Michael J. Fulham

A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans

Brown adipose tissue (BAT) plays a major role in energy homeostasis in animals. Detection of BAT using positron emission tomography (PET)-CT in humans has challenged the view that BAT disappears after infancy. Several recent studies, based on analysis of single scans, have reported a low prevalence of only 5-10% in humans, casting doubt on its significance. We undertook a critical analysis of the sensitivity, reproducibility, and accuracy of PET-CT to deduce the prevalence of BAT and factors associated with its detection in adult humans. In a retrospective evaluation of PET-CT, using [18F]fluorodeoxyglucose, performed in 2,934 patients, BAT was identified in 250 patients, yielding an apparent prevalence of 8.5%. Among those patients with BAT, 145 were scanned more than once. The frequency of another scan being positive increased from 8 to 65% for one to more than four additional studies. The average probability of obtaining another positive scan among patients with BAT is 13%, from which the prevalence of BAT is estimated at 64%. BAT was more commonly detected in women, in younger (36 ± 1 vs. 52 ± 1 years, P < 0.001) and leaner (20.1 ± 0.9 vs. 24.9 ± 0.9 kg/m2, P < 0.01) individuals. Fasting glucose was lower in those with BAT than those without (4.9 ± 0.1 vs. 5.5 ± 0.1 mmol/l, P < 0.01). Among patients scanned more than once, BAT was detected when body weight and fasting glucose were lower (54.9 ± 0.5 vs. 58.2 ± 0.8 kg, P < 0.001 and 4.9 ± 0.3 vs. 5.5 ± 0.3 mmol/l, P = 0.03). We conclude that BAT is present in the majority of adult humans. Presence of BAT correlates negatively with body mass index and glucose concentration. BAT may play an important role in energy homeostasis in adults.

Randomized Controlled Trial of the Role of Positron Emission Tomography in the Management of Stage I and II Non-Small-Cell Lung Cancer

PURPOSE Positron emission tomography (PET) is a costly new technology with potential to improve preoperative evaluation for patients with non-small-cell lung cancer (NSCLC). There is increasing pressure for PET to be included in standard diagnostic work-up before decisions about surgical management of NSCLC. The resource implications of its widespread use in staging NSCLC are significant. METHODS A randomized controlled trial was conducted to investigate the impact of PET on clinical management and surgical outcomes for patients with stage I-II NSCLC. The primary hypothesis was that PET would reduce the proportion of patients with stage I-II NSCLC who underwent thoracotomy by at least 10% through identification of patients with inoperable disease. RESULTS One hundred eighty-four patients with stage I-II NSCLC were recruited and randomly assigned; 92% had stage I disease. Following exclusion of one ineligible patient, 92 patients were assigned to no PET and 91 to PET. Compared with conventional staging, PET upstaged 22 patients, confirmed staging in 61 and staged two patients as benign. Stage IV disease was rarely detected (two patients). PET led to further investigation or a change in clinical management in 13% of patients and provided information that could have affected management in a further 13% of patients. There was no significant difference between the trial arms in the number of thoracotomies avoided (P =.2). CONCLUSION For patients who are carefully and appropriately staged as having stage I-II disease, PET provides potential for more appropriate stage-specific therapy but may not lead to a significant reduction in the number of thoracotomies avoided.

Correction for head movements in positron emission tomography using an optical motion tracking system

Methods capable of correcting for head motion in all six degrees of freedom have been proposed for positron emission tomography (PET) brain imaging but not yet demonstrated in human studies. These methods rely on the accurate measurement of head motion in relation to the reconstruction coordinate frame. We present methodology for the direct calibration of an optical motion-tracking system to the reconstruction coordinate frame using paired coordinate measurements obtained simultaneously from a PET scanner and tracking system. We also describe the implementation of motion correction, based on the multiple acquisition frame method originally described by Picard and Thompson (1997), using data provided by the motion tracking system. Effective compensation for multiple six-degree-of-freedom movements is demonstrated in dynamic PET scans of the Hoffman brain phantom and a normal volunteer. We conclude that reduced distortion and improved quantitative accuracy can be achieved with this method in PET brain studies degraded by head movements.

Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype

Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimers disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290–319 of PS-1(PS-1 Δ290–319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 Δ290–319 and ρ278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.

Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma

BACKGROUND We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkins lymphoma. METHODS Patients with newly diagnosed advanced classic Hodgkins lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points. RESULTS A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkins lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%. CONCLUSIONS Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.).

Positron Emission Tomography–Computed Tomography (PET-CT) After Induction Therapy Is Highly Predictive of Patient Outcome in Follicular Lymphoma: Analysis of PET-CT in a Subset of PRIMA Trial Participants

PURPOSE The utility of [(18)F]fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in assessing response at the end of induction therapy is well documented in Hodgkins and diffuse large B-cell lymphomas, but its role in follicular lymphoma (FL) remains undetermined. We investigated the prognostic significance of PET-CT performed after first-line therapy in patients with FL treated in the prospective Primary Rituximab and Maintenance (PRIMA) study. PATIENTS AND METHODS Results of PET-CT scans performed after induction immunochemotherapy were recorded retrospectively. Patients went on to either observation or rituximab maintenance per protocol independent of the PET-CT result. Patient characteristics and outcomes were then evaluated. RESULTS Of 122 PET-CT scans performed at the end of the induction immunochemotherapy, 32 (26%) were reported as positive by the local investigator. Initial demographic or disease characteristics did not differ between PET-CT-positive (PET-positive) and PET-CT-negative (PET-negative) patients. PET status correlated with conventional response criteria (P < .001). Patients remaining PET positive had a significantly (P < .001) inferior progression-free survival at 42 months of 32.9% (95% CI, 17.2% to 49.5%) compared with 70.7% (95% CI, 59.3% to 79.4%) in those who became PET negative. PET status, but not conventional response (complete response or complete response unconfirmed v partial response) according to IWC 1999, was an independent predictive factor for lymphoma progression. The risk of death was also increased in PET-positive patients (hazard ratio 7.0; P = .0011). CONCLUSION [(18)F]FDG PET-CT status at the end of immunochemotherapy induction in patients with FL is strongly predictive of outcome and should be considered a meaningful clinical end point in future studies.

Quality of Life and Survival in the 2 Years After Surgery for Non–Small-Cell Lung Cancer

PURPOSE Although surgery for early-stage non-small-cell lung cancer (NSCLC) is known to have a substantial impact on health-related quality of life (HRQOL), there are few published studies about HRQOL in the longer term. This article examines HRQOL and survival in the 2 years after surgery. PATIENTS AND METHODS Patients with clinical stage I or II NSCLC (n = 173) completed HRQOL questionnaires before surgery, at discharge, 1 month after surgery, and then every 4 months for 2 years. HRQOL was measured with a generic cancer questionnaire (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-QLQ] C30) and a lung cancer-specific questionnaire (EORTC QLQ-LC13). Data were analyzed to examine the impact of surgery and any subsequent therapy, and to describe the trajectories of those who remained disease free at 2 years and those with recurrent cancer diagnosed during follow-up. RESULTS Disease recurred within 2 years for 36% of patients and 2-year survival was 65%. Surgery substantially reduced HRQOL across all dimensions except emotional functioning. HRQOL improved in the 2 years after surgery for patients without disease recurrence, although approximately half continued to experience symptoms and functional limitations. For those with recurrence within 2 years, there was some early postoperative recovery in HRQOL, with subsequent deterioration across most dimensions. CONCLUSION Surgery had a substantial impact on HRQOL, and although many disease-free survivors experienced recovery, some lived with long-term HRQOL impairment. HRQOL generally worsened with disease recurrence. The study results are important for informed decision making and ongoing supportive care for patients with operable NSCLC.

Evaluation of two population-based input functions for quantitative neurological FDG PET studies

The conventional measurement of the regional cerebral metabolic rate of glucose (rCMRGlc) with fluorodeoxyglucose (FDG) and positron emission tomography (PET) requires arterial or arterialised-venous (a–v) blood sampling at frequent intervals to obtain the plasma input function (IF). We evaluated the accuracy of rCMRGlc measurements using population-based IFs that were calibrated with two a–v blood samples. Population-based IFs were derived from: (1) the average of a–v IFs from 26 patients (Standard IF) and (2) a published model of FDG plasma concentration (Feng IF). Values for rCMRGlc calculated from the population-based IFs were compared with values obtained with IFs derived from frequent a–v blood sampling in 20 non-diabetic and six diabetic patients. Values for rCMRGlc calculated with the different IFs were highly correlated for both patient groups (r≥0.992) and root mean square residuals about the regression line were less than 0.24 mg/min/100 g. The Feng IF tended to underestimate high rCMRGlc. Both population-based IFs simplify the measurement of rCMRGlc with minimal loss in accuracy and require only two a–v blood samples for calibration. The reduced blood sampling requirements markedly reduce radiation exposure to the blood sampler.

Content-Based Medical Image Retrieval: A Survey of Applications to Multidimensional and Multimodality Data

Medical imaging is fundamental to modern healthcare, and its widespread use has resulted in the creation of image databases, as well as picture archiving and communication systems. These repositories now contain images from a diverse range of modalities, multidimensional (three-dimensional or time-varying) images, as well as co-aligned multimodality images. These image collections offer the opportunity for evidence-based diagnosis, teaching, and research; for these applications, there is a requirement for appropriate methods to search the collections for images that have characteristics similar to the case(s) of interest. Content-based image retrieval (CBIR) is an image search technique that complements the conventional text-based retrieval of images by using visual features, such as color, texture, and shape, as search criteria. Medical CBIR is an established field of study that is beginning to realize promise when applied to multidimensional and multimodality medical data. In this paper, we present a review of state-of-the-art medical CBIR approaches in five main categories: two-dimensional image retrieval, retrieval of images with three or more dimensions, the use of nonimage data to enhance the retrieval, multimodality image retrieval, and retrieval from diverse datasets. We use these categories as a framework for discussing the state of the art, focusing on the characteristics and modalities of the information used during medical image retrieval.

Simultaneous estimation of physiological parameters and the input function - in vivo PET data

Dynamic imaging with positron emission tomography (PET) is widely used for the in-vivo measurement of the regional cerebral metabolic rate for glucose (rCMRGlc) with [/sup 18/F]fluorodeoxy-D-glucose (FDG), and is used for the clinical evaluation of neurological diseases. However, in addition to the acquisition of dynamic images, continuous arterial blood sampling is the conventional method of obtaining the tracer time-activity curve in blood (or plasma) for the numerical estimation of rCMRGlc in mg glucose/100 g tissue/min. The insertion of arterial lines and the subsequent collection and processing of multiple blood samples are impractical for clinical PET studies because it is invasive, it has the remote (but real) potential for producing limb ischemia, and it exposes personnel to additional radiation and the risks associated with handling blood. Based on a method for extracting kinetic parameters from dynamic PET images, we developed a modified version (post-estimation method) to improve the numerical identifiability of the parameter estimates when we deal with data obtained from clinical studies. We applied both methods to dynamic neurological FDG PET studies in three adults. We found that the input function and parameter estimates obtained with our noninvasive methods agreed well with those estimated from the gold-standard method of arterial blood sampling and that rCMRGlc estimates were highly correlated. No significant difference was found between rCMRGlc estimated by our methods and the gold-standard method. We suggest that our proposed noninvasive methods may offer an advance over existing methods.