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Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA., (© 2024 British Society for Haematology and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals 1,2 , but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: Liquid biopsy (LBx) for tumor profiling is increasingly used, but concerns remain regarding negative results. A lack of results may truly reflect tumor genomics, or it may be a false negative that would be clarified by tissue testing. A method of distinguishing between these scenarios could help clarify when follow-on tissue testing is valuable., Experimental Design: Here we evaluate circulating tumor DNA (ctDNA) tumor fraction (TF), a quantification of ctDNA in LBx samples, for utility in identifying true negative results. We assessed concordance between LBx and tissue-based results, stratified by ctDNA TF, in a real-world genomic dataset of paired samples across multiple disease types. We also evaluated the frequency of tissue results identifying driver alterations in patients with lung cancer after negative LBx in a real-world clinicogenomic database., Results: The positive percent agreement and negative predictive value between liquid and tissue samples for driver alterations increased from 63% and 66% for all samples to 98% and 97% in samples with ctDNA TF ≥1%. Among 505 patients with lung cancer with no targetable driver alterations found by LBx who had subsequent tissue-based profiling, 37% had a driver, all of which had ctDNA TF <1%., Conclusions: Patients with lung cancer with negative LBx and ctDNA TF ≥1% are unlikely to have a driver detected on confirmatory tissue testing; such informative negative results may benefit instead from prompt treatment initiation. Conversely, negative LBx with ctDNA TF <1% will commonly have a driver identified by follow-up tissue testing and should be prioritized for reflex testing., (©2024 The Authors; Published by the American Association for Cancer Research.)

JAK2 V617F is the most common driver mutation in primary or secondary myelofibrosis for which allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. Knowledge of the prognostic utility of JAK2 alterations in the HCT setting is limited. We identified all patients with MF who received HCT between 2000 and 2016 and had a pre-HCT blood sample (N = 973) available at the Center of International Blood and Marrow Transplant Research biorepository. PacBio sequencing and single nucleotide polymorphism-array genotyping were used to identify JAK2V617F mutation and associated mosaic chromosomal alterations (mCAs), respectively. Cox proportional hazard models were used for HCT outcome analyses. Genomic testing was complete for 924 patients with MF (634 primary MF [PMF], 135 postpolycythemia vera [PPV-MF], and 155 postessential thrombocytopenia [PET-MF]). JAK2V617F affected 562 patients (57.6% of PMF, 97% of PPV-MF, and 42.6% of PET-MF). Almost all patients with mCAs involving the JAK2 region (97.9%) were JAK2V617-positive. In PMF, JAK2V617F mutation status, allele burden, or identified mCAs were not associated with disease progression/relapse, nonrelapse mortality (NRM), or overall survival. Almost all PPV-MF were JAK2V617F-positive (97%), with no association between HCT outcomes and mutation allele burden or mCAs. In PET-MF, JAK2V617F high mutation allele burden (≥60%) was associated with excess risk of NRM, restricted to transplants received in the era of JAK inhibitors (2013-2016; hazard ratio = 7.65; 95% confidence interval = 2.10-27.82; P = .002). However, allele burden was not associated with post-HCT disease progression/relapse or survival. Our findings support the concept that HCT can mitigate the known negative effect of JAK2V617F in patients with MF, particularly for PMF and PPV-MF., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Age-related clonal expansion of cells harbouring mosaic chromosomal alterations (mCAs) is one manifestation of clonal haematopoiesis. Identifying factors that influence the generation and promotion of clonal expansion of mCAs are key to investigate the role of mCAs in health and disease. Herein, we report on widely measured serum biomarkers and their possible association with mCAs, which could provide new insights into molecular alterations that promote acquisition and clonal expansion. We performed a cross-sectional investigation of the association of 32 widely measured serum biomarkers with autosomal mCAs, mosaic loss of the Y chromosome, and mosaic loss of the X chromosome in 436 784 cancer-free participants from the UK Biobank. mCAs were associated with a range of commonly measured serum biomarkers such as lipid levels, circulating sex hormones, blood sugar homeostasis, inflammation and immune function, vitamins and minerals, kidney function, and liver function. Biomarker levels in participants with mCAs were estimated to differ by up to 5% relative to mCA-free participants, and individuals with higher cell fraction mCAs had greater deviation in mean biomarker values. Polygenic scores associated with sex hormone binding globulin, vitamin D, and total cholesterol were also associated with mCAs. Overall, we observed commonly used clinical serum biomarkers related to disease risk are associated with mCAs, suggesting mechanisms involved in these diseases could be related to mCA proliferation and clonal expansion., (Published by Oxford University Press 2023.)

Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk., (© 2023. Springer Nature Limited.)

Objectives: People with HIV (PWH) have an elevated risk of non-Hodgkin lymphoma (NHL) and other diseases. Studying clonal hematopoiesis (CH), the clonal expansion of mutated hematopoietic stem cells, could provide insights regarding elevated NHL risk., Design: Cohort analysis of participants in the Multicenter AIDS Cohort Study ( N  = 5979)., Methods: Mosaic chromosomal alterations (mCAs), a type of CH, were detected from genotyping array data using MoChA. We compared CH prevalence in men with HIV (MWH) to HIV-uninfected men using logistic regression, and among MWH, assessed the associations of CH with NHL incidence and overall mortality using Poisson regression., Results: Comparing MWH to HIV-uninfected men, we observed no difference in the frequency of autosomal mCAs (3.9% vs. 3.6%, P -value = 0.09) or mosaic loss of the Y chromosome (mLOY) (1.4% vs. 2.9%, P -value = 0.13). Autosomal mCAs involving copy-neutral loss of heterozygosity (CN-LOH) of chromosome 14q were more common in MWH. Among MWH, mCAs were not associated with subsequent NHL incidence (autosomal mCA P -value = 0.65, mLOY P -value = 0.48). However, two MWH with diffuse large B-cell lymphoma had overlapping CN-LOH mCAs on chromosome 19 spanning U2AF2 (involved in RNA splicing), and one MWH with Burkitt lymphoma had high-frequency mCAs involving chromosome 1 gain and chromosome 17 CN-LOH (cell fractions 22.1% and 25.0%, respectively). mCAs were not associated with mortality among MWH (autosomal mCA P -value = 0.52, mLOY P -value = 0.93)., Conclusions: We found limited evidence for a relationship between HIV infection and mCAs. Although mCAs were not significantly associated with NHL, mCAs detected in several NHL cases indicate a need for further investigation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Mosaic chromosomal alterations (mCAs) are the clonal expansion of large somatically acquired structural chromosomal changes present on the autosomes and sex chromosomes. Most studies of mCAs use existing genotype array intensity data from large populations to investigate potential risk factors and disease outcomes associated with mCAs. In this review, we perform a comprehensive examination of existing evidence for mCA disease and mortality associations and provide a framework for interpreting these associations in the context of important biases specific to mCA studies. Our goal is to motivate well-designed mCA studies to assist in unlocking the potential of mCAs to improve understanding of the effects of ageing and accelerate translational applications for improving public health., Competing Interests: Conflicts of interests The authors declare no competing interests., (Published by Elsevier Ltd.)

Background: An association has been identified between concussion and lower extremity musculoskeletal injury (LEMSKI) after return to sports participation. However, the collegiate student-athlete studies have relied on relatively small single-institution studies, which limits generalizability., Purpose: To assess odds of, and time to, LEMSKI after concussion in US collegiate athletes, using the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP)., Study Design: Descriptive epidemiology study., Methods: Data from the NCAA ISP during the 2010-2011 through 2019-2020 athletic seasons were considered for analysis. Frequency distributions were examined for details related to the initial and subsequent injuries (injuries to bone, bursa, joint, ligament, muscle, or tendon). Multivariable logistic regression models and random-effects Poisson regression models examined odds of time loss (TL) and non-time loss (NTL) LEMSKI after concussion, as well as the time interval between initial concussion and subsequent LEMSKI in a single athletic season, or initial musculoskeletal injury (MSKI) and subsequent LEMSKI in a single athletic season. Analyses were performed separately for football and other sports., Results: A total of 31,556 initial injuries were recorded (football: 11,900; other sports: 19,656), which were followed by 0 or 1 injury in the same season. Overall, first injury type was not a significant predictor of subsequent LEMSKI, although certain contrasts yielded significant estimates. In football, the odds of NTL LEMSKI were higher after concussion than after upper extremity MSKI (UEMSKI; adjusted odds ratio [OR Adj ], 1.56; 95% CI, 1.06-2.31). In football, the odds of TL LEMSKI were lower after concussion than after UEMSKI (OR Adj , 0.71; 95% CI, 0.51-0.99). No other significant effect estimates were observed for football or other sports., Conclusion: First injury type, either concussion or upper extremity, was not associated with an elevated risk of LEMSKI. Specifically, the results of this study did not identify an elevated odds of LEMSKI after a concussion. However, the authors observed greater odds of NTL LEMSKI and lower odds of TL LEMSKI in football.

Purpose: Our purpose was to investigate the effect of physicist-patient consults on patient anxiety and patient satisfaction with a randomized prospective phase III clinical trial., Methods and Materials: Sixty-six patients were randomly assigned to the physics direct patient care (PDPC) arm or the control arm of the trial. Patients assigned to the PDPC arm received 2 physicist-patient consults to educate them on the technical aspects of their radiation therapy, while patients assigned to the control arm received the standard of care (ie, standard radiation therapy workflow without any additional physicist-patient consults). Questionnaires were administered to all patients at 4 time points (after enrollment, after the simulation, after the first treatment, and after the last treatment) to assess anxiety and satisfaction., Results: The decrease in anxiety for the PDPC arm, compared with the control arm, was statistically significant at the first treatment (P = .027) time point. The increase in technical satisfaction for the PDPC arm, compared with the control arm, was statistically significant at the simulation (P = .005), first treatment (P < .001), and last treatment (P = .002) time points. The increase in overall satisfaction for the PDPC arm, compared with the control arm, was statistically significant at the first treatment (P = .014) and last treatment (P = .001) time points., Conclusions: Physicist-patient consults improved the patient experience by decreasing anxiety and increasing satisfaction. Future work is needed to modify current radiation oncology workflows and medical physics responsibilities to allow all patients to benefit from this advancement in patient care., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Myelofibrosis is a rare myeloproliferative neoplasm (MPN) with high risk for progression to acute myeloid leukemia. Our integrated genomic analysis of up to 933 myelofibrosis cases identifies 6 germline susceptibility loci, 4 of which overlap with previously identified MPN loci. Virtual karyotyping identifies high frequencies of mosaic chromosomal alterations (mCAs), with enrichment at myelofibrosis GWAS susceptibility loci and recurrently somatically mutated MPN genes (e.g., JAK2). We replicate prior MPN associations showing germline variation at the 9p24.1 risk haplotype confers elevated risk of acquiring JAK2 V617F mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2 V617F mutations. Germline variation associated with longer telomeres is associated with increased myelofibrosis risk. Myelofibrosis cases with high-frequency JAK2 mCAs have marked reductions in measured telomere length - suggesting a relationship between telomere biology and myelofibrosis clonal expansion. Our results advance understanding of the germline-somatic interaction at JAK2 and implicate mCAs involving JAK2 as strong promoters of clonal expansion of those mutated clones., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: The Federal Aviation Administration quantifies hazardous attitudes (HAs) among pilots using a scale. HAs have been linked to aviation risk. We assessed the influence of HAs and other factors in treatment decision making in radiation oncology (RO)., Methods and Materials: An anonymous survey was sent to 809 radiation oncologists in US cities housing the top 25 cancer centers. The survey included an HA scale adapted for RO and presented 9 cases assessing risk-tolerant radiation therapy prescribing habits and compliance with the American Society for Radiation Oncology's Choosing Wisely recommendations. Demographic and treatment decision data were dichotomized to identify factors associated with prescribing habits using univariable and multivariable (MVA) logistic regression analyses., Results: A total of 139 responses (17.1%) were received, and 103 were eligible for analysis. Among respondents, 40% were female, ages were evenly distributed, and 83% were in academics. Median scores for all attitudes (macho, anti-authority, worry, resignation, and impulsivity) were below the aviation thresholds for hazard and data from surgical specialties. On MVA, responders >50 years old with >5 years' experience were 4.45 times more likely to recommend risk-tolerant radiation ( P  = .016). Macho attitude was negatively associated with Choosing Wisely compliant treatments (odds ratio [OR], 0.12; P  = .001). Physicians who reported having previously retreated the supraclavicular fossa without complication were more likely to recommend retreatment in medically unfit patients if they felt the complication was avoided owing to careful planning (OR, 5.2; P  = .008)., Conclusions: To our knowledge, this represents the first study analyzing physician attitudes in RO and their effect on self-reported treatment decisions. This work suggests that attitude may be among the factors that influence risk-tolerant prescribing practices and compliance with Choosing Wisely recommendations., (© 2022 The Authors.)

Purpose: The U.S. military health system provides universal health care access to beneficiaries. However, whether the universal access has translated into improved patient outcome is unknown. We compared survival of small-cell lung cancer patients in the military health system with that in the U.S. general population. Stage and receipt of cancer treatment were also compared to see if they could contribute to survival difference., Methods: The data were obtained from The Department of Defense's Automated Central Tumor Registry (ACTUR) and the national Surveillance, Epidemiology, and End Results (SEER) program, respectively. ACTUR (N = 3040) and SEER patients (N = 12,160) were matched on age, sex, race and diagnosis year. Multivariable Cox regression model was used to compare all-cause mortality between ACTUR and SEER. Multivariable logistic regression was performed to compare cancer stage and treatment., Results: ACTUR patients exhibited significantly better survival than SEER counterparts (HR = 0.77, 95% CI= 0.71-0.83). ACTUR and SEER patients had similar stage, but ACTUR patients were more likely to receive radiation treatment (OR = 1.26, 95% CI = 1.12-1.42). The survival advantage of ACTUR patients remained across all tumor stages and radiation groups., Conclusions: Survival of small-cell lung cancer patients with universal health care access had better survival than similar patients in the U.S. general population. Future studies are warranted to identify factors that may contribute to the improved survival., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Zidovudine (ZDV) has been extensively used in pregnant women to prevent vertical transmission of HIV but few studies have evaluated potential mutagenic effects of ZDV during fetal development., Design: Our study investigated clonal hematopoiesis in HIV-exposed uninfected (HEU) newborns, 94 of whom were ZDV-exposed and 91 antiretroviral therapy (ART)-unexposed and matched for potential confounding factors., Methods: Utilizing high depth sequencing and genotyping arrays, we comprehensively examined blood samples collected during the first week after birth for potential clonal hematopoiesis associated with fetal ZDV exposure, including clonal single nucleotide variants (SNVs), small insertions and deletions (indels), and large structural copy number or copy neutral alterations., Results: We observed no statistically significant difference in the number of SNVs and indels per person in ZDV-exposed children (adjusted ratio [95% confidence interval, CI] for expected number of mutations = 0.79 [0.50--1.22], P = 0.3), and no difference in the number of large structural alterations. Mutations in common clonal hematopoiesis driver genes were not found in the study population. Mutational signature analyses on SNVs detected no novel signatures unique to the ZDV-exposed children and the mutational profiles were similar between the two groups., Conclusion: Our results suggest that clonal hematopoiesis at levels detectable in our study is not strongly influenced by in-utero ZDV exposure; however, additional follow-up studies are needed to further evaluate the safety and potential long-term impacts of in-utero ZDV exposure in HEU children as well as better investigate genomic aberrations occurring late in pregnancy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Mosaic chromosomal alterations (mCAs) are large chromosomal gains, losses and copy-neutral losses of heterozygosity (LOH) in peripheral leukocytes. While many individuals with detectable mCAs have no notable adverse outcomes, mCA-associated gene dosage alterations as well as clonal expansion of mutated leukocyte clones could increase susceptibility to disease., Results: We performed a phenome-wide association study (PheWAS) using existing data from 482,396 UK Biobank (UKBB) participants to investigate potential associations between mCAs and incident disease. Of the 1290 ICD codes we examined, our adjusted analysis identified a total of 50 incident disease outcomes associated with mCAs at PheWAS significance levels. We observed striking differences in the diseases associated with each type of alteration, with autosomal mCAs most associated with increased hematologic malignancies, incident infections and possibly cancer therapy-related conditions. Alterations of chromosome X were associated with increased lymphoid leukemia risk and, mCAs of chromosome Y were linked to potential reduced metabolic disease risk., Conclusions: Our findings demonstrate that a wide range of diseases are potential sequelae of mCAs and highlight the critical importance of careful covariate adjustment in mCA disease association studies., (© 2021. The Author(s).)

Background: Studies evaluating the association between peripheral blood leukocyte telomere length (LTL) and testicular germ cell tumor (TGCT) risk have produced conflicting results., Methods: Using available genotype data from the Testicular Cancer Consortium (TECAC), polygenic risk score and Mendelian randomization analyses of genetic variants previously associated with LTL were used to assess potential etiologic associations between telomere length and TGCT risk., Results: Genetically inferred telomere length was not associated with TGCT risk among 2,049 cases and 6,921 controls with individual-level genotype data (OR, 1.02; 95% confidence interval, 0.97-1.07). Mendelian randomization analyses using summary statistic data further indicated no evidence for an association between telomere length and TGCT risk among all available TECAC participants (3,558 cases and 13,971 controls)., Conclusions: Our analyses in the largest molecular genetic testicular cancer study to date provide no evidence for an association between genetically inferred peripheral blood LTL and TGCT risk., Impact: The lack of evidence for an overall association indicates that peripheral blood LTL is likely not a strong biomarker for TGCT risk., (©2021 American Association for Cancer Research.)

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10 -7 ), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10 -28 ), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10 -15 ), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10 -9 ) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10 -4 ). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.

Summary: A concern when conducting genome-wide association studies (GWAS) is the potential for population stratification, i.e. ancestry-based genetic differences between cases and controls, that if not properly accounted for, could lead to biased association results. We developed PCAmatchR as an open source R package for performing optimal case-control matching using principal component analysis (PCA) to aid in selecting controls that are well matched by ancestry to cases. PCAmatchR takes user supplied PCA outputs and selects matching controls for cases by utilizing a weighted Mahalanobis distance metric which weights each principal component by the percentage of genetic variation explained. Results from the 1000 Genomes Project data demonstrate both the functionality and performance of PCAmatchR for selecting matching controls for case populations as well as reducing inflation of association test statistics. PCAmatchR improves genomic similarity between matched cases and controls, which minimizes the effects of population stratification in GWAS analyses., Availability and Implementation: PCAmatchR is freely available for download on GitHub (https://github.com/machiela-lab/PCAmatchR) or through CRAN (https://CRAN.R-project.org/package=PCAmatchR)., Supplementary Information: Supplementary data are available at Bioinformatics online., (Published by Oxford University Press 2020.)

Background: Cancer epidemiology studies require sufficient power to assess spatial relationships between exposures and cancer incidence accurately. However, methods for power calculations of spatial statistics are complicated and underdeveloped, and therefore underutilized by investigators. The spatial relative risk function, a cluster detection technique that detects spatial clusters of point-level data for two groups (e.g., cancer cases and controls, two exposure groups), is a commonly used spatial statistic but does not have a readily available power calculation for study design., Results: We developed sparrpowR as an open-source R package to estimate the statistical power of the spatial relative risk function. sparrpowR generates simulated data applying user-defined parameters (e.g., sample size, locations) to detect spatial clusters with high statistical power. We present applications of sparrpowR that perform a power calculation for a study designed to detect a spatial cluster of incident cancer in relation to a point source of numerous environmental emissions. The conducted power calculations demonstrate the functionality and utility of sparrpowR to calculate the local power for spatial cluster detection., Conclusions: sparrpowR improves the current capacity of investigators to calculate the statistical power of spatial clusters, which assists in designing more efficient studies. This newly developed R package addresses a critically underdeveloped gap in cancer epidemiology by estimating statistical power for a common spatial cluster detection technique.

Although machine learning techniques that estimate propensity scores for observational studies with multivalued treatments have advanced rapidly in recent years, the development of propensity score adjustment techniques has not kept pace. While machine learning propensity models provide numerous benefits, they do not produce a single variable balancing score that can be used for propensity score stratification and matching. This issue motivates the development of a flexible ordinal propensity scoring methodology that does not require parametric assumptions for the propensity model. The proposed method fits a one-parameter power function to the cumulative distribution function (CDF) of the generalized propensity score (GPS) vector resulting from any machine learning propensity model, and is henceforth called the GPS-CDF method. The estimated parameter from the GPS-CDF method, ã , is a scalar balancing score that can be used to group similar subjects in outcome analyses. Specifically, subjects who received different levels of the treatment are stratified or matched based on their ã value to produce unbiased estimates of the average treatment effect (ATE). Simulation studies presented show remediation of covariate balance, minimal bias in ATEs, and maintain coverage probability. The proposed method is applied to the Mexican-American Tobacco use in Children (MATCh) study to determine whether an ordinal treatment of exposure to smoking imagery in movies causes cigarette experimentation in Mexican-American adolescents., (© 2020 John Wiley & Sons, Ltd.)

Continuous treatments propensity scoring remains understudied as the majority of methods are focused on the binary treatment setting. Current propensity score methods for continuous treatments typically rely on weighting in order to produce causal estimates. It has been shown that in some continuous treatment settings, weighting methods can result in worse covariate balance than had no adjustments been made to the data. Furthermore, weighting is not always stable, and resultant estimates may be unreliable due to extreme weights. These issues motivate the current development of novel propensity score stratification techniques to be used with continuous treatments. Specifically, the generalized propensity score cumulative distribution function (GPS-CDF) and the nonparametric GPS-CDF approaches are introduced. Empirical CDFs are used to stratify subjects based on pretreatment confounders in order to produce causal estimates. A detailed simulation study shows superiority of these new stratification methods based on the empirical CDF, when compared with standard weighting techniques. The proposed methods are applied to the "Mexican-American Tobacco use in Children" study to determine the causal relationship between continuous exposure to smoking imagery in movies, and smoking behavior among Mexican-American adolescents. These promising results provide investigators with new options for implementing continuous treatment propensity scoring., (© 2020 John Wiley & Sons, Ltd.)

Introduction: We compared the stage at diagnosis for non-small cell lung cancer (NSCLC) patients in the military healthcare system (MHS) and the general public to assess differences between these two groups as well as to assess the trends in stage at diagnosis in the recent past., Method: This study was based on the non-identifiable data from the U.S. Department of Defense Automated Central Tumor Registry (ACTUR) and the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Patients diagnosed with NSCLC between 1989 and 2012 were included. The distributions of tumor stage at diagnosis and trends in tumor stage were compared between the two populations., Results: The cohorts were predominately male in both ACTUR (65.3%) and SEER (55.1%) and white patients accounted for greater than 80% of patients in both ACTUR and SEER. Among 21,031 patients in ACTUR and 773,356 patients in SEER, stage IV lung cancers predominated (ACTUR 33.6%, SEER 40.5%) followed by stage III (ACTUR 26.1%, SEER 26.4%) and stage I (ACTUR 24.7%, SEER 20.6%). Notable differences between the two populations were the higher percentage of stage I and lower percentage of stage IV, along with a lower rate of unknown stage patients after 2004, in ACTUR than SEER. Between 1989 and 2012, the percentage of stage IV disease increased in ACTUR and SEER coincident with a decrease in unknown stage disease., Conclusions: The majority of NSCLC patients in the MHS and general population are diagnosed with stage IV NSCLC and the percentage is increasing. Compared to the general population, NSCLC patients in the MHS have a higher percentage of stage I, a lower percentage of stage IV, and of unknown stage cancer. Universal care along with more rigorous staging across the MHS may play a role in these findings., (© Association of Military Surgeons of the United States 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To evaluate the efficacy of a training program designed to teach medical physicists how to communicate with patients effectively in the clinical environment., Methods and Materials: The training program was offered 3 times between 2016 and 2019. Participants were asked to rank their level of confidence in 5 categories relevant to patient communication on a 5-point Likert scale at 3 separate time points over the course of the training program. Participants were also asked to provide written responses to 5 common questions from patients at 2 separate time points, and these responses were numerically scored using the Constant Comparative Method. Competency in patient communication was assessed during simulated patient consults using a 9-element clinical competency assessment form. Changes in participants' stated level of confidence over the course of the training program and differences between faculty and residents were analyzed using the Student t test, and participants' scored responses to common questions were analyzed using analysis of variance., Results: Fifteen medical physicists participated in the training program: 6 resident physicists (4 first year and 2 second year) and 9 faculty physicists. Mean participant-stated level of confidence increased significantly across all categories (P < .05) between the first and second training intervention and between the second and third training intervention. There was no significant difference in mean participant-stated level of confidence between faculty and resident medical physicists. We observed statistically significant improvements in scored responses to common patient questions between the 2 assessment time points (P < .05). Of the 15 participants, 14 met competency assessment goals during simulated patient consults., Conclusions: The patient communication skills training program increases medical physicists' level of confidence across 5 patient communication categories and improves their responses to common questions from patients. In addition, the program can discern differences in communication competency between physicists., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05-1.09, P = 1.61×10-15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; Phet = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; Phet = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (β = 0.004, 95% CI = 0.002-0.007, P = 6.61×10-4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential., Competing Interests: The authors declare no competing interests.

Purpose: Linked cancer registry and medical claims data have increased the capacity for cancer research. However, few efforts have described methods to select information between data sources, which may affect data use. We developed a systematic process to evaluate and consolidate cancer diagnosis and treatment information between the linked Department of Defense Central Cancer Registry (CCR) and Military Health System Data Repository (MDR) administrative claims database, called Military Cancer Epidemiology Data System (MilCanEpi)., Methods: MilCanEpi contains information on cancer diagnosis and treatment of patients receiving care from 1998 to 2014. We used an iterative process guided by knowledge of data features, current literature, and logical comparisons between the CCR and MDR data to evaluate and consolidate cancer diagnosis and treatment received (yes or no) and their dates. We applied the processes to breast cancer data as an example. Agreement between diagnosis and treatment dates in the two data sources was evaluated using Cohen's κ with 95% CIs., Results: In MilCanEpi, we identified 15,965 patients with a breast cancer diagnosis and 15,145 patients who underwent breast cancer surgery; 97.9% and 84.1% of patients had records in both CCR and MDR for diagnosis and surgery, respectively. Exact agreement was 13.7% for diagnosis dates (Cohen's κ = 0.14; 95% CI, 0.13 to 0.14) and 68.9% for surgery dates (Cohen's κ = 0.69; 95% CI, 0.68 to 0.70) between the two data sources. After applying systematic processes, 98.1% of patients with a breast cancer diagnosis and 99.7% of patients with surgery had information selected for analytic data sets., Conclusion: The developed processes resulted in high consolidation rates of breast cancer data in MilCanEpi and may serve as a data selection template for other tumor sites and linked data sources.

Genome-wide association studies (GWAS) have identified thousands of germline susceptibility loci associated with risk for cancer as well as a wide range of other traits and diseases. An interest of many investigators is identifying traits or diseases that share common susceptibility loci. We developed LDtrait (https://ldlink.nci.nih.gov/?tab=ldtrait) as an open access web tool for finding germline variation associated with multiple traits. LDtrait searches the NHGRI-EBI GWAS Catalog to identify susceptibility loci in linkage disequilibrium (LD) with a user-provided list of query variants. Options allow for modifying LD thresholds, calculating LD from a diverse set of reference populations, and downloading annotated variant lists. Results from example query searches highlight the utility of LDtrait in uncovering cross-trait associations for cancer risk and other traits. LDtrait accelerates etiologic understanding of cancer genetics by rapidly identifying genetic similarities with other traits or diseases. SIGNIFICANCE: The new GWAS search tool LDtrait will expedite discovery of shared genetic components underlying seemingly unrelated diseases and may offer novel insights into cancer research., (©2020 American Association for Cancer Research.)

Purpose: To provide insight into the types of questions asked to medical physicists by patients during one-on-one physicist-patient consults at one institution., Materials and Methods: Medical physicists trained in patient communication techniques met with patients to provide an overview of the treatment planning and delivery processes, discuss the patient's treatment plan, and answer any technical questions. From August 2016 to December 2019, 152 physicist-patient consults were conducted. In the initial months of the study (August 2016-December 2017), following each physicist-patient consult, all patient questions were documented by the physicists. For the remaining time period (January 2018-December 2019), any newly encountered questions were periodically added to the list. The questions were compiled into a comprehensive list and organized into categories., Results: There were a total of 88 unique patient questions. These questions fit into four topical categories. Fifty-four questions (61.4%) were in the "Treatment Planning and Delivery Questions" category, 15 questions (17.1%) were in the "General Radiation Questions or Concerns" category, 13 questions (14.8%) were in the "Safety and Quality Assurance Questions" category, and 6 questions (6.8%) were in the "Medical Questions" category. Overall, patients were primarily concerned about how radiation works, the treatment planning and delivery processes, and what is being done to keep them safe throughout their treatment., Conclusion: Physicist-patient consults provided an opportunity to address the technical aspects of radiation therapy with patients in greater detail. The fact that patient questions could be conveniently grouped into only four topical categories indicates that it may be straightforward for other medical physicists to prepare for effectively addressing technical questions during physicist-patient consults., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Aim/objectives/background: Timely, accurate, and effective communications are critical to quality in contemporary medical practices. Radiation oncology incorporates the science and technology of complex integrated radiation treatment delivery and the art of managing individual patients. Through written physical and/or electronic reports and direct communication, radiation oncologists convey critical information regarding patient care, services provided, and quality of care. Applicable practice parameters need to be revised periodically regarding medical record documentation for professional and technical components of services delivered., Methods: The ACR-ASTRO Practice Parameter for Communication: Radiation Oncology was revised according to the process described on the American College of Radiology (ACR) Web site ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parametersand-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the American Society for Radiation Oncology (ASTRO). Both societies then reviewed and approved the document., Results: This practice parameter addresses radiation oncology communications in general, including (a) medical record, (b) electronic, and (c) doctor-patient communications, as well as specific documentation for radiation oncology reports such as (a) consultation, (b) clinical treatment management notes (including inpatient communication), (c) treatment (completion) summary, and (d) follow-up visits., Conclusions: The radiation oncologist's participation in the multidisciplinary management of patients is reflected in timely, medically appropriate, and informative communication with the referring physician and other members of the health care team. The ACR-ASTRO Practice Parameter for Communication: Radiation Oncology is an educational tool designed to assist practitioners in providing appropriate communication regarding radiation oncology care for patients.

Currently, methods for conducting multiple treatment propensity scoring in the presence of high-dimensional covariate spaces that result from "big data" are lacking-the most prominent method relies on inverse probability treatment weighting (IPTW). However, IPTW only utilizes one element of the generalized propensity score (GPS) vector, which can lead to a loss of information and inadequate covariate balance in the presence of multiple treatments. This limitation motivates the development of a novel propensity score method that uses the entire GPS vector to establish a scalar balancing score that, when adjusted for, achieves covariate balance in the presence of potentially high-dimensional covariates. Specifically, the generalized propensity score cumulative distribution function (GPS-CDF) method is introduced. A one-parameter power function fits the CDF of the GPS vector and a resulting scalar balancing score is used for matching and/or stratification. Simulation results show superior performance of the new method compared to IPTW both in achieving covariate balance and estimating average treatment effects in the presence of multiple treatments. The proposed approach is applied to a study derived from electronic medical records to determine the causal relationship between three different vasopressors and mortality in patients with non-traumatic aneurysmal subarachnoid hemorrhage. Results suggest that the GPS-CDF method performs well when applied to large observational studies with multiple treatments that have large covariate spaces., (© 2020 John Wiley & Sons, Ltd.)

Purpose: Medical devices in radiation therapy undergo a complex process of Food and Drug Administration (FDA) approval. Little is known about which processes within the radiation therapy medical device industry are most prone to events involving wrong dose, volume, or targeting in radiation therapy treatment., Methods and Materials: We carried out a retrospective analysis of the United States FDA Medical Device Recalls database for recalls of products classified as "Accelerator, Linear, Medical" from 2010 to 2016. Each recall event was classified using a modified Delphi method among 3 experts in safety according to product type, error category, and severity score. Error categories included inconvenience; suboptimal plan or treatment; incorrect dose, volume, or targeting; and nonradiation injury risk. Variables investigated were product type, recall year, FDA-determined cause, and quantity of units recalled. Univariate and multivariate logistic regression were used to identify factors prognostic of incorrect dose, volume, or targeting., Results: We identified a total of 250 recall events between 2010 and 2016, with 165 eligible for analysis. Linear accelerators (LINACs) (28%) and LINAC control software (19%) were the most frequently recalled products. The most common FDA-determined causes for recalls were software design (42%) and device design (26%). On univariate analysis (P < .05), LINAC control software (odds ratio [OR] 5.4) and oncology information system or treatment management system (OR 3.9) versus LINACs and software design (OR 3.4) versus device design were associated with wrong dose, volume, or targeting events. On multivariate analysis, only the association with LINAC control software (OR 3.7) persisted for wrong dose, volume, or targeting events., Conclusions: Review of these data shows that problems with LINAC control software were associated with incorrect dose delivery at a 4-fold higher rate than errors with LINACs. Manufacturers should focus on improvements in software design to minimize dose- and targeting-related errors to patients., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: CpG Island Methylator Phenotype (CIMP) is an epigenetic phenotype in CRC characterized by hypermethylation of CpG islands in promoter regions of tumor suppressor genes, leading to their transcriptional silencing and loss of function. While the prevalence of CRC differs across geographical regions, no studies have compared prevalence of CIMP-High phenotype across regions. The purpose of this project was to compare the prevalence of CIMP across geographical regions after adjusting for variations in methodologies to measure CIMP in a meta-analysis., Methods: We searched PubMed, Medline, and Embase for articles focusing on CIMP published from 2000 to 2018. Two reviewers independently identified 111 articles to be included in final meta-analysis. We classified methods used to quantify CIMP into 4 categories: a) Classical (MINT marker) Panel group b) Weisenberg-Ogino (W-O) group c) Human Methylation Arrays group and d) Miscellaneous group. We compared the prevalence of CIMP across geographical regions after correcting for methodological variations using meta-regression techniques., Results: The pooled prevalence of CIMP-High across all studies was 22% (95% confidence interval:21-24%; I 2  = 94.75%). Pooled prevalence of CIMP-H across Asia, Australia, Europe, North America and South America was 22, 21, 21, 27 and 25%, respectively. Meta-regression analysis identified no significant differences in the prevalence of CIMP-H across geographical regions after correction for methodological variations. In exploratory analysis, we observed variations in CIMP-H prevalence across countries., Conclusion: Although no differences were found for CIMP-H prevalence across countries, further studies are needed to compare the influence of demographic, lifestyle and environmental factors in relation to the prevalence of CIMP across geographical regions.

Background: The Mount Fuji sign (MFS) is a radiological sign on computed tomographic scans depicting air between the frontal lobes. Air in this location indicates tension pneumocephalus (TP), considered a neurosurgical emergency.We evaluate the correlation between the MFS and perioperative mortality attributed to TP in nonagenarians who have undergone evacuation of chronic subdural hemorrhage (cSDH)., Materials and Methods: We retrospectively reviewed the records of nonagenarians who had cSDH evacuation between 2006 and 2015. Postoperative computed tomographic images were evaluated for findings consistent with the MFS., Results: Of 45 patients, 15 patients (33%) had radiological MFS, and 3 patients (20%) with MFS required reoperation because of new blood collection. No patient required reoperation because of TP. Perioperative (30-day) mortality in patients demonstrating the MFS was 6.67% caused by cardiac arrhythmia versus 13.33% mortality in patients with no evidence of the MFS., Conclusion: Mount Fuji sign in nonagenarians after cSDH evacuation is not a specific sign of TP.

Background: The mortality of trauma patients requiring massive transfusion to treat hemorrhagic shock approaches 17% at 24 hours and 26% at 30 days. The use of stored RBCs is limited to less than 42 days, so older RBCs are delivered first to rapidly bleeding trauma patients. Patients who receive a greater quantity of older RBCs may have a higher risk for mortality., Methods and Materials: Characterizing blood age exposure requires accounting for the age of each RBC unit and the quantity of transfused units. To address this challenge, a novel Scalar Age of Blood Index (SBI) that represents the relative distribution of RBCs received is introduced and applied to a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized controlled trial (NCT01545232, https://clinicaltrials.gov/ct2/show/NCT01545232). The effect of the SBI is assessed on the primary PROPPR outcome, 24-hour and 30-day mortality., Results: The distributions of blood storage ages successfully maps to a parameter (SBI) that fully defines the blood age curve for each patient. SBI was a significant predictor of 24-hour and 30-day mortality in an adjusted model that had strong predictive ability (odds ratio, 1.15 [1.01-1.29], p = 0.029, C-statistic, 0.81; odds ratio, 1.14 [1.02-1.28], p = 0.019, C-statistic, 0.88, respectively)., Conclusion: SBI is a simple scalar metric of blood age that accounts for the relative distribution of RBCs among age categories. Transfusion of older RBCs is associated with 24-hour and 30-day mortality, after adjustment for total units and clinical covariates., (© 2019 AABB.)

Purpose: To investigate a new clinical role for medical physicists in direct patient care with a prospective phase 2 clinical trial., Materials and Methods: Medical physicists participated in the Physics Direct Patient Care (PDPC) protocol, establishing independent professional relationships with radiation oncology patients. After attending a dedicated patient communication training program, medical physicists routinely met with patients for 2 physicist-patient consults to explain the treatment planning and delivery process, review the patient's treatment plan, and answer all technical questions. The first physicist-patient consult took place immediately before the computed tomography simulation, and the second took place immediately before the first treatment. Questionnaires were administered to each patient on the PDPC protocol at 3 time points to assess both anxiety and satisfaction. The first questionnaire was given shortly after the first physicist-patient consult, the second questionnaire was given shortly after the second physicist-patient consult, and the third questionnaire was given after the last treatment appointment, with no associated physicist-patient consult., Results: The mean patient anxiety score was considered to be low at all questionnaire time points. There was a statistically significant decrease (P < .0001) in anxiety from the simulation time point to the first treatment time point. The mean patient technical satisfaction score was considered to be high at all measurement time points. There was a statistically significant increase (P = .0012) in technical satisfaction from the simulation time point to the first treatment time point. There was a statistically significant decrease (P < .023) in technical satisfaction from the first treatment time point to the last treatment time point., Conclusions: Establishing a new clinical role for medical physicists and investigating its effects on patient anxiety and satisfaction have created the foundation for future studies. Based on the results of this trial, the PDPC protocol will be expanded to a larger group of medical physicists, radiation oncologists, and patient disease sites and investigated with a randomized phase 3 clinical trial., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To develop a training program designed to meet the specific needs of medical physicists as they transition into a clinical role with direct patient care responsibilities., Materials and Methods: The training program was designed in collaboration with the faculty at the UC San Diego School of Medicine and incorporates training techniques that have been shown to be effective in improving communication skills. The program emphasizes experiential, practice-based learning over didactic presentations., Results: The training program is comprised of 5 components: 1) a 1-day Clinician-Patient Communication Workshop run by the UC San Diego School of Medicine, 2) Communication Strategies for Radiation Oncology, which consists of two, 2-hour sessions designed to provide trainees with patient communication skills that are specific to patient interactions in radiation oncology, 3) Simulated Patient Interactions, in which trainees perform mock physicist-patient consults with trained patient actors, 4) Faculty-Observed Patient Consults, and 5) a Case-Based Treatment Toxicity Course. A competency assessment mechanism was also developed to provide a clear set of objectives and to guide trainer feedback. [Correction added after first online publication on November 7, 2018: The phrase ", which consists of two, 2-hour" was added above.] CONCLUSIONS: The training program that we have developed incorporates an array of established education techniques and provides a comprehensive, accessible, means of improving medical physicists' patient communication skills., (© 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: We propose a novel compensator-based IMRT system designed to provide a simple, reliable, and cost-effective adjunct technology, with the goal of expanding global access to advanced radiotherapy techniques. The system would employ easily reusable tungsten bead compensators that operate independent of a gantry (e.g., mounted in a ring around the patient). Thereby the system can be retrofitted to existing linac and cobalt teletherapy units. This study explores the quality of treatment plans from the proposed system and the dependence on associated design parameters., Methods: We considered 60 Co-based plans as the most challenging scenario for dosimetry and benchmarked them against clinical MLC-based plans delivered on a linac. Treatment planning was performed in the Pinnacle treatment planning system with commissioning based on Monte Carlo simulations of compensated beams. 60 Co-compensator IMRT plans were generated for five patients with head-and-neck cancer and five with gynecological cancer and compared to respective IMRT plans using a 6 MV linac beam with an MLC. The dependence of dosimetric endpoints on compensator resolution, thickness, position, and number of beams was assessed. Dosimetric accuracy was validated by Monte Carlo simulations of dose distribution in a water phantom from beams with the IMRT plan compensators., Results: The 60 Co-compensator plans had on average equivalent PTV coverage and somewhat inferior OAR sparing compared to the 6 MV-MLC plans, but the differences in dosimetric endpoints were clinically acceptable. Calculated treatment times for head-and-neck plans were 7.6 ± 2.0 min vs 3.9 ± 0.8 min (6 MV-MLC vs 60 Co-compensator) and for gynecological plans were 8.7 ± 3.1 min vs 4.3 ± 0.4 min. Plan quality was insensitive to most design parameters over much of the ranges studied, with no degradation found when the compensator resolution was finer than 6 mm, maximum thickness at least 2 tenth-value-layers, and more than five beams were used. Source-to-compensator distances of 53 and 63 cm resulted in very similar plan quality. Monte Carlo simulations suggest no increase in surface dose for the geometries considered here. Simulated dosimetric validation tests had median gamma pass rates of 97.6% for criteria of 3% (global)/3 mm with a 10% threshold., Conclusions: The novel ring-compensator IMRT system can produce plans of comparable quality to standard 6 MV-MLC systems. Even when 60 Co beams are used the plan quality is acceptable and treatment times are substantially reduced. 60 Co-compensator IMRT plans are adequately modeled in an existing commercial treatment planning system. These results motivate further development of this low-cost adaptable technology with translation through clinical trials and deployment to expand the reach of IMRT in low- and middle-income countries., (© 2018 American Association of Physicists in Medicine.)

Purpose: There is a lack of prescriptive, practical information for those doing the work of commissioning high-dose-rate (HDR) gynecologic (GYN) treatment equipment. The purpose of this work is to develop a vendor-neutral, consensus-based, commissioning template to improve standardization of the commissioning process., Methods and Materials: A series of commissioning procedures and tests specific to HDR GYN treatments were compiled within one institution. The list of procedures and tests was then sent to five external reviewers at clinics engaged in HDR GYN treatments. External reviewers were asked to (1) suggest deletions, additions, and improvements/modifications to descriptions, (2) link the procedures and tests to common, severe failure modes based on their effectiveness at mitigating those failure modes, and (3) rank the procedures and tests based on perceived level of importance., Results: External reviewers suggested the addition of 14 procedures and tests. The final template consists of 67 procedures and tests. "Treatment process" and "staff training" sections were identified as mitigating the highest number of commonly reported failure modes. The mean perceived importance for all procedures and tests was 4.4 of 5, and the mean for each section ranged from 3.6 to 4.8. Sections of the template that were identified as mitigating the highest number of commonly reported failure modes were not assigned the highest perceived importance., Conclusion: The commissioning template developed here provides a standardized approach to process and equipment commissioning. The discord between perceived importance and mitigation of the highest number of failure modes suggests that increased focus should be placed on procedures and tests in "treatment process" and "staff training" sections., (Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Both humans and software are notoriously challenging to account for in traditional hazard analysis models. The purpose of this work is to investigate and demonstrate the application of a new, extended accident causality model, called systems theoretic accident model and processes (STAMP), to radiation oncology. Specifically, a hazard analysis technique based on STAMP, system-theoretic process analysis (STPA), is used to perform a hazard analysis., Methods: The STPA procedure starts with the definition of high-level accidents for radiation oncology at the medical center and the hazards leading to those accidents. From there, the hierarchical safety control structure of the radiation oncology clinic is modeled, i.e., the controls that are used to prevent accidents and provide effective treatment. Using STPA, unsafe control actions (behaviors) are identified that can lead to the hazards as well as causal scenarios that can lead to the identified unsafe control. This information can be used to eliminate or mitigate potential hazards. The STPA procedure is demonstrated on a new online adaptive cranial radiosurgery procedure that omits the CT simulation step and uses CBCT for localization, planning, and surface imaging system during treatment., Results: The STPA procedure generated a comprehensive set of causal scenarios that are traced back to system hazards and accidents. Ten control loops were created for the new SRS procedure, which covered the areas of hospital and department management, treatment design and delivery, and vendor service. Eighty three unsafe control actions were identified as well as 472 causal scenarios that could lead to those unsafe control actions., Conclusions: STPA provides a method for understanding the role of management decisions and hospital operations on system safety and generating process design requirements to prevent hazards and accidents. The interaction of people, hardware, and software is highlighted. The method of STPA produces results that can be used to improve safety and prevent accidents and warrants further investigation.

We present a practical, generic, easy-to-use framework for the implementation of new radiation therapy technologies and treatment techniques in low-income countries. The framework is intended to standardize the implementation process, reduce the effort involved in generating an implementation strategy, and provide improved patient safety by reducing the likelihood that steps are missed during the implementation process. The 10 steps in the framework provide a practical approach to implementation. The steps are, 1) Site and resource assessment, 2) Evaluation of equipment and funding, 3) Establishing timelines, 4) Defining the treatment process, 5) Equipment commissioning, 6) Training and competency assessment, 7) Prospective risk analysis, 8) System testing, 9) External dosimetric audit and incident learning, and 10) Support and follow-up. For each step, practical advice for completing the step is provided, as well as links to helpful supplementary material. An associated checklist is provided that can be used to track progress through the steps in the framework. While the emphasis of this paper is on addressing the needs of low-income countries, the concepts also apply in high-income countries., (Copyright © 2014 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

The electronic portal imaging device (EPID) has the potential to be used for in vivo dosimetry during radiation therapy as an additional dose delivery check. In this study we have extended a method developed by A. Piermattei and colleagues in 2006 that made use of EPID transit images (acquired during treatment) to calculate dose in the isocenter point. The extension allows calculation of two-dimensional dose maps of the entire radiation field at the depth of isocenter. We quantified the variability of the ratio of EPID signal to dose in the isocenter plane in Solid Water phantoms of various thicknesses and with various field sizes, and designed a field edge dose calculation correction. To validate the method, we designed three realistic conventional radiation therapy treatment plans on a thorax and head anthropomorphic phantom (whole brain, brain primary, lung tumor). Using CT data, EPID transit images, EPID signal-to-dose correlation, and our edge correction, we calculated dose in the isocenter plane and compared it with the treatment planning system's prediction. Gamma evaluation (3%, 3 mm) showed good agreement (Pγ&lt;1 ≥ 96.5%) for all fields of the whole brain and brain primary plans. In the presence of lung, however, our algorithm overestimated dose by 7%-9%. This 2D EPID-based in vivo dosimetry method can be used for posttreatment dose verification, thereby improving the safety and quality of patient treatments. With future work, it may be extended to measure dose in real time and to prevent harmful delivery errors.

The international growth of cancer and lack of available treatment is en route to become a global crisis. With >60% of cancer patients needing radiation therapy at some point during their treatment course, the lack of available facilities and treatment programs worldwide is extremely problematic. The number of deaths from treatable cancers is projected to increase to 11.5 million deaths in 2030 because the international population is aging and growing. In this review, we present how best to answer the need for radiation therapy facilities from a technical standpoint. Specifically, we examine whether cobalt teletherapy machines or megavoltage linear accelerator machines are best equipped to handle the multitudes in need of radiation therapy treatment in the developing world., (Copyright © 2014 Elsevier Inc. All rights reserved.)