Recurrent medical imaging exposures for the care of patients: one way forward.

Medical imaging is both valuable and essential in the care of patients. Much of this imaging depends on ionizing radiation with attendant responsibilities for judicious use when performing an examination. This responsibility applies in settings of both individual as well as multiple (recurrent) imaging with associated repeated radiation exposures. In addressing the roles and responsibilities of the medical communities in the paradigm of recurrent imaging, both the International Atomic Energy Agency (IAEA) and the American Association of Physicists in Medicine (AAPM) have issued position statements, each affirmed by other organizations. The apparent difference in focus and approach has resulted in a lack of clarity and continued debate. Aiming towards a coherent approach in dealing with radiation exposure in recurrent imaging, the IAEA convened a panel of experts, the purpose of which was to identify common ground and reconcile divergent perspectives. The effort has led to clarifying recommendations for radiation exposure aspects of recurrent imaging, including the relevance of patient agency and the provider-patient covenant in clinical decision-making. CLINICAL RELEVANCE STATEMENT: An increasing awareness, generating some lack of clarity and divergence in perspectives, with patients receiving relatively high radiation doses (e.g., ≥ 100 mSv) from recurrent imaging warrants a multi-stakeholder accord for the benefit of patients, providers, and the imaging community. KEY POINTS: • Recurrent medical imaging can result in an accumulation of exposures which exceeds 100 milli Sieverts. • Professional organizations have different perspectives on roles and responsibilities for recurrent imaging. • An expert panel reconciles differing perspectives for addressing radiation exposure from recurrent medical imaging.

Transfer Learning Approach to Vascular Permeability Changes in Brain Metastasis Post-Whole-Brain Radiotherapy.

The purpose of this study is to further validate the utility of our previously developed CNN in an alternative small animal model of BM through transfer learning. Unlike the glioma model, the BM mouse model develops multifocal intracranial metastases, including both contrast enhancing and non-enhancing lesions on DCE MRI, thus serving as an excellent brain tumor model to study tumor vascular permeability. Here, we conducted transfer learning by transferring the previously trained GBM CNN to DCE MRI datasets of BM mice. The CNN was re-trained to learn about the relationship between BM DCE images and target permeability maps extracted from the Extended Tofts Model (ETM). The transferred network was found to accurately predict BM permeability and presented with excellent spatial correlation with the target ETM PK maps. The CNN model was further tested in another cohort of BM mice treated with WBRT to assess vascular permeability changes induced via radiotherapy. The CNN detected significantly increased permeability parameter Ktrans in WBRT-treated tumors (p < 0.01), which was in good agreement with the target ETM PK maps. In conclusion, the proposed CNN can serve as an efficient and accurate tool for characterizing vascular permeability and treatment responses in small animal brain tumor models.

Ca2+ and CACNA1H mediate targeted suppression of breast cancer brain metastasis by AM RF EMF.

BACKGROUND: Brain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofrequency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF). METHODS: 27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metastasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to animals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic underpinnings associated with cancer inhibition was identified using an agnostic approach. FINDINGS: Animal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca2+ influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, activated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of ß-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H. INTERPRETATION: We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.

Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation.

Radiation injury to the lung is the result of acute and chronic free radical formation, and there are currently few effective means of mitigating such injury. Studies in rodents indicate that superoxide dismutase mimetics may be effective in this regard; however, studies in humans or large animals are lacking. We hypothesized that post-exposure treatment with the lipophilic mitochondrial superoxide dismutase mimetic, MnTnHex-2-PyP5+ (hexyl), would reduce radiation-induced pneumonitis and fibrosis in the lungs of nonhuman primates. Rhesus monkeys (Macaca mulatta) received 10 Gy whole thorax irradiation, 10 Gy + hexyl treatment, sham irradiation, or sham irradiation + hexyl. Hexyl was given twice daily, subcutaneously, at 0.05 mg/kg, for 2 months. Animals were monitored daily, and respiratory rates, pulse oximetry, hematology and serum chemistry panels were performed weekly. Computed tomography scans were performed at 0, 2, and 4 months after irradiation. Supportive fluid therapy, corticosteroids, analgesics, and antibiotics were given as needed. All animals were humanely euthanized 4.5 months after irradiation, and pathologic assessments were made. Multifocal, progressive lung lesions were seen at 2 and 4 months in both irradiated groups. Hexyl treatment delayed the onset of radiation-induced lung lesions, reduced elevations of respiratory rate, and reduced pathologic increases in lung weight. No adverse effects of hexyl treatment were found. These results demonstrate (1) development of a nonhuman primate model of radiation-induced lung injury, (2) a significant mitigating effect of hexyl treatment on lung pathology in this model, and (3) no evidence for toxicity of hexyl at the dose studied.

Gamma Knife radiosurgery for brain metastases from gastrointestinal primary.

INTRODUCTION: In this study, we assessed clinical outcomes of patients with brain metastases from a gastrointestinal (GI) primary cancer and patterns of failure after stereotactic radiosurgery including failure within the radiosurgical volume, distant failure and leptomeningeal failure (LMF). We also assessed other factors associated with the patients' neurologic and extraneuraxial disease that may affect clinical outcomes. METHODS: We reviewed our institutional series of 62 consecutive patients with brain metastases treated with stereotactic radiosurgery, which included 17 patients with oesophageal, 44 patients with colorectal and one patient with anal canal primary. The median marginal dose to the radiosurgery volume was 17 Gy (range 10-24 Gy). Thirteen patients were treated with whole-brain radiotherapy (WBRT) prior to GKS. RESULTS: The median dose delivered to the margin of the tumour was 17 Gy (range: 10-24 Gy). The median largest tumour diameter was 2.7 cm (range: 0.60-6.1 cm). The median overall survival (OS) was 7.1 months with a median follow-up of 6.1 months and a range of 0-31.7 months. Freedom from local failure was 86.5% and 62.2% at 6 and 12 months respectively. Freedom from distant failure was 73.2% and 42.2% at 6 and 12 months, respectively, and 40% of patients died of neurologic death. LMF occurred in seven patients, all of whom had colorectal primaries. Multivariate analysis revealed that craniotomy for resection of brain metastasis (HR = 2.63, P < 0.02), an absence of extracranial disease (HR = 2.28, P < 0.03), and prolonged time to distant brain failure (HR = 2.85, P < 0.01) predicted for improved survival. CONCLUSIONS: Colorectal cancer metastases tend to have a higher rate of leptomeningeal failure than other types of GI cancer metastases. Radiosurgical management of brain metastases from GI primary represents an acceptable management option. Neurologic death remains problematic.

Competing Risk Analysis of Neurologic versus Nonneurologic Death in Patients Undergoing Radiosurgical Salvage After Whole-Brain Radiation Therapy Failure: Who Actually Dies of Their Brain Metastases?

PURPOSE: To estimate the hazard for neurologic (central nervous system, CNS) and nonneurologic (non-CNS) death associated with patient, treatment, and systemic disease status in patients receiving stereotactic radiosurgery after whole-brain radiation therapy (WBRT) failure, using a competing risk model. PATIENTS AND METHODS: Of 757 patients, 293 experienced recurrence or new metastasis following WBRT. Univariate Cox proportional hazards regression identified covariates for consideration in the multivariate model. Competing risks multivariable regression was performed to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for both CNS and non-CNS death after adjusting for patient, disease, and treatment factors. The resultant model was converted into an online calculator for ease of clinical use. RESULTS: The cumulative incidence of CNS and non-CNS death at 6 and 12 months was 20.6% and 21.6%, and 34.4% and 35%, respectively. Patients with melanoma histology (relative to breast) (aHR 2.7, 95% CI 1.5-5.0), brainstem location (aHR 2.1, 95% CI 1.3-3.5), and number of metastases (aHR 1.09, 95% CI 1.04-1.2) had increased aHR for CNS death. Progressive systemic disease (aHR 0.55, 95% CI 0.4-0.8) and increasing lowest margin dose (aHR 0.97, 95% CI 0.9-0.99) were protective against CNS death. Patients with lung histology (aHR 1.3, 95% CI 1.1-1.9) and progressive systemic disease (aHR 2.14, 95% CI 1.5-3.0) had increased aHR for non-CNS death. CONCLUSION: Our nomogram provides individual estimates of neurologic death after salvage stereotactic radiosurgery for patients who have failed prior WBRT, based on histology, neuroanatomical location, age, lowest margin dose, and number of metastases after adjusting for their competing risk of death from other causes.

Predictive nomogram for the durability of pain relief from gamma knife radiation surgery in the treatment of trigeminal neuralgia.

PURPOSE: To determine factors associated with the durability of stereotactic radiation surgery (SRS) for treatment of trigeminal neuralgia (TN). METHODS AND MATERIALS: Between 1999 and 2008, 446 of 777 patients with TN underwent SRS and had evaluable follow-up in our electronic medical records and phone interview records. The median follow-up was 21.2 months. The Barrow Neurologic Institute (BNI) pain scale was used to determine pre- and post-SRS pain. Dose-volume anatomical measurements, Burchiel pain subtype, pain quality, prior procedures, and medication usage were included in this retrospective cohort to identify factors impacting the time to BNI 4-5 pain relapse by using Cox proportional hazard regression. An internet-based nomogram was constructed based on predictive factors of durable relief pre- and posttreatment at 6-month intervals. RESULTS: Rates of freedom from BNI 4-5 failure at 1, 3, and 5 years were 84.5%, 70.4%, and 46.9%, respectively. Pain relief was BNI 1-3 at 1, 3, and 5 years in 86.1%, 74.3%, and 51.3% of type 1 patients; 79.3%, 46.2%, and 29.3% of type 2 patients; and 62.7%, 50.2%, and 25% of atypical facial pain patients. BNI type 1 pain score was achieved at 1, 3, and 5 years in 62.9%, 43.5%, and 22.0% of patients with type 1 pain and in 47.5%, 25.2%, and 9.2% of type 2 patients, respectively. Only 13% of patients with atypical facial pain achieved BNI 1 response; 42% of patients developed post-Gamma Knife radiation surgery (GKRS) trigeminal dysfunction. Multivariate analysis revealed that post-SRS numbness (hazard ratio [HR], 0.47; P<.0001), type 1 (vs type 2) TN (HR, 0.6; P=.02), and improved post-SRS BNI score at 6 months (HR, 0.009; P<.0001) were predictive of a durable pain response. CONCLUSIONS: The durability of SRS for TN depends on the presenting Burchiel pain type, the post-SRS BNI score, and the presence of post-SRS facial numbness. The durability of pain relief can be estimated pre- and posttreatment by using our nomogram for situations when the potential of relapse may guide the decision for initial intervention.

Invited review--neuroimaging response assessment criteria for brain tumors in veterinary patients.

The evaluation of therapeutic response using cross-sectional imaging techniques, particularly gadolinium-enhanced MRI, is an integral part of the clinical management of brain tumors in veterinary patients. Spontaneous canine brain tumors are increasingly recognized and utilized as a translational model for the study of human brain tumors. However, no standardized neuroimaging response assessment criteria have been formulated for use in veterinary clinical trials. Previous studies have found that the pathophysiologic features inherent to brain tumors and the surrounding brain complicate the use of the response evaluation criteria in solid tumors (RECIST) assessment system. Objectives of this review are to describe strengths and limitations of published imaging-based brain tumor response criteria and propose a system for use in veterinary patients. The widely used human Macdonald and response assessment in neuro-oncology (RANO) criteria are reviewed and described as to how they can be applied to veterinary brain tumors. Discussion points will include current challenges associated with the interpretation of brain tumor therapeutic responses such as imaging pseudophenomena and treatment-induced necrosis, and how advancements in perfusion imaging, positron emission tomography, and magnetic resonance spectroscopy have shown promise in differentiating tumor progression from therapy-induced changes. Finally, although objective endpoints such as MR imaging and survival estimates will likely continue to comprise the foundations for outcome measures in veterinary brain tumor clinical trials, we propose that in order to provide a more relevant therapeutic response metric for veterinary patients, composite response systems should be formulated and validated that combine imaging and clinical assessment criteria.