Development of an exosomal gene signature to detect residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning.

Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma in mouse xenografts to distinguish tumor-derived from host-response exosomal messenger RNAs (mRNAs). The model allows for the identification of canine osteosarcoma-specific gene signatures by RNA sequencing and a species-differentiating bioinformatics pipeline. An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by real-time quantitative reverse transcription PCR (qRT-PCR), while a machine learning model assigned dogs into healthy or disease groups. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups ("healthy", "osteosarcoma", "other bone tumor", or "non-neoplastic disease"). Pre-treatment samples from osteosarcoma cases were used as the training set, and a validation set from post-treatment samples was used for testing, classifying as "osteosarcoma detected" or "osteosarcoma-NOT detected". Dogs in a validation set whose post-treatment samples were classified as "osteosarcoma-NOT detected" had longer remissions, up to 15 months after treatment. In conclusion, we identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof of concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response.

Intracranial disease control for EGFR-mutant and ALK-rearranged lung cancer with large volume or symptomatic brain metastases.

PURPOSE/OBJECTIVE(S): Tyrosine kinase inhibitors (TKIs) are commonly employed for patients with brain metastases from lung cancer and specific driver mutations. We sought to identify the correlation between intracranial tumor burden and outcomes in patients with brain metastases treated with TKIs. MATERIALS/METHODS: We identified and retrospectively reviewed cases of EGFR-mutant or ALK-rearranged lung cancer with brain metastases at any time during their cancer course. Clinical characteristics and treatment information were abstracted from the medical records. Brain metastases were contoured to calculate total volume of disease at diagnosis and after initial therapy. High intracranial burden was defined as either > 10 brain metastases, volume of brain metastases > 15 cc, or largest lesion > 3 cm. Intracranial response was determined according to Response Assessment in Neuro-Oncology (RANO) criteria on the patient level. We determined the correlation between clinical and imaging characteristics and intracranial progression free survival (IC-PFS) and overall survival (OS). RESULTS: Fifty-seven patients with EGFR (n = 49) and ALK (n = 8) alterations were identified. Median follow-up from initial brain metastasis diagnosis was 17 months. Neurological symptoms were present in 54% at brain metastasis diagnosis. For those receiving TKIs alone or TKIs with radiation, at least a partial intracranial response (≥ 65% volume reduction) at 3 months from starting therapy was achieved in 94% and 58%. Progressive intracranial disease at 3 months occurred in 6.3% and 8.3%. Patients with high intracranial burden (n = 21) had a median 17 brain metastases, 6.5 cc volume, and 1.9 cm maximal tumor diameter. Median IC-PFS and OS for patients with high intracranial burden was 13.9 and 35.4 months. Patients with high intracranial burden and neurological symptoms at diagnosis had similar IC-PFS and OS compared to those with low burden and absence of neurological symptoms (p > 0.05 for each). CONCLUSION: Most patients receiving TKIs as part of their initial therapy achieve an early and durable volumetric intracranial response, irrespective of presenting disease burden or neurologic symptoms.

Functional genomics analysis reveals a MYC signature associated with a poor clinical prognosis in liposarcomas.

Liposarcomas, which are malignant fatty tumors, are the second most common soft-tissue sarcomas. Several histologically defined liposarcoma subtypes exist, yet little is known about the molecular pathology that drives the diversity in these tumors. We used functional genomics to classify a panel of diverse liposarcoma cell lines based on hierarchical clustering of their gene expression profiles, indicating that liposarcoma gene expression profiles and histologic classification are not directly correlated. Boolean probability approaches based on cancer-associated properties identified differential expression in multiple genes, including MYC, as potentially affecting liposarcoma signaling networks and cancer outcome. We confirmed our method with a large panel of lipomatous tumors, revealing that MYC protein expression is correlated with patient survival. These data encourage increased reliance on genomic features in conjunction with histologic features for liposarcoma clinical characterization and lay the groundwork for using Boolean-based probabilities to identify prognostic biomarkers for clinical outcome in tumor patients.

Evaluating the relationship between vaginal apex "dog ears" and patterns of recurrence in endometrial cancer following adjuvant image guided vaginal cuff brachytherapy.

PURPOSE: The aim of this investigation is to characterize vaginal apex "dog ears" and their association with patterns of treatment failure in patients with endometrial cancer treated with adjuvant high-dose-rate (HDR) single-channel vaginal cuff brachytherapy (VCB). METHODS: A retrospective review of patients treated with HDR VCB from 2012 to 2021 for medically operable endometrial cancer at a single institution was conducted. Dog ears, defined as tissue at the apex extending at least 10 mm from the brachytherapy applicator were identified on CT simulation images. Fisher exact test and a multivariate logistic regression model evaluated the association between factors of interest with treatment failure. Vaginal cuff failure free survival (VCFFS) was calculated from first brachytherapy to vaginal cuff recurrence (VCR). RESULTS: A total of 219 patients were reviewed. In this sample, 57.5% of patients met criteria for having dog ears. In total, 13 patients (5.9%) developed a VCR. There was no statistically significant difference in the rate of VCR between patients with and without dog ears (7.1% vs. 4.3%, p = 0.56). There was a trend toward increased risk of recurrence with higher grade histology identified in the multivariate logistic regression model (p = 0.085). The estimated 3-year probability of VCFFS was 86%. CONCLUSIONS: Vaginal apex dog ears are prevalent but are not found to statistically increase the risk of VCR after VCB in our single institution experience. However, while local failure remains low in this population, we report an absolute value of over twice as many VCRs in patients with dog ears, indicating that with improved dog ear characterization this may remain a relevant parameter for consideration in treatment planning.

Long-Term Adherence to Adjuvant Endocrine Therapy Following Various Radiotherapy Modalities in Early Stage Hormone Receptor Positive Breast Cancer.

INTRODUCTION: We compared the rates of long-term adjuvant endocrine therapy (AET) adherence after various radiation therapy (RT) modalities among patients with early stage breast cancer. MATERIALS AND METHODS: Medical records from patients with stage 0, I, or IIA (tumors ≤3 cm), hormone receptor (HR) positive breast cancer that received adjuvant radiation therapy (RT) from 2013 to 2015 at a single institution were retrospectively reviewed. All patients received breast conserving surgery (BCS) followed by adjuvant RT via one of the following modalities: whole breast radiotherapy (WBI), partial breast irradiation (PBI) with either external beam radiation therapy (EBRT) or fractionated intracavitary high-dose rate (HDR) brachytherapy, or single fraction HDR-brachytherapy intraoperative-radiation therapy (IORT). RESULTS: One hundred fourteen patients were reviewed. Thirty patients received WBI, 41 PBI, and 43 IORT with a median follow up of 64.2, 72.0, and 58.6 months, respectively. For the entire cohort, AET adherence was approximately 64% at 2 years and 56% at 5 years. Among patients in the IORT clinical trial, adherence to AET was approximately 51% at 2 years and 40% at 5 years. After controlling for additional factors, DCIS histology (vs invasive disease) and IORT (compared to other radiation modalities) were associated with decreased endocrine therapy adherence (P < 0.05). CONCLUSION: DCIS histology and receipt of IORT were associated with lower rates of adherence to AET at 5 years. Our findings suggest that examination of the efficacy of RT interventions such as PBI and IORT in patients who do not receive AET is warranted.

Dose differentiated high-dose-rate prostate brachytherapy: a feasibility assessment of MRI-guided dose escalation to dominant intra-prostatic lesions.

Purpose: Prostate brachytherapy is routinely performed with trans-rectal ultrasound (TRUS)- or computed tomography (CT)-based planning that cannot delineate dominant intra-prostatic lesions (DILs). In contrast, magnetic resonance imaging (MRI)-based planning allows for more accurate DIL delineation and dose escalation. This study assessed the maximum achievable dose escalation to DILs. Material and methods: We retrospectively identified 24 patients treated with high-dose-rate (HDR) prostate brachytherapy boost (15 Gy in 1 fraction). All patients had a pre-treatment prostate MRI with 1-3 DILs. MRIs were used to delineate DILs and were co-registered to TRUS intra-procedure. Treatment plans were experimentally re-optimized to escalate DIL dose. Dosimetric indices from the original and re-optimized plans were compared using two-tailed paired t-test. Re-optimized plans were deemed acceptable if they achieved all of the following criteria: prostate D90 > 100%, prostate V100 > 90%, urethra D10 < 118%, rectum V80 < 0.5 cc, bladder D1cc < 75%, or if they did not exceed organs at risk (OARs) doses of the original plan. Results: The mean DIL D90 was significantly increased from 134% of the prescription dose on the original plans to 154% on the re-optimized plans. The mean urethra D10 and mean bladder D1cc were significantly reduced from 123% to 117% and from 72% to 65%, respectively. Prostate D90 was reduced from 106% to 102%, and prostate V100 was reduced from 93% to 91%. Conclusions: We re-optimized HDR brachytherapy plans to escalate DILs dose to a mean D90 of > 150% while maintaining favorable prostate coverage and OARs doses. We propose DIL D90 dose of > 150% (22.5 Gy) as an achievable goal.

T Stage and Pretreatment Standardized Uptake Values Predict Tumor Recurrence With 5-Fraction SABR in Early-Stage Non-Small Cell Lung Cancer.

Purpose: Five-fraction stereotactic ablative radiotherapy (SABR) regimens are frequently used to treat centrally located early-stage non-small cell lung cancer or disease in the proximity of the chest wall as a means of optimizing tumor control and reducing treatment toxicity. However, increasing these SABR regimens to 5 fractions may reduce tumor control outcomes. We sought to identify the clinical parameters predictive of treatment failures with these 5-fraction courses. Methods: Ninety patients with T1-2 non-small cell lung cancer were treated with 50 or 60 Gy in 5 fractions. Failure over time was modeled using cumulative incidences of local, regional, or distant failure, with death as a competing risk. Cox proportional hazards analysis for incidences of failure was performed to control for patient variables. Results: Of 90 patients, 24 of 53 patients with T1 tumors and 19 of 37 patients with T2 tumors received 50 Gy SABR, and the other 47 patients received 60 Gy. Two-year overall survival and progression-free survival for the whole cohort were 75.8% and 59.3%, respectively. Total SABR dose (50 vs 60 Gy) did not influence survival nor failure rates at 2 and 5 years. Within 2 years of treatment, 7.8% of all patients developed local failure. For all patient and tumor characteristics evaluated, only T stage and pretreatment positron emission tomography standardized uptake values served as predictors of local, regional, and distant failure at 2 and 5 years posttreatment on univariate and multivariable analysis. Conclusions: Five-fraction SABR provides excellent in-field control. T2 and high fluorodeoxyglucose uptake tumors have increased failure rates, suggesting the potential need for adjuvant therapies, which are being assessed in randomized phase 3 trials.

Context matters: real-world and utilization-focused evaluation strategies to support change and improvement in child welfare.

This article examines the importance of context in evaluative inquiry. Following guidelines from real-world and utilization-focused evaluation frameworks, four projects are described to illustrate one foundation's pragmatic approach to evaluation that values collaboration, methodological appropriateness, and utilization. The authors contend that such an approach helps to ensure meaningful and actionable results in child welfare because it is responsive to local agency information and capacity needs while simultaneously contributing to the knowledge base of the field.

Coordinated community response to family violence: the role of domestic violence service organizations.

There is increasing awareness that domestic violence (DV) and child maltreatment often overlap and that there are significant negative consequences to women and children who are victims in the same families. The present study contains data from a participatory evaluation of a multisite national demonstration project on family violence (the Greenbook Initiative), funded jointly by the U.S. Departments of Health and Human Services and Justice. The goal of this initiative was to increase community capacity to assist dually victimized families. This article focuses on the DV service organizations in the demonstration with regard to collaborations with other agencies and work within the DV system to respond to dually victimized families. Findings suggest that DV agencies participated in leadership roles, cross-system collaborations, and cross-system trainings throughout the initiative. Within-agency practice changes were less apparent. Research and policy implications are discussed.

Emerging strategies for reducing racial disproportionality and disparate outcomes in child welfare: the results of a national breakthrough series collaborative.

Racial disproportionality in child welfare has been discussed as a seemingly intractable challenge with complex contributing factors. Some argue that these dynamics are far too difficult to be significantly impacted by public child welfare systems alone. The Breakthrough Series Collaborative (BSC) methodology, incorporating an analysis of structural racism and potential system bias, was proffered as a tool for engaging public child welfare agencies in a rapid, action-oriented process for identifying innovative strategies and practices to reduce racial disproportionality and disparate outcomes. This article describes the Disproportionality BSC process, as well as the work of participating jurisdictions with respect to transforming organizational culture and testing/implementing child welfare practice improvements. A theory of change is presented and critical lessons learned are shared in the form of collaborative reflections.

Effectiveness of an Adaptation of the Project Connect Health Systems Intervention: Youth and Clinic-Level Findings.

BACKGROUND: The Project Connect Health Systems Intervention (Project Connect) uses a systematic process of collecting community and healthcare infrastructure information to craft a referral guide highlighting local healthcare providers who provide high quality sexual and reproductive healthcare. Previous self-report data on healthcare usage indicated Project Connect was successful with sexually experienced female youth, where it increased rates of human immunodeficiency virus (HIV) and sexually transmitted disease (STD) testing and receipt of contraception. This adaption of Project Connect examined its effectiveness in a new context and via collection of clinic encounter-level data. METHODS: Project Connect was implemented in 3 high schools. (only 2 schools remained open throughout the entire project period). Participant recruitment and data collection occurred in 5 of 8 participating health clinics. Students completed Youth Surveys (N = 608) and a Clinic Survey (paired with medical data abstraction in 2 clinics [N = 305]). RESULTS: Students were more likely than nonstudents to report having reached a clinic via Project Connect. Nearly 40% of students attended a Project Connect school, with 32.7% using Project Connect to reach the clinic. Students were most likely to have been referred by a school nurse or coach. CONCLUSIONS: Project Connect is a low-cost, sustainable structural intervention with multiple applications within schools, either as a standalone intervention or in combination with ongoing efforts.

Nurses' perceptions of nurse residency: identifying barriers to implementation.

The purpose of this project was to describe the benefits and components of successful nurse residency programs, as well as gain insight into the perceptions of staff nurses, nurse educators, and nurse leaders regarding value, feasibility, and barriers to implementing nurse residency programs in acute care settings. This study has important implications for implementing an effective residency program.

Office-based management of diabetes: two-year trial of primary care quality improvement.

BACKGROUND AND OBJECTIVES: The goals of this study were to learn different approaches to improve the quality of care for the diabetic patients of the family practice setting FMC. METHODS: Participants of the study were 34 adult diabetic patients (Type 1 or 2) seen in the University of Arkansas of Medical Sciences' Family Medical Center by either family practice residents or faculty. Each CQI innovation was introduced in a stepwise fashion. The study team used a biopsychosocial, economic and environmental model of care to impact each dimension of ambulatory care. Not all cycles included all patients in the study, but patients and physicians received multiple interventions designed to improve hypertension control. RESULTS: The project intended to assess the feasibility of introducing a "package" of approaches to improve the outpatient management of diabetes rather than assess whether a specific innovation was efficacious. Improvement in blood pressure control, increased referral for eye exams, improved prescribing and/or use of aspirin and improved patient satisfaction with care were noted. CONCLUSION: The study demonstrated that the biopsychosocial and economic dimensions of the patients' diabetes must be addressed to achieve optimal care and that many approaches to improving outcomes can feasibly be introduced in a family practice setting.