Protocol: Can coronary artery calcium score identified on thoracic planning CT scans be used and actioned to identify cancer survivors at high risk of cardiac events: A feasibility study in cancer survivors undergoing radiotherapy in Australia.

INTRODUCTION: A coronary artery calcium (CAC) CT scan can identify calcified plaque and predict risk of future cardiac events. Cancer survivors undergoing thoracic radiotherapy routinely undergo a planning CT scan, which presents a unique opportunity to use already obtained medical imaging to identify those at the highest risk of cardiac events. While radiation therapy is an important modality for many cancer treatments, radiation dose to the heart in thoracic radiotherapy leads to cardiotoxicity and may accelerate pre-existing atherosclerosis. The primary aims of this study are to investigate the feasibility of using CAC scores calculated on thoracic radiotherapy planning CT scans to identify a subset of cancer survivors at an increased risk of future cardiac events, and to establish and evaluate a referral pathway for assessment and management in a cardio-oncology clinic. An optional substudy aims to investigate using abdominal aortic calcification (AAC) as a practical, low-radiation alternative to CAC to evaluate and monitor vascular health. METHODS AND ANALYSIS: This is an observational, prospective study in a minimum of 100 cancer survivors commencing radiotherapy. Participants will have CAC scored from thoracic radiotherapy planning CT scans. Those identified as high risk (CAC score>0) will be referred to a cardio-oncology clinic. Feasibility, determined by adherence to the recommended pathway, and impact on quality of life and anxiety measured via questionnaire, will be assessed. Participants in Western Australia will be invited to participate in a 12-month observational pilot substudy, investigating lifestyle behaviours and the use of a dual-energy X-ray absorptiometry machine to measure musculoskeletal health and AAC. ETHICS AND DISSEMINATION: Ethics approval has been obtained from St Vincent's Hospital, Sydney (Project number 2021/ETH11847), GenesisCare and Edith Cowan University (2022-03326-DALLAVIA). Study results will be reported in peer-reviewed academic journals, at scientific conferences, and at clinical forums, irrespective of the results observed. TRIAL REGISTRATION NUMBER: ACTRN12621001343897.

Cardiovascular Manifestations From Therapeutic Radiation: A Multidisciplinary Expert Consensus Statement From the International Cardio-Oncology Society.

Radiation therapy is a cornerstone of cancer therapy, with >50% of patients undergoing therapeutic radiation. As a result of widespread use and improved survival, there is increasing focus on the potential long-term effects of ionizing radiation, especially cardiovascular toxicity. Radiation therapy can lead to atherosclerosis of the vasculature as well as valvular, myocardial, and pericardial dysfunction. We present a consensus statement from the International Cardio-Oncology Society based on general principles of radiotherapy delivery and cardiovascular risk assessment and risk mitigation in this population. Anatomical-based recommendations for cardiovascular management and follow-up are provided, and a priority is given to the early detection of atherosclerotic vascular disease on imaging to help guide preventive therapy. Unique management considerations in radiation-induced cardiovascular disease are also discussed. Recommendations are based on the most current literature and represent a unanimous consensus by the multidisciplinary expert panel.

High prevalence of xylazine among fentanyl screen-positive urines from hospitalized patients, Philadelphia, 2021.

BACKGROUND: Xylazine is an α-2 adrenoreceptor agonist used as a sedative/analgesic in veterinary medicine. Xylazine is known to be present within the street supply of opiates in urban Philadelphia. Medical staff at our hospital asked if we could test for xylazine in fentanyl screen-positive urine samples. We developed an LC-MS/MS assay for this purpose, and determined prevalence of xylazine among fentanyl screen-positive urine samples at our hospital. METHODS: The LC-MS/MS assay utilized d5-norfentanyl as internal standard (IS). One hundred microliter samples were extracted with 200 µl of MeOH/IS. LC was performed using a Phenomenex Kinetix C18 column (100 A, 5 µm, 50 × 4.6 mm) at 40 °C. Time-variable mobile phases (A = H2O, 0.1% formic acid; B = MeOH, 0.1% formic acid) were used at a fixed flow rate of 0.5 ml/min. MS/MS used positive electrospray ionization, monitoring m/z transitions of 221 > 164 for xylazine (primary), 221 > 90 for xylazine (qualifier), and 238 > 84 for d5-norfentanyl (IS). Retention time was 3.9 min for both xylazine and IS. RESULTS: Calibration curve was linear (0-500 ng/ml; r > 0.99). Inter-assay CVs (n = 20) were 5.2% (18 ng/ml) and 6.6% (95 ng/ml). Lower limit of detection was set at 10 ng/ml (CV = 15%). Among 81 urine samples that were screen-positive for fentanyl (Ark Diagnostics immunoassay), 63 (78%) were positive for xylazine (>10 ng/ml). CONCLUSIONS: By LC-MS/MS, there was high prevalence (78%) of xylazine in fentanyl screen-positive urine samples submitted to the laboratory. Because α-2 adrenoreceptor agonists may be used in treatment of opioid addiction, knowledge of xylazine exposure may be clinically useful to guide patient management.

Models for the bystander effect in gradient radiation fields: Range and signalling type.

Bystander responses to radiation are responsible for a significant fraction of cell death, but are not included in the conventional linear-quadratic (LQ) radiobiological model. Strong dose gradients in radiation fields affect the distribution of bystander signals and can be used to decrease the survival of cancer cells. Predictive models incorporating bystander effects are needed to design the dose gradients in modulated fields to improve cancer treatments. Fundamental questions concern the nature and range of bystander signalling. Some authors propose bystander signals are carried by diffusing molecular factors expressed into the extracellular medium and that strong dose gradients drive their diffusion. Others propose bystander effects occur between neighbouring cells through gap-junctions, leaving no universal agreement. Here we test three assumptions concerning the effective range of bystander signals using both average and local measures of survival. Model 1 assumes short range signalling (e.g. gap-junction mediated) proportional to the local dose gradient, without relying on diffusion across the extracellular medium; Model 2 assumes metabolite diffusion governed by Fick's second law with either negative or both signs of bystander effect; Model 3 assumes that the extent of signal production is dependent on the average of the dose gradient over the field and that the signals have long range distribution. A single bystander parameter for each model was fitted to observed average survival of cancer cells in uniform and modulated fields. All models gave better fits than the classical LQ model. Model 2 fitted best with one sign of bystander effect on survival. Model 3 gave the best overall fit of average survival. The models were then used to predict local survival and survival as a function of dose in modulated fields, using independent datasets, without changing the bystander parameter. Model 3 gave the best overall prediction. This study demonstrates that the bystander effect can be controlled by design of the radiation field modulation.

miR-139-5p Modulates Radiotherapy Resistance in Breast Cancer by Repressing Multiple Gene Networks of DNA Repair and ROS Defense.

Radiotherapy is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage, and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome in radiotherapy-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant breast cancer xenografts highly amenable to sensitization by cotreatment with a miR-139-5p mimetic.Significance: The microRNA described in this study offers a potentially useful predictive biomarker of radiosensitivity in solid tumors and a generally applicable druggable target for tumor radiosensitization. Cancer Res; 78(2); 501-15. ©2017 AACR.

Assessment of voluntary deep inspiration breath-hold with CINE imaging for breast radiotherapy.

Deep Inspiration Breath-Hold (DIBH) techniques for breast cancer radiation therapy (RT) have reduced cardiac dose compared to Free Breathing (FB). Recently, a voluntary deep inspiration breath-hold (vDIBH) technique was established using in-room lasers and skin tattoos to monitor breath-hold. An in-house quality assessment of positional reproducibility during RT delivery with vDIBH in patients with left-sided breast cancer was evaluated. The electronic portal imaging device (EPID) was used in cinematographic (CINE) mode to capture a sequence of images during beam delivery. Weekly CINE images were retrospectively assessed for 20 left-sided breast cancer patients receiving RT in vDIBH, and compared with CINE images of 20 patients treated in FB. The intra-beam motion was assessed and the distance from the beam central axis (CA) to the internal chest wall (ICW) was measured on each CINE image. These were then compared to the planned distance on digitally reconstructed radiograph (DRR). The maximum intra-beam motion for any one patient measurement was 0.30 cm for vDIBH and 0.20 cm for FB. The mean difference between the distance from the CA to ICW on DRR and the equivalent distance on CINE imaging (as treated) was 0.28 cm (SD 0.17) for vDIBH patients and 0.25 cm (SD 0.14) for FB patients (P = 0.458). The measured values were comparable for patients undergoing RT in vDIBH, and for those in FB. This quality assessment showed that using in-room lasers and skin tattoos to independently monitor breath-hold in vDIBH as detected by 'on-treatment' CINE imaging is safe and effective.

In vivo dosimetric impact of breast tissue expanders on post-mastectomy radiotherapy.

INTRODUCTION: Temporary tissue expanders with metallic ports for gradual saline injection are increasingly employed to facilitate breast reconstruction after post-mastectomy radiotherapy (PMRT). Treatment beams therefore pass through a high-density rare-earth magnet. Measurements ex vivo suggest attenuation of dose to the skin and chest wall at clinical risk of relapse. The purpose of the study was to quantify the resulting dose reduction in vivo, compared with treatment planning system (TPS). METHODS: Sixteen patients receiving PMRT had in vivo dosimetry prospectively performed with ethics board approval. Port was located within the expanded chest wall using the planning CT scan. Strips of radiochromic film were laid on the skin surface underneath the bolus. To aid interpretation, ex vivo measurements were also performed, including comparison with TPS predictions. RESULTS: An average 7% reduction in dose to skin surface was measured in 15 of 16 patients. This was reproducibly located in the 'shadow' of the magnet, corresponding to each of the paths of the medial and lateral tangents. The average area was 1.07 cm(2) (range 0.39 cm(2) to 2.36 cm(2)). Ex vivo measurements confirmed attenuation of the beam in the shadow of the port. The surface area of the 'cold-spot' varied with angle of the beam relative to the metallic port. Dose attenuation in vivo differed from that predicted by the TPS. CONCLUSION: Dose is attenuated in the 'shadow' of the tissue expander port in patients receiving PMRT. This is likely to be clinically insignificant for most, but centres should undertake appropriate measurements before utilising TPS predictions.

MicroRNA-Related DNA Repair/Cell-Cycle Genes Independently Associated With Relapse After Radiation Therapy for Early Breast Cancer.

PURPOSE: Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo. METHODS AND MATERIALS: With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers--TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1--were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis. RESULTS: We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy-treated patients but not in untreated matched control individuals (n=107; P<.05). CONCLUSIONS: Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available.