A Prospective Study on Deep Inspiration Breath Hold Thoracic Radiation Therapy Guided by Bronchoscopically Implanted Electromagnetic Transponders.

BACKGROUND: Electromagnetic transponders bronchoscopically implanted near the tumor can be used to monitor deep inspiration breath hold (DIBH) for thoracic radiation therapy (RT). The feasibility and safety of this approach require further study. METHODS: We enrolled patients with primary lung cancer or lung metastases. Three transponders were implanted near the tumor, followed by simulation with DIBH, free breathing, and 4D-CT as backup. The initial gating window for treatment was ±5 mm; in a second cohort, the window was incrementally reduced to determine the smallest feasible gating window. The primary endpoint was feasibility, defined as completion of RT using transponder-guided DIBH. Patients were followed for assessment of transponder- and RT-related toxicity. RESULTS: We enrolled 48 patients (35 with primary lung cancer and 13 with lung metastases). The median distance of transponders to tumor was 1.6 cm (IQR 0.6-2.8 cm). RT delivery ranged from 3 to 35 fractions. Transponder-guided DIBH was feasible in all but two patients (96% feasible), where it failed because the distance between the transponders and the antenna was >19 cm. Among the remaining 46 patients, 6 were treated prone to keep the transponders within 19 cm of the antenna, and 40 were treated supine. The smallest feasible gating window was identified as ±3 mm. Thirty-nine (85%) patients completed one year of follow-up. Toxicities at least possibly related to transponders or the implantation procedure were grade 2 in six patients (six incidences, cough and hemoptysis), grade 3 in three patients (five incidences, cough, dyspnea, pneumonia, and supraventricular tachycardia), and grade 4 pneumonia in one patient (occurring a few days after implantation but recovered fully and completed RT). Toxicities at least possibly related to RT were grade 2 in 18 patients (41 incidences, most commonly cough, fatigue, and pneumonitis) and grade 3 in four patients (seven incidences, most commonly pneumonia), and no patients had grade 4 or higher toxicity. CONCLUSIONS: Bronchoscopically implanted electromagnetic transponder-guided DIBH lung RT is feasible and safe, allowing for precise tumor targeting and reduced normal tissue exposure. Transponder-antenna distance was the most common challenge due to a limited antenna range, which could sometimes be circumvented by prone positioning.

Stereotactic Body Radiation Therapy for Stage IIA to IIIA Inoperable Non-Small Cell Lung Cancer: A Phase 1 Dose-Escalation Trial.

PURPOSE: Larger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase 1 trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3 cm. METHODS AND MATERIALS: A 3 + 3 dose-escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3 cm (T2-4) were eligible. Select ipsilateral hilar and single-station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute grade (G) 4+ or persistent G3 toxicities (Common Terminology Criteria for Adverse Events version 4.03). Secondary endpoints included local failure (LF), distant metastases, disease progression, and overall survival. RESULTS: The median age was 80 years; tumor size was >3 cm and ≤5 cm in 20 (59%) and >5 cm in 14 patients (41%). In cohort A (n = 9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose-expansion cohort B (n = 25), no radiation therapy-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year overall survival was 53%. A biologically effective dose (BED) <100 Gy was associated with higher LF (P = .006); advanced stage and higher neutrophil/lymphocyte ratio were associated with greater disease progression (both P = .004). CONCLUSIONS: Fifty Gy in 5 fractions is the MTD for SBRT to tumors >3 cm. A higher BED is associated with fewer LFs even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy.

A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma.

Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma. Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT. Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2). Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study.

Four-Dimensional Computed Tomography-Based Correlation of Respiratory Motion of Lung Tumors With Implanted Fiducials and an External Surrogate.

PURPOSE: Our purpose was to assess the suitability of airway-implanted internal fiducial markers and an external surrogate of respiratory motion for motion management during radiation therapy of lung tumors. METHODS AND MATERIALS: We analyzed 4-dimensional computed tomography scans acquired during radiation therapy simulation for 28 patients with lung tumors who had anchored fiducial markers bronchoscopically implanted inside small airways in or near the tumor in a prospective trial. We used a linear mixed model to build population-based correlative models of tumor and surrogate motion. The first 24 of the 28 patients were used to build correlative models, and 4 of the 28 consecutive patients were excluded and used as an internal validation cohort. Of the 24 patients from the model building cohort, all were used for the models based on the internal fiducial. The external surrogate was completely visualized in 11 patients from the model building cohort, so only those were used for the models based on the external surrogate. Furthermore, we determined the predicted residual error sum of squares for our correlative models, which may serve as benchmarks for future research. RESULTS: The motion of the internal fiducials was significantly associated with the tumor motion in the anterior-posterior (P < .0001) and superior-inferior (SI) directions (P < .0001). We also observed a strong correlation of the external surrogate anterior-posterior motion to the tumor dominant SI motion (P < .0001). In the validation cohort, the internal fiducial SI motion was the only reliable predictor of lung tumor motion. CONCLUSIONS: The internal fiducials appear to be more reliable predictors of lung tumor motion than the external surrogate. The suitability of such airway-implanted internal fiducial markers for advanced motion management techniques should be further investigated. Although the external surrogate seems to be less reliable, its wide availability and noninvasive application support its clinical utility, albeit the greater uncertainty will need to be compensated for.

Community Veterinary Medicine Programs: Pet Owners' Perceptions and Experiences.

Many American pet owners struggle financially, and the COVID-19 pandemic has only exacerbated this problem. Yet, the positive effects that companion animals have in people's lives create the need for supportive systems to ensure that financial limitations, and other barriers, do not preclude pet ownership. To help address these barriers, and reach underserved communities, various forms of community-based veterinary medicine programs have been developed across the country. This study assesses two community-based veterinary programs in North Carolina, USA. In addition to perceptions surrounding veterinary services, this study paid specific attention to communication and respect; two additional elements needed for successful community-based veterinary programs. Surveys were given to clients accessing Asheville Humane Society (AHS) mobile veterinary care clinic and Asheville Humane Society (AHS) Affordable Pet Care Clinic. Results of the anonymous survey indicate that the majority of clients had positive veterinary care experiences in terms of both veterinary services and client communication. In conclusion, low-cost or free community veterinary programs-with effective communication, empathy, and cultural competence-can help open the door to future positive veterinary experiences for disadvantaged pet owners.

Predictive Modeling of Thoracic Radiotherapy Toxicity and the Potential Role of Serum Alpha-2-Macroglobulin.

Background: To investigate the impact of alpha-2-macroglobulin (A2M), a suspected intrinsic radioprotectant, on radiation pneumonitis and esophagitis using multifactorial predictive models. Materials and Methods: Baseline A2M levels were obtained for 258 patients prior to thoracic radiotherapy (RT). Dose-volume characteristics were extracted from treatment plans. Spearman's correlation (Rs) test was used to correlate clinical and dosimetric variables with toxicities. Toxicity prediction models were built using least absolute shrinkage and selection operator (LASSO) logistic regression on 1,000 bootstrapped datasets. Results: Grade ≥2 esophagitis and pneumonitis developed in 61 (23.6%) and 36 (14.0%) patients, respectively. The median A2M level was 191 mg/dL (range: 94-511). Never/former/current smoker status was 47 (18.2%)/179 (69.4%)/32 (12.4%). We found a significant negative univariate correlation between baseline A2M levels and esophagitis (Rs = -0.18/p = 0.003) and between A2M and smoking status (Rs = 0.13/p = 0.04). Further significant parameters for grade ≥2 esophagitis included age (Rs = -0.32/p < 0.0001), chemotherapy use (Rs = 0.56/p < 0.0001), dose per fraction (Rs = -0.57/p < 0.0001), total dose (Rs = 0.35/p < 0.0001), and several other dosimetric variables with Rs > 0.5 (p < 0.0001). The only significant non-dosimetric parameter for grade ≥2 pneumonitis was sex (Rs = -0.32/p = 0.037) with higher risk for women. For pneumonitis D15 (lung) (Rs = 0.19/p = 0.006) and D45 (heart) (Rs = 0.16/p = 0.016) had the highest correlation. LASSO models applied on the validation data were statistically significant and resulted in areas under the receiver operating characteristic curve of 0.84 (esophagitis) and 0.78 (pneumonitis). Multivariate predictive models did not require A2M to reach maximum predictive power. Conclusion: This is the first study showing a likely association of higher baseline A2M values with lower risk of radiation esophagitis and with smoking status. However, the baseline A2M level was not a significant risk factor for radiation pneumonitis.

Correlation Between Tumor Metabolism and Semiquantitative Perfusion Magnetic Resonance Imaging Metrics in Non-Small Cell Lung Cancer.

PURPOSE: To correlate semiquantitative parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) for non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Twenty-four NSCLC patients who underwent pretreatment 18F-FDG-PET and DCE-MRI were analyzed. The maximum standardized uptake value (SUVmax) was measured from 18F-FDG-PET. Dynamic contrast-enhanced MRI was obtained on a 3T MRI scanner using 4-dimensional T1-weighted high-resolution imaging with a volume excitation sequence. The DCE-MRI parameters, consisting of mean, median, standard deviation (SD), and median absolute deviation (MAD) of peak enhancement, time to peak (TTP), time to half peak (TTHP), wash-in slope (WIS), wash-out slope (WOS), initial gradient, wash-out gradient, signal enhancement ratio, and initial area under the relative signal enhancement curve taken up to 30, 60, 90, 120, 150, and 180 seconds, TTP, and TTHP (IAUCtthp), were calculated for each lesion. Univariate analysis (UVA) was performed using Spearman correlation. A linear regression model to predict SUVmax from DCE-MRI parameters was developed by multivariate analysis (MVA) using least absolute shrinkage selection operator in combination with leave-one-out cross-validation (LOOCV). RESULTS: In UVA, mean(WOS) (ρ = -0.456, P = .025), mean(IAUCtthp) (ρ = -0.439, P = .032), median(IAUCtthp) (ρ = -0.543, P = .006), and MAD(IAUCtthp) (ρ = -0.557, P = .005) were statistically significant; all these parameters were negatively correlated with SUVmax. In MVA, a linear combination of SD(WIS), SD(TTP), MAD(TTHP), and MAD(IAUCtthp) was statistically significant for predicting SUVmax (LOOCV-based adjusted R2 = 0.298, P = .0006). A decrease in SD(WIS), MAD(TTHP), and MAD(IAUCtthp) and an increase in SD(TTP) were associated with a significant increase in SUVmax. CONCLUSION: An association was found between SUVmax, the SD, and MAD of DCE-MRI metrics derived during contrast uptake in NSCLC, reflecting that intratumoral heterogeneity in wash-in contrast kinetics is associated with tumor metabolism. Although MAD(IAUCtthp) was a significant feature in both UVA and MVA, the LASSO-based multivariate regression model yielded better predictability of SUVmax than a univariate regression model using MAD(IAUCtthp). This study will facilitate understanding of the complex relationship between tumor vascularization and metabolism and eventually help in guiding targeted therapy.

Morphologic Features of Magnetic Resonance Imaging as a Surrogate of Capsular Contracture in Breast Cancer Patients With Implant-based Reconstructions.

PURPOSE: Capsular contracture (CC) is a serious complication in patients receiving implant-based reconstruction for breast cancer. Currently, no objective methods are available for assessing CC. The goal of the present study was to identify image-based surrogates of CC using magnetic resonance imaging (MRI). METHODS AND MATERIALS: We analyzed a retrospective data set of 50 patients who had undergone both a diagnostic MRI scan and a plastic surgeon's evaluation of the CC score (Baker's score) within a 6-month period after mastectomy and reconstructive surgery. The MRI scans were assessed for morphologic shape features of the implant and histogram features of the pectoralis muscle. The shape features, such as roundness, eccentricity, solidity, extent, and ratio length for the implant, were compared with the Baker score. For the pectoralis muscle, the muscle width and median, skewness, and kurtosis of the intensity were compared with the Baker score. Univariate analysis (UVA) using a Wilcoxon rank-sum test and multivariate analysis with the least absolute shrinkage and selection operator logistic regression was performed to determine significant differences in these features between the patient groups categorized according to their Baker's scores. RESULTS: UVA showed statistically significant differences between grade 1 and grade ≥2 for morphologic shape features and histogram features, except for volume and skewness. Only eccentricity, ratio length, and volume were borderline significant in differentiating grade ≤2 and grade ≥3. Features with P<.1 on UVA were used in the multivariate least absolute shrinkage and selection operator logistic regression analysis. Multivariate analysis showed a good level of predictive power for grade 1 versus grade ≥2 CC (area under the receiver operating characteristic curve 0.78, sensitivity 0.78, and specificity 0.82) and for grade ≤2 versus grade ≥3 CC (area under the receiver operating characteristic curve 0.75, sensitivity 0.75, and specificity 0.79). CONCLUSIONS: The morphologic shape features described on MR images were associated with the severity of CC. MRI has the potential to further improve the diagnostic ability of the Baker score in breast cancer patients who undergo implant reconstruction.

PIK3CA mutation is associated with increased local failure in lung stereotactic body radiation therapy (SBRT).

OBJECTIVES: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway has been associated with radioresistance. It is unclear whether such mutations confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT). Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT. METHODS: We retrospectively reviewed 166 patients who underwent SBRT to primary or metastatic lung lesions from 2007-2015 for whom genetic testing data was available for EGFR, AKT, and PIK3CA genes. Association between clinical factors, including molecular mutation status, and LF was evaluated. RESULTS: Six patients (4%) had PIK3CA mutation, 36 patients (22%) had EGFR mutation, and one patient (0.6%) had AKT1 mutation. Median lesion size was 2.0 cm (range, 0.6-5.6 cm); median dose was 48Gy in 4 fractions (range, 30-70Gy in 3-10 fractions). Median follow-up for survivors was 27.3 months (range, 3.8-66.7 months). LF occurred in 16 patients (10%). On univariate analysis, PIK3CA mutation was associated with LF (HR 10.44 [95% CI 2.16-50.46], p=0.003), while tumor histology, tumor size, primary tumor site, BED and EGFR mutation were not. At one year, probability of LF in lesions with PIK3CA mutation was 20.0% vs. 2.9% in lesions without mutation (p<0.001 by log rank test). CONCLUSION: Although the number of patients affected was small, PIK3CA mutation was significantly associated with higher risk of LF in patients undergoing lung SBRT. This association has not previously been reported for lung SBRT and indicates the need for further validation.