Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.

Long-term mood, quality of life, and seizure freedom in intracranial EEG epilepsy surgery.

OBJECTIVES: To determine the long-term outcomes in patients undergoing intracranial EEG (iEEG) evaluation for epilepsy surgery in terms of seizure freedom, mood, and quality of life at St. Vincent's Hospital, Melbourne. METHODS: Patients who underwent iEEG between 1999 and 2016 were identified. Patients were retrospectively assessed between 2014 and 2017 by specialist clinic record review and telephone survey with standardized validated questionnaires for: 1) seizure freedom using the Engel classification; 2) Mood using the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E); 3) Quality-of-life outcomes using the QOLIE-10 questionnaire. Summary statistics and univariate analysis were performed to investigate variables for significance. RESULTS: Seventy one patients underwent iEEG surgery: 49 Subdural, 14 Depths, 8 Combination with 62/68 (91.9%) of those still alive, available at last follow-up by telephone survey or medical record review (median of 8.2 years). The estimated epileptogenic zone was 62% temporal and 38% extra-temporal. At last follow-up, 69.4% (43/62) were Engel Class I and 30.6% (19/62) were Engel Class II-IV. Further, a depressive episode (NDDI-E > 15)was observed in 34% (16/47), while a 'better quality of life' (QOLIE-10 score < 25) was noted in 74% (31/42). Quality of life (p < 0.001) but not mood (p = 0.24) was associated with seizure freedom. SIGNIFICANCE: Long-term seizure freedom can be observed in patients undergoing complex epilepsy surgery with iEEG evaluation and is associated with good quality of life.

6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.

BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. FUNDING: UK National Institute for Health Research, Health Technology Assessment Programme.

Adherence to ESC cardiac resynchronization therapy guidelines: findings from the ESC CRT Survey II.

AIMS: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with heart failure (HF) and electrical dyssynchrony. The European Society of Cardiology (ESC) Guidelines provide evidence-based recommendations indicating optimal patient selection for CRT implantation in both the 2013 European Heart Rhythm Association (EHRA) and the 2016 Heart Failure Association (HFA) Guidelines. We assessed the adherence to guidelines and identified factors associated with guideline adherence. METHODS AND RESULTS: In 2016, the HFA and EHRA conducted the CRT Survey II in 42 ESC countries. The data collected were sufficient to evaluate adherence to guidelines in 8021 patients. Of these, 67% had a Class I guideline indication for CRT implantation, which was significantly correlated with female gender (1.70, P < 0.0001), age <75 years (1.55, P < 0.0001), non-ischaemic HF aetiology (1.22, P < 0.0001), and elective admission (1.87, P < 0.0001). A further 26% of implants had a Class IIa indication, 5% IIb and only 2% a contraindication to CRT-a Class III indication. Patients implanted under Level IIa indications were much more likely to have more comorbidities than patients implanted under Level I indications. However, there were large variations in guideline adherence between ESC countries. CONCLUSION: Implanters in ESC member states demonstrate a high degree of adherence to ESC guidelines with 98% of implants having a documented Class I, IIa or IIb indication. Cardiac resynchronization therapy implantation without a Class I indication was more likely in men, patients age ≥75 years, with HF of ischaemic origin and in patients admitted to hospital acutely.

Interictal and ictal source localization for epilepsy surgery using high-density EEG with MEG: a prospective long-term study.

Drug-resistant focal epilepsy is a major clinical problem and surgery is under-used. Better non-invasive techniques for epileptogenic zone localization are needed when MRI shows no lesion or an extensive lesion. The problem is interictal and ictal localization before propagation from the epileptogenic zone. High-density EEG (HDEEG) and magnetoencephalography (MEG) offer millisecond-order temporal resolution to address this but co-acquisition is challenging, ictal MEG studies are rare, long-term prospective studies are lacking, and fundamental questions remain. Should HDEEG-MEG discharges be assessed independently [electroencephalographic source localization (ESL), magnetoencephalographic source localization (MSL)] or combined (EMSL) for source localization? Which phase of the discharge best characterizes the epileptogenic zone (defined by intracranial EEG and surgical resection relative to outcome)? Does this differ for interictal and ictal discharges? Does MEG detect mesial temporal lobe discharges? Thirteen patients (10 non-lesional, three extensive-lesional) underwent synchronized HDEEG-MEG (72-94 channel EEG, 306-sensor MEG). Source localization (standardized low-resolution tomographic analysis with MRI patient-individualized boundary-element method) was applied to averaged interictal epileptiform discharges (IED) and ictal discharges at three phases: 'early-phase' (first latency 90% explained variance), 'mid-phase' (first of 50% rising-phase, 50% mean global field power), 'late-phase' (negative peak). 'Earliest-solution' was the first of the three early-phase solutions (ESL, MSL, EMSL). Prospective follow-up was 3-21 (median 12) months before surgery, 14-39 (median 21) months after surgery. IEDs (n = 1474) were recorded, seen in: HDEEG only, 626 (42%); MEG only, 232 (16%); and both 616 (42%). Thirty-three seizures were captured, seen in: HDEEG only, seven (21%); MEG only, one (3%); and both 25 (76%). Intracranial EEG was done in nine patients. Engel scores were I (9/13, 69%), II (2/13,15%), and III (2/13). MEG detected baso-mesial temporal lobe epileptogenic zone sources. Epileptogenic zone OR [odds ratio(s)] were significantly higher for earliest-solution versus early-phase IED-surgical resection and earliest-solution versus all mid-phase and late-phase solutions. ESL outperformed EMSL for ictal-surgical resection [OR 3.54, 95% confidence interval (CI) 1.09-11.55, P = 0.036]. MSL outperformed EMSL for IED-intracranial EEG (OR 4.67, 95% CI 1.19-18.34, P = 0.027). ESL outperformed MSL for ictal-surgical resection (OR 3.73, 95% CI 1.16-12.03, P = 0.028) but was outperformed by MSL for IED-intracranial EEG (OR 0.18, 95% CI 0.05-0.73, P = 0.017). Thus, (i) HDEEG and MEG source solutions more accurately localize the epileptogenic zone at the earliest resolvable phase of interictal and ictal discharges, not mid-phase (as is common practice) or late peak-phase (when signal-to-noise ratios are maximal); (ii) from empirical observation of the differential timing of HDEEG and MEG discharges and based on the superiority of ESL plus MSL over either modality alone and over EMSL, concurrent HDEEG-MEG signals should be assessed independently, not combined; (iii) baso-mesial temporal lobe sources are detectable by MEG; and (iv) MEG is not 'more accurate' than HDEEG-emphasis is best placed on the earliest signal (whether HDEEG or MEG) amenable to source localization. Our findings challenge current practice and our reliance on invasive monitoring in these patients. 10.1093/brain/awz015_video1 awz015media1 6018582479001.

Expert recommendations on the management of hypertension in patients with ovarian and cervical cancer receiving bevacizumab in the UK.

Bevacizumab is an anti-vascular endothelial growth factor monoclonal antibody that may prolong survival in ovarian and cervical cancer when given in combination with chemotherapy. It works by blocking the signalling pathways that are required for tumour angiogenesis, potentially limiting the cancer's ability to grow and spread. Hypertension is a known side effect of all angiogenesis inhibitors and could lead to interruption or premature discontinuation of effective anti-cancer treatment. Hypertension may also act as a barrier to the initiation of such treatment. In this review, we aim to present clear and practical recommendations on the management of blood pressure in ovarian and cervical cancer patients before, during and after bevacizumab treatment. This guidance covers considerations before initiating bevacizumab therapy and recommendations on the management of patients who develop hypertension, or who experience worsening of pre-existing hypertension, during bevacizumab treatment, and once the course of bevacizumab has been completed. These recommendations were developed collaboratively by a group of clinicians, comprising cardiologists, oncologists, a general practitioner and specialist oncology nurses, with expertise and practical experience in either oncology or hypertension. The aim of these recommendations is to support oncologists with hypertension assessment and management to facilitate starting or continuing bevacizumab.

Trastuzumab-associated cardiac events in the Persephone trial.

BACKGROUND: We report cardiac events in the Persephone trial which compares 6-12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer. METHODS: Clinical cardiac events were defined as any of the following: symptoms and/or signs of congestive heart failure (CHF) and new or altered CHF medication. In addition, left ventricular ejection fraction (LVEF) was measured at baseline and then 3 monthly for 12 months. RESULTS: A total of 2500 patients, aged 22-82, were included: 1251 randomised to 12 months and 1249 to 6 months of trastuzumab treatment. A total of 93% (2335/2500) received anthracyclines, 49% of these (1136/2335) with taxanes. Cardiotoxicity delayed treatment in 6% of 12-month and 4% of 6-month patients (P=0.01), and stopped treatment early in 8% (96/1214) of 12-month and 4% (45/1216) of 6-month patients (P<0.0001). Between 7 and 12 months, more 12-month than 6-month patients had LVEFs<50% (8% vs 5%; P=0.004). LVEFs showed quadratic change over time, and 6-month patients had a more rapid recovery (P=0.02). In a landmark analysis twice as many 12-month patients, free of cardiac events at 6 months, had cardiac problems in months 7-12 (6% (66/1046) vs 3% (29/1035) of 6-month patients (P=0.0002)). Lower baseline LVEF predicted more cardiac dysfunction in both arms (reference ⩾65%: 55 to <65% OR 1.61 (95% CI 1.26-2.04); <55% OR 5.22 (3.42-7.95)) as did increasing age (reference <50: 50-59 OR 1.58 (1.17-2.12), 60-69 OR 1.91 (1.42-2.57)) 70+ OR 2.72 (1.82-4.08)) and prior use of cardiac medication (OR 8.46 (4.69-15.25)). >3 cycles of anthracycline was associated with higher risk of cardiac events only for 12-month patients (OR 1.41 (1.04-1.90)), and not for 6-month patients (OR 1.28 (0.91-1.79)). CONCLUSIONS: We demonstrate significantly fewer cardiac events from 6 months of adjuvant trastuzumab compared with that from 12 months. This cardiac signal adds importance to the question of the optimum duration of adjuvant trastuzumab treatment. If 6 months is proven to have non-inferior outcomes to 12 months treatment, these data would support 6 months as the standard of care.

Australia's seizure divide - indigenous versus non-indigenous seizure hospitalization.

Indigenous Australians suffer the highest mortality and morbidity rates of any ethnic minority in the developed world. To determine if the health outcome gulf between indigenous and non-indigenous Australians also applied to seizures, we conducted a retrospective analysis of seizure hospitalization (1998-2004) based on ethnicity (indigenous (I) and non-indigenous (NI)) for four Australian jurisdictions - Northern Territory (NT), Queensland (Qld), South Australia (SA), and Western Australia (WA). Total admissions were converted to age-standardized rates (ASR) and I/NI ASR ratios (I/NIRR) and compared across multiple variables. The summed admission (combined jurisdictions over six years) was 71,185 (I=11,593 and NI=59,592). Seizure hospitalization rate was always higher in the indigenous population (six-year I/NIRR - NT=5.6, Qld=4.0, SA=6.4, and WA=10.9; combined jurisdictions=5.6). Disparity was greatest for ages 40-64years (13.8) and 15-39years (7.0) and for indigenous males (7.4). As socioeconomic status rose, non-indigenous admission rates fell (ASR=1.7 to 1.1), yet indigenous admission rates rose (ASR=7.9 to 14.0). Indigenous emergency to elective admission ratios were higher (I=27 and NI=8), as were readmissions (1.5-2 fold), self-discharge separations (I=9.4% and NI=1.4%), bed days (I/NIRR=5.1), and admissions with an additional diagnosis (I/NIRR=3.3) or procedure (I/NIRR=3.4). Indigenous Australians maintained disproportionately high rates of emergency seizure hospitalization; from 1998 to 2004, the combined jurisdiction rate was more than five times the mean non-indigenous rate. Indigenous males aged 15-64years were overrepresented. Indigenous patients had lengthier admissions but higher self-discharge and readmission rates. The socioeconomic data raise the concern that social disadvantage restricts access to hospital-based seizure care for indigenous patients.

EEG Source Imaging-Clinical Considerations for EEG Acquisition and Signal Processing for Improved Temporo-Spatial Resolution.

SUMMARY: EEG source imaging (ESI) has gained traction in recent years as a useful clinical tool for the noninvasive surgical work-up of patients with drug-resistant focal epilepsy. Despite its proven benefits for the temporo-spatial modeling of spike and seizure sources, ESI remains widely underused in clinical practice. This partly relates to a lack of clarity around an optimal approach to the acquisition and processing of scalp EEG data for the purpose of ESI. Here, we describe some of the practical considerations for the clinical application of ESI. We focus on patient preparation, the impact of electrode number and distribution across the scalp, the benefit of averaging raw data for signal analysis, and the relevance of modeling different phases of the interictal discharge as it evolves from take-off to peak. We emphasize the importance of recording high signal-to-noise ratio data for reliable source analysis. We argue that the accuracy of modeling cortical sources can be improved using higher electrode counts that include an inferior temporal array, by averaging interictal waveforms rather than limiting ESI to single spike analysis, and by careful interrogation of earlier phase components of these waveforms. No amount of postacquisition signal processing or source modeling sophistication, however, can make up for suboptimally recorded scalp EEG data in a poorly prepared patient.

Association between patent foramen ovale and migraine: evidence from a resting-state fMRI study.

A relationship between migraine without aura (MO) and patent foramen ovale (PFO) has been observed, but the neural basis underlying this relationship remains elusive. Utilizing independent component analysis via functional magnetic resonance imaging, we examined functional connectivity (FC) within and across networks in 146 patients with MO (75 patients with and 71 patients without PFO) and 70 healthy controls (35 patients each with and without PFO) to elucidate the individual effects of MO and PFO, as well as their interaction, on brain functional networks. The main effect of PFO manifested exclusively in the FC among the visual, auditory, default mode, dorsal attention and salience networks. Furthermore, the interaction effect between MO and PFO was discerned in brain clusters of the left frontoparietal network and lingual gyrus network, as well as the internetwork FC between the left frontoparietal network and the default mode network (DMN), the occipital pole and medial visual networks, and the dorsal attention and salience networks. Our findings suggest that the presence of a PFO shunt in patients with MO is accompanied by various FC changes within and across networks. These changes elucidate the intricate mechanisms linked to PFO-associated migraines and provide a basis for identifying novel noninvasive biomarkers.

How far back do we need to look to capture diagnoses in electronic health records? A retrospective observational study of hospital electronic health record data.

OBJECTIVES: Analysis of routinely collected electronic health data is a key tool for long-term condition research and practice for hospitalised patients. This requires accurate and complete ascertainment of a broad range of diagnoses, something not always recorded on an admission document at a single point in time. This study aimed to ascertain how far back in time electronic hospital records need to be interrogated to capture long-term condition diagnoses. DESIGN: Retrospective observational study of routinely collected hospital electronic health record data. SETTING: Queen Elizabeth Hospital Birmingham (UK)-linked data held by the PIONEER acute care data hub. PARTICIPANTS: Patients whose first recorded admission for chronic obstructive pulmonary disease (COPD) exacerbation (n=560) or acute stroke (n=2142) was between January and December 2018 and who had a minimum of 10 years of data prior to the index date. OUTCOME MEASURES: We identified the most common International Classification of Diseases version 10-coded diagnoses received by patients with COPD and acute stroke separately. For each diagnosis, we derived the number of patients with the diagnosis recorded at least once over the full 10-year lookback period, and then compared this with shorter lookback periods from 1 year to 9 years prior to the index admission. RESULTS: Seven of the top 10 most common diagnoses in the COPD dataset reached >90% completeness by 6 years of lookback. Atrial fibrillation and diabetes were >90% coded with 2-3 years of lookback, but hypertension and asthma completeness continued to rise all the way out to 10 years of lookback. For stroke, 4 of the top 10 reached 90% completeness by 5 years of lookback; angina pectoris was >90% coded at 7 years and previous transient ischaemic attack completeness continued to rise out to 10 years of lookback. CONCLUSION: A 7-year lookback captures most, but not all, common diagnoses. Lookback duration should be tailored to the conditions being studied.

Flash pulmonary edema in multiple sclerosis.

BACKGROUND: Neurogenic pulmonary edema (NPE) occurs in the setting of an acute neurological insult and in the absence of a primary cardiopulmonary cause. No unifying theory on NPE pathogenesis exists. NPE triggered by a discrete neurological lesion is rare, but such cases offer valuable insight into NPE pathogenesis. OBJECTIVE: To describe an unusual and instructive case of NPE in multiple sclerosis. CASE REPORT: A young woman with multiple sclerosis presented to the Emergency Department in acute respiratory failure. She was cyanotic centrally, hypertensive, and tachycardic. The chest X-ray study suggested pulmonary edema. She required non-invasive mechanical ventilation for 12 h. Echocardiography revealed left ventricular hypokinesis. The asymmetrical pulmonary infiltrate raised the suspicion of pneumonia; she was given intravenous antibiotics. By 36 h, she had persistent dyspnea, paroxysmal tachycardia, nausea, and facial flushing; carcinoid syndrome was excluded. By 48 h, she had facial numbness and ataxia. Magnetic resonance imaging (MRI) revealed a demyelinating lesion at the rostromedial medulla. Her symptoms promptly resolved with intravenous steroids, as did the perilesional edema on follow-up MRI. CONCLUSION: Life-threatening pulmonary edema can complicate medullary demyelination. Lack of awareness of this diagnostic possibility and an asymmetrical pulmonary infiltrate culminated in diagnostic delay in this case. The case provides clinico-radiological evidence of the pathogenic link between medullary lesions and NPE. The pathogenesis is likely to rely on lesion involvement of the nucleus tractus solitarius or its immediate pathways. Non-uniform vasoconstriction of the pulmonary arterial bed might account for the other peculiarity of this case: the asymmetrical pulmonary infiltrate. Timely diagnosis of NPE is essential because the condition is best managed by nullifying the "neurogenic" trigger.

Impact of computerised provider order entry on the quality and quantity of clinical information included with investigation requests: an interrupted time series analysis.

INTRODUCTION: Relevant clinical information is vital to inform the analytical and interpretative phases of most investigations. The aim of this study is to evaluate the impact of implementation of computerised provider order entry (CPOE), featuring order-specific electronic order entry forms (eOEFs), on the quality and quantity of clinical information included with investigation requests. METHODS: The CPOE module of a commercially available electronic health record (Cerner Millennium) was implemented at a large, tertiary care centre. The laboratory information management system was interrogated to collect data on specimens sent for microbiological culture 1 year before implementation of CPOE (2018), immediately post implementation (2019) and 6 months post implementation (2020). An interrupted time series analysis was performed, using text mining, to evaluate the quality and quantity of free-text clinical information. RESULTS: In total, 39 919 specimens were collected from 16 458 patients. eOEFs were used to place 10 071 out of 13 735 orders in 2019 (73.3%), and 9155 out of 12 229 orders in 2020 (74.9%). No clinical details were included with 653 out of 39 919 specimens (1.6%), of which 22 (3.4%) were ordered using eOEFs. The median character count increased from 14 in 2018, to 41 in 2019, and 38 in 2020. An anti-infective agent was specified in 581 out of 13 955 requests (4.2%) in 2018; 5545 out of 13 735 requests (40.4%) in 2019; and 5215 out of 12 229 requests (42.6%) in 2020. Ciprofloxacin or piperacillin-tazobactam (Tazocin) were mentioned in the clinical details included with 421 out of 15 335 urine culture requests (2.7%), of which 406 (96.3%) were ordered using eOEFs. Subsequent detection of in vitro non-susceptibility led to a change in anti-infective therapy for five patients. CONCLUSIONS: Implementation of CPOE, featuring order-specific eOEFs, significantly and sustainably improves the quality and quantity of clinical information included with investigation requests, resulting in changes to patient management that would not otherwise have occurred.

An artificial intelligence-based pipeline for automated detection and localisation of epileptic sources from magnetoencephalography.

Objective.Magnetoencephalography (MEG) is a powerful non-invasive diagnostic modality for presurgical epilepsy evaluation. However, the clinical utility of MEG mapping for localising epileptic foci is limited by its low efficiency, high labour requirements, and considerable interoperator variability. To address these obstacles, we proposed a novel artificial intelligence-based automated magnetic source imaging (AMSI) pipeline for automated detection and localisation of epileptic sources from MEG data.Approach.To expedite the analysis of clinical MEG data from patients with epilepsy and reduce human bias, we developed an autolabelling method, a deep-learning model based on convolutional neural networks and a hierarchical clustering method based on a perceptual hash algorithm, to enable the coregistration of MEG and magnetic resonance imaging, the detection and clustering of epileptic activity, and the localisation of epileptic sources in a highly automated manner. We tested the capability of the AMSI pipeline by assessing MEG data from 48 epilepsy patients.Main results.The AMSI pipeline was able to rapidly detect interictal epileptiform discharges with 93.31% ± 3.87% precision based on a 35-patient dataset (with sevenfold patientwise cross-validation) and robustly rendered accurate localisation of epileptic activity with a lobar concordance of 87.18% against interictal and ictal stereo-electroencephalography findings in a 13-patient dataset. We also showed that the AMSI pipeline accomplishes the necessary processes and delivers objective results within a much shorter time frame (∼12 min) than traditional manual processes (∼4 h).Significance.The AMSI pipeline promises to facilitate increased utilisation of MEG data in the clinical analysis of patients with epilepsy.

A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer.

PURPOSE: Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer. PATIENTS AND METHODS: This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics. RESULTS: During dose escalation, 40 patients received AZD3965 at 5-30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity. CONCLUSIONS: AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

European Society of Cardiology Core Curriculum for cardio-oncology.

Cardio-oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio-oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy-related cardiovascular toxicity (CTR-CVT); (iii) risk stratification, prevention and monitoring protocols for CTR-CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long-term survivorship programmes and cardio-oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio-oncology services; (viii) research in cardio-oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio-oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists.

Dynamical Network Models From EEG and MEG for Epilepsy Surgery-A Quantitative Approach.

There is an urgent need for more informative quantitative techniques that non-invasively and objectively assess strategies for epilepsy surgery. Invasive intracranial electroencephalography (iEEG) remains the clinical gold standard to investigate the nature of the epileptogenic zone (EZ) before surgical resection. However, there are major limitations of iEEG, such as the limited spatial sampling and the degree of subjectivity inherent in the analysis and clinical interpretation of iEEG data. Recent advances in network analysis and dynamical network modeling provide a novel aspect toward a more objective assessment of the EZ. The advantage of such approaches is that they are data-driven and require less or no human input. Multiple studies have demonstrated success using these approaches when applied to iEEG data in characterizing the EZ and predicting surgical outcomes. However, the limitations of iEEG recordings equally apply to these studies-limited spatial sampling and the implicit assumption that iEEG electrodes, whether strip, grid, depth or stereo EEG (sEEG) arrays, are placed in the correct location. Therefore, it is of interest to clinicians and scientists to see whether the same analysis and modeling techniques can be applied to whole-brain, non-invasive neuroimaging data (from MRI-based techniques) and neurophysiological data (from MEG and scalp EEG recordings), thus removing the limitation of spatial sampling, while safely and objectively characterizing the EZ. This review aims to summarize current state of the art non-invasive methods that inform epilepsy surgery using network analysis and dynamical network models. We also present perspectives on future directions and clinical applications of these promising approaches.