Machine learning and glioma imaging biomarkers.

AIM: To review how machine learning (ML) is applied to imaging biomarkers in neuro-oncology, in particular for diagnosis, prognosis, and treatment response monitoring. MATERIALS AND METHODS: The PubMed and MEDLINE databases were searched for articles published before September 2018 using relevant search terms. The search strategy focused on articles applying ML to high-grade glioma biomarkers for treatment response monitoring, prognosis, and prediction. RESULTS: Magnetic resonance imaging (MRI) is typically used throughout the patient pathway because routine structural imaging provides detailed anatomical and pathological information and advanced techniques provide additional physiological detail. Using carefully chosen image features, ML is frequently used to allow accurate classification in a variety of scenarios. Rather than being chosen by human selection, ML also enables image features to be identified by an algorithm. Much research is applied to determining molecular profiles, histological tumour grade, and prognosis using MRI images acquired at the time that patients first present with a brain tumour. Differentiating a treatment response from a post-treatment-related effect using imaging is clinically important and also an area of active study (described here in one of two Special Issue publications dedicated to the application of ML in glioma imaging). CONCLUSION: Although pioneering, most of the evidence is of a low level, having been obtained retrospectively and in single centres. Studies applying ML to build neuro-oncology monitoring biomarker models have yet to show an overall advantage over those using traditional statistical methods. Development and validation of ML models applied to neuro-oncology require large, well-annotated datasets, and therefore multidisciplinary and multi-centre collaborations are necessary.

ATRX immunohistochemistry can help refine 'not elsewhere classified' categorisation for grade II/III gliomas.

Purpose: The 2016 WHO tumour classification highlights the role of IDH1/2 gene mutation and 1p/19q co-deletion in classifying grade II/III gliomas. A recent cIMPACT-NOW update proposes the use of the term 'Not Elsewhere Classified' (NEC) for IDH-mutant, non co-deleted tumours. Here we show how the incorporation of ATRX immunohistochemistry can be used to better delineate the NEC group. Methods: Clinical data was collected for 112 patients (59% male) treated at our unit. Mutations in IDH1/2 genes were detected by pyrosequencing or immunohistochemistry, 1p/19q co-deletion was assessed with fluorescence in situ hybridisation and ATRX status was determined using immunohistochemical techniques. Tumours were grouped on the basis of molecular markers and outcomes compared. Results: The mean age of diagnosis was 42.6 years (20-73 years). There were 88 oligodendrogliomas (II = 47, III = 41), 18 diffuse astrocytomas (II = 9, III = 9) and 6 oligoastrocytomas (II = 4, III = 2). The majority of gliomas (87.5%) had mutations in IDH1/2. 1p/19q co-deletion was significantly associated with oligodendroglial morphology (p = < 0.001) and was mutually exclusive with ATRX mutation. Classification on the basis of molecular information showed a significant different in survival between the groups. Conclusions: ATRX immunohistochemisty is a useful adjunct which can be used with IDH mutation status, 1p/19q co-deletion and histological findings to further define tumour groups. More work is needed to understand the molecular profiles and prognostic implications for non co-deletion, ATRX preserved cases.

Surgery in space.

BACKGROUND: There has been renewed public interest in manned space exploration owing to novel initiatives by private and governmental bodies. Long-term goals include manned missions to, and potential colonization of, nearby planets. Travel distances and mission length required for these would render Earth-based treatment and telemedical solutions unfeasible. These issues present an anticipatory challenge to planners, and novel or adaptive medical technologies must therefore be devised to diagnose and treat the range of medical issues that future space travellers will encounter. METHODS: The aim was to conduct a search of the literature pertaining to human physiology, pathology, trauma and surgery in space. RESULTS: Known physiological alterations include fluid redistribution, cardiovascular changes, bone and muscle atrophy, and effects of ionizing radiation. Potential pathological mechanisms identified include trauma, cancer and common surgical conditions, such as appendicitis. CONCLUSION: Potential surgical treatment modalities must consist of self-sufficient and adaptive technology, especially in the face of uncertain pathophysiological mechanisms and logistical concerns.

Implementation of design of experiments approach for the micronization of a drug with a high brittle-ductile transition particle diameter.

OBJECTIVE: To optimize air-jet milling conditions of ibuprofen (IBU) using design of experiment (DoE) method, and to test the generalizability of the optimized conditions for the processing of another non-steroidal anti-inflammatory drug (NSAID). METHODS: Bulk IBU was micronized using an Aljet mill according to a circumscribed central composite (CCC) design with grinding and pushing nozzle pressures (GrindP, PushP) varying from 20 to 110 psi. Output variables included yield and particle diameters at the 50th and 90th percentile (D50, D90). Following data analysis, the optimized conditions were identified and tested to produce IBU particles with a minimum size and an acceptable yield. Finally, indomethacin (IND) was milled using the optimized conditions as well as the control. RESULTS: CCC design included eight successful runs for milling IBU from the ten total runs due to powder "blowback" from the feed hopper. DoE analysis allowed the optimization of the GrindP and PushP at 75 and 65 psi. In subsequent validation experiments using the optimized conditions, the experimental D50 and D90 values (1.9 and 3.6 µm) corresponded closely with the DoE modeling predicted values. Additionally, the optimized conditions were superior over the control conditions for the micronization of IND where smaller D50 and D90 values (1.2 and 2.7 µm vs. 1.8 and 4.4 µm) were produced. CONCLUSION: The optimization of a single-step air-jet milling of IBU using the DoE approach elucidated the optimal milling conditions, which were used to micronize IND using the optimized milling conditions.

Has the survival of patients with glioblastoma changed over the years?

BACKGROUND: Over the last decade, the approach to the management of brain tumours and the understanding of glioblastoma tumour biology has advanced and a number of therapeutic interventions have evolved, some of which have shown statistically significant effects on overall survival (OS) and progression-free survival in glioblastoma. The aim of this study is to compare survival in glioblastoma patients over a 10-year period (1999-2000 and 2009-2010). METHODS: A retrospective cohort study was performed. Identification of all histologically confirmed glioblastoma in a single centre in years 1999, 2000, 2009 and 2010, and production of survival analysis comparing 1999-2000 and 2009-2010 were achieved. RESULTS: A total of 317 patients were included in the analysis (133 in year 1999-2000, and 184 in year 2009-2010). Cox regression analysis showed that the survival was significantly longer in patients in years 2009-2010 than those in 1999-2000 at P<0.001 with HR=0.56, confidence interval (CI) (0.45-0.71). The 1- and 3-year survival rates were 20.7% and 4.4%, respectively, for patients in 1999-2000, improving to 40.0% and 10.3%, respectively, for patients in 2009-2010. The comparisons between the two groups in survival at 1, 2 and 3 years are all statistically significant at P<0.001, respectively. The median OS was 0.36 and 0.74 in 1999-2000 and 2009-2010 groups, respectively. CONCLUSIONS: Over this period, OS from glioblastoma has increased significantly in our unit. We believe this is due to the institution of evidence-based surgical and oncological strategies practised in a multidisciplinary setting.

The timing of deep brain stimulation for Parkinson disease in the UK from 1997 to 2012.

BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) for Parkinson disease (PD) has traditionally been reserved for the late stages of the disease. There is evidence that DBS is also effective if applied earlier in the disease course. Changes in the frequency of DBS procedures in the UK over a 15-year period were investigated. METHODS: A retrospective review was performed of patient age and disease duration for DBS surgery for PD in UK neurosurgical units from 1997 to 2012 using departmental databases. RESULTS: The number of DBS procedures in the UK increased from three in 1997 to over 80 per year during this period. The mean age at the time of surgery (60 years) and the mean duration of PD at the time of DBS (11 years) remained unchanged over 15 years. CONCLUSIONS: The age and disease duration at which DBS is performed for PD in the UK has been static over a 15-year period and DBS appears to remain a therapy for PD applied late in its course. This may change in the light of clinical evidence suggesting a benefit for earlier DBS.

A single thalamic target for deep brain stimulation to treat hemi-body pain syndrome.

BACKGROUND: Patients experiencing hemi-body pain represent a difficult problem when using the thalamus as a DBS target given its anatomical topology. METHODS: A 50-year-old HIV positive male underwent a right unilateral thalamic DBS to treat his severe left hemi-body central post-stroke pain following years of unsuccessful medication therapy. RESULTS: The final active contact of the electrode corresponded to stimulation of the nucleus ventrocaudalis parvocellularis internis, which has provided prolonged pain relief. CONCLUSION: To our knowledge this was the first time this pattern of pain was treated by a single thalamic DBS electrode, suggesting stimulation in this region may be a feasible target for achieving relief from chronic severe hemi-body pain.

Neurobehavioural changes in patients following brain tumour: patients and relatives perspective.

PURPOSE: Patients and relatives experiences of behavioural and personality changes following brain tumour were assessed to determine whether these changes are more prominent in the experience of patients with frontal tumours and their relatives as a first step to evaluate the need to develop appropriate support and management of such changes, which have a substantial impact on social functioning, and ultimately to improve quality of life. METHODS: Patients and relatives rated the patients' current levels of apathy, disinhibition and executive dysfunction on the Frontal Systems Behaviour Scale. Patients also completed the Hospital Anxiety and Depression Scale. The data from 28 patients with frontal tumours and 24 of their relatives, and 27 patients with nonfrontal tumours and 25 of their relatives, were analysed. RESULTS: Patients with frontal tumours rated themselves significantly higher than patients with nonfrontal tumours on all frontal systems-related behaviours. The number of patients reporting clinical levels of difficulty was significantly greater in patients with frontal tumours for disinhibition. The ratings of relatives of patients with frontal tumours were significantly higher than those of relatives of patients with nonfrontal tumours for apathy. Clinically significant levels of apathy and executive dysfunction were however reported by at least 40 % of patients and relatives regardless of tumour location. Clinical levels of anxiety were reported by significantly more patients with frontal tumours than those with nonfrontal tumours. CONCLUSION: Support and management of behavioural and personality change for patients with brain tumours and their relatives, regardless of tumour location, would be most appropriate.

Identifying functional cortical plasticity after spinal tumour resection using navigated transcranial magnetic stimulation.

Our aim was to investigate the effectiveness of navigated transcranial magnetic stimulation (nTMS) brain mapping to characterise preoperative motor impairment caused by an intradural extramedullary (IDEM) tumour and postoperative cortical functional reorganisation. Preoperative and 1-year follow-up clinical, radiological and nTMS data from a case of thoracic spinal meningioma that underwent surgical resection of the lesion were collected and compared. A 67-year-old patient presented with severe progressive thoracic myelopathy (hypertonic paraparesis, clonus, insensate urinary retention) secondary to an IDEM tumour. Initial nTMS assessment showed bilateral upper limb representation with no positive responses for both lower limbs. He underwent successful surgical resection for his IDEM (meningioma WHO grade 1). At 1-year follow-up, the patient's gait was improved and his bladder function normalised. nTMS documented positive responses for both upper and lower limbs and a decrease in the area (right side: 1.01 vs 0.39cm2; left side: 1.92 vs 0.81cm2) and volume (right side: 344.2 vs 42.4uVcm2; left side: 467.1 vs 119uVcm2) of cortical activation for both upper limbs, suggesting a functional reorganisation of the motor areas after tumour resection. nTMS motor mapping and derived metrics can characterise preoperative motor deficit and cortical plasticity during follow-up after IDEM resection.

Papillary glioneuronal tumour: a review of the literature with two illustrative cases.

We report two cases of papillary glioneuronal tumour (PGNT). One was located in the supratentorial parenchyma and the other was intraventricular. Both patients underwent gross total resection of their tumour and have returned to normal lifestyle. Papillary glioneuronal tumor is a recently described rare cerebral neoplasm. Recently classified by the World Health Organization in 2007 as a Grade I neuronal-glial tumour, these tumours are infrequent lesions that can be challenging to the practising pathologist. Patients commonly present with headaches or seizures, but may be asymptomatic with the mass discovered incidentally. The characteristic radiological, histological and immunohistochemical features are discussed. Surgical excision has been curative in most of the cases with only a handful of cases of recurrence reported. The increasing number of reports in the literature shows how PGNT forms a good example of a newly diagnosed tumour category in evolution. New classifications and re-classifications of broad categories of brain tumours will hopefully lead to a narrower diagnostic, prognostic and therapeutic profile. The even rarer presence of atypia calls for longer follow-up to help elucidate further its biological behaviour.

Peripartum haemorrhage from an intramedullary conus medullaris cavernous malformation: a rare but serious complication.

Cavernous malformations (CMs) represent about 5% of all spinal intramedullary lesions in adults. There is growing evidence to suggest that pregnancy may increase the risk of haemorrhage from CMs. We report the case of a 28-year-old woman who presented with bilateral lower limb paraparesis following an intramedullary haemorrhage from conus medullaris CM during the peripartum period. To the best of our knowledge, this is the first such case. We also review a handful of other reported cases of peripartum symptomatic spinal intramedullary CMs from the literature highlighting the pathogenesis of such cases and the best timing for intervention.

Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients.

BACKGROUND: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective therapeutic intervention in severe Parkinson's disease, its mechanism of action remains unclear. One possibility is that DBS suppresses local pathologically synchronised oscillatory activity. METHODS: To explore this, the authors recorded from DBS electrodes implanted in the STN of 16 patients with Parkinson's disease during simultaneous stimulation (pulse width 60 µs; frequency 130 Hz) of the same target using a specially designed amplifier. The authors analysed data from 25 sides. RESULTS: The authors found that DBS progressively suppressed peaks in local field potential activity at frequencies between 11 and 30 Hz as voltage was increased beyond a stimulation threshold of 1.5 V. Median peak power had fallen to 54% of baseline values by a stimulation intensity of 3.0 V. CONCLUSION: The findings suggest that DBS can suppress pathological 11-30 Hz activity in the vicinity of stimulation in patients with Parkinson's disease. This suppression occurs at stimulation voltages that are clinically effective.

Mind on Canvas: anatomy, signs and neurosurgery in art.

Throughout the ages, art and neuroscience have had a delicate yet definite relationship with reciprocal influence. By virtue of their superior power of observation, artists have often preserved neurological signs through detailed brush strokes or meticulous carvings long before it is described in scientific literature. There has been an increasing tendency to use paintings and drawings as independent sources for investigation of scientific history. In neuroanatomy, these tools have helped reveal the complex interrelation between arts and neurosciences that on the surface often appear as highly polarized worlds. In this article we begin by giving a brief introduction to the general relationship between neuroscience and art as depicted in paintings and drawings, and describe the artistic tendencies of the early neuroanatomists. We aim to highlight the existence of neurosurgical themes within paintings and drawings from different eras.

Effect of electrode contact location on clinical efficacy of pallidal deep brain stimulation in primary generalised dystonia.

OBJECTIVES: To determine the effect of electrode contact location on efficacy of bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for primary generalised dystonia (PGD). SUBJECTS AND METHODS: A consecutive series of 15 patients with PGD (10 females, mean age 42 years, seven DYT1) who underwent bilateral GPi DBS, were assessed using the Burke-Fahn-Marsden (BFM) dystonia scale before and 6 months after surgery. The position of the stimulated electrode contact(s) was determined from the postoperative stereotactic MRI. Contralateral limb and total axial BFM subscores were compared with the location of the stimulated contact(s) within the GPi. RESULTS: The mean total BFM score decreased from 38.9 preoperatively to 11.9 at 6 months, an improvement of 69.5% (p<0.00001). Cluster analysis of the stimulated contact coordinates identified two groups, distributed along an anterodorsal to posteroventral axis. Clinical improvement was greater for posteroventral than anterodorsal stimulation for the arm (86% vs 52%; p<0.05) and trunk (96% vs 65%; p<0.05) and inversely correlated with the y coordinate. For the leg, posteroventral and anterodorsal stimulation were of equivalent efficacy. Overall clinical improvement was maximal with posteroventral stimulation (89% vs 67%; p<0.05) and inversely correlated with the y (A-P) coordinate (r = -0.62, p<0.05). CONCLUSION: GPi DBS is effective for PGD but outcome is dependent on contact location. Posteroventral GPi stimulation provides the best overall effect and is superior for the arm and trunk. These results may be explained by the functional anatomy of GPi and its outflow tracts.

Recurrence of a metastatic tumour in association with a cranial fixation device.

We present a case of recurrent metastatic brain tumour spread across a cranial fixation device.

Carrier-free high-dose dry powder inhaler formulation of ibuprofen: Physicochemical characterization and in vitro aerodynamic performance.

OBJECTIVE: To investigate influences of capsule fill weight, batch size, and storage conditions on in vitro aerodynamic performance of jet-milled ibuprofen (IBU) carrier-free, dry powder inhaler formulations. MATERIALS AND METHODS: Milled and unmilled IBU samples were characterized thermally and spectroscopically. Physicochemical characterization was performed by quantifying specific surface area, density, and angle of repose. Performance testing was conducted on IBU formulations in combination with a high resistance Monodose RS01 using Next Generation Impactor. RESULTS AND DISCUSSION: There were no detectable differences between IBU samples thermally and spectroscopically. The milled IBU sample exhibited improved powder flow in comparison with the unmilled sample. The milled IBU powders possessed surprisingly high in vitro aerodynamic performance with a fine particle fraction percentage between 67 and 85%, and a minimum respirable fraction percentage of 49%. The capsule fill weights, from 10 to 50mg, and milling batch sizes did not significantly influence performance. The importance of powder conditioning following milling was illustrated as the storage duration and temperature negatively affected performance. CONCLUSION: In vitro aerodynamic performance of IBU is independent of capsule fill weight and batch size; however, some period of powder conditioning is recommended to reduce variability in formulation performance.

Hollow crystalline straws of diclofenac for high-dose and carrier-free dry powder inhaler formulations.

OBJECTIVE: To crystallize diclofenac (DF) from diclofenac sodium (DFNa), to micronize DF and DFNa, and to evaluate in vitro aerodynamic performance of the jet-milled formulations MATERIALS AND METHODS: From the acidic titration of aqueous DFNa, DF crystals were formed and were identified using thermal analysis, spectroscopy, and X-ray powder diffraction. Following the micronization of the DF and DFNa powders, the recovered samples were imaged, and their particle size distributions were evaluated. Samples before and after jet millings were characterized, and in vitro aerodynamic performance testing was performed on the DF sample before jet milling and the DF and DFNa samples following jet milling. RESULTS AND DISCUSSION: Hollow needles of DF were precipitated. With similar particle size distributions, the jet-milled DFNa sample from the collection bag, and the DF sample from the cyclone were used for further characterization. Despite different deposition patterns in the Next Generation Impactor, the DF hollow needles had a comparable respirable fraction percentage to the jet-milled DF and DFNa particles. However, the jet-milled DF formulation had the best in vitro aerodynamic performance. CONCLUSIONS: Hollow, crystalline needles of DF were formed and possessed promising aerosol performance in comparison with the jet-milled powders.