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Background Diffuse gliomas have an increased biological aggressiveness across the World Health Organization (WHO) grading system. The implications of glioma grading on the primary motor cortex (M1)-corticospinal tract (CST) excitability is unknown. Objective To assess the excitability of the motor pathway with navigated transcranial magnetic stimulation (nTMS). Methods Retrospective cohort study of patients admitted for surgery with diffuse gliomas within motor eloquent areas. Demographic, clinical, and nTMS-related variables were collected. The Cortical Excitability Score (CES 0 to 2 according to the number of abnormal interhemispheric resting motor threshold (RMT) ratios) was calculated for patients where bilateral upper and lower limb mapping was performed. Results A total of 45 patients were included: 9 patients had a low-grade glioma and 36 patients had a high-grade glioma. The unadjusted analysis revealed an increase in the latency of the motor evoked potential of the lower limb with an increase of the WHO grade (P = .038). The adjusted analysis confirmed this finding (P = .013) and showed a relation between the increase in the WHO and a decreased RMT (P = .037) of the motor evoked responses in the lower limb. When CES was calculated, an increase in the score was related with an increase in the WHO grade (unadjusted analysis-P = .0001; adjusted analysis-P = .001) and in isocitrate dehydrogenase (IDH) wild-type tumors (unadjusted analysis-P = .020). Conclusion An increase in the WHO grading system and IDH wild-type tumors are associated with an abnormal excitability of the motor eloquent areas in patients with diffuse gliomas.

BACKGROUND This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status. METHODS Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health). RESULTS With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P

Background Lesions within the corticospinal tract (CST) represent significant surgical challenge with a delicate functional trade-off that should be integrated in the overall patient-centred treatment plan. Methods Patients with lesions within the CST with preoperative cortical and subcortical mapping (nTMS and tractography), intraoperative mapping and intraoperative provisional histological information (smear +- 5-ALA) were included. This independently acquired information was integrated in a decision-making process model to determine the intraoperative extent of resection. Results 10 patients (6 patients with metastatic precentral tumour; 1 patient with Grade III and 2 patients with grade IV gliomas; 1 patient with precentral vascular malformation) were included in the study. Majority of the patient had pre-operative motor deficit (60%). 50% patients underwent gross total resection and 40% patients underwent near total resection of the lesions. In only one patient, no surgical resection was possible after both pre-operative and intraoperative mapping. 70% of patients remained stable postoperatively and 20% improved from previous motor weakness. Conclusion The independently acquired anatomical (anatomical MRI) and functional (nTMS and tractography) in patients with CST lesions provide a more accurate guide for resection. The inclusion of the histological information (smear +- 5-ALA) further allows the surgical team to balance the potential functional risks within the global treatment plan. Therefore, the patient is kept at the centre of the informed decision making process.

OBJECTIVES: Surgery for lesions in eloquent brain areas is challenging due to the underlying risk of causing permanent neurological deficits. To date, Direct Cortical Stimulation (DCS) and intra-operative neuro-monitoring (IOM) represent the gold standard in minimising such risk. Recently, Transcranial Magnetic Stimulation (TMS) has emerged as a mapping tool that assists in optimising surgical planning. The aim of this study is to validate our TMS findings against DCS. METHODS: Retrospective single-centre analysis of 35 adult patients with TMS, DCS and IOM for space occupying lesion (SOL) at King’s College Hospital from February 2017 to February 2018. Patients with arteriovenous malformation were excluded from analysis. We collected data on patient demographics, tumour entity/location, extent of resection (EoR), change of surgical strategy, neurological outcome, and correlated TMS with DCS/IOM. RESULTS: 24/35 patients (68.6%) had pre-operative motor mapping and 11/35 (31.4%) were mapped for language. Histopathology demonstrated a glioma in 85.7% of patients (high grade n=24; low grade n=6) and metastasis (n=2), cavernoma (n=1) and other cases (n=2). TMS resulted in a change of surgical strategy in 34.3% (craniotomy size n=7; surgical pathway n=3; EoR n=1; surgical indication n=1). Sensitivity of TMS for language was 70.6% with a positive predictive value of 60.0% (n=9). TMS motor mapping correlated with DCS/IOM in all cases with snapshot hotspot conformity of 100% (n=5). A total of 12 patients had a new transient neurological deficit which resolved/significantly improved except for one case (expressive dysphasia). CONCLUSIONS: TMS is a non-invasive, safe and effective adjunct in surgery planning in eloquent brain areas. It is reliable in predicting M1/motor mapping and shows promising results for language mapping. Larger randomised controlled trials are needed to validate these findings.

Sylvian fissure meningiomas (SFMs) represent a rare subgroup of nondural-based tumors arising from the meningothelial cells within the arachnoid of the Sylvian fissure. SFMs are more frequent in young males, usually manifest with seizures and display the same radiological features of meningiomas in other locations. Although the absence of dural attachment makes these tumors suitable for a complete resection, their anatomical relationships with the middle cerebral artery branches have impaired its achievement in half of them. To the best of our knowledge, only five atypical WHO grade II SFMs have been previously described. We provide a literature review of SFMs WHO grades I–II and discuss common characteristics and surgical challenges we found in a similar case.

Background Surgery for lesions in eloquent brain areas remains challenging owing to the risk of permanent neurological deficits. To date, direct electrical stimulation (DES) and intraoperative neuromonitoring represent the reference standard. Recently, navigated transcranial magnetic stimulation (nTMS) has emerged as a mapping tool to optimize surgical planning. Our aim was to correlate nTMS with the intraoperative findings and assess its effects on surgical decision-making. Methods We retrospectively reviewed our series of patients who had undergone craniotomy for removal of a brain tumor at our institution with preoperative nTMS, intraoperative neuromonitoring, and DES from February 2017 to February 2018. Demographic data, tumor entity and location, extent of resection, change in surgical approach, and neurological outcome were collected. Results Of 35 patients, 24 (68.6%) had undergone preoperative motor mapping and 11 (31.4%) had undergone mapping for language. Histopathological examination demonstrated glioma in 88.6% (high grade, n = 24; low grade, n = 6), metastasis (n = 2), epidermoid cyst (n = 1), and cavernoma (n = 1). nTMS resulted in change in the surgical strategy in 31.5% (craniotomy size, n = 7; access pathway, n = 3; surgical indication, n = 1). The specificity of nTMS for language was 66.7%, with a negative predictive value of 74.1%. nTMS motor mapping correlated with DES in all cases, with a mean abductor pollicis brevis hotspot distance of 3.50 ± 0.66 mm (n = 9). Conclusions nTMS is a safe, noninvasive adjunctive tool for preoperative mapping of brain tumors in eloquent areas. Furthermore, nTMS can influence the surgical decisions in up to one third of patients in our experience.

Background Navigated transcranial magnetic stimulation (nTMS) is a nonsurgical mapping technique used in mapping of motor and language eloquent areas within and/or surrounding brain tumors. Previous reports support this as a safe technique with minor side effects associated with minor headaches and discomfort around the stimulation area. Currently there are no published reports concerning the accuracy and safety of this procedure in patients with a titanium cranioplasty in situ. Case Presentation A 59-year-old lady was diagnosed with a recurrent glioma in the context of increasing seizure frequency, left-sided numbness, and weakness. She was diagnosed with a World Health Organization grade 2 oligodendroglioma 10 years before her presentation, which was initially treated with radiotherapy and then surgical resection of this lesion 5 years later. The procedure was complicated with a wound infection, treated with a craniectomy and wound washout, followed by a titanium cranioplasty. Before proceeding with surgery for recurrence, nTMS was performed for motor mapping. No complications were identified. She underwent a craniotomy for tumor resection with aminolevulinic acid HCl (Gliolan), and the tumor was completely removed. Intraoperatively, the direct cortical stimulation correlated with the preoperative nTMS. The pathologic diagnosis on recurrence was an anaplastic oligodendroglioma grade III, and the patient is currently undergoing adjuvant chemotherapy. Conclusion This report confirms that nTMS is a safe and accurate procedure in patients who have a titanium cranioplasty in situ.

Background: Intradural disc herniations (IDH) are rare, particularly in the cervical spine, where they account for less than 5% of all discs. Adhesions between the ossified/calcified posterior longitudinal ligament (OPLL), dura, and ossified/calcified disc herniations increase the complexity of resecting these cervical lesions. Case Description: A 42-year-old male presented with a rapidly progressive cervical myelopathy over a 2-month period. This was attributed to an ossified/calcified intradural cervical disc herniation in conjunction with OPLL. The anterior cervical discectomy and fusion (ACDF) resulted in a dural defect but there was no cerebrospinal fluid (CSF) fistula as the arachnoid membrane remained intact. Had there been a CSF leak, it would have warranted both wound-peritoneal (WP) and lumbo-peritoneal shunts (LP). The surgeons should have anticipated that a CSF leak would likely occur prior to performing the ACDF, and should have prophylactically prepared and draped the abdomen for a potential WP, followed by a LP shunt. Three months postoperatively, the patient's proprioceptive deficit improved, and he almost completely recovered motor function. Conclusion: Performing an ACDF for resection of an intradural calcified/ossified disc with OPLL often results in both a dural defect and CSF fistula. As the arachnoid membrane rarely remains intact, the spine surgeon should be prepared to immediately perform both a WP shunt, and subsequently, an LP. In this case, following an ACDF, resection of an intradural ossified disc with OPLL resulted in an isolated dural defect without a CSF fistula and did not require no dural repair or shunting procedures.

External ventricular drain (EVD) insertion is a common neurosurgical procedure with a significant risk of ventriculostomy-associated infections (VAIs), other morbidities and mortality. Several risk factors have been identified but their effect is unclear. Our primary objective was to assess whether recurrent EVD sampling increased the risk of VAIs. The secondary objective was to explore the effect of sampling frequency, duration of EVD stay, presence of cerebrospinal fluid leak and concurrent infections. Ours was a retrospective, single-centre, age-matched, case control study of 83 patients and 249 controls who underwent EVD insertion between 1 January 2010 – 31 December 2016. Patients with primary CNS infections, age under 1 year and death within 5 days of EVD insertion were excluded. Blinded abstractors collected all patient data through the electronic patient record system and regression analysis was used to compare the two groups. Sampling the EVD more than once did not increase the risk of infection (OR 0.47, 95% CI 0.27–0.83, p = 0.01). Risk factors significantly associated with VAI included CSF leak (OR 2.06, 95% CI 1.16–3.67, p = 0.01), concurrent infection (OR 1.85, 95% CI 1.09–3.16, p = 0.02), and an EVD duration of >10 days (OR 2.28, 95% CI 1.24–4.18, p = 0.01). Our findings do not support the notion that increased sampling of EVDs is associated with a higher risk of VAI. CSF leaks, concurrent infection and long-term EVDs are also statistically significant risk factors for infection.

Introduction Tumor biopsies for detecting EGFR mutations in advanced NSCLC are invasive, costly, and not always feasible for patients with late-stage disease. The clinical utility of the cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc., Pleasanton, CA) with plasma samples from patients with NSCLC at disease progression after previous EGFR tyrosine kinase inhibitor therapy was investigated to determine eligibility for osimertinib treatment. Methods Matched tumor tissue and plasma samples from patients screened for the AURA extension and AURA2 phase II studies were tested for EGFR mutations by using tissue- and plasma-based cobas EGFR mutation tests. Plasma test performance was assessed by using the cobas tissue test and a next-generation sequencing method (MiSeq [Illumina Inc., San Diego, CA]) as references. The objective response rate, measured by blinded independent central review, was assessed in patients receiving osimertinib with a plasma T790M mutation–positive status. Results During screening, 551 patients provided matched tumor tissue and plasma samples. Pooled analysis of the positive and negative percent agreements between the cobas plasma and tissue tests for detection of T790M mutation were 61% and 79%, respectively. Comparing cobas plasma test with next-generation sequencing demonstrated positive and negative percent agreements of 90% or higher. The objective response rate was 64% (95% confidence interval: 57–70) in T790M mutation–positive patients by both cobas tissue and plasma tests (evaluable for response). Conclusions The cobas plasma test detected the T790M mutation in 61% of tumor tissue T790M mutation–positive patients. To mitigate the risk of false-negative plasma results, patients with a negative plasma result should undergo a tissue test where feasible.

ObjectivesMacrophages are central to the inflammatory processes driving rheumatoid arthritis (RA) synovitis. The molecular pathways that are induced in synovial macrophages and thereby promote RA disease pathology remain poorly understood.MethodsWe used microarray to characterise the transcriptome of synovial fluid (SF) macrophages compared with matched peripheral blood monocytes from patients with RA (n=8).ResultsUsing in silico pathway mapping, we found that pathways downstream of the cholesterol activated liver X receptors (LXRs) and those associated with Toll-like receptor (TLR) signalling were upregulated in SF macrophages. Macrophage differentiation and tumour necrosis factor α promoted the expression of LXRα. Furthermore, in functional studies we demonstrated that activation of LXRs significantly augmented TLR-driven cytokine and chemokine secretion.ConclusionsThe LXR pathway is the most upregulated pathway in RA synovial macrophages and activation of LXRs by ligands present within SF augments TLR-driven cytokine secretion. Since the natural agonists of LXRs arise from cholesterol metabolism, this provides a novel mechanism that can promote RA synovitis.

Magnesium is the second most abundant intracellular cation and plays an essential role in neuronal, skeletal and cardiac tissue. Hypomagnesaemia can cause hypocalcaemia by inhibiting parathyroid hormone release and inducing resistance at its receptor sites. Untreated hypomagnesaemia can lead to tetany, recurrent seizures, status epilepticus and life-threatening arrhythmias. Primary hypomagnesaemia with secondary hypocalcaemia (HSH) is a rare metabolic disorder of intestinal magnesium absorption. The condition typically presents in the neonatal period with neuromuscular excitability and seizures refractory to antiepileptic therapy. Early diagnosis and prompt magnesium replacement are essential to prevent death or long-term neurodevelopmental sequelae. Fewer than a hundred cases are reported in the literature. Recent advances have added significantly to our understanding of the genetic basis of HSH. We report the presentation and long-term follow-up of an affected female who was found to have a mutation in the transient receptor potential melastatin 6 (TRPM6) gene, encoding a transient receptor potential cation channel.

Objective To determine whether elevation of a biological marker of inflammation would be a better predictor of bronchopulmonary dysplasia (BPD) development than lung function measurement results. Design Prospective study. Setting Tertiary neonatal intensive care unit. Patients 78 prematurely born infants (median gestational age 29 (range 24–32) weeks) were studied; 39 developed BPD. Interventions BPD was diagnosed as oxygen dependence at 28 days. Main outcome measures Levels of a biological marker of inflammation (carbon monoxide) were assessed by measurement of end-tidal carbon monoxide (ETCO) and lung function by measurement of functional residual capacity (FRC) and compliance (Crs) and resistance (Rrs) of the respiratory system on days 3 and 14 after birth. Possible predictive factors were modelled for BPD and for BPD severity. Results Gestational age, birth weight, ETCO, FRC and Crs results on days 3 and 14 differed significantly between infants who did and did not develop BPD. In multifactorial logistic regression, only birth weight and ETCO results (on day 14) remained significant predictors of BPD with an area under the curve of 0.97. The final multifactorial model for the severity of BPD included those two factors, plus septic episodes. Conclusion These results emphasise the importance of ongoing inflammation in the development of BPD; ETCO levels, rather than lung function test results, were the more accurate predictor of BPD development.

TPS3120Background: Immune checkpoint inhibitor (ICI) containing regimens have significantly improved survival outcomes in first- and second-line non-small cell lung cancer (NSCLC). However, the maj...

Previously, proteomic methods were applied to characterise differentially expressed proteins in microdissected pancreatic ductal adenocarcinoma cells.To report that CapG and a related protein, gelsolin, which have established roles in cell motility, are overexpressed in metastatic pancreatic cancer; and to describe their pattern of expression in pancreatic cancer tissue and their effect on cell motility in pancreatic cancer cell lines.CapG was identified by mass spectrometry and immunoblotting. CapG and gelsolin expression was assessed by immunohistochemical analysis on a pancreatic cancer tissue microarray and correlated with clinical and pathological parameters. CapG and gelsolin levels were reduced using RNA interface in Suit-2, Panc-1 and MiaPaCa-2 cells. Cell motility was assessed using modified Boyden chamber or wound-healing assays.Multiple isoforms of CapG were detected in pancreatic cancer tissue and cell lines. Immunohistochemical analysis of benign (n = 44 patients) and malignant (n = 69) pancreatic ductal cells showed significantly higher CapG staining intensity in nuclear (p0.001) and cytoplasmic (p0.001) compartments of malignant cells. Similarly, gelsolin immunostaining of benign (n = 24 patients) and malignant (n = 68 patients) pancreatic ductal cells showed higher expression in both compartments (both p0.001). High nuclear CapG was associated with increased tumour size (p = 0.001). High nuclear gelsolin was associated with reduced survival (p = 0.01). Reduction of CapG or gelsolin expression in cell lines by RNAi was accompanied by significantly impaired motility.Up regulation of these actin-capping proteins in pancreatic cancer and their ability to modulate cell motility in vitro suggest their potentially important role in pancreatic cancer cell motility and consequently dissemination.

carotid artery stump pressures of 75yrs (p 75yrs versus 11% in those 75yrs versus 3.4% in those 75yrs was not associated with an increased morbidity or mortality. Intra-operatively reduced carotid stump pressures and MCA velocities were not associated with increased use of shunting or patching. This study supports CE as a safe procedure in the elderly, especially in centres with low complication rates.

A 47 year old Zimbabwean woman presented with gradual onset shortness of breath of two months’ duration. She was breathless at rest, with a non-productive cough, and had had a fever for one week. She had no history of haemoptysis or night sweats but had lost 5 kg in weight over two months. No cardiac symptoms were elicited. She had no previous medical problems, history of smoking, or recent foreign travel. On examination, she had a regular pulse of 122 beats per minute and a respiratory rate of 22 breaths per minute. Her temperature was 39°C and she had an oxygen saturation of 91% on air. There was no palpable lymphadenopathy. Her chest was resonant to percussion, with vesicular breath sounds and no added sounds. Examination of all other systems was normal. A chest radiograph was taken. (1) Describe the chest radiograph findings. (2) What is the differential diagnosis and most likely diagnosis? (3) …