Glucagon increases energy expenditure independently of brown adipose tissue activation in humans.

AIMS: To investigate, for a given energy expenditure (EE) rise, the differential effects of glucagon infusion and cold exposure on brown adipose tissue (BAT) activation in humans. METHODS: Indirect calorimetry and supraclavicular thermography was performed in 11 healthy male volunteers before and after: cold exposure; glucagon infusion (at 23 °C); and vehicle infusion (at 23 °C). All volunteers underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT scanning with cold exposure. Subjects with cold-induced BAT activation on (18)F-FDG PET/CT (n = 8) underwent a randomly allocated second (18)F-FDG PET/CT scan (at 23 °C), either with glucagon infusion (n = 4) or vehicle infusion (n = 4). RESULTS: We observed that EE increased by 14% after cold exposure and by 15% after glucagon infusion (50 ng/kg/min; p < 0.05 vs control for both). Cold exposure produced an increase in neck temperature (+0.44 °C; p < 0.001 vs control), but glucagon infusion did not alter neck temperature. In subjects with a cold-induced increase in the metabolic activity of supraclavicular BAT on (18)F-FDG PET/CT, a significant rise in the metabolic activity of BAT after glucagon infusion was not detected. Cold exposure increased sympathetic activation, as measured by circulating norepinephrine levels, but glucagon infusion did not. CONCLUSIONS: Glucagon increases EE by a similar magnitude compared with cold activation, but independently of BAT thermogenesis. This finding is of importance for the development of safe treatments for obesity through upregulation of EE.

Comparison of the utility of Cocaine- and Amphetamine-Regulated Transcript (CART), chromogranin A, and chromogranin B in neuroendocrine tumor diagnosis and assessment of disease progression.

CONTEXT: Prognosis in patients with neuroendocrine tumors (NETs) is often poor, frequently reflecting delayed diagnosis. Hence, accurate and practical NET markers are needed. Cocaine- and amphetamine-regulated transcript (CART) peptide is a potential novel NET marker. DESIGN AND PARTICIPANTS: Circulating levels of CART peptide and the established NET markers chromogranin A (CgA) and chromogranin B (CgB) were measured using RIA in 353 patients with NET (normal renal function) and in controls. Clinical data were collected retrospectively. MAIN OUTCOME MEASURE(S): The comparative and combined utility of CART, CgA, and CgB for diagnosis and assessment of disease progression was measured in different NET subtypes. RESULTS: CgA and CgB in combination improved diagnostic accuracy in patients with gut NETs, nongastroenteropancreatic NETs, and NETs with an unknown primary origin compared with each biomarker alone. Measuring CART did not further improve diagnosis in these NET subtypes. For pancreatic NETs, CgB was superior to CgA and CART in detecting stable disease (P < .007), whereas CgA and CART in combination were most effective in identifying progressive disease. In phaeochromocytomas/paragangliomas (PCC/PGL), CART was the most useful biomarker for identifying stable (P < .001) and progressive (P = .001) disease. Consistent with this, plasma CART decreased following PCC/PGL tumor resection, remaining low in all patients in remission, but increasing in those with progressive disease. CONCLUSIONS: CART is a useful marker for identifying progressive pancreatic NETs. CART is superior to CgA and CgB in detecting stable and progressive PCC/PGLs, and may have a role as a surveillance marker for PCC/PGL patients.

A comparison of the performance of 68Ga-DOTATATE PET/CT and ¹²³I-MIBG SPECT in the diagnosis and follow-up of phaeochromocytoma and paraganglioma.

PURPOSE: To compare the sensitivity of (123)I-metaiodobenzylguanidine (MIBG) SPECT and (68)Ga-DOTATATE PET/CT in detecting phaeochromocytomas (PCC) and paragangliomas (PGL) in the initial diagnosis and follow-up of patients with PCC and PGL disease. METHODS: Retrospective analysis of 15 patients with PCC/PGL who had contemporaneous (123)I-MIBG and (68)Ga-DOTATATE imaging. RESULTS: Of the 15 patients in the series, 8 were concordant with both modalities picking up clinically significant lesions. There were no patients in whom both modalities failed to pick up clinically significant lesions. There was discordance in seven patients: 5 had positive (68)Ga-DOTATATE and negative (123)I-MIBG, and 2 (12 and 14) had negative (68)Ga-DOTATATE and positive (123)I-MIBG. Utilizing (123)I-MIBG as the gold standard, (68)Ga-DOTATATE had a sensitivity of 80 % and a positive predictive value of 62 %. The greatest discordance was in head and neck lesions, with the lesions in 4 patients being picked up by (68)Ga-DOTATATE and missed by (123)I-MIBG. On a per-lesion analysis, cross-sectional (CT and MRI) and (68)Ga-DOTATATE was superior to (123)I-MIBG in detecting lesions in all anatomical locations, and particularly bony lesions. CONCLUSION: First, (68)Ga-DOTATATE should be considered as a first-line investigation in patients at high risk of PGL and metastatic disease, such as in the screening of carriers for mutations associated with familial PGL syndromes. Second, if (123)I-MIBG does not detect lesions in patients with a high pretest probability of PCC or PGL, (68)Ga-DOTATATE should be considered as the next investigation. Third, (68)Ga-DOTATATE hould be considered in preference to (123)I-MIBG in patients in whom metastatic spread, particularly to the bone, is suspected.

Observer accuracy in the detection of pulmonary nodules on CT: effect of cine frame rate.

AIM: To assess the effect of cine frame rate on the accuracy of the detection of pulmonary nodules at computed tomography (CT). MATERIALS AND METHODS: CT images of 15 consecutive patients with (n = 13) or without (n = 2) pulmonary metastases were identified. Initial assessment by two thoracic radiologists provided the "actual" or reference reading. Subsequently, 10 radiologists [board certified radiologists (n = 4) or radiology residents (n = 6)] used different fixed cine frame rates for nodule detection. Within-subjects analysis of variance (ANOVA) was used to evaluate the data. RESULTS: Eighty-nine nodules were identified by the thoracic radiologists (median 8, range 0-29 per patient; median diameter 9 mm, range 4-40 mm). There was a non-statistically significant trend to reduced accuracy at higher frame rates (p=0.113) with no statistically significant difference between experienced observers and residents (p = 0.79). CONCLUSION: The accuracy of pulmonary nodule detection at higher cine frame rates is reduced, unrelated to observer experience.

Multiorgan dysfunctions in diabetic patients: the role of functional imaging.

Functional imaging plays a central role in the evaluation of some of the clinical problems faced by diabetic patients. In cardiovascular disease, myocardial perfusion imaging, particularly when complemented by gated SPECT, is a powerful tool not only for establishing the diagnosis of coronary artery disease, but also for providing prognostic information in both the general and diabetic populations. Although promising, its role in screening of asymptomatic diabetic patients is yet to be established, and its role as a potential 'one-stop shop' also needs further study. PET is currently the gold standard for viability assessment, and also provides prognostic data, but its widespread use is limited by cost and availability. Hybrid imaging with PET/CT is promising, and could revolutionise cardiac imaging by combining functional and anatomic information. In the investigation of the diabetic foot, labelled leukocyte imaging is the nuclear medicine test of choice to diagnose osteomyelitis. It is likely that SPECT/CT will further improve diagnostic accuracy, but more studies are needed. Combined leukocyte and bone marrow imaging is of value in distinguishing osteomyelitis from neuropathic osteoarthropathy in the diabetic foot; PET and PET/CT may also be of value in these cases, but their wider role is currently inconclusive. The value of bone scintigraphy in the diabetic foot, even as a screening test, is questionable. Functional imaging methods can also be employed in the evaluation of other diabetic complications, including the assessment of left ventricular function, renal scarring and gastric emptying, but these methods are not widely used in current clinical practice.

Clinical indications for Gallium-68 positron emission tomography imaging.

BACKGROUND: (68)Ga-PET imaging is showing slow but steady progress when compared to (18)F-FDG PET. The advantage of in-house preparation of (68)Ga without necessity of a cyclotron, and the new generator configuration with future possibility of freeze-dried kits would make it a promising PET agent for the future. METHODS: An exhaustive literature exploration was performed using the search engines High-Wire Press, Pubmed, Embase and library databases. Recent reviews on the subject and up-to-date studies on the topic were found that described the role of (68)Ga-PET imaging. Clinical experiences, including our own are described. RESULTS: Recent resurgence in development of peptides labelled with radiometals, for diagnostic and therapeutic purposes, resulted in a new beginning for (68)Ga-PET imaging. Pre-clinical experience employing animal models and investigation of tracer kinetics/tumour uptake measurements using dynamic (68)Ga-PET have provided data regarding identification of Somatostatin receptors subtypes on many tumours. Present published experiences including our own support these and highlight current clinical utility of (68)Ga-PET imaging. (68)Ga-DOTATOC and (68)Ga-DOTANOC are the most prominent radiopharmaceuticals used nowadays. CONCLUSION: (68)Ga-PET is employed in the management of neuroendocrine tumours and neural crest tumours (phaeochromocytoma and paraganglioma) with diagnostic and therapeutic implications where it compliments present radiologic and scintigraphic procedures. Diagnosis and radiotherapy treatment planning for meningiomas in pertinent clinical setting is another potential use of (68)Ga-PET. Limited studies have shown its utility in prostate cancer but further studies are contemplated. Therefore, current experience tends to open a new horizon for the clinical utility of (68)Ga-PET imaging in future.

Multimodality imaging of the parathyroid glands in primary hyperparathyroidism.

Primary hyperparathyroidism is a common endocrine disorder, affecting approximately 1 in 500 women and 1 in 2,000 men. Surgical removal of the hyperfunctioning parathyroid gland is the primary curative treatment. The last decade has witnessed the development of minimally invasive parathyroidectomy, which is based on the fact that the vast majority of cases are caused by single adenomas. However, the success of this technique relies on accurate preoperative localisation of the parathyroid lesions. The imaging modalities used vary at different institutions according to local expertise and availability, but include high resolution ultrasound, radionuclide studies, computed tomography (CT) and magnetic resonance imaging (MRI). Ultrasound and 99mTc sestamibi scintigraphy, particularly when complemented by single photon emission computed tomography (SPECT), are currently the imaging techniques of choice for preoperative localisation of parathyroid adenomas; a combination of the two methods further improves the sensitivity and accuracy of detection. CT is less commonly used for preoperative localisation and usually reserved for cases of failed parathyroidectomy, for the detection of suspected ectopic glands. MRI appears to be useful in patients with persistent or recurrent hyperparathyroidism, who have previously undergone surgery. Cross-sectional imaging is also useful in cases where the findings at sonography and scintigraphy are discordant. SPECT/CT appears promising, but further studies are needed to evaluate its role in preoperative localisation.

Comparative study of experienced vs non-experienced radiologists in assessing parametric CT images of the response of the prostate gland to radiotherapy.

Functional CT can demonstrate acute quantitative increases in perfusion, permeability and fractional vascular volume in the prostate gland of patients with prostate cancer following radiotherapy (RT). We hypothesize that these quantitative changes can also be demonstrated visually by presenting them as colour parametric maps using custom software. 21 patients with prostate cancer were studied before, and 1-2 weeks after, RT. Repeated CT scans through a single section of the prostate was performed following contrast injection. Capillary permeability, fractional vascular volume and tissue perfusion were calculated and converted to colour maps using a customized Matlab imaging programme. Five "expert" and five "novice" radiologists scored pairs of randomized prostate images as an "increase", "decrease" or "no change" in intensity following RT. Kappa (kappa) statistics was used to assess the concordance of opinions. Significant quantitative increases in all indices occurred after RT, and almost all of the parametric images were scored as an increase in intensity following RT (perfusion = 95%, permeability = 88%, volume = 84%). There was substantial agreement between the experts and novices (kappa: perfusion = 0.93, permeability = 0.80, volume = 0.90), as well as within the expert (kappa: perfusion = 1, permeability = 0.86, volume = 1) and novice (kappa: perfusion = 0.82, permeability = 0.78, volume = 0.78) groups. Functional colour maps of the prostate can reliably portray the hyperaemic response following RT in a group with quantitative increases in perfusion, permeability and fractional vascular volume, and provides a potentially accessible and convenient method for image analysis by radiologists of varying experience.

PET imaging in endocrine tumours.

The role of PET in the assessment of endocrine tumours has been, until recently, restricted to the use of (18)F-fluoro-deoxy-D-glucose ((18)F-FDG). Being a marker of metabolically active lesions that show high grading and low differentiation, FDG is not ideal for this purpose since the majority of endocrine tumours are slow growing and highly differentiated. It is however useful when dedifferentiation takes place and provides excellent prognostic information. A number of hormone precursors and amino acids are labelled with (11)C and used successfully in the management of parathyroid, adrenal and pituitary tumours. However, the short half-life of (11)C radiopharmaceuticals restricts their use to centres with access to an on-site cyclotron, while the high cost of production may limit their use to research purposes. A promising new positron-emission tomography (PET) tracer is Gallium-68 obtained by elution from a long shelf-life generator that makes it economic and cyclotron-independent. Its short half-life and flexible labelling ability to a wide range of peptides and antibodies makes it ideal for PET imaging. In addition to imaging GEP-NETs and phaeochromocytoma, it has the potential to be used in a wider range of endocrine tumours.

Anatomic and functional imaging in the management of lymphoma.

Lymphoma has become one of the most successfully treated malignancies. The success of treatment and long-term prognosis depend on accurate staging in which imaging plays a pivotal role. In addition to staging, imaging assists in the evaluation of early and late response to therapy, detecting disease activity in a residual mass and locating sites of recurrence. The mainstay of imaging remains computed tomography (CT), which has replaced lymphangiography, and staging laparotomy. Magnetic resonance imaging (MRI) has additional value in detecting disease in bone marrow, the musculoskeletal and central nervous system. Recent technical developments in CT and MRI have improved acquisition times and resolution, but the main drawback of cross-sectional imaging techniques is their reliance on size criteria to define disease, with consequent failure to detect disease in small lymph nodes and exclude disease in large, but treated, masses. Diffuse visceral involvement is likewise difficult to detect by both modalities. Functional imaging with nuclear medicine techniques offers an answer to these problems. Imaging with the fluorinated glucose analogue, [18F]FDG positron emission tomography (PET), can detect metabolically active disease by its increased glycolysis that is proportional to mitotic activity. It can separate high from low-grade tumors and aid in prognostication. Recent publications suggest that imaging with [18F]FDG PET should be an important component in staging; assessment of response to therapy and restaging. Like other imaging modalities, it has its own drawbacks including inability to detect very small lesions (<5 mm) and reduced specificity due to increased uptake in metabolically active inflammatory and infective tissues. The new generation of hybrid PET-CT combines anatomical and functional imaging and is considered the state-of-the-art imaging technique for the assessment of lymphoma and other malignancies.

Somatostatin receptor PET imaging with Gallium-68 labeled peptides.

Imaging somatostatin receptor status with 68Ga labeled peptides has progressed rapidly over the last several years. It has generated great interest, and stimulated further research into the development of DOTA-derivative peptides. It has expanded our knowledge of receptor imaging and enhanced our appreciation of the difference between receptor-based and metabolic imaging, as well as more in-depth evaluation of tumor biology. The availability of the 68Ge/68Ga generator provides an attractive alternative to cyclotron-based positron-emitters, especially if kit-based radiopharmaceutical formulations based upon 68Ga are developed in the future.

Gallium-68 PET: a new frontier in receptor cancer imaging.

Neuroendocrine tumours (NET) are rare tumours that occur most commonly in the GI tract. Various labelled somatostatin analogues are used to image NET expressing somatostatin receptors (SSTR). In traditional nuclear medicine, most peptides used in imaging NET have been labelled with indium-111, the commonest being indium-111-octreotide (111In-octreotide). Unfortunately, the unfavourable physical qualities of In-111 make it unsuitable for detecting small tumour deposits. The recent introduction of gallium-68-1,4, 7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (gallium-68-DOTA) compounds for positron emission tomography (PET) imaging has significantly improved the quality of imaging NET through improved resolution of PET and higher affinity of the new generation of peptides to SSTR. In the present paper, we discuss the clinical and research applications of PET radio-tracers for evaluating NET, in particular gallium-68-DOTA compounds. The recent introduction of PET imaging with gallium-68 has major bearings in current and future clinical practice. Its labelling with DOTA compounds has cleared the way for somatostatin receptor imaging with a viable PET agent, with all its inherent imaging advantages compared to single photon imaging. The pre-clinical and clinical applications of this technique has been successful in a variety of tumours, particularly NET and its labelling with other ligands and molecules will improve the management of other tumours and the assessment of infection.

A comparative environmental and medical study of dust exposure in jute and cotton mills in Burma.

Jute is extensively cultivated and processed in Burma, as well as "lower-grade" cotton. This study was conducted there to compare dust exposure in jute and cotton mills, to study the acute and chronic effects of dust exposure on workers, and to establish exposure-response relationship. A sample of 799 male and female workers in two jute mills and two cotton textile mills, as well as a control group of 153 matching subjects, was examined, and dust exposure in the work environment was evaluated. Very high dust concentrations existed in the early stages of jute processing and sorting, which were reduced when jute fibers got cleaner, as in drawing and spinning, and were related to the grade of the processed fiber. Much lower concentrations of dust existed in the cotton mills, but exceeded the TLV (ACGIH) only in opening and cleaning and in carding operations. However, byssinosis occurred only in workers exposed to cotton dust, particularly among males, and its prevalence was related to the level and duration of dust exposure. Chronic bronchitis, cough and wheezing occurred at higher rates among all workers than in the control, while irritation to nose and throat, eyes and skin prevailed only among jute workers. A significant reduction in FVC, FEV1.0 and PEF (before and during shift) was observed in workers compared to control subjects, and was related to workers' exposure and age; however, this reduction was not related to symptoms of different respiratory conditions. "Cheroots" smoking was found to be an important potentiating factor in the occurrence of non-specific respiratory diseases and reduction in FEV1.0, particularly among jute workers.