A roadmap for modelling radiation-induced cardiac disease.

Cardiac risk mitigation is a major priority in improving outcomes for cancer survivors as advances in cancer screening and treatments continue to decrease cancer mortality. More than half of adult cancer patients will be treated with radiotherapy (RT); therefore it is crucial to develop a framework for how to assess and predict radiation-induced cardiac disease (RICD). Historically, RICD was modelled solely using whole heart metrics such as mean heart dose. However, data over the past decade has identified cardiac substructures which outperform whole heart metrics in predicting for significant cardiac events. Additionally, non-RT factors such as pre-existing cardiovascular risk factors and toxicity from other therapies contribute to risk of future cardiac events. In this review, we aim to discuss the current evidence and knowledge gaps in predicting RICD and provide a roadmap for the development of comprehensive models based on three interrelated components, (1) baseline CV risk assessment, (2) cardiac substructure radiation dosimetry linked with cardiac-specific outcomes and (3) novel biomarker development.

Feasibility of Left Anterior Descending Coronary Artery Sparing Radiotherapy for Locally Advanced Lung Cancer.

PURPOSE: Efforts to mitigate radiotherapy (RT) associated cardiotoxicity have focused on constraining mean heart dose (MHD). However, recent studies have shown greater predictive power with cardiac substructure dose metrics such as the left anterior descending (LAD) coronary artery volume (V) receiving 15Gy (V15Gy) ≥10%. Herein, we investigated the feasibility of LAD radiation sparing in contemporary IMRT/VMAT lung cancer plans. METHODS AND MATERIALS: Single institution retrospective analysis of 54 locally advanced lung cancer patients treated with thoracic RT between February 2018-August 2021. After excluding 33 (5=non-IMRT/VMAT or intentionally LAD-optimized; 28=LAD V15Gy<10%), 21 plans with LAD V15Gy ≥10% were identified for LAD re-optimization with intent to meet LAD V15Gy <10% while maintaining meeting organ-at-risk (OAR) metrics and target coverage with original plan parameters. Dosimetric variables were compared using paired t tests. RESULTS: Most (57.1%, 12/21) were treated with definitive RT, 8/21 (38.1%) with post-operative RT, and one with neoadjuvant RT. The median prescribed RT dose was 60Gy (range 50.4-66Gy) in 30 fractions (range 28-33). LAD re-optimized plans (vs original) led to significant reductions in mean LAD V15Gy (39.4% ±13.9% vs 9.4% ±13.0%; p<0.001) and mean LAD dose (12.9Gy ± 4.6Gy vs 7.6Gy ±2.8Gy; p<0.001). Most (85.7%; 18/21) LAD re-optimized plans achieved LAD V15Gy <10%. There were no statistically significant differences in overall lung, esophageal, or spinal cord dose metrics. Only one re-optimization (1/21) exceeded an OAR constraint that was initially met in the original plan. CONCLUSIONS: To our knowledge, this is the first report describing the feasibility of LAD-optimized lung cancer RT planning using the newly identified LAD V15 Gy constraint. We observed that LAD V15Gy <10% is achievable in more than 85% of plans initially exceeding this constraint, with minimal dosimetric tradeoffs. Our results support the feasibility of routine incorporation of the LAD as an OAR in modern thoracic IMRT/VMAT planning.

True Rate of Allergy among Pediatric Inpatients with Penicillin Allergy Labels (TRIAL).

Background: Penicillin allergy is a common drug allergy diagnosis in pediatric patients; however, upon appropriate allergy testing, many of these patients are found not to have a true allergy. For patients with a reported allergy, alternative antibiotics are prescribed, which are less effective, more toxic, or more expensive. There is a lack of data evaluating allergies in hospitalized children and comparing allergy assessments conducted by pediatric allergists and pharmacists. Objective: To estimate the percentage of pediatric patients admitted with reported penicillin allergy who did not have a true penicillin allergy. Methods: This single-centre prospective cohort study included inpatients between 6 months and 17 years of age, with a documented penicillin allergy, who were admitted to the general pediatric and oncology units of a tertiary care children's hospital between November 2019 and March 2023. The allergy history, evaluation, and risk categorization were performed by pharmacists. The history was reviewed with the allergist, and the patient was then referred, underwent skin testing, or received oral amoxicillin challenge with monitoring for 1 hour. Results: Thirty patients were included, of whom 29 (97%) had delabelling of their penicillin allergy. Four patients (13%) had delabelling on the basis of history alone, without risk assessment. Twenty-five (83%) of the patients were assessed as having low risk; 24 of these had delabelling following oral challenge, and 1 did not complete the oral challenge because of transfer to another hospital. One patient (3%) was assessed as having moderate risk, with delabelling on the basis of results of skin testing and oral challenge. The pharmacist's and allergist's risk assessments were in agreement in 29 (97%) of the 30 cases. Conclusions: Pediatric patients, including those with oncologic malignancies, are often mislabelled as having a penicillin allergy. Pharmacists are able to accurately determine true allergy risk and delabel penicillin allergies for pediatric patients in the hospital setting.

Contexte: L'allergie à la pénicilline est un diagnostic d'allergie médicamenteuse courant chez les patients pédiatriques; cependant, après des tests d'allergie appropriés, bon nombre de ces patients ne présentent pas de véritable allergie. Pour ceux présentant une allergie signalée, des antibiotiques alternatifs sont prescrits, moins efficaces, plus toxiques ou plus coûteux. Peu de données permettent d'évaluer les allergies chez les enfants hospitalisés et de comparer les évaluations des allergies réalisées par les allergologues pédiatriques et les pharmaciens. Objectif: Estimer le pourcentage de patients pédiatriques admis avec une allergie à la pénicilline signalée, mais qui n'avaient pas de véritable allergie à la pénicilline. Méthodologie: Cette étude de cohorte prospective monocentrique comprenait des patients hospitalisés âgés de 6 mois à 17 ans, présentant une allergie documentée à la pénicilline, qui ont été admis dans les unités de pédiatrie générale et d'oncologie d'un hôpital pour enfants de soins tertiaires entre novembre 2019 et mars 2023. Les antécédents, l'évaluation et la catégorisation des risques de l'allergie ont été renseignés par les pharmaciens. L'anamnèse a été revue avec l'allergologue, et le patient a ensuite été référé, a subi un test cutané ou a reçu une provocation orale à l'amoxicilline avec surveillance pendant 1 heure. Résultats: Sur 30 patients inclus, 29 (97 %) ont vu un désétiquetage de leur allergie à la pénicilline. Quatre patients (13 %) ont bénéficié d'un désétiquetage sur la seule base de leurs antécédents, sans évaluation des risques. Vingt-cinq (83 %) patients ont été évalués comme présentant un faible risque; 24 d'entre eux ont bénéficié d'un désétiquetage à la suite d'une provocation orale, et 1 n'a pas terminé la provocation orale en raison d'un transfert vers un autre hôpital. Un patient (3 %) a été évalué comme présentant un risque modéré, avec un désétiquetage basé sur les résultats des tests cutanés et de la provocation orale. Les évaluations des risques par le pharmacien et l'allergologue concordaient dans 29 (97 %) des 30 cas. Conclusions: Les patients pédiatriques, y compris ceux atteints de cancers malins, sont souvent étiquetés à tort comme ayant une allergie à la pénicilline. Les pharmaciens sont en mesure de déterminer avec précision le risque réel d'allergie et de désétiqueter les allergies à la pénicilline chez les patients pédiatriques en milieu hospitalier.

Lung sparing in MR-guided non-adaptive SBRT treatment of peripheral lung tumors.

Objective.We aim to: (1) quantify the benefits of lung sparing using non-adaptive magnetic resonance guided stereotactic body radiotherapy (MRgSBRT) with advanced motion management for peripheral lung cancers compared to conventional x-ray guided SBRT (ConvSBRT); (2) establish a practical decision-making guidance metric to assist a clinician in selecting the appropriate treatment modality.Approach.Eleven patients with peripheral lung cancer who underwent breath-hold, gated MRgSBRT on an MR-guided linear accelerator (MR linac) were studied. Four-dimensional computed tomography (4DCT)-based retrospective planning using an internal target volume (ITV) was performed to simulate ConvSBRT, which were evaluated against the original MRgSBRT plans. Metrics analyzed included planning target volume (PTV) coverage, various lung metrics and the generalized equivalent unform dose (gEUD). A dosimetric predictor for achievable lung metrics was derived to assist future patient triage across modalities.Main results.PTV coverage was high (median V100% > 98%) and comparable for both modalities. MRgSBRT had significantly lower lung doses as measured by V20 (median 3.2% versus 4.2%), mean lung dose (median 3.3 Gy versus 3.8 Gy) and gEUD. Breath-hold, gated MRgSBRT resulted in an average reduction of 47% in PTV volume and an average increase of 19% in lung volume. Strong correlation existed between lung metrics and the ratio of PTV to lung volumes (RPTV/Lungs) for both modalities, indicating that RPTV/Lungsmay serve as a good predictor for achievable lung metrics without the need for pre-planning. A threshold value of RPTV/Lungs< 0.035 is suggested to achieve V20 < 10% using ConvSBRT. MRgSBRT should otherwise be considered if the threshold cannot be met.Significance.The benefits of lung sparing using MRgSBRT were quantified for peripheral lung tumors; RPTV/Lungswas found to be an effective predictor for achievable lung metrics across modalities. RPTV/Lungscan assist a clinician in selecting the appropriate modality without the need for labor-intensive pre-planning, which has significant practical benefit for a busy clinic.

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

BACKGROUND: The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. PATIENTS AND METHODS: Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. RESULTS: Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. CONCLUSION: We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.

Body Composition in Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy.

Importance: The association between body composition (BC) and cancer outcomes is complex and incompletely understood. Previous research in non-small-cell lung cancer (NSCLC) has been limited to small, single-institution studies and yielded promising, albeit heterogeneous, results. Objectives: To evaluate the association of BC with oncologic outcomes in patients receiving immunotherapy for advanced or metastatic NSCLC. Design, Setting, and Participants: This comprehensive multicohort analysis included clinical data from cohorts receiving treatment at the Dana-Farber Brigham Cancer Center (DFBCC) who received immunotherapy given alone or in combination with chemotherapy and prospectively collected data from the phase 1/2 Study 1108 and the chemotherapy arm of the phase 3 MYSTIC trial. Baseline and follow-up computed tomography (CT) scans were collected and analyzed using deep neural networks for automatic L3 slice selection and body compartment segmentation (skeletal muscle [SM], subcutaneous adipose tissue [SAT], and visceral adipose tissue). Outcomes were compared based on baseline BC measures or their change at the first follow-up scan. The data were analyzed between July 2022 and April 2023. Main Outcomes and Measures: Hazard ratios (HRs) for the association of BC measurements with overall survival (OS) and progression-free survival (PFS). Results: A total of 1791 patients (878 women [49%]) with NSCLC were analyzed, of whom 487 (27.2%) received chemoimmunotherapy at DFBCC (DFBCC-CIO), 825 (46.1%) received ICI monotherapy at DFBCC (DFBCC-IO), 222 (12.4%) were treated with durvalumab monotherapy on Study 1108, and 257 (14.3%) were treated with chemotherapy on MYSTIC; median (IQR) ages were 65 (58-74), 66 (57-71), 65 (26-87), and 63 (30-84) years, respectively. A loss in SM mass, as indicated by a change in the L3 SM area, was associated with worse oncologic outcome across patient groups (HR, 0.59 [95% CI, 0.43-0.81] and 0.61 [95% CI, 0.47-0.79] for OS and PFS, respectively, in DFBCC-CIO; HR, 0.74 [95% CI, 0.60-0.91] for OS in DFBCC-IO; HR, 0.46 [95% CI, 0.33-0.64] and 0.47 [95% CI, 0.34-0.64] for OS and PFS, respectively, in Study 1108; HR, 0.76 [95% CI, 0.61-0.96] for PFS in the MYSTIC trial). This association was most prominent among male patients, with a nonsignificant association among female patients in the MYSTIC trial and DFBCC-CIO cohorts on Kaplan-Meier analysis. An increase of more than 5% in SAT density, as quantified by the average CT attenuation in Hounsfield units of the SAT compartment, was associated with poorer OS in 3 patient cohorts (HR, 0.61 [95% CI, 0.43-0.86] for DFBCC-CIO; HR, 0.62 [95% CI, 0.49-0.79] for DFBCC-IO; and HR, 0.56 [95% CI, 0.40-0.77] for Study 1108). The change in SAT density was also associated with PFS for DFBCC-CIO (HR, 0.73; 95% CI, 0.54-0.97). This was primarily observed in female patients on Kaplan-Meier analysis. Conclusions and Relevance: The results of this multicohort study suggest that loss in SM mass during systemic therapy for NSCLC is a marker of poor outcomes, especially in male patients. SAT density changes are also associated with prognosis, particularly in female patients. Automated CT-derived BC measurements should be considered in determining NSCLC prognosis.

Biomarkers associated with pulmonary exacerbations in a randomized trial of nintedanib for radiation pneumonitis.

BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP. MATERIALS AND METHODS: We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes. RESULTS: Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-ß1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036). CONCLUSION: We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.

Foundation model for cancer imaging biomarkers.

Foundation models in deep learning are characterized by a single large-scale model trained on vast amounts of data serving as the foundation for various downstream tasks. Foundation models are generally trained using self-supervised learning and excel in reducing the demand for training samples in downstream applications. This is especially important in medicine, where large labelled datasets are often scarce. Here, we developed a foundation model for cancer imaging biomarker discovery by training a convolutional encoder through self-supervised learning using a comprehensive dataset of 11,467 radiographic lesions. The foundation model was evaluated in distinct and clinically relevant applications of cancer imaging-based biomarkers. We found that it facilitated better and more efficient learning of imaging biomarkers and yielded task-specific models that significantly outperformed conventional supervised and other state-of-the-art pretrained implementations on downstream tasks, especially when training dataset sizes were very limited. Furthermore, the foundation model was more stable to input variations and showed strong associations with underlying biology. Our results demonstrate the tremendous potential of foundation models in discovering new imaging biomarkers that may extend to other clinical use cases and can accelerate the widespread translation of imaging biomarkers into clinical settings.

Bypassing the build-up phase for oral immunotherapy in shrimp-allergic children.

Background: Oral immunotherapy is an effective treatment for food allergies; however, its use in clinical practice is limited by resources and lack of standardized protocols for foods other than peanut. Previous studies have suggested that shrimp has a higher threshold for reaction than other allergenic foods, suggesting it may be safe to directly administer maintenance doses of immunotherapy. Methods: Children aged 3-17 years who had 1) skin prick test ≥3 mm and/or specific IgE level ≥0.35 kU/L and convincing objective IgE-mediated reaction to shrimp, or 2) no ingestion history and specific IgE level ≥5 kU/L, underwent a low-dose oral food challenge to 300 mg shrimp protein, with the goal of continuing daily ingestion of the 300 mg maintenance dose as oral immunotherapy. Results: Between January 2020 and April 2023, 17 children completed the low-dose oral food challenge. Nine (53%) tolerated this amount with no reaction, and 8 (47%) had a mild reaction (isolated oral pruritis or redness on chin). Sixteen (94%) continued maintenance low-dose oral immunotherapy eating 300 mg shrimp protein daily. None of the patients developed anaphylaxis related to the immunotherapy. Conclusion: Our case series suggests that some shrimp allergic patients being considered for oral immunotherapy should be offered a low-dose oral food challenge, to potentially bypass the build-up phase of immunotherapy.

Safety and Effectiveness of Bypassing Oral Immunotherapy Buildup With an Initial Phase of Sublingual Immunotherapy for Higher-Risk Food Allergy.

BACKGROUND: Because of its favorable safety, sublingual immunotherapy (SLIT) for food allergy has been proposed as an alternative treatment for those in whom oral immunotherapy (OIT) is of higher risk-older children, adolescents, adults, and those with a history of severe reactions. Although safe, SLIT has been shown to be less effective than OIT. OBJECTIVE: To describe the safety of multifood SLIT in pediatric patients aged 4 to 18 years and the effectiveness of bypassing OIT buildup with an initial phase of SLIT. METHODS: Patients aged 4 to 18 years were offered (multi)food SLIT. Patients built up to 2 mg protein SLIT maintenance over the course of 3 to 5 visits under nurse supervision. After 1 to 2 years of daily SLIT maintenance, patients were offered a low-dose oral food challenge (OFC) (cumulative dose, 300 mg protein) with the goal of bypassing OIT buildup. RESULTS: Between summer 2020 and winter 2023, 188 patients were enrolled in SLIT (median age, 11 years). Four patients (2.10%) received epinephrine during buildup and went to the emergency department, but none experienced grade 4 (severe) reaction. A subset of 20 patients had 50 low-dose OFCs to 300 mg protein and 35 (70%) OFCs were successful, thereby bypassing OIT buildup. CONCLUSIONS: In combination with very favorable safety of SLIT, with no life-threatening reactions and few reactions requiring epinephrine, we propose that an initial phase of SLIT to bypass supervised OIT buildup be considered for children in whom OIT is considered to be of higher risk.

Edge roughness quantifies impact of physician variation on training and performance of deep learning auto-segmentation models for the esophagus.

Manual segmentation of tumors and organs-at-risk (OAR) in 3D imaging for radiation-therapy planning is time-consuming and subject to variation between different observers. Artificial intelligence (AI) can assist with segmentation, but challenges exist in ensuring high-quality segmentation, especially for small, variable structures, such as the esophagus. We investigated the effect of variation in segmentation quality and style of physicians for training deep-learning models for esophagus segmentation and proposed a new metric, edge roughness, for evaluating/quantifying slice-to-slice inconsistency. This study includes a real-world cohort of 394 patients who each received radiation therapy (mainly for lung cancer). Segmentation of the esophagus was performed by 8 physicians as part of routine clinical care. We evaluated manual segmentation by comparing the length and edge roughness of segmentations among physicians to analyze inconsistencies. We trained eight multiple- and individual-physician segmentation models in total, based on U-Net architectures and residual backbones. We used the volumetric Dice coefficient to measure the performance for each model. We proposed a metric, edge roughness, to quantify the shift of segmentation among adjacent slices by calculating the curvature of edges of the 2D sagittal- and coronal-view projections. The auto-segmentation model trained on multiple physicians (MD1-7) achieved the highest mean Dice of 73.7 ± 14.8%. The individual-physician model (MD7) with the highest edge roughness (mean ± SD: 0.106 ± 0.016) demonstrated significantly lower volumetric Dice for test cases compared with other individual models (MD7: 58.5 ± 15.8%, MD6: 67.1 ± 16.8%, p < 0.001). A multiple-physician model trained after removing the MD7 data resulted in fewer outliers (e.g., Dice ≤ 40%: 4 cases for MD1-6, 7 cases for MD1-7, Ntotal = 394). While we initially detected this pattern in a single clinician, we validated the edge roughness metric across the entire dataset. The model trained with the lowest-quantile edge roughness (MDER-Q1, Ntrain = 62) achieved significantly higher Dice (Ntest = 270) than the model trained with the highest-quantile ones (MDER-Q4, Ntrain = 62) (MDER-Q1: 67.8 ± 14.8%, MDER-Q4: 62.8 ± 15.7%, p < 0.001). This study demonstrates that there is significant variation in style and quality in manual segmentations in clinical care, and that training AI auto-segmentation algorithms from real-world, clinical datasets may result in unexpectedly under-performing algorithms with the inclusion of outliers. Importantly, this study provides a novel evaluation metric, edge roughness, to quantify physician variation in segmentation which will allow developers to filter clinical training data to optimize model performance.

Large language models to identify social determinants of health in electronic health records.

Social determinants of health (SDoH) play a critical role in patient outcomes, yet their documentation is often missing or incomplete in the structured data of electronic health records (EHRs). Large language models (LLMs) could enable high-throughput extraction of SDoH from the EHR to support research and clinical care. However, class imbalance and data limitations present challenges for this sparsely documented yet critical information. Here, we investigated the optimal methods for using LLMs to extract six SDoH categories from narrative text in the EHR: employment, housing, transportation, parental status, relationship, and social support. The best-performing models were fine-tuned Flan-T5 XL for any SDoH mentions (macro-F1 0.71), and Flan-T5 XXL for adverse SDoH mentions (macro-F1 0.70). Adding LLM-generated synthetic data to training varied across models and architecture, but improved the performance of smaller Flan-T5 models (delta F1 + 0.12 to +0.23). Our best-fine-tuned models outperformed zero- and few-shot performance of ChatGPT-family models in the zero- and few-shot setting, except GPT4 with 10-shot prompting for adverse SDoH. Fine-tuned models were less likely than ChatGPT to change their prediction when race/ethnicity and gender descriptors were added to the text, suggesting less algorithmic bias (p < 0.05). Our models identified 93.8% of patients with adverse SDoH, while ICD-10 codes captured 2.0%. These results demonstrate the potential of LLMs in improving real-world evidence on SDoH and assisting in identifying patients who could benefit from resource support.

Widening the therapeutic window for central and ultra-central thoracic oligometastatic disease with stereotactic MR-guided adaptive radiation therapy (SMART).

BACKGROUND/PURPOSE: Central/ultra-central thoracic tumors are challenging to treat with stereotactic radiotherapy due potential high-grade toxicity. Stereotactic MR-guided adaptive radiation therapy (SMART) may improve the therapeutic window through motion control with breath-hold gating and real-time MR-imaging as well as the option for daily online adaptive replanning to account for changes in target and/or organ-at-risk (OAR) location. MATERIALS/METHODS: 26 central (19 ultra-central) thoracic oligoprogressive/oligometastatic tumors treated with isotoxic (OAR constraints-driven) 5-fraction SMART (median 50 Gy, range 35-60) between 10/2019-10/2022 were reviewed. Central tumor was defined as tumor within or touching 2 cm around proximal tracheobronchial tree (PBT) or adjacent to mediastinal/pericardial pleura. Ultra-central was defined as tumor abutting the PBT, esophagus, or great vessel. Hard OAR constraints observed were ≤ 0.03 cc for PBT V40, great vessel V52.5, and esophagus V35. Local failure was defined as tumor progression/recurrence within the planning target volume. RESULTS: Tumor abutted the PBT in 31 %, esophagus in 31 %, great vessel in 65 %, and heart in 42 % of cases. 96 % of fractions were treated with reoptimized plan, necessary to meet OAR constraints (80 %) and/or target coverage (20 %). Median follow-up was 19 months (27 months among surviving patients). Local control (LC) was 96 % at 1-year and 90 % at 2-years (total 2/26 local failure). 23 % had G2 acute toxicities (esophagitis, dysphagia, anorexia, nausea) and one (4 %) had G3 acute radiation dermatitis. There were no G4-5 acute toxicities. There was no symptomatic pneumonitis and no G2 + late toxicities. CONCLUSION: Isotoxic 5-fraction SMART resulted in high rates of LC and minimal toxicity. This approach may widen the therapeutic window for high-risk oligoprogressive/oligometastatic thoracic tumors.

Stereotactic Magnetic Resonance-guided Adaptive Radiation Therapy for Localized Kidney Cancer: Early Outcomes from a Prospective Phase 1 Trial and Supplemental Cohort.

Stereotactic magnetic resonance (MR)-guided adaptive radiotherapy (SMART) for renal cell carcinoma may result in more precise treatment delivery through the capabilities for improved image quality, daily adaptive planning, and accounting for respiratory motion during treatment with real-time MR tracking. In this study, we aimed to characterize the safety and feasibility of SMART for localized kidney cancer. Twenty patients with localized kidney cancer (ten treated in a prospective phase 1 trial and ten in the supplemental cohort) were treated to 40 Gy in five fractions on a 0.35 T MR-guided linear accelerator with daily adaptive planning and a cine MR-guided inspiratory breath hold technique. The median follow-up time was 17 mo (interquartile range: 13-20 months). A single patient developed local failure at 30 mo. No grade ≥3 adverse events were reported. The mean decrease in estimated glomerular filtration rate was -1.8 ml/min/1.73 m2 (95% confidence interval or CI [-6.6 to 3.1 ml/min/1.73 m2]), and the mean decrease in tumor diameter was -0.20 cm (95% CI [-0.6 to 0.2 cm]) at the last follow-up. Anterior location and overlap of the 25 or 28 Gy isodose line with gastrointestinal organs at risk were predictive of the benefit from online adaptive planning. Kidney SMART is feasible and, at the early time point evaluated in this study, was well tolerated with minimal decline in renal function. More studies are warranted to further evaluate the safety and efficacy of this technique. PATIENT SUMMARY: For patients with localized renal cell carcinoma who are not surgical candidates, stereotactic magnetic resonance--guided adaptive radiotherapy is a feasible and safe noninvasive treatment option that results in minimal impact on kidney function.

Automated temporalis muscle quantification and growth charts for children through adulthood.

Lean muscle mass (LMM) is an important aspect of human health. Temporalis muscle thickness is a promising LMM marker but has had limited utility due to its unknown normal growth trajectory and reference ranges and lack of standardized measurement. Here, we develop an automated deep learning pipeline to accurately measure temporalis muscle thickness (iTMT) from routine brain magnetic resonance imaging (MRI). We apply iTMT to 23,876 MRIs of healthy subjects, ages 4 through 35, and generate sex-specific iTMT normal growth charts with percentiles. We find that iTMT was associated with specific physiologic traits, including caloric intake, physical activity, sex hormone levels, and presence of malignancy. We validate iTMT across multiple demographic groups and in children with brain tumors and demonstrate feasibility for individualized longitudinal monitoring. The iTMT pipeline provides unprecedented insights into temporalis muscle growth during human development and enables the use of LMM tracking to inform clinical decision-making.

Safety and effectiveness of the Canadian food ladders for children with IgE-mediated food allergies to cow's milk and/or egg.

BACKGROUND: Food ladders are tools designed to facilitate home-based dietary advancement in children with food allergies through stepwise exposures to increasingly allergenic forms of milk and egg. Several studies have now documented safety and efficacy of food ladders. In 2021, we published a Canadian adaptation of the previously existing milk and egg ladders originating in Europe using foods more readily available/consumed in Canada. Our study adds to the growing body of evidence supporting food ladder use and provides safety and effectiveness data for our Canadian adaptation of the milk and egg ladders. METHODS: Surveys were distributed to families of children using the Canadian Milk Ladder and/or the Canadian Egg Ladder at baseline, with follow up surveys at 3 months, 6 months, and 12 months. Data were analyzed using REDCap and descriptive and inferential statistics are presented. RESULTS: One hundred and nine participants were started on milk/egg ladders between September 2020 and June 2022. 53 participants responded to follow up surveys. Only 2 of 53 (3.8%) participants reported receiving epinephrine during the study. Severe grade 4 reactions (defined according to the modified World Allergy Organization grading system) were not reported by any participants. Minor cutaneous adverse reactions were common, with about 71% (n = 10/14) of respondents reporting cutaneous adverse reactions by 1 year of food ladder use. An increasing proportion of participants could tolerate most foods from steps 2-4 foods after 3, 6, and 12 months of the food ladder compared to baseline. CONCLUSION: The Canadian food ladders are safe tools for children with cow's milk and/or egg allergies, and participants tolerated a larger range of foods with food ladder use compared to baseline.

Risk factors associated with safety of preschool peanut oral immunotherapy.

Background: An understanding of how patient characteristics such as age, baseline peanut-specific IgE, and atopic comorbidities may influence potential safety outcomes during peanut oral immunotherapy (P-OIT) could aid in shared decision making between clinicians and patient families. Objective: This study explored the relationship between baseline patient characteristics and reactions during P-OIT using a large sample size to better understand potential risk factors influencing P-OIT safety. Methods: Data were obtained from the Food Allergy Immunotherapy (FAIT) registry, which collects real-world OIT data from community and academic allergy clinics across Canada. Multivariable logistic regression modeling was performed to examine the relationship between baseline patient characteristics and reactions during P-OIT. Multiple imputation was applied to reduce potential bias caused by missingness and to maximize the use of available information to preserve statistical power. Results: Between April 2017 and June 2021, a total of 653 eligible patients initiated P-OIT. Multivariable regression analysis showed pre-OIT grade 2+ initial reaction (odds ratio [OR] = 1.33, 95% confidence interval [CI] 1.10, 1.61), allergic rhinitis (OR = 1.60, 95% CI 1.08, 2.38), older age (OR = 1.01, 95% CI 1.00, 1.02), and higher baseline peanut-specific IgE (OR = 1.02, 95% CI 1.02, 1.03) were associated with grade 2+ reaction during P-OIT after adjusting for potential risk factors. Conclusion: Our study identified several clinically important risk factors for grade 2+ reactions during P-OIT: pre-OIT grade 2+ initial reaction, allergic rhinitis, older age, and higher baseline peanut-specific IgE. These results highlight the need for individualized risk stratification for OIT.