The Association of Incidental Radiation Dose to the Heart Base with Overall Survival and Cardiac Events after Curative-intent Radiotherapy for Non-small Cell Lung Cancer: Results from the NI-HEART Study.

AIMS: Cardiac disease is a dose-limiting toxicity in non-small cell lung cancer radiotherapy. The dose to the heart base has been associated with poor survival in multiple institutional and clinical trial datasets using unsupervised, voxel-based analysis. Validation has not been undertaken in a cohort with individual patient delineations of the cardiac base or for the endpoint of cardiac events. The purpose of this study was to assess the association of heart base radiation dose with overall survival and the risk of cardiac events with individual heart base contours. MATERIALS AND METHODS: Patients treated between 2015 and 2020 were reviewed for baseline patient, tumour and cardiac details and both cancer and cardiac outcomes as part of the NI-HEART study. Three cardiologists verified cardiac events including atrial fibrillation, heart failure and acute coronary syndrome. Cardiac substructure delineations were completed using a validated deep learning-based autosegmentation tool and a composite cardiac base structure was generated. Cox and Fine-Gray regressions were undertaken for the risk of death and cardiac events. RESULTS: Of 478 eligible patients, most received 55 Gy/20 fractions (96%) without chemotherapy (58%), planned with intensity-modulated radiotherapy (71%). Pre-existing cardiovascular morbidity was common (78% two or more risk factors, 46% one or more established disease). The median follow-up was 21.1 months. Dichotomised at the median, a higher heart base Dmax was associated with poorer survival on Kaplan-Meier analysis (20.2 months versus 28.3 months; hazard ratio 1.40, 95% confidence interval 1.14-1.75, P = 0.0017) and statistical significance was retained in multivariate analyses. Furthermore, heart base Dmax was associated with pooled cardiac events in a multivariate analysis (hazard ratio 1.75, 95% confidence interval 1.03-2.97, P = 0.04). CONCLUSIONS: Heart base Dmax was associated with the rate of death and cardiac events after adjusting for patient, tumour and cardiovascular factors in the NI-HEART study. This validates the findings from previous unsupervised analytical approaches. The heart base could be considered as a potential sub-organ at risk towards reducing radiation cardiotoxicity.

Specialist corallivores dominate butterflyfish assemblages in coral-dominated reef habitats.

This study examined the dietary habits and functional composition of butterflyfishes in the Chagos Archipelago, central Indian Ocean. Eighteen species of butterflyfishes were recorded in Chagos, including six obligate corallivores (Chaetodon bennetti, Chaetodon guttatissimus, Chaetodon meyeri, Chaetodon trifascialis, Chaetodon trifasciatus and Chaetodon zanzibarensis), five facultative corallivores (Chaetodon auriga, Chaetodon falcula, Chaetodon interruptus, Chaetodon kleinii and Chaetodon madagaskariensis), two non-corallivores (Chaetodon lunula and Chaetodon xanthocephalus) and a further five species (Chaetodon citrinellus, Chaetodon lineolatus, Heimitaurichthys zoster, Heniochus monoceros and Forcipiger flavissimus), for which local dietary habits were not studied. There were marked differences in the abundance of butterflyfishes among sites and between reef zones, mostly associated with variation in abundance of scleractinian corals. Obligate coral-feeding species (mostly C. trifascialis) dominated across all sites. This study suggests that coral feeding and high levels of dietary specialization contribute to high population-level fitness among coral reef butterflyfishes. Despite being more vulnerable to habitat disturbances and coral loss, it appears likely that specialist coral-feeding butterflyfishes are also much more resilient to occasional disturbances, and therefore dominate in a wide range of coral reef habitats.

Radiomics for Predicting Lung Cancer Outcomes Following Radiotherapy: A Systematic Review.

Lung cancer's radiomic phenotype may potentially inform clinical decision-making with respect to radical radiotherapy. At present there are no validated biomarkers available for the individualisation of radical radiotherapy in lung cancer and the mortality rate of this disease remains the highest of all other solid tumours. MEDLINE was searched using the terms 'radiomics' and 'lung cancer' according to the Preferred Reporting Items for Systematic Reviews and Met-Analyses (PRISMA) guidance. Radiomics studies were defined as those manuscripts describing the extraction and analysis of at least 10 quantifiable imaging features. Only those studies assessing disease control, survival or toxicity outcomes for patients with lung cancer following radical radiotherapy ± chemotherapy were included. Study titles and abstracts were reviewed by two independent reviewers. The Radiomics Quality Score was applied to the full text of included papers. Of 244 returned results, 44 studies met the eligibility criteria for inclusion. End points frequently reported were local (17%), regional (17%) and distant control (31%), overall survival (79%) and pulmonary toxicity (4%). Imaging features strongly associated with clinical outcomes include texture features belonging to the subclasses Gray level run length matrix, Gray level co-occurrence matrix and kurtosis. The median cohort size for model development was 100 (15-645); in the 11 studies with external validation in a separate independent population, the median cohort size was 84 (21-295). The median number of imaging features extracted was 184 (10-6538). The median Radiomics Quality Score was 11% (0-47). Patient-reported outcomes were not incorporated within any studies identified. No studies externally validated a radiomics signature in a registered prospective study. Imaging-derived indices attained through radiomic analyses could equip thoracic oncologists with biomarkers for treatment response, patterns of failure, normal tissue toxicity and survival in lung cancer. Based on routine scans, their non-invasive nature and cost-effectiveness are major advantages over conventional pathological assessment. Improved tools are required for the appraisal of radiomics studies, as significant barriers to clinical implementation remain, such as standardisation of input scan data, quality of reporting and external validation of signatures in randomised, interventional clinical trials.

Tubular proteinuria in mice and humans lacking the intrinsic lysosomal protein SCARB2/Limp-2.

Deficiency of the intrinsic lysosomal protein human scavenger receptor class B, member 2 (SCARB2; Limp-2 in mice) causes collapsing focal and segmental glomerular sclerosis (FSGS) and myoclonic epilepsy in humans, but patients with no apparent kidney damage have recently been described. We now demonstrate that these patients can develop tubular proteinuria. To determine the mechanism, mice deficient in Limp-2, the murine homolog of SCARB2, were studied. Most low-molecular-weight proteins filtered by the glomerulus are removed in the proximal convoluted tubule (PCT) by megalin/cubilin-dependent receptor-mediated endocytosis. Expression of megalin and cubilin was unchanged in Limp-2(-/-) mice, however, and the initial uptake of injected Alexa Fluor 555-conjugated bovine serum albumin (Alexa-BSA) was similar to wild-type mice, indicating that megalin/cubilin-dependent, receptor-mediated endocytosis was unaffected. There was a defect in proteolysis of reabsorbed proteins in the Limp-2(-/-) mice, demonstrated by the persistence of Alexa-BSA in the PCT compared with controls. This was associated with the failure of the lysosomal protease cathepsin B to colocalize with Alexa-BSA and endogenous retinol-binding protein in kidneys from Limp-2(-/-) mice. The data suggest that tubular proteinuria in Limp-2(-/-) mice is due to failure of endosomes containing reabsorbed proteins to fuse with lysosomes in the proximal tubule of the kidney. Failure of proteolysis is a novel mechanism for tubular proteinuria.

Observation of peak neoclassical toroidal viscous force in the DIII-D tokamak.

Observation of a theoretically predicted peak in the neoclassical toroidal viscosity (NTV) force as a function of toroidal plasma rotation rate Ω is reported. The NTV was generated by applying n=3 magnetic fields from internal coils to low Ω plasmas produced with nearly balanced neutral beam injection. Locally, the peak corresponds to a toroidal rotation rate Ω(0) where the radial electric field E(r) is near zero as determined by radial ion force balance.

A Qualitative Assessment of Radiotherapy Training at a UK Regional Cancer Centre.

AIMS: Specialty trainees in clinical oncology must be competent in the coordination of both radiotherapy and systemic therapy at the completion of their training. Radiotherapy technology and postgraduate medical education have evolved significantly over the last two decades, but little is known of the educational impact of those changes within the dual training of the clinical oncology programme. A qualitative assessment of the radiotherapy component of training was undertaken at a single regional cancer centre in order to identify potential areas for improvement. MATERIALS AND METHODS: Consultants and trainees (n = 10) at a regional cancer centre underwent semi-structured interviews regarding their lived experience of learning radiotherapy skills and knowledge. As consultants and trainees can be considered equal co-investors in the process of radiotherapy learning, the same question stems were used for both groups. An interpretative phenomenological analysis was undertaken by the investigators to elicit the perception of both groups. RESULTS: Consultant and trainee assessments of current radiotherapy learning standards differ for several aspects of training, as do their expectations of the other in learning processes. A lack of time is a major barrier in modern practice, and both groups can propose novel measures to improve learning locally. CONCLUSIONS: Arrangements for learning radiotherapy have not kept pace with the rate of change in the clinical oncology discipline. Trainees and consultants have contrasting views on the state of training, its strengths and weaknesses, and pathways to improvement, which should be reconciled by programme coordinators charged with upgrading the training system.

Periodic epileptiform discharges in hypoxic encephalopathy: BiPLEDs and GPEDs as a poor prognosis for survival.

INTRODUCTION: Electrophysiologic tests in hypoxic encephalopathy consist of EEG and evoked/event-related potential studies. In most studies the generalized periodic epileptiform complexes have been reported combined with other EEG patterns and were indicators of a poor outcome in different etiologies of hypoxic encephalopathy (HE), but these have rarely been examined independently. METHODOLOGY: We analyzed from 2000 to 2007 the outcome of patients with HE and generalized periodic epileptiform complexes. We abstracted and tabulated clinical information, imaging findings, and outcome from the medical records. RESULTS: We found 52 patients in our database. Fourteen patients (eight BiPLEDs and six GPEDs) were associated with HE. Patients with BIPLEDs were 68+/-19.4 years old, 5 female (62%) and 3 (38%) men. GPEDs patients were 52.5+/-19.1 years old, 2 women (20%) and 4 (80%) men. Myocardial infarction and ventricular tachycardia were responsible of 57% of the HE cases. Neuroimaging studies in both groups showed cortical structural lesions in 84%. All patients were comatose and died. Two GPEDs patients developed status epilepticus. CONCLUSION: GPEDs and BIPLEDs after an anoxic insult carried a poor prognosis for survival. Aggressive treatment of patients may not be warranted when these EEG patterns are seen after anoxic brain injury.

Toward adaptive radiotherapy for lung patients: feasibility study on deforming planning CT to CBCT to assess the impact of anatomical changes on dosimetry.

Changes in lung architecture during a course of radiotherapy can alter the planned dose distribution to the extent that it becomes clinically unacceptable. This study aims to validate a quantitative method of determining whether a replan is required during the course of conformal radiotherapy. The proposed method uses deformable image registration (DIR) to flexibly map planning CT (pCT) data to the anatomy of online CBCT images. The resulting deformed CT (dCT) images are used as a basis for assessing the effect of anatomical change on dose distributions. The study used retrospective data from a sample of seven replanned lung patients. The settings of an in-house, open-source DIR algorithm were first optimised for CT-to-CBCT registrations of the anatomy of the thorax. Using these optimised parameters, each patient's pCT was deformed to the CBCT acquired immediately before the replan. Registration accuracy was rigorously validated both geometrically and dosimetrically to confirm that the dCTs could reliably be used to inform replan decisions. A retrospective evaluation of the changes in dose delivered over time was then carried out for a single patient to demonstrate the clinical application of the proposed method. The geometric analysis showed good agreement between deformed structures and those same structures manually outlined on the CBCT images. Results were consistently better than those achieved with rigid-only registration. In the dosimetric analysis, dose distributions derived from the dCTs were found to match closely to the 'gold standard' replan CT (rCT) distributions across dose volume histogram and absolute dose difference measures. The retrospective analysis of serial CBCTs of a single patient produced reliable quantitative assessment of the dose delivery. Had the proposed method been available at the time of treatment, it would have enabled a more objective replan decision. DIR is a valuable clinical tool for dose recalculation in adaptive radiotherapy protocols for lung cancer patients.

Relevance of postmortem radiology to the diagnosis of fatal cerebral gas embolism from compressed air diving.

AIMS: To test the hypothesis that artefact caused by postmortem off-gassing is at least partly responsible for the presence of gas within the vascular system and tissues of the cadaver following death associated with compressed air diving. METHODS: Controlled experiment sacrificing sheep after a period of simulated diving in a hyperbaric chamber and carrying out sequential postmortem computed tomography (CT) on the cadavers. RESULTS: All the subject sheep developed significant quantities of gas in the vascular system within 24 hours, as demonstrated by CT and necropsy, while the control animals did not. CONCLUSIONS: The presence of gas in the vascular system of human cadavers following diving associated fatalities is to be expected, and is not necessarily connected with gas embolism following pulmonary barotrauma, as has previously been claimed.

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients.

OBJECTIVE: To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS: Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS: MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION: Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

Decision analysis of intracranial monitoring in non-lesional epilepsy.

PURPOSE: Up to one third of epilepsy patients develop pharmacoresistant seizures and many benefit from resective surgery. However, patients with non-lesional focal epilepsy often require intracranial monitoring to localize the seizure focus. Intracranial monitoring carries operative morbidity risk and does not always succeed in localizing the seizures, making the benefit of this approach less certain. We performed a decision analysis comparing three strategies for patients with non-lesional focal epilepsy: (1) intracranial monitoring, (2) vagal nerve stimulator (VNS) implantation and (3) medical management to determine which strategy maximizes the expected quality-adjusted life years (QALYs) for our base cases. METHOD: We constructed two base cases using parameters reported in the medical literature: (1) a young, otherwise healthy patient and (2) an elderly, otherwise healthy patient. We constructed a decision tree comprising strategies for the treatment of non-lesional epilepsy and two clinical outcomes: seizure freedom and no seizure freedom. Sensitivity analyses of probabilities at each branch were guided by data from the medical literature to define decision thresholds across plausible parameter ranges. RESULTS: Intracranial monitoring maximizes the expected QALYs for both base cases. The sensitivity analyses provide estimates of the values of key variables, such as the surgical risk or the chance of localizing the focus, at which intracranial monitoring is no longer favored. CONCLUSION: Intracranial monitoring is favored over VNS and medical management in young and elderly patients over a wide, clinically-relevant range of pertinent model variables such as the chance of localizing the seizure focus and the surgical morbidity rate.

Optimizing geometric accuracy of four-dimensional CT scans acquired using the wall- and couch-mounted Varian® Real-time Position Management™ camera systems.

OBJECTIVE: The aim of this study was to identify sources of anatomical misrepresentation owing to the location of camera mounting, tumour motion velocity and image processing artefacts in order to optimize the four-dimensional CT (4DCT) scan protocol and improve geometrical-temporal accuracy. METHODS: A phantom with an imaging insert was driven with a sinusoidal superior-inferior motion of varying amplitude and period for 4DCT scanning. The length of a high-density cube within the insert was measured using treatment planning software to determine the accuracy of its spatial representation. Scan parameters were varied, including the tube rotation period and the cine time between reconstructed images. A CT image quality phantom was used to measure various image quality signatures under the scan parameters tested. RESULTS: No significant difference in spatial accuracy was found for 4DCT scans carried out using the wall- or couch-mounted camera for sinusoidal target motion. Greater spatial accuracy was found for 4DCT scans carried out using a tube rotation speed of 0.5 s rather than 1.0 s. The reduction in image quality when using a faster rotation speed was not enough to require an increase in patient dose. CONCLUSION: The 4DCT accuracy may be increased by optimizing scan parameters, including choosing faster tube rotation speeds. Peak misidentification in the recorded breathing trace may lead to spatial artefacts, and this risk can be reduced by using a couch-mounted infrared camera. ADVANCES IN KNOWLEDGE: This study explicitly shows that 4DCT scan accuracy is improved by scanning with a faster CT tube rotation speed.

Migraine with vasospasm and delayed intracerebral hemorrhage.

Three women with well-documented migraine associated with intracerebral hemorrhage are described. In each case, migraine headaches began during adulthood. Unusually severe and protracted headache heralded the onset of fixed neurological deficits associated with lobar intracerebral hemorrhage. Striking carotid artery tenderness was characteristic. Except for a history of migraine, no cause for intracerebral hemorrhage could be established. In each case arteriography showed extensive spasm of the appropriate extracranial or intracranial artery. Surgical pathology following evacuation of two hematomata demonstrated signs of vessel wall necrosis associated with subacute inflammatory changes. Vasospasm associated with severe migraine attacks may result in ischemia of intracranial vessel walls, leading to necrosis and subsequent vessel rupture when perfusion pressure is restored.

Epileptic pseudodementia.

Dementia is a frequent cause of memory loss with aging. The incidence of complex partial seizures sharply rises after age 60. Complex partial seizures that occur with subtle clinical signs or loss of awareness, or occur during sleep may defy identification. We report five elderly patients fearing dementia in whom memory dysfunction was due to unrecognized complex partial seizures.

The Landau-Kleffner syndrome of acquired epileptic aphasia: unusual clinical outcome, surgical experience, and absence of encephalitis.

The syndrome of acquired verbal auditory agnosia in childhood with mutism and epileptic discharges has been described in over 100 cases. An encephalitic etiology has often been postulated but never proved. We report two patients with this syndrome who were treated surgically. Despite careful search, no pathologic evidence of encephalitis was found. One patient, with the typical course, had no seizures but striking positive correlation between epileptic discharge and language disorder; the second, after classic onset, developed intractable temporal lobe epilepsy, a previously unreported outcome of this syndrome. EEG discharges are generalized, bilateral, multifocal, or with shifting predominance but mainly temporal in 85% of reported cases, and unilateral, also predominantly temporal, in 15%. Language areas are preferentially involved. This syndrome has certain biologic features that resemble the benign epilepsies of childhood and may be the result of the unusual localization of the epileptic abnormality.

Early-life seizures in rats increase susceptibility to seizure-induced brain injury in adulthood.

BACKGROUND: Early childhood convulsions have been correlated with the finding of subsequent hippocampal neuronal loss and memory impairment in patients with intractable temporal lobe epilepsy. There is little direct evidence, however, that links early seizures with the later development of epilepsy and selective hippocampal neuronal loss. OBJECTIVE: To study the long-term effect of early seizures on later seizure-induced neuronal damage and behavior. METHODS: We used a "two hit" rat seizure mode in which systemic kainate was used to induce seizures during the second week of life (P15) and again in adulthood (P45). Memory was subsequently tested using a Morris water maze, and brains were examined for histologic evidence of injury. RESULTS: Although the first kainate-induced seizure is not associated with detectable injury or cell death, it predisposes animals to more extensive neuronal injury after kainate-induced seizures in adulthood. Moreover, although early-life kainate-induced seizures cause no impairment of spatial learning, animals that have early-life and adult kainate-induced seizures perform significantly worse than those that have seizures only as adults. CONCLUSIONS: We concluded that early-life seizures, without causing overt cellular injury, predispose the brain to the damaging effect of seizures later in life.

Visual discrimination after anterior temporal lobectomy in humans.

OBJECTIVE: To determine whether right anterior temporal lobectomy (RTL) results in perceptual deficits, and whether the perception of particular stimulus features (i.e., shape, motion, color) is affected differentially. BACKGROUND: RTL results in abnormal visual discrimination, recognition, and recall of pictorial material that cannot be easily specified verbally, such as designs and faces. It is unclear whether stimuli must be conceptually meaningful to elicit perceptual deficits. METHODS: Tests were constructed to assess a wide spectrum of basic visual discrimination abilities with simple, meaningless stimuli. The performance of nine patients who underwent left temporal lobectomy (LTL) and nine patients who underwent RTL were compared with that of normal control individuals. The mean excision size along lateral cortex was 3.7 cm for the LTL group and 5.6 cm for the RTL group; mean mesial excision size was 5.2 cm for LTL and 4.6 cm for RTL. RESULTS: Basic visual discrimination capacities were demonstrated to be essentially intact after LTL and RTL, except for a mild loss of blue color discrimination after RTL. CONCLUSIONS: There is little evidence that RTL produces perceptual impairments limited to the domain of pattern perception, or generalizable to nonmeaningful stimuli. The perceptual loss after RTL may be largely restricted to extraction of meaning, and related to the disruption of the circuits that connect the outcome of visual analysis to previously stored semantic information.

Anatomical studies of DNA fragmentation in rat brain after systemic kainate administration.

Rats treated systemically with kainate develop stereotyped epileptic seizures involving mainly limbic structures that may last for hours. This model of limbic status epilepticus has been widely studied using classical neuropathological techniques. We used in situ nick translation histochemistry to examine patterns of DNA fragmentation in this model. We found a stereotyped and reproducible pattern of neuronal populations that demonstrate evidence of DNA fragmentation from 24 h to one week after kainate treatment. Neither blockade of new protein synthesis nor blockade of the N-methyl-D-aspartate-type glutamate receptors significantly altered this response. Moreover, we saw no evidence of the regular internucleosomal cleavage of DNA that produces a characteristic laddered appearance of 180-200 bp DNA fragments after gel electrophoresis in samples obtained from microdissected affected regions. These studies suggest that DNA fragmentation after systemic kainate-induced seizures is not the result of programmed cell death. This assay may be useful for quantitative testing of both neuroprotective agents and mechanistic hypotheses.

Nerve stimulation and denervation induce differential patterns of immediate early gene mRNA expression in skeletal muscle.

Many properties of skeletal muscle cells are closely regulated by motor nerves. Neuromuscular synaptic transmission (including the 'activity' it triggers) mediates many of these effects, while denervation results in a different spectrum of muscle cell changes. However, little is known about the early regulatory events that occur in mature muscle cells in response to muscle activity or denervation. We have examined the effects of motor nerve stimulation and denervation on the expression of 4 immediate early genes (IEGs)--c-jun, junB, zif268, and nur77--in mature mouse gastrocnemius muscle. Electrical stimulation of the sciatic nerve in a pattern of brisk intermittent exercise induced a marked rise in zif268 and c-jun mRNA levels within 45 min, a minimal rise in junB, and no change in nur77 mRNA levels. By contrast, surgical denervation resulted in a marked increase of c-jun, a slight rise in junB, and no change in nur77 or zif268 mRNA levels. These findings show that neural stimulation and denervation lead to differential patterns of IEG expression. The selectivity of these patterns suggests that differential IEG expression may play an important role in regulating the specific phenotypic changes in skeletal muscles that result from denervation, innervation, and various patterns of stimulation.