The Clinical Utility of a 7-Gene Biosignature on Radiation Therapy Decision Making in Patients with Ductal Carcinoma In Situ Following Breast-Conserving Surgery: An Updated Analysis of the DCISionRT® PREDICT Study.

BACKGROUND: Breast-conserving surgery (BCS) followed by adjuvant radiotherapy (RT) is a standard treatment for ductal carcinoma in situ (DCIS). A low-risk patient subset that does not benefit from RT has not yet been clearly identified. The DCISionRT test provides a clinically validated decision score (DS), which is prognostic of 10-year in-breast recurrence rates (invasive and non-invasive) and is also predictive of RT benefit. This analysis presents final outcomes from the PREDICT prospective registry trial aiming to determine how often the DCISionRT test changes radiation treatment recommendations. METHODS: Overall, 2496 patients were enrolled from February 2018 to January 2022 at 63 academic and community practice sites and received DCISionRT as part of their care plan. Treating physicians reported their treatment recommendations pre- and post-test as well as the patient's preference. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendation. The impact of the test on RT treatment recommendation was physician specialty, treatment settings, individual clinical/pathological features and RTOG 9804 like criteria. Multivariate logisitc regression analysis was used to estimate the odds ratio (ORs) for factors associated with the post-test RT recommendations. RESULTS: RT recommendation changed 38% of women, resulting in a 20% decrease in the overall recommendation of RT (p < 0.001). Of those women initially recommended no RT (n = 583), 31% were recommended RT post-test. The recommendation for RT post-test increased with increasing DS, from 29% to 66% to 91% for DS <2, DS 2-4, and DS >4, respectively. On multivariable analysis, DS had the strongest influence on final RT recommendation (odds ratio 22.2, 95% confidence interval 16.3-30.7), which was eightfold greater than clinicopathologic features. Furthermore, there was an overall change in the recommendation to receive RT in 42% of those patients meeting RTOG 9804-like low-risk criteria. CONCLUSIONS: The test results provided information that changes treatment recommendations both for and against RT use in large population of women with DCIS treated in a variety of clinical settings. Overall, clinicians changed their recommendations to include or omit RT for 38% of women based on the test results. Based on published clinical validations and the results from current study, DCISionRT may aid in preventing the over- and undertreatment of clinicopathological 'low-risk' and 'high-risk' DCIS patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03448926 ( https://clinicaltrials.gov/study/NCT03448926 ).

The Clinical Utility of DCISionRT® on Radiation Therapy Decision Making in Patients with Ductal Carcinoma In Situ Following Breast-Conserving Surgery.

BACKGROUND: The role of radiation therapy (RT) following breast-conserving surgery (BCS) in ductal carcinoma in situ (DCIS) remains controversial. Trials have not identified a low-risk cohort, based on clinicopathologic features, who do not benefit from RT. A biosignature (DCISionRT®) that evaluates recurrence risk has been developed and validated. We evaluated the impact of DCISionRT on clinicians' recommendations for adjuvant RT. METHODS: The PREDICT study is a prospective, multi-institutional, observational registry in which patients underwent DCISionRT testing. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendations. RESULTS: Overall, 539 women were included in this study. Pre DCISionRT testing, RT was recommended to 69% of patients; however, post-testing, a change in the RT recommendation was made for 42% of patients compared with the pre-testing recommendation; the percentage of women who were recommended RT decreased by 20%. For women initially recommended not to receive an RT pre-test, 35% had their recommendation changed to add RT following testing, while post-test, 46% of patients had their recommendation changed to omit RT after an initial recommendation for RT. When considered in conjunction with other clinicopathologic factors, the elevated DCISionRT score risk group (DS > 3) had the strongest association with an RT recommendation (odds ratio 43.4) compared with age, grade, size, margin status, and other factors. CONCLUSIONS: DCISionRT provided information that significantly changed the recommendations to add or omit RT. Compared with traditional clinicopathologic features used to determine recommendations for or against RT, the factor most strongly associated with RT recommendations was the DCISionRT result, with other factors of importance being patient preference, tumor size, and grade.

Patients with rib fractures: use of incentive spirometry volumes to guide care.

Rib fractures pose significant risk to trauma patients. Effective pain control and the ability to take deep breaths are crucial for optimal recovery, and these are key elements in current clinical guidelines. These guidelines use incentive spirometry volumes along with other assessment values to guide patient care. However, despite current guidelines, nurses do not routinely document inspired respiratory volumes. This article provides trauma nurses with the rationale for documenting and tracking incentive spirometry volumes to improve outcomes for patients with rib fractures. This promotes early detection of respiratory decline and early interventions to improve pain control and pulmonary function.

Characterisation and natural progression of SARS-CoV-2 infection in ferrets.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the infectious disease COVID-19, which has rapidly become an international pandemic with significant impact on healthcare systems and the global economy. To assist antiviral therapy and vaccine development efforts, we performed a natural history/time course study of SARS-CoV-2 infection in ferrets to characterise and assess the suitability of this animal model. Ten ferrets of each sex were challenged intranasally with 4.64 × 104 TCID50 of SARS-CoV-2 isolate Australia/VIC01/2020 and monitored for clinical disease signs, viral shedding, and tissues collected post-mortem for histopathological and virological assessment at set intervals. We found that SARS-CoV-2 replicated in the upper respiratory tract of ferrets with consistent viral shedding in nasal wash samples and oral swab samples up until day 9. Infectious SARS-CoV-2 was recovered from nasal washes, oral swabs, nasal turbinates, pharynx, and olfactory bulb samples within 3-7 days post-challenge; however, only viral RNA was detected by qRT-PCR in samples collected from the trachea, lung, and parts of the gastrointestinal tract. Viral antigen was seen exclusively in nasal epithelium and associated sloughed cells and draining lymph nodes upon immunohistochemical staining. Due to the absence of clinical signs after viral challenge, our ferret model is appropriate for studying asymptomatic SARS-CoV-2 infections and most suitable for use in vaccine efficacy studies.

In vitro characterisation of SARS-CoV-2 and susceptibility of domestic ferrets (Mustela putorius furo).

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an emerging virus that has caused significant human morbidity and mortality since its detection in late 2019. With the rapid emergence has come an unprecedented programme of vaccine development with at least 300 candidates under development. Ferrets have proven to be an appropriate animal model for testing safety and efficacy of SARS-CoV-2 vaccines due to quantifiable virus shedding in nasal washes and oral swabs. Here, we outline our efforts early in the SARS-CoV-2 outbreak to propagate and characterize an Australian isolate of the virus in vitro and in an ex vivo model of human airway epithelium, as well as to demonstrate the susceptibility of domestic ferrets (Mustela putorius furo) to SARS-CoV-2 infection following intranasal challenge.

Type I Hypersensitivity in Ferrets Following Exposure to SARS-CoV-2 Inoculum: Lessons Learned.

This case report discusses Type I hypersensitivity in ferrets following exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inoculum, observed during a study investigating the efficacy of candidate COVID-19 vaccines. Following a comprehensive internal root-cause investigation, it was hypothesized that prior prime-boost immunization of ferrets with a commercial canine C3 vaccine to protect against the canine distemper virus had resulted in primary immune response to fetal bovine serum (FBS) in the C3 preparation. Upon intranasal exposure to SARS-CoV-2 virus cultured in medium containing FBS, an allergic airway response occurred in 6 out of 56 of the ferrets. The 6 impacted ferrets were randomly dispersed across study groups, including different COVID-19 vaccine candidates, routes of vaccine candidate administration, and controls (placebo). The root-cause investigation and subsequent analysis determined that the allergic reaction was unrelated to the COVID-19 vaccine candidates under evaluation. Histological assessment suggested that the allergic response was characterized by eosinophilic airway disease; increased serum immunoglobulin levels reactive to FBS further suggested this response was caused by immune priming to FBS present in the C3 vaccine. This was further supported by in vivo studies demonstrating ferrets administered diluted FBS also presented clinical signs consistent with a hyperallergic response, while clinical signs were absent in ferrets that received a serum-free SARS-CoV-2 inoculum. It is therefore recommended that vaccine studies in higher order animals should consider the impact of welfare vaccination and use serum-free inoculum whenever possible.

ChAdOx1 nCoV-19 (AZD1222) vaccine candidate significantly reduces SARS-CoV-2 shedding in ferrets.

Vaccines against SARS-CoV-2 are likely to be critical in the management of the ongoing pandemic. A number of candidates are in Phase III human clinical trials, including ChAdOx1 nCoV-19 (AZD1222), a replication-deficient chimpanzee adenovirus-vectored vaccine candidate. In preclinical trials, the efficacy of ChAdOx1 nCoV-19 against SARS-CoV-2 challenge was evaluated in a ferret model of infection. Groups of ferrets received either prime-only or prime-boost administration of ChAdOx1 nCoV-19 via the intramuscular or intranasal route. All ChAdOx1 nCoV-19 administration combinations resulted in significant reductions in viral loads in nasal-wash and oral swab samples. No vaccine-associated adverse events were observed associated with the ChAdOx1 nCoV-19 candidate, with the data from this study suggesting it could be an effective and safe vaccine against COVID-19. Our study also indicates the potential for intranasal administration as a way to further improve the efficacy of this leading vaccine candidate.

Initial radiation experience evaluating early tolerance and toxicities in patients undergoing accelerated partial breast irradiation using the Contura Multi-Lumen Balloon breast brachytherapy catheter.

PURPOSE: We reviewed our institution's experience treating patients with the Contura Multi-Lumen Balloon (SenoRx, Inc., Irvine, CA) breast brachytherapy catheter to deliver accelerated partial breast irradiation. METHODS AND MATERIALS: Forty-one patients treated with breast-conserving therapy received adjuvant radiation using the Contura catheter (34Gy in 3.4Gy fractions). Thirteen patients had Stage 0, 21 had Stage I, and 7 had Stage II breast cancer. Median followup was 8 months (range, 1-17). RESULTS: Median, minimum skin spacing was 10mm (range, 2-17). Median, maximum skin doses (% of prescribed dose [PD]) were 99.7 (range, 57.1-124.1). Eight patients were treated with a skin spacing

Three-year clinical outcome using the Contura multilumen balloon breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI): improving radiation standards for the optimal application of APBI.

PURPOSE: We reviewed our institution's 3-year clinical experience in treating patients with the Contura multilumen balloon (SenoRx, Inc., Aliso Viejo, CA) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: Forty-six patients treated with breast-conserving therapy received adjuvant radiation using the Contura catheter (34Gy in 3.4Gy fractions). Fourteen patients had Stage 0, 24 had Stage I, and 8 had Stage II breast cancer. Median follow-up was 36 months (range, 1-44 months). RESULTS: Only one local recurrence developed (2%). The rate of persistent seroma formation at latest reported follow-up was 4.3% (2 patients) and the incidence of any clinically detectable telengiectasias was 2.2%. No major toxicities (0% Grade III) have occurred. The median skin dose (% of the prescribed dose) was 99.7. The median dose to 95% of the planning target volume for evaluation was 98.8%. The percentage of patients with excellent/good cosmetic results at 24 (n=23) and 36 (n=22) months was 100% and 97%, respectively. CONCLUSION: Adjuvant APBI using the Contura multilumen balloon catheter exhibited similar locoregional control, cosmesis, and toxicities to other forms of APBI with similar lengths of follow-up. In addition, improved radiation standards for the delivery of APBI were demonstrated.

Factors associated with chest wall toxicity after accelerated partial breast irradiation using high-dose-rate brachytherapy.

PURPOSE: The purpose of this analysis was to evaluate dose-volume relationships associated with a higher probability for developing chest wall toxicity (pain) after accelerated partial breast irradiation (APBI) by using both single-lumen and multilumen brachytherapy. METHODS AND MATERIALS: Rib dose data were available for 89 patients treated with APBI and were correlated with the development of chest wall/rib pain at any point after treatment. Ribs were contoured on computed tomography planning scans, and rib dose-volume histograms (DVH) along with histograms for other structures were constructed. Rib DVH data for all patients were sampled at all volumes ≥0.008 cubic centimeter (cc) (for maximum dose related to pain) and at volumes of 0.5, 1, 2, and 3 cc for analysis. Rib pain was evaluated at each follow-up visit. Patient responses were marked as yes or no. No attempt was made to grade responses. Eighty-nine responses were available for this analysis. RESULTS: Nineteen patients (21.3%) complained of transient chest wall/rib pain at any point in follow-up. Analysis showed a direct correlation between total dose received and volume of rib irradiated with the probability of developing rib/chest wall pain at any point after follow-up. The median maximum dose at volumes ≥0.008 cc of rib in patients who experienced chest wall pain was 132% of the prescribed dose versus 95% of the prescribed dose in those patients who did not experience pain (p = 0.0035). CONCLUSIONS: Although the incidence of chest wall/rib pain is quite low with APBI brachytherapy, attempts should be made to keep the volume of rib irradiated at a minimum and the maximum dose received by the chest wall as low as reasonably achievable.

A dosimetric comparison of the Contura multilumen balloon breast brachytherapy catheter vs. the single-lumen MammoSite balloon device in patients treated with accelerated partial breast irradiation at a single institution.

PURPOSE: A comparison of dosimetric findings in 33 patients treated with the Contura multilumen balloon (SenoRx Inc., Irvine, CA) (C-MLB) breast brachytherapy catheter vs. 33 patients treated with the MammoSite (Hologic Inc., Bedford, MA) (MS) at a single institution to deliver accelerated partial breast irradiation (APBI) was performed. METHODS AND MATERIALS: CT-based 3-dimensional planning with dose optimization was completed. APBI treatment of 34Gy in 3.4Gy fractions was delivered. Endpoints analyzed included: (1) The percentage of the prescribed dose (PD) covering the planning target volume (PTV), (2) the maximum skin dose as a percentage of the PD, (3) the maximum rib dose as a percentage of the PD, and (4) the V150 and V200. RESULTS: The C-MLB was placed more frequently in patients with closer skin spacing (<7mm) and rib spacing (<7mm) than in MS patients (45.5% vs. 12.1%, p=0.0057 and 57.6 vs. 33.3, p=0.0131, respectively). Despite closer skin spacing, the overall median skin dose was significantly lower in C-MLB patients (112% of the PD vs. 134%, p=0.0282). No statistically significant differences in the V150 or V200 were observed. In patients with very limited rib spacing (<4mm), the C-MLB delivered significantly lower rib doses than the MS (144% of the PD vs. 191%, p=0.0107). In all clinical scenarios, coverage of the PTV with the C-MLB was either equal to or significantly better than with the MS (p=0.0024). CONCLUSION: The C-MLB catheter produced clinically significant improvements in dosimetric endpoints (e.g., reduced skin and rib doses and improved PTV coverage) in most clinical scenarios.