Christophe Van de Wiele

Apoptosis-detecting radioligands: current state of the art and future perspectives

This review provides a critical and thorough overview of the radiopharmaceutical development and in vivo evaluation of all apoptosis-detecting radioligands that have emerged so far, along with their possible applications in nuclear medicine. The following SPECT and PET radioligands are discussed: all forms of halogenated Annexin V (i.e. 123I-labelled, 124I-labelled, 125I-labelled, 18F-labelled), 99mTc/94mTc-labelled Annexin V derivatives using different chelators and co-ligands (i.e. BTAP, Hynic, iminothiolane, MAG3, EDDA, EC, tricarbonyl, SDH) or direct 99mTc-labelling, 99mTc-labelled Annexin V mutants and 99mTc/18F-radiopeptide constructs (i.e. AFIM molecules), 111In-DTPA-PEG-Annexin V, 11C-Annexin V and 64Cu-, 67Ga- and 68Ga-DOTA-Annexin V. In addition, the potential role and clinical relevance of anti-PS monoclonal antibodies and other alternative apoptosis markers are reviewed, including: anti-Annexin V monoclonal antibodies, radiolabelled caspase inhibitors and substrates and mitochondrial membrane permeability targeting radioligands. Nevertheless, major emphasis is placed on the group of Annexin V-based radioligands, in particular 99mTc-Hynic-Annexin V, since this molecule is by far the most extensively investigated and best-characterised apoptosis marker at present. Furthermore, the newly emerging imaging modalities for in vivo detection of programmed cell death, such as MRI, MRS, optical, bioluminescent and ultrasound imaging, are briefly described. Finally, some future perspectives are presented with the aim of promoting the development of potential new strategies in pursuit of the ideal cell death-detecting radioligand.

Molecular imaging of hypoxia with radiolabelled agents

Tissue hypoxia results from an inadequate supply of oxygen (O2) that compromises biological functions. Structural and functional abnormalities of the tumour vasculature together with altered diffusion conditions inside the tumour seem to be the main causes of tumour hypoxia. Evidence from experimental and clinical studies points to a role for tumour hypoxia in tumour propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and non-invasive approaches have been developed to measure tumour oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), autoradiography and immunohistochemistry. This review aims to give a detailed overview of non-invasive molecular imaging modalities with radiolabelled PET and SPECT tracers that are available to measure tumour hypoxia.

Quantitative Tumor Apoptosis Imaging Using Technetium-99m–HYNIC Annexin V Single Photon Emission Computed Tomography

PURPOSE Radiolabeled annexin V may allow for repetitive and selective in vivo identification of apoptotic cell death without the need for invasive biopsy. This study reports on the relationship between quantitative technetium-99m- (99mTc-) 6-hydrazinonicotinic (HYNIC) radiolabeled annexin V tumor uptake, and the number of tumor apoptotic cells derived from histologic analysis. PATIENTS AND METHODS Twenty patients (18 men, two women) suspected of primary (n = 19) or recurrent (n = 1) head and neck carcinoma were included. All patients underwent a spiral computed tomography (CT) scan, 99mTc-HYNIC annexin V tomography, and subsequent surgical resection of the suspected primary or recurrent tumor. Quantitative 99mTc-HYNIC annexin V uptake in tumor lesions divided by the tumor volume, derived from CT, was related to the number of apoptotic cells per tumor high-power field derived from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assays performed on sectioned tumor slices. RESULTS Diagnosis was primary head and neck tumor in 18 patients, lymph node involvement of a cancer of unknown primary origin in one patient, and the absence of recurrence in one patient. Mean percentage absolute tumor uptake of the injected dose per cubic centimeter tumor volume derived from tomographic images was 0.0003% (standard deviation [SD], 0.0004%) at 1 hour postinjection (PI) and 0.0001% (SD, 0.0000%) at 5 to 6 hours PI (P =.012). Quantitative 99mTc-HYNIC annexin V tumor uptake correlated well with the number of apoptotic cells if only tumor samples with no or minimal amounts of necrosis were considered. CONCLUSION In the absence of necrosis, absolute 99mTc-HYNIC annexin V tumor uptake values correlate well with the number of apoptotic cells derived from TUNEL assays.

Predictive and prognostic value of metabolic tumour volume and total lesion glycolysis in solid tumours

Data available in patients suffering from squamous cell carcinoma of the head and neck, lung carcinoma, oesophageal carcinoma and gynaecological malignancies suggest that metabolic tumour volume and to a lesser extent total lesion glycolysis have the potential to become valuable in the imaging of human solid tumours as prognostic biomarkers for short- to intermediate-term survival outcomes, adding value to clinical staging, for assessment of response to treatment with neoadjuvant and concurrent chemotherapy, and for treatment optimization; for example, based on early treatment response assessment using changes in metabolic tumour volume over time, it might be possible to select patients who require a more aggressive treatment to improve their outcome. Prospective studies enrolling consecutive patients, adopting standardized protocols for FDG PET acquisition and processing, adjusting for potential confounders in the analysis (tumour size and origin) and determining the optimal methodology for determination of these novel markers are mandatory.

Maximum tolerated dose in a phase I trial on adaptive dose painting by numbers for head and neck cancer

PURPOSE To determine the maximum tolerated dose (MTD) in a phase I trial on adaptive dose-painting-by-numbers (DPBN) for non-metastatic head and neck cancer. MATERIALS AND METHODS Adaptive intensity-modulated radiotherapy was based on voxel intensity of pre-treatment and per-treatment [(18)F]fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) scans. Dose was escalated to a median total dose of 80.9 Gy in the high-dose clinical target volume (dose level I) and 85.9 Gy in the gross tumor volume (dose level II). The MTD would be reached, if ≥ 33% of patients developed any grade ≥ 4 toxicity (DLT) up to 3 months follow-up. RESULTS Between February 2007 and August 2009, seven patients at dose level I and 14 at dose level II were treated. All patients completed treatment without interruption. At a median follow-up for surviving patients of 38 (dose level I) and 22 months (dose level II) there was no grade ≥ 4 toxicity during treatment and follow-up but six cases of mucosal ulcers at latency of 4-10 months, of which five (36%) were observed at dose level II. Mucosal ulcers healed spontaneously in four patients. CONCLUSIONS Considering late mucosal ulcers as DLT, the MTD of a median dose of 80.9 Gy has been reached in our trial.

Receptor Imaging in Oncology by Means of Nuclear Medicine: Current Status

To date, our understanding of the role of receptors and their cognate ligands in cancer is being successfully translated into the design and development of an arsenal of new, less toxic, and more specific anticancer drugs. Because most of these novel drugs are cytostatic, objective response as measured by morphologic imaging modalities (eg, computed tomography or magnetic resonance imaging) cannot be used as a surrogate marker for drug development or for clinical decision making. Positron emission tomography (PET) can be used to image and quantify the in vivo distribution of positron-emitting radioisotopes such as oxygen-15, carbon-11, and fluorine-18 that can be substituted or added into biologically relevant and specific receptor radioligands. Similarly, single-photon emission computed tomography (SPECT) can be used to image and quantify the in vivo distribution of receptor targeting compounds labeled with indium-111, technetium-99m, and iodine-123. By virtue of their whole-body imaging capacity and the absence of errors of sampling and tissue manipulation as well as preparation, both techniques have the potential to address locoregional receptor status noninvasively and repetitively. This article reviews available data on the in vivo evaluation of receptor systems by means of PET or SPECT for identifying and monitoring patients with sufficient receptor overexpression for tailored therapeutic interventions, and also for depicting tumor tissue and determining the currently largely unknown heterogeneity in receptor expression among different tumor lesions within and between patients.

Nuclear medicine imaging to predict response to radiotherapy: a review

PURPOSE To review available literature on positron emission tomography (PET) and single photon emission computerized tomography (SPECT) for the measurement of tumor metabolism, hypoxia, growth factor receptor expression, and apoptosis as predictors of response to radiotherapy. METHODS AND MATERIALS Medical literature databases (Pubmed, Medline) were screened for available literature and critically analyzed as to their scientific relevance. RESULTS Studies on 18F-fluorodeoxyglucose PET as a predictor of response to radiotherapy in head-and-neck carcinoma are promising but need confirmation in larger series. 18F-fluorothymine is stable in human plasma, and preliminary clinical data obtained with this marker of tumor cell proliferation are promising. For imaging tumor hypoxia, novel, more widely available radiopharmaceuticals with faster pharmacokinetics are mandatory. Imaging of ongoing apoptosis and growth factor expression is at a very early stage, but results obtained in other domains with radiolabeled peptides appear promising. Finally, for most of the tracers discussed, validation against a gold standard is needed. CONCLUSION Optimization of the pharmacokinetics of relevant radiopharmaceuticals as well as validation against gold-standard tests in large patient series are mandatory if PET and SPECT are to be implemented in routine clinical practice for the purpose of predicting response to radiotherapy.

18-Fluorine fluorodeoxyglucose positron emission tomography for the diagnosis of infection in the postoperative spine.

Background. Using conventional imaging methods, including magnetic resonance imaging and labeled leukocyte scanning, the diagnosis of infection in the postoperative spine remains a diagnostic challenge. Recently, promising results have been reported using 18F-fluorodeoxyglucose positron emission tomography for various infectious problems. This study aimed to investigate the value of 18F-fluorodeoxyglucose positron emission tomography in patients suspected of having spinal infection after previous surgery of the spine. Methods. Fifty-seven consecutive patients with a history of previous spinal surgery were prospectively included between February 1999 and June 2001. 18F-fluorodeoxyglucose positron emission tomography was performed 60 to 90 minutes after injection of 370 MBq 18F-fluorodeoxyglucose. Images were scored visually and semiquantitatively by two blinded, independent, certified nuclear medicine physicians, experienced with positron emission tomography. Differences were assessed by consensus. Results were correlated with final diagnosis allowing calculation of sensitivity, specificity and accuracy. Receiver operating characteristic analysis was performed to find optimal cut-off values. Results. Fifteen patients had spinal infection. Using the most sensitive cut-off values sensitivity, specificity and accuracy were 100%, 81%, and 86%, respectively, for both visual and semiquantitative scoring. In the group without metallic implants (n = 27), false positives (n = 2) only occurred in the first 6 months after surgery. In the group with metallic implants (n = 30), false positives (n = 6) were not confined to recently operated patients. Conclusions. Overall accuracy was excellent (86%) with a negative predictive value of 100%. 18F-fluorodeoxyglucose positron emission tomography holds promise to become the standard imaging technique in this difficult patient population, as it is straightforward, provides a rapid result (2 hours) and because accurate alternatives are lacking.

Dual time-point FDG PET-CT for differentiating benign from malignant solitary pulmonary nodules in a TB endemic area

OBJECTIVE Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an accurate non-invasive imaging test for differentiating benign from malignant solitary pulmonary nodules (SPNs). We aimed to assess its diagnostic accuracy for differentiating benign from malignant SPNs in a tuberculosis (TB)-endemic area. METHODS Thirty patients, 22 men and 8 women, mean age 60 years, underwent dual time point FDG-PET/computed tomography (CT) imaging, followed by histological examination of the SPN. Maximum standard uptake values (SUVmax) with the greatest uptake in the lesion were calculated for two time points (SUV1 and SUV2), and the percentage change over time per lesion was calculated (%DSUV). Routine histological findings served as the gold standard. RESULTS Histological examination showed that 14 lesions were malignant and 16 benign, 12 of which were TB. SUVmax for benign and malignant lesions were 11.02 (standard deviation (SD) 6.6) v. 10.86 (SD 8.9); however, when tuberculomas were excluded from the analysis, a significant difference in mean SUV1max values between benign and malignant lesions was observed (p=0.0059). Using an SUVmax cut-off value of 2.5, a sensitivity of 85.7% and a specificity of 25% was obtained. Omitting the TB patients from analysis resulted in a sensitivity of 85.7% and a specificity of 100%. Mean %DSUV of benign lesions did not differ significantly from mean %DSUV of malignant lesions (17.1% (SD 16.3%) v. 19.4% (SD 23.7%)). Using a cut-off of %DSUV>10% as indicative of malignancy, a sensitivity of 85.7% and a specificity of 50% was obtained. Omitting the TB patients from the analysis yielded a sensitivity of 85.7% and a specificity of 75%. CONCLUSION Our findings suggest that FDG-PET cannot distinguish malignancy from tuberculoma and therefore cannot reliably be used to reduce futile biopsy/thoracotomy.

FDG uptake, a surrogate of tumour hypoxia?

IntroductionTumour hyperglycolysis is driven by activation of hypoxia-inducible factor-1 (HIF-1) through tumour hypoxia. Accordingly, the degree of 2-fluro-2-deoxy-d-glucose (FDG) uptake by tumours might indirectly reflect the level of hypoxia, obviating the need for more specific radiopharmaceuticals for hypoxia imaging.DiscussionIn this paper, available data on the relationship between hypoxia and FDG uptake by tumour tissue in vitro and in vivo are reviewed. In pre-clinical in vitro studies, acute hypoxia was consistently shown to increase FDG uptake by normal and tumour cells within a couple of hours after onset with mobilisation or modification of glucose transporters optimising glucose uptake, followed by a delayed response with increased rates of transcription of GLUT mRNA. In pre-clinical imaging studies on chronic hypoxia that compared FDG uptake by tumours grown in rat or mice to uptake by FMISO, the pattern of normoxic and hypoxic regions within the human tumour xenografts, as imaged by FMISO, largely correlated with glucose metabolism although minor locoregional differences could not be excluded. In the clinical setting, data are limited and discordant.ConclusionFurther evaluation of FDG uptake by various tumour types in relation to intrinsic and bioreductive markers of hypoxia and response to radiotherapy or hypoxia-dependent drugs is needed to fully assess its application as a marker of hypoxia in the clinical setting.