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PURPOSE: Total neoadjuvant therapy (TNT) is a newly established standard treatment for rectal adenocarcinoma. Current methods to communicate magnitudes of regression during TNT are subjective and imprecise. Magnetic resonance tumor regression grade (MR-TRG) is an existing, but rarely used, regression grading system. Prospective validation of MR-TRG correlation with pathologic response in patients undergoing TNT is lacking. Utility of adding diffusion-weighted imaging to MR-TRG is also unknown. METHODS: We conducted a multi-institutional prospective imaging substudy within NRG-GI002 (ClinicalTrials.gov identifier: NCT02921256) examining the ability of MR-based imaging to predict pathologic complete response (pCR) and correlate MR-TRG with the pathologic neoadjuvant response score (NAR). Serial MRIs were needed from 110 patients. Three radiologists independently, then collectively, reviewed each MRI for complete response (mriCR), which was tested for positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity with pCR. MR-TRG was examined for association with the pathologic NAR score. All team members were blinded to pathologic data. RESULTS: A total of 121 patients from 71 institutions met criteria: 28% were female (n = 34), 84% White (n = 101), and median age was 55 (24-78 years). Kappa scores for T- and N-stage after TNT were 0.38 and 0.88, reflecting fair agreement and near-perfect agreement, respectively. Calling an mriCR resulted in a kappa score of 0.82 after chemotherapy and 0.56 after TNT reflected near-perfect agreement and moderate agreement, respectively. MR-TRG scores were associated with pCR (P < .01) and NAR (P < .0001), PPV for pCR was 40% (95% CI, 26 to 53), and NPV was 84% (95% CI, 75 to 94). CONCLUSION: MRI alone is a poor tool to distinguish pCR in rectal adenocarcinoma undergoing TNT. However, the MR-TRG score presents a now validated method, correlated with pathologic NAR, which can objectively measure regression magnitude during TNT.

PURPOSE: Intermediate-risk prostate cancer is a heterogeneous disease state with diverse treatment options. The 22-gene Decipher genomic classifier (GC) retrospectively has shown to improve risk stratification in these patients. We assessed the performance of the GC in men with intermediate-risk disease enrolled in NRG Oncology/RTOG 01-26 with updated follow-up. METHODS AND MATERIALS: After National Cancer Institute approval, biopsy slides were collected from NRG Oncology/RTOG 01-26, a randomized phase 3 trial of men with intermediate-risk prostate cancer randomized to 70.2 Gy versus 79.2 Gy of radiation therapy without androgen deprivation therapy. RNA was extracted from the highest-grade tumor foci to generate the locked 22-gene GC model. The primary endpoint for this ancillary project was disease progression (composite of biochemical failure, local failure, distant metastasis, prostate cancer-specific mortality, and use of salvage therapy). Individual endpoints were also assessed. Fine-Gray or cause-specific Cox multivariable models were constructed adjusting for randomization arm and trial stratification factors. RESULTS: Two-hundred fifteen patient samples passed quality control for analysis. The median follow-up was 12.8 years (range, 2.4-17.7). On multivariable analysis, the 22-gene GC (per 0.1 unit) was independently prognostic for disease progression (subdistribution hazard ratio [sHR], 1.12; 95% confidence interval [CI], 1.00-1.26; P = .04), biochemical failure (sHR, 1.22; 95% CI, 1.10-1.37; P < .001), distant metastasis (sHR, 1.28; 95% CI, 1.06-1.55; P = .01), and prostate cancer-specific mortality (sHR, 1.45; 95% CI, 1.20-1.76; P < .001). Ten-year distant metastasis in GC low-risk patients was 4% compared with 16% for GC high-risk patients. In patients with lower GC scores, the 10-year difference in metastasis-free survival rate between arms was -7%, compared with 21% for higher GC patients (P-interaction = .04). CONCLUSIONS: This study represents the first validation of a biopsy-based gene expression classifier, assessing both its prognostic and predictive value, using data from a randomized phase 3 trial of intermediate-risk prostate cancer. Decipher improves risk stratification and can aid in treatment decision-making in men with intermediate-risk disease.

PURPOSE: The immunoinflammatory state has been shown to be associated with poor outcomes after radiation therapy (RT). We conducted an a priori designed validation study using serum specimens from Radiation Therapy Oncology Group (RTOG) 0521. It was hypothesized the pretreatment inflammatory state would correlate with clinical outcomes. METHODS AND MATERIALS: Patients on RTOG 0521 had serum banked for biomarker validation. This study was designed to validate previous findings showing an association between elevations in C-reactive protein (CRP) and shorter biochemical disease free survival (bDFS). CRP levels were measured in pretreatment samples. An exploratory panel of related cytokines was also measured including: monocyte chemotactic protein-1, granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-23, and tumor necrosis factor. The primary endpoint examined was bDFS. Additional exploratory endpoints included overall survival, distant metastases, and toxicity events attributed to RT. RESULTS: Two hundred and two patients in RTOG/NRG 0521 had serum samples available. Median age was 66 years (48-83), and 90% of patients were White. There was not an association between CRP and bDFS (adjusted hazard ratio [HR], 1.07 per 1 log increase in CRP; 95% confidence interval, 0.83-1.38; P = .60). In the exploratory, unplanned analysis, pretreatment IL-10 was significantly associated with worse bDFS (adjusted HR, 1.61 per log increase; P = .0027) and distant metastases (HR, 1.55 per log increase; P = .028). The association of IL-10 with bDFS was maintained on a multiplicity adjustment. The exploratory analyses of pretreatment levels of interferon-γ, IL-1b, IL-2, IL-13, IL-23 were negatively associated with grade 2 or higher pollakiuria (adjusted odds ratio, 0.64, 0.65, 0.71, 0.72, and 0.74, respectively, all P < .05), and IL-6 was negatively associated with grade 2 or higher erectile dysfunction (odds ratio, 0.62; P = .027). CONCLUSIONS: Pretreatment CRP was not associated with a poorer bDFS after RT. In a hypothesis- generating analysis, higher baseline levels of IL-10 were associated with lower rates of bDFS. These findings require additional prospective evaluation.

In this work, we discuss the development of descriptive actions that facilitators take in semester-long online professional development geared at supporting instructional change at the undergraduate level. Current work in undergraduate mathematics education includes various large-scale projects aimed to support individuals or departments in reforming their instruction to align with recommendations from professional organizations and existing mathematics education research standards. One research area that has recently grown is the use of online synchronous environments to form collaborations to support the inclusion of student-centered instruction in mathematics. This paper discusses the actions that facilitators take in these collaborative environments and highlights how these actions supported the overall goal of the semester-long online faculty development.

Radiation therapy (RT) continues to play an important role in the treatment of cancer. Adaptive RT (ART) is a novel method through which RT treatments are evolving. With the ART approach, computed tomography or magnetic resonance (MR) images are obtained as part of the treatment delivery process. This enables the adaptation of the irradiated volume to account for changes in organ and/or tumor position, movement, size, or shape that may occur over the course of treatment. The advantages and challenges of ART maybe somewhat abstract to oncologists and clinicians outside of the specialty of radiation oncology. ART is positioned to affect many different types of cancer. There is a wide spectrum of hypothesized benefits, from small toxicity improvements to meaningful gains in overall survival. The use and application of this novel technology should be understood by the oncologic community at large, such that it can be appropriately contextualized within the landscape of cancer therapies. Likewise, the need to test these advances is pressing. MR-guided ART (MRgART) is an emerging, extended modality of ART that expands upon and further advances the capabilities of ART. MRgART presents unique opportunities to iteratively improve adaptive image guidance. However, although the MRgART adaptive process advances ART to previously unattained levels, it can be more expensive, time-consuming, and complex. In this review, the authors present an overview for clinicians describing the process of ART and specifically MRgART.

Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy.

Bullying is a significant school problem. Policies have been developed to reduce bullying, yet little is known about their implementation, which must occur for these policies to have an effect. This study examines associations between the overall implementation of a state anti-bullying policy and implementation of specific components outlined in the policy with two outcomes: bullying among students and teacher protection of students. Data were collected from 588 educators in K-12 schools across North Carolina a year following the enactment of an anti-bullying law in the state. Results show that overall policy implementation fidelity is inversely related to student bullying and positively related to teacher protection. In addition, the implementation of certain policy components (i.e., educator and student knowledge of bullying reporting procedures, training of educators about protected classes from bullying, student knowledge of protected classes, and educators reporting and remediating bullying based on protected classes) is significantly related to the outcomes. Thus, the implementation of certain anti-bullying policy components may be more potent in addressing bullying. Future research should identify constellations of policy strategies that need to be activated in schools to eliminate bullying.

PurposeIn 2009, the Radiation Therapy Oncology Group (RTOG) genitourinary members published a consensus atlas for contouring prostate pelvic nodal clinical target volumes (CTVs). Data have emerged further informing nodal recurrence patterns. The objective of this study is to provide an updated prostate pelvic nodal consensus atlas.Methods and materialsA literature review was performed abstracting data on nodal recurrence patterns. Data were presented to a panel of international experts, including radiation oncologists, radiologists, and urologists. After data review, participants contoured nodal CTVs on 3 cases: postoperative, intact node positive, and intact node negative. Radiation oncologist contours were analyzed qualitatively using count maps, which provided a visual assessment of controversial regions, and quantitatively analyzed using Sorensen-Dice similarity coefficients and Hausdorff distances compared with the 2009 RTOG atlas. Diagnostic radiologists generated a reference table outlining considerations for determining clinical node positivity.ResultsEighteen radiation oncologists' contours (54 CTVs) were included. Two urologists' volumes were examined in a separate analysis. The mean CTV for the postoperative case was 302 cm3, intact node positive case was 409 cm3, and intact node negative case was 342 cm3. Compared with the original RTOG consensus, the mean Sorensen-Dice similarity coefficient for the postoperative case was 0.63 (standard deviation [SD] 0.13), the intact node positive case was 0.68 (SD 0.13), and the intact node negative case was 0.66 (SD 0.18). The mean Hausdorff distance (in cm) for the postoperative case was 0.24 (SD 0.13), the intact node positive case was 0.23 (SD 0.09), and intact node negative case was 0.33 (SD 0.24). Four regions of CTV controversy were identified, and consensus for each of these areas was reached.ConclusionsDiscordance with the 2009 RTOG consensus atlas was seen in a group of experienced NRG Oncology and international genitourinary radiation oncologists. To address areas of variability and account for new data, an updated NRG Oncology consensus contour atlas was developed.

Background/purposeStratification of Gleason score (GS) into three categories (2-6, 7, and 8-10) may not fully utilize its prognostic discrimination, with Gleason pattern 5 (GP5) previously identified as an independent adverse factor.Materials/methodsPatients treated on RTOG 9202 (n = 1292) or RTOG 9902 (n = 378) were pooled and assessed for association of GS and GP5 on biochemical failure (BF), local failure (LF), distant metastasis (DM), and overall survival (OS). Fine and Gray's regression and cumulative incidence methods were used for univariate and multivariate analyses.ResultsWith median follow-up of 9.4 years, patients with GS 8-10 with GP5 had worse outcome than GS 4 + 4 for DM on both RTOG9202 (p = 0.038) and RTOG9902 (p

Background/objectivesTo optimize health and well-being for all older people, we must collectively develop leaders to pioneer models of care, educate the healthcare workforce, advance research, and engage the community.MethodsThe Emerging Leaders in Aging (ELIA) program was created to train a multiprofessional cadre of leaders focused on the health and well-being of older people. ELIA uses the social change curricular framework and addresses knowledge of self, community, and engagement with change. Program impact measured included scholar satisfaction, confidence related to curricular domains before and after the program, project progress, and scholar productivity.ResultsFour cohorts of 65 scholars in seven health professions from 24 states were selected for the year-long 55-hour program. Overall satisfaction from members of the first three cohorts who have completed the program (n = 46) was 4.86 (scale = 1-5), and scholar confidence increased from 5.8 to 8.0 (scale = 1-9) (p < .001). These scholars reported 85 presentations, 63 publications, and 21 awards subsequent to training. All scholars described the importance of a program focused on early and mid-career leaders in health and aging.DiscussionThe ELIA program leverages longitudinal, distance mentor communities, and project-based learning strategies. It has improved confidence and skills in emerging leaders who commit their efforts toward the care of older persons. Programs like ELIA are critical to preparing a healthcare workforce to optimize care for all as our health needs and expectations change with age. J Am Geriatr Soc 67:437-442, 2019.

To provide a comprehensive review of the means by which to optimize target volume definition for the purposes of treatment planning for patients with intact prostate cancer with a specific emphasis on focal boost volume definition. Here we conduct a narrative review of the available literature summarizing the current state of knowledge on optimizing target volume definition for the treatment of localized prostate cancer. Historically, the treatment of prostate cancer included a uniform prescription dose administered to the entire prostate with or without coverage of all or part of the seminal vesicles. The development of prostate magnetic resonance imaging (MRI) and positron emission tomography (PET) using prostate-specific radiotracers has ushered in an era in which radiation oncologists are able to localize and focally dose-escalate high-risk volumes in the prostate gland. Recent phase 3 data has demonstrated that incorporating focal dose escalation to high-risk subvolumes of the prostate improves biochemical control without significantly increasing toxicity. Still, several fundamental questions remain regarding the optimal target volume definition and prescription strategy to implement this technique. Given the remaining uncertainty, a knowledge of the pathological correlates of radiographic findings and the anatomic patterns of tumor spread may help inform clinical judgement for the definition of clinical target volumes. Advanced imaging has the ability to improve outcomes for patients with prostate cancer in multiple ways, including by enabling focal dose escalation to high-risk subvolumes. However, many questions remain regarding the optimal target volume definition and prescription strategy to implement this practice, and key knowledge gaps remain. A detailed understanding of the pathological correlates of radiographic findings and the patterns of local tumor spread may help inform clinical judgement for target volume definition given the current state of uncertainty. [ABSTRACT FROM AUTHOR]

The use of radiation therapy (RT) for pancreatic cancer continues to be controversial, despite recent technical advances. Improvements in systemic control have created an evolving role for RT and the need for improved local tumor control, but currently, no standardized approach exists. Advances in stereotactic body RT, motion management, real-time image guidance, and adaptive therapy have renewed hopes of improved outcomes in this devastating disease with one of the lowest survival rates. This case-based guide provides a practical framework for delivering stereotactic body RT for locally advanced pancreatic cancer. In conjunction with multidisciplinary care, an intradisciplinary approach should guide treatment of the high-risk cases outlined within these guidelines for prospective peer review and treatment safety discussions. [ABSTRACT FROM AUTHOR]

PURPOSE: This study aims to combine multiparametric magnetic resonance imaging (MRI) and digitized pathology with machine learning to generate predictive maps of histologic features for prostate cancer localization. METHODS AND MATERIALS: Thirty-nine patients underwent MRI prior to prostatectomy. After surgery, tissue was sliced according to MRI orientation using patient-specific 3-dimensionally printed slicing jigs. Whole-mount sections were annotated by our pathologist and digitally contoured to differentiate the lumen and epithelium. Slides were co-registered to the T2-weighted MRI scan. A learning curve was generated to determine the number of patients required for a stable machine-learning model. Patients were randomly stratified into 2 training sets and 1 test set. Two partial least-squares regression models were trained, each capable of predicting lumen and epithelium density. Predicted density values were calculated for each patient in the test dataset, mapped into the MRI space, and compared between regions confirmed as high-grade prostate cancer. RESULTS: The learning-curve analysis showed that a stable fit was achieved with data from 10 patients. Maps indicated that regions of increased epithelium and decreased lumen density, generated from each independent model, corresponded with pathologist-annotated regions of high-grade cancer. CONCLUSIONS: We present a radio-pathomic approach to mapping prostate cancer. We find that the maps are useful for highlighting high-grade tumors. This technique may be relevant for dose-painting strategies in prostate radiation therapy.

Multiparametric magnetic resonance imaging (MP-MRI), including diffusion-weighted imaging, is commonly used to diagnose prostate cancer. This radiology-pathology study correlates prostate cancer grade and morphology with common b-value combinations for calculating apparent diffusion coefficient (ADC). Thirty-nine patients undergoing radical prostatectomy were recruited for MP-MRI prior to surgery. Diffusion imaging was collected with seven b-values, and ADC was calculated. Excised prostates were sliced in the same orientation as the MRI using 3-D printed slicing jigs. Whole-mount slides were digitized and annotated by a pathologist. Annotated samples were aligned to the MRI, and ADC values were extracted from annotated peripheral zone (PZ) regions. A receiver operating characteristic (ROC) analysis was performed to determine accuracy of tissue type discrimination and optimal ADC b-value combination. ADC significantly discriminates Gleason (G) G4-5 cancer from G3 and other prostate tissue types. The optimal b-values for discriminating high from low-grade and noncancerous tissue in the PZ are 50 and 2000, followed closely by 100 to 2000 and 0 to 2000. Optimal ADC cut-offs are presented for dichotomized discrimination of tissue types according to each b-value combination. Selection of b-values affects the sensitivity and specificity of ADC for discrimination of prostate cancer.

Lesbian, gay, bisexual, and queer (LGBQ) students are a substantial minority group within U.S. elementary, middle, and high schools. Many LGBQ students face harassment and discrimination, which can contribute to educational and psychological problems. Teachers play key roles in students' school experiences, and their attitudes about homosexuality can influence their behavior toward LGBQ students. The purpose of this study was to examine the prevalence of teachers' positive and negative LGBQ-related attitudes, potential changes in attitudes over time, and demographic and social variables that may be related to teachers' attitudes. This study uses data from 305 pre-kindergarten through 12th grade teachers, collected in waves 2006-2014 of the General Social Survey. Results indicate that teachers' attitudes toward homosexuality have become more favorable over time; however, many teachers still hold negative attitudes. Just under half of teachers exhibited at least one negative LGBQ-related attitude. Age, political conservativeness, religious attendance, and carryover of religious beliefs were significantly associated with negative LGBQ attitudes. Teachers with a fundamentalist religious orientation tended to have more negative attitudes about homosexuality than teachers with more progressive religious orientations. Negative attitudes were more often found among teachers of color, compared to White teachers, and teachers in the South, Midwest, and Mountain regions tended toward more negative attitudes than teachers in the Northeast and Pacific regions. Teachers have an ethical responsibility to see that all students, regardless of sexual orientation, receive a quality education. Education and training are needed to address problematic attitudes that may negatively affect LGBQ students.

PurposeConventional radiotherapy (C-RT) treatment schedules for patients with prostate cancer typically require 40 to 45 treatments that take place from > 8 to 9 weeks. Preclinical and clinical research suggest that hypofractionation-fewer treatments but at a higher dose per treatment-may produce similar outcomes. This trial was designed to assess whether the efficacy of a hypofractionated radiotherapy (H-RT) treatment schedule is no worse than a C-RT schedule in men with low-risk prostate cancer.Patients and methodsA total of 1,115 men with low-risk prostate cancer were randomly assigned 1:1 to C-RT (73.8 Gy in 41 fractions over 8.2 weeks) or to H-RT (70 Gy in 28 fractions over 5.6 weeks). This trial was designed to establish (with 90% power and an α of .05) that treatment with H-RT results in 5-year disease-free survival (DFS) that is not worse than C-RT by more than 7.65% (H-RT/C-RT hazard ratio [HR] < 1.52).ResultsA total of 1,092 men were protocol eligible and had follow-up information; 542 patients were assigned to C-RT and 550 to H-RT. Median follow-up was 5.8 years. Baseline characteristics were not different according to treatment assignment. The estimated 5-year DFS was 85.3% (95% CI, 81.9 to 88.1) in the C-RT arm and 86.3% (95% CI, 83.1 to 89.0) in the H-RT arm. The DFS HR was 0.85 (95% CI, 0.64 to 1.14), and the predefined noninferiority criterion that required that DFS outcomes be consistent with HR < 1.52 was met (P < .001). Late grade 2 and 3 GI and genitourinary adverse events were increased (HR, 1.31 to 1.59) in patients who were treated with H-RT.ConclusionIn men with low-risk prostate cancer, the efficacy of 70 Gy in 28 fractions over 5.6 weeks is not inferior to 73.8 Gy in 41 fractions over 8.2 weeks, although an increase in late GI/genitourinary adverse events was observed in patients treated with H-RT.

Bullying is a significant problem in U.S. schools. Policies have been developed to reduce bullying, yet policy implementation by educators is an essential yet difficult and complex process. Few studies have investigated factors that act as barriers to or facilitators of bullying policy implementation and teacher protection of students. This study examined the influence of school context on educators' capacity to implement a statewide bullying law and protect students from bullying following the enactment of the policy. Data were collected from 505 educators in 324 schools. School administrators tended to rate fidelity of policy implementation and teacher protection of students higher than teachers, education support professionals, and student service professionals. Policy implementation fidelity scores were higher in high schools than elementary schools. School size and the prevalence of student suspensions were inversely related to implementation fidelity. Higher levels of teacher protection were reported in elementary schools.

Bullying threatens the mental and educational well-being of students. All states have enacted antibullying laws. This study surveyed 634 educators about the implementation of the North Carolina School Violence Prevention Act, which enumerated social classes protected from bullying: race, national origin, gender, socioeconomic status, sexual orientation, gender identity, appearance, and disability. Results showed that local antibullying policies most often included race as a protected class and least often included sexual orientation and gender identity. More educators had been trained on bullying based on race than any other social class. Students were more often informed that bullying based on race was prohibited and were least often informed about prohibitions regarding sexual orientation and gender identity. Reporting, investigating, and remediating bullying was highest for racial bullying, followed by disability bullying, and was lowest for bullying based on sexual orientation and gender identity.

Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease.