Preoperative intravenous iron therapy and survival after colorectal cancer surgery: long-term results from the IVICA randomised controlled trial.

AIM: Preoperative iron is frequently used for the correction of anaemia in colorectal cancer surgery. However, enteral iron intake may promote tumour growth and progression which could influence cancer recurrence and patient survival. We explore the long-term outcomes of patients receiving either oral or intravenous iron replacement therapy as part of a previous randomized controlled trial. METHODS: The IVICA trial randomized anaemic colorectal cancer patients to receive either oral (OI, control) or intravenous (IVI, treatment) iron prior to their elective operation. Follow-up analysis of all patients recruited to this multicentre trial who underwent surgical resection with curative intent was performed. Kaplan-Meier survival estimates and Cox proportional hazard models were used to compare groups. A pooled group multivariable analysis comparing patients who achieved resolution of anaemia preoperatively to those who did not was also undertaken. RESULTS: In all, 110 of the 116 patients previously enrolled were eligible for analysis (OI n = 56, IVI n = 54). Median overall follow-up duration was 61 months (interquartile range 46-67). No significant difference in 5-year overall survival (hazard ratio (HR) 1.22, 95% CI 0.65-2.28, P = 0.522) or disease-free survival (HR 1.08, 95% CI 0.61-1.92, P = 0.79) was observed between OI and IVI. A pooled analysis of treatment groups found that preoperative resolution of anaemia led to improved 5-year overall survival on multivariable analysis (HR 3.38, 95% CI 1.07-11.56, P = 0.044). CONCLUSION: We recommend IVI for the preoperative correction of anaemia. Route of iron therapy did not significantly influence survival. Preoperative anaemia correction may lead to an overall survival advantage following elective colorectal cancer surgery.

The impact of pre-operative intravenous iron on quality of life after colorectal cancer surgery: outcomes from the intravenous iron in colorectal cancer-associated anaemia (IVICA) trial.

Anaemia is associated with a reduction in quality of life, and is common in patients with colorectal cancer . We recently reported the findings of the intravenous iron in colorectal cancer-associated anaemia (IVICA) trial comparing haemoglobin levels and transfusion requirements following intravenous or oral iron replacement in anaemic colorectal cancer patients undergoing elective surgery. In this follow-up study, we compared the efficacy of intravenous and oral iron at improving quality of life in this patient group. We conducted a multicentre, open-label randomised controlled trial. Anaemic colorectal cancer patients were randomly allocated at least two weeks pre-operatively, to receive either oral (ferrous sulphate) or intravenous (ferric carboxymaltose) iron. We assessed haemoglobin and quality of life scores at recruitment, immediately before surgery and at outpatient review approximately three months postoperatively, using the Short Form 36, EuroQoL 5-dimension 5-level and Functional Assessment of Cancer Therapy - Anaemia questionnaires. We recruited 116 anaemic patients across seven UK centres (oral iron n = 61 (53%), and intravenous iron n = 55 (47%)). Eleven quality of life components increased by a clinically significant margin in the intravenous iron group between recruitment and surgery compared with one component for oral iron. Median (IQR [range]) visual analogue scores were significantly higher with intravenous iron at a three month outpatient review (oral iron 70, (60-85 [20-95]); intravenous iron 90 (80-90 [50-100]), p = 0.001). The Functional Assessment of Cancer Therapy - Anaemia score comprises of subscales related to cancer, fatigue and non-fatigue items relevant to anaemia. Median outpatient scores were higher, and hence favourable, for intravenous iron on the Functional Assessment of Cancer Therapy - Anaemia subscale (oral iron 66 (55-72 [23-80]); intravenous iron 71 (66-77 [46-80]); p = 0.002), Functional Assessment of Cancer Therapy - Anaemia trial outcome index (oral iron 108 (90-123 [35-135]); intravenous iron 121 (113-124 [81-135]); p = 0.003) and Functional Assessment of Cancer Therapy - Anaemia total score (oral iron 151 (132-170 [69-183]); intravenous iron 168 (160-174 [125-186]); p = 0.005). These findings indicate that intravenous iron is more efficacious at improving quality of life scores than oral iron in anaemic colorectal cancer patients.

Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer.

BACKGROUND: Treatment of preoperative anaemia is recommended as part of patient blood management, aiming to minimize perioperative allogeneic red blood cell transfusion. No clear evidence exists outlining which treatment modality should be used in patients with colorectal cancer. The study aimed to compare the efficacy of preoperative intravenous and oral iron in reducing blood transfusion use in anaemic patients undergoing elective colorectal cancer surgery. METHODS: Anaemic patients with non-metastatic colorectal adenocarcinoma were recruited at least 2 weeks before surgery and randomized to receive oral (ferrous sulphate) or intravenous (ferric carboxymaltose) iron. Perioperative changes in haemoglobin, ferritin, transferrin saturation and blood transfusion use were recorded until postoperative outpatient review. RESULTS: Some 116 patients were included in the study. There was no difference in blood transfusion use from recruitment to trial completion in terms of either volume of blood administered (P = 0·841) or number of patients transfused (P = 0·470). Despite this, increases in haemoglobin after treatment were higher with intravenous iron (median 1·55 (i.q.r. 0·93-2·58) versus 0·50 (-0·13 to 1·33) g/dl; P < 0·001), which was associated with fewer anaemic patients at the time of surgery (75 versus 90 per cent; P = 0·048). Haemoglobin levels were thus higher at surgery after treatment with intravenous than with oral iron (mean 11·9 (95 per cent c.i. 11·5 to 12·3) versus 11·0 (10·6 to 11·4) g/dl respectively; P = 0·002), as were ferritin (P < 0·001) and transferrin saturation (P < 0·001) levels. CONCLUSION: Intravenous iron did not reduce the blood transfusion requirement but was more effective than oral iron at treating preoperative anaemia and iron deficiency in patients undergoing colorectal cancer surgery.

How reliable are MEG resting-state connectivity metrics?

MEG offers dynamic and spectral resolution for resting-state connectivity which is unavailable in fMRI. However, there are a wide range of available network estimation methods for MEG, and little in the way of existing guidance on which ones to employ. In this technical note, we investigate the extent to which many popular measures of stationary connectivity are suitable for use in resting-state MEG, localising magnetic sources with a scalar beamformer. We use as empirical criteria that network measures for individual subjects should be repeatable, and that group-level connectivity estimation shows good reproducibility. Using publically-available data from the Human Connectome Project, we test the reliability of 12 network estimation techniques against these criteria. We find that the impact of magnetic field spread or spatial leakage artefact is profound, creates a major confound for many connectivity measures, and can artificially inflate measures of consistency. Among those robust to this effect, we find poor test-retest reliability in phase- or coherence-based metrics such as the phase lag index or the imaginary part of coherency. The most consistent methods for stationary connectivity estimation over all of our tests are simple amplitude envelope correlation and partial correlation measures.

Predicting haemodynamic networks using electrophysiology: The role of non-linear and cross-frequency interactions.

Understanding the electrophysiological basis of resting state networks (RSNs) in the human brain is a critical step towards elucidating how inter-areal connectivity supports healthy brain function. In recent years, the relationship between RSNs (typically measured using haemodynamic signals) and electrophysiology has been explored using functional Magnetic Resonance Imaging (fMRI) and magnetoencephalography (MEG). Significant progress has been made, with similar spatial structure observable in both modalities. However, there is a pressing need to understand this relationship beyond simple visual similarity of RSN patterns. Here, we introduce a mathematical model to predict fMRI-based RSNs using MEG. Our unique model, based upon a multivariate Taylor series, incorporates both phase and amplitude based MEG connectivity metrics, as well as linear and non-linear interactions within and between neural oscillations measured in multiple frequency bands. We show that including non-linear interactions, multiple frequency bands and cross-frequency terms significantly improves fMRI network prediction. This shows that fMRI connectivity is not only the result of direct electrophysiological connections, but is also driven by the overlap of connectivity profiles between separate regions. Our results indicate that a complete understanding of the electrophysiological basis of RSNs goes beyond simple frequency-specific analysis, and further exploration of non-linear and cross-frequency interactions will shed new light on distributed network connectivity, and its perturbation in pathology.

A symmetric multivariate leakage correction for MEG connectomes.

Ambiguities in the source reconstruction of magnetoencephalographic (MEG) measurements can cause spurious correlations between estimated source time-courses. In this paper, we propose a symmetric orthogonalisation method to correct for these artificial correlations between a set of multiple regions of interest (ROIs). This process enables the straightforward application of network modelling methods, including partial correlation or multivariate autoregressive modelling, to infer connectomes, or functional networks, from the corrected ROIs. Here, we apply the correction to simulated MEG recordings of simple networks and to a resting-state dataset collected from eight subjects, before computing the partial correlations between power envelopes of the corrected ROItime-courses. We show accurate reconstruction of our simulated networks, and in the analysis of real MEGresting-state connectivity, we find dense bilateral connections within the motor and visual networks, together with longer-range direct fronto-parietal connections.

The feasibility and clinical efficacy of intravenous iron administration for preoperative anaemia in patients with colorectal cancer.

AIM: The study aimed to analyse the feasibility and efficacy of administration of a single intravenous iron infusion (IVI) in the preoperative optimization of colorectal cancer patients with anaemia. METHOD: Twenty patients were recruited at least 14 days before the planned date of surgery. A single 1000 mg dose of ferric carboxymaltose (Ferinject) was administered as an outpatient procedure. Blood samples were taken at recruitment prior to drug administration (REC), on the day of surgery prior to any intervention (DOS) and on the first postoperative day. Allogeneic red blood cell transfusions (ARBT) and outcomes were recorded from recruitment throughout the study period. RESULTS: There was a significant median rise in haemoglobin levels (Hb) from REC to DOS of 1.8 g/dl [interquartile range (IQR) 0.75-2.45, P < 0.001] for the entire cohort. Two patients received ARBT preoperatively, and for those not transfused preoperatively (n = 18), this incremental Hb rise remained significant (P < 0.001, median 1.65 g/dl, IQR 0.5-2.3). Of these patients, those who responded to IVI had higher erythropoietin (EPO) levels at recruitment (P < 0.01) and lower recruitment Hb values, transferrin-saturation (TSAT) and C-reactive protein (CRP) levels (P < 0.05). REC Hb (Rs = -0.62, P < 0.01), REC TSAT levels (Rs = -0.67, P < 0.01) and REC EPO (Rs = 0.69, P < 0.01) correlated with the magnitude of treatment change in Hb levels. Five patients received ARBT until the fourth postoperative day, which was significantly fewer than predicted (P < 0.05). CONCLUSION: IVI can be administered preoperatively in the outpatient clinic to colorectal cancer patients with anaemia, with associated reduction in ARBT use and increase in Hb levels.

Measuring functional connectivity in MEG: a multivariate approach insensitive to linear source leakage.

A number of recent studies have begun to show the promise of magnetoencephalography (MEG) as a means to non-invasively measure functional connectivity within distributed networks in the human brain. However, a number of problems with the methodology still remain--the biggest of these being how to deal with the non-independence of voxels in source space, often termed signal leakage. In this paper we demonstrate a method by which non-zero lag cortico-cortical interactions between the power envelopes of neural oscillatory processes can be reliably identified within a multivariate statistical framework. The method is spatially unbiased, moderately conservative in false positive rate and removes linear signal leakage between seed and target voxels. We demonstrate this methodology in simulation and in real MEG data. The multivariate method offers a powerful means to capture the high dimensionality and rich information content of MEG signals in a single imaging statistic. Given a significant interaction between two areas, we go on to show how classical statistical tests can be used to quantify the importance of the data features driving the interaction.

Paired pulse depression in the somatosensory cortex: associations between MEG and BOLD fMRI.

Interpretation of the blood oxygen level dependent (BOLD) response measured using functional magnetic resonance imaging (fMRI) requires an understanding of the underlying neuronal activity. Here we report on a study using both magnetoencephalography (MEG) and BOLD fMRI, to measure the brain's functional response to electrical stimulation of the median nerve in a paired pulse paradigm. Interstimulus Intervals (ISIs) of 0.25, 0.5, 0.75, 1.0, 1.5 and 2.0 s are used to investigate how the MEG detected neural response to a second pulse is affected by that from a preceding pulse and if these MEG modulations are reflected in the BOLD response. We focus on neural oscillatory activity in the ß-band (13-30 Hz) and the P35m component of the signal averaged evoked response in the sensorimotor cortex. A spatial separation of ß ERD and ERS following each pulse is demonstrated suggesting that these two effects arise from separate neural generators, with ERS exhibiting a closer spatial relationship with the BOLD response. The spatial distribution and extent of BOLD activity were unaffected by ISI, but modulations in peak amplitude and latency were observed. Non-linearities in both induced oscillatory activity ERS and in the signal averaged evoked response are found for ISIs of up to 2s when the signal averaged evoked response has returned to baseline, with the P35m component displaying paired pulse depression effects. The ß-band ERS magnitude was modulated by ISI, however the ERD magnitude was not. These results support the assumption that BOLD non-linearity arises not only from a non-linear vascular response to neural activity but also a non-linear neural response to the stimulus with ISI up to 2 s.

Inferring task-related networks using independent component analysis in magnetoencephalography.

A novel framework for analysing task-positive data in magnetoencephalography (MEG) is presented that can identify task-related networks. Techniques that combine beamforming, the Hilbert transform and temporal independent component analysis (ICA) have recently been applied to resting-state MEG data and have been shown to extract resting-state networks similar to those found in fMRI. Here we extend this approach in two ways. First, we systematically investigate optimisation of time-frequency windows for connectivity measurement. This is achieved by estimating the distribution of functional connectivity scores between nodes of known resting-state networks and contrasting it with a distribution of artefactual scores that are entirely due to spatial leakage caused by the inverse problem. We find that functional connectivity, both in the resting-state and during a cognitive task, is best estimated via correlations in the oscillatory envelope in the 8-20 Hz frequency range, temporally down-sampled with windows of 1-4s. Second, we combine ICA with the general linear model (GLM) to incorporate knowledge of task structure into our connectivity analysis. The combination of ICA with the GLM helps overcome problems of these techniques when used independently: namely, the interpretation and separation of interesting independent components from those that represent noise in ICA and the correction for multiple comparisons when applying the GLM. We demonstrate the approach on a 2-back working memory task and show that this novel analysis framework is able to elucidate the functional networks involved in the task beyond that which is achieved using the GLM alone. We find evidence of localised task-related activity in the area of the hippocampus, which is difficult to detect reliably using standard methods. Task-positive ICA, coupled with the GLM, has the potential to be a powerful tool in the analysis of MEG data.

Task induced modulation of neural oscillations in electrophysiological brain networks.

In recent years, one of the most important findings in systems neuroscience has been the identification of large scale distributed brain networks. These networks support healthy brain function and are perturbed in a number of neurological disorders (e.g. schizophrenia). Their study is therefore an important and evolving focus for neuroscience research. The majority of network studies are conducted using functional magnetic resonance imaging (fMRI) which relies on changes in blood oxygenation induced by neural activity. However recently, a small number of studies have begun to elucidate the electrical origin of fMRI networks by searching for correlations between neural oscillatory signals from spatially separate brain areas in magnetoencephalography (MEG) data. Here we advance this research area. We introduce two methodological extensions to previous independent component analysis (ICA) approaches to MEG network characterisation: 1) we show how to derive pan-spectral networks that combine independent components computed within individual frequency bands. 2) We show how to measure the temporal evolution of each network with millisecond temporal resolution. We apply our approach to ~10h of MEG data recorded in 28 experimental sessions during 3 separate cognitive tasks showing that a number of networks could be identified and were robust across time, task, subject and recording session. Further, we show that neural oscillations in those networks are modulated by memory load, and task relevance. This study furthers recent findings on electrodynamic brain networks and paves the way for future clinical studies in patients in which abnormal connectivity is thought to underlie core symptoms.

Bespoke magnetic field design for a magnetically shielded cold atom interferometer.

Quantum sensors based on cold atoms are being developed which produce measurements of unprecedented accuracy. Due to shifts in atomic energy levels, quantum sensors often have stringent requirements on their internal magnetic field environment. Typically, background magnetic fields are attenuated using high permeability magnetic shielding, with the cancelling of residual and introduction of quantisation fields implemented with coils inside the shield. The high permeability shield, however, distorts all magnetic fields, including those generated inside the sensor. Here, we demonstrate a solution by designing multiple coils overlaid on a 3D-printed former to generate three uniform and three constant linear gradient magnetic fields inside the capped cylindrical magnetic shield of a cold atom interferometer. The fields are characterised in-situ and match their desired forms to high accuracy. For example, the uniform transverse field, Bx, deviates by less than 0.2% over more than 40% of the length of the shield. We also map the field directly using the cold atoms and investigate the potential of the coil system to reduce bias from the quadratic Zeeman effect. This coil design technology enables targeted field compensation over large spatial volumes and has the potential to reduce systematic shifts and noise in numerous cold atom systems.

Advances in image enhancement for sarcoma surgery.

The recurrence rate of soft tissue and bone sarcomas strongly correlates to the status of the surgical margin after excision, yet excessive removal of tissue may lead to distinct, otherwise avoidable morbidity. Therefore, adequate margination of sarcomas both pre- and intra-operatively is a clinical necessity that has not yet fully been met. Current guidance for soft-tissue sarcomas recommends an ultrasound scan followed by magnetic resonance imaging (MRI). For bone sarcomas, two plane radiographs are required, followed similarly by an MRI scan. The introduction of more precise imaging modalities may reduce the morbidity associated with sarcoma surgery; the PET-CT and PET-MRI approaches in particular demonstrating high clinical efficacy. Despite advancements in the accuracy in pre-operative imaging, translation of an image to surgical margins is difficult, regularly resulting in wider resection margins than required. For soft tissue sarcomas there is currently no standard technique for image guided resections, while for bone sarcomas fluoroscopy may be used, however margins are not easily discernible during the surgical procedure. Near infra-red (NIR) fluorescence guided surgery offers an intra-operative modality through which complete tumour resection with adequate tumour-free margins may be achieved, while simultaneously minimising surgical morbidity. NIR imaging presents a potentially valuable adjunct to sarcoma surgery. Early reports indicate that it may be able to provide the surgeon with helpful information on anatomy, perfusion, lymphatic drainage, tumour margins and metastases. The use of NIR fluorochromes have also been demonstrated to be well tolerated by patients. However, prior to widespread implementation, studies related to cost-effectiveness and the development of protocols are essential. Nevertheless, NIR imaging may become ubiquitous in the future, carrying the potential to transform the surgical management of sarcoma.

Radiological appearances of papillary breast lesions.

This review illustrates the varied appearances of benign and malignant papillary breast tumours, as identified by a breast cancer-screening programme. The commonest mammographic appearance of a papillary tumour is as a soft-tissue mass, with calcification present in less than half of cases. When calcification is present the pattern is variable, but clusters of pleomorphic calcification can occur, sometimes resembling the mammographic appearance of invasive ductal carcinoma. Ultrasonography of papillary lesions typically shows a solid, oval, intraductal mass, often associated with duct dilatation. A cystic component is also commonly seen, and lesions may appear hypervascular on colour Doppler ultrasound. Magnetic resonance imaging (MRI) has a high sensitivity, but low specificity for detecting papillary tumours, and is useful in establishing the extent and distribution of lesions in patients with multiple papillomatosis. Despite a benign histology on core biopsy, an argument exists for complete surgical excision of all papillary tumours, as a significant proportion of papillomas will contain foci of atypia or overt malignant change.

Hypertension and fatty liver: guilty by association?

Essential hypertension is associated with the metabolic syndrome, insulin resistance and the development of fatty liver. Fatty liver disease is a spectrum of liver diseases ranging from simple hepatic steatosis through steato-hepatitis to cirrhosis and hepatoma. The purpose of this review is to discuss the evidence for an association between essential hypertension and non-alcoholic fatty liver disease, and to consider the diagnosis and management of non-alcoholic fatty liver disease. We conclude that it is important to consider the diagnosis of fatty liver disease in hypertensive patients, to measure the liver function tests at diagnosis and not to ignore minor elevations of serum aminotransferases. Hypertensive patients with raised liver enzymes should be referred for further assessment, particularly if risk factors for progressive liver disease, such as obesity and diabetes, are present.

Modulation of iron transport proteins in human colorectal carcinogenesis.

BACKGROUND AND AIMS: Total body iron and high dietary iron intake are risk factors for colorectal cancer. To date there is no comprehensive characterisation of iron transport proteins in progression to colorectal carcinoma. In this study, we examined expression of iron import (duodenal cytochrome b (DCYTB), divalent metal transporter 1 (DMT1), and transferrin receptor 1 (TfR1)) and export (hephaestin (HEPH) and ferroportin (FPN)) proteins in colorectal carcinoma. METHODS: Perl's staining was used to examine colonocyte iron content. Real time polymerase chain reaction (PCR) and western blotting were used to examine mRNA and protein levels of the molecules of interest in 11 human colorectal cancers. Semiquantitative immunohistochemistry was used to verify protein levels and information on cellular localisation. The effect of iron loading on E-cadherin expression in SW480 and Caco-2 cell lines was examined by promoter assays, real time PCR and western blotting. RESULTS: Perl's staining showed increased iron in colorectal cancers, and there was a corresponding overexpression of components of the intracellular iron import machinery (DCYTB, DMT1, and TfR1). The iron exporter FPN was also overexpressed, but its intracellular location, combined with reduced HEPH levels, suggests reduced iron efflux in the majority of colorectal cancers examined. Loss of HEPH and FPN expression was associated with more advanced disease. Iron loading Caco-2 and SW480 cells caused cellular proliferation and E-cadherin repression. CONCLUSIONS: Progression to colorectal cancer is associated with increased expression in iron import proteins and a block in iron export due to decreased expression and aberrant localisation of HEPH and FPN, respectively. This results in increased intracellular iron which may induce proliferation and repress cell adhesion.

The effect of physical fatigue on oscillatory dynamics of the sensorimotor cortex.

AIM: While physical fatigue is known to arise in part from supraspinal mechanisms within the brain, exactly how brain activity is modulated during fatigue is not well understood. Therefore, this study examined how typical neural oscillatory responses to voluntary muscle contractions were affected by fatigue. METHODS: Eleven healthy adults (age 27 ± 4 years) completed two experimental sessions in a randomized crossover design. Both sessions first assessed baseline maximal voluntary isometric wrist-flexion force (MVFb ). Participants then performed an identical series of fourteen test contractions (2 × 100%MVFb , 10 × 40%MVFb , 2 × 100%MVFb ) both before and after one of two interventions: forty 12-s contractions at 55%MVFb (fatigue intervention) or 5%MVFb (control intervention). Magnetoencephalography (MEG) was used to characterize both the movement-related mu and beta decrease (MRMD and MRBD) and the post-movement beta rebound (PMBR) within the contralateral sensorimotor cortex during the 40%MVFb test contractions, while the 100%MVFb test contractions were used to monitor physical fatigue. RESULTS: The fatigue intervention induced a substantial physical fatigue that endured throughout the post-intervention measurements (28.9-29.5% decrease in MVF, P < 0.001). Fatigue had a significant effect on both PMBR (anova, session × time-point interaction: P = 0.018) and MRBD (P = 0.021): the magnitude of PMBR increased following the fatigue but not the control interventions, whereas MRBD was decreased post-control but not post-fatigue. Mu oscillations were unchanged throughout both sessions. CONCLUSION: Physical fatigue resulted in an increased PMBR, and offset attenuations in MRBD associated with task habituation.

Office landscape: does it work?

A field study of the effects of changes in office environment, from a conventional rectilinear bull pen and cubicle style to a modern office landscaped, was conducted. The attitudes and perception of 120 employees were recorded using a semantic scaling instrument, and an attempt was made to apply this data in a meaningful redesign, before the subjects were moved to the landscaped office interior. The judgements of aesthetic value changed positively on retest, but perceptions of noise level, loss of privacy and visual distractions also were recorded. Some of the problems in utilizing the data are discussed.