Sabina Dizdarevic

Tumour heterogeneity in non-small cell lung carcinoma assessed by CT texture analysis: a potential marker of survival.

AbstractPurposeTo establish the potential for tumour heterogeneity in non-small cell lung cancer (NSCLC) as assessed by CT texture analysis (CTTA) to provide an independent marker of survival for patients with NSCLC.Materials and methodsTumour heterogeneity was assessed by CTTA of unenhanced images of primary pulmonary lesions from 54 patients undergoing 18F-fluorodeoxyglucose (FDG) PET-CT for staging of NSCLC. CTTA comprised image filtration to extract fine, medium and coarse features with quantification of the distribution of pixel values (uniformity) within the filtered images. Receiver operating characteristics identified thresholds for PET and CTTA parameters that were related to patient survival using Kaplan-Meier analysis.ResultsThe median (range) survival was 29.5 (1–38) months. 24, 10, 14 and 6 patients had tumour stages I, II, III and IV respectively. PET stage and tumour heterogeneity assessed by CTTA were significant independent predictors of survival (PET stage: Odds ratio 3.85, 95% confidence limits 0.9–8.09, P = 0.002; CTTA: Odds ratio 56.4, 95% confidence limits 4.79–666, p = 0.001). SUV was not a significantly associated with survival.ConclusionAssessment of tumour heterogeneity by CTTA of non-contrast enhanced images has the potential for to provide a novel, independent predictor of survival for patients with NSCLC.Key Points• Computed tomography is a routine staging procedure in non-small cell lung cancer • CT texture analysis (CTTA) can quantify heterogeneity within these lung tumours • CTTA seems to offer a novel independent predictor of survival for NSCLC • CTTA could contribute to disease risk-stratification for patients with NSCLC

Accumulation of (18)F-FDG in the liver in hepatic steatosis.

OBJECTIVE Nonalcoholic fatty liver disease is associated with hepatic inflammation. An emerging technique to image inflammation is PET using the glucose tracer, (18)F-FDG. The purpose of this study was to determine whether in hepatic steatosis the liver accumulates FDG in excess of FDG physiologically exchanging between blood and hepatocyte. MATERIALS AND METHODS Hepatic FDG uptake, as SUV = [voxel counts / administered activity] × body weight), and CT density were measured in a liver region in images obtained 60 minutes after injection of FDG in 304 patients referred for routine PET/CT. Maximum SUV (region voxel with the highest count rate, SUVmax) and average SUV ( SUVave) were measured. Blood FDG concentration was measured as the maximum SUV over the left ventricular cavity (SUVLV). SUVave was adjusted for hepatic fat using a formula equating percentage fat to CT density. Patients were divided in subgroups on the basis of blood glucose (< 4, 4 to < 5, 5 to < 6, 6 to < 8, 8 to < 10, and > 10 mmol/L). Hepatic steatosis was defined as CT density less than 40 HU (n = 71). RESULTS The percentage of hepatic fat increased exponentially with blood glucose. SUVmax / SUVLV and fat-adjusted SUVave / SUVLV but not SUVave / SUVLV correlated with blood glucose. Fat-adjusted SUVave was higher in patients with hepatic steatosis (p < 0.001) by ~0.4 in all blood glucose groups. There was a similar difference (~0.3) in SUVmax (p < 0.005) but no difference in SUVave. SUVmax / SUVLV and fat-adjusted SUVave / SUVLV correlated with blood glucose in patients with hepatic steatosis but not in those without. SUVave / SUVLV correlated with blood glucose in neither group. CONCLUSION FDG uptake is increased in hepatic steatosis, probably resulting from irreversible uptake in inflammatory cells superimposed on reversible hepatocyte uptake.

PET brain imaging in HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy

Effective combination antiretroviral therapy (cART) has lead to a significant reduction in the prevalence and incidence of central nervous system (CNS) HIV-associated brain disease, particularly CNS opportunistic infections and HIV encephalitis. Despite this, cognitive deficits in people living with HIV, also known as HIV-associated neurocognitive disorders (HAND) have become more prevalent in recent years. The pathogenesis of HAND is likely to be multifactorial, however recent evidence suggests that brain microglial activation is the most likely pathogenic mechanism. Recent developments in positron emission tomography (PET) brain neuroimaging using novel brain radioligands targeting a variety of physiological changes in the brains of HIV-positive individuals have improved our understanding of the mechanisms associated with the development of HAND. This review will highlight recent PET brain neuroimaging studies in the cART era, focusing on physiological and neurochemical changes associated with HAND in people living with HIV.

Association between bile acid turnover and osteoporosis in postmenopausal women.

ObjectiveThe intestinal absorption of vitamin D is linked to bile acid absorption. This link may be abnormal in patients with osteoporosis. The aim of this study was to investigate a possible relation between osteoporosis and bile acid turnover, measured as whole-body Se-75-HCAT retention (WBR), in postmenopausal women. Patients and methodsWhole-body counts were recorded using an uncollimated gamma camera 3 h and 7 days after oral administration of Se-75-homocholic acid taurine (Se-75-HCAT) in 16 women aged 58–85 years with dual-photon X-ray absorptiometry (DEXA)-proven osteoporosis. WBR was expressed as physical decay-corrected counts at 7 days as a percentage of the counts at 3 h. ResultsSeven patients had unexplained diarrhoea. Six patients (five with diarrhoea) had WBR less than 19%. There was a significant difference in DEXA t-score between women with and without diarrhoea (P<0.02). There was a significant negative correlation (R s=−0.58; P<0.02) between WBR and alcohol consumption rated on a three-point scale: <1, 2–7 and >7 U/week. ConclusionOur results indicate an association between osteoporosis and diarrhoea that may be the result of abnormal bile acid turnover. The role of alcohol requires further investigation.

Necessity for long-term follow-up of patients with head and neck paraganglioma and mutation in the succinate dehydrogenase genes: an index case report and literature review.

OBJECTIVE To describe a patient with hereditary head and neck paraganglioma (HNPGL) and to review the literature on these rare tumors. METHODS We review the English-language literature regarding SDH mutations, HNPGL, hereditary paraganglioma-pheochromocytoma syndrome, and the role of functional imaging in the follow-up of these tumors. We also describe the clinical findings, imaging results, and follow-up of a man who initially presented with HNPGL and subsequently developed metastatic pheochromocytoma 20 years later. RESULTS A 66-year-old man presented with a history of hypertension, palpitations, sweating, and elevated urinary norepinephrine. Iodine-123-metaiodobenzylguanidine (123I-MIBG) scan demonstrated a left suprarenal mass and multiple avid lesions in the abdomen, chest, and posterior cranial fossa. Histologic examination confirmed a metastatic pheochromocytoma, and molecular genetic testing revealed a mutation in the SDHD gene. The patient had had surgery 20 years earlier for HNPGL. Although most HNPGLs arise sporadically, susceptibility genes have been identified in approximately one-third of cases. Optimal follow-up remains controversial. We reiterate a need for long-term follow-up of patients with a mutation in an SDH gene. 123I-MIBG, highly specific for identifying ectopic neuroendocrine tissue, may have a role in long-term follow-up. CONCLUSIONS Although HNPGLs rarely metastasize, their malignant potential is difficult to predict. Routine surveillance for at-risk patients is recommended. Patients with a mutation in an SDH gene should therefore undergo regular surveillance.

Unusual Initial Manifestation of Metastatic Follicular Carcinoma of the Thyroid with Thyrotoxicosis Diagnosed by Technetium Tc 99m Pertechnetate Scan: Case Report and Review of Literature

OBJECTIVE To report a case of metastatic thyroid cancer diagnosed on a technetium Tc 99m pertechnetate (TcO4-) thyroid scan. METHODS We present the clinical findings, laboratory results, imaging studies, and surgical pathology report in a man with thyrotoxicosis in whom metastatic well-differentiated thyroid cancer was diagnosed incidentally on a routine TcO4- thyroid scan in the setting of a presumed diagnosis of benign toxic thyroid disease. In addition, we review the literature regarding coexistence of metastatic thyroid cancer and thyrotoxicosis. RESULTS A 68-year-old man with thyrotoxicosis was referred for radioiodine therapy. A routine TcO4- thyroid scan revealed high-grade extrathyroidal uptake in the right upper hemithorax as well as in the left side of the thorax. In view of this finding, radioiodine treatment was deferred; further imaging with computed tomography revealed a 6.5-cm mass in a rib on the right side. A biopsy of the rib confirmed the presence of metastatic follicular carcinoma of the thyroid. Scintigraphy revealed sites of metastatic involvement predominantly in the bones along with a cold nodule in the left thyroid lobe, consistent with the primary tumor. CONCLUSION This case emphasizes the impact of scintigraphic findings on determining the correct management of a patient who would have otherwise undergone inappropriate treatment. Through an extensive literature review, the incidence of malignant involvement in hyperfunctioning thyroid glands and the possible role of sodium iodide symporter expression by thyroid cancer metastatic lesions in preoperative detection of metastatic sites are addressed.

Combined 99mTc-methoxyisobutylisonitrile scintigraphy and fine-needle aspiration cytology offers an accurate and potentially cost-effective investigative strategy for the assessment of solitary or dominant thyroid nodules: reply to comments by Riazi et al.

Dear Sir, We thank Riazi et al. for their interest in our paper [1] and for their comments [2]. We agree that the sensitivity of thyroid FNAC is variable; for example a literature review conducted by Tee et al. showed that the sensitivity of FNAC for thyroid malignancy can be as low as 66 % [3]. In our institution the sensitivity of FNAC is 87% [1]. In addition it is important to note that thyroid FNAC is performed in our institution with ultrasound guidance and on-site cytology support so the incidence of inadequate samples is reduced, thus demonstrating the importance of optimizing the FNAC technique, as advocated by the British Thyroid Association guidelines [4–6]. Furthermore, thyroid FNAC performed in combination with ultrasound allows morphological assessment of the thyroid gland and any suspicious lymph nodes [5]. We would recommend a combined approach of thyroid FNAC (with an optimized technique, including ultrasound guidance and on-site cytology assessment [6]) as the firstline investigation with MIBI scintigraphy as a routine complementary modality. Our cost effectiveness analysis indicates that the combined FNA–MIBI investigative strategy would be more cost effective if the sensitivity of thyroid FNA was reduced [1] and therefore in institutions where the thyroid FNAC sensitivity is lower the more routine use of MIBI scintigraphy with thyroid FNAC as a first-line investigation could be employed. The low specificity of MIBI scintigraphy for thyroid malignancy (in our study the average specificity of MIBI scintigraphy for thyroid malignancy was 46 % vs. the average specificity of FNAC for thyroid malignancy which was 89 % [1]) means that MIBI scintigraphy cannot be recommended as the isolated firstline investigation without prospective data. However, MIBI scintigraphy should be used as a complementary examination with ultrasound and FNAC where, in combination, these examinations provide an evidence-based, cost-effective investigative strategy for the management of cold thyroid nodules [7]. In clinical practice, we consider ultrasound-guided FNAC and MIBI scintigraphy to be complementary, and this investigative strategy has been proven to be cost effective, especially as the negative predictive value of MIBI scintigraphy is 97 % [1]. Further prospective studies are needed to validate the diagnostic effectiveness of MIBI scintigraphy.

Renal and Hepatic Kinetics of Tc-99m-labelled Hexakis-methoxy-isobutyl Isonitrile

OBJECTIVE Technetium-99m-labelled hexakis-methoxy-isobutyl isonitrile (Tc-99m-MIBI) is a substrate for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter protein, and can be used to image P-gp expression. The aim was to study normal kinetics of Tc-99m-MIBI in the kidney and liver to help understand physiological studies of P-gp expression in these organs. METHODS Thirty healthy kidney transplant donors received intravenous Tc-99m-MIBI followed by dynamic scintigraphy for 20 min and static imaging at 30 and 120 min. Time-activity curves were generated from parenchymal ROI. An assumed mono-exponential Tc-99m-MIBI blood clearance with rate constant of 0.3 min-1 was used to predict the Tc-99m- MIBI that would have accumulated in the organs had none left. The activities leaving were then calculated by subtraction and expressed as percentages of the predicted total accumulated activities. RESULTS Kidney time-activity curves peaked at 2-4 min then declined to a plateau from ~15-16 min equal to 31 [SD 5]% of the total activity accumulated (corresponding to 69 [5]% rapidly eliminated) (phase 1). Bladder activity followed a similar but opposite time course. Between 30 and 120 min (phase 2), activity left at 0.36 (0.13) %.min-1. Liver curves peaked at 8-10 min. Differentiation of the elimination curve revealed that a variable proportion of tracer (5-56%; mean 30 [14]%) was rapidly excreted over ~11 min. From 30 min, activity left at 1.02 (0.23) %.min-1. There was no correlation between renal and hepatic elimination rates in either phase or between early and late phase elimination rates in either organ. CONCLUSIONS Early renal elimination is predominantly via glomerular filtration and urinary excretion. The liver rapidly excretes a more variable and lower proportion of Tc-99m-MIBI than the kidney. P-gp located at the urine/tubule and bile/hepatocyte boundaries prevents Tc-99m-MIBI re-entering cells and thereby influences elimination and retention in both phases, although other ABC transporters are probably also involved.

Nuclear medicine RIP (radiation induced phobia); improving the image

Dear Sir, Nuclear medicine has always suffered from the twin criticisms of its frightening but impressive name and ‘unclear’ images. The patient perception of nuclear medicine and its use of radioactivity should be addressed. Many patients remain frightened of the words Nuclear Medicine because of its connotation of atomic bombs. In 1983/4 it was suggested that the name Nuclear Magnetic Imaging should change to Magnetic Resonance Imaging to improve patient acceptability [1]. Thus, there is a precedent for reassessing the name ‘Nuclear Medicine’ to reduce patient worries when being referred for a Nuclear Medicine investigation. Since we already have Molecular Imaging and Molecular Radiotherapy there is an argument for modifying Nuclear Medicine to Molecular Radiomedicine. Molecular Imaging uses clinical images which do not have the same resolution and contrast as those found in radiology. Although, modern techniques of imaging and reconstruction have improved the situation [2, 3]. Scientifically, molecular imaging has particularly benefited from its unique ability to use radiotracers to image pathophysiology for the diagnosis and therapy of human disease. However, the situation has changed with the introduction of magnetic resonance imaging (MRI), computerised tomography (CT) and ultrasound imaging (US). The use of these ‘competing’ modalities has to some extent been dependent upon economics rather than for their scientific qualities and accuracy. Magnetic resonance imaging especially combines high resolution and contrast with the ability to measure different aspects of physiology, and in many cases the use of MRI would be an improvement in resolution on the equivalent radionuclide technique. Examples of this may be MRI renography with a Gadolinium chelate outperforming the corresponding study with radionuclide labeled DTPA [4] or MR perfusion imaging giving higher resolution and detail than the radionuclide technique [5]. Of course there is the question of cost. MRI is probably more expensive per unit time than the equivalent radionuclide technique. However, like CT, the cost of MRI may not always be a deterrent so there is a strong case for further improving radionuclide imaging now. This is especially true when using radionuclide imaging for the diagnosis and treatment of malignant disease. The quality of the radionuclide image is dependent upon the count density, which in turn is dependent upon the administered activity and the uptake from the blood into the organ or lesion being studied. The administered activity has changed little since the days of rectilinear imaging when the limited activity from a Mo 100 mCi generator was conveniently divided into ten aliquots of 10 mCi, now rounded up to 400 MBq. The resulting images were assessed by the reporting physician as being adequate. The usual administered activities have been enshrined in Diagnostic Reference Levels which have a strong influence on the level of administered activity used, possibly in case there is a misguided legal challenge of radiation-induced side effects. In the background, there has always been the worry that diagnostic radiation could induce cancer; therefore, lower activities are constantly being recommended and, in the case of SPECT/CT and PET/ CT, novel reconstruction techniques are being used to help compensate for the lower information density [3]. The result of low molecular imaging count density is particularly evident in SPECT/CT imaging which dramatically contrasts the resolution of the radioactive image with that of the CT scan. What is missing is a study of how much administered activity should be given to diagnose lesions of a specific size with an expected lesion-to-background ratio on the various types of radionuclide images, taking into account the time limitation by patient movement. Published literature shows that the addition of molecular imaging can change patient management [6]. The question remains if enhanced images using higher administered * V. Ralph McCready Ralph.McCready@bsuh.nhs.uk

Old tracer for a new purpose: potential role for 99mTc-2-Methoxyisobutylisonitrile (99mTc-MIBI) in renal transplant care.

AimCalcineurin inhibitors are substrates for P-glycoprotein (P-gp), the expression of which is associated with ABCB1 C3435T polymorphism. Individual P-gp response to calcineurin inhibitor may be linked to nephrotoxicity or rejection. 99mTc-2-Methoxyisobutylisonitrile (99mTc-MIBI) is also a P-gp substrate. The aim of this study, therefore, was to determine 99mTc-MIBI organ kinetics and compare them with ABCB1 genotype with a view to replacing 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) with 99mTc-MIBI in renal transplant care. MethodsThirty prospective donors (13 male) were imaged for 20 min after administration of 99mTc-MIBI (400 MBq) intravenously. Posterior images of the abdomen were acquired at 30 and 120 min. Organ 30 min/peak count rate ratios and exponential two-point (30–120 min) rate constants (k, min−1) were calculated. Nineteen donors were genotyped for C3435T (exon 26), G2677T (exon 21), C1236T (exon 12), and G1199A (exon 11) ABCB1 polymorphisms using a PCR-based technique. Results99mTc-MIBI and 99mTc-MAG3 gave similar perfusion images. Although their patterns of renal elimination were different, differential renal function was not significantly different. There was a negative trend between the hepatic 30 min/peak ratio and C3435T genotype (CC: 0.8374±0.0502; TC: 0.6806±0.1300; TT: 0.6919±0.1506; P=0.083). Renal k showed a negative trend with C3435T (CC: 0.0021±0.0020; TC: 0.0037±0.0013; TT: 0.0040±0.0012 min−1; P=0.087) but with no other genotypes. There were no significant sex-related differences in 99mTc-MIBI kinetics. Conclusion99mTc-MIBI can replace 99mTc-MAG3 for pretransplant workup. The ABCB1 C3435T polymorphism may influence 99mTc-MIBI kinetics and thus have a role in renal transplant care. Further prospective trials are required to establish the full potential of 99mTc-MIBI in renal transplant management.