Best practice considerations on the assessment of robotic assisted surgical systems: results from an international consensus expert panel.

BACKGROUND: Health technology assessments (HTAs) of robotic assisted surgery (RAS) face several challenges in assessing the value of robotic surgical platforms. As a result of using different assessment methods, previous HTAs have reached different conclusions when evaluating RAS. While the number of available systems and surgical procedures is rapidly growing, existing frameworks for assessing MedTech provide a starting point, but specific considerations are needed for HTAs of RAS to ensure consistent results. This work aimed to discuss different approaches and produce guidance on evaluating RAS. METHODS: A consensus conference research methodology was adopted. A panel of 14 experts was assembled with international experience and representing relevant stakeholders: clinicians, health economists, HTA practitioners, policy makers, and industry. A review of previous HTAs was performed and seven key themes were extracted from the literature for consideration. Over five meetings, the panel discussed the key themes and formulated consensus statements. RESULTS: A total of ninety-eight previous HTAs were identified from twenty-five total countries. The seven key themes were evidence inclusion and exclusion, patient- and clinician-reported outcomes, the learning curve, allocation of costs, appropriate time horizons, economic analysis methods, and robotic ecosystem/wider benefits. CONCLUSIONS: Robotic surgical platforms are tools, not therapies. Their value varies according to context and should be considered across therapeutic areas and stakeholders. The principles set out in this paper should help HTA bodies at all levels to evaluate RAS. This work may serve as a case study for rapidly developing areas in MedTech that require particular consideration for HTAs.

Purchasing high-cost medical devices and equipment in hospitals: a systematic review.

OBJECTIVES: To systematically review academic literature for studies on any processes, procedures, methods or approaches to purchasing high-cost medical devices and equipment within hospitals in high-income countries. METHODS: On 13 August 2020, we searched the following from inception: Cost-Effectiveness Analysis Registry, EconLit and ProQuest Dissertations & Theses A&I via ProQuest, Embase, MEDLINE, and MEDLINE in Process via Ovid SP, Google and Google Scholar, Health Management and Policy Database via Ovid SP, IEEE Xplore Digital Library, International HTA Database, NHS EED via CRD Web, Science Citation Index-Expanded, Conference Proceedings Citation Index-Science, and Emerging Sources Citation Index via Web of Science, Scopus, and Zetoc conference search. Studies were included if they described the approach to purchasing (also known as procurement or acquisition) of high-cost medical devices and/or equipment conducted within hospitals in high-income countries between 2000 and 2020. Studies were screened, data extracted and results summarised in tables under themes identified. RESULTS: Of 9437 records, 24 were included, based in 12 different countries and covering equipment types including surgical robots, medical imaging equipment, defibrillators and orthopaedic implants. We found heterogeneity in methods and approaches; including descriptions of processes taking place within or across hospitals (n=14), out of which three reported cost savings; empirical studies in which hospital records or participant data were analysed (n=8), and evaluations or pilots of proposed purchasing processes (n=2). Studies emphasise the importance of balancing technical, financial, safety and clinical requirements for device selection through multidisciplinary involvement (especially clinical engineers and clinicians) in decision-making, and the potential of increasing evidence-based purchasing decisions using approaches such as hospital-based health technology assessments, ergonomics and device 'user trials'. CONCLUSIONS: We highlight the need for more empirical work that evaluates purchasing approaches or interventions, and greater specificity in study reporting (eg, equipment type, evaluation outcomes) to build the evidence base required to influence policy and practice for medical equipment purchasing. PROTOCOL REGISTRATION: This review was registered in Open Science Framework: Shokraneh F, Hinrichs-Krapels S, Chalkidou A et al. Purchasing high-cost medical equipment in hospitals in OECD countries: A systematic review. Open Science Framework 2021; doi:10.17605/OSF.IO/GTXN8. Available at: https://osf.io/gtxn8/ (accessed 12 February 2022).

Recommendations for the development and use of imaging test sets to investigate the test performance of artificial intelligence in health screening.

Rigorous evaluation of artificial intelligence (AI) systems for image classification is essential before deployment into health-care settings, such as screening programmes, so that adoption is effective and safe. A key step in the evaluation process is the external validation of diagnostic performance using a test set of images. We conducted a rapid literature review on methods to develop test sets, published from 2012 to 2020, in English. Using thematic analysis, we mapped themes and coded the principles using the Population, Intervention, and Comparator or Reference standard, Outcome, and Study design framework. A group of screening and AI experts assessed the evidence-based principles for completeness and provided further considerations. From the final 15 principles recommended here, five affect population, one intervention, two comparator, one reference standard, and one both reference standard and comparator. Finally, four are appliable to outcome and one to study design. Principles from the literature were useful to address biases from AI; however, they did not account for screening specific biases, which we now incorporate. The principles set out here should be used to support the development and use of test sets for studies that assess the accuracy of AI within screening programmes, to ensure they are fit for purpose and minimise bias.

Clinical utility of DaTscan in patients with suspected Parkinsonian syndrome: a systematic review and meta-analysis.

Images of DaTscan (ioflupane [123I] SPECT) have been used as an adjunct to clinical diagnosis to facilitate the differential diagnosis of neurodegenerative (ND) Parkinsonian Syndrome (PS) vs. non-dopamine deficiency aetiologies of Parkinsonism. Despite several systematic reviews having summarised the evidence on diagnostic accuracy, the impact of imaging results on clinical utility has not been systematically assessed. Our objective was to examine the available evidence on the clinical utility of DaTscan imaging in changing diagnosis and subsequent management of patients with suspected PS. We performed a systematic review of published studies of clinical utility from 2000 to 2019 without language restrictions. A meta-analysis of change in diagnosis and management rates reported from each study was performed using a random-effects model and logit transformation. Sub-group analysis, meta-regression and sensitivity analysis was performed to explore heterogeneity. Twenty studies met the inclusion criteria. Thirteen of these contributed to the meta-analyses including 950 and 779 patients with a reported change in management and change in diagnosis, respectively. The use of DaTscan imaging resulted in a change in management in 54% (95% CI: 47-61%) of patients. Change in diagnosis occurred in 31% (95% CI: 22-42%) of patients. The two pooled analyses were characterised by high levels of heterogeneity. Our systematic review and meta-analysis show that imaging with DaTscan was associated with a change in management in approximately half the patients tested and the diagnosis was modified in one third. Regardless of time from symptom onset to scan results, these changes were consistent. Further research focusing on specific patient subgroups could provide additional evidence on the impact on clinical outcomes.

Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is increasingly being used to treat oligometastatic cancers, but high-level evidence to provide a basis for policy making is scarce. Additional evidence from a real-world setting is required. We present the results of a national study of patients with extracranial oligometastases undergoing SABR, representing the largest dataset, to our knowledge, on outcomes in this population so far. METHODS: In 2015, National Health Service (NHS) England launched a Commissioning through Evaluation scheme that funded a prospective, registry-based, single-arm, observational, evaluation study of patients with solid cancer and extracranial oligometastases treated with SABR. Prescribed doses ranged from 24-60 Gy administered in three to eight fractions. The study was done at 17 NHS radiotherapy centres in England. Patients were eligible for the scheme if aged 18 years or older with confirmed primary carcinoma (excluding haematological malignancies), one to three extracranial metastatic lesions, a disease-free interval from primary tumour development to metastases of longer than 6 months (with the exception of synchronous colorectal liver metastases), a WHO performance status of 2 or lower, and a life expectancy of at least 6 months. The primary outcome was overall survival at 1 year and 2 years from the start of SABR treatment. The study is now completed. FINDINGS: Between June 15, 2015, and Jan 30, 2019, 1422 patients were recruited from 17 hospitals in England. The median age of the patients was 69 years (IQR 62-76), and the most common primary tumour was prostate cancer (406 [28·6%] patients). Median follow-up was 13 months (IQR 6-23). Overall survival was 92·3% (95% CI 90·5-93·9) at 1 year and 79·2% (76·0-82·1) at 2 years. The most common grade 3 adverse event was fatigue (28 [2·0%] of 1422 patients) and the most common serious (grade 4) event was increased liver enzymes (nine [0·6%]). Notreatment-related deaths were reported. INTERPRETATION: In patients with extracranial oligometastatic cancer, use of SABR was associated with high overall survival and low toxicity. 'The study findings complement existing evidence from a randomised, phase 2 trial, and represent high-level, real-world evidence supporting the use of SABR in this patient cohort, with a phase 3 randomised, controlled trial to confirm these findings underway. Based on the selection criteria in this study, SABR was commissioned by NHS England in March, 2020, as a treatment option for patients with oligometastatic disease. FUNDING: NHS England Commissioning through Evaluation scheme.

A Retrospective Clinical Audit of the ImmunoCAP ISAC 112 for Multiplex Allergen Testing.

INTRODUCTION: Complex cases of multiple allergies can be particularly difficult to diagnose using standard methods such as skin prick tests and assessment of a patient's allergic history. Multiplex allergy testing may improve outcomes for allergy patients by avoiding misdiagnosis and providing reassurance. The ImmunoCAP Immuno Solid-Phase Allergen Chip (ISAC) 112 is a CE-marked, molecular, multiplex, allergy test that can test for IgE antibodies to 112 components from 51 allergen sources. However, its clinical utility is unknown and is difficult to estimate due to the complexity of the diagnostic pathway in which it is used. OBJECTIVE: To assess how the ImmunoCAP ISAC 112 is currently being used in UK practice. The patient populations in which it may have the most benefit were examined, and the sequence of other tests implemented alongside ISAC was determined. METHODS: A retrospective audit of 100 patient cases from 2 UK tertiary allergy clinics was performed. Fifty paediatric and fifty adult cases were selected for audit. The indications for ordering an ISAC test, the other tests used alongside ISAC, and changes in management actioned by the ISAC test were investigated. RESULTS: 73.6% of paediatric and 78% of adult patients referred for an ISAC test were suspected to have multiple sensitizations. The sequence of testing varied greatly between cases, but 70% of adult and 98% of paediatric patients had at least one other investigation prior to an ISAC test. In most cases, ISAC testing confirmed clinical suspicion. CONCLUSIONS: A prospective research study is necessary to further investigate the clinical utility and cost-effectiveness of the ISAC. A UK national registry would be of great benefit but will require a large resource base.

Correction to: The Future of Precision Medicine: Potential Impacts for Health Technology Assessment.

The article The Future of Precision Medicine: Potential Impacts for Health Technology Assessment written by James Love­Koh, Alison Peel Juan, Carlos Rejon­Parrilla, KateAnastasia Chalkidou, Hannah Wood, Matthew Taylor was originally published electronically on the publisher's internet portal (currently Springer Link) on [13th July, 2018] with incorrect spelling of the co-author "Juan Carlos Rejon-Parilla". The correct spelling is "Juan Carlos Rejon-Parrilla".

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 Crohn's 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.

SecurAcath for Securing Peripherally Inserted Central Catheters: A NICE Medical Technology Guidance.

Central venous catheters are commonly used to deliver therapies and to monitor patients, and require securing at the point of percutaneous entry to avoid dislodgement. SecurAcath is a catheter securement device designed for central venous catheters. The National Institute for Health and Care Excellence, as a part of its Medical Technologies Evaluation Programme, selected this device for evaluation and invited the manufacturer, Interrad Medical, to submit clinical and economic evidence. The King's Technology Evaluation Centre, an External Assessment Centre commissioned by the National Institute for Health and Care Excellence, independently critiqued the manufacturer's submissions. The External Assessment Centre found a lack of evidence comparing SecurAcath with alternative approaches to securement (StatLock, suturing, tape securement), with one unpublished randomised controlled trial providing the strongest evidence. The External Assessment Centre conducted a new systematic review and meta-analysis and concluded that there is some evidence indicating the non-inferiority of SecurAcath compared to StatLock. The External Assessment Centre considered the manufacturer's economic model to be appropriate but made revisions to some parameters and noted significant heterogeneity in the included studies. The revised model indicated that StatLock was more cost effective than SecurAcath for catheter indwell times of up to 5 days; however, for medium- and long-term indwell times, SecurAcath was the most cost-effective option. The National Institute for Health and Care Excellence Medical Technologies Guidance MTG 34, issued in June 2017, recommended the adoption of SecurAcath for securing peripherally inserted central catheters within the National Health Service in England.

Identification of catheter misplacement in early port CVC dysfunction.

The use of port central venous catheters (CVCs) for chemotherapeutical use has seen exponential growth over the last decades. However, port CVC misplacement may lead to catheter malfunction (such as partial or total catheter blockade), which might be complicated by thrombosis and catheter superinfections, and these in turn may lead to pulmonary embolism and bloodstream infections. The overall occurrence of port CVC misplacement is up to 6%; nonetheless, port CVC misplacement may occur in up to 67% of patients with early CVC dysfunction (occurring within three months of catheter insertion). Thereafter, the prompt evaluation of catheter position among patients with first-trimester CVC dysfunction is extremely important. The aim of the present manuscript is to support medical oncologists, haematologists, and clinicians in timely suspicion and recognition of port CVC misplacement among patients with early CVC dysfunction. Radiological educational iconographic materials that will assist a prompt estimate of port-CVC dislocation are provided.

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 Future of Precision Medicine: Potential Impacts for Health Technology Assessment.

OBJECTIVE: Precision medicine allows healthcare interventions to be tailored to groups of patients based on their disease susceptibility, diagnostic or prognostic information, or treatment response. We analysed what developments are expected in precision medicine over the next decade and considered the implications for health technology assessment (HTA) agencies. METHODS: We performed a pragmatic literature search to account for the large size and wide scope of the precision medicine literature. We refined and enriched these results with a series of expert interviews up to 1 h in length, including representatives from HTA agencies, research councils and researchers designed to cover a wide spectrum of precision medicine applications and research. RESULTS: We identified 31 relevant papers and interviewed 13 experts. We found that three types of precision medicine are expected to emerge in clinical practice: complex algorithms, digital health applications and 'omics'-based tests. These are expected to impact upon each stage of the HTA process, from scoping and modelling through to decision-making and review. The complex and uncertain treatment pathways associated with patient stratification and fast-paced technological innovation are central to these effects. DISCUSSION: Innovation in precision medicine promises substantial benefits but will change the way in which some health services are delivered and evaluated. The shelf life of guidance may decrease, structural uncertainty may increase and new equity considerations will emerge. As biomarker discovery accelerates and artificial intelligence-based technologies emerge, refinements to the methods and processes of evidence assessments will help to adapt and maintain the objective of investing in healthcare that is value for money.

A Systematic Review and Aggregated Analysis on the Impact of Amyloid PET Brain Imaging on the Diagnosis, Diagnostic Confidence, and Management of Patients being Evaluated for Alzheimer's Disease.

BACKGROUND: Amyloid PET (aPET) imaging could improve patient outcomes in clinical practice, but the extent of impact needs quantification. OBJECTIVE: To provide an aggregated quantitative analysis of the value added by aPET in cognitively impaired subjects. METHODS: Systematic literature searches were performed in Embase and Medline until January 2017. 1,531 cases over 12 studies were included (1,142 cases over seven studies in the primary analysis where aPET was the key biomarker; the remaining cases included as defined groups in the secondary analysis). Data was abstracted by consensus among two observers and assessed for bias. Clinical utility was measured by diagnostic change, diagnostic confidence, and patient management before and after aPET. Three groups were further analyzed: control patients for whom feedback of aPET scan results was delayed; aPET Appropriate Use Criteria (AUC+) cases; and patients undergoing additional FDG/CSF testing. RESULTS: For 1,142 cases with only aPET, 31.3% of diagnoses were revised, whereas 3.2% of diagnoses changed in the delayed aPET control group (p < 0.0001). Increased diagnostic confidence following aPET was found for 62.1% of 870 patients. Management changes with aPET were found in 72.2% of 740 cases and in 55.5% of 299 cases in the control group (p < 0.0001). The diagnostic value of aPET in AUC+ patients or when FDG/CSF were additionally available did not substantially differ from the value of aPET alone in the wider population. CONCLUSIONS: Amyloid PET contributed to diagnostic revision in almost a third of cases and demonstrated value in increasing diagnostic confidence and refining management plans.

Virtual Touch™ Quantification to Diagnose and Monitor Liver Fibrosis in Hepatitis B and Hepatitis C: A NICE Medical Technology Guidance.

Virtual Touch™ Quantification (VTq) is a software application used with Siemens Acuson ultrasound scanners to assess the stiffness of liver tissue. The National Institute for Health and Care Excellence (NICE) Medical Technologies Advisory Committee (MTAC) selected VTq for evaluation and invited the company to submit clinical and economic evidence. King's Technology Evaluation Centre, an External Assessment Centre (EAC) commissioned by NICE, independently assessed the evidence submitted. The EAC conducted its own systematic review, meta-analysis and economic analysis to supplement the company's submitted evidence. The meta-analyses comparing VTq and transient elastography (TE) with liver biopsy (LB) provided pooled estimates of liver stiffness and stage of fibrosis for the study populations (hepatitis B, hepatitis C or combined populations). When comparing significant fibrosis (Metavir score F ≥ 2) for both hepatitis B and C, VTq had slightly higher values for both sensitivity and specificity (77 and 81 %) than TE (76 and 71 %). The overall prevalence of cirrhosis (F4, combined populations) was similar with VTq and TE (23 vs. 23 %), and significant fibrosis (F ≥ 2) was lower for VTq than for TE (55 vs. 62 %). The EAC revised the company's de novo cost model, which resulted in a cost saving of £53 (against TE) and £434 (against LB). Following public consultation, taking into account submitted comments, NICE Medical Technology Guidance MTG27 was published in September 2015. This recommended the adoption of the VTq software to diagnose and monitor liver fibrosis in patients with hepatitis B or hepatitis C.

Diagnostic accuracy of (18)F 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 (18)F-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.

A method for accurate spatial registration of PET images and histopathology slices.

BACKGROUND: Accurate alignment between histopathology slices and positron emission tomography (PET) images is important for radiopharmaceutical validation studies. Limited data is available on the registration accuracy that can be achieved between PET and histopathology slices acquired under routine pathology conditions where slices may be non-parallel, non-contiguously cut and of standard block size. The purpose of this study was to demonstrate a method for aligning PET images and histopathology slices acquired from patients with laryngeal cancer and to assess the registration accuracy obtained under these conditions. METHODS: Six subjects with laryngeal cancer underwent a (64)Cu-copper-II-diacetyl-bis(N4-methylthiosemicarbazone) ((64)Cu-ATSM) PET computed tomography (CT) scan prior to total laryngectomy. Sea urchin spines were inserted into the pathology specimen to act as fiducial markers. The specimen was fixed in formalin, as per standard histopathology operating procedures, and was then CT scanned and cut into millimetre-thick tissue slices. A subset of the tissue slices that included both tumour and fiducial markers was taken and embedded in paraffin blocks. Subsequently, microtome sectioning and haematoxylin and eosin staining were performed to produce 5-µm-thick tissue sections for microscopic digitisation. A series of rigid registration procedures was performed between the different imaging modalities (PET; in vivo CT-i.e. the CT component of the PET-CT; ex vivo CT; histology slices) with the ex vivo CT serving as the reference image. In vivo and ex vivo CTs were registered using landmark-based registration. Histopathology and ex vivo CT images were aligned using the sea urchin spines with additional anatomical landmarks where available. Registration errors were estimated using a leave-one-out strategy for in vivo to ex vivo CT and were estimated from the RMS landmark accuracy for histopathology to ex vivo CT. RESULTS: The mean ± SD accuracy for registration of the in vivo to ex vivo CT images was 2.66 ± 0.66 mm, and the accuracy for registration of histopathology to ex vivo CT was 0.86 ± 0.41 mm. Estimating the PET to in vivo CT registration accuracy to equal the PET-CT alignment accuracy of 1 mm resulted in an overall average registration error between PET and histopathology slices of 3.0 ± 0.7 mm. CONCLUSIONS: We have developed a registration method to align PET images and histopathology slices with an accuracy comparable to the spatial resolution of the PET images.

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.

Interstitial diffusion and the relationship between compartment modelling and multi-scale spatial-temporal modelling of (18)F-FLT tumour uptake dynamics.

Tumour cell proliferation can be imaged via positron emission tomography of the radiotracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT). Conceptually, the number of proliferating cells might be expected to correlate more closely with the kinetics of 18F-FLT uptake than with uptake at a fixed time. Radiotracer uptake kinetics are standardly visualized using parametric maps of compartment model fits to time-activity-curves (TACs) of individual voxels. However the relationship between the underlying spatiotemporal accumulation of FLT and the kinetics described by compartment models has not yet been explored. In this work tumour tracer uptake is simulated using a mechanistic spatial-temporal model based on a convection-diffusion-reaction equation solved via the finite difference method. The model describes a chain of processes: the flow of FLT between the spatially heterogeneous tumour vasculature and interstitium; diffusion and convection of FLT within the interstitium; transport of FLT into cells; and intracellular phosphorylation. Using values of model parameters estimated from the biological literature, simulated FLT TACs are generated with shapes and magnitudes similar to those seen clinically. Results show that the kinetics of the spatial-temporal model can be recovered accurately by fitting a 3-tissue compartment model to FLT TACs simulated for those tumours or tumour sub-volumes that can be viewed as approximately closed, for which tracer diffusion throughout the interstitium makes only a small fractional change to the quantity of FLT they contain. For a single PET voxel of width 2.5-5 mm we show that this condition is roughly equivalent to requiring that the relative difference in tracer uptake between the voxel and its neighbours is much less than one.