E. K. J. Pauwels

Positron-emission tomography with [18F]fluorodeoxyglucose. Part I. Biochemical uptake mechanism and its implication for clinical studies.

Abstract Over the past decades, Positron Emission Tomography has opened a new field of imaging. Nowadays, this technique is being used for diagnosing, staging disease as well as for prognostic stratification and monitoring therapy. In this respect, [18F]fluorodeoxyglucose (FdGlc) is by far the most commonly used PET agent. Many factors have been identified being responsible for a high uptake of this agent in malignancy. However, additional factors such as tumour treatment may interfere with the uptake mechanism. Knowledge of all these factors is a prerequisite for an optimal interpretation of PET studies and, consequently, for a reliable judgement of tumour status. In this article, a review is given of the factors influencing FdGlc uptake and the implications for clinical studies.

Antibacterial Activity of Human Neutrophil Defensins in Experimental Infections in Mice Is Accompanied by Increased Leukocyte Accumulation

Neutrophil defensins (or human neutrophil peptides-HNP) are major constituents of the azurophilic granules of human neutrophils and have been shown to display broad-spectrum antimicrobial activity. Other activities of these defensins, which are released from stimulated neutrophils, include cytotoxic, stimulatory, and chemotactic activities toward a variety of target cells. We studied the potential use of HNP-1 for antibacterial therapy of experimental bacterial infections in mice. In experimental peritoneal Klebsiella pneumoniae infections in mice, HNP-1 injection was shown to markedly reduce bacterial numbers in the infected peritoneal cavity 24 h after infection. This antibacterial effect was found to be associated with an increased influx of macrophages, granulocytes, and lymphocytes into the peritoneal cavity. These leukocytes appeared to be a requirement for the antibacterial effect, since in leukocytopenic mice administration of HNP-1 did not display antibacterial activity. HNP-1 treatment also reduced bacterial numbers in experimental K. pneumoniae or Staphylococcus aureus thigh muscle infections. In this model, radiolabeled HNP-1 was found to accumulate at the site of infection, whereas most of the injected HNP-1 was rapidly removed from the circulation via renal excretion. These results demonstrate that neutrophil defensins display marked in vivo antibacterial activity in experimental infections in mice and that this activity appears to be mediated, at least in part, by local leukocyte accumulation.

Positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose in oncology. Part II. The clinical value in detecting and staging primary tumours.

Abstract The tumoral uptake of 2-[18F]fluoro-2-deoxy-D-glucose (18FdGlc) is based upon enhanced glycolysis. Positron-emission tomography (PET) using 18FdGlc provides the physiological and metabolic information. 18FdGlc PET has been used successfully for assessing primary tumours and metastases, prognosis, and planning and for monitoring tumour therapy as well as for early detection of recurrent tumour growth. This review summarises the uptake mechanism of 18FdGlc in benign and malignant lesions, its relation to histolopathology, and its clinical value for detecting and staging primary tumours.

The mechanism of accumulation of tumour-localising radiopharmaceuticals.

It has been the aim of almost every nuclear medicine physician to develop and use the so-called magic bullet. This would be the radiopharmaceutical of choice in tumour imaging owing to its ability to concentrate only in malignant tumours with a high degree of uptake. This ideal tumour-localising radiopharmaceutical would be valuable not only for diagnosis of tumours, but also for therapy since the labelled radionuclide could be changed to deliver beta or gamma radiation to ablate the malignant tumour. Over the course of the years many attempts have been made to discover the magic bullet: virtually every available radionuclide has been incorporated into different radiopharmaceuticals and injected into animals or humans to discover its tumour-localising abilities. Nearly all of them have had some degree of success since almost any radiopharmaceutical is turned over more slowly in the extracellular space of a tumour than in normal tissues. However, most tumour-localisation agents have shown poor uptake; this has resulted in very limited use in the clinic, reflecting their lack of clinical value in differential diagnosis or in determining the effectiveness of the various therapies. In only a few cases has there been a specific attempt at producing a designer molecule which might have a higher chance of success than the usual “try it and see” approach. It is therefore of value to review what is known about the mechanisms behind the uptake of the currently available radiopharmaceuticals used for tumour imaging. In the following, we shall first deal with the general characteristics of tumour cells, which provide a basis for elucidating the uptake mechanisms of tumour-localising radiopharmaceuticals. Thereafter, the radiopharmaceuticals currently used for tumour localisation are reviewed, concentrating on their mechanisms of uptake into tumour cells. An attempt is made to classify the various tumour-localising radiopharmaceuticals into groups with common methods of uptake. Finally, suggestions are made on how to improve our approach to the development of tumour-localising radiopharmaceuticals.

Positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose in oncology

Abstract Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) is considered to be a very useful adjunct to anatomic imaging techniques and is now primarily used for oncological indications. These indications include diagnosis, staging, and therapy monitoring. In this review, we discuss the articles in which FDG-PET is clinically used for monitoring therapy in breast cancer, lymphomas and gliomas. It is found that the amount of FDG uptake strongly correlates with response to therapy in breast cancer, lymphomas, and gliomas; a decrease in FDG uptake after therapy indicates a positive response to therapy. However, this conclusion is based on small patient numbers, whereas the exact response mechanism is still unknown. Therefore, more studies in comparable patient groups are required to achieve a better understanding of FDG uptake patterns after therapy. Part IIIb deals with lung, and head and neck cancer, hepatocellular and colorectal tumours, and sarcoma.

Dysphagia in Ambulant Patients with Parkinson's Disease: common, not dangerous

To assess the frequency of subjective and objective dysphagia and its possible pulmonary sequelae, we prospectively studied 22 out-patients with Parkinsons disease; 15 spouses served as controls. All subjects answered a standard questionnaire concerning swallowing and respiratory functions and underwent barium swallow videofluoroscopy. Possible pulmonary infection was investigated by recordings of body temperature, ESR, leucocyte count, and chest X-ray. Patients had significantly more symptoms than controls, especially choking, piece-meal deglutition and regurgitation. Videofluoroscopy revealed tracheal aspiration in one patient, vestibular aspiration in one patient and in one control. Non-fluent swallowing movements were common in patients: abnormal bolus formation, delayed swallowing reflex, vallecular stasis, and piriform sinus residue. None of the subjects had signs of pulmonary infection. Both subjective and objective oro-pharyngeal dysfunction is frequent in ambulant Parkinson patients, but apparently does not produce demonstrable pulmonary infection.

MRI screening of kindred at risk of developing paragangliomas: support for genomic imprinting in hereditary glomus tumours.

Paragangliomas of the head and neck (glomus tumours) can occur in a hereditary pattern and may be hormonally active as well as being associated with paragangliomas elsewhere. A number of these tumours may be present without symptoms. To detect the presence of subclinical paragangliomas we screened 83 members of a family at risk of developing hereditary paragangliomas using whole body MRI and urinary catecholamine testing. In eight previously diagnosed members, eight known glomus tumours of which one functioning, and two unknown glomus tumours and one unknown pheochromocytoma were present. Six unsuspected members showed ten glomus tumours and one pheochromocytoma. It has been suggested that the manifestation of hereditary glomus tumours is determined by the sex of the transmitting parent. There were no tumours in the descendants of female gene carriers. Comparing the likelihood of inheritance with genomic imprinting versus inheritance without genomic imprinting we found an odds ratio of 23375 in favour of genomic imprinting.

Applications of 99mTC-Sestamibi in Oncology

Hexakis (2-methoxyisobutylisonitrile) technetium-99m (99mTc-SestaMIBI) is a radiopharmaceutical used in nuclear medicine for myocardial perfusion imaging. In the literature different non-cardiac applications of 99mTc-SestaMIBI have been reported. Clinical studies have been performed also in non-oncologic diseases (such as thyroid adenoma, diabetic foot, osteomyelitis, pulmonary actinomycosis, aneurysmal bone cyst, Sudecks atrophy). Several models for the uptake mechanism of this radiopharmaceutical have been proposed such as binding to an 8-10 kDa cytosolic protein, simple lipid partitioning, or a membrane translocation mechanism involving diffusion and passive transmembrane distribution. Most evidence points in the direction of the third hypothesis. Many studies have indicated that uptake of hexakis (alkylisonitrile) technetium complexes is dependent on mitochondrial and plasma membrane potentials like other lipophilic cations. This explains the initial biodistribution of 99mTc-SestaMIBI to tissues with negative plasma membrane potentials and with a relatively high mitochondrial content (like heart, liver, kidney and skeletal muscle tissue). Malignant tumours also possess these properties in order to maintain their increased metabolism. This behaviour encouraged the study of 99mTc-SestaMIBI as an interesting tracer imaging various tumour types: osteosarcoma, brain, lung, breast, nasopharyngeal, parathyroid, and thyroid cancer. Recent research on cell cellular physiology has further revealed an active transport of 99mTc-SestaMIBI out of the tumour cells, against the potential gradient. The same mechanism is also responsible for resistance to a structurally and functionally different group of cytotoxic agents, such as vinca alkaloids, epipodophyllotoxins, anthracyclins and actinomycin D. This peculiar type of resistance is due to amplification of the mammalian MDR1 gene, located on chromosome 7. For this reason the 99mTc- SestaMIBI uptake in vivo could permit the prediction of the response to the chemotherapy, when the decreased accumulation of 99mTc-SestaMlBI implies the presence of P-gp enriched tissues. In the next future a particular attention should be dedicated to this matter since one of the most important goals of the clinical trials is the demonstration of the usefulness of 99mTc-SestaMIBI for in vivo assessment of multidrug resistance.

99Tcm-labelled polyclonal human immunoglobulin G scintigraphy before and after intra-articular knee injection of triamcinolone hexacetonide in patients with rheumatoid arthritis.

The ability of 99Tcm-labelled polyclonal human immunoglobulin G (99Tcm-IgG) scintigraphy to monitor intra-individual variation in arthritis activity was studied in seven patients with rheumatoid arthritis (RA). These patients were treated with an intra-articular injection of 20 mg triamcinolone hexacetonide. The results of semiquantitative 99Tcm-IgG scintigraphy were compared with the degree of joint swelling and the histological changes observed in synovial biopsies before and 14 days after the injection. In all seven patients the local treatment resulted in a decreased arthritis activity of the treated knee as measured clinically or histologically. This decrease was parallelled, in all patients except one, by a lower uptake of 99Tcm-IgG after the injection when compared to uptake prior to treatment. This study shows that 99Tcm-IgG scintigraphy is able to reflect intra-individual variations in arthritis activity in patients with RA.

Quantitative scintigraphic parameters for the assessment of renal transplant patients

Radionuclide renal diagnostic studies play an important role in assessing renal allograft function especially in the early post transplant period. In the last two decades various quantitative parameters have been derived from the radionuclide renogram to facilitate and confirm the changes in perfusion and/or function of the kidney allograft. In this review article we discuss the quantitative parameters that have been used to assess graft condition with emphasis on the early post-operative period. These quantitative methods were divided into parameters used for assessing renal graft perfusion and parameters used for evaluating parenchymal function. The blood flow in renal transplants can be quantified by measuring (a) the rate of activity appearance in the kidney graft; (b) the ratio of the integral activity under the transplanted kidney and arterial curves e.g. Hilsons perfusion index and Kirchers kidney/aortic ratio; (c) calculating the renal vascular transit time by deconvolution analysis. The literature overview on these parameters showed us that they have some practical disadvantages of requiring high quality bolus injection and numerical variations related to changes in the site and size of regions of interest. In addition, the perfusion parameter values suffer from significant overlap when various graft pathologies coexist. Quantitative evaluation of the graft parenchymal extraction and excretion was assessed by parameters derived from 123I/131I-OIH, 99mTc-DTPA or 99mTc-MAG3 renograms. We review in this article a number of parenchymal parameters which include (1) plasma clearance methods like glomerular filtration rate (GFR) and effective renal plasma flow (ERPF); (2) renal transit times such as parenchymal mean transit time, Tmax, T1/2; (3) parenchymal uptake and excretion indices as the accumulation index, graft uptake capacity at 2 and 10 min, excretion index and elimination index. These indices, however, are non-specific and far from defining a specific cause for graft parenchymal dysfunction. In conclusion, despite that the literature is replete with mathematical strategies for quantitating perfusion and parenchymal functions, none of these have enough diagnostic power for specific diagnosis of graft dysfunction. In addition, no universal agreement on the use of certain quantitation parameters in transplant patients has been reached.