Neurosurgical experience of managing optic pathway gliomas

Background: Optic pathway gliomas (OPGs), also known as visual pathway gliomas, are debilitating tumors that account for 3–5% of all pediatric brain tumors. They are most commonly WHO grade 1 pilocytic astrocytomas and frequently occur in patients with neurofibromatosis type 1. The location of these tumors results in visual loss and blindness, endocrine and hypothalamic dysfunction, hydrocephalus, and premature death. Their involvement of the visual pathways and proximity to other eloquent brain structures typically precludes complete resection or optimal radiation dosing without incurring significant neurological injury. There are various surgical interventions that can be performed in relation to these lesions including biopsy, cerebrospinal fluid diversion, and partial or radical resection, but their role is a source of debate. This study catalogues our surgical experience and patient outcomes in order to support decision-making in this challenging pathology. Methods: A retrospective review of all cases of OPGs treated in a single center from July 1990 to July 2020. Data was collected on patient demographics, radiographic findings, pathology, and management including surgical interventions. Outcome data included survival, visual function, endocrine, and hypothalamic dysfunction. Results: One hundred twenty-one patients with OPG were identified, and 50 of these patients underwent a total of 104 surgical procedures. These included biopsy (31), subtotal or gross total resection (20 operations in 17 patients), cyst drainage (17), Ommaya reservoir insertion (9), or cerebrospinal fluid diversion (27). During the study period, there was 6% overall mortality, 18% hypothalamic dysfunction, 20% endocrine dysfunction, and 42% had some cognitive dysfunction. At diagnosis 75% of patients had good or moderate visual function in at least one eye, and overall, this improved to 83% at the end of the study period. In comparison the worst eye had good or moderate visual function in 56%, and this reduced to 53%. Baseline and final visual function were poorer in patients who had a surgical resection, but improvements in vision were still found—particularly in the best eye. Discussion/conclusion: OPG are debilitating childhood tumor that have lifelong consequences in terms of visual function and endocrinopathies/hypothalamic dysfunction; this can result in substantial patient morbidity. Decisions regarding management and the role of surgery in this condition are challenging and include cerebrospinal fluid diversion, biopsy, and in highly select cases cystic decompression or surgical resection. In this paper, we review our own experience, outcomes, and surgical philosophy

Multimorbidity patterns and risk of hospitalisation in children: A population cohort study of 3.6 million children in England, with illustrative examples from childhood cancer survivors

Background: Population-level estimates of hospitalisation risk in children are currently limited. The study aims to characterise morbidity patterns in all children, focusing on childhood cancer survivors versus children without cancer. Methods: Employing hospital records of children aged <19 years between 1997 to 2018 in England, we characterised morbidity patterns in childhood cancer survivors compared with children without cancer. The follow-up began on the 5th anniversary of the index hospitalisation and the primary outcome was the incidence of comorbidities. Findings: We identified 3,559,439 eligible participants having 12,740,666 hospital admissions, with a mean age at study entry of 11.2 years. We identified 32,221 patients who survived for at least 5 years since their initial cancer diagnosis. During the follow-up period and within the whole population of 3.6 million children, the leading conditions for admission were (i) metabolic, endocrine, digestive renal and genitourinary conditions (84,749, 2.5%), (ii) neurological (35,833, 1.0%) and (iii) musculoskeletal or skin conditions (23,574, 0.7%), fever, acute respiratory and sepsis (22,604, 0.7%). Stratified analyses revealed that females and children from socioeconomically deprived areas had a higher cumulative incidence for morbidities requiring hospitalisation (p < 0.001). At baseline (5 years after the initial cancer diagnosis or initial hospitalisation for survivors and population comparisons, respectively), cancer survivors experienced a higher prevalence of individual conditions and multimorbidity (≥ 2 morbidities) compared with children without cancer. Cox regression analyses showed that survivors had at least a 4-fold increase in the risk of hospitalisation for conditions such as chronic eye conditions (hazard ration (HR):4.0, 95% confidence interval (CI): 3.5-4.7), fever requiring hospitalisation (HR: 4.4, 95% CI: 3.8-5.0), subsequent neoplasms (HR: 5.7, 95% CI:5.0-6.5), immunological disorders (HR: 6.5, 95% CI:4.5-9.3) and metabolic conditions (HR: 7.1, 95% CI:5.9-8.5). Interpretation: The overall morbidity burden among children was low in general; however, childhood cancer survivors experienced a higher prevalence and subsequent risk of hospitalisation for a range of morbidities. Targeted policies may be required to promote awareness on health vulnerabilities and gender disparity and to improve advocacy for healthcare in deprived communities. Funding: Wellcome Trust, National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre and Academy of Medical Sciences. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report

Surveillance imaging of grade 1 astrocytomas in children: can duration and frequency of follow-up imaging and the use of contrast agents be reduced?

Purpose: The optimum strategy for the surveillance of low-grade gliomas in children has not been established, and there is concern about the use of gadolinium-based contrast agents (GBCAs), particularly in children, due to their deposition in the brain. The number of surveillance scans and the use of GBCAs in surveillance of low-risk tumours should ideally be limited. We aimed to investigate the consistency and utility of our surveillance imaging and also determine to what extent the use of GBCAs contributed to decisions to escalate treatment in children with grade 1 astrocytomas. / Methods: This was a retrospective single-centre study at a tertiary paediatric hospital. All children with a new diagnosis of a non-syndromic World Health Organization (WHO) grade 1 astrocytoma between 2007 and 2013 were included, with surveillance imaging up to December 2018 included in analysis. The intervals of surveillance imaging were recorded, and imaging and electronic health records were examined for decisions related to treatment escalation. / Results: Eighty-eight patients had 690 surveillance scans in the study period. Thirty-one patients had recurrence or progression leading to treatment escalation, 30 of whom were identified on surveillance imaging. The use of GBCAs did not appear to contribute to multidisciplinary team (MDT) decisions in the majority of cases. / Conclusion: Surveillance imaging could be reduced in number and duration for completely resected cerebellar tumours. MDT decisions were rarely made on the basis of post-contrast imaging, and GBCA administration could therefore potentially be restricted in the setting of surveillance of grade 1 astrocytomas in children

X-Rays from NGC 3256: High-Energy Emission in Starburst Galaxies and Their Contribution to the Cosmic X-Ray Background

The infrared-luminous galaxy NGC3256 is a classic example of a merger induced nuclear starburst system. We find here that it is the most X-ray luminous star-forming galaxy yet detected (~10^42 ergs/s). Long-slit optical spectroscopy and a deep, high-resolution ROSAT X-ray image show that the starburst is driving a "superwind" which accounts for ~20% of the observed soft (kT~0.3 keV) X-ray emission. Our model for the broadband X-ray emission of NGC3256 contains two additional components: a warm thermal plasma (kT~0.8 keV) associated with the central starburst, and a hard power-law component with an energy index of ~0.7. We find that the input of mechanical energy from the starburst is more than sufficient to sustain the observed level of emission. We also examine possible origins for the power-law component, concluding that neither a buried AGN nor the expected population of high-mass X-ray binaries can account for this emission. Inverse-Compton scattering, involving the galaxy's copious flux of infrared photons and the relativistic electrons produced by supernovae, is likely to make a substantial contribution to the hard X-ray flux. Such a model is consistent with the observed radio and IR fluxes and the radio and X-ray spectral indices. We explore the role of X-ray-luminous starbursts in the production of the cosmic X-ray background radiation. The number counts and spectral index distribution of the faint radio source population, thought to be dominated by star-forming galaxies, suggest that a significant fraction of the hard X-ray background could arise from starbursts at moderate redshift.Comment: 31 pages (tex, epsf), 8 figures (postscript files), accepted for publication in Part 1 of The Astrophysical Journa

A 40-Year Cohort Study of Evolving Hypothalamic Dysfunction in Infants and Young Children (<3 years) with Optic Pathway Gliomas

Despite high survival, paediatric optic pathway hypothalamic gliomas are associated with significant morbidity and late mortality. Those youngest at presentation have the worst outcomes. We aimed to assess presenting disease, tumour location, and treatment factors implicated in the evolution of neuroendocrine, metabolic, and neurobehavioural morbidity in 90 infants/children diagnosed before their third birthday and followed-up for 9.5 years (range 0.5–25.0). A total of 52 (57.8%) patients experienced endo-metabolic dysfunction (EMD), the large majority (46) of whom had hypothalamic involvement (H+) and lower endocrine event-free survival (EEFS) rates. EMD was greatly increased by a diencephalic syndrome presentation (85.2% vs. 46%, p = 0.001)), H+ (OR 6.1 95% CI 1.7–21.7, p 0.005), radiotherapy (OR 16.2, 95% CI 1.7–158.6, p = 0.017) and surgery (OR 4.8 95% CI 1.3–17.2, p = 0.015), all associated with anterior pituitary disorders. Obesity occurred in 25% of cases and was clustered with the endocrinopathies. Neurobehavioural deficits occurred in over half (52) of the cohort and were associated with H+ (OR 2.5 95% C.I. 1.1–5.9, p = 0.043) and radiotherapy (OR 23.1 C.I. 2.9–182, p = 0.003). Very young children with OPHG carry a high risk of endo-metabolic and neurobehavioural comorbidities which deserve better understanding and timely/parallel support from diagnosis to improve outcomes. These evolve in complex, hierarchical patterns over time whose aetiology appears predominantly determined by injury from the hypothalamic tumour location alongside adjuvant treatment strategies

The Electron Energy Distribution in the Hotspots of Cygnus A: Filling the Gap with the Spitzer Space Telescope

Here we present Spitzer Space Telescope imaging of Cyg A with the Infrared Array Camera, resulting in the detection of the high-energy tails or cut-offs in the synchrotron spectra for all four hotspots of this archetype radio galaxy. When combined with the other data collected from the literature, our observations allow for detailed modeling of the broad-band emission for the brightest spots A and D. We confirm that the X-ray flux detected previously from these features is consistent with the synchrotron self-Compton radiation for the magnetic field intensity 170 muG in spot A, and 270 muG in spot D. We also find that the energy density of the emitting electrons is most likely larger by a factor of a few than the energy density of the hotspots' magnetic field. We construct energy spectra of the radiating ultrarelativistic electrons. We find that for both hotspots A and D these spectra are consistent with a broken power-law extending from at least 100 MeV up to 100 GeV, and that the spectral break corresponds almost exactly to the proton rest energy of 1 GeV. We argue that the shape of the electron continuum reflects two different regimes of the electron acceleration process at mildly relativistic shocks, rather than resulting from radiative cooling and/or absorption effects. In this picture the protons' inertia defines the critical energy for the hotspot electrons above which Fermi-type acceleration processes may play a major role, but below which the operating acceleration mechanism has to be of a different type. At energies >100 GeV, the electron spectra cut-off/steepen again, most likely as a result of spectral aging due to radiative loss effects. We discuss several implications of the presented analysis for the physics of extragalactic jets.Comment: 29 pages, 8 figures and 2 tables included. Accepted for publication in Ap

Evaluating preclinical evidence for clinical translation in childhood brain tumours: Guidelines from the CONNECT, PNOC, and ITCC brain networks

Clinical outcomes for many childhood brain tumours remain poor, despite our increasing understanding of the underlying disease biology. Advances in molecular diagnostics have refined our ability to classify tumour types and subtypes, and efforts are underway across multiple international paediatric neuro-oncology consortia to take novel biological insights in the worst prognosis entities into innovative clinical trials. Whilst for the first time we are designing such studies on the basis of disease-specific biological data, the levels of preclincial evidence in appropriate model systems on which these trials are initiated is still widely variable. We have considered these issues between CONNECT, PNOC and ITCC-Brain, and developed a framework in which we can assess novel concepts being brought forward for possible clinical translation. Whilst not intended to be proscriptive for every possible circumstance, these criteria provide a basis for self-assessment of evidence by laboratory scientists, and a platform for discussion and rational decision-making prior to moving forward clinically

The origins of X-ray emission from the hotspots of FRII radio sources

We use new and archival Chandra data to investigate the X-ray emission from a large sample of compact hotspots of FRII radio galaxies and quasars from the 3C catalogue. We find that only the most luminous hotspots tend to be in good agreement with the predictions of a synchrotron self-Compton model with equipartition magnetic fields. At low hotspot luminosities inverse-Compton predictions are routinely exceeded by several orders of magnitude, but this is never seen in more luminous hotspots. We argue that an additional synchrotron component of the X-ray emission is present in low-luminosity hotspots, and that the hotspot luminosity controls the ability of a given hotspot to produce synchrotron X-rays, probably by determining the high-energy cutoff of the electron energy spectrum. It remains plausible that all hotspots are close to the equipartition condition.Comment: 49 pages, 16 figures. ApJ accepted. Revised version fixes a typo in one of the Tables and corrects a statement about 3C27

Spectrum of neuroimaging findings post-proton beam therapy in a large pediatric cohort

PURPOSE: Proton beam therapy (PBT) is now well established for the treatment of certain pediatric brain tumors. The intrinsic properties of PBT are known to reduce long-term negative effects of photon radiotherapy (PRT). To better understand the intracranial effects of PBT, we analyzed the longitudinal imaging changes in a cohort of children with brain tumors treated by PBT with clinical and radiotherapy dose correlations. MATERIALS AND METHODS: Retrospective imaging review of 46 patients from our hospital with brain tumors treated by PBT. The imaging findings were correlated with clinical and dose parameters. RESULTS: Imaging changes were assessed by reviewing serial magnetic resonance imaging (MRI) scans following PBT over a follow-up period ranging from 1 month to 7 years. Imaging changes were observed in 23 patients undergoing PBT and categorized as pseudoprogression (10 patients, 43%), white matter changes (6 patients, 23%), parenchymal atrophy (6 patients, 23%), and cerebral large vessel arteriopathy (5 patients, 25%). Three patients had more than one type of imaging change. Clinical symptoms attributable to PBT were observed in 13 (28%) patients. CONCLUSION: In accordance with published literature, we found evidence of varied intracranial imaging changes in pediatric brain tumor patients treated with PBT. There was a higher incidence (10%) of large vessel cerebral arteriopathy in our cohort than previously described in the literature. Twenty-eight percent of patients had clinical sequelae as a result of these changes, particularly in the large vessel arteriopathy subgroup, arguing the need for angiographic and perfusion surveillance to pre-empt any morbidities and offer potential neuro-protection

A Chandra X-ray Study of Cygnus A - II. The Nucleus

We report Chandra ACIS and quasi-simultaneous RXTE observations of the nearby, powerful radio galaxy Cygnus A, with the present paper focusing on the properties of the active nucleus. In the Chandra observation, the hard (> a few keV) X-ray emission is spatially unresolved with a size \approxlt 1 arcsec (1.5 kpc, H_0 = 50 km s^-1 Mpc^-1) and coincides with the radio and near infrared nuclei. In contrast, the soft (< 2 keV) emission exhibits a bi-polar nebulosity that aligns with the optical bi-polar continuum and emission-line structures and approximately with the radio jet. In particular, the soft X-ray emission corresponds very well with the [O III] \lambda 5007 and H\alpha + [N II] \lambda\lambda 6548, 6583 nebulosity imaged with HST. At the location of the nucleus there is only weak soft X-ray emission, an effect that may be intrinsic or result from a dust lane that crosses the nucleus perpendicular to the source axis. The spectra of the various X-ray components have been obtained by simultaneous fits to the 6 detectors. The compact nucleus is detected to 100 keV and is well described by a heavily absorbed power law spectrum with \Gamma_h = 1.52^{+0.12}_{-0.12} (similar to other narrow line radio galaxies) and equivalent hydrogen column N_H (nuc) = 2.0^{+0.1}_{-0.2} \times 10^{23} cm^-2. (Abstract truncated).Comment: To be published in the Astrophysical Journal, v564 January 1, 2002 issue; 34 pages, 11 figures (1 color