Epidemiology of gastrointestinal worm infections in pigs reared in Enugu State, Nigeria.

Gastrointestinal worm infections (GWI) constrain pig production and zoonotic pig parasites make pork unsafe for human consumption. This study determined the distributions, determinants and dynamics of GWI and also the effect of the infection on production parameters in pigs reared in Enugu State, Nigeria. The GWI were determined by faecal egg counts following standard procedure. Sixty piggeries and 564 pigs were randomly selected for the study. Questionnaire survey was conducted to obtain data on some production parameters and risk practices aiding GWI in the piggeries. An overall prevalence of 88.3% (53/60) and 68.1% (384/564) at farm and individual pig levels respectively were recorded. High egg counts of single and mixed infections involving Strongyle, Ascaris and Trichuris species were found. The infection predominated in young (74.1%, 240/324) and female (72.3%, 272/376) pigs during the rainy/wet season (74.5%, 204/274). Rearing pigs of different ages together, feeding pigs with untreated abattoir/poultry waste, and unhygienic on-farm feed compounding were the major risk practices underpinning acquisition and spread of GWI. Infected piggeries had less litter weight and reduced mean weight at weaning and maturity. Pre-weaning piglet mortality was 15.5%. The seasonality and preponderance of the infection in young and female pigs are useful epidemiological findings which could be exploited for development of an effective control strategy against the parasitic infections. An overhaul of parasitic disease control measures in piggeries in Enugu State is imperative for greater productivity and profitability in swine production, and to boost availability of safe and wholesome pork for human consumption. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12639-021-01377-y.

Pseudo-pseudo Meigs' syndrome: a rare presentation of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic inflammatory multisystem autoimmune disease. Ascites when associated with pleural effusion and raised CA-125 levels in SLE patient, is known as pseudo-pseudo Meigs' syndrome (PPMS). This is the case of a 22-year-old lady who presented with complaints of abdominal distension for one month and had a history of spontaneous abortion in the past. Abdominal imaging did not reveal any tumor and after extensive workup a diagnosis of PPMS was made. She was successfully treated with steroids, hydroxychloroquine and cyclophosphamide.

Dose-response inhibitory effects of purified cathinone from khat (Catha edulis) on cortisol and prolactin release in vervet monkeys (Chlorocebus aethiops).

This study reports acute and sub-chronic effects of cathinone on hormonal alterations in single-caged vervet monkeys. Fourteen adult vervet monkeys were used, 12 of which were treated and 2 controls. Pre-treatment phase of 1 month aimed at establishing baseline levels of hormones while treatment phase of 4 months considered the dose- and time-response effects of cathinone on serum cortisol and prolactin levels. Test animals were allocated four groups of three animals each and administered 0.8, 1.6, 3.2 and 6.4 mg/kg body weight of cathinone orally while controls were administered normal saline. Treatment was done at alternate days of each week. Serum prolactin and cortisol immunoassays were done. Hormonal data was analysed by repeated measures ANCOVA. Results indicate a dose [F (4, 8) = 218, P < 0.001] and time [F (18, 142) = 21.7, P < 0.001] dependent effect of cathinone on cortisol levels with a significant dose by week interaction [F (71, 142) = 4.86, P < 0.001]. Similarly, there was a decrease in serum prolactin [F (4, 8) = 267, P < 0.001] with escalating doses of cathinone with a significant dose x week interaction [F (59, 118) = 13.03, P < 0.001]. The findings demonstrate that at high doses and long-term exposure, cathinone causes hormonal alterations probably via changes in hypothalamo-hypophyseo-adrenocortical and gonadal axes integrity.

Acute and sub-chronic effects of purified cathinone from khat (Catha edulis) on behavioural profiles in vervet monkeys (Chlorocebus aethiops).

We investigated the cumulative effects of cathinone on behavioural alterations in single-caged vervet monkeys. Fourteen adult vervets were divided into tests (12 animals) and controls (2 animals), and exposed to escalating doses of cathinone at alternate days of each week for 4 months in presence and absence of cage enrichment. One month of pre-treatment phase served to establish baseline values. Composite behavioural scores of aggression, anxiety, abnormal responses, withdrawal and appetite loss were done. A series of repeated measures analysis of variances were conducted to examine the extent to which cathinone administration was associated with patterns of changes in behavioural data. Results indicate a dose-dependent effect of cathinone on increases of aggression, anxiety, abnormal responses, withdrawal, and appetite loss. The findings demonstrate that at high doses and long-term exposure, cathinone causes behavioural alterations probably via changes in presynaptic striatal dopamine system.

In vitro and in vivo evaluation of [18F]-FDEGPECO as a PET tracer for imaging the metabotropic glutamate receptor subtype 5 (mGluR5).

(E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone O-2-(2-(18)F-fluoroethoxy)ethyl oxime, ([(18)F]-FDEGPECO), a novel high affinity radioligand for the metabotropic glutamate receptor subtype 5 (mGluR5) was assessed for its potential as a PET imaging agent. In vitro autoradiography on rat brain slices resulted in a heterogeneous and displaceable binding to mGluR5-rich brain regions. [(18)F]-FDEGPECO showed high stability in rat plasma and brain homogenate as well as in human plasma and microsomes. Good blood-brain barrier passage was predicted from an in vitro transport assay with P-glycoprotein-transfected hMDR1-MDCK cells. In vivo PET imaging on rats revealed specific uptake of radioactivity in the mGluR5-rich brain regions such as hippocampus, striatum and cortex while the cerebellum, a region with low mGluR5-expression, showed negligible uptake. Blockade experiments by co-injection of [(18)F]-FDEGPECO and M-MPEP (6mg/kg), an antagonist for mGluR5, reduced the level of radioactivity in mGluR5-regions to that of the cerebellum, pointing to an effective blockade of specifically bound [(18)F]-FDEGPECO. Postmortem biodistribution studies at 15min p.i. confirmed the distribution pattern observed in PET. HPLC analysis of rat brain extracts indicated that 98.5% and 91% of the total radioactivity were parent compound at 5min and 17min p.i., respectively. Taken together, the high affinity and the high in vivo specificity of [(18)F]-FDEGPECO for mGluR5 in the rat brain as well as the lack of in vivo defluorination make this new [(18)F]-labeled ABP688 derivative a suitable ligand for the preclinical PET imaging of mGluR5. These favorable characteristics warrant further evaluation in humans.

18F-labeled bombesin analog for specific and effective targeting of prostate tumors expressing gastrin-releasing peptide receptors.

UNLABELLED: Bombesin is a peptide exhibiting high affinity for the gastrin-releasing peptide receptor (GRPr), which is highly overexpressed on prostate cancer cells. In the present study, we developed an (18)F-labeled bombesin analog, (18)F-BAY 86-4367, which is currently being clinically tested for use in PET of prostate cancer. METHODS: In vitro pharmacologic studies were performed to characterize the nonradioactive ((19)F) standard of the bombesin analog for binding affinity and selectivity for GRPr. The stability of (18)F-BAY 86-4367 was determined in murine and human plasma. In vivo, the tumor-targeting potential and pharmacokinetic profile of the (18)F tracer were analyzed with biodistribution experiments and PET studies of prostate tumor-bearing mice. RESULTS: The nonradioactive ((19)F) standard of the bombesin analog showed subnanomolar and GRPr-selective binding affinity. The stability of the tracer in murine and human plasma was found to be high. In 2 prostate cancer xenograft models (PC-3 and LNCaP), (18)F-BAY 86-4367 showed more specific and effective GRPr-based targeting in vivo than the benchmark radiotracers (18)F-fluoroethylcholine and (18)F-FDG. In addition, rapid tumor targeting and fast renal excretion (∼70%) and hepatobiliary excretion (∼10%) were identified in both xenograft models. Furthermore, PET studies provided clear and specific visualization of PC-3 tumors in mice. CONCLUSION: Favorable preclinical data showing specific and effective tumor targeting by (18)F-BAY 86-4367 suggest that a clinical trial be undertaken to test its diagnostic utility in PET for prostate carcinoma patients.

In vitro and in vivo characterization of novel 18F-labeled bombesin analogues for targeting GRPR-positive tumors.

The gastrin-releasing peptide receptor (GRPR) is overexpressed on a number of human tumors and has been targeted with radiolabeled bombesin analogues for the diagnosis and therapy of these cancers. Seven bombesin analogues containing various linkers and peptide sequences were designed, synthesized, radiolabeled with (18)F, and characterized in vitro and in vivo as potential PET imaging agents. Binding studies displayed nanomolar binding affinities toward human GRPR for all synthesized bombesin analogues. Two high-affinity peptide candidates 6b (K(i) = 0.7 nM) and 7b (K(i) = 0.1 nM) were chosen for further in vivo evaluation. Both tracers revealed specific uptake in GRPR-expressing PC-3 tumors and the pancreas. Compared to [(18)F]6b, compound [(18)F]7b was characterized by superior tumor uptake, higher specificity of tracer uptake, and more favorable tumor-to-nontarget ratios. In vivo PET imaging allowed for the visualization of PC-3 tumor in nude mice suggesting that [(18)F]7b is a promising PET tracer candidate for the diagnosis of GRPR-positive tumors in humans.

Anti-Angiogenic/Vascular Effects of the mTOR Inhibitor Everolimus Are Not Detectable by FDG/FLT-PET.

Noninvasive functional imaging of tumors can provide valuable early-response biomarkers, in particular, for targeted chemotherapy. Using various experimental tumor models, we have investigated the ability of positron emission tomography (PET) measurements of 2-deoxy-2-[(18)F]fluoro-glucose (FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) to detect response to the allosteric mammalian target of rapamycin (mTOR) inhibitor everolimus. Tumor models were declared sensitive (murine melanoma B16/BL6 and human lung H596) or relatively insensitive (human colon HCT116 and cervical KB31), according to the IC(50) values (concentration inhibiting cell growth by 50%) for inhibition of proliferation in vitro (<10 nM and >1 microM, respectively). Everolimus strongly inhibited growth of the sensitive models in vivo but also significantly inhibited growth of the insensitive models, an effect attributable to its known anti-angiogenic/vascular properties. However, although tumor FDG and FLT uptake was significantly reduced in the sensitive models, it was not affected in the insensitive models, suggesting that endothelial-directed effects could not be detected by these PET tracers. Consistent with this hypothesis, in a well-vascularized orthotopic rat mammary tumor model, other antiangiogenic agents also failed to affect FDG uptake, despite inhibiting tumor growth. In contrast, the cytotoxic patupilone, a microtubule stabilizer, blocked tumor growth, and markedly reduced FDG uptake. These results suggest that FDG/FLT-PET may not be a suitable method for early markers of response to antiangiogenic agents and mTOR inhibitors in which anti-angiogenic/vascular effects predominate because the method could provide false-negative responses. These conclusions warrant clinical testing.

Syntheses and pharmacological characterization of novel thiazole derivatives as potential mGluR5 PET ligands.

Four novel thiazole containing ABP688 derivatives were synthesized and evaluated for their binding affinity towards the metabotropic glutamate receptor subtype 5 (mGluR5). (E)-3-((2-(Fluoromethyl)thiazol-4-yl)ethynyl)cyclohex-2-enone O-methyl oxime (FTECMO), the ligand with the highest binding affinity (K(i)=5.5+/-1.1 nM), was labeled with fluorine-18. [(18)F]-FTECMO displayed optimal lipophilicity (log D(pH7.4)=1.6+/-0.2) and high stability in rat and human plasma as well as sufficient stability in rat liver microsomes. In vitro autoradiography with [(18)F]-FTECMO revealed a heterogeneous and displaceable binding in mGluR5-rich brain regions. PET imaging with [(18)F]-FTECMO in Wistar rats, however, showed low brain uptake. Uptake of radioactivity into the skull was observed suggesting in vivo defluorination. Thus, although [(18)F]-FTECMO is an excellent ligand for the detection of mGluR5 in vitro, its in vivo characteristics are not optimal for the imaging of mGluR5 in rats in vivo.

Structure-activity relationships of fluorinated (E)-3-((6-methylpyridin-2-yl)ethynyl)cyclohex-2-enone-O-methyloxime (ABP688) derivatives and the discovery of a high affinity analogue as a potential candidate for imaging metabotropic glutamate recepors subtype 5 (mGluR5) with positron emission tomography (PET).

The metabotropic glutamate receptor subtype 5 (mGluR5) is recognized to be involved in numerous brain disorders. In an effort to obtain a fluorine-18 labeled analogue of the mGluR5 PET tracer [(11)C]ABP688, 13 novel ligands based on the core structure of ABP688 were synthesized. Molecules in which the methyl group at the oxime functionality of ABP688 was replaced by fluorobenzonitriles, fluoropyridines, and fluorinated oxygen containing alkyl side chains were investigated. Substituents at the oxime functionality are well tolerated and resulted in five candidates with K(i) values below 10 nM. The most promising candidate, (E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone-O-2-(2-fluoroethoxy)ethyloxime (38, K(i) = 3.8 nM), was radiolabeled with fluorine-18. Scatchard analysis of [(18)F]38 which modeled best for two sites pointed to high binding affinity (K(D1) = 0.61 +/- 0.19 nM and K(D2) = 13.73 +/- 4.69 nM) too. These data strongly suggest the further evaluation of [(18)F]38 as a candidate for imaging the mGluR5.

Direct one-step 18F-labeling of peptides via nucleophilic aromatic substitution.

Methods for the radiolabeling molecules of interest with [18F]-fluoride need to be rapid, convenient, and efficient. Numerous [18F]-labeled prosthetic groups, e.g., N-succinimidyl 4 [18F]-fluorobenzoate ([18F]-SFB), 4-azidophenacyl-[18F]-fluoride ([18F]-APF), and 1-(3-(2-[18F]fluoropyridin-3-yloxy)propyl)pyrrole-2,5-dione ([18F]-FpyMe), for conjugating to biomolecules have been developed. As the synthesis of these prosthetic groups usually requires multistep procedures, there is still a need for direct methods for the nucleophilic [18F]-fluorination of biomolecules. We report here on the development of a procedure based on the trimethylammonium (TMA) leaving group attached to an aromatic ring and activated with different electron-withdrawing groups (EWGs). A series of model compounds containing different electron-withdrawing substituents, a trimethylammonium leaving group, and carboxylic functionality for subsequent coupling to peptides were designed and synthesized. The optimal model compound, 2-cyano-4-(methoxycarbonyl)-N,N,N-trimethylbenzenaminium trifluoromethanesulfonate, was converted to carboxylic acid and coupled to peptides. The results of the one-step [18F]-fluorination of tetrapeptides and bombesin peptides show that the direct 18F-labeling of peptides is feasible under mild conditions and in good radiochemical yields.

Faster analysis of radiopharmaceuticals using ultra performance liquid chromatography (UPLC) in combination with low volume radio flow cell.

With the aim of reducing analysis time of radiopharmaceuticals, especially for carbon-11 and fluorine-18, radio-high performance liquid chromatography (radio-HPLC) is the analysis method of choice. Faster and more sensitive analytic methods are needed. Recently, ultra performance liquid chromatography (UPLC) has become an accepted analysis method but has not yet been established in radiopharmacy. This study demonstrates with the established positron emission tomography (PET) tracer [(18)F]fluoromisonidazole (FMISO) the applicability of using UPLC) in combination with low volume radio flow cell for a fast, sensitive and efficient analytic method. The developed UPLC) method showed a sharp and high radio signal. The total analysis time was thus reduced from 15 to 2 min.

Synthesis and characterization of a C6 nucleoside analogue for the in vivo imaging of the gene expression of herpes simplex virus type-1 thymidine kinase (HSV1 TK).

The synthesis and biological evaluation of '6-(1,3-dihydroxyisobutyl)thymine' (DHBT; 1), which corresponds to 6-[3-hydroxy-2-(hydroxymethyl)propyl]-5-methylpyrimidine-2,4(1H,3H)-dione, is reported. DHBT (1) was designed as a new substrate for herpes simplex virus type-1 thymidine kinase (HSV1 TK). The compound was found to be exclusively phosphorylated by HSV1 TK, and to exhibit good binding affinity (Ki = 35.3+/-1.3 microM). Cell-proliferation assays with HSV1-TK-transduced human osteosarcoma cells (143B-TK+-HSV1-WT) and with both human-thymidine-kinase-1-negative (143B-TK-) and non-transduced parental (MG-63) cells indicate that 1 is less cytotoxic than the standard drug Ganciclovir. Thus, DHBT (1) represents a promising precursor of a nontoxic reporter probe for the monitoring of HSV1 TK gene expression by means of positron-emission tomography (PET).

Comparison of [18F]FDOPA, [18F]FMT and [18F]FECNT for imaging dopaminergic neurotransmission in mice.

INTRODUCTION: The clinically established positron emission tomography (PET) tracers 6-[(18)F]-fluoro-l-DOPA ([(18)F]FDOPA), 6-[(18)F]-fluoro-l-m-tyrosine ([(18)F]FMT) and 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-[(18)F]-fluoroethyl)-nortropane ([(18)F]FECNT) serve as markers of presynaptic integrity of dopaminergic nerve terminals in humans. This study describes our efforts to adopt the methodology of human Parkinson's disease (PD) PET studies to mice. METHODS: The PET imaging characteristics of [(18)F]FDOPA, [(18)F]FMT and [(18)F]FECNT were analyzed in healthy C57BL/6 mice using the dedicated small-animal PET tomograph quad-HIDAC. Furthermore, [(18)F]FECNT was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. RESULTS: [(18)F]FDOPA and [(18)F]FMT failed to clearly visualize the mouse striatum, whereas PET experiments using [(18)F]FECNT proved that the employed methodology is capable of delineating the striatum in mice with exquisite resolution. Moreover, [(18)F]FECNT PET imaging of healthy and MPTP-lesioned mice demonstrated that the detection and quantification of striatal degeneration in lesioned mice can be accomplished. CONCLUSIONS: This study shows the feasibility of using [(18)F]FECNT PET to analyze noninvasively the striatal degeneration in the MPTP mouse model of PD. This methodology can be therefore considered as a viable complement to established in vivo microdialysis and postmortem techniques.

Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5.

UNLABELLED: (11)C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-(11)C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. METHODS: ABP688 was radiolabeled with (11)C by reacting (11)C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime). The affinity of (11)C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with (11)C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. RESULTS: The overall synthesis time was 45-50 min from the end of radionuclide production. (11)C-ABP688 was obtained in good radiochemical yield (35% +/- 8%, n = 17, decay corrected), and the specific radioactivity was 150 +/- 50 GBq/mumol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 +/- 0.2 nmol/L and a maximum number of binding sites of 231 +/- 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of (11)C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of (11)C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of (11)C-ABP688 binding to mGluR5. CONCLUSION: (11)C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.

NanoPET imaging of [(18)F]fluoromisonidazole uptake in experimental mouse tumours.

PURPOSE: The purpose of this study was to assess the potential and utility of ultra-high-resolution hypoxia imaging in various murine tumour models using the established hypoxia PET tracer [(18)F]fluoromisonidazole ([(18)F]FMISO). METHODS: [(18)F]FMISO PET imaging was performed with the dedicated small-animal PET scanner NanoPET (Oxford Positron Systems) and ten different human tumour xenografts in nude mice as well as B16 melanoma tumours in syngeneic Balb/c mice. For comparison, [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET scans were also performed in the mice bearing human tumour xenografts. RESULTS: In 10 out of 11 experimental tumour models, [(18)F]FMISO PET imaging allowed clear-cut visualisation of the tumours. Inter- and intratumoural heterogeneity of tracer uptake was evident. In addition to average TMRR (tumour-to-muscle retention ratio including all voxels in a volume of interest (VOI)), the parameters TMRR(75%) and TMRR(5) (tumour-to-muscle retention ratio including voxels of 75% or more of the maximum radioactivity in a VOI and the five hottest pixels, respectively) also served as measures for quantifying the heterogeneous [(18)F]FMISO uptake in the tumours. The variability observed in [(18)F]FMISO uptake was related neither to tumour size nor to the injected mass of the radiotracer. The pattern of normoxic and hypoxic regions within the human tumour xenografts, however, correlated with glucose metabolism as revealed by comparison of [(18)F]FDG and [(18)F]FMISO images. CONCLUSION: This study demonstrates the feasibility and utility of [(18)F]FMISO for imaging murine tumour models using NanoPET.

Measurement of tumor hypoxia in spontaneous canine sarcomas.

We used positron emission tomography (PET) with [18F]fluoromisonidazole ([18F]FMISO) to study tumor hypoxia in six dogs with spontaneous sarcomas. The tumors were regarded as hypoxic if [18F]FMISO uptake exceeded normal tissue radioactivity by 40% (tumor/muscle ratio > 1.4) or if kinetic analysis indicated a positive [18F]FMISO tissue influx rate (Ki > 0) by a Patlak plot. Using these criteria, we found hypoxia in a fibrosarcoma grade II, an undifferentiated sarcoma, and an ostoeosarcoma, but not in a fibrosarcoma grade I, another osteosarcoma, and a myxosarcoma. In three animals, the tumor oxygen partial pressure (pO2) was also measured invasively using Eppendorf needle electrodes. In these cases, the Eppendorf measurements were confirmed by the [18F]FMISO PET results. In addition, [15O]H2O PET was performed in four dogs in order to assess tumor perfusion. Comparisons of the [18F]FMISO with [15O]H2O PET images in two cases showed that tumor hypoxia occurred in the tumor center with low perfusion, whereas perfusion was heterogeneous in a nonhypoxic tumor.

Mental health policy and programmes in Kenya.

Following a 10-year war of liberation (fought by the Mau Mau against the British), Kenya attained full independence from colonial rule in 1963. For 10 years the country enjoyed rapid economic growth (6-7% per annum) but this slowed steadily to near stagnation in the 1990s. Poor governance, abuse of human rights, internal displacements of citizens, large numbers of refugees from neighbouring countries and the AIDS pandemic conspired to reduce Kenyans' life expectancy to 47 years (in the UK it is presently 77 years). Some 42% of the population now live below the poverty line, and 26% of Kenyans exist on less than US$1 per day. The annual per capita income in Kenya is US$360 (in the UK it is $24 000) (World Bank, 2002). AIDS currently has an estimated prevalence rate of 12%. In large parts of rural Kenya many sexually active adults are unable to work, and elderly grandparents are left to look after orphaned children (some already infected with HIV), as they struggle to deal with their own grief for the loss of many of their own children. In December 2002 a new government was elected, which gives some grounds for optimism in an otherwise bleak situation.

Assessment of hypoxia and perfusion in human brain tumors using PET with 18F-fluoromisonidazole and 15O-H2O.

UNLABELLED: Hypoxia predicts poor treatment response of malignant tumors. We used PET with (18)F-fluoromisonidazole ((18)F-FMISO) and (15)O-H(2)O to measure in vivo hypoxia and perfusion in patients with brain tumors. METHODS: Eleven patients with various brain tumors were investigated. We performed dynamic (18)F-FMISO PET, including arterial blood sampling and the determination of (18)F-FMISO stability in plasma with high-performance liquid chromatography (HPLC). The (18)F-FMISO kinetics in normal brain and tumor were assessed quantitatively using standard 2- and 3-compartment models. Tumor perfusion ((15)O-H(2)O) was measured immediately before (18)F-FMISO PET in 10 of the 11 patients. RESULTS: PET images acquired 150-170 min after injection revealed increased (18)F-FMISO tumor uptake in all glioblastomas. This increased uptake was reflected by (18)F-FMISO distribution volumes >1, compared with (18)F-FMISO distribution volumes <1 in normal brain. The (18)F-FMISO uptake rate K(1) was also higher in all glioblastomas than in normal brain. In meningioma, which lacks the blood-brain barrier (BBB), a higher K(1) was observed than in glioblastoma, whereas the (18)F-FMISO distribution volume in meningioma was <1. Pixel-by-pixel image analysis generally showed a positive correlation between (18)F-FMISO tumor uptake at 0-5 min after injection and perfusion ((15)O-H(2)O) with r values between 0.42 and 0.86, whereas late (18)F-FMISO images (150-170 min after injection) were (with a single exception) independent of perfusion. Spatial comparison of (18)F-FMISO with (15)O-H(2)O PET images in glioblastomas showed hypoxia both in hypo- and hyperperfused tumor areas. HPLC analysis showed that most of the (18)F-FMISO in plasma was still intact 90 min after injection, accounting for 92%-96% of plasma radioactivity. CONCLUSION: Our data suggest that late (18)F-FMISO PET images provide a spatial description of hypoxia in brain tumors that is independent of BBB disruption and tumor perfusion. The distribution volume is an appropriate measure to quantify (18)F-FMISO uptake. The perfusion-hypoxia patterns described in glioblastoma suggest that hypoxia in these tumors may develop irrespective of the magnitude of perfusion.