisystem, debilitating, and progressive rare diseases with few treatment options, this study aimed to explore unmet health care needs and patient treatment preferences for two neuromuscular disorders, myotonic dystrophy type 1 (DM1) and mitochondrial myopathies (MM) to inform early stages of drug development., Methods: Fifteen semi-structured interviews and five focus group discussions (FGDs) were held with DM1 and MM adult patients and caregivers. Topics discussed included (1) reasons for study participation; (2) disease signs/symptoms and their impact on daily lives; (3) top desired benefits; and (4) acceptability of risks and tolerance levels for a hypothetical new treatment. Data were analyzed following a thematic 'code' approach., Results: A total of 52 participants representing a wide range of disease severities participated. 'Muscle strength' and 'energy and endurance' were the disease-related unmet needs most often mentioned. Additionally, improved 'balance', 'cognition' and 'gut function' were the top desired treatment benefits, while 'damage to the liver, kidneys or eyes' was the most concerning risk. Factors influencing their tolerance to risks related to previously having experienced the risk and differentiation between permanent and temporary risks. A few differences were elicited between patients and caregivers., Conclusions: This qualitative study provided an open forum to elicit treatment-desired benefits and acceptable risks to be established by patients themselves. These findings can inform decisions for developing new treatments and the design of clinical trials for DM1 and MM., (© 2021. The Author(s).)

Although active immunotherapies are effective strategies to induce activation of CD8 + T cells, advanced stage tumors require further improvements for efficient control. Concerning the burden of cancer-related to Human papillomavirus (HPV), particularly the high incidence and mortality of cervical cancer, our group developed an approach based on a DNA vaccine targeting the HPV-16 E7 oncoprotein (pgDE7h). This immunotherapy is capable of inducing an antitumour CD8 + T cell response but show only partial control of tumors in more advanced growth stages. Here, we combined a chemotherapeutic agent (gemcitabine- Gem) with pgDE7h to overcome immunosuppression and improve antitumour responses in a preclinical mouse tumor model. Our results demonstrated that administration of Gem had synergistic antitumor effects when combined with pgDE7h leading to eradication of both early-stages and established tumors. Overall, the antiproliferative effects of Gem observed in vitro and in vivo provided an optimal window for immunotherapy. In addition, the enhanced antitumour responses induced by the combined therapeutic regimen included enhanced frequencies of antigen-presenting cells (APCs), E7-specific IFN-γ-producing CD8 + T cells, and cytotoxic CD8 + T cells and, concomitantly, less pronounced accumulation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). These findings demonstrated that the combination of Gem and an active immunotherapy strategy show increased effectiveness, leading to a reduced need for multiple drug doses and, therefore, decreased deleterious side effects avoiding resistance and tumor relapses. Altogether, our results provide evidence for a new and feasible chemoimmunotherapeutic strategy that supports future clinical translation., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

This project sought to evaluate if business card distribution improved the utility of Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys by serving as a feedback mechanism for trainees. Between fall 2018 and spring 2019, patient encounters for 6 cardiovascular disease fellows were tracked over two 60-day periods. Six weeks were allowed for HCAHPS surveys to be returned. Business cards were subsequently deployed and encounters similarly tracked. During the control-group monitoring period, 721 patient encounters were logged and 80 (11.1%) surveys were returned. Qualitative feedback, in the form of free-response comments, was provided in 41 (51.3%) surveys. Business cards were then deployed and encounters similarly tracked. During the business card period, 508 patient encounters occurred and 97 (19.1%) surveys were returned. Qualitative feedback was provided in 52 (53.6%) surveys. No fellow-specific feedback was returned in either group. Business card use by trainees was associated with an improved rate of survey return, from 11.1% to 19.1%, but no effect on feedback to fellows or patient satisfaction scores was found. HCAHPS surveys were not useful in providing trainees with feedback. Immediate verbal feedback from patients via ancillary staff was observed. A method of relaying communication from patients to ancillary staff and medical education programs is needed., Competing Interests: Conflict of interest None., (© 2021 Aurora Health Care, Inc.)

Integrated, data-driven criteria are necessary to evaluate delivery outcomes in pregnancies affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the ongoing COVID-19 pandemic. This study analyzed maternal demographics, clinical characteristics, treatments, and delivery outcomes of 85 ethnically diverse, adult pregnant women who tested positive for SARS-CoV-2 at the time of delivery. Median maternal and gestational ages were 27 years (interquartile range [IQR]: 23-31) and 39 weeks (IQR: 37.3-40.0), respectively. Of the 85 SARS-CoV-2-positive participants, 67 (79%) had no COVID-19 symptoms at the time of routine COVID-19 admission testing, 14 (16%) reported mild COVID-19 symptoms, and 4 (5%) presented severe COVID-19 symptoms that required hospitalization. Patients in the severe COVID-19 group had significantly longer hospitalizations than those with nonsevere COVID-19 (7 [IQR: 4.5-9.5] vs 2 [IQR: 2-3] days; P<0.01). Neonatal outcomes included 100% live births with a median 1-minute Apgar score of 8 and 15% preterm births. No neonatal deaths or vertical transmissions were reported, and all neonatal intensive care unit admissions were related to prematurity. Overall, maternal symptom prevalence and peripartum complication rates were low, suggesting a generally good prognosis for pregnant women with SARS-CoV-2 infections at the time of delivery., Competing Interests: Conflict of interest None., (© 2021 Aurora Health Care, Inc.)

Purpose: To characterize our experience and the disease control and toxicity of proton therapy (PT) for patients with head and neck cancer (HNC)., Patients and Methods: Clinical outcomes for patients with HNC treated with PT at our institution were prospectively collected in 2 institutional review board-approved prospective studies. Descriptive statistics were used to summarize patient characteristics and outcomes. Overall survival, local-regional control, and disease-free survival were estimated by the Kaplan-Meier method. Treatment-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events (version 4.03) scale., Results: The cohort consisted of 573 patients treated from February 2006 to June 2018. Median patient age was 61 years. Oropharynx (33.3%; n = 191), paranasal sinus (11%; n = 63), and periorbital tissues (11%; n = 62) were the most common primary sites. Patients with T3/T4 or recurrent disease comprised 46% (n = 262) of the cohort. The intent of PT was definitive in 53% (n = 303), postoperative in 37% (n = 211), and reirradiation in 10% (n = 59). Median dose was 66 Gy (radiobiological equivalent). Regarding systemic therapy, 43% had received concurrent (n = 244), 3% induction (n = 19), and 15% (n = 86) had both. At a median follow-up of 2.4 years, 88 patients (15%) had died and 127 (22%) developed disease recurrence. The overall survival, local-regional control, and disease-free survival at 2 and 5 years were, respectively, 87% and 75%, 87% and 78%, and 74% and 63%. Maximum toxicity (acute or late) was grade 3 in 293 patients (51%), grade 2 in 234 patients (41%), and grade 1 in 31 patients (5%). There were 381 acute grade 3 and 190 late grade 3 unique toxicities across 212 (37%) and 150 (26%) patients, respectively. There were 3 late-grade 4 events across 2 patients (0.3%), 2 (0.3%) acute-grade 5, and no (0%) late-grade 5 events., Conclusions: The overall results from this prospective study of our initial decade of experience with PT for HNC show favorable disease control and toxicity outcomes in a multidisease-site cohort and provide a reference benchmark for future comparison and study., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank is a scientific advisory board member of Breakthrough Chronic Care; he has received research grants from C4 Imaging, Eli Lilly, Elekta, and Hitachi, and he has reported personal fees from Varian Medical Systems, Inc (consultant/advisory board), C4 Imaging (founder and director), Hitachi (honoraria/advisory board), Augmenix (honoraria), and National Comprehensive Cancer Center (board member). Stephen G. Chun, MD, is a consultant for AstraZeneca, PLC. The authors report no other conflicts of interest., (©Copyright 2021 The Author(s).)

Aims: Myocardial work (MW) is a novel parameter that can be used in a clinical setting to assess left ventricular (LV) pressures and deformation. We sought to distinguish patterns of global MW index in hypertensive vs. non-hypertensive patients and to look at differences between categories of hypertension., Methods and Results: Sixty-five hypertensive patients (mean age 65 ± 13 years; 30 male) and 15 controls (mean age 38 ± 12 years; 7 male) underwent transthoracic echocardiography at rest. Hypertensive patients were subdivided into Stage 1 (n = 32) and Stage 2 (n = 33) hypertension based on 2017 American College of Cardiology guidelines. Exclusion criteria were suboptimal image quality for myocardial deformation analysis, reduced ejection fraction, valvular heart disease, intracardiac shunt, and arrhythmia. Global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency were estimated from LV pressure-strain loops utilizing proprietary software from speckle-tracking echocardiography. LV systolic and diastolic pressures were estimated using non-invasive brachial artery cuff pressure. Global longitudinal strain and LV ejection fraction were preserved between the groups with no statistically significant difference, whereas there was a statically significant difference between the control and two hypertension groups in GWI (P = 0.01), GCW (P < 0.001), and GWW (P < 0.001)., Conclusion: Non-invasive MW analysis allows better understanding of LV response under conditions of increased afterload. MW is an advanced assessment of LV systolic function in hypertension patients, giving a closer look at the relationship between LV pressure and contractility in settings of increased load dependency than LV ejection fraction and global longitudinal strain., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: Myocardial work is a novel echocardiographic algorithm that corrects speckle-tracking-derived global longitudinal strain (GLS) for afterload using non-invasive systolic blood pressure as a surrogate for left ventricular systolic pressure (LVSP). Yet, in patients with severe aortic stenosis, non-invasive systolic blood pressure does not equal LVSP., Methods and Results: We evaluated 35 patients with severe aortic stenosis who underwent transcatheter aortic valve replacement (TAVR). Transthoracic echocardiography, including myocardial mechanics, was performed pre- and post-TAVR. We performed simultaneous echocardiographic and cardiac catheterization measurements in 23 of the 35 patients at the time of TAVR. Peak and mean aortic gradients were calculated from echocardiographic and cardiac catheterization data. Peak-to-peak LV-aortic gradient correlated highly with mean LV-aortic gradient (r = 0.96); measured LVSP correlated highly with our novel method of non-invasively estimated LVSP (non-invasive systolic blood pressure cuff + Doppler-derived mean aortic gradient, r = 0.92). GLS improved from pre- to post-TAVR (-14.2% ± 4.3 vs. -15.1% ± 3.2), and myocardial work reduced from corrected pre-TAVR to post-TAVR (global work index: 1856.2 mmHg% ± 704.6 vs. 1534.8 ± 385.0)., Conclusion: We propose that non-invasive assessment of myocardial work can be reliably performed in aortic stenosis by the addition of mean aortic gradient to non-invasive systolic blood pressure. From this analysis, we note the novel and unique finding that GLS can improve as myocardial work reduces post-TAVR in patients with severe aortic stenosis. Both GLS and myocardial work post-TAVR remain below normal values, requiring further studies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objective: There is limited research comparing demographic and clinical characteristics between patients who present with atrial fibrillation (AF) and new-onset cardiomyopathy (CM) to patients with new-onset CM without dysrhythmia. We aimed to evaluate clinical characteristics and outcomes in patients with new-onset CM with and without AF and to report their real-world treatment., Methods and Results: The study population was identified using patient records from our healthcare system from January 1, 2012 to September 30, 2016. Patients with a left ventricular ejection fraction ≤40% without a prior history of CM were divided into two groups; those with an antecedent or concomitant diagnosis of AF (AF-CM group) and those with no history of dysrhythmia (CM group). Patients in the AF-CM group (n=196) were older, more likely to be male, had a higher burden of comorbidities but lower levels of cardiac biomarkers, and had lower voltage on surface electrocardiogram than the CM group (n=197). In AF-CM, symptom onset was insidious, leading to a higher likelihood of outpatient diagnosis; 88.3% of AF-CM patients presented with atypical symptoms of AF. The AF-CM group had higher mortality on follow-up. Only 8.7% of patients in this group underwent an ablation procedure. Women, those with a history of coronary artery disease, and older patients were less likely to receive a cardioversion or ablation procedure., Conclusions: Patients presenting with new-onset CM associated with AF have a markedly different risk factor and demographic profile, clinical presentation, and outcomes. In real-world practice, a minority of patients undergo a rhythm control strategy.

The COVID-19 pandemic led to a nationwide shutdown of elective medical procedures. Upon resumption of services, preprocedure nasopharyngeal swab testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was introduced for all patients requiring surgical or other aerosol-generating procedures. We investigated preprocedure COVID-19 testing in one of the largest U.S. health systems. Patients included in this retrospective, observational study were asymptomatic and scheduled for a procedure or surgery. All patients underwent a nasopharyngeal swab test for SARS-CoV-2 performed 24-72 hours prior to a planned procedure. Clinical demographics, type of procedure, test results, and subsequent procedure status were evaluated. Of 38,608 total patients, there were 277 COVID-19-positive patients (positivity rate: 0.72%). Of those 277, 244 (88%) had procedural delays or cancellations. Of the COVID-19-negative patients, 50 (0.13%) required later hospitalization for COVID-19. Median time from preprocedure negative test to admission was 46.3 ± 27.2 days. In the largest series published on preprocedure COVID-19 testing in the early phase of the pandemic, preprocedure COVID-19 positivity was low. Preprocedure COVID-19 testing had a significant impact on clinical management. Rate of COVID-19 cases requiring hospitalization in the months following the procedure was negligible, suggesting health system policies adequately protected patient safety., Competing Interests: Conflicts of Interest None., (© 2021 Aurora Health Care, Inc.)

Objective: To assess the association between variant repeat (VR) interruptions in patients with myotonic dystrophy type 1 (DM1) and clinical symptoms and outcome measures after cognitive behavioral therapy (CBT) intervention., Methods: Adult patients with DM1 were recruited within the OPTIMISTIC trial (NCT02118779). Disease-related history, current clinical symptoms and comorbidities, functional assessments, and disease- and health-related questionnaires were obtained at baseline and after 5 and 10 months. After genetic analysis, we assessed the association between the presence of VR interruptions and clinical symptoms' long-term outcomes and compared the effects of CBT in patients with and without VR interruptions. Core trial outcome measures analyzed were: 6-minute walking test, DM1-Activ-C, Checklist Individual Strength Fatigue Score, Myotonic Dystrophy Health Index, McGill-Pain questionnaire, and Beck Depression inventory-fast screen. Blood samples for DNA testing were obtained at the baseline visit for determining CTG length and detection of VR interruptions., Results: VR interruptions were detectable in 21/250 patients (8.4%)-12 were assigned to the standard-of-care group (control group) and 9 to the CBT group. Patients with VR interruptions were significantly older when the first medical problem occurred and had a significantly shorter disease duration at baseline. We found a tendency toward a milder disease severity in patients with VR interruptions, especially in ventilation status, mobility, and cardiac symptoms. Changes in clinical outcome measures after CBT were not associated with the presence of VR interruptions., Conclusions: The presence of VR interruptions is associated with a later onset of the disease and a milder phenotype. However, based on the OPTIMISTIC trial data, the presence of VR interruptions was not associated with significant changes on outcome measures after CBT intervention., Trial Registration Information: ClinicalTrials.gov NCT02118779., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Patients who are surgically treated for stage I to III non-small cell lung cancer (NSCLC) have dismal prognosis after incomplete (R1-R2) resection. Our study aimed to develop a prediction model to estimate the chance of incomplete resection based on preoperative patient-, tumor-, and treatment-related factors., Methods: From a Dutch national cancer database, NSCLC patients who had surgical treatment without neoadjuvant therapy were selected. Thirteen possible predictors were analyzed. Multivariable logistic regression was used to create a prediction model. External validation was applied in the American National Cancer Database, whereupon the model was adjusted. Discriminatory ability and calibration of the model was determined after internal and external validation. The prediction model was presented as nomogram., Results: Of 7156 patients, 511 had an incomplete resection (7.1%). Independent predictors were histology, cT stage, cN stage, extent of surgery, and open vs thoracoscopic approach. After internal validation, the corrected C statistic of the resulting nomogram was 0.72. Application of the nomogram to an external data set of 85,235 patients with incomplete resection in 2485 patients (2.9%) resulted in a C statistic of 0.71. Calibration revealed good overall fit of the nomogram in both cohorts., Conclusions: An internationally validated nomogram is presented providing the ability to predict the individual chance of incomplete resection in patients with stage I to III NSCLC planned for resection. In case of a high predicted risk of incomplete resection, alternative treatment strategies could be considered, whereas a low risk further supports the use of surgical procedures., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Coronavirus disease 2019 (COVID-19) presents with a spectrum of disease severity, the most serious cases requiring intensive care. Echocardiography is a front-line tool in evaluating cardiovascular complications of COVID-19 in the intensive care unit (ICU); we analyzed transthoracic echocardiograms obtained from this patient population with state-of-the-art ultrasound technology., Methods: All patients with COVID-19 requiring ICU admission on whom a transthoracic echocardiogram was obtained were included in the study. Focused transthoracic protocols were performed by experienced sonographers. Echocardiographic variables, including speckle-tracking echocardiography, were collected and analyzed. Clinical information was obtained from the electronic medical record. Patients were followed until discharge., Results: Of 52 total patients (mean age: 59.9 ± 11.6 years), 59.6% were male and 15 (29%) had known prior cardiac disease. Cardiac complications identified on echocardiography were prevalent, occurring in 55.7% of patients. Patients with known prior cardiac disease were more likely to have new or worsening left ventricular dysfunction. Right ventricular dysfunction was the most common abnormality (assessed qualitatively in 18 cases and with advanced echocardiographic methods in 34 cases). Known prior cardiac disease, right ventricular enlargement, and pulmonary hypertension were significantly associated with morbidity and mortality., Conclusions: Patients requiring intensive care for COVID-19 face significant morbidity and mortality, and cardiac complications occur in the majority of patients admitted to the ICU with COVID-19. Those with known prior cardiac disease fare worse, and other echocardiographic findings (right ventricular enlargement, pulmonary hypertension) are also associated with worse outcomes. State-of-the-art echocardiography performed by experienced sonographers can be critical to identifying cardiac complications and guiding ICU strategy., Competing Interests: Conflicts of Interest None., (© 2021 Aurora Health Care, Inc.)

Purpose: To determine the optimal dose-volume constraint for laryngeal sparing using three commonly employed intensity modulated radiation therapy (IMRT) approaches in patients with oropharyngeal cancer treated to the bilateral neck., Materials and Methods: Thirty patients with stage II-IVA oropharynx cancers received definitive radiotherapy with split-field IMRT (SF-IMRT) to the bilateral neck between 2008 and 2013. Each case was re-planned using whole-field IMRT (WF-IMRT) and volumetric modulated arc therapy (VMAT) and plan quality metrics and dose to laryngeal structures was evaluated. Two larynx volumes were defined and compared on the current study: the Radiation Therapy Oncology Group (RTOG) larynx as defined per the RTOG 1016 protocol and the MDACC larynx defined as the components of the larynx bounded by the superior and inferior extent of the thyroid cartilage., Results: Target coverage, conformity, and heterogeneity indices were similar in all techniques. The RTOG larynx mean dose was lower with WF-IMRT than SF-IMRT (22.1 vs 25.8 Gy; P < 0.01). The MDACC larynx mean dose was 17.5 Gy ± 5.4 Gy with no differences between the 3 techniques. WF-IMRT and VMAT plans were associated with lower mean doses to the supraglottic larynx (42.1 vs 41.2 vs 54.8 Gy; P < 0.01) and esophagus (18.1 vs 18.2 vs 36 Gy; P < 0.01)., Conclusions: Modern whole field techniques can provide effective laryngeal sparing in patients receiving radiotherapy to the bilateral neck for advanced oropharyngeal cancers., Summary: We evaluated laryngeal dose in patients with locally advanced oropharyngeal cancer treated to the bilateral neck using split-field IMRT (SF-IMRT), whole-field IMRT (WF-IMRT) and volumetric arc therapy (VMAT). All three techniques provided good sparing of laryngeal structures and were able to achieve a mean larynx dose < 33 Gy. There were no significant differences in dose to target structures or non-laryngeal organs at risk among techniques., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Objectives: Patient preference studies are increasingly used to inform decision-making during the medical product lifecycle but are rarely used to inform early stages of drug development.  The primary aim of this study is to quantify treatment preferences of patients with neuromuscular disorders, which represent serious and debilitating conditions with limited or no treatment options available. Methods: This quantitative patient preferences study was designed as an online survey, with a cross-over design.  This study will target two different diseases from the neuromuscular disorders disease group, myotonic dystrophy type 1 (DM1) and mitochondrial myopathies (MM). Despite having different physio-pathological pathways both DM1 and MM manifest in a clinically similar manner and may benefit from similar treatment options.  The sample will be stratified into three subgroups: two patient groups differentiated by age of symptom onset and one caregivers group.   Each subgroup will be randomly assigned to complete two of three different preference elicitation methods at two different time points: Q-methodology survey, discrete choice experiment, and best-worst scaling type 2, allowing cross-comparisons of the results across each study time within participants and within elicitation methods. Additional variables such as sociodemographic, clinical and health literacy will be collected to enable analysis of potential heterogeneity. Ethics and Dissemination: This study protocol has undergone ethical review and approval by the Newcastle University R&D Ethics Committee (Ref: 15169/2018). All participants will be invited to give electronic informed consent to take part in the study prior accessing the online survey. All electronic data will be anonymised prior analysis. This study is part of the Patient Preferences in Benefit-Risk Assessments during the Drug Life Cycle (IMI-PREFER) project, a public-private collaborative research project aiming to develop expert and evidence-based recommendations on how and when patient preferences can be assessed and used to inform medical product decision making., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Jimenez-Moreno AC et al.)

Purpose: Intensity modulated radiation therapy delivered with deep-inspiration breath hold (IMRT-BH) provides favorable normal tissue dosimetric profiles when treating patients with mediastinal lymphoma. However, it is unclear if IMRT-BH plans are comparable to free breathing (FB) proton plans. We performed a retrospective, comparative dosimetric study between IMRT-BH and FB passive scatter proton therapy (P-FB) or intensity modulated proton therapy (IMPT-FB). Hypothesizing that BH would provide superior normal tissue sparing when added to proton therapy, we also compared plans to passive scatter BH (P-BH)., Methods and Materials: For 15 patients who received involved-site RT with "butterfly" IMRT-BH, 3 additional proton plans (P-FB, IMPT-FB, P-BH) were optimized to deliver 30.6 Gy/Gy relative biological effectiveness. Dosimetric variables (mean dose, V30, V25, V15, and V5) for organs at risk (OARs) were calculated and compared using nonparametric Wilcoxon signed-rank tests., Results: Of 57 studied OAR parameters, IMRT-BH plans were comparable in 37 (65%) parameters with P-FB plans, 32 (56%) of IMPT-FB parameters, and 30 (53%) of P-BH parameters. Doses to breasts were generally equivalent among plans while esophageal dosing was worse with IMRT-BH. Mean doses and V5 of the total lung and heart were the highest with IMRT-BH; however, IMRT-BH resulted in comparable coronary and superior lung V30 relative to proton plans. The addition of BH with proton therapy resulted in the greatest lung sparing, with mean lung dose reductions of 11% to 38%., Conclusions: The use of BH with IMRT reduces the disparity in OAR doses with equivalence achieved in nearly two-thirds of OAR metrics compared with P-FB and 50% compared with IMPT-BH. Because each modality exhibited unique benefits, personalization of modality selection is recommended. Proton therapy via BH provides additional benefits in heart and lung sparing., (© 2020 The Author(s).)

Introduction: Tongue-deviating oral stents (TDOS) are commonly used during unilateral neck radiation therapy to reduce unnecessary dose to nontarget oral structures. Their benefit in the setting of highly conformal treatment techniques, however, is not defined. The goal of this study was to investigate the potential benefit of TDOS use on dosimetric parameters in unilateral intensity modulated radiation therapy (IMRT) and intensity modulated proton therapy (IMPT)., Methods: A total of 16 patients with T1-2 tonsil cancer treated at a single institution were selected, of which 8 were simulated/treated with a TDOS and 8 without a TDOS. All received definitive unilateral IMRT to a dose of 66 Gy in 30 fx. IMPT plans were generated for each patient for study purposes and optimized according to standard institutional practice., Results: For IMRT plans, the presence of a TDOS (vs without) was associated with a significantly lower oral mucosa mean dose (31.4 vs 35.3 Gy; P = .020) and V30 (42.7% vs 57.1%; P = .025). For IMPT plans, the presence of TDOS (vs without) was not associated with any improvement in oral mucosa mean dose (18.3 vs 19.9 Gy; P = .274) or V30 (25.0% vs 26.2%; P = .655). IMPT plans without TDOS compared with IMRT plans with TDOS demonstrated reduced oral mucosa mean dose ( P < .001) and V30 ( P < .001)., Conclusion: The use of a TDOS for the unilateral treatment of well-lateralized tonsil cancers was associated with oral mucosa sparing for IMRT, but not for IMPT. Moreover, mucosa sparing was improved for IMPT plans without a TDOS compared to IMRT plans with a TDOS., (© 2020 The Author(s).)

In treatment planning, multiple imaging modalities can be employed to improve the accuracy of tumor delineation but this can be costly. This study aimed to compare the interobserver consistency of using dual energy computed tomography (DECT) versus magnetic resonance imaging (MRI) for delineating tumors in the head and neck cancer (HNC) re-irradiation scenario. Twenty-three patients with recurrent HNC and had planning DECT and MRI were identified. Contoured tumor volumes by seven radiation oncologists were compared. Overall, T1c MRI performed the best with median DSC of 0.58 (0-0.91) for T1c. T1c MRI provided higher interobserver agreement for skull base sites and 60 kV DECT provided higher interobserver agreement for non-skull base sites., 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 Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Objectives: A factor contributing to the value of patient preference studies is patient centricity. This study aimed to explore how patients want to be involved in the design and conduct of patient preference studies. In addition, we investigated patients' expectations regarding the communication of study results back to patients. Methods: Semi-structured interviews were conducted with patient representatives within three different disease areas: rheumatic diseases, cancer, and neuromuscular disorders. For each disease area, interviews were conducted with interviewees from Belgium, the Netherlands and the United Kingdom. Interviews followed a predefined interview guide covering topics relating to timing, level, and requirements for patient involvement in patient preference studies, as well as communication of results. Interviews were audio-recorded, transcribed and analyzed using framework analysis in NVivo 12. Results: A total of 14 interviews were conducted. Some interviewees believed that patients should be involved in all steps of a patient preference study. Patient involvement seemed most valuable during the design phase to support defining research questions and instrument design. During analysis, patients can be involved for optimal interpretation of results. Most interviewees mentioned that patient involvement should be on the level of advice or collaboration, not control. Interviewees expressed requirements for patient involvement relating to the knowledge of the involved patient, time investment, compensation and other incentives. Regarding communication of results, most interviewees wished to receive a brief and lay summary of the results, followed by a detailed explanation of both individual and average results accompanied by visuals. Conclusions: Patient involvement in patient preference studies could increase question comprehension by study participants and ensure correct interpretation of results by researchers. Patients want to be involved as advisors or collaborators, and considering their personal situation as well as establishing agreements on roles, time involvement and compensation early on will result in a most optimal partnership., (Copyright © 2020 van Overbeeke, Vanbinst, Jimenez-Moreno and Huys.)

Introduction: Stereotactic body radiotherapy (SBRT) results in excellent local control of stage I NSCLC. Radiobiology models predict greater tumor response when higher biologically effective doses (BED 10 ) are given. Prior studies support a BED 10 greater than or equal to 100 Gy with SBRT; however, data are limited comparing outcomes after various SBRT regimens. We therefore sought to evaluate national trends and the effect of using "low" versus "high" BED 10 SBRT courses on overall survival (OS)., Methods: This retrospective study used the National Cancer Data Base to identify patients diagnosed with clinical stage I (cT1-2aN0M0) NSCLC from 2004 to 2014 treated with SBRT. Patients were categorized into LowBED (100-129 Gy) or HighBED (≥130 Gy) groups. A 1:1 matched analysis based on patient and tumor characteristics was used to compare OS by BED 10 group. Tumor centrality was not assessed., Results: O 25,039 patients treated with LowBED (n = 14,756; 59%) or HighBED (n = 10,283; 41%) SBRT, 20,542 were matched. Shifts in HighBED to LowBED SBRT regimen use correlated with key publications in the literature. In the matched cohort, 5-year OS rates were 26% for LowBED and 34% for HighBED groups (p = 0.039). On multivariate analysis, receipt of LowBED was associated with significantly worse survival (hazard ratio = 1.046, 95% confidence interval: 1.004-1.090, p = 0.032)., Conclusions: LowBED SBRT for treating stage I NSCLC is becoming more common. However, our findings suggest SBRT regimens with BED 10 greater than or equal to 130 Gy may confer an additional survival benefit. Additional studies are required to evaluate the dose-response relationship and toxicities associated with modern HighBED SBRT., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose : Metaplastic breast cancer (BC) is an uncommon yet aggressive histologic subtype of BC. We sought to identify factors associated with its diagnosis and compare the management and outcomes of metaplastic BC with those of other BCs and triple negative invasive ductal carcinoma in particular given how often it has a triple negative phenotype. Patients and Methods : We identified women diagnosed with invasive BC in 2010-2014 in the National Cancer Data Base, and used univariate analysis to compare baseline patient and tumor characteristics by BC subtype. Overall survival (OS) was estimated with the Kaplan-Meier method, and multivariate Cox proportional hazards models were used to identify independent predictors of OS. Results : Of 247,355 cases, 2,084 (0.8%) were metaplastic BC, 55,998 (23%) triple negative BC, and 77% other BC. Relative to non-metaplastic BC, women with metaplastic BC were more likely to be older at diagnosis (median age, 62 vs. 59 years), have ≥1 comorbid conditions (22% vs. 18%), and be on Medicare (41% vs. 33%; P <0.001). Metaplastic BCs tended to be basal-like (77%), and relative to triple-negative or other BC, metaplastic BC was associated with higher clinical T status (cT3-4, 18% vs. 11%, 8%), no clinical nodal involvement (cN0, 86%, 77%, 80%), no lymphovascular invasion (72%, 65%, 62%), and high-grade tumors (71%, 77%, 35%) ( P <0.001). Most metaplastic BCs were treated with mastectomy (58%), sentinel lymph node dissection (65%), chest wall or breast irradiation (74%), and chemotherapy (75%) as adjuvant therapy (60%). At a median follow-up time of 44.5 months, OS rates were lower for metaplastic BC than for triple-negative or other BC across all clinical stages at 5 years (stage I, 85%, 87%, 91%; II, 73%, 77%, 87%; III, 43%, 53%, 75%) and at 3 years (Stage IV, 15%, 22%, 64%; P <0 . 001). On multivariate analysis, increasing age, advanced clinical stage, lymphovascular invasion, axillary (vs. sentinel) node dissection, and no radiation or chemotherapy were associated with worse outcomes in metaplastic BC. Extent of surgery affected survival for triple-negative and other BC but not for metaplastic BC. Conclusion : Outcomes for metaplastic BC continue to be worse than those for other BC subtypes despite modern treatments. Optimizing systemic therapy options, which was a significant predictor of survival, should be a priority in managing metaplastic BC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Defining clinically relevant outcome measures for myotonic dystrophy type 1 (DM1) that can be valid and feasible for different phenotypes has proven problematic. The Outcome Measures for Myotonic Dystrophy (OMMYD) group proposed a battery of functional outcomes: 6-minute walk test, 30 seconds sit and stand test, timed 10 m walk test, timed 10 m walk/run test, and nine-hole peg test. This, however, required a large-scale investigation, METHODS: A cohort of 213 patients enrolled in the natural history study, PhenoDM1, was analyzed in cross-sectional analysis and subsequently 98 patients were followed for longitudinal analysis. We aimed to assess: (1) feasibility and best practice; (2) intra-session reliability; (3) validity; and (4) behavior over time, of these tests., Results: OMMYD outcomes proved feasible as 96% of the participants completed at least one trial for all tests and more than half (n = 113) performed all three trials of each test. Body mass index and disease severity associate with functional capacity. There was a significant difference between the first and second trials of each test. There was a moderate to strong correlation between these functional outcomes and muscle strength, disease severity and patient-reported outcomes. All outcomes after 1 year detected a change in functional capacity except the nine-hole peg test., Conclusions: These tests can be used as a battery of outcomes or independently based on the shown overlapping psychometric features and strong cross-correlations. Due to the large and heterogeneous sample of this study, these results can serve as reference values for future studies., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Objective: To validate the Intra-aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) score in patients with cardiogenic shock after ST elevation myocardial infarction (STEMI) treated with pharmacoinvasive strategy (PhIS) and to analyse the influence of ischaemia time on different risk strata., Methods: We analysed 2143 patients with STEMI who underwent reperfusion with tenecteplase in primary health services between May 2010 and April 2017 and were transferred to a tertiary hospital for cardiac catheterisation and continuity of care. Those who evolved to cardiogenic shock were scored as low (0-2), moderate (3-4) or high (5-9) risk of death in 30 days and pairwise-log-rank test was used to compare strata. Time intervals between symptoms onset and lytic (pain-to-needle) and fibrinolytic-catheterisation were also compared., Results: Cardiogenic shock occurred in 212 (9.9%) individuals. The 30-day mortality using the IABP-SHOCK II score was 26.6% for low-risk (n=94), 53.2% for moderate-risk (n=62) and 76% for high-risk (n=25) analysed patients (p<0.001). Validation of the score showed good discrimination for death, area under the curve of 0.73 (CI: 0.66 to 0.81; p<0.001). The median intervals of pain-to-needle and fibrinolytic-catheterisation showed no association with the group stratification (220 vs 251 vs 200 min; p=0.22 and 390 vs 435 vs 315 min; p=0.18, respectively)., Conclusions: In patients with cardiogenic shock after STEMI treated with PhIS, risk stratification using IABP-SHOCK II score was adequate. There was no influence of pain-to-needle and fibrinolytic-catheterisation times on the ability to the score model stratification., Competing Interests: Competing interests: None declared.