Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours.

BACKGROUND AND PURPOSE: The aim of the study was to identify hypoxia in human soft tissue sarcomas (STS) by PET scanning using the hypoxia marker [18F]-fluoromisonidazole ([18F]FMISO) and invasive oxygen sensitive probes (Eppendorf pO2 Histograph, Germany). MATERIALS AND METHODS: Thirteen patients with tumours suspected to be STS were examined by [18F]FMISO PET scanning, and eleven of these patients completed a set of Eppendorf pO2 Histograph measurements following the scanning. RESULTS AND DISCUSSION: By histopathological diagnosis, seven tumours were shown to be STS and six tumours were benign. Ratios between tumour and muscle radioactivity and time activity curves for tumours and muscle tissue were examined in defined regions of interest. Only two malignant tumours showed [18F]FMISO uptake in higher amounts than muscle tissue over time. Hypoxia was present in both benign and malignant tumours as measured by the oxygen electrode method. CONCLUSIONS: [18F]FMISO PET in our setting seemed not to be feasible for the detection of tumour hypoxia in human soft tissue tumours. Neither did it reflect the extent of hypoxia as determined with the oxygen electrode measurements.     

[18F] FDG PET in Gastric Non-Hodgkin's Lymphoma

The possibility of using [¹⁸F] FDG PET for assessment of tumor extension in primary gastric non-Hodgkin's lymphoma (NHL) was studied in 8 patients (6 high-grade and 2 Iow-grade, one of the MALT type) and in a control group of 7 patients (5 patients with NHL without clinical signs of gastric involvement, 1 patient with NHL and benign gastric ulcer and 1 patient with adenocarcinoma of the stomach). All patients with gastric NHL and the two with benign gastric ulcer and adenocarcinoma, respectively, underwent endoscopy including multiple biopsies for histopathological diagnosis. All patients with high-grade and one of the two with low-grade NHL and the patient with adenocarcinoma displayed high gastric uptake of [¹⁸F] FDG corresponding to the pathological findings at endoscopy and/or CT. No pathological tracer uptake was seen in the patient with low-grade gastric NHL of the MALT type. In 6/8 patients with gastric NHL, [¹⁸F] FDG PET demonstrated larger tumor extension in the stomach than was found at endoscopy, and there was high tracer uptake in the stomach in two patients who were evaluated as normal on CT. [¹⁸F] FDG PET correctly excluded gastric NHL in the patient with a benign gastric ulcer and in the patients with NHL without clinical signs of gastric involvement. Although the experience is as yet limited, [¹⁸F] FDG PET affords a novel possibility for evaluation of gastric NHL and would seem valuable as a complement to endoscopy and CT in selected patients, where the technique can yield additional information decisive for the choice of therapy.     

Assessment of hypoxia in experimental mice tumours by [18F]fluoromisonidazole PET and pO2 electrode measurements. Influence of tumour volume and carbogen breathing

The aim of this study was to compare a non-invasive 18 F-fluoromisonidazole ([ 18 F]FM ISO) PET assessment of tumour hypoxia with invasive Eppendorf pO 2 measurements in 150-1500 mm 3 C3H mammary carcinomas transplanted on the back of CDF1 mice. The tumour-bearing mice breathed either carbogen gas (95% oxygen, 5% CO 2 ) or normal air during both examinations. Additional autoradiography was performed in separate tumours treated similarly. The PET [18F]FM ISO examination significantly discriminated between tumours of carbogen and air-breathing mice. For the pO 2 measurements, there was a significantly lower percentage of measurements below 2.5 mmHg for carbogen-treated mice compared with air-breathing mice. However, no direct correlation between the methods was seen. A correlation was found between tumour volume and Eppendorf estimates of tumour hypoxia for the animals breathing normal air, but no correlation was found between the PET endpoint and tumour volume. This may be due to low pO 2 measurements obtained in necrotic tissue. Autoradiography confirmed lower [ 18 F]FM ISO uptake in tumours of carbogen-breathing animals compared with air-breathing animals, and demonstrated the heterogeneity of the tracer uptake in small compared with larger tumours.     

Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging.

PURPOSE: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). (18)F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of (18)F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake. EXPERIMENTAL DESIGN: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue:blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane. RESULTS: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r = 0.24), with highly significant differences among the different tumor types (P < 0.005). CONCLUSIONS: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.     

Effect of intratumoral heterogeneity in oxygenation status on FMISO PET, autoradiography, and electrode Po2 measurements in murine tumors

PURPOSE: To explore conflicting results obtained when tumor hypoxia is assessed with Eppendorf electrode Po(2) measurements and with positron emission tomography (PET) by use of [(18)F]fluoromisonidazole (FMISO). METHODS AND MATERIALS: We compared the 2 methods in conjunction with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) PET, dual-tracer ex vivo autoradiography (FMISO and 2-deoxy-D-[1-(14)C]glucose (2DG)), and histology in 2 murine tumor models, the C3H mammary carcinoma and the SCCVII squamous cell carcinoma. RESULTS: 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-PET showed tumor-to-reference tissue ratios of 3.5 in both tumor models after 2 hours. C3H mammary carcinoma reached an FMISO PET ratio of 11 after 3.5 hours. Autoradiography showed large confluent areas of FMISO and 2DG uptake. Median Po(2) was 7 mm Hg and necrotic fraction was 10% to 30%. SCCVII squamous-cell carcinoma reached an FMISO PET tumor-to-reference tissue ratio of 2 after 2.5 hours. Autoradiography showed homogeneous 2DG uptake and scattered foci of high FMISO uptake. Median Po(2) was 1 mm Hg and necrotic fraction was below 5%. CONCLUSIONS: Ex vivo dual-tracer autoradiography documented the ability of in vivo FMISO PET to distinguish between confluent areas of either viable tissue or necrosis. Electrode Po(2) measurements could not be ascribed to specific areas in the tumors. Less uptake of FMISO in SCCVII squamous-cell carcinoma than in C3H mammary carcinoma could be caused by scattered foci versus confluent areas of viable hypoxic tissue in the 2 tumors, respectively.     

Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole.

Fluoromisonidazole (FMISO) has been shown to bind selectively to hypoxic cells in vitro and in vivo at radiobiologically significant oxygen levels. When labeled with the positron emitter fluorine-18 (F-18), its uptake in tissue can be detected quantitatively with high precision by positron emission transaxial tomography (PETT). This paper presents the first experiences with PETT imaging of [F-18]FMISO uptake in human malignancies, and describes the development of this technique as a tool for the non-invasive assessment of tumor hypoxia. Eight patients with selected cancers were imaged prior to primary radiotherapy, and 3 returned for follow-up scans, for a total of 11 imaging studies. Six of eight pre-radiotherapy studies revealed retention of [F-18]FMISO in tumors that significantly exceeded plasma concentrations by 2 hr after drug injection; all five patients with head and neck primaries had such "positive" scans. An analytic method for the interpretation of [F-18] FMISO PETT images is presented, defining hypoxic elements within a tumor volume as regions with a threshold regional tumor:plasma [F-18]FMISO ratio of greater than or equal to 1.4 by 2 or more hours after injection. Toward the end of a course of fractionated radiotherapy, three repeat studies in patients with initially positive scans showed no tumor accumulation of drug above the threshold ratio of 1.4, suggesting reoxygenation had occurred. Pharmacokinetic and dosimetry data support continued use of [F-18]FMISO as a safe hypoxia probe. Two imaging protocols have been developed for human studies; a long protocol allows for more complete biodistribution and dosimetry information, and a shorter protocol facilitates increased patient accrual by applying a simple, clinically expedient imaging procedure. When correlated with tumor outcome, [F-18]FMISO PETT imaging may be developed as a predictor of tumor response to conventional radiotherapy. The implications of this technique in addressing persistent questions of tumor hypoxia in human oncology is discussed.     

Biokinetics of the Monoclonal Antibodies MOv 18, OV 185 and OV 197 Labelled with 125I According to the m-MeATE Method or the Iodogen Method in Nude Mice with Ovarian Cancer Xenografts

The biodistribution of the radiolabelled monoclonal antibodies MOv18, OV185 and OV197 in nude mice with subcutaneous tumours of the human ovarian cancer cell line OVCAR3 was investigated. The early uptake of MOv18 (1-24 h) and the uptake in relation to tumour size were also studied. The antibodies were labelled with ¹²⁵I according to the Iodogen method or the m-MeATE method, the latter also being suitable for labelling with ²¹¹     

Evaluation of hypoxia in an experimental rat tumour model by [(18)F]fluoromisonidazole PET and immunohistochemistry

This study aimed to evaluate tumour hypoxia by comparing [(18)F]Fluoromisonidazole uptake measured using positron emission tomography ([(18)F]FMISO-PET) with immunohistochemical (IHC) staining techniques. Syngeneic rhabdomyosarcoma (R1) tumour pieces were transplanted subcutaneously in the flanks of WAG/Rij rats. Tumours were analysed at volumes between 0.9 and 7.3 cm(3). Hypoxic volumes were defined using a 3D region of interest on 2 h postinjection [(18)F]FMISO-PET images, applying different thresholds (1.2-3.0). Monoclonal antibodies to pimonidazole (PIMO) and carbonic anhydrase IX (CA IX), exogenous and endogenous markers of hypoxia, respectively, were used for IHC staining. Marker-positive fractions were microscopically measured for each tumour, and hypoxic volumes were calculated. A heterogeneous distribution of hypoxia was observed both with histology and [(18)F]FMISO autoradiography. A statistically significant correlation (P<0.05) was obtained between the hypoxic volumes defined with [(18)F]FMISO-PET and the volumes derived from the PIMO-stained tumour sections (r=0.9066; P=0.0001), regardless of the selected threshold between 1.4 and 2.2. A similar observation was made with the CA IX staining (r=0.8636; P=0.0006). The relationship found between [(18)F]FMISO-PET and PIMO- and additionally CA IX-derived hypoxic volumes in rat rhabdomyosarcomas indicates the value of the noninvasive imaging method to measure hypoxia in whole tumours.     

Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer.

PURPOSE: Advanced head and neck cancer shows hypoxia that results in biological changes to make the tumor cells more aggressive and less responsive to treatment resulting in poor survival. [F-18] fluoromisonidazole (FMISO) positron emission tomography (PET) has the ability to noninvasively quantify regional hypoxia. We investigated the prognostic effect of pretherapy FMISO-PET on survival in head and neck cancer. EXPERIMENTAL DESIGN: Seventy-three patients with head and neck cancer had pretherapy FMISO-PET and 53 also had fluorodeoxyglucose (FDG) PET under a research protocol from April 1994 to April 2004. RESULTS: Significant hypoxia was identified in 58 patients (79%). The mean FMISO tumor/bloodmax (T/Bmax) was 1.6 and the mean hypoxic volume (HV) was 40.2 mL. There were 28 deaths in the follow-up period. Mean FDG standard uptake value (SUV)max was 10.8. The median time for follow-up was 72 weeks. In a univariate analysis, T/Bmax (P=0.002), HV (P=0.04), and the presence of nodes (P=0.01) were strong independent predictors. In a multivariate analysis, including FDG SUVmax, no variable was predictive at P<0.05. When FDG SUVmax was removed from the model (resulting in n=73 with 28 events), nodal status and T/Bmax (or HV) were both highly predictive (P=0.02, 0.006 for node and T/Bmax, respectively; P=0.02 and 0.001 for node and HV, respectively). CONCLUSIONS: Pretherapy FMISO uptake shows a strong trend to be an independent prognostic measure in head and neck cancer.     

Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors.

PURPOSE: Hypoxia is one of the reasons for radiation therapy resistance. Positron emission tomography using (18)F-labeled misonidazole ([(18)F]FMISO) is a non-invasive method of imaging tumor hypoxia. Aim of this study was to validate [(18)F]FMISO against the clinically most widely used hypoxic cell marker pimonidazole under different oxygenation conditions. MATERIALS AND METHODS: One human head and neck squamous cell carcinoma (SCCNij3) and two human glioblastoma (E102 and E106) xenograft tumor lines were studied after injection of [(18)F]FMISO and pimonidazole. Control mice were compared with a second group breathing carbogen to reduce tumor hypoxia and with a third group with clamped tumors to increase hypoxia. Tumor sections were analyzed on a phosphor imaging system and consecutively stained immunohistochemically (IHC) for visualization of pimonidazole. Pixel-by-pixel analysis was performed and the hypoxic fraction, obtained after segmentation of the pimonidazole signal, was related to the mean optical density of [(18)F]FMISO and pimonidazole. RESULTS: A moderate pixel-by-pixel correlation between [(18)F]FMISO autoradiography and pimonidazole IHC was found for the control tumors, after carbogen breathing and after clamping for SCCNij3. For E102 and E106, mean signal intensities for pimonidazole significantly decreased after carbogen breathing and increased after clamping, mean [(18)F]FMISO signal intensities increased significantly after clamping and a significant correlation between the hypoxic fractions and the mean [(18)F]FMISO signal intensities was found. CONCLUSIONS: [(18)F]FMISO autoradiography and pimonidazole immunohistochemistry can both be used to visualize treatment induced changes in tumor hypoxia. However, the response to these modifications differs widely between xenograft tumor lines.     

Combined uptake of [18F]FDG and [18F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients.

PURPOSE: FDG PET is frequently used for radiotherapy (RT) planning to determine the tumour extent. Similarly, FMISO is used to assess the hypoxic sub-volume. The relationship between the volumes determined on the basis of FDG and FMISO was investigated. Additionally, the quantitative correlation of the tracers on a voxel basis was studied. METHODS: Twelve head-and-neck cancer (HNC) patients underwent FDG and FMISO PET examinations prior to RT treatment. The tumour volumes assessed by the two tracers and also the voxel-based joint uptake values were investigated. The characteristic shapes and patterns of the determined scatter plots were analyzed. A number of different variables such as the maximum uptake values of FDG and FMISO, the FDG and FMISO positive volumes, the slope m of the regression line and the scatter width sigma of the scatter plots were tested for their ability to stratify the patient group with respect to treatment outcome. RESULTS: A diversity of characteristic FDG-FMISO distributions was observed in the patient group. However, no general correlation of enhanced glucose metabolism and FMISO uptake was observed. The maximum uptake of FMISO (p=0.045) showed borderline significance for stratifying the patient group. FDG positive tumour volume, hypoxic fraction, maximum FDG uptake and m were not significant. Sigma turned out to be the most significant variable (p=0.008) to predict treatment success probabilities. CONCLUSION: FMISO and FDG PET data provide independent information about the examined tumour. A quantification of the correlated tracer uptake seems to be meaningful.     

Somatostatin Receptor Scintigraphy of Carcinoid Tumours Using the [111In-Dtpa-D-Phe1]-Octreotide

Somatostatin-receptor scintigraphy using the ¹¹¹In-labelled somatostatin-analogue octreotide ([¹¹¹In-DTPA-D-Phe¹]-octreotide) was performed in 40 patients with carcinoid tumours. In 31/40 patients, this scintigraphy proved positive compared with the 33/40 patients whose tumours were disclosed on CT scans. In addition, 18 previously unidentified lesions were detected with this scintigraphy. Two of these lesions represented previously undetectable primary tumours. It is concluded that somatostatin receptor scintigraphy using [¹¹¹In-DTPA-D-Phe¹]-octreotide has a future role in the staging of patients with carcinoid disease.     

Imaging hypoxia in xenografted and murine tumors with 18F-fluoroazomycin arabinoside: a comparative study involving microPET, autoradiography, PO2-polarography, and fluorescence microscopy

PURPOSE: Positron emission tomography (PET) allows noninvasive assessment of tumor hypoxia; however the combination of low resolution and slow tracer clearance from nonhypoxic tissue is problematic. The aim of this study was to examine the in vivo hypoxia selectivity of fluoroazomycin arabinoside ([18F]-FAZA), a promising tracer with improved washout kinetics from oxygenated tissue. METHODS AND MATERIALS: Three squamous cell carcinomas and one fibrosarcoma with widely differing spatial patterns of vascularization, hypoxia, and necrosis were grown in mice and evaluated with PET and complementary methods. RESULTS: Eppendorf electrode measurements consistently demonstrated median PO2 values<1 mm Hg. In accordance with that, PET revealed that all tumors accumulated [18F]-FAZA in excess of reference tissue. Next the two-dimensional spatial distribution of [18F]-FAZA (from autoradiography) was compared with fluorescence images of the same tumor sections showing localization of the hypoxia marker pimonidazole and the perfusion marker Hoechst 33342. Pixel-by-pixel analysis of co-registered images showed a highly significant co-localization between the two hypoxia markers and an inverse correlation (except for the fibrosarcoma) between the distribution of [18F]-FAZA and Hoechst dye. Moreover intratumoral heterogeneity in tracer distribution was clearly visible on autoradiograms, with a [18F]-FAZA concentration approximately six times higher in poorly oxygenated areas than in vascular hot spots. CONCLUSIONS: The distribution of [18F]-FAZA is consistent with hypoxia as the key driving force for tracer tissue retention in a selection of tumors with widely differing physiology.     

Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours

Peptide Receptor Radionuclide Therapy (PRRT) with radiolabelled somatostatin analogues is a promising treatment option for patients with inoperable or metastasised neuroendocrine tumours. Symptomatic improvement may occur with all of the various ¹¹¹In, ⁹⁰Y, or ¹⁷⁷Lu-labelled somatostatin analogues that have been used. Since tumour size reduction was seldom achieved with ¹¹¹Indium labelled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like ⁹⁰Y and ¹⁷⁷Lu were developed. Reported anti-tumour effects of [⁹⁰Y-DOTA⁰,Tyr³]octreotide vary considerably between various studies: Tumour regression of 50% or more was achieved in 9 to 33% (mean 22%). With [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate treatments, tumour regression of 50% or more was achieved in 28% of patients and tumour regression of 25 to 50% in 19% of patients, stable disease was demonstrated in 35% and progressive disease in 18%. Predictive factors for tumour remission were high tumour uptake on somatostatin receptor scintigraphy and limited amount of liver metastases. The side-effects of PRRT are few and mostly mild, certainly when using renal protective agents: Serious side-effects like myelodysplastic syndrome or renal failure are rare. The median duration of the therapy response for [⁹⁰Y-DOTA⁰,Tyr³]octreotide and [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate is 30 months and more than 36 months respectively. Lastly, quality of life improves significantly after treatment with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. These data compare favourably with the limited number of alternative treatment approaches, like chemotherapy. If more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasised or inoperable gastroenteropancreatic neuroendocrine tumours. Also the role in somatostatin receptor expressing non-GEP tumours, like metastasised paraganglioma/pheochromocytoma and non-radioiodine-avid differentiated thyroid carcinoma might become more important.     

Measurement of hypoxia using invasive oxygen-sensitive electrode, pimonidazole binding and 18F-FDG uptake in anaemic or erythropoietin-treated mice bearing human glioma xenografts

Relationship between haemoglobin levels and tumour oxygenation has been already reported. The purpose of this work was to compare in human malignant glioma-bearing mice the sensitivity of two well established techniques of tumour hypoxia assessment, especially their ability to detect expected weak variations of tumour oxygenation status associated to haemoglobin level modifications. The relationship between tumour hypoxia and glucose metabolism was also investigated. Experiments were performed on a human malignant glioma (GBM Nan1) xenografted into nude mice. Twenty-four hours after tumour implantation, animals were randomized into three groups: 'Anaemia' for mice subjected to repeated blood samplings, 'Control', and 'rHuEPO' for mice receiving recombinant human erythropoietin. Once the tumours reached a volume of 300+/-100 mm(3), tumour hypoxia was assessed both using the pO(2)-Histograph, Eppendorftrade mark and the pimonidazole binding assay. Glucose metabolism was evaluated by (18)F-FDG autoradiography and compared with the pimonidazole binding distribution pattern. Repeated blood samplings significantly reduced mean haemoglobin levels (10.9+/-2.0 g/dl), inducing chronic anaemia in mice, while daily administration of rHuEPO led to increase of haemoglobin levels (15.8+/-2.0 g/dl). Oxygenation status evaluated by a microelectrode was worsened in anaemic mice (mean pO(2) in tumour = 6.9+/-0.8 mmHg) and improved in rHuEPO-treated animals (mean pO(2)in tumour = 11.4+/-1.2 mmHg). No correlation was observed between the oxygen-sensitive probe and pimonidazole labelling results: both techniques give different but complementary information about tumour hypoxia. Areas of high pimonidazole binding and areas of high (18)F-FDG uptake superimposed well. Present results confirm that modification of haemoglobin levels leads to alteration of tumour oxygenation status. These variations were detectable using the oxygen-sensitive electrode but not the pimonidazole binding assay. The strong correlation between pimonidazole labelling and (18)F-FDG uptake suggests a positive relationship between hypoxia and increased glucose metabolism in this tumour model.     

Development of molecular imaging probes in oncology

Molecular imaging probes used for positron emission tomography(PET)in oncology are reviewed. Although [18F] FDG is presently the most useful probe for imaging tumors, there is a need for complementary probes of FDG with some limitations on detection in the brain or inflammatory region. The review is mostly focused on 18F-labeled probes designed for amino acid transport and protein synthesis, DNA synthesis, membrane lipid, and hypoxia such as FET, FLT, FMAU, fluorocholine, and FMISO, together with our original probes of FMT and FRP-170.     

Imagerie moléculaire de l’hypoxie tumorale

By allowing an earlier diagnosis and a more exhaustive assessment of extension of the disease, the tomography by emission of positrons (TEP) transforms the care of numerous cancers. At present, ¹⁸F-fluorodesoxyglucose ([¹⁸F]-FDG) imaging appears as the only one available but new molecular markers are being developed. In the next future they would modify the approach of cancers. In this context, the molecular imaging of the hypoxia and especially the ¹⁸Ffluoromisonidazole TEP ([¹⁸F]-MISO TEP) can give supplementary information allowing the mapping of hypoxic regions within the tumour. Because of the links, which exist between tumour hypoxia and treatment resistance of very numerous cancers, this information can have an interest, for determination of prognosis as well as for the delineation, volumes to be irradiated. Head and neck tumours are doubtless those for which the literature gives the most elements on the therapeutic impact of tumour hypoxia. Targeted therapies, based on hypoxia, already exist and the contribution of the molecular imaging could be decisive in the evaluation of the impact of such treatment. Molecular imaging of brain tumours remains to be developed. The potential contributions of the [¹⁸F]-MISO TEP for the care of these patients need to be confirmed. In this context, we propose a review of hypoxia molecular imaging taking as examples head and neck tumours and glioblastomas (GB), two tumours for which hypoxia is one of the key factors to overcome in order to increase therapeutics results.     

Uncoupling of fatty acid and glucose metabolism in malignant lymphoma: a PET study.

Increased use of glucose through glycolysis is characteristic for neoplastic growth while the significance of serum-free fatty acids for regulation of energy metabolism in cancer is poorly understood. We studied whether serum-free fatty acids (FFA) interfere with glycolytic metabolism of lymphoproliferative neoplasms as assessed with 2-F18-fluoro-2-deoxy-D-glucose ([F18]FDG) and positron emission tomography (PET). Twelve patients with newly diagnosed non-Hodgkin's lymphoma (n = 9) or Hodgkin's disease (n = 3) participated in this study before start of oncologic treatment. Each patient underwent two [F18]FDG PET studies within 1 week after overnight fast: once during high fasting serum FFA concentrations and once after reduction of serum FFA by administration of acipimox. Acipimox is a nicotinic acid derivative that inhibits lipolysis in peripheral tissues and induces a striking reduction in circulating FFA concentration. In all cases, dynamic PET imaging over the tumour area was performed for 60 min after injection of [F18]FDG. Both graphical analysis (rMR(FDG)) and single scan approach (SUV) were used to compare tumour uptake of [F18]FDG under high fasting FFA concentrations and after pharmacologically decreased FFA concentrations. Serum FFA concentrations were reduced significantly from 0.92+/-0.42 mmol I(-1)at baseline to 0.26+/-0.31 mmol I(-1) after acipimox administration (P = 0.0003). Plasma glucose, serum insulin and lactate concentrations were similar during both approaches. The retention of glucose analogue [F18]FDG in tumour was similar between baseline and acipimox studies. Median rMR(FDG) of a total of 12 involved lymph nodes in 12 patients was 21.9 micromol 100 g(-1) min(-1) (range 8.7-82.5) at baseline and 20.1 micromol 100 g(-1) min(-1)(range 10.7-81.7) after acipimox. The respective values for median SUV were 7.8 (range 3.6-18.6) and 6.0 (range 4.1-20.2). As expected, [F18]FDG uptake in myocardium was clearly enhanced by acipimox due to reduction of circulating FFAs. In conclusion, blood fatty acids appear to have minor significance for [F18]FDG uptake in lymphoma. This suggests that glucose utilization is uncoupled of FFA metabolism and indicates that glucose-free fatty acid cycle does not operate in lymphomatous tissue. Glucose appears to be the preferred substrate for energy metabolism in tumours, in spite of the high supply of FFAs in the fasting state. Although acipimox and other anti-lipolytic drugs have potential for treatment of catabolic state induced by cancer, they are not likely to interfere with tumour energy metabolism which is fuelled by glucose.     

Kinetics of [methyl-11 C]Thymidine in Patients with Squamous Cell Carcinoma of the Head and Neck

Thymidine labelled with a position emitter and imaging by positron emission tomography has been suggested to measure tumour proliferation in vivo non-invasively. The present study presents a compartmental model which describes the behavior of [methyl-¹¹C]thymidine in tumour tissue and allows quantification of the data using a proliferation parameter (PP). In nine patients with squamous cell carcinoma of the head and neck, ¹¹C-activity over the tumour and the adjacent blood vessels was measured. The median PP without correction for blood pool activity was found to be 8.61 10^-4 min^-1. With correction this parameter changed from -14% to +40%. We found no correlation between either sex or tumour differentiation and PP. The described model can be used to quantitate [methyl-¹¹C] thymidine uptake in human tumours. Indivdual correction for tumour blood volume is mandatory.     

Tumour Oxygenation Assessed by Polarographic Needle Electrodes and Bioenergetic Status Measured by 31P Magnetic Resonance Spectroscopy in Human Soft Tissue Tumours

The purpose of this study was to evaluate the feasibility of polarographic oxygen electrode measurements and phosphorus magnetic resonance spectroscopy (³¹P-MRS) in extravisceral soft tissue tumours, designated to receive preoperative radiotherapy. Pretreatment tumour oxygenation was determined in 41 cases and ³¹P-MRS was amenable to lesions in 34 patients. Biopsies were characterized histopathologically as 25 primary soft tissue sarcomas (STS), 2 recurrent STS, 9 benign and 5 other malignancies. Evaluation of phosphorus (³¹P) spectra was possible in 11 cases. The oxygenation status of normal tissue was higher than that of tumours, whereas no difference was found between oxygenation status of benign lesions and that of STS. There was substantial variation between tumours in the median pO₂ and the bioenergetic status (β-NTP/Pi). No correlation was found between tumour pO₂ and volume (n = 25). Moreover, there was no correlation between β-NTP/Pi and the median tumour pO₂, the fraction of pO₂ values $2.5 mmHg or tumour volume (n = 10), respectively. In conclusion, oxygen electrode assessment was found to be a clinically applicable and feasible technique for measuring tumour oxygenation status, whereas the success of ³¹P-MRS in human neoplasms was limited by a very poor resolution in the phosphorus signal that allowed analysis of ³¹P spectra in 11 tumours out of 34 cases.