Computational modeling of first responders' willingness to accept radiation exposure during radiological or nuclear events.

Since the events of 9/11, a concerted interagency effort has been undertaken to create comprehensive emergency planning and preparedness strategies for the management of a radiological or nuclear event in the US. These planning guides include protective action guidelines, medical countermeasure recommendations, and systems for diagnosing and triaging radiation injury. Yet, key areas such as perception of risk from radiation exposure by first responders have not been addressed. In this study, we identify the need to model and develop new strategies for medical management of large-scale population exposures to radiation and examine the phenomena of radiation dread and its role in emergency response using an agent-based modeling approach. Using the computational modeling platform NetLogo, we developed a series of models examining factors affecting first responders' willingness to work (WTW) in the context of entering areas where radioactive contamination is present or triaging individuals potentially contaminated with radioactive materials. In these models, the presence of radiation subject matter experts (SMEs) was found to increase WTW. Degree of communication was found to be a dynamic variable with either positive or negative effects on WTW dependent on the initial WTW demographics of the test population. Our findings illustrate that radiation dread is a significant confounder for emergency response to radiological or nuclear events and that increasing the presence of radiation SME in the field and communication among first responders when such radiation SMEs are present will help mitigate the effect of radiation dread and improve first responder WTW during future radiological or nuclear events.

Modifying quantitative sensory testing to investigate behavioral reactivity in a pediatric global developmental delay sample: Relation to peripheral innervation and chronic pain outcomes.

Early tactile and nociceptive (pain) mechanisms in children with global developmental delay at risk for intellectual and developmental disability are not well understood. Sixteen children with global developmental delay (mean age = 5.1 years, SD = 1.4; 50% male) completed a modified quantitative sensory testing (mQST) protocol, an epidermal (skin) punch biopsy procedure, and parent-endorsed measures of pain. Children with reported chronic pain had significantly greater epidermal nerve fiber density (ENFd) compared to children without chronic pain. Based on the mQST trials, ENFd values were associated with increased vocal reactivity overall and specifically during the light touch and cool thermal stimulus trials. The findings support the feasibility of an integrative biobehavioral approach to test nociceptive and tactile peripheral innervation and behavioral reactivity during a standardized sensory test in a high-risk sample for which there is often sensory dysfunction and adaptive behavior impairments.

TNFα and IFNγ cooperate for efficient pro- to anti-inflammatory transition of macrophages during muscle regeneration.

IFNγ is traditionally known as a proinflammatory cytokine with diverse roles in antimicrobial and antitumor immunity. Yet, findings regarding its sources and functions during the regeneration process following a sterile injury are conflicting. Here, we show that natural killer (NK) cells are the main source of IFNγ in regenerating muscle. Beyond this cell population, IFNγ production is limited to a small population of T cells. We further show that NK cells do not play a major role in muscle regeneration following an acute injury or in dystrophic mice. Surprisingly, the absence of IFNγ per se also has no effect on muscle regeneration following an acute injury. However, the role of IFNγ is partially unmasked when TNFα is also neutralized, suggesting a compensatory mechanism. Using transgenic mice, we showed that conditional inhibition of IFNGR1 signaling in muscle stem cells or fibro-adipogenic progenitors does not play a major role in muscle regeneration. In contrast to common belief, we found that IFNγ is not present in the early inflammatory phase of the regeneration process but rather peaks when macrophages are acquiring an anti-inflammatory phenotype. Further transcriptomic analysis suggests that IFNγ cooperates with TNFα to regulate the transition of macrophages from pro- to anti-inflammatory states. The absence of the cooperative effect of these cytokines on macrophages, however, does not result in significant regeneration impairment likely due to the presence of other compensatory mechanisms. Our findings support the arising view of IFNγ as a pleiotropic inflammatory regulator rather than an inducer of the inflammatory response.

Implementing stereotactic accelerated partial breast irradiation using magnetic resonance guided radiation therapy.

INTRODUCTION: Accelerated partial breast irradiation (APBI) seeks to reduce irradiated volumes and radiation exposure for patients while maintaining acceptable clinical outcomes. Magnetic resonance image-guided radiotherapy (MRgRT) provides excellent soft-tissue contrast for treatment localization, which can reduce setup uncertainty, thus reducing margins in the external beam setting. Additionally, stereotactic body radiotherapy (SBRT)-style regimens with high gradients can also be executed. This MR-guided stereotactic APBI (MRgS-APBI) approach can be utilized for a lower number of fractions and spare a greater volume of healthy tissues compared to conventional 3D external beam APBI. METHODS: Our MRgS-APBI program was developed for two prospective non-randomized phase I/II clinical trials (20Gyx1 and 8.5Gyx3). Both breast SBRT treatment planning and MRgRT delivery techniques were described in this study. Simulation included both CT and MRI with specialized immobilization to accommodate MR-guided setup and cine-MRI treatment gating. Dosimetry data from 48 single-fraction and 19 three-fraction patients were collected and evaluated. This included planning objectives and SBRT-specific indices. During treatment, setup errors were calculated to evaluate setup reproducibility and duty cycle was calculated using cine-MRI data during gated delivery. RESULTS: In both the single- and three- fraction trials combined, 88.5% of the possible dosimetric objectives across all patients were met during planning. The majority of the planning objectives were easily achievable indicating the potential for stricter objectives for subsequent S-APBI treatments. The average magnitude of setup uncertainties was 1.0 cm ±â€¯0.6 cm across all treatments. In the three-fraction trial, the average beam-on duty-cycle for the MRI-gated delivery was 83.0 ±â€¯13.0%. There were no technical MRgS-APBI related issues that resulted in discontinuation of treatment across all patients. CONCLUSION: SBRT-style dosimetry and delivery for APBI is feasible using MR-guidance. The program development and dosimetric outcomes reported here can serve as a guide for other institutions considering the clinical implementation of MR-guided stereotactic APBI.

The impact of radiation dread on mass casualty medical management during a radiological or nuclear event.

Since the events of 9/11, a concerted interagency effort has been undertaken to create comprehensive emergency planning and preparedness strategies for management of a radiological or nuclear event in the US. These planning guides include protective action guidelines, medical countermeasure recommendations, and systems for diagnosing and triaging radiation injury. Yet, key areas such as perception of risk from radiation exposure by first responders have not been addressed. In this article, we identify the need to model and develop new strategies for the medical manage-ment of large-scale population exposures to radiation, examine the phenomena of radiation dread and its role in emergency response, and review recent findings on the willingness to work of first responders and other personnel involved in mass casualty medical management during a radiological or nuclear event.

Pre-intervention SNOT-22 scores predict outcomes in aspirin exacerbated respiratory disease.

PURPOSE: This study evaluated whether stratified preoperative, pre- aspirin desensitization (AD) sinonasal symptom scores predict postoperative, post-AD outcomes in Aspirin exacerbated respiratory disease (AERD). MATERIALS AND METHODS: Retrospective chart review of patients with aspirin challenge-proven AERD who underwent endoscopic sinus surgery followed by AD was performed. Preoperative, postoperative/pre-AD, and postoperative/post-AD sinonasal symptom scores were collected (22-item Sino-Nasal Outcomes Test, SNOT-22). A longitudinal linear mixed-effects model was used for data analysis. RESULTS: Forty-seven patients (59.6% female) aged 48.0 ± 13.2 were included. Average time from surgery to AD was 70.0 ± 52.8 days. Preoperative SNOT-22 scores (n = 47) were divided into tertiles (cutoffs of 36 and 54 indicating mild [22.5 ± 13.7], moderate [44.3 ± 12.2], and severe [72.9 ± 19.7] disease). This corresponded to 12 (25.5%), 18 (38.3%), and 17 (36.2%) subjects being categorized into mild, moderate, and severe tertiles, respectively. Postoperative, pre-AD SNOT-22 in all disease groups decreased and were not significantly different (12.3 ± 13.7, 11.1 ± 12.2, 22.7 ± 19.7; p = 0.074). At short-term post-AD, only the severe group worsened (35.0 ± 20.3, p < 0.001), whereas other groups demonstrated negligible change (9.3 ± 14.3 and 14.4 ± 12.2). At long-term post-AD, all groups redemonstrated convergence in symptom scores (23.7 ± 20.9, 19.4 ± 15.4, and 31.0 ± 27.6, p = 0.304). CONCLUSION: Preoperative SNOT-22 scores may be used as a predictor of postoperative, post-AD patient-reported outcomes in AERD. Patients with mild and moderate disease may derive benefit from surgery and AD alone, while those with severe disease may require additional interventions (e.g., biologics).

Dosimetric predictors of symptomatic radiation necrosis after five-fraction radiosurgery for brain metastases.

BACKGROUND: To identify factors predictive of developing symptomatic radiation necrosis (sRN) among patients with either intact or resected brain metastases undergoing five-fraction stereotactic radiosurgery (5fSRS). METHODS: Multi-institutional retrospective review of 117 brain metastases from 83 patients treated with 5fSRS. The cumulative incidence of sRN and predictors of sRN were calculated using Gray's competing risks and Cox regression. RESULTS: The median dose of 5fSRS was 30 Gy (range: 25-40), and 21 lesions (18%) had prior SRS. After a median follow-up of 10.3 months (range: 3-52), the cumulative sRN incidence was 15%, with a median time to sRN of 6.9 months (range: 1.8-31.7). sRN incidence was significantly higher among the lesions treated with prior SRS: hazard ratio (HR): 7.48 [95% confidence interval: 2.57-21.8]. Among lesions without prior SRS, higher volume of uninvolved brain receiving 25 Gy (BrainV25; HR: 1.07 [1.02-1.12]) and 30 Gy (BrainV30; HR: 1.07 [1.01-1.33]) were the most significant factors associated with sRN. Similar results were also observed among the patients with prior SRS. For lesions without prior SRS, BrainV25 > 16 cm3 (HR: 11.7 [1.47-93.3]) and BrainV30 > 10 cm3 (HR: 7.08 [1.52-33.0]) were associated with significantly higher risk of sRN. At two years, the sRN incidence was 21% if violating either dosimetric threshold and 2% if violating neither (p = .007). CONCLUSION: BrainV25 and BrainV30 are significant dosimetric predictors of sRN of brain metastases treated with 5fSRS. In the absence of prior SRS, maintaining BrainV25Gy < 16 cm3 and BrainV30Gy < 10 cm3 may minimize sRN risk.

Internal dose escalation associated with increased local control for melanoma brain metastases treated with stereotactic radiosurgery.

OBJECTIVE: The internal high-dose volume varies widely for a given prescribed dose during stereotactic radiosurgery (SRS) to treat brain metastases (BMs). This may be altered during treatment planning, and the authors have previously shown that this improves local control (LC) for non-small cell lung cancer BMs without increasing toxicity. Here, they seek to identify potentially actionable dosimetric predictors of LC after SRS for melanoma BM. METHODS: The records of patients with unresected melanoma BM treated with single-fraction Gamma Knife RS between 2006 and 2017 were reviewed. LC was assessed on a per-lesion basis, defined as stability or a decrease in lesion size. Outcome-oriented approaches were utilized to determine optimal dichotomization for dosimetric variables relative to LC. Univariable and multivariable Cox regression analysis was implemented to evaluate the impact of collected parameters on LC. RESULTS: Two hundred eighty-seven melanoma BMs in 79 patients were identified. The median age was 56 years (range 31-86 years). The median follow-up was 7.6 months (range 0.5-81.6 months), and the median survival was 9.3 months (range 1.3-81.6 months). Lesions were optimally stratified by volume receiving at least 30 Gy (V30) greater than or equal to versus less than 25%. V30 was ≥ and < 25% in 147 and 140 lesions, respectively. For all patients, 1-year LC was 83% versus 66% for V30 ≥ and < 25%, respectively (p = 0.001). Stratifying by volume, lesions 2 cm or less (n = 215) had 1-year LC of 82% versus 70% (p = 0.013) for V30 ≥ and < 25%, respectively. Lesions > 2 to 3 cm (n = 32) had 1-year LC of 100% versus 43% (p = 0.214) for V30 ≥ and < 25%, respectively. V30 was still predictive of LC even after controlling for the use of immunotherapy and targeted therapy. Radionecrosis occurred in 2.8% of lesions and was not significantly associated with V30. CONCLUSIONS: For a given prescription dose, an increased internal high-dose volume, as indicated by measures such as V30 ≥ 25%, is associated with improved LC but not increased toxicity in single-fraction SRS for melanoma BM. Internal dose escalation is an independent predictor of improved LC even in patients receiving immunotherapy and/or targeted therapy. This represents a dosimetric parameter that is actionable at the time of treatment planning and warrants further evaluation.

Canadian 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older: an integration of physical activity, sedentary behaviour, and sleep.

The Canadian Society for Exercise Physiology assembled a Consensus Panel representing national organizations, content experts, methodologists, stakeholders, and end-users and followed an established guideline development procedure to create the Canadian 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older: An Integration of Physical Activity, Sedentary Behaviour, and Sleep. These guidelines underscore the importance of movement behaviours across the whole 24-h day. The development process followed the strategy outlined in the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A large body of evidence was used to inform the guidelines including 2 de novo systematic reviews and 4 overviews of reviews examining the relationships among movement behaviours (physical activity, sedentary behaviour, sleep, and all behaviours together) and several health outcomes. Draft guideline recommendations were discussed at a 4-day in-person Consensus Panel meeting. Feedback from stakeholders was obtained by survey (n = 877) and the draft guidelines were revised accordingly. The final guidelines provide evidence-based recommendations for a healthy day (24-h), comprising a combination of sleep, sedentary behaviours, and light-intensity and moderate-to-vigorous-intensity physical activity. Dissemination and implementation efforts with corresponding evaluation plans are in place to help ensure that guideline awareness and use are optimized. Novelty First ever 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older with consideration of a balanced approach to physical activity, sedentary behaviour, and sleep Finalizes the suite of 24-Hour Movement Guidelines for Canadians across the lifespan.

Impact of invasive nodal staging on regional and distant recurrence rates after SBRT for inoperable stage I NSCLC.

PURPOSE/OBJECTIVES: Before definitive stereotactic body radiation therapy (SBRT) for presumably node-negative, early-stage NSCLC, many patients are staged with PET/CT alone. In patients undergoing PET/CT prior to SBRT, the role of invasive nodal staging (INS) with endobronchial ultrasound (EBUS) or mediastinoscopy is uncertain. We sought to characterize the impact of nodal staging modality on outcomes. MATERIALS/METHODS: Patients receiving definitive SBRT for T1-2N0 NSCLC deemed node-negative by either PET/CT plus INS (EBUS or mediastinoscopy) or PET/CT alone were identified. Patients with initially equivocal or positive nodes on PET/CT were excluded from this analysis. All patients received 3-5 fraction SBRT according to institutional guidelines. Control was assessed by at least one follow-up CT in all patients. Multivariable logistic regression (MVA) was performed to identify variables independently associated with use of INS. RESULTS: We identified 651 eligible patients at our institution from 2005-2016. INS was performed in 15.2% of patients (n = 99) with EBUS (n = 78) or mediastinoscopy (n = 21). Median follow-up was 19.4 months (0.2-135.1). Median survival was 28.5 months (0.6-140). Factors predictive of increased likelihood of INS after negative PET/CT on MVA were age (OR for decreasing age 1.033; 95% CI 1.058-1.010), Caucasian race (OR vs. non-white 1.852; 1.044-3.289), male sex (1.629; 1.031-2.575), central location (1.978; 1.218-3.211) and squamous histology (2.564; 1.243-5.287). Nodal and/or distant control at 2 years was similar between PET/CT alone (78%, 95% CI 74-82%) and INS + PET/CT (75%, 95% CI 65-85%) (p = 0.877) as well as on MVA. Overall survival did not differ based on staging modality. CONCLUSIONS: In patients with early-stage NSCLC deemed node-negative by PET/CT, addition of INS did not appreciably alter patterns of failure or survival after definitive SBRT. This study does not question the established value of INS for equivocal or suspicious nodes.

Intracranial Stereotactic Radiation Therapy With a Jawless Ring Gantry Linear Accelerator Equipped With New Dual Layer Multileaf Collimator.

PURPOSE: To test the feasibility of a simplified, robust, workflow for intracranial stereotactic radiation therapy (SRT) using a ring gantry linear accelerator (RGLA) equipped with a dual-layer stacked, staggered, and interdigitating multileaf collimator. MATERIALS AND METHODS: Twenty recent clinical SRT cases treated using a radiosurgery c-arm linear accelerator were anonymized. From these data sets, a new planning workflow was developed and used to replan these cases, which then were compared to their clinical counterparts. Population-based dose-volume histograms were analyzed for target coverage and sparing of healthy brain. All plans underwent plan review and quality assurance and were delivered on an end-to-end verification phantom using image guidance to simulate treatment. RESULTS: The RGLA plans were able to meet departmental standards for target coverage and organ-at-risk sparing and showed plan quality similar to the clinical plans. RGLA plans showed increases in the 50% isodose in the axial plane but decreases in the sagittal and coronal planes. There were no statistically significant differences in the homogeneity index or number of monitor units between the 2 systems. There were statistically significant increases in conformity and gradient indices, with median values of 1.09 versus 1.11 and 2.82 versus 3.13, respectively, for the c-arm versus RGLA plans. These differences were not believed to be clinically significant because they met clinical goals. The population-based dose-volume histograms showed target coverage and organ-at-risk sparing similar to that of the clinical plans. All plans were able to meet the departmental quality assurance requirements and were delivered under image guidance on an end-to-end phantom with measurements agreeing within 3% of the expected value. RGLA plans showed a median reduction in delivery time of ≈50%. CONCLUSIONS: This work describes a simplified and efficient workflow that could reduce treatment times and expand access to SRT to centers using an RGLA.

The Impact of the Pandemic on Otolaryngology Patients With Negative COVID-19 Status: Commentary and Insights From Orbital Emergencies.

Efforts aimed at minimizing the spread of COVID-19 and "flattening the curve" may be affecting clinical care delivery for non-COVID-19 cases that include otolaryngologic and orbital conditions. We are witnessing changes in the manner that patients present, as well as modifications in clinical management strategies. An improved understanding of these phenomena and the contributing factors is essential for otolaryngologists to provide sound clinical care during this unprecedented pandemic.

Prognostic Significance of Smoking in Human Papillomavirus-Positive Oropharyngeal Cancer Under American Joint Committee on Cancer Eighth Edition Stage.

OBJECTIVE: To determine the prognostic significance of smoking in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) when considering American Joint Committee on Cancer eighth edition (AJCC-8) stage. STUDY DESIGN: Retrospective cohort study. METHODS: Three hundred seventeen HPV-positive OPSCC patients with known AJCC-8 stage and smoking status (<10 or ≥10 pack-years) seen at a tertiary center from 1997 to 2017 were studied. We used the Kaplan-Meier method to compare 5-year overall survival (OS) by smoking status and by clinical AJCC-8 stage and smoking status combined. Hazard ratios (HRs) were estimated with Cox proportional hazard regression for the independent effects of smoking and AJCC-8 stage. We also studied pathologic stage and estimated the combined effects of smoking and clinical stage. RESULTS: The ≥10 pack-years smokers had worse 5-year OS than <10 pack-years smokers (93.6%; 95% confidence interval (CI): 89.7-97.8 vs. 82.3%; 95% CI: 76.0%-89.1%). When stratified by AJCC-8 clinical stage, only stage I <10 pack-years smokers (98.7%; 95% CI: 96.3%-100.0%) had significantly better 5-year OS than their ≥10 pack-years (84.8%; 95% CI: 76.4%-94.1%) counterparts. In a multivariable analysis, ≥10 pack-years smoking was associated with increased hazard of death when adjusting for AJCC-8 clinical (HR: 2.52; 95% CI: 1.16-5.46) and pathologic (HR: 5.21; 95% CI: 1.47-18.5) stage. In both analyses, stage III patients demonstrated worse survival than stage I, and smoking had greater impact at lower stages. CONCLUSIONS: Smoking is a negative prognosticator in HPV-positive OPSCC and interacts with AJCC-8 clinical stage. It is important to understand the impact of smoking in HPV-positive disease when considering treatment plans and deintensification trials. LEVEL OF EVIDENCE: 2b Laryngoscope, 130: 1961-1966, 2020.

Predictors of Distant Metastases in Triple-Negative Breast Cancer Without Pathologic Complete Response After Neoadjuvant Chemotherapy.

BACKGROUND: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) predicts decreased distant metastasis. However, most patients do not experience pCR, and other risk factors for distant metastasis after NAC are poorly characterized. This study investigated factors predictive of distant metastasis in TNBC without pCR after NAC. METHODS: Women with TNBC treated with NAC, surgery, and radiation therapy in 2000 through 2013 were reviewed. Freedom from distant metastasis (FFDM) was compared between patients with and without pCR using the Kaplan-Meier method. In patients without pCR, univariate and multivariable Cox analyses were used to determine factors predictive of distant metastasis. RESULTS: We identified 153 patients with median follow-up of 4.0 years (range, 0.5-14.0 years). After NAC, 108 had residual disease (pCR, 29%). Five-year FFDM was 98% and 55% in patients with and without pCR, respectively (P<.001). Factors independently predicting FFDM in patients without pCR were pathologic nodal positivity (hazard ratio, 3.08; 95% CI, 1.54-6.14; P=.001) and lymphovascular space invasion (hazard ratio, 1.91; 95% CI, 1.07-3.43; P=.030). Patients with a greater number of factors had worse FFDM; 5-year FFDM was 76.5% for patients with no factors (n=38) versus 54.9% and 27.5% for patients with 1 (n=44) and 2 factors (n=26), respectively (P<.001). CONCLUSIONS: Lack of pCR after NAC resulted in worse overall survival and FFDM, despite trimodality therapy. In patients with residual disease after NAC, pathologic lymph node positivity and lymphovascular space invasion predicted worse FFDM.

Single-Institution Phase 1/2 Prospective Clinical Trial of Single-Fraction, High-Gradient Adjuvant Partial-Breast Irradiation for Hormone Sensitive Stage 0-I Breast Cancer.

PURPOSE: We sought to evaluate the feasibility and tolerability of a novel accelerated partial breast irradiation regimen delivered in a single fraction postoperatively. METHODS AND MATERIALS: We enrolled 50 patients with low-risk, hormone-sensitive breast cancer from 2015 to 2018 on a prospective phase 1/2 trial to receive single-fraction, high-gradient partial-breast irradiation (SFHGPBI) 2 to 8 weeks after lumpectomy for node-negative, invasive, or in situ breast cancer. The high gradient was achieved by prescribing 20 Gy to the surgical bed and 5 Gy to the breast tissue within 1 cm of the surgical bed simultaneously in 1 fraction using external beam. RESULTS: The median age was 65 (range, 52-84). Ten patients (20%) had small-volume ductal carcinoma in situ while the remainder had stage I disease. At a median follow-up of 25 months, we evaluated toxicity, patient- and physician-reported cosmesis, patient-reported quality of life (QOL), and initial tumor control. There was no Common Terminology Criteria for Adverse Events v4.0 grade 3+ toxicity. Only 34% of patients experienced grade 1 erythema. Good-to-excellent pretreatment cosmesis was present in 100% and 98% per physicians and patients, respectively, and did not change post-SFHGPBI. Quantitative cosmesis by percentage of breast retraction assessment significantly improved over time during the post-SFHGPBI period per mixed repeated measures modeling (P = .0026). QOL per European Organization for Research and Treatment of Cancer QOL Questionnaires C30 and BR-23 did not decline other than temporarily in the systemic therapy effects and hair loss domains, both of which returned to pretreatment values. There was 1 noninvasive in-breast recurrence in a separate untreated quadrant 18 months post-SFHGPBI and 1 isolated axillary recurrence 30 months post-SFHGPBI, both salvaged successfully. There were no distant recurrences or cancer-related deaths observed. CONCLUSIONS: Accelerated partial-breast irradiation delivered in a single fraction postoperatively using external beam techniques is a novel, feasible, well-tolerated regimen. SFHGPBI does not adversely affect cosmesis or QOL as reported by both physicians and patients. Initial tumor control rates are excellent, with longer follow-up required to confirm efficacy.

Long-Term Outcomes with 3-Dimensional Conformal External Beam Accelerated Partial Breast Irradiation.

PURPOSE: Long-term tumor control and cosmetic outcomes for accelerated partial breast radiation (APBI) delivered with 3-dimensional conformal external beam radiation (3D-CRT) remain limited. We seek to address these concerns by reporting our experience of 3D-CRT APBI with extended follow-up. METHODS AND MATERIALS: All patients treated with APBI delivered with 3D-CRT from January 2006 through December 2012 at a single institution were identified. Those with more than a year of follow-up were analyzed for ipsilateral breast tumor recurrence (IBTR), progression-free survival (PFS), cosmesis, and pain. Disease outcomes were analyzed by margin status (<2 mm, ≥2 mm), total radiation dose prescribed, presence of invasive disease, and American Society for Radiation Oncology (ASTRO) 2016 updated consensus groupings (suitable, cautionary, and unsuitable). RESULTS: Two hundred ninety-three patients were identified, of whom 266 had >1 year of follow-up. Median follow-up was 87 months (range, 13-156). Of the 266, 162 (60.9%) were ASTRO "suitable," 87 (32.7%) were "cautionary," and 17 (6.4%) were "unsuitable." Seven-year rates of IBTR and PFS were 1.8% and 95.2%, respectively. Margin status, invasive versus in situ disease, prescribed dose, and ASTRO grouping were not prognostic for either IBTR or PFS on univariate analysis. Cosmesis was good to excellent in 75.2%. Two patients (0.8%) had subsequent plastic surgery owing to poor cosmesis. Narcotic medication for treatment site pain was needed by 6 (2.3%). CONCLUSIONS: External beam APBI results in excellent long-term disease control. Good to excellent cosmetic outcomes are achieved in most patients, although increasing dose per fraction and greater percentage of irradiated breast were predictive of adverse posttreatment cosmetic outcomes. Select patients in "cautionary" and "unsuitable" consensus groupings do not appear to have inferior outcomes.

Repeat stereotactic body radiation therapy (SBRT) for salvage of isolated local recurrence after definitive lung SBRT.

PURPOSE: Optimal management of isolated local recurrences after stereotactic body radiation therapy (SBRT) for early non-small cell lung cancer (NSCLC) is unknown and literature describing repeat SBRT for in-field recurrences after initial SBRT are sparse. We investigate the safety and efficacy of salvage SBRT for isolated local failures after initial SBRT for NSCLC. METHODS/MATERIALS: Patients receiving SBRT for isolated local recurrence after initial SBRT for early NSCLC were identified using a prospective registry. Both courses were 3-5 fractions with a biologically effective dose (BED10) of ≥100 Gy. Local failure was defined as within 1 cm of the initial planning target volume (PTV) or an overlap of the ≥25% isodose lines of the first and second treatments. Failures >1 cm beyond the PTV and without ≥25% overlap, or with additional recurrence sites were excluded. Kaplan-Meier analysis was used to estimate survival. RESULTS: A total 21 patients receiving salvage SBRT from 2008 to 2017 were identified. Median interval from initial SBRT to salvage SBRT was 23 months (7-52). Six patients (29%) had central tumors. Median follow-up time from salvage SBRT was 24 months (3-60). Median overall survival after salvage was 39 months. After reirradiation, two-year primary tumor control was 81%, regional nodal control was 89%, distant control was 75% and overall survival was 68%. Grade 2 pneumonitis occurred in 2 patients (10%) and grade 2 chest wall toxicity in 4 patients (19%). No grade 3+ toxicity was observed. CONCLUSIONS: Salvage SBRT for isolated local failures after initial SBRT appears safe, with low treatment-related toxicity and encouraging rates of tumor control.

Treatment patterns of high-dose-rate and low-dose-rate brachytherapy as monotherapy for prostate cancer.

PURPOSE: Monotherapy with high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy are both recommended modalities for prostate cancer. The choice between HDR and LDR is dependent on patient, physician, and hospital preferences. We sought to identify treatment patterns and factors associated with receipt of HDR or LDR monotherapy. MATERIAL AND METHODS: We queried the National Cancer Database (NCDB) for patients with localized low- or intermediate-risk prostate cancer treated with HDR or LDR monotherapy. Descriptive statistics were used to analyze patterns of HDR vs. LDR. Patient characteristics were correlated with HDR vs. LDR using multivariable logistic regression. RESULTS: We identified 50,326 patients from 2004-2014: LDR 37,863 (75.2%) vs. HDR 12,463 (24.8%). Median follow-up was 70.3 months. The overall use of monotherapy declined over time. HDR application declined relative to LDR. In 2004, 27.0% of cases were HDR compared to 19.2% in 2014. Factors associated with increased likelihood of HDR on multivariable analysis included: increasing age (OR: 1.01, 95% CI: 1.01-1.01), cT2c disease (OR: 1.25, 95% CI: 1.11-1.41), treatment at an academic center (OR: 2.45, 95% CI: 2.24-2.65), non-white race (OR: 1.34, 95% CI: 1.27-1.42), and income > $63,000 (OR: 1.73, 95% CI: 1.59-1.88). LDR was more common in 2010-2014 (OR: 0.59, 95% CI: 0.54-0.65), Charlson-Deyo comorbidity index > 0 (OR: 0.89, 95% CI: 0.84-0.95), and for patients receiving hormone therapy (OR: 0.88, 95% CI: 0.83-0.93). No difference in prostate-specific antigen (PSA) or Gleason score and receipt of HDR vs. LDR was observed. Mean overall survival was 127.0 months for HDR and 125.4 for LDR, and was not statistically different. CONCLUSIONS: We observed an overall decrease in brachytherapy (BT) monotherapy use since 2004 for localized prostate cancer. Despite similar survival outcomes, the use of HDR monotherapy declined relative to LDR.

Synthetic CT reconstruction using a deep spatial pyramid convolutional framework for MR-only breast radiotherapy.

PURPOSE: The superior soft-tissue contrast achieved using magnetic resonance imaging (MRI) compared to x-ray computed tomography (CT) has led to the popularization of MRI-guided radiation therapy (MR-IGRT), especially in recent years with the advent of first and second generation MRI-based therapy delivery systems for MR-IGRT. The expanding use of these systems is driving interest in MRI-only RT workflows in which MRI is the sole imaging modality used for treatment planning and dose calculations. To enable such a workflow, synthetic CT (sCT) data must be generated based on a patient's MRI data so that dose calculations may be performed using the electron density information derived from CT images. In this study, we propose a novel deep spatial pyramid convolutional framework for the MRI-to-CT image-to-image translation task and compare its performance to the well established U-Net architecture in a generative adversarial network (GAN) framework. METHODS: Our proposed framework utilizes atrous convolution in a method named atrous spatial pyramid pooling (ASPP) to significantly reduce the total number of parameters required to describe the model while effectively capturing rich, multi-scale structural information in a manner that is not possible in the conventional framework. The proposed framework consists of a generative model composed of stacked encoders and decoders separated by the ASPP module, where atrous convolution is applied at increasing rates in parallel to encode large-scale features. The performance of the proposed method is compared to that of the conventional GAN framework in terms of the time required to train the model and the image quality of the generated sCT as measured by the root mean square error (RMSE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR) depending on the size of the training data set. Dose calculations based on sCT data generated using the proposed architecture are also compared to clinical plans to evaluate the dosimetric accuracy of the method. RESULTS: Significant reductions in training time and improvements in image quality are observed at every training data set size when the proposed framework is adopted instead of the conventional framework. Over 1042 test images, values of 17.7 ± 4.3 HU, 0.9995 ± 0.0003, and 71.7 ± 2.3 are observed for the RMSE, SSIM, and PSNR metrics, respectively. Dose distributions calculated based on sCT data generated using the proposed framework demonstrate passing rates equal to or greater than 98% using the 3D gamma index with a 2%/2 mm criterion. CONCLUSIONS: The deep spatial pyramid convolutional framework proposed here demonstrates improved performance compared to the conventional GAN framework that has been applied to the image-to-image translation task of sCT generation. Adopting the method is a first step toward an MRI-only RT workflow that enables widespread clinical applications for MR-IGRT including online adaptive therapy.

A clinical case-control comparison of epidermal innervation density in Rett syndrome.

INTRODUCTION: Rett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10-15,000 female live births), is most often caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT. METHODS: We compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients (N = 4, aged 12-19 years) against an archived approximate age-, sex-, body-site matched comparison sample of healthy adolescent females (N = 8, ages 11-17). RESULTS: Confocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co-stained calcitonin gene-related protein [CGRP]) innervation density compared with healthy female control individuals. CONCLUSIONS: Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.