Ashley M. Groves

Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) and 18F-FDG.

The aim was to assess the relevant distribution of the novel PET tracer 68Ga‐DOTATATE in neuroendocrine tumors (NETs) with combined positron emission tomography / computed tomography (PET/CT) and compare its performance with that of 18F‐FDG PET/CT.

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.ConclusionsWith resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.

A Comparison of 68Ga-DOTATATE and 18F-FDG PET/CT in Pulmonary Neuroendocrine Tumors

Our purpose was to compare the performance of 68Ga-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-d-Phe1,Tyr3-octreotate (DOTATATE), a novel selective somatostatin receptor 2 PET ligand, and 18F-FDG in the detection of pulmonary neuroendocrine tumors using PET/CT, with correlation of uptake and tumor grade on histology. Methods: The imaging findings of the first 18 consecutive patients (8 men and 10 women) with pulmonary neuroendocrine tumors (11 typical carcinoids, 2 atypical carcinoids, 1 large cell neuroendocrine tumor, 1 small cell neuroendocrine carcinoma, 1 non–small cell lung cancer with neuroendocrine differentiation, and 2 cases of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia) who underwent 68Ga-DOTATATE and 18F-FDG PET/CT were reviewed. In all cases, the diagnosis was established on histology. Results: Of 18 patients, 15 had primary tumors (median size, 2.7 cm; range, 0.5–8 cm) and 3 had recurrent tumors. All typical carcinoids showed high uptake of 68Ga-DOTATATE (maximum standardized uptake value [SUVmax] ≥ 8.2), but 4 of 11 showed negative or minimal 18F-FDG uptake (SUVmax = 1.7–2.9). All tumors of higher grade showed high uptake of 18F-FDG (SUVmax ≥ 11.7), but 3 of 5 showed only minimal accumulation of 68Ga-DOTATATE (SUVmax = 2.2–2.8). Neither case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia showed uptake of 68Ga-DOTATATE or 18F-FDG. Typical carcinoids showed significantly higher uptake of 68Ga-DOTATATE and significantly less uptake of 18F-FDG than did tumors of higher grade (P = 0.002 and 0.005). There was no instance of false-positive uptake of 68Ga-DOTATATE, but there were 3 sites of 18F-FDG uptake secondary to inflammation. 68Ga-DOTATATE was superior to 18F-FDG in discriminating endobronchial tumor from distal collapsed lung (P = 0.02). Conclusion: Typical bronchial carcinoids showed higher and more selective uptake of 68Ga-DOTATATE than of 18F-FDG. Atypical carcinoids and higher grades had less 68Ga-DOTATATE avidity but were 18F-FDG–avid.

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

AbstractDynamic 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

Tumor heterogeneity and permeability as measured on the CT component of PET/CT predict survival in patients with non-small cell lung cancer.

Purpose: We prospectively examined the role of tumor textural heterogeneity on positron emission tomography/computed tomography (PET/CT) in predicting survival compared with other clinical and imaging parameters in patients with non–small cell lung cancer (NSCLC). Experimental Design: The feasibility study consisted of 56 assessed consecutive patients with NSCLC (32 males, 24 females; mean age 67 ± 9.7 years) who underwent combined fluorodeoxyglucose (FDG) PET/CT. The validation study population consisted of 66 prospectively recruited consecutive consenting patients with NSCLC (37 males, 29 females; mean age, 67.5 ± 7.8 years) who successfully underwent combined FDG PET/CT-dynamic contrast-enhanced (DCE) CT. Images were used to derive tumoral PET/CT textural heterogeneity, DCE CT permeability, and FDG uptake (SUVmax). The mean follow-up periods were 22.6 ± 13.3 months and 28.5± 13.2 months for the feasibility and validation studies, respectively. Optimum threshold was determined for clinical stage and each of the above biomarkers (where available) from the feasibility study population. Kaplan–Meier analysis was used to assess the ability of the biomarkers to predict survival in the validation study. Cox regression determined survival factor independence. Results: Univariate analysis revealed that tumor CT-derived heterogeneity (P < 0.001), PET-derived heterogeneity (P = 0.003), CT-derived permeability (P = 0.002), and stage (P < 0·001) were all significant survival predictors. The thresholds used in this study were derived from a previously conducted feasibility study. Tumor SUVmax did not predict survival. Using multivariable analysis, tumor CT textural heterogeneity (P = 0.021), stage (P = 0.001), and permeability (P < 0.001) were independent survival predictors. These predictors were independent of patient treatment. Conclusions: Tumor stage and CT-derived textural heterogeneity were the best predictors of survival in NSCLC. The use of CT-derived textural heterogeneity should assist the management of many patients with NSCLC. Clin Cancer Res; 19(13); 3591–9. ©2013 AACR.

Non-[18F]FDG PET in clinical oncology

PET is an exquisitely sensitive molecular imaging technique using positron-emitting radioisotopes coupled to specific ligands. Many biological targets of great interest can be imaged with these radiolabelled ligands. This review describes the current status of non-18-fluorodeoxyglucose PET tracers that have a potential clinical effect in oncology. With the help of these tracers, knowledge is being acquired on the molecular characterisation of specific tumours, their biological signature, and postinterventional response. The potential role of these imaging probes for tumour detection and monitoring is progressively being recognised by clinical oncologists, biologists, and pharmacologists.

Comparison of shuttle walk with measured peak oxygen consumption in patients with operable lung cancer

Background: The relationship between the shuttle walk test and peak oxygen consumption in patients with lung cancer has not previously been reported. A study was undertaken to examine this relationship in patients referred for lung cancer surgery to test the hypothesis that the shuttle walk test would be useful in this clinical setting. Methods: 125 consecutive patients with potentially operable lung cancer were prospectively recruited. Each performed same day shuttle walking and treadmill walking tests. Results: Shuttle walk distances ranged from 104 m to 1020 m and peak oxygen consumption ranged from 9 to 35 ml/kg/min. The shuttle walk distance significantly correlated with peak oxygen consumption (r = 0.67, p<0.001). All 55 patients who achieved more than 400 m on the shuttle test had a peak oxygen consumption of at least 15 ml/kg/min. Seventy of 125 patients failed to achieve 400 m on the shuttle walk test; in 22 of these the peak oxygen consumption was less than 15 ml/kg/min. Nine of 17 patients who achieved less than 250 m had a peak oxygen consumption of more than 15 ml/kg/min. Conclusion: The shuttle walk is a useful exercise test to assess potentially operable lung cancer patients with borderline lung function. However, it tends to underestimate exercise capacity at the lower range compared with peak oxygen consumption. Our data suggest that patients achieving 400 m on the shuttle walk test do not require formal measurement of oxygen consumption. In patients failing to achieve this distance we recommend assessment of peak oxygen consumption, particularly in those unable to walk 250 m, because a considerable proportion would still qualify for surgery as they had an acceptable peak oxygen consumption.

Cardiopulmonary exercise tests and lung cancer surgical outcome

STUDY OBJECTIVES Surgical resection remains the treatment of choice for anatomically resectable non-small cell lung cancer. However, the presence of associated comorbid conditions increases the risk of death and surgical complications. Several studies have evaluated the usefulness of preoperative exercise testing for predicting postoperative morbidity and mortality. The aim of this study was to establish whether exercise testing could predict poor surgical outcome in lung cancer surgery and whether the absolute value or percentage of predicted value is the better predictor of the surgical outcome. DESIGN The study was designed as a prospective study. PATIENTS AND SETTING One hundred thirty patients with potentially operable lung cancer at Papworth Hospital over 2 years were recruited; of these, 101 underwent curative surgery. INTERVENTIONS Spirometry and cardiopulmonary exercise tests were performed for every patient (n = 99), except for two patients with back problems. We also recorded the outcome of surgery, in particular, complications and mortality. MEASUREMENTS AND RESULTS Mean maximum oxygen transport at peak exercise (Vo(2)peak) was 18.3 mL/kg/min (SD, 4.7 mL/kg/min), and mean percentage of predicted Vo(2)peak value was 84.4% (SD, 30%). Poor surgical outcome was significantly related to Vo(2)peak percentage of predicted (p < 0.01) but not to the actual oxygen uptake value. CONCLUSIONS The use of the percentage of predicted Vo(2)peak value would be a better indicator of surgical outcome, since it predicts the surgical outcome better, and corrects for normal physiologic ranges. The threshold of Vo(2)peak for surgical intervention could be set between 50% and 60% of predicted without excess surgical mortality.

Idiopathic Pulmonary Fibrosis and Diffuse Parenchymal Lung Disease: Implications from Initial Experience with 18F-FDG PET/CT

The purpose of this study was to evaluate integrated 18F-FDG PET/CT in patients with idiopathic pulmonary fibrosis (IPF) and diffuse parenchymal lung disease (DPLD). Methods: Thirty-six consecutive patients (31 men and 5 women; mean age ± SD, 68.7 ± 9.4 y) with IPF (n = 18) or other forms of DPLD (n = 18) were recruited for PET/CT and high-resolution CT (HRCT), acquired on the same instrument. The maximal pulmonary 18F-FDG metabolism was measured as a standardized uptake value (SUVmax). At this site, the predominant lung parenchyma HRCT pattern was defined for each patient: ground-glass or reticulation/honeycombing. Patients underwent a global health assessment and pulmonary function tests. Results: Raised pulmonary 18F-FDG metabolism in 36 of 36 patients was observed. The parenchymal pattern on HRCT at the site of maximal 18F-FDG metabolism was predominantly ground-glass (7/36), reticulation/honeycombing (26/36), and mixed (3/36). The mean SUVmax in patients with ground-glass and mixed patterns was 2.0 ± 0.4, and in reticulation/honeycombing it was 3.0 ± 1.0 (Mann–Whitney U test, P = 0.007). The mean SUVmax in patients with IPF was 2.9 ± 1.1, and in other DPLD it was 2.7 ± 0.9 (Mann–Whitney U test, P = 0.862). The mean mediastinal lymph node SUVmax (2.7 ± 1.3) correlated with pulmonary SUVmax (r = 0.63, P < 0.001). Pulmonary 18F-FDG uptake correlated with the global health score (r = 0.50, P = 0.004), forced vital capacity (r = 0.41, P = 0.014), and transfer factor (r = 0.37, P = 0.042). Conclusion: Increased pulmonary 18F-FDG metabolism in all patients with IPF and other forms of DPLD was observed. Pulmonary 18F-FDG uptake predicts measurements of health and lung physiology in these patients. 18F-FDG metabolism was higher when the site of maximal uptake corresponded to areas of reticulation/honeycomb on HRCT than to those with ground-glass patterns.

Qualitative and Quantitative Comparison of PET/CT and PET/MR Imaging in Clinical Practice

The aim of this study was to prospectively compare whole-body PET/MR imaging and PET/CT, qualitatively and quantitatively, in oncologic patients and assess the confidence and degree of inter- and intraobserver agreement in anatomic lesion localization. Methods: Fifty patients referred for staging with known cancers underwent PET/CT with low-dose CT for attenuation correction immediately followed by PET/MR imaging with 2-point Dixon attenuation correction. PET/CT scans were obtained according to standard protocols (56 ± 20 min after injection of an average 367 MBq of 18F-FDG, 150 MBq of 68Ga-DOTATATE, or 333.8 MBq of 18F-fluoro-ethyl-choline; 2.5 min/bed position). PET/MR was performed with 5 min/bed position. Three dual-accredited nuclear medicine physicians/radiologists identified the lesions and assigned each to an exact anatomic location. The image quality, alignment, and confidence in anatomic localization of lesions were scored on a scale of 1–3 for PET/CT and PET/MR imaging. Quantitative analysis was performed by comparing the standardized uptake values. Intraclass correlation coefficients and the Wilcoxon signed-rank test were used to assess intra- and interobserver agreement in image quality, alignment, and confidence in lesion localization for the 2 modalities. Results: Two hundred twenty-seven tracer-avid lesions were identified in 50 patients. Of these, 225 were correctly identified on PET/CT and 227 on PET/MR imaging by all 3 observers. The confidence in anatomic localization improved by 5.1% when using PET/MR imaging, compared with PET/CT. The mean percentage interobserver agreement was 96% for PET/CT and 99% for PET/MR imaging, and intraobserver agreement in lesion localization across the 2 modalities was 93%. There was 10% (5/50 patients) improvement in local staging with PET/MR imaging, compared with PET/CT. Conclusion: In this first study, we show the effectiveness of whole-body PET/MR imaging in oncology. There is no statistically significant difference between PET/MR imaging and PET/CT in respect of confidence and degree of inter- and intraobserver agreement in anatomic lesion localization. The PET data on both modalities were similar; however, the observed superior soft-tissue resolution of MR imaging in head and neck, pelvis, and colorectal cancers and of CT in lung and mediastinal nodal disease points to future tailored use in these locations.