Search

OBJECTIVE The CyberKnife (CK) has emerged as an effective frameless and noninvasive method for treating a myriad of neurosurgical conditions. Here, the authors conducted an extensive retrospective analysis and review of the literature to elucidate the trend for CK use in the management paradigm for common neurosurgical diseases at their institution. METHODS A literature review (January 1990–June 2019) and clinical review (January 1999–December 2018) were performed using, respectively, online research databases and the Stanford Research Repository of patients with intracranial and spinal lesions treated with CK at Stanford. For each disease considered, the coefficient of determination (r2) was estimated as a measure of CK utilization over time. A change in treatment modality was assessed using a t-test, with statistical significance assessed at the 0.05 alpha level. RESULTS In over 7000 patients treated with CK for various brain and spinal lesions over the past 20 years, a positive linear trend (r2 = 0.80) in the system's use was observed. CK gained prominence in the management of intracranial and spinal arteriovenous malformations (AVMs; r2 = 0.89 and 0.95, respectively); brain and spine metastases (r2 = 0.97 and 0.79, respectively); benign tumors such as meningioma (r2 = 0.85), vestibular schwannoma (r2 = 0.76), and glomus jugulare tumor (r2 = 0.89); glioblastoma (r2 = 0.54); and trigeminal neuralgia (r2 = 0.81). A statistically significant difference in the change in treatment modality to CK was observed in the management of intracranial and spinal AVMs (p < 0.05), and while the treatment of brain and spine metastases, meningioma, and glioblastoma trended toward the use of CK, the change in treatment modality for these lesions was not statistically significant. CONCLUSIONS Evidence suggests the robust use of CK for treating a wide range of neurological conditions.

OBJECTIVES We investigated differences in quality of life (QoL) in patients enrolled on a phase I/II dose-escalation study of 3-fraction resection cavity stereotactic radiosurgery (SRS) for large brain metastases. METHODS Eligible patients had 1 to 4 brain metastases, one of which was a resection cavity 4.2 to 33.5 cm3. European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires core-30 (QLQ-30) and brain cancer specific module (QLQ-BN20) were obtained before SRS and at each follow-up. Nine scales were analyzed (global health status; physical, social, and emotional functioning; motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty). QoL was assessed with mixed effects models. Differences ≥10 points with q-value (adjusted P-value to account for multiplicity of testing)

BACKGROUND To better counsel vestibular schwannoma patients, it is necessary to understand the tumor control rates of stereotactic radiosurgery (SRS). OBJECTIVES To determine tumor control rates, factors determining control and complication rates following SRS. METHODS Tertiary hospital retrospective cohort. RESULTS 579 tumors (576 patients) were treated with SRS. 477 tumors (474 patients, 82%) had ≥1 year follow up and 60% (344) ≥3 years follow up. 88% of tumors had primary SRS and 6.7% salvage SRS. Median follow up time was 4.6 years. At 3 years, the tumor control rate of primary SRS was 89% (258 of 290) in sporadic tumors compared to 43% in Neurofibromatosis type II (3 of 17) (p

Background: data on vaccine immunogenicity against SARS-CoV-2 are needed for the 40 million people globally living with HIV who might have less functional immunity and more associated comorbidities than the general population. We aimed to explore safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV. Methods: in this single-arm open-label vaccination substudy within the protocol of the larger phase 2/3 trial COV002, adults aged 18–55 years with HIV were enrolled at two HIV clinics in London, UK. Eligible participants were required to be on antiretroviral therapy (ART), with undetectable plasma HIV viral loads (0·05 for all analyses). Interpretation: in this study of people with HIV, ChAdOx1 nCoV-19 was safe and immunogenic, supporting vaccination for those well controlled on ART. Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

This paper summarizes the 2020 Diversity in Radiology and Molecular Imaging: What We Need to Know Conference, a three-day virtual conference held September 9–11, 2020. The World Molecular Imaging Society (WMIS) and Stanford University jointly organized this event to provide a forum for WMIS members and affiliates worldwide to openly discuss issues pertaining to diversity in science, technology, engineering, and mathematics (STEM). The participants discussed three main conference themes, “racial diversity in STEM,” “women in STEM,” and “global health,” which were discussed through seven plenary lectures, twelve scientific presentations, and nine roundtable discussions, respectively. Breakout sessions were designed to flip the classroom and seek input from attendees on important topics such as increasing the representation of underrepresented minority (URM) members and women in STEM, generating pipeline programs in the fields of molecular imaging, supporting existing URM and women members in their career pursuits, developing mechanisms to effectively address microaggressions, providing leadership opportunities for URM and women STEM members, improving global health research, and developing strategies to advance culturally competent healthcare. Supplementary Information The online version contains supplementary material available at 10.1007/s11307-021-01610-3.

Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group (P = 0.001), 46% in the calcium group (P = 0.002), and 34% in the calcium + vitamin D group (P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D–binding protein isoform DBP2 (GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% (P = 0.0006), 75% (P = 0.0002), and 60% (P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD—biomarkers of inflammation that are strongly linked to colorectal carcinogenesis—in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). Prevention Relevance: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer.

Objective Immunotherapy for patients with melanoma with brain metastasis has significantly improved outcomes; however, it has also been characterized by potentially dangerous immune-related adverse events (IRAEs). Several reports have suggested that these reactions can precede improved treatment responses. For intracranial disease control, we sought to identify if such an association exists. Methods We conducted a retrospective chart review of patients with melanoma who underwent immunotherapy treatment after diagnosis of brain metastasis. The study cohort was then stratified into 2 groups based on their history of developing an IRAE that prompted discontinuation of that regimen. The primary outcome variable included intracranial progression-free survival (PFS). Kaplan-Meier and Cox proportional hazard analyses were used to evaluate survival and predictors of outcomes. Results Fifty-two patients met the inclusion criteria, 17 of whom experienced severe IRAEs that led to discontinuation of immunotherapy. Median intracranial PFS was 19.9 versus 10.5 months (P = 0.053) in patients who did and did not experience severe IRAEs prompting discontinuation, respectively. No additional outcome benefits were identified for systemic PFS or overall survival (mean, 33.1 months and 27.6 months, respectively). Multivariable analysis identified BRAF mutation status as a negative prognosticator of brain progression (P = 0.013; hazard ratio, 3.90). Initial treatment with BRAF inhibitor was also a negative predictor of all-cause mortality (P = 0.015; hazard ratio, 10.73). Conclusions Immune-related adverse events may signify an underlying immunogenic response that has intracranial disease control benefits. Despite their associated side effects, immunotherapies continue to show promising outcomes as a first-line agent for melanoma with brain metastasis.

Aim To examine the proportion of nurses meeting the strength training recommendation and its associated cardiometabolic, psychological and musculoskeletal benefits. Background Strength training targets poor physical and mental health often reported by nurses; however, it is unknown whether nurses are meeting the strength training guidelines. Methods Nurses from 14 hospitals completed a seven-day physical activity log. Nurses were considered meeting the recommendation if they reported ≥2 strength training sessions per week. Cardiometabolic, psychological and musculoskeletal health, and levels of motivation were compared between nurses meeting and not meeting the guidelines. Results Of the 307 nurses (94% female; age: 43±12 years), 29 (9.4%) met the strength training recommendation. These nurses had: lower body mass index (24.1±2.6 vs. 27.3±5.5 kg/m2 , p=0.007) and waist circumference (73.8±8.3 vs. 81.1±11.7 cm, p=0.017); and, higher vigor-activity (18.0±5.8 vs. 15.6±6.5 points, p=0.046) and self-determined motivation (relative autonomic index: 54.9±20.3 vs. 45.0±23.8 points, p=0.042) scores compared to nurses not meeting the recommendation. Conclusion While the proportion of nurses meeting the strength training recommendation was small ( Implications for nursing management Strategies to increase the strength training engagement may improve the cardiometabolic health and increase vigor among nurses.

Black physicians remain disproportionately underrepresented in certain medical specialties, yet comprehensive assessments in radiation oncology (RO) are lacking. Our purpose was to report current and historical representation trends for Black physicians in the US RO workforce.Public registries were used to assess significant differences in 2016 representation for US vs RO Black academic full-time faculty, residents, and applicants. Historical changes from 1970 to 2016 were reported descriptively. Linear regression was used to assess significant changes for Black residents and faculty from 1995 to 2016.In 2016, Black people represented 3.2% vs 1.5% (P.001), 5.6% vs 3.2% (P = .005), and 6.5% vs 5.4% (P = .352) of US vs RO faculty, residents, and applicants, respectively. Although RO residents nearly doubled from 374 (1974) to 720 (2016), Black residents peaked at 31 in 1984 (5.9%; 31 of 522) and fell to 23 (3.2%; 23 of 720) in 2016 across 91 accredited programs; Black US graduate medical education trainees nearly doubled over the same period: 3506 (1984) to 6905 (2016). From 1995 to 2016, Black US resident representation significantly increased by 0.03%/y, but decreased significantly in RO by -0.20%/y before 2006 and did not change significantly thereafter. Over the same period, Black US faculty representation significantly increased by 0.02%/y, whereas Black RO faculty significantly increased by 0.07%/y before 2006, then decreased significantly by -0.16%/y thereafter. The number of Black RO faculty peaked at 37 in 2006 (3.1%; 37 of 1203) and was 27 (1.5%; 27 of 1769) in 2016, despite the nearly 1.5-fold increase in the number of both RO faculty and Black US faculty overall (4169 in 2006 and 6047 in 2016) during that period.Black physicians remain disproportionately underrepresented in RO despite an increasing available pipeline in the US physician workforce. Deliberate efforts to understand barriers to specialty training and inclusion, along with evidence-based targeted interventions to overcome them, are needed to ensure diversification of the RO physician workforce.

Recent events have reaffirmed that racism is a pervasive disease plaguing the United States and infiltrating the fabric of this nation. As health care professionals dedicated to understanding and alleviating disease, many radiation oncologists have failed to acknowledge how structural racism affects the health and well-being of the patients we aim to serve. The literature is full of descriptive statistics showing the higher incidence and mortality experienced by the Black population for health conditions ranging from infant mortality to infectious disease, including coronavirus disease 2019 (COVID-19). Acknowledgment that the root of health disparities experienced by Black people in this country are based in racism is essential to moving the nation and the field of radiation oncology forward. With this lens, a brief overview of structural and institutional racism shapes a discussion of what radiation oncologists and the organizations that represent them can do to address this scourge. As members of a technological field, we often harness the power of data to advance human health and approach challenging diseases with optimism that multidisciplinary effort can produce cure. A few principles to mitigate the longstanding issues of Black marginalization within the field have been recommended via the ATIP (Acknowledgment, Transparency, Intentionality, and rePresentation) and LEADS (Learn, Engage, Advocate, Defend, Support) approaches. However, additional introspection is encouraged. Just as individuals, practices, and organizations rallied to determine how best to address the issues related to the COVID-19 pandemic, the same investigational fervor must be applied to the issue of racism to combat this sinister and often deadly disease.

BACKGROUND Basic science literature strongly supports a role of oxidative stress in colorectal cancer (CRC) etiology, but in epidemiologic studies, associations of most individual exposures with CRC have been weak or inconsistent. However, recent epidemiologic evidence suggests that the collective effects of these exposures on oxidative balance and CRC risk may be substantial. METHODS Using food frequency and lifestyle questionnaire data from the prospective Iowa Women's Health Study (1986-2012), we investigated associations of 11-component dietary and 4-component lifestyle oxidative balance scores (OBS) with incident CRC using multivariable Cox proportional hazards regression. RESULTS Of the 33,736 cancer-free women aged 55-69 years at baseline, 1,632 developed CRC during follow-up. Among participants in the highest relative to the lowest dietary and lifestyle OBS quintiles (higher anti-oxidant relative to pro-oxidant exposures), the adjusted hazard ratios (HRs) and their 95% confidence intervals (CI) were, respectively, 0.77 (0.63, 0.94) (Ptrend=0.02) and 0.61 (0.52, 0.71) (Ptrend

Purpose Although consensus guidelines for postresection stereotactic radiosurgery (SRS) for brain metastases recommend the surgical corridor leading to the resection cavity be included in the SRS plan, no study has reported patterns of tumor recurrence based on inclusion or exclusion of the corridor as a target. We reviewed tumor control and toxicity outcomes of postresection SRS for deep brain metastases based on whether or not the surgical corridor was targeted. Materials and Methods We retrospectively reviewed patients who had resected brain metastases treated with SRS between 2007 and 2018 and included only “deep” tumors (defined as located ≥1.0 cm from the pial surface before resection). Results In 66 deep brain metastases in 64 patients, the surgical corridor was targeted in 43 (65%). There were no statistical differences in the cumulative incidences of progression at 12 months for targeting versus not targeting the corridor, respectively, for overall local failure 2% (95% confidence interval [CI], 0%-11%) versus 9% (95% CI, 1%-25%; P = .25), corridor failure 0% (95% CI, 0%-0%) versus 9% (95% CI, 1%-25%; P = .06), cavity failure 2% (95% CI, 0%-11%) versus 0% (95% CI, 0%-0%; P = .91), and adverse radiation effect 5% (95% CI, 1%-15%) versus 13% (95% CI, 3%-30%; P = .22). Leptomeningeal disease (7%; 95% CI, 2%-18%) versus 26% (95% CI, 10%-45%; P = .03) was higher in those without the corridor targeted. Conclusions Omitting the surgical corridor in postoperative SRS for resected brain metastases was not associated with statistically significant differences in corridor or cavity recurrence or adverse radiation effect. As seen in recent prospective trials of postresection SRS, the dominant pattern of progression is within the resection cavity; omission of the corridor would yield a smaller SRS volume that could allow for dose escalation to potentially improve local cavity control.

Continuing the thematic focus on fostering wellness and professional fulfillment in our workplace, the 2019 Radiology Intersociety Committee Conference focused on understanding and leading multigenerational workforces and developing high-functioning teams. To lead a multigenerational workforce and to understand and embrace traditional versus emerging cultures in our workplace, effective leaders should foster diversity of their teams. Sustaining such teams requires an understanding of different styles and preferences for bidirectional communication and clarity of information sharing and learning; active efforts may be needed to focus on practical approaches to succession planning, breaking down traditional hierarchies, clarifying role delineation, and managing authority gradients. An effective team requires attention to the well-being of team members and professional behavior in and out of the workplace. Conference participants unanimously endorsed multi-organizational support statements and activities assuring professional behavior of their members, along with the desire to explore codes of conduct and ethics.

Minimally invasive therapeutic interventions and the field of stereotactic radiosurgery have advanced enormously in recent years. We briefly review the field of stereotactic radiosurgery and propose its use as a novel treatment modality for benign gynecologic conditions such as uterine fibroids. Computerized searches of Medline and PubMed were conducted using the key words “stereotactic radiosurgery,” “CyberKnife®,” “uterine fibroids,” and “radiation therapy.” References from identified sources were manually searched to allow for a thorough review. Data from relevant sources was compiled to create this review article. Stereotactic techniques have not only significantly reshaped the field of neurosurgery from open to noninvasive treatment, but also has impacted the field of radiation oncology by improving precision and reducing radiation exposure of normal tissues. Stereotactic radiation has proven to be a safe and effective method for the treatment of both benign and malignant conditions. Over the past two decades, new technologies have expanded the application of stereotactic radiosurgery to include spinal, renal, cardiac, lung, liver, prostate, and gynecologic cancers, and very recently even for the treatment of some non-neoplastic conditions such as cardiac arrhythmias. With success in so many disciplines, it is proposed that stereotactic radiosurgery may be a promising tool for the treatment of benign gynecologic conditions. Additional clinical experience is needed to further define the safety and efficacy of this proposed new treatment paradigm.

Background Regular exercise is advocated in osteoporosis guidelines to prevent fractures. Few studies have evaluated the effect of exercise on functional performance, posture, and other outcomes that are important to patients after vertebral fractures. Objective This pilot study will explore the effect of home exercise versus control on functional performance, posture, and patient-reported outcome measures. Design This study was a parallel 2-arm pilot feasibility trial with 1:1 randomization to exercise or attentional control groups. Setting This study took place in 5 Canadian and 2 Australian academic or community hospitals/centers. Participants This study included 141 women ≥65 years of age with radiographically confirmed vertebral fractures. Intervention A physical therapist delivered exercise and behavioral counseling in 6 home visits over 8 months and monthly calls. Participants were to exercise ≥3 times weekly. Controls received equal attention. Measurements Functional performance, posture, quality of life, pain, and behavior-change outcomes were assessed at baseline and after 6 (questionnaires only) and 12 months. Adherence to exercise was assessed by calendar diary. All t tests examined between-group mean differences (MD) in change from baseline in intention-to-treat and per-protocol analyses. Results There was a small effect of exercise on 5 times sit-to-stand test versus control (MD = −1.58 [95% CI = −3.09 to −0.07], intention-to-treat; MD = −1.49 [95% CI = −3.12 to 0.16], per-protocol). There were no other major or statistically significant MDs for any other measured outcomes after follow-up. Adherence declined over time. Limitations Treatment effects on variables may have been underestimated due to multiple comparisons and underpowered analyses. Conclusions Our exploratory estimate of the effect of exercise on functional leg muscle strength was consistent in direction and magnitude with other trials in individuals with vertebral fractures. Declining adherence to home exercise suggests that strategies to enhance long-term adherence might be important in future confirmatory trials.

Genome-wide association studies (GWAS) and candidate pathway studies have identified low-penetrant genetic variants associated with cutaneous melanoma. We investigated the association of melanoma-risk variants with primary melanoma tumor prognostic characteristics and melanoma-specific survival. The Genes, Environment, and Melanoma Study enrolled 3285 European origin participants with incident invasive primary melanoma. For each of 47 melanoma-risk single nucleotide polymorphisms (SNPs), we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and odds ratios for presence of ulceration, mitoses, and tumor-infiltrating lymphocytes (TILs). We also used Cox proportional hazards regression modeling to estimate the per allele hazard ratios for melanoma-specific survival. Passing the false discovery threshold (p = 0.0026) were associations of IRF4 rs12203592 and CCND1 rs1485993 with log of Breslow thickness, and association of TERT rs2242652 with presence of mitoses. IRF4 rs12203592 also had nominal associations (p < 0.05) with presence of mitoses and melanoma-specific survival, as well as a borderline association (p = 0.07) with ulceration. CCND1 rs1485993 also had a borderline association with presence of mitoses (p = 0.06). MX2 rs45430 had nominal associations with log of Breslow thickness, presence of mitoses, and melanoma-specific survival. Our study indicates that further research investigating the associations of these genetic variants with underlying biologic pathways related to tumor progression is warranted.

Trunk muscle endurance may be associated with balance and falls self-efficacy for people with osteoporosis. However, all previous studies have examined trunk muscle strength rather than endurance.To explore the relationships between trunk muscle endurance and standing balance and falls self-efficacy for women with vertebral fractures.This is an exploratory, secondary analysis of baseline data of a pilot randomized controlled trial in Ontario, Canada. Thirty-one women with osteoporosis, aged 65 years or older, with at least one vertebral fracture were included. The associations between balance (Balance Outcome Measure for Elder Rehabilitation) and trunk muscle endurance (Timed Loaded Standing Test) and falls self-efficacy (Falls Efficacy Scale International) and trunk muscle endurance were testedTrunk muscle endurance was correlated with better balance performance on the Balance Outcome Measure for Elder Rehabilitation [Spearman correlation coefficient, 0.71; 95% confidence interval: 0.47-0.85;Trunk muscle endurance was moderately associated with better standing balance performance but not falls self-efficacy, highlighting the importance of trunk muscle endurance for standing balance for older adults with osteoporosis and vertebral fractures.Implications for RehabilitationOlder adults with osteoporosis and vertebral fractures who have better trunk muscle endurance may also have better standing balance.There was no association between trunk muscle endurance and how confident a person is that they will not fall while completing various activities of daily living.Trunk muscle endurance training could be included as part of a standing balance rehabilitation program for this population.

We present a robust fiber-based setup for Bessel-like beam extended depth-of-focus Fourier-domain optical coherence microscopy, where the Bessel-like beam is generated in a higher order mode fiber module. In this module a stable guided LP02 core mode is selectively excited by a long period grating written in the higher order mode fiber. Imaging performance of this system in terms of lateral resolution and depth of focus was analyzed using samples of suspended microbeads and compared to the case where illumination is provided by the fundamental LP01 mode of a single mode fiber. Illumination with the LP02 mode allowed for a lateral resolution down to 2.5 µm as compared to 4.5 µm achieved with the LP01 mode of the single mode fiber. A three-fold enhancement of the depth of focus compared to a Gaussian beam with equally tight focus is achieved with the LP02 mode. Analysis of the theoretical lateral point spread functions for the case of LP01 and LP02 illumination agrees well with the experimental data. As the design space of waveguides and long-period gratings allows for further optimization of the beam parameters of the generated Bessel-like beams in an all-fiber module, this approach offers a robust and yet flexible alternative to free-space optics approaches or the use of conical fiber tips.

From the combined perspective of biologists, microscope instrumentation developers, imaging core facility scientists, and high performance computing experts, we discuss the challenges faced when selecting imaging and analysis tools in the field of light-sheet microscopy. Our goal is to provide a contextual framework of basic computing concepts that cell and developmental biologists can refer to when mapping the peculiarities of different light-sheet data to specific existing computing environments and image analysis pipelines. We provide our perspective on efficient processes for tool selection and review current hardware and software commonly used in light-sheet image analysis, as well as discuss what ideal tools for the future may look like.

We introduce a computational approach to build three-dimensional (3D) surface mesh models of the early-stage zebrafish brain primordia from time-series microscopy images. The complexity of the early-stage brain primordia and lack of recognizable landmarks pose a distinct challenge for feature segmentation and 3D modeling. Additional difficulty arises because of noise and variations in pixel intensity. We overcome these by using a hierarchical approach in which simple geometric elements, such as "beads" and "bonds," are assigned to represent local features and their connectivity is used to smoothen the surface while retaining high-curvature regions. We apply our method to build models of two zebrafish embryo phenotypes at discrete time points between 19 and 28 h post-fertilization and collect measurements to quantify development. Our approach is fast and applicable to building models of other biological systems, as demonstrated by models from magnetic resonance images of the human fetal brain. The source code, input scripts, sample image files, and generated outputs are publicly available on GitHub.

PurposeMedulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma.MethodsWe performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy.ResultsTwenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities.ConclusionsGiven the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival.Clinical Trial RegistrationClinicalTrials.gov identifier: NCT00031590

BACKGROUND: Vertebral fractures are associated with increased morbidity (e.g. pain, reduced quality of life) and mortality. Therapeutic exercise is a non‐pharmacological conservative treatment that is often recommended for patients with vertebral fractures to reduce pain and restore functional movement. This is an update of a Cochrane Review first published in 2013. OBJECTIVES: To assess the effects (benefits and harms) of exercise intervention of four weeks or greater (alone or as part of a physical therapy intervention) versus non‐exercise/non‐active physical therapy intervention, no intervention or placebo among adults with a history of vertebral fractures on incident fragility fractures of the hip, vertebra or other sites. Our secondary objectives were to evaluate the effects of exercise on the following outcomes: falls, pain, physical performance, health‐related quality of life (disease‐specific and generic), and adverse events. SEARCH METHODS: We searched the following databases until November 2017: the Cochrane Library (Issue 11 of 12), MEDLINE (from 2005), Embase (from 1988), CINAHL (Cumulative Index to Nursing and Allied Health Literature, from 1982), AMED (from 1985), and PEDro (Physiotherapy Evidence Database, from 1929). Ongoing/recently completed trials were identified by searching the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Conference proceedings were searched via ISI and SCOPUS, and targeted searches of proceedings of the American Congress of Rehabilitation Medicine and American Society for Bone and Mineral Research. Search terms or MeSH headings included terms such as vertebral fracture AND exercise OR physical therapy. For this update, the search results were limited from 2011 onward. SELECTION CRITERIA: We included all randomized controlled trials and quasi‐randomized trials comparing exercise or active physical therapy interventions with placebo/non‐exercise/non‐active physical therapy interventions or no intervention implemented in individuals with a history of vertebral fracture. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data using a pre‐tested data extraction form. Disagreements were resolved by consensus, or third‐party adjudication. We used Cochrane's tool for assessing risk of bias to evaluate each study. Studies were grouped according to duration of follow‐up (i.e. a) 4‐12 weeks; b) 16‐24 weeks; c) 52 weeks); a study could be represented in more than one group depending on the number of follow‐up assessments. For dichotomous data, we reported risk ratios (RR) and corresponding 95% confidence intervals (95% CI). For continuous data, we reported mean differences (MD) of the change from baseline and 95% CI. Data were pooled for Timed Up and Go test, self‐reported physical function measured by the QUALEFFO‐41 physical function subscale score (scale of zero to 100; lower scores indicate better self‐reported physical function), and disease‐specific quality of life measured by the QUALEFFO‐41 total score (scale of zero to 100; lower scores indicate better quality of life) at 12 weeks using a fixed‐effect model. MAIN RESULTS: Nine trials (n = 749, 68 male participants; two new trials in this review update) were included. Substantial variability across the trials prevented any meaningful pooling of data for most outcomes. Risk of bias across all studies was variable; low risk across most domains in four studies, and unclear/high risk in most domains for five studies. Performance bias and blinding of subjective outcome assessment were almost all high risk of bias. One trial reported no between‐group difference in favor of the effect of exercise on incident fragility fractures after 52 weeks (RR 0.54, 95% CI 0.17 to 1.71; very low‐quality evidence with control: 184 per 1000 and exercise: 100 per 1000, 95% CI 31 to 315; absolute difference: 8%, 95% CI 2 to 30). One trial reported no between‐group difference in favor of the effect of exercise on incident falls after 52 weeks (RR 1.06, 95% CI 0.53 to 2.10; very low‐quality evidence with control: 262 per 1000 and exercise: 277 per 1000; 95% CI 139 to 550; absolute difference: 2%, 95% CI ‐12 to 29). These findings should be interpreted with caution because of the very serious risk of bias in these studies and the small sample sizes resulting in imprecise estimates. We are uncertain that exercise could improve pain, self‐reported physical function, and disease‐specific quality of life, because certain studies showed no evidence of clinically important differences for these outcomes. Pooled analyses revealed a small between‐group difference in favor of exercise for Timed Up and Go (MD ‐1.13 seconds, 95% CI ‐1.85 to ‐0.42; studies = 2), which did not change following a sensitivity analysis (MD ‐1.09 seconds, 95% CI ‐1.78 to ‐0.40; studies = 3; moderate‐quality evidence). Exercise improved QUALEFFO‐41 physical function score (MD ‐2.84 points, 95% CI ‐5.57 to ‐0.11; studies = 2; very low‐quality evidence) and QUALEFFO‐41 total score (MD ‐3.24 points, 95% CI ‐6.05 to ‐0.43; studies = 2; very low‐quality evidence), yet it is unlikely that we observed any clinically important differences. Three trials reported four adverse events related to the exercise intervention (costal cartilage fracture, rib fracture, knee pain, irritation to tape, very low‐quality evidence). AUTHORS' CONCLUSIONS: In conclusion, we do not have sufficient evidence to determine the effects of exercise on incident fractures, falls or adverse events. Our updated review found moderate‐quality evidence that exercise probably improves physical performance, specifically Timed Up and Go test, in individuals with vertebral fracture (downgraded due to study limitations). However, a one‐second improvement in Timed Up and Go is not a clinically important improvement. Although individual trials did report benefits for some pain and disease‐specific quality of life outcomes, the findings do not represent clinically meaningful improvements and should be interpreted with caution given the very low‐quality evidence due to inconsistent findings, study limitations and imprecise estimates. The small number of trials and variability across trials limited our ability to pool outcomes or make conclusions. Evidence regarding the effects of exercise after vertebral fracture in men is scarce. A high‐quality randomized trial is needed to inform safety and effectiveness of exercise to lower incidence of fracture and falls and to improve patient‐centered outcomes (pain, function) for individuals with vertebral fractures (minimal sample size required is approximately 2500 untreated participants or 4400 participants if taking anti‐osteoporosis therapy).

There are very few reported cases of stereotactic radiosurgery (SRS) delivered in children under 3 years of age. We report an 18-month-old boy with metastatic recurrence of undifferentiated round cell sarcoma to the brain which was treated with chemotherapy, resection and robotic frameless SRS. Frameless SRS was delivered without technical difficulties, acute adverse events, or clinical sequelae 1.5 months post-radiation. Longer term follow-up will be needed to evaluate local tumor control and effects on neurocognitive development, endocrine function and growth. This report adds to the literature of the few reported cases of successfully attempted SRS in very young children.

In higher education, business students with different learning styles may not all respond successfully to a straight lecture format. The authors analyze the impact that an experiential learning act...

Background and purpose We sought to evaluate the Balance Outcome Measure for Elder Rehabilitation (BOOMER) in community-dwelling women 65 years and older with vertebral fracture and to describe score distributions and potential ceiling and floor effects. Methods This was a secondary data analysis of baseline data from the Build Better Bones with Exercise randomized controlled trial using the BOOMER. A total of 141 women with osteoporosis and radiographically confirmed vertebral fracture were included. Concurrent validity and internal consistency were assessed in comparison to the Short Physical Performance Battery (SPPB). Normality and ceiling/floor effects of total BOOMER scores and component test items were also assessed. Exploratory analyses of assistive aid use and falls history were performed. Results and discussion Tests for concurrent validity demonstrated moderate correlation between total BOOMER and SPPB scores. The BOOMER component tests showed modest internal consistency. Substantial ceiling effect and nonnormal score distributions were present among overall sample and those not using assistive aids for total BOOMER scores, although scores were normally distributed for those using assistive aids. The static standing with eyes closed test demonstrated the greatest ceiling effects of the component tests, with 92% of participants achieving a maximal score. Conclusions While the BOOMER compares well with the SPPB in community-dwelling women with vertebral fractures, researchers or clinicians considering using the BOOMER in similar or higher-functioning populations should be aware of the potential for ceiling effects.

Background Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are increasingly used together to manage brain metastases (BMs). We assessed adverse radiation effect, disease control, and overall survival in patients with BMs who received SRS with anticytotoxic T-lymphocyte–associated protein 4 and/or anti– programmed cell death protein receptor/ligand therapies. Methods We retrospectively reviewed the records of patients with intact or resected BMs treated with SRS and ICIs within 5 months of SRS between 2010 and 2018. Patients were defined as receiving concurrent SRS and ICI if a dose of ICI was given within 4 weeks of SRS. Local failure, distant intracranial failure, extracranial failure, and adverse radiation effect were assessed using cumulative incidence rates and competing risk regressions with death as a competing risk. Overall survival was assessed using the Kaplan-Meier method and Cox proportional hazards models. Results A total of 97 patients with 580 BMs were included in our analysis. Competing risk analyses showed that concurrent SRS-ICI therapy is associated with higher rates of adverse radiation effect (6.4% vs. 2.0% at 1 year; multivariable hazard ratio [HR], 4.47; 95% confidence interval [CI], 1.57–12.73; P = 0.005), lower rates of extracranial failure (69.7% vs. 80.8% at 1 year; multivariable HR, 0.60; 95% CI, 0.42–0.87; P = 0.007), and better overall survival (48.6% vs. 25.4% at 1 year; multivariable HR, 0.57; 95% CI, 0.33–0.99; P = 0.044) compared with nonconcurrent therapy. SRS-ICI timing was not associated with local failure or distant intracranial failure. Conclusions Concurrent SRS-ICI therapy has a tolerable adverse event profile and may improve extracranial disease control and overall survival, supporting concurrent use in the management of BMs.

Notre etude pilote a evalue la faisabilite, l'efficacite et la mise en œuvre du programme d'exercices fonctionnels en groupe integres au mode de vie (Lifestyle-integrated Functional Exercise; Mi-LiFE) cree pour des personnes âgees, dans le cadre d'une pratique interprofessionnelle en soins de premiere ligne. Un physiotherapeute a enseigne aux participants comment integrer des exercices de force et d'equilibre dans la routine quotidienne au cours d'une seance individuelle et de quatre seances de groupe, suivis de deux rendez-vous telephoniques. Les resultats concernant la faisabilite incluaient le recrutement, l'adhesion et la retention sur une periode de six mois. L'activite physique (AP) (accelerometre, IPAQ), une version courte de la batterie de tests de performance physique (SPPB) et la qualite de vie liee a la sante (EQ5D-3L) ont ete evaluees au debut de l'intervention et 6 mois plus tard. Des 123 personnes admissibles, 39 % ont participe a l'intervention et 61 % n'etaient pas interessees ou non joignables. Quarante-huit participants (âge moyen ± ET = 81 ± 5 ans ; IMC = 28 ± 5 kg/m2 ; 60 % de femmes ; AP moderee a vigoureuse = 49 ± 87 minutes par semaine) ont pris part a cette etude. Quatre participants se sont retires avant le debut de l'intervention. Trente-deux participants (67 %) etaient presents au suivi. Le taux d'adhesion quotidien documente dans le journal de bord etait de 50 % a 6 mois, et 77 % des participants ont assiste a au moins 4 seances. Aucun changement statistiquement significatif n'a ete observe dans les resultats de l'AP moderee a forte et de la SPPB. Cependant, les participants ont declare lors du suivi que leur force et leur equilibre dans l'AP se sont ameliores, tout comme leur qualite de vie. Le programme Mi-LiFE presente une bonne faisabilite, avec des taux de recrutement et d'assiduite acceptables. Des modifications pourraient etre apportees pour ameliorer la retention et l'adhesion a l'intervention. Ces resultats renseignent sur la faisabilite de programames d'exercices pragmatiques qui pourraient etre developpes pour etre offerts aux personnes âgees se presentant pour des soins de premiere ligne. Our pilot study evaluated the feasibility, effectiveness, and implementation of a group-based lifestyle-integrated functional exercise (Mi-LiFE) program for older adults in an interprofessional primary care practice. A physical therapist taught participants how to integrate strength and balance activities into daily routines during one individual and four group sessions, and two follow-up phone calls. Feasibility outcomes were recruitment, adherence, and retention over 6 months. Physical activity (PA) (accelerometer, International Physical Activity Questionnaire [IPAQ]), Short Physical Performance Battery (SPPB), and health-related quality of life (EuroQol Five-Dimensional Questionnaire with 3 Levels [EQ5D-3L]) were evaluated at baseline and 6 months. Of the 123 eligible individuals, 39 per cent participated and 61 per cent were not interested or unreachable. Forty-eight participants (mean ± standard deviation [SD] age = 81 ± 5 years; body mass index [BMI] = 28 ± 5 kg/m2; 60% women; moderate-to-vigorous PA = 49 ± 87 minutes/week) enrolled. Four participants withdrew prior to intervention. Thirty-two participants (67%) were retained at follow-up. Daily diary-documented adherence was 50 per cent at 6 months, and 77 per cent attended more than four sessions. No statistically significant changes in moderate-to-vigorous PA and SPPB outcomes were observed; yet self-reported strength and balance PA and quality of life significantly improved at follow-up. The Mi-LiFE program is feasible with acceptable recruitment and attendance rates alongside modifications to address retention and adherence challenges. These findings inform the feasibility of future pragmatic exercise programs in primary care for older adults.

Introduction The CyberKnife, a frameless, robotic, stereotactic device, has been developed to radiosurgically treat arteriovenous malformations (AVMs). While most AVMs are obliterated within two-to-three years, a subset remain recalcitrant; long-term data on these difficult to treat AVMs are limited in the neurosurgical literature. Materials and methods A retrospective analysis of all patients who underwent CyberKnife treatment for intracranial AVMs at a single U.S. institution between 2002 and 2012, whose AVMs had failed to obliterate within 48 months or longer from the treatment start date, were eligible for inclusion. Results Eleven patients (9 AVMs; 7 males, 2 females) were followed for an average of 85.2 months (range 56.2–119.4). The median lesion size was 3.5 cm (range: 2.8–8.0 cm) and median Spetzler-Martin grade was 3 (range: 2–5). All AVMs were treated with one radiation dose (median prescribed dose was 18.0 Gy; median Dmax: 23.7 Gy). Six (66.7%) were obliterated in a median time of 84 months (range: 52–94 months), while 3 (33.3%) remained active after a median of 90.8 months (range 69.7–119.4). Transient, post-radiosurgery adverse radiation effects occurred in 5 (55.6%) cases. One (11.1%) patient had an acute hemorrhage from the AVM after radiosurgery. Four (44.4%) patients underwent repeat radiosurgery and/or embolization. Three of these lesions eventually obliterated, while 1 did not. Conclusion The median time to obliteration was 84 months. Two-thirds of AVMs which persisted for over 4 years following initial radiosurgery treatment eventually obliterated. Transient post-radiosurgery adverse effects were common; delayed hemorrhages were rare in our case series.

Malignant hyperthermia is a rare condition that occurs in susceptible patients exposed to triggering anesthetic agents. It is associated with a high mortality rate if not recognized immediately and treated appropriately. A 52-year-old man presented to our clinic 2 days after an assault for management of jaw pain. A minimally displaced right parasymphyseal fracture and moderately displaced left body fracture of the mandible were diagnosed. There were no known drug allergies. The patient reported no previous difficulty with anesthesia, as well as no known prior adverse reactions to anesthesia in any relatives. The planned surgical intervention was open reduction-internal fixation of bilateral mandibular fractures. The patient received succinylcholine and desflurane during the procedure. A full 70 minutes elapsed before initial signs of hypermetabolism were noted, namely a rise in end-tidal carbon dioxide level. The patient received dantrolene sodium approximately 120 minutes after induction of anesthesia. Signs of hypermetabolism began to abate within 45 minutes of commencement of the malignant hyperthermia treatment protocol. He was subsequently transferred to the surgical intensive care unit for continued management and had a favorable postoperative course. This case underscores the importance of awareness of malignant hyperthermia and its presentation. This condition carries a potential high risk of complications after exposure to triggering anesthetic agents. Taking a complete and detailed history may help to identify potential cases. In this case, it was subsequently discovered that the patient's biological sister had a nearly fatal reaction to general anesthesia several years before this incident. Intraoperative vigilance in the monitoring of vital signs cannot be overemphasized. An increase in end-tidal carbon dioxide values, in addition to other clinical signs that cannot be easily attributed to other causes, should increase the clinical index of suspicion for a diagnosis of malignant hyperthermia.

CONTEXT: Endocrine-metabolic disease (EMD) is associated with functional disability, social isolation, hospitalization and even death in individuals living with a chronic spinal cord injury (SCI). There is currently very low-quality evidence that rehabilitation interventions can reduce EMD risk during chronic SCI. Non-randomized trials and alternative study designs are excluded from traditional knowledge synthesis. OBJECTIVE: To characterize evidence from level 3–4 studies evaluating rehabilitation interventions for their effectiveness to improve EMD risk in community-dwelling adults with chronic SCI. METHODS: Systematic searches of MEDLINE PubMed, EMBASE Ovid, CINAHL, Cochrane Database of Systematic Reviews, and PsychInfo were completed. All longitudinal trials, prospective cohort, case–control studies, and case series evaluating the effectiveness of rehabilitation/therapeutic interventions to modify/associate with EMD outcomes in adults with chronic SCI were eligible. Two authors independently selected studies and abstracted data. Mean changes from baseline were reported for EMD outcomes. The Downs and Black Checklist was used to rate evidence quality. RESULTS: Of 489 articles identified, 44 articles (N = 842) were eligible for inclusion. Individual studies reported statistically significant effects of electrical stimulation-assisted training on lower-extremity bone outcomes, and the combined effects of exercise and dietary interventions to improve body composition and cardiometabolic biomarkers (lipid profiles, glucose regulation). In contrast, there were also reports of no clinically important changes in EMD outcomes, suggesting lower quality evidence (study bias, inconsistent findings). CONCLUSION: Longitudinal multicentre pragmatic studies involving longer-term exercise and dietary intervention and follow-up periods are needed to fully understand the impact of these rehabilitation approaches to mitigate EMD risk. Our broad evaluation of prospective cohort and case–control studies provides new perspectives on alternative study designs, a multi-impairment paradigm approach of studying EMD outcomes, and knowledge gaps related to SCI rehabilitation.

INTRODUCTION: Immune checkpoint inhibitors have become standard of care for many patients with non-small cell lung cancer (NSCLC). These agents often cause immune-related adverse events (IRAEs), which have been associated with increased overall survival (OS). Intracranial disease control and OS for patients experiencing IRAEs with metastatic NSCLC and brain metastases have not yet been described. METHODS: We performed a single-institution, retrospective review of patients with NSCLC and existing diagnosis of brain metastasis, who underwent pembrolizumab treatment and developed any grade IRAE. The primary outcome of the study was intracranial time to treatment failure (TTF), defined from time of pembrolizumab initiation to new intracranial disease progression or death. Kaplan-Meier and Cox proportional hazard analyses were performed. RESULTS: A total of 63 patients with NSCLC brain metastasis were identified, and 24 developed IRAEs. Patients with any grade IRAEs had longer OS (21 versus 10 months (p=0.004), systemic TTF (15 versus 4 months, p

Service is an important component of academic life that can lend meaning to one’s career and contribute to professional advancement, but these obligations should be actively evaluated and managed. There are many forms of service, and it is important to understand the advantages and disadvantages of participating in various types. Some forms of service may lead to leadership training and opportunities while others may be undervalued by the institution or profession. Leadership ideally includes a component of service to others and often grows from experiences in service work. Leadership should be flexible to meet the needs of contemporary organizations. Leadership style may evolve to meet the needs of specific situations or contexts. Developing a personal leadership style is a gradual process that arises from previous experiences as well as intentional self-development and is unique to each person.

For patients with brain metastases, radiotherapy management with stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT) has evolved over the years, guided by results from randomized controlled trials. These prospective data support the increasing utilization of SRS, with deferral of WBRT, for most patients with a limited number of brain metastases and good performance status, in both the definitive and post-resection settings. We highlight the general principles of SRS target delineation, dosing, and constraints to organs at risk.

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine is immunogenic and protects against COVID-19. However, data on vaccine immunogenicity are needed for the 40 million people living with HIV (PWH), who may have less functional immunity and more associated co-morbidities than the general population. Methods: Between the 5th and 24th November 2020, 54 adults with HIV, aged 18-55 years, were enrolled into a single arm open label vaccination study within the protocol of the larger phase 2/3 COV002 trial. A prime-boost regimen of ChAdOx1 nCoV-19, with two doses (5 × 1010 vp) was given 4-6 weeks apart. All participants were on antiretroviral therapy (ART) with undetectable plasma HIV viral loads and CD4+ T cell counts >350 cells/µl at enrolment. Data were captured on adverse events. Humoral responses were measured by anti-spike IgG ELISA and antibody-mediated live virus neutralisation. Cell-mediated immune responses were measured by ex-vivo interferon-γ enzyme-linked immunospot assay (ELISpot) and T cell proliferation. All outcomes were compared with a HIV uninfected group from the main COV002 study. Findings: 54 participants with HIV (median age 42.5 years (IQR 37.2-49.8)) received two doses of ChAdOx1 nCoV-19. Median CD4+ T cell count at enrolment was 694 cells/µl (IQR 562-864). Results are reported for 56 days of follow-up. Local and systemic reactions occurring during the first 7 days after prime vaccination included pain at the injection site (49%), fatigue (47%), headache (47%), malaise (34%), chills (23%), and muscle or (36%) joint pain (9%), the frequencies of which were similar to the HIV-negative participants. There were no serious adverse events. Anti-spike IgG responses by ELISA peaked at Day 42 (median 1440 ELISA units, IQR 704-2728) and were sustained out to Day 56. There was no correlation with CD4+ T cell count or age and the magnitude of the anti-spike IgG response at Day 56 (P>0.05 for both). ELISpot and T cell proliferative responses peaked between Day 14 and 28 after prime and were sustained through to Day 56. When compared to participants without HIV there was no statistical difference in magnitude or persistence of SARS-CoV-2 spike-specific humoral or cellular responses (P>0.05 for all analyses). Interpretation: In this study of PWH, vaccination with ChAdOx1 nCoV-19 was well tolerated and there was no difference in humoral and cell-mediated immune responses compared to an adult cohort without HIV who received the same vaccination regime. Trial Registration: Trial Registration number is NCT04400838. Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Declaration of Interest: Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19 (AZD1222). AstraZeneca reviewed the data from the study and the final manuscript before 474 submission, but the authors retained editorial control. SCG is cofounder of Vaccitech (a collaborator in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care’s JCVI, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AVSH is a cofounder of and consultant to Vaccitech and is named as an inventor on a patent covering design and use of ChAdOx1-vectored vaccines (PCT/GB2012/000467). Ethical Approval: Written informed consent was obtained from all participants, and the trial was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. This study was approved in the UK by the Medicines and Healthcare products Regulatory Agency (reference 21584/0424/001-0001) and the South Central Berkshire Research Ethics Committee (reference 20/SC/0145). Vaccine use was authorised by Genetically Modified Organisms Safety Committees at each participating site.

ObjectivesInforming research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.DesignIn the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.SettingUK stroke services.Participants3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.ResultsOf those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.ConclusionIt is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration numberISRCTN83290762; Post-results.

Purpose We evaluated the impact of a virtual radiation oncology clerkship. Methods and Materials We developed a 2-week virtual radiation oncology clerkship that launched on April 27, 2020. Clerkship components included a virtual clinic with radiation oncology faculty and residents, didactic lectures, student talks, and supplemental sessions such as tumor boards and chart rounds. Medical students completed pre- and post-clerkship self-assessments. Faculty and resident participants also completed surveys on their experience with virtual lectures and clinics. Pre- and post-clerkship results were compared using a 2-sided paired t test. An analysis of variance model was used to analyze the clerkship components. Results Twenty-six medical students, including 4 visiting students, enrolled over 2 clerkship periods (4 weeks). All students completed the pre- and post-clerkship self-assessments and agreed that the clerkship improved their understanding of radiation oncology. Compared with 3 (11.5%) students who agreed that they understood the daily responsibilities of a radiation oncologist before the clerkship, 22 (84.6%) students agreed and 3 (11.5%) strongly agreed that they understood the daily responsibilities of a radiation oncologist after the clerkship (P < .0001). Although 15 students (57.7%) reported an increased interest in radiation oncology because of the clerkship, the mean level of interest in radiation oncology as a career remained the same, with pre- and post-clerkship scores of 3.0 (±0.9) and 3.0 (±1.1) on a 5-point scale, respectively (P = .7). Students found virtual clinic and didactic lectures to be the most valuable components of the clerkship. Most respondents agreed (30.8%) or strongly agreed (65.4%) to recommend the clerkship to their classmates. Conclusions Our virtual clerkship was effective in increasing medical student interest in and knowledge about radiation oncology. These data will help optimize a new paradigm of virtual radiation oncology education for medical students during COVID-19 and beyond.

Purpose We sought to investigate the tumor control probability (TCP) of spinal metastases treated with stereotactic body radiation therapy (SBRT) in 1 to 5 fractions. Methods and Materials PubMed-indexed articles from 1995 to 2018 were eligible for data extraction if they contained SBRT dosimetric details correlated with actuarial 2-year local tumor control rates. Logistic dose-response models of collected data were compared in terms of physical dose and 3-fraction equivalent dose. Results Data were extracted from 24 articles with 2619 spinal metastases. Physical dose TCP modeling of 2-year local tumor control from the single-fraction data were compared with data from 2 to 5 fractions, resulting in an estimated α/β = 6 Gy, and this was used to pool data. Acknowledging the uncertainty intrinsic to the data extraction and modeling process, the 90% TCP corresponded to 20 Gy in 1 fraction, 28 Gy in 2 fractions, 33 Gy in 3 fractions, and (with extrapolation) 40 Gy in 5 fractions. The estimated TCP for common fractionation schemes was 82% at 18 Gy, 90% for 20 Gy, and 96% for 24 Gy in a single fraction, 82% for 24 Gy in 2 fractions, and 78% for 27 Gy in 3 fractions. Conclusions Spinal SBRT with the most common fractionation schemes yields 2-year estimates of local control of 82% to 96%. Given the heterogeneity in the tumor control estimates extracted from the literature, with variability in reporting of dosimetry data and the definition of and statistical methods of reporting tumor control, care should be taken interpreting the resultant model-based estimates. Depending on the clinical intent, the improved TCP with higher dose regimens should be weighed against the potential risks for greater toxicity. We encourage future reports to provide full dosimetric data correlated with tumor local control to allow future efforts of modeling pooled data.

Background Metastasectomy is standard of care for pediatric patients with metastatic sarcoma with limited disease. For patients with unresectable disease, stereotactic body radiotherapy (SBRT) may serve as an alternative. Herein, the authors report the results of a prospective, multi-institutional phase 2 trial of SBRT in children and young adults with metastatic sarcoma. Methods Patients aged >3 years and ≤40 years with unresected, osseous metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone were eligible. Patients received SBRT to a dose of 40 Gray (Gy) in 5 fractions. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method. Results Fourteen patients with a median age of 17 years (range, 4-25 years) were treated to 37 distinct metastatic lesions. With a median follow-up of 6.8 months (30.5 months in surviving patients), the Kaplan-Meier patient-specific and lesion-specific LC rates at 6 months were 89% and 95%, respectively. The median PFS was 6 months and the median OS was 24 months. In a post hoc analysis, PFS (median, 9.3 months vs 3.7 months; log-rank P = .03) and OS (median not reached vs 12.7 months; log-rank P = .02) were improved when all known sites of metastatic disease were consolidated with SBRT compared with partial consolidation. SBRT was well tolerated, with 2 patients experiencing grade 3 toxicities. Conclusions SBRT achieved high rates of LC in pediatric patients with inoperable metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone. These results suggest that the ability to achieve total consolidation of metastatic disease with SBRT is associated with improved PFS and OS.

BACKGROUND: Exogenous exposures collectively may contribute to chronic, low-grade inflammation and increase risks for major chronic diseases and mortality. We previously developed, validated, and reported a novel, FFQ-based and lifestyle questionnaire–based, inflammation biomarker panel–weighted, predominantly whole foods–based 19-component dietary inflammation score (DIS) and 4-component lifestyle inflammation score (LIS; comprising physical activity, alcohol intake, BMI, and current smoking status). Both scores were more strongly associated with circulating biomarkers of inflammation in 3 populations than were previously reported dietary inflammation indices. Associations of the DIS and LIS with mortality risk have not been reported. OBJECTIVES: To investigate separate and joint associations of the DIS and LIS with all-cause, all-cancer, and cardiovascular disease (CVD) mortality risks in the prospective Iowa Women's Health Study (1986–2012; n = 33,155 women, ages 55–69 years, of whom 17,431 died during follow-up, including 4379 from cancer and 6574 from CVD). METHODS: We summed each study participant's scores’ components, weighted by their published weights, to yield the participant's inflammation score; a higher score was considered more pro-inflammatory. We assessed DIS and LIS mortality associations using multivariable Cox proportional hazards regression. RESULTS: Among participants in the highest relative to the lowest DIS and LIS quintiles, the adjusted HRs for all-cause mortality were 1.11 (95% CI: 1.05–1.16) and 1.60 (95% CI: 1.53–1.68), respectively; for all-cancer mortality were 1.07 (95% CI: 0.97–1.17) and 1.51 (95% CI: 1.38–1.66), respectively; and for CVD mortality were 1.12 (95% CI: 1.03–1.21) and 1.79 (95% CI: 1.66–1.94), respectively (all P(trend) values

Purpose Our institution cancelled all in-person clerkships due to the COVID-19 pandemic. In response, we designed a virtual radiation oncology medical student clerkship. Methods and Materials We convened an advisory panel to design a virtual clerkship curriculum. We implemented clerkship activities using a cloud-based learning management system, video web conferencing systems and a telemedicine portal. Students completed assessments pre- and post-clerkship to provide data to improve future versions of the clerkship. Results The virtual clerkship spans 2 weeks and is graded pass or fail. Students attend interactive didactic sessions during the first week and participate in virtual clinic and give talks to the department during the second week. Didactic sessions include lectures, case-based discussions, treatment planning seminars and material adapted from the Radiation Oncology Education Collaborative Study Group curriculum. Students also attend virtual departmental quality assurance rounds, cancer center seminars and multi-disciplinary tumor boards. The enrollment cap was met during the first virtual clerkship period (April 27 through May 8, 2020), with a total of 12 students enrolling. Conclusions Our virtual clerkship can increase student exposure and engagement in radiation oncology. Data on clerkship outcomes are forthcoming., In response to cancelation of all in-person clerkships at our institution due to the COVID-19 pandemic, we designed a virtual radiation oncology clerkship. We fulfilled clerkship learning objectives using an array of digital education tools and were able to broaden our reach in educating medical students about our field.

Lower prediagnostic circulating 25-hydroxyvitamin D (25[OH]D)—considered the best marker of total vitamin D exposure—is associated with higher mortality risk among colorectal cancer (CRC) patients. However, it is unknown whether this association differs by the vitamin D-binding protein (GC) isoform Gc2 (encoded by GC rs4588*C>A, Thr436Lys), which may substantially affect vitamin D metabolism and modify associations of 25(OH)D with colorectal neoplasm risk. Prediagnostic 25(OH)D-mortality associations according to Gc2 isoform were estimated using multivariable Cox proportional hazards regression among 1281 CRC cases (635 deaths, 483 from CRC) from two large prospective cohorts conducted in the United States (Cancer Prevention Study-II) and Europe (European Prospective Investigation into Cancer and Nutrition). 25(OH)D measurements were calibrated to a single assay, season standardized, and categorized using Institute of Medicine recommendations (deficient [interaction =.0002). The corresponding HRs for all-cause mortality were 1.80 (95% CI 1.24-2.60) among those with Gc2, and 1.12 (95% CI 0.84-1.51) among those without Gc2 (P interaction =.004). Our findings suggest that the association of prediagnostic vitamin D status with mortality among CRC patients may differ by functional GC isoforms, and patients who inherit the Gc2 isoform (GC rs4588*A) may particularly benefit from higher circulating 25(OH)D for improved CRC prognosis.

Advances in multimodality therapy have led to childhood cancer cure rates over 80%. However, surgery, chemotherapy, and radiotherapy may lead to debilitating or even fatal long-term effects among childhood survivors beyond those inflicted by the primary disease process. It is critical to understand, mitigate, and prevent these late effects of cancer therapy to improve the quality of life of childhood cancer survivors. This review summarizes the various late effects of radiotherapy and acknowledges the Pediatric Normal Tissue Effects in the Clinic (PENTEC), an international collaboration that is systematically analyzing the association between radiation treatment dose/volume and consequential organ toxicities, in developing children as a basis to formulate recommendations for clinical practice of pediatric radiation oncology. We also summarize initiatives for survivorship and surveillance of late normal tissue effects related to radiation therapy among long-term survivors of childhood cancer treated in the past.

A compact, prism-based spectrograph was designed for 2-photon light sheet microscopy based on broadband, ultrashort optical pulses that corrects for chromatic aberrations and distortion. Gaussian or Bessel beams of broadband optical pulses may be used to create narrow cylindrical, nonlinear excitation volumes from which fluorophores emit characteristic spectra. In practice, a slit aperture is often used to optically section the excitation volume before being imaged onto the camera chip. Optical dispersion of the fluorescence in the transverse direction of the imaging slit allows for hyperspectral image acquisition. Hyperspectral imaging systems may be used to simultaneously image and segment multiple fluorescent reporters in biological tissue. However, current systems have properties which are undesirable for low-light microscopy including chromatic aberrations, distortion, low optical transmission, and large footprint which consumes precious laboratory real estate. Here, we present a novel spectrograph that has sufficient optical transmission, achromaticity, and distortion correction for microscopy of fluorescent reporters spanning the visible spectrum (400 – 650 nm). Across the spatial dimension of the excitation volume, the spectrograph has uniform separation of the spectral bands while maintaining a compact size and profile. A second order deconvolution algorithm is used to spectrally deconvolve overlapping fluorophores.

Background We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM). Methods We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3 + 3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3–5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis. Results From 2010 to 2015, thirty patients were enrolled. The median age was 66 years (range, 51–86 y). The median target volume was 60 cm3 (range, 14.7–137.3 cm3). DLT occurred in 2 patients: one for posttreatment cerebral edema and progressive disease at 3 weeks (grade 4, dose 40 Gy); another patient died 1.5 weeks following SRS from postoperative complications (grade 5, dose 40 Gy). Late grades 1–2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2–12.6 mo). No grades 3–5 ARE occurred. With a median follow-up of 13.8 months (range 1.7–64.4 mo), the median survival times were: progression-free survival, 8.2 months (95% CI: 4.6–10.5); overall survival, 14.8 months (95% CI: 10.9–19.9); O6-methylguanine-DNA methyltransferase hypermethylated, 19.9 months (95% CI: 10.5–33.5) versus 11.3 months (95% CI: 8.9–17.6) for no/unknown hypermethylation (P = 0.03), and 27.2 months (95% CI: 11.2–48.3) if late ARE occurred versus 11.7 months (95% CI: 8.9–17.6) for no ARE (P = 0.08). Conclusions The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grades 1–2 and did not statistically impact survival.

Fear of falling is a common issue among older adults, which decreases quality of life and leads to an avoidance of activities they are still able to do. The goal of this secondary data analysis was to explore the relationship between fear of falling and exercise self-efficacy in 141 women with at least one nontraumatic Genant Grade 2 vertebral fracture. Fear of falling, exercise self-efficacy, history of falling, the number of falls, the use of assisting devices, and pain at rest or during movement were obtained using medical history and health status questionnaires. There was a negative association between fear of falling and exercise self-efficacy (pseudo R2 = .253; p = .004), which persisted when the analysis was adjusted for history and number of falls, use of assistive devices, and pain at rest (pseudo R2 = .329; p R2 = .321; p

Background Stereotactic radiosurgery (SRS) for benign intracranial tumors is an established standard of care. The widespread implementation of SRS for benign spinal tumors has been limited by lack of long-term data. Objective To update our institutional experience of safety and efficacy outcomes after SRS for benign spinal tumors. Methods We performed a retrospective cohort study of 120 patients with 149 benign spinal tumors (39 meningiomas, 26 neurofibromas, and 84 schwannomas) treated with SRS between 1999 and 2016, with follow-up magnetic resonance imaging available for review. The primary endpoint was the cumulative incidence of local failure (LF), with death as a competing risk. Secondary endpoints included tumor shrinkage, symptom response, toxicity, and secondary malignancy. Results Median follow-up was 49 mo (interquartile range: 25-103 mo, range: 3-216 mo), including 61 courses with >5 yr and 24 courses with >10 yr of follow-up. We observed 9 LF for a cumulative incidence of LF of 2%, 5%, and 12% at 3, 5, and 10 yr, respectively. Excluding 10 tumors that were previously irradiated or that arose within a previously irradiated field, the 3-, 5-, and 10-yr cumulative incidence rates of LF were 1%, 2%, and 8%, respectively. At last follow-up, 35% of all lesions had decreased in size. With a total of 776 patient-years of follow-up, no SRS-related secondary malignancies were observed. Conclusion Comparable to SRS for benign intracranial tumors, SRS provides longer term local control of benign spinal tumors and is a standard-of-care alternative to surgical resection.

BRAF and NRAS mutations arise early in melanoma development, but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism's relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features. IRF4 rs12203592*T was associated with BRAF V600E (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.43-0.79) and V600K (OR = 0.65, 95% CI = 0.41-1.03), but not BRAF other or NRAS+ melanoma. A global test of etiologic heterogeneity (Pglobal = 0.001) passed false discovery (Pglobal = 0.0026). PLA2G6 rs132985*T was associated with BRAF V600E (OR = 1.32, 95% CI = 1.05-1.67) and BRAF other (OR = 1.82, 95% CI = 1.11-2.98), but not BRAF V600K or NRAS+ melanoma. The test for etiologic heterogeneity (Pglobal) was 0.005. The IRF4 rs12203592 associations were slightly attenuated after adjustment for melanoma-risk phenotypes. The PLA2G6 rs132985 associations were independent of phenotypes. IRF4 and PLA2G6 inherited genotypes may influence melanoma BRAF/NRAS subtype development.