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IMPORTANCE: Stereotactic body radiotherapy (SBRT) for oligometastases is hypothesized to improve survival and is increasingly used. Little evidence supports its safe use to treat patients with multiple metastases. OBJECTIVE: To establish safety of SBRT dose schedules in patients with 3 to 4 metastases or 2 metastases in close proximity to each other. DESIGN, SETTING, AND PARTICIPANTS: This phase 1 trial opened on August 4, 2014, and closed to accrual on March 20, 2018. Metastases to 7 anatomic locations were included: bone/osseous (BO), spinal/paraspinal (SP), peripheral lung (PL), central lung (CL), abdominal-pelvic (AP), mediastinal/cervical lymph node (MC), and liver (L). Six patients could be enrolled per anatomic site. The setting was a consortium of North American academic and community practice cancer centers participating in NRG Oncology trials. Patients with breast, prostate, or non–small cell lung cancer with 3 to 4 metastases or 2 metastases in close proximity (≤5 cm) amenable to SBRT were eligible for this phase 1 study. Statistical analyses were performed from December 31, 2017, to September 19, 2019. INTERVENTIONS: The starting dose was 50 Gy in 5 fractions (CL, MC), 45 Gy in 3 fractions (PL, AP, L), and 30 Gy in 3 fractions (BO, SP). MAIN OUTCOMES AND MEASURES: The primary end point was dose-limiting toxicity (DLT) defined by the Common Terminology Criteria for Adverse Events, version 4.0, as specific adverse events (AEs) of grades 3 to 5 (definite or probable per the protocol DLT definition) related to SBRT within 180 days of treatment. Dose levels were considered safe if DLTs were observed in no more than 1 of 6 patients per location; otherwise, the dose at that location would be de-escalated. RESULTS: A total of 42 patients enrolled, 39 were eligible, and 35 (mean [SD] age, 63.1 [14.2] years; 20 men [57.1%]; 30 White patients [85.7%]) were evaluable for DLT. Twelve patients (34.3%) had breast cancer, 10 (28.6%) had non–small cell lung cancer, and 13 (37.1%) had prostate cancer; there was a median of 3 metastases treated per patient. Median survival was not reached. No protocol-defined DLTs were observed. When examining all AEs, 8 instances of grade 3 AEs, most likely related to protocol therapy, occurred approximately 125 to 556 days from SBRT initiation in 7 patients. CONCLUSIONS AND RELEVANCE: This phase 1 trial demonstrated the safety of SBRT for patients with 3 to 4 metastases or 2 metastases in close proximity. There were no treatment-related deaths. Late grade 3 AEs demonstrate the need for extended follow-up in long-surviving patients with oligometastatic disease. Treatment with SBRT for multiple metastases has been expanded into multiple ongoing randomized phase 2/3 National Cancer Institute–sponsored trials (NRG-BR002, NRG-LU002). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02206334

Many are interested in how to safely ramp up elective surgeries after national, state, and voluntary shutdowns of operating rooms to minimize the spread of COVID-19 infections to patients and providers. We conducted an analysis of diverse perspectives from stakeholders regarding how to trade off risks and benefits to patients, healthcare providers, and the local community. Our findings indicate that there are a large number of different categories of stakeholders impacted by the post-pandemic decisions to reschedule delayed treatments and surgeries. For a delayed surgery, the primary stakeholders are the surgeon with expertise about the clinical benefits of undergoing an operation and the patient’s willingness to tolerate uncertainty and the increased risk of infection. For decisions about how much capacity in the operating rooms and in the inpatient setting after the surgery, the primary considerations are minimizing staff infections, preventing patients from getting COVID-19 during operations and during post-surgical recovery at the hospital, conserving critical resources such as PPE, and meeting the needs of hospital staff for quality of life, such as child care needs and avoiding infecting members of their household. The timing and selection of elective surgery cases has an impact on the ability of hospitals to steward finances, which in turns affects decisions about maintaining employment of staff when operating rooms and inpatient rooms are not being used.

Middle grades education has been the object of efforts to remediate US education to address an array of social problems. Districts have sought out K-8 models to create smaller learning communities, require fewer school transitions, and allow sustained student connections. This paper offers a historical analysis of K-8 schools, drawing on statistical and spatial methods and a DisCrit intersectional lens to illustrate how creating K-8 schools produced enclaves of privilege in one urban school district. K-8 schools in our target district became whiter and wealthier than district averages. Students with disabilities attending K-8 schools tended to be placed in more inclusive classrooms, where they were more likely to be integrated alongside nondisabled peers than counterparts attending traditional middle schools. We consider how the configuration of K-8 schools, which could be considered an administrative decision to better serve students, has obscured interworkings of power and privilege.

IMPORTANCE: Mastectomy is standard for recurrence of breast cancer after breast conservation therapy with whole breast irradiation. The emergence of partial breast irradiation led to consideration of its application for reirradiation after a second lumpectomy for treatment of recurrence of breast cancer in the ipsilateral breast. OBJECTIVES: To assess the effectiveness and adverse effects of partial breast reirradiation after a second lumpectomy and whether the treatment is an acceptable alternative to mastectomy. DESIGN, SETTING, AND PARTICIPANTS: The NRG Oncology/Radiation Therapy Oncology Group 1014 trial is a phase 2, single-arm, prospective clinical trial of 3-dimensional, conformal, external beam partial breast reirradiation after a second lumpectomy for recurrence of breast cancer in the ipsilateral breast after previous whole breast irradiation. The study opened on June 4, 2010, and closed June 18, 2013. Median follow-up was 5.5 years. This analysis used all data received at NRG Oncology through November 18, 2018. Eligible patients experienced a recurrence of breast tumor that was less than 3 cm and unifocal in the ipsilateral breast more than 1 year after breast-conserving therapy with whole breast irradiation and who had undergone excision with negative margins. INTERVENTIONS: Adjuvant partial breast reirradiation, 1.5 Gy twice daily for 30 treatments during 15 days (45 Gy), using a 3-dimensional conformal technique. MAIN OUTCOMES AND MEASURES: The main outcomes of the present study were the predefined secondary study objectives of recurrence of breast cancer in the ipsilateral breast, late adverse events (>1 year after treatment), mastectomy incidence, distant metastasis–free survival, overall survival, and circulating tumor cell incidence. RESULTS: A total of 65 women were enrolled, with 58 evaluable for analysis (mean [SD] age, 65.12 [9.95] years; 48 [83%] white). Of the recurrences of breast cancer in the ipsilateral breast, 23 (40%) were noninvasive and 35 (60%) were invasive. In all 58 patients, 53 (91%) had tumors 2 cm or smaller. All tumors were clinically node negative. A total of 44 patients (76%) tested positive for estrogen receptor, 33 (57%) for progesterone receptor, and 10 (17%) for ERBB2 (formerly HER2 or HER2/neu) overexpression. Four patients had breast cancer recurrence, with a 5-year cumulative incidence of 5% (95% CI, 1%-13%). Seven patients underwent ipsilateral mastectomies for a 5-year cumulative incidence of 10% (95% CI, 4%-20%). Both distant metastasis–free survival and overall survival rates were 95% (95% CI, 85%-98%). Four patients (7%) had grade 3 and none had grade 4 or higher late treatment adverse events. CONCLUSIONS AND RELEVANCE: For patients experiencing recurrence of breast cancer in the ipsilateral breast after lumpectomy and whole breast irradiation, a second breast conservation was achievable in 90%, with a low risk of re-recurrence of cancer in the ipsilateral breast using adjuvant partial breast reirradiation. This finding suggests that this treatment approach is an effective alternative to mastectomy.

Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation.

IMPORTANCE: There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing at the time of this narrative review. The objective of this review is to describe the current status of immunotherapy in breast cancer, highlighting its potential in both early-stage and metastatic disease. OBSERVATIONS: After searching ClinicalTrials.gov on April 24, 2018, and PubMed up to June 30, 2018, to identify breast cancer immunotherapy trials, we found that immune checkpoint blockade (ICB) is the most investigated form of immunotherapy in breast cancer. Use of ICB as monotherapy has achieved objective responses in patients with breast cancer, with higher rates seen when administered in earlier lines of therapy. For responding patients, those responses are durable. More recent data suggest clinical efficacy when ICB is given in combination with chemotherapy. Ongoing studies are evaluating combination strategies pairing ICB with additional chemotherapeutic agents, targeted therapy, vaccines, and local ablative therapies to enhance response. To date, robust predictive biomarkers for response to ICB have not been established. CONCLUSIONS AND RELEVANCE: It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions. Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors.

A digital filter based on non-negative matrix factorization (NMF) enables blind deconvolution of temporal information from large data sets, simultaneously recovering both photon arrival times and the instrument impulse response function (IRF). In general, the measured digital signals produced by modern analytical instrumentation are convolved by the corresponding IRFs, which can complicate quantitative analyses. Common examples include photon counting (PC), chromatography, super resolution imaging, fluorescence imaging, and mass spectrometry. Scintillation counting, in particular, provides a signal-to-noise advantage in measurements of low intensity signals, but has a limited dynamic range due to pulse overlap. This limitation can complicate the interpretation of data by masking temporal and amplitude information on the underlying detected signal. Typical methods for deconvolution of the photon events require advanced knowledge of the IRF, which is not generally trivial to obtain. In this work, a sliding window approach was developed to perform NMF one pixel at a time on short segments of large (e.g., 25 million point) data sets. Using random initial guesses for the IRF, the NMF filter simultaneously recovered both the deconvolved photon arrival times and the IRF. Applying the NMF filter to the analysis of triboluminescence (TL) data traces of active pharmaceutical ingredients enabled discrimination between different hypothesized physical origins of the signal.

The breast cosmetic outcome after breast conserving therapy is essential for evaluating breast treatment and determining patient’s remedy selection. This prompts the need of objective and efficient methods for breast cosmesis evaluations. However, current evaluation methods rely on ratings from a small group of physicians or semi-automated pipelines, making the processes time-consuming and their results inconsistent. To solve the problem, in this study, we proposed: 1. a fully-automaticMachine Learning Breast Cosmetic evaluation algorithm leveraging the state-of-the-art Deep Learning algorithms for breast detection and contour annotation, 2. a novel set of Breast Cosmesis features, 3. a new Breast Cosmetic dataset consisting 3k+ images from three clinical trials with human annotations on both breast components and their cosmesis scores. We show our fully-automatic framework can achieve comparable performance to state-of-the-art without the need of human inputs, leading to a more objective, low-cost and scalable solution for breast cosmetic evaluation in breast cancer treatment.

The TASH Inclusive Education National Committee responded to Horner and Dunlap’s call to ensure that future research integrates inclusive values with strong science by developing an inclusive education national research advocacy agenda. Qualitative methods were implemented to answer three questions: (a) What is the state of inclusive education research? (b) What research still must be done?and (c) What are recommendations for a national inclusive education research advocacy agenda? The findings include 15 areas organized within three domains advocating for continued research across systems-level capacity building, building and classroom capacity, and student learning and development. Implications for research and policy reform are discussed.

Neoadjuvant systemic therapy is being used increasingly in the treatment of early-stage breast cancer. Response, in the form of pathological complete response, is a validated and evaluable surrogate end point of survival after neoadjuvant therapy. Thus, pathological complete response has become a primary end point for clinical trials. However, there is a current lack of uniformity in the definition of pathological complete response. A review of standard operating procedures used by 28 major neoadjuvant breast cancer trials and/or 25 sites involved in such trials identified marked variability in specimen handling and histologic reporting. An international working group was convened to develop practical recommendations for the pathologic assessment of residual disease in neoadjuvant clinical trials of breast cancer and information expected from pathology reports. Systematic sampling of areas identified by informed mapping of the specimen and close correlation with radiological findings is preferable to overly exhaustive sampling, and permits taking tissue samples for translational research. Controversial areas are discussed, including measurement of lesion size, reporting of lymphovascular space invasion and the presence of isolated tumor cells in lymph nodes after neoadjuvant therapy, and retesting of markers after treatment. If there has been a pathological complete response, this must be clearly stated, and the presence/absence of residual ductal carcinoma in situmust be described. When there is residual invasive carcinoma, a comment must be made as to the presence/absence of chemotherapy effect in the breast and lymph nodes. The Residual Cancer Burden is the preferred method for quantifying residual disease in neoadjuvant clinical trials in breast cancer; other methods can be included per trial protocols and regional preference. Posttreatment tumor staging using the Tumor–Node–Metastasis system should be included. These recommendations for standardized pathological evaluation and reporting of neoadjuvant breast cancer specimens should improve prognostication for individual patients and allow comparison of treatment outcomes within and across clinical trials.

Neoadjuvant systemic therapy is being used increasingly in the treatment of early-stage breast cancer. Response, in the form of pathological complete response, is a validated and evaluable surrogate end point of survival after neoadjuvant therapy. Thus, pathological complete response has become a primary end point for clinical trials. However, there is a current lack of uniformity in the definition of pathological complete response. A review of standard operating procedures used by 28 major neoadjuvant breast cancer trials and/or 25 sites involved in such trials identified marked variability in specimen handling and histologic reporting. An international working group was convened to develop practical recommendations for the pathologic assessment of residual disease in neoadjuvant clinical trials of breast cancer and information expected from pathology reports. Systematic sampling of areas identified by informed mapping of the specimen and close correlation with radiological findings is preferable to overly exhaustive sampling, and permits taking tissue samples for translational research. Controversial areas are discussed, including measurement of lesion size, reporting of lymphovascular space invasion and the presence of isolated tumor cells in lymph nodes after neoadjuvant therapy, and retesting of markers after treatment. If there has been a pathological complete response, this must be clearly stated, and the presence/absence of residual ductal carcinoma in situ must be described. When there is residual invasive carcinoma, a comment must be made as to the presence/absence of chemotherapy effect in the breast and lymph nodes. The Residual Cancer Burden is the preferred method for quantifying residual disease in neoadjuvant clinical trials in breast cancer; other methods can be included per trial protocols and regional preference. Posttreatment tumor staging using the Tumor–Node–Metastasis system should be included. These recommendations for standardized pathological evaluation and reporting of neoadjuvant breast cancer specimens should improve prognostication for individual patients and allow comparison of treatment outcomes within and across clinical trials.

AbstractFederal laws mandate students with disabilities, including students with complex instructional needs (SWCIN), be involved and progress in the general education curriculum and that schools be accountable for continuous and substantial improvement of academic achievement for all students. The limited research on teaching academic content to SWCIN indicates that they achieve more positive outcomes when standards aligned instruction occurs within general education contexts. However, long-term change for instruction in general education contexts typically seems to be personality dependent rather than embedded within a sustainable system. We present content analysis findings of an expert panel concerning one state's initiative to address these issues, organized around four themes: (a) defining inclusive practices, (b) rethinking instruction for SWCIN, (c) rethinking the individualized education program (IEP), and (d) building sustainable inclusive practices across a system. Finally, we extend the panelists' conclusions to provide implications for professional development, practice, policy and administrative procedures, monitoring the quality of services, and research.

AbstractThe outcomes of a new universal program aimed at preventing depressive symptoms and disorders in 8- to 9-year-old children are presented. The Positive Thinking Program is a mental health promotion program based on cognitive and behavioural strategies. It is designed to meet the developmental needs of children in the middle primary school Years 4 and 5. Four state primary schools were randomly assigned to receive the program implemented by psychologists or to a control condition involving their regular Health Education curriculum. Seventy-two children participated in the intervention condition and 48 children in the control condition. Children completed measures of depressive and anxiety symptomatology, depressive disorders, and attribution style. The intervention was associated with reductions in depressive symptoms and more positive attributions at post-intervention. Compared to the control group, there was a lower prevalence of depressive disorders at posttest and fewer intervention group children developed a depressive disorder at a 9-month follow-up.

The outcomes of a new universal program aimed at preventing depressive symptoms and disorders in 8- to 9-year-old children are presented. The Positive Thinking Program is a mental health promotion program based on cognitive and behavioural strategies. It is designed to meet the developmental needs of children in the middle primary school Years 4 and 5. Four state primary schools were randomly assigned to receive the program implemented by psychologists or to a control condition involving their regular Health Education curriculum. Seventy-two children participated in the intervention condition and 48 children in the control condition. Children completed measures of depressive and anxiety symptomatology, depressive disorders, and attribution style. The intervention was associated with reductions in depressive symptoms and more positive attributions at post-intervention. Compared to the control group, there was a lower prevalence of depressive disorders at posttest and fewer intervention group children developed a depressive disorder at a 9-month follow-up.

Breast conservation therapy is fully accepted as a recommended treatment instead of mastectomy for suitable early stage breast cancer patients. Long term results from the initial randomized trial comparing BCT to mastectomy have demonstrated comparable local control and equivalent survival. The diagnosis and treatment of breast cancer has evolved over the past 2 decades since the randomized trials were initiated. For example, there is now widespread mammography screening, better understanding of breast cancer pathology, and emergence of numerous effective systemic therapy agents. This makes it timely to review the current methods for BCT. This review will focus on the radiation component of BCT, its impact on local cancer control, and how newer radiation technologies may help preserve local control while reducing toxicity and burden of care.

Multiple treatment guidelines and practice standards have been developed regarding the management of patients with breast carcinoma. Few evaluations of the penetration and utility of these practice standards have been performed. In 1992, the American College of Surgeons (ACOS), the American College of Radiology, the College of American Pathologists, and the Society of Surgical Oncology collaborated in establishing standards for breast-conservation treatment (BCT). The authors sought to determine whether practice patterns for patients with breast carcinoma who underwent BCT were consistent with these standards 2 years after their dissemination and to establish whether compliance varied by the same patient and hospital variables that predicted for the amount of BCT performed. A study specific questionnaire was circulated to cancer registrars through the Commission on Cancer of the ACOS asking them to submit reports on patients with Stage I and II breast carcinoma who were diagnosed in 1994. Eight hundred forty-two predominantly community hospitals throughout the United States responded, yielding a total of 16,643 analyzable patients. The frequency of compliance to the 1992 published practice standards for 7097 patients who received BCT was determined. The variation in compliance rates by patient age, race, and insurance status and the treating hospital's geographic locations and cancer programs were evaluated. Of the 22 standards that were evaluated in the areas of preoperative mammography (2 standards), labeling of the surgical specimen (3 standards), pathology report content (10 standards), radiation after lumpectomy (6 standards), and systemic therapy for patients with positive lymph nodes (1 standard), treatment adherence was ≥ 80% for 16 standards (73%). Poor compliance was demonstrated for six standards: the documentation of an abnormality's size in the mammogram report, labeling the lumpectomy specimen with the affected quadrant of the breast, spatial orientation of the lumpectomy specimen and inclusion of lymphatic/vascular invasion, ductal carcinoma in situ, and macroscopic margin assessment in the pathology report. Variation in compliance to a standard occurred frequently across the type of hospital cancer program and geographic region (77% for both), and variation occurred less across the patient variables of age (32%), race (41%), and payer (23%). There was not a pattern of more frequent compliance among variables associated with more BCT use. Large-scale evaluation of the penetration of treatment standards is feasible. For patients who underwent lumpectomy, practice appeared to be consistent (≥ 80% compliance), with 73% of 22 treatment standards evaluated. The standards with poor compliance represent areas for targeted physician education and reevaluation. Significant differences in adherence to a standard were seen frequently based on a hospital's geographic location and type of cancer program. This emphasizes the importance of adequate dissemination of treatment standards to ensure penetration into medical practices of all types.Cancer 2003;97:893–904. © 2003 American Cancer Society. DOI 10.1002/cncr.11141

Midwives' attitudes and practices regarding antenatal HIV testing, including integration of testing into routine antenatal care, were analysed using a self-administered structured questionnaire. This was completed by hospital and community-based midwives in an area of high HIV prevalence. In total, 162 responses were received. Most midwives (71%) agreed that HIV testing is an integral part of antenatal care but 61% also believed that only individuals with a counselling qualification should offer tests. Fifty seven per cent had attended a recent course about the management of HIV infection in pregnancy. Midwives who had attended a course were more likely to agree with integrated testing (odds ratio 5.2, 95% confidence interval 2.0–13.5). Midwives qualified between 5 and 9years ago were less likely than more recently qualified or more experienced midwives to offer tests, and this was not explained by differences in access to educational courses. Midwives' attitudes towards antenatal HIV testing are generally favourable. Despite an observed increase in uptake rates, many midwives continue to believe that only qualified counsellors should offer tests. All midwives should receive ongoing education that emphasizes the changing management of HIV infection in pregnancy and encourages testing.

The expression of mammalian G protein coupled receptors (GPCRs) in S. cerevisiae provides a powerful assay system for functional analysis, ligand identification and pharmaceutical screening. However, relatively few receptors have been coupled to the pheromone response pathway via the yeast Gα, Gpa1p, or chimeric yeast/mammalian Gα subunits containing long C-terminal regions of mammalian Gα proteins. We tested an extended range of seven such chimeras for Gα sub-types of three major classes (Gαi/o, Gαs and Gαq), against eight human GPCRs (SST2, SST5, 5-HT1A, 5-HT1Dα, ML1B, P2Y1 and P2Y2). Although the Gαi/o chimeras increased the range of receptors that coupled efficiently, the Gαs and Gαq chimeras were inactive when expressed using the GPA1 promoter. We describe 10 novel Gpa1p chimeras, designated ‘transplants’, in which the C-terminal five amino acids of Gpa1p were exchanged with mammalian residues. Coupling efficiency and ligand sensitivity improved significantly using the transplants. For the P2Y purinergic receptors, coupling could only be detected with the transplants; this is the first report of Gq specificity coupling in yeast. Thus, the transplants offer major advantages over previously described approaches, in terms of both the range of receptors coupled and the efficiency of coupling. Copyright © 2000 John Wiley & Sons, Ltd.

The expression of mammalian G protein coupled receptors (GPCRs) in S. cerevisiaeprovides a powerful assay system for functional analysis, ligand identification and pharmaceutical screening. However, relatively few receptors have been coupled to the pheromone response pathway via the yeast Gα, Gpa1p, or chimeric yeast/mammalian Gαsubunits containing long C‐terminal regions of mammalian Gαproteins. We tested an extended range of seven such chimeras for Gαsub‐types of three major classes (Gαi/o, Gαsand Gαq), against eight human GPCRs (SST2, SST5, 5‐HT1A, 5‐HT1Dα, ML1B, P2Y1and P2Y2). Although the Gαi/ochimeras increased the range of receptors that coupled efficiently, the Gαsand Gαqchimeras were inactive when expressed using the GPA1promoter. We describe 10 novel Gpa1p chimeras, designated ‘transplants’, in which the C‐terminal five amino acids of Gpa1p were exchanged with mammalian residues. Coupling efficiency and ligand sensitivity improved significantly using the transplants. For the P2Y purinergic receptors, coupling could only be detected with the transplants; this is the first report of Gqspecificity coupling in yeast. Thus, the transplants offer major advantages over previously described approaches, in terms of both the range of receptors coupled and the efficiency of coupling. Copyright © 2000 John Wiley & Sons, Ltd.