Anastasia Chalkidou

Correlation between Ki-67 immunohistochemistry and 18F-Fluorothymidine uptake in patients with cancer: A systematic review and meta-analysis

BACKGROUND Positron emission tomography (PET) imaging using the radiotracer 18F-Fluorothymidine (FLT) has been proposed as an imaging biomarker of tumour proliferation. If FLT-PET can be established as such it will provide a non-invasive, quantitative measurement of tumour proliferation across the entire tumour. Results from validation studies have so far been conflicting with some studies confirming a good correlation between FLT uptake and Ki-67 score and others presenting negative results. METHODS Firstly we performed a systematic review of published studies between 1998 and 2011 that explored the correlation between FLT uptake and Ki-67 score and examined possible variations in the methods used. Studies were eligible if they: (a) included patients with cancer, (b) investigated the correlation between Ki-67 measured by immunohistochemistry and FLT uptake measured with PET scanning, and (c) were published as a full paper in a peer-reviewed scientific journal. Secondly a meta-analysis of the correlation coefficient values reported from each study was performed. Correlation coefficient (r) values were extracted from each study and 95% confidence intervals (CIs) were calculated after applying Fishers z transformation. For subgroup analysis, studies were classified by the index used to characterise Ki-67 expression (average or maximum expression), the nature of the sample (whole specimen or biopsy) and the cancer type. FINDINGS Twenty-seven studies were identified as eligible for the meta-analysis. In the studies we examined there were variations in aspects of the methods and reporting. The meta-analysis showed that given an appropriate study design the FLT/Ki-67 correlation is significant and independent of cancer type. Specifically subgroup analysis showed that FLT/Ki-67 correlation was high in studies measuring the Ki-67 average expression regardless of use of surgery or biopsy samples (r=0.70, 95% CI=0.43-0.86, p<0.001). Of the studies that measured Ki-67 maximum expression, only those that used the whole surgical specimen provided a significant r value (r=0.72, 95% CI=0.54-0.84, p<0.001). Studies that used biopsy samples for Ki-67 maximum measurements did not produce a significant r value (r=0.04, 95% CI=-0.18-0.26, p=0.71). In terms of the cancer type subgroup analysis there is sufficient data to support a strong FLT/Ki-67 correlation for brain, lung and breast cancer. No publication bias was detected. INTERPRETATION This systematic review and meta-analysis highlights the importance of the methods used in validation studies comparing FLT-PET imaging with the biomarker Ki-67. The correlation is significant and independent of cancer type provided a study design that uses Ki-67 average measurements, regardless of nature of sample, or whole surgical samples when measuring Ki-67 maximum expression. Sufficient data to support a strong correlation for brain, lung and breast cancer exist. However, larger, prospective studies with improved study design are warranted to validate these findings for the rest of the cancer types.

False Discovery Rates in PET and CT Studies with Texture Features: A Systematic Review

Purpose A number of recent publications have proposed that a family of image-derived indices, called texture features, can predict clinical outcome in patients with cancer. However, the investigation of multiple indices on a single data set can lead to significant inflation of type-I errors. We report a systematic review of the type-I error inflation in such studies and review the evidence regarding associations between patient outcome and texture features derived from positron emission tomography (PET) or computed tomography (CT) images. Methods For study identification PubMed and Scopus were searched (1/2000–9/2013) using combinations of the keywords texture, prognostic, predictive and cancer. Studies were divided into three categories according to the sources of the type-I error inflation and the use or not of an independent validation dataset. For each study, the true type-I error probability and the adjusted level of significance were estimated using the optimum cut-off approach correction, and the Benjamini-Hochberg method. To demonstrate explicitly the variable selection bias in these studies, we re-analyzed data from one of the published studies, but using 100 random variables substituted for the original image-derived indices. The significance of the random variables as potential predictors of outcome was examined using the analysis methods used in the identified studies. Results Fifteen studies were identified. After applying appropriate statistical corrections, an average type-I error probability of 76% (range: 34–99%) was estimated with the majority of published results not reaching statistical significance. Only 3/15 studies used a validation dataset. For the 100 random variables examined, 10% proved to be significant predictors of survival when subjected to ROC and multiple hypothesis testing analysis. Conclusions We found insufficient evidence to support a relationship between PET or CT texture features and patient survival. Further fit for purpose validation of these image-derived biomarkers should be supported by appropriate biological and statistical evidence before their association with patient outcome is investigated in prospective studies.

Diagnostic accuracy of 18F amyloid PET tracers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis

Imaging or tissue biomarker evidence has been introduced into the core diagnostic pathway for Alzheimer’s disease (AD). PET using 18F-labelled beta-amyloid PET tracers has shown promise for the early diagnosis of AD. However, most studies included only small numbers of participants and no consensus has been reached as to which radiotracer has the highest diagnostic accuracy. First, we performed a systematic review of the literature published between 1990 and 2014 for studies exploring the diagnostic accuracy of florbetaben, florbetapir and flutemetamol in AD. The included studies were analysed using the QUADAS assessment of methodological quality. A meta-analysis of the sensitivity and specificity reported within each study was performed. Pooled values were calculated for each radiotracer and for visual or quantitative analysis by population included. The systematic review identified nine studies eligible for inclusion. There were limited variations in the methods between studies reporting the same radiotracer. The meta-analysis results showed that pooled sensitivity and specificity values were in general high for all tracers. This was confirmed by calculating likelihood ratios. A patient with a positive ratio is much more likely to have AD than a patient with a negative ratio, and vice versa. However, specificity was higher when only patients with AD were compared with healthy controls. This systematic review and meta-analysis found no marked differences in the diagnostic accuracy of the three beta-amyloid radiotracers. All tracers perform better when used to discriminate between patients with AD and healthy controls. The sensitivity and specificity for quantitative and visual analysis are comparable to those of other imaging or biomarker techniques used to diagnose AD. Further research is required to identify the combination of tests that provides the highest sensitivity and specificity, and to identify the most suitable position for the tracer in the clinical pathway.

Diagnostic accuracy of (18)F amyloid PET tracers for the diagnosis of Alzheimer's disease

Imaging or tissue biomarker evidence has been introduced into the core diagnostic pathway for Alzheimer’s disease (AD). PET using 18F-labelled beta-amyloid PET tracers has shown promise for the early diagnosis of AD. However, most studies included only small numbers of participants and no consensus has been reached as to which radiotracer has the highest diagnostic accuracy. First, we performed a systematic review of the literature published between 1990 and 2014 for studies exploring the diagnostic accuracy of florbetaben, florbetapir and flutemetamol in AD. The included studies were analysed using the QUADAS assessment of methodological quality. A meta-analysis of the sensitivity and specificity reported within each study was performed. Pooled values were calculated for each radiotracer and for visual or quantitative analysis by population included. The systematic review identified nine studies eligible for inclusion. There were limited variations in the methods between studies reporting the same radiotracer. The meta-analysis results showed that pooled sensitivity and specificity values were in general high for all tracers. This was confirmed by calculating likelihood ratios. A patient with a positive ratio is much more likely to have AD than a patient with a negative ratio, and vice versa. However, specificity was higher when only patients with AD were compared with healthy controls. This systematic review and meta-analysis found no marked differences in the diagnostic accuracy of the three beta-amyloid radiotracers. All tracers perform better when used to discriminate between patients with AD and healthy controls. The sensitivity and specificity for quantitative and visual analysis are comparable to those of other imaging or biomarker techniques used to diagnose AD. Further research is required to identify the combination of tests that provides the highest sensitivity and specificity, and to identify the most suitable position for the tracer in the clinical pathway.

Estimation of input functions from dynamic [18F]FLT PET studies of the head and neck with correction for partial volume effects

BackgroundWe present a method for extracting arterial input functions from dynamic [18F]FLT PET images of the head and neck, directly accounting for the partial volume effect. The method uses two blood samples, for which the optimum collection times are assessed.MethodsSix datasets comprising dynamic PET images, co-registered computed tomography (CT) scans and blood-sampled input functions were collected from four patients with head and neck tumours. In each PET image set, a region was identified that comprised the carotid artery (outlined on CT images) and surrounding tissue within the voxels containing the artery. The time course of activity in the region was modelled as the sum of the blood-sampled input function and a compartmental model of tracer uptake in the surrounding tissue.The time course of arterial activity was described by a mathematical function with seven parameters. The parameters of the function and the compartmental model were simultaneously estimated, aiming to achieve the best match between the modelled and imaged time course of regional activity and the best match of the estimated blood activity to between 0 and 3 samples. The normalised root-mean-square (RMSnorm) differences and errors in areas under the curves (AUCs) between the measured and estimated input functions were assessed.ResultsA one-compartment model of tracer movement to and from the artery best described uptake in the tissue surrounding the artery, so the final model of the input function and tissue kinetics has nine parameters to be estimated. The estimated and blood-sampled input functions agreed well when two blood samples, obtained at times between 2 and 8 min and between 8 and 60 min, were used in the estimation process (RMSnorm values of 1.1 ± 0.5 and AUC errors for the peak and tail region of the curves of 15% ± 9% and 10% ± 8%, respectively). A third blood sample did not significantly improve the accuracy of the estimated input functions.ConclusionsInput functions for FLT-PET studies of the head and neck can be estimated well using a one-compartment model of tracer movement and TWO blood samples obtained after the peak in arterial activity.

Letter to the editor re: positron emission tomography with [(18)F]-3'-deoxy-3'fluorothymidine (FLT) as a predictor of outcome in patients with locally advanced resectable rectal cancer: a pilot study.

Letter to the Editor re: Positron Emission Tomography with [F]-3′-Deoxy-3′ fluorothymidine (FLT) as a Predictor of Outcome in Patients with Locally Advanced Resectable Rectal Cancer: a Pilot Study A. Chalkidou, G. Mikhaeel, M. J. O’Doherty, P. K. Marsden Comprehensive Cancer Imaging Centre, Imaging Sciences and Biomedical Engineering, St. Thomas Hospital, Kings College London, 4th Floor, Lambeth Wing, SE1 7EH, London, UK Department of Clinical Oncology, St. Thomas Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, Lower Ground Floor, Lambeth Wing, SE1 7EH, London, UK Imaging Sciences and Biomedical Engineering, Kings College London, Lower Ground Floor, Lambeth Wing, SE1 7EH, London, UK PET Imaging Centre, Guy’s and St. Thomas’ NHS Foundation Trust, Lower Ground Floor, Lambeth Wing, SE1 7EH, London, UK

Evaluating the Diagnostic Accuracy of Reflectance Confocal Microscopy to Diagnose Skin Cancer: Protocol for a Prospective, Multicenter Study

Background In the United Kingdom, 350,000 patients per year are referred to hospital clinics with suspicious moles, and approximately half undergo a biopsy to identify the 5%-10% who require further treatment. If cancer cannot be ruled out clinically and on the basis of biopsy results, the lesion is surgically removed. One type of precancerous mole, called lentigo maligna, is particularly challenging to delineate and treat. Reflectance confocal microscopy (VivaScope, Caliber Imaging & Diagnostics) is an imaging technique that can supplement dermoscopy in identifying whether a clinically suspicious mole is malignant and can better assess lentigo maligna margins for excision. It allows clinicians to visualize the skin lesion to a depth of 200 microns with subcellular resolution, described as quasi-histological, and therefore better guide more accurate diagnoses. Objective The aim of this paper is to describe a prospective, single blinded, multicenter study to examine patients with clinically suspicious moles or lentigo maligna to determine whether confocal microscopy can both reduce the number of unnecessary biopsies of moles and more accurately guide the surgical excision margins of lentigo maligna. Methods This study will prospectively recruit adults into the following two cohorts: diagnostic accuracy and margin delineation. The diagnostic accuracy cohort will assess people with clinically suspicious lesions suspected of being diagnosed with melanoma and having an equivocal finding on dermoscopy or persistent clinical suspicion despite normal dermoscopy. Diagnostic accuracy will include the sensitivity and specificity of VivaScope in comparison with the histological diagnosis as the gold standard for patients. The margin delineation cohort will assess the ability of VivaScope to accurately delineate the margins of lentigo maligna compared with that of dermoscopy alone using margins taken during Mohs micrographic surgery as the gold standard. The primary study outcomes will be the diagnostic accuracy of VivaScope for the first cohort of patients and margin agreement between VivaScope and the final pathology report for the second cohort of patients. Results Funding for this proposed research is being secured. Conclusions The outcomes of the proposed study will indicate how many biopsies of nonmelanoma lesions, which are potentially unnecessary, could be prevented. This would reduce patient anxiety and cost to the National Health Service (NHS) in the United Kingdom. Improved margin delineation of lentigo maligna could also improve the surgical clearance rates and decrease overall cost. The results would demonstrate whether the adoption of VivaScope would potentially benefit patients and the NHS. Registered Report Identifier RR1-10.2196/9296

The Clinical and Cost-Effectiveness of 4 Enzyme-Linked Immunosorbent Assay Kits for Monitoring Infliximab in Crohn Disease Patients: Protocol for a Validation Study

Background Currently, treatment decisions for people with Crohn disease are based on clinical judgment and trial and error. Consequently, people may continue to receive high drug dosages and experience unnecessary toxicity when it is possible to reduce or discontinue without a detrimental effect on clinical outcomes. Therapeutic drug monitoring (TDM) involves regularly testing blood samples for drug and antibody levels that could help clinicians identify the optimal treatment strategy and pre-empt treatment failure. However, heterogeneity in the assays can lead to a discrepancy in results and difficulties in decision-making. Standardization of the kits, and therefore results, would allow clinicians to optimize the use of biologics. Currently, there is also a lack of evidence for the cost-effectiveness of TDM using commercial test kits. Objective This study aims to analyze the clinical and cost-effectiveness of 4 commercial enzyme-linked immunosorbent assay (ELISA) kits (LISA TRACKER, IDKmonitor, Promonitor, and RIDASCREEN) to generate evidence which could support a recommendation for wider adoption in the National Health Service. Methods We propose to carry out a prospective-retrospective predictive biomarker validation study using the blood samples and clinical/utilization data collected during the ongoing SPARE trial (NCT02177071). A total of 200 stored samples from people with Crohns disease who respond to treatment with infliximab will be used along with clinical and cost data from the trial. We will investigate the relationship between the drug and antidrug antibody levels with the main clinical outcomes (relapse rate at 2 years and time spent in remission), as well as resource utilization and quality of life. Results Funding is being sought to conduct this research. Conclusions This is the first study to compare the 4 ELISA kits for monitoring infliximab in patients with Crohn disease. It aims to address the uncertainties in the potential benefits of using the technologies for TDM. International Registered Report Identifier (IRRID) PRR1-10.2196/11218

Multi-Scale Spatial-Temporal Modelling of 18F-FLT Dynamics and its Relation to 3-Compartment Model

3′-Deoxy-3′-18F-fluorothymidine (18F-FLT) is a radiotracer which accumulates in proliferating cells and is used for positron emission tomography (PET) imaging. This study investigates the heterogeneous transport and uptake of FLT in tumors, aiming to understand the links between FLT dynamics described by a mechanistic spatial-temporal model and by a simplified 3-compartment model, and to study the validity of the compartment model.In the proposed multi-scale spatial-temporal model, the tumor consists of vasculature, interstitium and tumor cells. The heterogeneous spatial-temporal distribution of FLT is determined by a convection-diffusion-reaction equation, numerically solved using the finite difference method (FDM). Physiological parameters were collated from the literature and used as model coefficients, and vascular maps were created based on histological micro-vascular density (MVD). Results show that the multi-scale model can generate FLT time activity curves (TACs) similar to TACs derived from clinical PET images. And so long as the region of interest (ROI) is a near-closed system, a 3-compartment model can recover reasonable estimates of averaged FLT dynamics.Copyright