Improving prediction of malignancy of cytologically indeterminate thyroid nodules.

BACKGROUND: Fine-needle aspiration (FNA) is essential in the investigation of thyroid nodules. The British Thyroid Association guidelines recommend clarification of whether follicular nodules are probable follicular neoplasms that require surgical excision. This study assessed the value of the subclassification of cytologically indeterminate thyroid nodules into either follicular neoplasms or other pathology. METHODS: The cytology reports of all thyroid FNAs performed between November 2005 and December 2007 at a single institution reported as Thy 3 (follicular lesions) were reviewed. They were reclassified as Thy 3A (probable follicular neoplasm) or Thy 3B (probable non-neoplastic lesion), and subsequently correlated with final clinical outcome to determine the predictive value of this subclassification. RESULTS: Forty-nine specimens were categorized as Thy 3A and 55 as Thy 3B. Of excised lesions, 14 (29 per cent) of 48 Thy 3A and 4 (10 per cent) of 42 Thy 3B nodules were malignant. If Thy 3A were to predict malignancy and Thy 3B benign disease, the sensitivity of the classification was 88 per cent, with a specificity of 55 per cent and negative predictive value of 91 per cent. CONCLUSION: Subclassification of Thy 3 nodules into Thy 3A and Thy 3B improves the assessment of risk for thyroid malignancy.

A critical evaluation of the experimental design of studies of mechanism based enzyme inhibition, with implications for in vitro-in vivo extrapolation.

The published literature on mechanism based inhibition (MBI) of CYPs was evaluated with respect to experimental design, methodology and data analysis. Significant variation was apparent in the dilution factor, ratio of preincubation to incubation times and probe substrate concentrations used, and there were some anomalies in the estimation of associated kinetic parameters (k(inact), K(I), r). The impact of the application of inaccurate values of k(inact) and K(I) when extrapolating to the extent of inhibition in vivo is likely to be greatest for those compounds of intermediate inhibitory potency, but this also depends on the fraction of the net clearance of substrate subject to MBI and the pre-systemic and systemic exposure to the inhibitor. For potent inhibitors, the experimental procedure is unlikely to have a material influence on the maximum inhibition. Nevertheless, the bias in the values of the kinetic parameters may influence the time for recovery of enzyme activity following re-synthesis of the enzyme. Careful attention to the design of in vitro experiments to obtain accurate kinetic parameters is necessary for a reliable prediction of different aspects of the in vivo consequences of MBI. The review calls for experimental studies to quantify the impact of study design in studies of MBI, with a view to better harmonisation of protocols.

Training of staff for the delivery of PET/CT services in the UK.

Evidence for the cost effectiveness of PET/CT imaging is now driving the widespread introduction of PET/CT services throughout the UK. The provision of PET/CT facilities will require a workforce of medical, scientific, technical and engineering staff who are adequately trained and fit for purpose. Suitably trained staff in this speciality are scarce. The development and accreditation of training courses and other educational resources for training programmes in all disciplines will therefore be required at a national and regional level. The implementation of PET/CT training can be achieved more cost-effectively by developing multi-professional learning resources whenever possible. It is intended that the recommendations would be implemented by close co-operation of both public and private healthcare providers together with educational establishments.

Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent.

The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.

Bone scanning in metabolic and endocrine bone disease.

99mTc diphosphonate bone scanning has proved to be a sensitive, though nonspecific, way of detecting a wide variety of metabolic bone disorders. Classic scan appearances of generalized increased tracer uptake throughout the skeleton are found in many types of metabolic bone disease, and whole-body retention measurements can be used to detect early forms of disease. Focal disease identified on bone scanning such as pseudofractures and brown tumors are clearly identified on the 99mTc diphosphonate bone scan, with isotope scan changes preceding radiological changes by up to 18 months. The use of whole-body retention measurements will further increase sensitivity of detection in patients with metabolic bone disease.

The chemical identity of pentavalent technetium-99m-dimercaptosuccinic acid.

The tumor-targeting radiopharmaceutical known as pentavalent technetium-99m-meso dimercaptosuccinic acid (DMSA) has been studied by a variety of techniques in order to elucidate its structure and chemical behavior. The radiopharmaceutical is identical with a chemically characterized sample of [99TcO(DMSA)2]- when studied by mobility methods including thin-layer chromatography, reversed-phase high-performance liquid chromatography, gel filtration, and electrophoresis. The technetium is pentavalent and coordinated by an oxo-ligand and four thiolate sulfurs of two DMSA ligands. No-carrier-added preparations consist of mixtures of three stereoisomers of the square pyramidal, mononuclear complex. The isomers arise from differing orientations of the carboxylate groups in the DMSA ligands and may be designated syn-endo, syn-exo, and anti. All three isomers are significant components of the radiopharmaceutical, raising the question of which are tumor-specific. The carboxylate groups in the complex are almost completely ionized at pH 7, thus the average charge on the complex at this pH approaches -5.

SPECT bone scintigraphy of anterior cruciate ligament injury.

UNLABELLED: This retrospective analysis of SPECT bone scans of the knee was undertaken to define typical bone scan appearances and to assess the sensitivity of this method. We looked at 14 patients, mostly with chronic knee pain, who had anterior cruciate ligament (ACL) tears detected by MRI. METHOD: Of the 14 patients, 10 were referred for bone scanning following injury and 4 complained of chronic knee pain without injury. Planar scans were performed 4 hr after the injection of 750 MBq of 99mTc-MDP. Tomographic images were obtained by a 64 x 20-sec acquisition over 360 degrees using a high-resolution collimator. MRI imaging included axial and sagittal, T1 weighted and coronal fast field echo (FFE) sequences. Ten patients also had arthroscopy performed. RESULTS: MRI scans showed 6 lone ACL tears and 8 combined with other ligamentous injuries. SPECT scans showed abnormalities in 10 patients in the region of ACL insertions but only 4 planar studies were abnormal. SPECT identified focal activity at the upper (n = 8) or lower (n = 2) insertion of the ACL. Six of 10 arthroscopies confirmed ACL tears, 2 complete and 4 partial. Overall, agreement was found with MRI in 10 of 14 cases and in 8 of 10 with arthroscopy. Abnormalities were identified in 10 of 11 regions of other ligament or bone injury identified by MRI. CONCLUSION: SPECT bone scanning of the knee is superior to planar imaging in detecting ACL injury and is a sensitive technique. Focal activity may be seen at either end of ACL attachment but more commonly at the upper femoral insertion. Knee SPECT may be a valuable examination in suspected ACL injury, particularly if MRI is not available, is equivocal or where clinical signs are absent.

Technetium-99m-DMSA studies in pediatric urinary infection.

UNLABELLED: Urinary tract infection (UTI) is a common condition in children and may lead to renal scarring with a risk of later hypertension and renal insufficiency. We made a cross-sectional study of the 99mTc-DMSA findings in 496 children referred for following symptomatic UTI to a Department of Nuclear Medicine and we categorized the results, to provide a framework for further study. METHOD: A standard 99mTc-DMSA protocol was used to study 496 children (157 males, 339 females) aged from birth to 14 yr. Findings were classified according to the image appearance and relative function of each kidney. These were related to age, sex, history and timing of UTI and the results on micturating cysto-urethrography (MCU). RESULTS: Images were normal, with function within limits (45%-50% in one kidney), in approximately half the boys and girls studied. The other images were classified as equivocal in 68 children, abnormal unilaterally in 105 and bilaterally in 76, and they were subdivided according to the image appearance. No image changes could be identified that were specifically associated with acute UTI. Diffuse change alone was uncommon. A high proportion of abnormal images was found in infant boys, older girls with recurrent UTI and those children with vesico-ureteric reflux (VUR). Of the bilateral abnormal images, 98% were seen in children with VUR. CONCLUSION: Our findings suggest that infective renal change may be superimposed on underlying congenital lesions (perhaps detectable antenatally) or may be acquired following UTI in the presence of reflux and are thus potentially preventable. This study also suggests that VUR is almost certain to have occurred in a child who has bilateral abnormal 99mTc-DMSA images following UTI and is also commonly present in those with definite unilateral defects.

Pentavalent [99mTc]DMSA, [131I]MIBG, and [99mTc]MDP--an evaluation of three imaging techniques in patients with medullary carcinoma of the thyroid.

Nine patients with histologically proven medullary carcinoma of the thyroid (MCT) were imaged using pentavalent [99mTc]dimercaptosuccinic acid [(V)DMSA], [131I] metaiodobenzylguanidine (MIBG) and [99mTc]methylene diphosphonate (MDP). Technetium-99m (V)DMSA demonstrated most of the tumor sites in eight patients with proven metastases, with an overall sensitivity of 95% in lesion detection. Iodine-131 MIBG showed definite uptake in some of the tumor sites in three of the nine patients imaged, with equivocal uptake seen in a further one patient, with sensitivity of only 11% for lesion detection. Technetium-99m MDP demonstrated bony metastases only, in four of the patients imaged yielding a sensitivity of 61%. Technetium-99m (V)DMSA has been demonstrated in this study to be a useful imaging agent in patients with MCT, showing uptake in significantly more lesions and with better imaging qualities than [131I]MIBG, and with the ability to detect soft tissue as well as bony metastases.

The pharmacokinetics and biodistribution of technetium-99m(V)dimercaptosuccinic acid in an animal tumor model.

This study used an established rabbit tumor model with squamous carcinoma to evaluate the pharmacokinetics and biodistribution of technetium-99m-(V)dimercaptosuccinic acid. A total of 54 rabbits were studied (25 with no tumor; 29 with tumor). Technetium-99m(V)dimercaptosuccinic acid had a bi-exponential blood clearance in rabbits with no tumors (28 and 325 min) and in rabbits with tumors (27 and 352 min). There was no significant difference (p greater than 0.05) in mean clearance times between the two groups and clearance appeared unaffected by tumor mass. Technetium-99m(V)dimercaptosuccinic acid had a bi-exponential cumulative urine excretion with no apparent difference in half-times between non-tumor and tumor rabbit groups (200 and 240 min, respectively). Technetium-99m(V)dimercaptosuccinic acid had a major organ biodistribution in rabbits which included bone, kidneys, bladder and the blood pool. The major route of excretion was via the urine. There was no significant difference (p greater than 0.05) in organ biodistribution between rabbits with no tumors and rabbits with tumors and there was no evidence of active uptake of technetium-99m(V)dimercaptosuccinic acid by either squamous carcinoma or inflammatory tissue.

Scintigraphy and treatment of medullary carcinoma of the thyroid with iodine-131 metaiodobenzylguanidine.

We report our experience using [131I]metaiodobenzylguanidine (MIBG) to image nine patients with proven medullary carcinoma of the thyroid (MCT). Positive uptake was seen in four patients, equivocal uptake in one patient, and no uptake in four patients. Data is presented to demonstrate the pharmacokinetics of [131I]MIBG in three of the patients studied. Two patients, with diarrhea and severe pain from known bone metastases and positive uptake on [131I]MIBG diagnostic scanning, subsequently received therapeutic doses of [131I]MIBG, with marked improvement in both pain and diarrhea, but no evidence of significant biochemical response. Iodine-131 MIBG uptake in patients with MCT is variable, and gives a higher false-negative rate than is found when using [131I]MIBG to image other neuroectodermally derived tumors. The therapeutic potential of [131I]MIBG in patients with MCT warrants further evaluation, in view of the symptomatic relief experienced following therapy doses in two patients with extensive disease.

Technetium-99m (v) dimercaptosuccinic acid uptake in patients with head and neck squamous carcinoma: experience in imaging.

A recently developed imaging agent, technetium-99m (v) dimercaptosuccinic acid (99mTc (v) DMSA), has been used to assess head and neck squamous carcinoma (SCC). We have prospectively studied 62 patients of whom 53 had a histologically proven head and neck SCC. The remaining nine had benign lesions. The results of planar imaging in patients with primary disease yielded an 85% sensitivity and 78% specificity. Planar imaging in patients with cervical lymphadenopathy revealed a 59% sensitivity. Nineteen patients also had single photon emission computed tomography imaging which improved the image quality, spatial resolution and sensitivity of the investigation. Twenty-seven patients were scanned before and after radiotherapy and, of these, 96% showed positive uptake in the salivary glands with no evidence of tumor recurrence. This study has shown 99mTc (v) DMSA imaging provides a cheap and rapid method of investigating head and neck SCC and further studies are necessary to evaluate its role in the management of patients with this disease.

Radionuclide measurement of right ventricular function in atrial septal defect, ventricular septal defect and complete transposition of the great arteries.

Right ventricular (RV) function was assessed in 80 patients with congenital heart disease by first-pass and gated equilibrium radionuclide angiography. In 30 patients with a ventricular septal defect (VSD) the mean RV ejection fraction (+/- standard deviation) was 64 +/- 7%. In 30 patients with a secundum atrial septal defect it was 61 +/- 9% and in 20 patients with surgically corrected complete transposition of the great arteries it was 49 +/- 13%. These values are in close agreement with values established with cineangiography for similar groups of patients. The mean ejection fraction in the group with transposition of the great arteries was significantly less than in the group with VSD (p less than 0.001). Phase analysis of the equilibrium studies showed that there was delayed RV contraction in many patients in the absence of conduction abnormalities. This delay was significantly greater in patients with atrial septal defect than in those with VSD (p less than 0.05). There was a strong correlation between size of left-to-right shunt and phase delay in patients with VSD (r = -0.72). Thus, first-pass gated radionuclide angiography provides a valid measurement of RV ejection fraction, and delayed RV contraction on phase analysis may be a sensitive index of early RV dysfunction.

Characterization of SB-271046: a potent, selective and orally active 5-HT(6) receptor antagonist.

SB-271046, potently displaced [(3)H]-LSD and [(125)I]-SB-258585 from human 5-HT(6) receptors recombinantly expressed in HeLa cells in vitro (pK(i) 8.92 and 9.09 respectively). SB-271046 also displaced [(125)I]-SB-258585 from human caudate putamen and rat and pig striatum membranes (pK(i) 8.81, 9.02 and 8.55 respectively). SB-271046 was over 200 fold selective for the 5-HT(6) receptor vs. 55 other receptors, binding sites and ion channels. In functional studies on human 5-HT(6) receptors SB-271046 competitively antagonized 5-HT-induced stimulation of adenylyl cyclase activity with a pA(2) of 8.71. SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of < or =0.1 mg kg(-1) p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC(50) of 0.16 microM) and brain concentrations of 0.01-0.04 microM at C(max). These data, together with the observed anticonvulsant activity of other selective 5-HT(6) receptor antagonists, SB-258510 (10 mg kg(-1), 2-6 h pre-test) and Ro 04-6790 (1-30 mg kg(-1), 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT(6) receptors. Overall, these studies demonstrate that SB-271046 is a potent and selective 5-HT(6) receptor antagonist and is orally active in the rat MEST test. SB-271046 represents a valuable tool for evaluating the in vivo central function of 5-HT(6) receptors.

Incorporation of cytochrome b5 into rat liver microsomal membranes. Impairment of cytochrome P-450-dependent mixed function oxidase activity.

Cytochrome b5 was purified to electrophoretic homogeneity from the liver microsomes of untreated rats and reincorporated into liver microsomes from phenobarbital-treated rats, resulting in an approximate three-fold enrichment of the cytochrome b5 specific content (1.5 nmol haemoprotein X mg-1 protein). Our results have shown that the N-demethylation of benzphetamine was progressively inhibited in cytochrome b5-fortified microsomal preparations. Using stopped flow, visible difference spectrophotometry, the NADPH-driven reduction kinetics of cytochrome P-450 were examined in the modified microsomes over the first few seconds of reaction. Increasing the amount of incorporated cytochrome b5 resulted in a progressive inhibition of the initial, fast phase reduction rate constant of microsomal cytochrome P-450, both in the absence and presence of the type I substrate benzphetamine. Although the initial rate of NADPH-driven cytochrome b5 reduction was the same for both native and cytochrome b5-fortified microsomes, the extent of cytochrome b5 reduction was greater in the fortified microsomes. If cytochrome b5 has a positive role to play in cytochrome P-450-dependent mixed function oxidase activity either as an effector or in electron transfer or both, the former haemoprotein must be already present in sufficient concentrations in the native microsomes.

Isotopic evaluation and therapy in patients with malignant endocrine disease.

The contribution of nuclear medicine to the diagnosis and treatment of endocrine malignancy is increasing. Advances in molecular biology offer new opportunities for tumour targeting via surface receptor recognition and tumour-specific metabolic markers. Imaging the biodistribution of these markers allows quantitative, in vivo characterization of tumour function. There is growing interest in the therapeutic potential of nuclear medicine targeting, substituting therapeutic beta-emitting radionuclides for the gamma-emitters used in diagnostic imaging. Limited clinical experience supports the rationale of this approach in patients with inoperable or disseminated disease and controlled trials are in progress. This chapter outlines the place of nuclear medicine techniques in the routine management of endocrine malignancy and explores areas for further development.

Irrigated crop production is associated with less malaria than traditional agricultural practices in Tanzania.

There is concern that crop irrigation that results in increased numbers of vector mosquitoes will lead to a rise in malaria in local communities. We evaluated the level of malaria experienced in 3 communities in northern Tanzania with different agricultural practices: rice irrigation, sugar-cane irrigation and traditional maize cultivation. Five cross-sectional surveys were used to measure the prevalence of infection with falciparum malaria in 1-4 years old children in each community over a period of 12 months. Active case detection was also carried out to record clinical episodes of malaria during the study period. Information on antimalarial measures was also recorded. Results from the cross-sectional surveys showed that the overall prevalence of malaria parasites was less near the rice irrigation (12.5%) and sugar-cane (16.9%) schemes than the savannah village (29.4%). There were also significantly fewer clinical episodes of malaria in the rice village (15 cases/1000 child-weeks at risk [cwar]) than either the sugar-cane (36 cases/1000 cwar) or savannah (40 cases/1000 cwar) villages. Overall, rice irrigation was associated with less malaria than alternative agricultural practices, despite the considerable numbers of vectors produced in the paddies. This finding supports other studies that indicate that irrigation in much of sub-Saharan Africa will not lead to increased malaria. Nonetheless, African governments planning irrigation projects need effective policies to encourage local communities to use personal protection measures, such as insecticide-treated bednets, and to ensure that these communities have access to effective antimalarial drugs and efficient health services.

Do untreated bednets protect against malaria?

Bednets are thought to offer little, if any, protection against malaria, unless treated with insecticide. There is also concern that the use of untreated nets will cause people sleeping without nets to receive more mosquito bites, and thus increase the malaria risk for other community members. Regular retreatment of nets is therefore viewed as critical for malaria control. However, despite good uptake of nets, many control programmes in Africa have reported low re-treatment rates. We investigated whether untreated bednets had any protective benefit (in October and November 1996) in The Gambia where nets, although widely used, are mostly untreated. Cross-sectional prevalence surveys were carried out in 48 villages and the risk of malaria parasitaemia was compared in young children sleeping with or without nets. Use of an untreated bednet in good condition was associated with a significantly lower prevalence of Plasmodium falciparum infection (51% protection [95% CI 34-64%], P < 0.001). This finding was only partly explained by differences in wealth between households, and children in the poorest households benefited most from sleeping under an untreated net (62% protection [14-83%], P = 0.018). There was no evidence that mosquitoes were diverted to feed on children sleeping without nets. These findings suggest that an untreated net, provided it is in relatively good condition, can protect against malaria. Control programmes should target the poorest households as they may have the most to gain from using nets.

Cribriform variant papillary thyroid cancer: a characteristic of familial adenomatous polyposis.

Inherited cancer syndromes may predispose to more than one type of cancer, and these characteristically develop at an earlier age than their sporadic counterparts. The occurrence in a single individual of multiple, early onset primary cancers may indicate an inherited cancer susceptibility. Familial adenomatous polyposis (FAP), an autosomal, dominantly inherited susceptibility to colorectal adenomas and cancer also predisposes to childhood medulloblastomas and to a specific rare histologic type (cribriform variant) of papillary thyroid cancer. We describe a patient who developed a childhood medulloblastoma of the cerebellum, and subsequently a cribriform papillary thyroid cancer. These cancers predated the diagnosis of FAP in this patient, who was later found to have several relatives with FAP. The adenomatous polyposis coli (APC) mutation delineated in this family was in the region associated with those causing an increased risk of thyroid cancer. We submit that the diagnosis of the cribriform variant of papillary thyroid cancer in a young individual, especially after a previous cancer diagnosis, should alert the physician to the possibility of a diagnosis of FAP.

Carotid plaque characterization by magnetic resonance imaging: review of the literature.

Magnetic resonance imaging (MRI) of carotid plaque has undergone significant improvements in the last decade. Early studies utilizing ex vivo specimens and spin-echo or fast spin-echo imaging led to the conclusion that T2 weighting is the best single contrast to characterize carotid plaque morphology. On these images, the fibrous plaque appears bright and the lipid core is dark; thrombus can have variable intensity. There can be an overlap in T2-weighted signal intensities among the various plaque components, which can be partially offset by the use of multispectral analysis of multiple contrast images. With improvements in coil design, sequence design, and main field and gradient capabilities, accurate in vivo differentiation and measurement of these various carotid plaque components should be possible in 3 to 5 years. Ex vivo and in vivo studies have yielded high-resolution measurements of the complex three-dimensional lumen geometry, which are being used to predict hemodynamic forces acting on the lumenal surface. Carotid plaque burden can be accurately measured in vivo today; ongoing longitudinal studies should lead to a better understanding of the relationship between plaque burden and the risk of thromboembolic complications, as well as the effect of diet and drug therapy in hyperlipidemic patients. With these developments in place or soon to be available, MRI of the diseased carotid artery wall may prove to be even more important than magnetic resonance angiography.