Impact of solitary pulmonary nodule size on qualitative and quantitative assessment using 18F-fluorodeoxyglucose PET/CT: the SPUTNIK trial.

PURPOSE: To compare qualitative and semi-quantitative PET/CT criteria, and the impact of nodule size on the diagnosis of solitary pulmonary nodules in a prospective multicentre trial. METHODS: Patients with an SPN on CT ≥ 8 and ≤ 30 mm were recruited to the SPUTNIK trial at 16 sites accredited by the UK PET Core Lab. Qualitative assessment used a five-point ordinal PET-grade compared to the mediastinal blood pool, and a combined PET/CT grade using the CT features. Semi-quantitative measures included SUVmax of the nodule, and as an uptake ratio to the mediastinal blood pool (SURBLOOD) or liver (SURLIVER). The endpoints were diagnosis of lung cancer via biopsy/histology or completion of 2-year follow-up. Impact of nodule size was analysed by comparison between nodule size tertiles. RESULTS: Three hundred fifty-five participants completed PET/CT and 2-year follow-up, with 59% (209/355) malignant nodules. The AUCs of the three techniques were SUVmax 0.87 (95% CI 0.83;0.91); SURBLOOD 0.87 (95% CI 0.83; 0.91, p = 0.30 versus SUVmax); and SURLIVER 0.87 (95% CI 0.83; 0.91, p = 0.09 vs. SUVmax). The AUCs for all techniques remained stable across size tertiles (p > 0.1 for difference), although the optimal diagnostic threshold varied by size. For nodules < 12 mm, an SUVmax of 1.75 or visual uptake equal to the mediastinum yielded the highest accuracy. For nodules > 16 mm, an SUVmax ≥ 3.6 or visual PET uptake greater than the mediastinum was the most accurate. CONCLUSION: In this multicentre trial, SUVmax was the most accurate technique for the diagnosis of solitary pulmonary nodules. Diagnostic thresholds should be altered according to nodule size. TRIAL REGISTRATION: ISRCTN - ISRCTN30784948. ClinicalTrials.gov - NCT02013063.

CT-based texture analysis potentially provides prognostic information complementary to interim fdg-pet for patients with hodgkin's and aggressive non-hodgkin's lymphomas.

OBJECTIVES: The purpose of this study was to investigate the ability of computed tomography texture analysis (CTTA) to provide additional prognostic information in patients with Hodgkin's lymphoma (HL) and high-grade non-Hodgkin's lymphoma (NHL). METHODS: This retrospective, pilot-study approved by the IRB comprised 45 lymphoma patients undergoing routine 18F-FDG-PET-CT. Progression-free survival (PFS) was determined from clinical follow-up (mean-duration: 40 months; range: 10-62 months). Non-contrast-enhanced low-dose CT images were submitted to CTTA comprising image filtration to highlight features of different sizes followed by histogram-analysis using kurtosis. Prognostic value of CTTA was compared to PET FDG-uptake value, tumour-stage, tumour-bulk, lymphoma-type, treatment-regime, and interim FDG-PET (iPET) status using Kaplan-Meier analysis. Cox regression analysis determined the independence of significantly prognostic imaging and clinical features. RESULTS: A total of 27 patients had aggressive NHL and 18 had HL. Mean PFS was 48.5 months. There was no significant difference in pre-treatment CTTA between the lymphoma sub-types. Kaplan-Meier analysis found pre-treatment CTTA (medium feature scale, p=0.010) and iPET status (p<0.001) to be significant predictors of PFS. Cox analysis revealed that an interaction between pre-treatment CTTA and iPET status was the only independent predictor of PFS (HR: 25.5, 95% CI: 5.4-120, p<0.001). Specifically, pre-treatment CTTA risk stratified patients with negative iPET. CONCLUSION: CTTA can potentially provide prognostic information complementary to iPET for patients with HL and aggressive NHL. KEY POINTS: • CT texture-analysis (CTTA) provides prognostic information complementary to interim FDG-PET in Lymphoma. • Pre-treatment CTTA and interim PET status were significant predictors of progression-free survival. • Patients with negative interim PET could be further stratified by pre-treatment CTTA. • Provide precision surveillance where additional imaging reserved for patients at greatest recurrence-risk. • Assists in risk-adapted treatment strategy based on interim PET and CTTA.

Current status and guidelines for the assessment of tumour vascular support with dynamic contrast-enhanced computed tomography.

Dynamic contrast-enhanced computed tomography (DCE-CT) assesses the vascular support of tumours through analysis of temporal changes in attenuation in blood vessels and tissues during a rapid series of images acquired with intravenous administration of iodinated contrast material. Commercial software for DCE-CT analysis allows pixel-by-pixel calculation of a range of validated physiological parameters and depiction as parametric maps. Clinical studies support the use of DCE-CT parameters as surrogates for physiological and molecular processes underlying tumour angiogenesis. DCE-CT has been used to provide biomarkers of drug action in early phase trials for the treatment of a range of cancers. DCE-CT can be appended to current imaging assessments of tumour response with the benefits of wide availability and low cost. This paper sets out guidelines for the use of DCE-CT in assessing tumour vascular support that were developed using a Delphi process. Recommendations encompass CT system requirements and quality assurance, radiation dosimetry, patient preparation, administration of contrast material, CT acquisition parameters, terminology and units, data processing and reporting. DCE-CT has reached technical maturity for use in therapeutic trials in oncology. The development of these consensus guidelines may promote broader application of DCE-CT for the evaluation of tumour vascularity. Key Points • DCE-CT can robustly assess tumour vascular support • DCE-CT has reached technical maturity for use in therapeutic trials in oncology • This paper presents consensus guidelines for using DCE-CT in assessing tumour vascularity.

Molecular imaging with dynamic contrast-enhanced computed tomography.

Dynamic contrast-enhanced computed tomography (DCE-CT) is a quantitative technique that employs rapid sequences of CT images after bolus administration of intravenous contrast material to measure a range of physiological processes related to the microvasculature of tissues. By combining knowledge of the molecular processes underlying changes in vascular physiology with an understanding of the relationship between vascular physiology and CT contrast enhancement, DCE-CT can be redefined as a molecular imaging technique. Some DCE-CT derived parameters reflect tissue hypoxia and can, therefore, provide information about the cellular microenvironment. DCE-CT can also depict physiological processes, such as vasodilatation, that represent the physiological consequences of molecular responses to tissue hypoxia. To date the main applications have been in stroke and oncology. Unlike some other molecular imaging approaches, DCE-CT benefits from wide availability and ease of application along with the use of contrast materials and software packages that have achieved full regulatory approval. Hence, DCE-CT represents a molecular imaging technique that is applicable in clinical practice today.

Quantifying emerging drugs for very rare conditions.

BACKGROUND: EU legislation is encouraging pharmaceutical companies to develop drugs for rare conditions, but their often high cost, and potential for long-term administration has led to debate about their affordability and cost-effectiveness. AIM: To investigate how many drugs are in development for very rare conditions. METHODS: We defined very rare conditions as having a prevalence of <1:50,000, and identified pharmaceuticals in phase II, phase III trials or pre-registration for these conditions using commercial databases. RESULTS: We identified 42 very rare conditions with at least one drug in late-stage clinical development, with a total of 113 drugs in development (17 for at least two indications). Sixteen drugs were pre-registration, 29 were in phase III development, 65 were in phase II development, one drug was both pre-registration and phase II for different indications and two drugs were in both phase II and phase III trials for different indications. DISCUSSION: Not all the drugs in development will reach the market, but it is likely that a significant number will do so. Affordability and methods to assess cost-effectiveness will need debate and clear national policy for decision-makers to follow.

Accuracy and cost-effectiveness of dynamic contrast-enhanced CT in the characterisation of solitary pulmonary nodules-the SPUtNIk study.

INTRODUCTION: Solitary pulmonary nodules (SPNs) are common on CT. The most cost-effective investigation algorithm is still to be determined. Dynamic contrast-enhanced CT (DCE-CT) is an established diagnostic test not widely available in the UK currently. METHODS AND ANALYSIS: The SPUtNIk study will assess the diagnostic accuracy, clinical utility and cost-effectiveness of DCE-CT, alongside the current CT and 18-flurodeoxyglucose-positron emission tomography) (18FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for 18FDG-PET-CT and DCE-CT will follow a standardised protocol with central review of 10% to ensure quality assurance. Decision analytic modelling will assess the likely costs and health outcomes resulting from incorporation of DCE-CT into management strategies for patients with SPNs. ETHICS AND DISSEMINATION: Approval has been granted by the South West Research Ethics Committee. Ethics reference number 12/SW/0206. The results of the trial will be presented at national and international meetings and published in an Health Technology Assessment (HTA) Monograph and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN30784948; Pre-results.

Functional computed tomography in oncology.

Functional Computed Tomography (CT) describes the use of existing technologies and conventional contrast agents to capture physiological parameters that reflect the vasculature within tumours and other tissues. The technique is readily incorporated into routine conventional CT examinations and, in tumours, the physiological parameters obtained provide an in-vivo marker of angiogenesis. As well as providing a research tool, functional CT has clinical applications in tumour diagnosis, staging, risk stratification and therapy monitoring, including the characterisation of pulmonary nodules, detection of occult hepatic metastases, grading of cerebral glioma and monitoring of anti-angiogenesis drugs. With the recent commercial availability of appropriate software and the development of multislice CT systems, functional CT is poised to make a significant impact upon the imaging of patients with cancer.

Functional imaging of changes in human intrarenal perfusion using quantitative dynamic computed tomography.

RATIONALE AND OBJECTIVES: Quantitative dynamic computed tomography was used with perfusion imaging to characterize intrarenal variations in perfusion in normal and abnormal human kidneys. METHODS: Perfusion images were obtained from 14 normal and four abnormal kidneys, comprising a renal tumor, an infarcted renal allograft, and two kidneys in a patient with cyclosporin toxicity. RESULTS: Images demonstrating quantifiable intrarenal variations in perfusion were consistently obtained. Normal cortical and medullary perfusion were 4.7 mL/min/mL and 1.1 mL/min/mL, respectively, consistent with accepted normal ranges. The changes in the abnormal kidneys corresponded with known pathophysiology. CONCLUSION: Computed tomography perfusion imaging creates quantifiable images of renal perfusion with a spatial resolution currently higher than any other functional imaging technique. It offers the opportunity to characterize renal diseases by their relative effects on cortical and medullary perfusion.

Longitudinal distribution of O3 absorption in the lung: gender differences and intersubject variability.

Because the National Ambient Air Quality Standard for ozone (O3) is intended to protect the most sensitive individuals in the general population, it is necessary to identify sources of intersubject variation in the exposure-dose-response cascade. We hypothesize that differences in lung anatomy can modulate exposure-dose relationships between individuals, and this results in differences between their responsiveness to O3 at a fixed exposure condition. During quiet breathing, the conducting airways remove the majority of inhaled O3, so the volume of this region should have an important impact on O3 dose distribution. Employing the bolus inhalation method, we measured the distribution of O3 absorption with respect to penetration volume (Vp), and using the Fowler single-breath N2 washout method, we determined the dead space volume (VD) in the lungs of 10 men and 10 women at a fixed respiratory flow of 250 ml/s. On average, the women absorbed O3 at smaller Vp than the men, and the women had smaller VD than the men. When expressed in terms of Vp/VD, the absorption distribution of the men and women was indistinguishable. Moreover, an interpretation of the O3 distribution in terms of an intrinsic mass transfer parameter (Ka) indicated that differences between the O3 dosimetry in all subjects, whether men or women, could be explained by a unique correlation with anatomic dead space: Ka (in s-1) = 610 VD-105 (in ml). Application of this result to measurements of O3 exposure response indicated that previously reported gender differences may be due to a failure in properly accounting for tissue surface within the conducting airways.

Assessment of quantitative computed tomographic cerebral perfusion imaging with H2(15)O positron emission tomography.

Assessment of quantitative cerebral blood flow on a conventional fast CT machine without the use of specialized equipment may be valuable in the investigation of acute stroke and head injury. We aimed to compare a single slice CT perfusion sequence with H2(15)O positron emission tomography using the sagittal sinus as an input function, a method that avoids unnecessary orbital irradiation. Eight patients were studied, two patients with gliomas, and six with arteriovenous malformations. The dynamic CT perfusion sequence was performed by acquiring the same 10 mm slice 10 times over 30 sec during a 50 ml bolus of intravenous contrast medium given at a rate of 7.5 ml sec-1 using a power injector. The CT perfusion studies were completed without complication. Co-registration was sub-optimal in one patient. Overall the correlation between the two methodologies was encouraging with an average r2 value of 0.524 for individual analyses. When two patients with high flow arteriovenous malformations were excluded the average r2 value increased to 0.640. The results of this CT perfusion methodology are encouraging. Having shown its feasibility, further studies in conditions with lower rates of cerebral blood flow are warranted.

Brain perfusion: computed tomography applications.

Within recent years, the broad introduction of fast multi-detector computed tomography (CT) systems and the availability of commercial software for perfusion analysis have made cerebral perfusion imaging with CT a practical technique for the clinical environment. The technique is widely available at low cost, accurate and easy to perform. Perfusion CT is particularly applicable to those clinical circumstances where patients already undergo CT for other reasons, including stroke, head injury, subarachnoid haemorrhage and radiotherapy planning. Future technical developments in multi-slice CT systems may diminish the current limitations of limited spatial coverage and radiation burden. CT perfusion imaging on combined PET-CT systems offers new opportunities to improve the evaluation of patients with cerebral ischaemia or tumours by demonstrating the relationship between cerebral blood flow and metabolism. Yet CT is often not perceived as a technique for imaging cerebral perfusion. This article reviews the use of CT for imaging cerebral perfusion, highlighting its advantages and disadvantages and draws comparisons between perfusion CT and magnetic resonance imaging.

Measurement of tissue perfusion by dynamic computed tomography.

A method for quantifying tissue perfusion by dynamic computed tomography (CT) is described. By applying a nuclear medicine data processing technique to time-density data from a single-location dynamic CT sequence, tissue perfusion can be determined from the maximum gradient of the tissue time-density curve divided by the peak enhancement of the aorta. Using this method, splenic perfusion was measured at 1.2 ml min-1 ml-1, normal renal cortical perfusion at 2.5 ml min-1 ml-1 and normal renal medullary perfusion at 1.1 ml min-1 ml-1. Changes in cortical and medullary perfusion in renal failure and hypertension were demonstrated. The ability of dynamic CT to provide quantitative functional information is not well recognized and is potentially of value when studying structures, such as the renal cortex and medulla, that cannot be anatomically resolved by standard functional imaging techniques.

Perfusion CT for the assessment of tumour vascularity: which protocol?

Perfusion CT is a technique that can be readily incorporated into the existing CT protocols that continue to provide the mainstay for anatomical imaging in oncology to provide an in vivo marker of tumour angiogenesis. By capturing physiological information reflecting the tumour vasculature, perfusion CT can be useful for diagnosis, risk-stratification and therapeutic monitoring. However, a wide range of perfusion CT techniques have evolved and the various commercial implementations advocate different acquisition protocols and processing methods. Acquisition choices include first pass studies or delayed imaging, temporal resolution versus image noise, and single location sequences or multiple spiral acquisitions. Data processing may be semi-quantitative or, using either compartmental analysis or deconvolution, produce results that are quantified in absolute physiological terms such as perfusion, blood volume and permeability. This article discusses the advantages and disadvantages of the more common CT perfusion protocols and offers proposals that could allow for easier comparison between studies employing different techniques.

Technical note: bone SPECT of the wrist.

A technique for single photon emission computed tomography (SPECT) during bone scintigraphy of the wrist is described. The technique has been developed as a means to improve localization of abnormalities observed on 99Tcm-MDP planar bone scintigraphy. A wrist phantom and 15 wrists in 13 symptomatic patients were examined. Good spatial detail was achieved, with the pisiform readily identifiable as a separate bone in six wrists. In seven cases the tomograms permitted better localization of planar image abnormalities and in four cases additional lesions were visible which were missed on planar scintigraphy. This technique can be applied to all patients with suspected carpal injury and allows better anatomical localization and greater sensitivity than planar scintigraphy alone.

CT measurements of capillary permeability within nodal masses: a potential technique for assessing the activity of lymphoma.

Analysis of time-attenuation data has enabled CT to measure capillary permeability within the brain and kidney. As yet, such techniques have not been applied to nodal masses in patients with lymphoma. Tumour angiogenesis is known to produce capillaries that exhibit increased permeability and CT measurements of permeability could therefore potentially provide a marker of tumour viability. This study aims to determine the feasibility and limitations of CT measurement of capillary permeability within lymphoma nodal masses. Six patients with biopsy proven lymphoma have been studied. Time-attenuation curves from the aorta and nodal mass were generated from a single-location dynamic sequence of images acquired over 3 min following an intravenous bolus of iopamidol. A nuclear medicine data processing technique, Patlak analysis, was used to calculate capillary permeability and blood volume within the nodal mass. Renal blood vessel permeability was also determined in four patients. Median lymph node permeability to iopamidol was 88.5 microliters min-1 ml-1 (range 36.4-198.5 microliters min-1 ml-1). The correlation coefficient of the linear fit for the Patlak analysis ranged from 0.74 to 0.95 and was greater than 0.9 for regions of interest of 150 pixels or more (256 x 256 matrix). The values for renal permeability (442 microliters min-1 ml-1; range: 349-589 microliters min-1 ml-1) were comparable to those previously reported. Functional images of permeability were also obtained. The study has confirmed the feasibility of CT measurements of capillary permeability within nodal masses. The technique combines anatomical imaging and functional information within one examination and has potential application in monitoring the response of lymphoma to therapy.

Measurement of human pancreatic perfusion using dynamic computed tomography with perfusion imaging.

Absolute quantification of pancreatic perfusion in man has been extremely difficult to date. This paper describes a relatively simple application of dynamic computed tomography to provide perfusion imaging of the human pancreas. Values for perfusion in eight normal pancreases ranged between 1.25 and 1.66 ml min-1 ml-1 (mean: 1.52 ml min-1 ml-1). Increased perfusion values were present in a patient with an islet cell tumour (overall perfusion 2.11 ml min-1 ml-1) and a patient with Wilson's disease (3.43 ml min-1 ml-1). Pancreatic perfusion was reduced in a patient with diabetes (0.60 ml min-1 ml-1) and in a failing pancreatic transplant (0.97 ml min-1 ml-1). The combination of functional information and good spatial detail afforded by computed tomography (CT) perfusion imaging means the technique is well suited for the evaluation of the human pancreas. It is currently the only technique which allows non-invasive absolute quantification of pancreatic perfusion.

Can 99Tcm HMPAO leucocyte scintigraphy distinguish between Crohn's disease and ulcerative colitis?

This paper has retrospectively analysed the ability of 99Tcm HMPAO leucocyte scintigraphy to distinguish Crohn's disease from ulcerative colitis. The diagnostic criteria were established by reviewing 99Tcm HMPAO leucocyte scintigrams in 123 patients with histologically proven Crohn's disease (83) or ulcerative colitis (40). Uptake in the right iliac fossa with or without other segments of colon, irregular bowel uptake, small bowel uptake or colonic activity with rectal sparing were all strongly suggestive of Crohn's disease. Left sided colitis was found to indicate ulcerative colitis. Total colitis occurred in both ulcerative colitis and Crohn's disease. The criteria were later tested in an additional 62 patients with excellent results (accuracy 98%). In 63 patients in whom the results of barium radiology were also available, the accuracy of scintigraphy was higher (93% and 83%, respectively). We conclude that 99Tcm HMPAO leucocyte scintigraphy can accurately distinguish between Crohn's disease and ulcerative colitis in a large proportion of cases and appears to be more reliable than conventional radiology.

Scintigraphic abnormalities in patients with painful hip replacements treated conservatively.

A retrospective review of the scintigraphic appearances of 98 painful hip replacements was made. 16 patients (16%) underwent revision surgery whereas in the remaining 82 hips (84%), symptoms settled with conservative management. 73 of these (89%) had at least one area of increased activity on delayed diphosphonate scintigraphy with 27% having increased activity in three or more areas around the femoral component. Hips with increased activity at the lesser trochanter and tip were less likely to undergo spontaneous resolution of symptoms. Uncemented prostheses were more likely to have multiple areas of increased activity. Abnormalities in dynamic bone scintigraphy and gallium studies were also seen in patients whose symptoms resolved without surgery. Whereas a normal bone scintigram indicates that loosening or infection is most unlikely, the presence of increased activity does not necessarily indicate a need for revision surgery, even when multiple areas are present. A period of conservative management should be considered before operative intervention is undertaken.

CT derived Patlak images of the human kidney.

This study aimed to produce Patlak images of the kidney from dynamic CT data and to determine whether such images are substantially affected by fluid movement between renal tubular segments. Renal permeability was measured in 31 kidneys by applying Patlak analysis to time-density data from kidney and aorta during dynamic CT. Permeability parameters were correlated against plasma urea. The renal region (cortex or medulla) with the greatest permeability was determined from parametric images generated using pixel by pixel analysis. The mean value for whole kidney permeability was 517.5 microliters min-1 ml-1. A correlation was found between whole kidney permeability and plasma urea (p < 0.01). Permeability values were highest in the renal medulla in 24 (77%) kidneys. The higher medullary values of permeability are artefactual, resulting from movement of fluid and contrast medium between cortex and medulla. Although Patlak images do not reflect true intrarenal permeability values, the apparent medullary permeability may provide diagnostically useful information about the concentrating ability of the kidney. CT measurements of whole kidney permeability reflect filtration function but the apparent intrarenal variations in permeability will result in measurement errors dependent upon the relative amounts of renal cortex and medulla included in the CT slice studied.

The significance of low grade right iliac fossa uptake on 99Tcm-HMPAO labelled white cell scans.

Technetium-99m HMPAO labelled white cell scanning is now an accepted method for assessing the activity of inflammatory bowel disease. However, false positive results have been demonstrated. This study was conducted to assess the significance of low grade uptake on 99Tcm-HMPAO labelled white cell scans in the right iliac fossa (RIF) in the context of possible inflammatory bowel disease (IBD). 32 patients over a period of 1 year had low grade RIF uptake as the predominant abnormality. 20 of these had no prior diagnosis of inflammatory bowel disease. Only one case in this group was subsequently diagnosed as having Crohn's disease. Nodular lymphoid hyperplasia (NLHP) and non-steroidal anti-inflammatory drugs (NSAIDs) were also associated with low grade RIF uptake. Possible explanations for these findings are discussed.