Frans H.M. Corstens

Reflex sympathetic dystrophy of the hand : an excessive inflammatory response?

&NA; In 23 patients with reflex sympathetic dystrophy (RSD) of the hand, scintigraphy with indium‐111 labeled human non‐specific polyclonal immunoglobulin G (In‐111‐IgG) was performed to investigate whether inflammatory characteristics are present in RSD. Both blood flow and accumulation over 48 h were assessed. Nineteen patients had increased flow to the affected hand, and 3 had decreased flow. One patient had bilateral RSD. Exercise provoked aggravation of complaints and signs in all patients. The affected/non‐affected hand ratio (target‐to‐background, T/B) immediately before and after exercise did not change significantly. The T/B ratios 48 h after In‐111‐IgG injection were significantly higher in patients with RSD less than 5 months than in patients with RSD existing 5 months or longer. The T/B ratios 24 and 48 h after In‐111‐IgG injection were not correlated with the flow T/B ratios. In fact, 2 of the 3 patients with a decreased flow showed excess accumulation on the late images. Significantly more patients with early RSD, existing less than 5 months, had a positive In‐111‐IgG scintigraphy (14 of 17) than the patients with late RSD (1 of 6). Increased vascular permeability for macromolecules, an important characteristic of inflammation, appears to play a role in the development of RSD. This phenomenon is not flow‐dependent.

Clinical value of FDG PET in patients with fever of unknown origin and patients suspected of focal infection or inflammation

Fever of unknown origin (FUO) and suspected focal infection or inflammation are challenging medical problems. The aim of this study was to assess the value of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) in patients with FUO and patients with suspected focal infection or inflammation. All FDG PET scans ordered because of FUO or suspected focal infection or inflammation in the last 4 years were reviewed. These results were compared with the final diagnosis. Thirty-five FDG PET scans were performed in 35 patients with FUO. A final diagnosis was established in 19 patients (54%). Of the total number of scans, 37% were clinically helpful. The positive predictive value of FDG PET in these patients was 87% and the negative predictive value was 95%. Fifty-five FDG PET scans were performed in 48 patients with suspected focal infection or inflammation. A final diagnosis was established in 38 patients (82%). Of the total number of scans, 65% were clinically helpful. The positive predictive value of FDG PET in these 55 episodes of suspected infection or inflammation was 95% and the negative predictive value was 100%. It is concluded that FDG PET appears to be a valuable imaging technique in the evaluation of FUO and suspected focal infection or inflammation. Furthermore, FDG PET could become a useful tool for evaluating the effect of treatment of infectious and inflammatory processes that cannot reliably be visualised by conventional techniques. However, to assess the additional diagnostic value of this technique, prospective studies of FDG PET as part of a structured diagnostic protocol are warranted.

Fluorinated amino acids for tumour imaging with positron emission tomography

Abstract. The currently preferred radiopharmaceutical for positron emission tomography (PET) in oncology is 2-[18F]fluoro-deoxyglucose (FDG). Increased accumulation of this deoxyglucose analogue in tumour cells is based on elevated glucose metabolism by tumour cells and subsequent trapping in the cells. In the search for new PET tracers, amino acids have been widely studied. A new amino acid tracer should preferably have similar high uptake in tumour cells but low non-specific uptake in normal tissues and any pathology other than tumour. In recent years, several amino acids have been labelled with either gamma radiation-emitting radionuclides or positron-emitting radionuclides, the most commonly used being carbon-11. However, the longer half-life of fluorine-18 matches better with the relatively slow process of protein synthesis and also facilitates shipping of the radiolabelled amino acids to hospitals without an on-site cyclotron or dedicated radiochemistry laboratory. The number of fluorinated amino acids under investigation is increasing, and one of the major points of discussion is the underlying mechanism of the tumour visualisation. While it has been shown that some amino acids can be used to measure the protein synthesis rate, others are used with the sole aim of measuring the rate of uptake into the cell. The differences between measuring amino acid transport (rate) and protein synthesis rate with 18F-labelled amino acids are discussed.

A prospective multi-centre study of the value of FDG-PET as part of a structured diagnostic protocol in patients with fever of unknown origin.

PurposeSince 18F-fluorodeoxyglucose (FDG) accumulates in neoplastic cells and in activated inflammatory cells, positron emission tomography (PET) with FDG could be valuable in diagnosing patients with fever of unknown origin (FUO). The aim of this study was to validate the use of FDG-PET as part of a structured diagnostic protocol in the general patient population with FUO.MethodsFrom December 2003 to July 2005, 70 patients with FUO were recruited from one university hospital (n=38) and five community hospitals (n=32). A structured diagnostic protocol including FDG-PET was used. A dedicated, full-ring PET scanner was used for data acquisition. FDG-PET scans were interpreted by two staff members of the department of nuclear medicine without further clinical information. The final clinical diagnosis was used for comparison with the FDG-PET results.ResultsOf all scans, 33% were clinically helpful. The contribution of FDG-PET to the final diagnosis did not differ significantly between patients diagnosed in the university hospital and patients diagnosed in the community hospitals. FDG-PET contributed significantly more often to the final diagnosis in patients with continuous fever than in patients with periodic fever. FDG-PET was not helpful in any of the patients with normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).ConclusionFDG-PET is a valuable imaging technique as part of a diagnostic protocol in the general patient population with FUO and a raised ESR or CRP.

Comparison of a monomeric and dimeric radiolabeled RGD-peptide for tumor targeting.

The alpha v beta 3 integrin, a transmembrane heterodimeric protein expressed on sprouting endothelial cells, binds to the arginine-glycine-aspartic acid (RGD) amino acid sequence of extracellular matrix proteins such as vitronectin. Growing malignant tumors continuously require angiogenesis. As a result, alpha v beta 3 is preferentially expressed in growing tumors and is a potential target for radiolabeled RGD-peptides. In this study we compared the tumor targeting characteristics of a monomeric radiolabeled RGD-peptide with those of a dimeric analogue. Both peptides were radiolabeled with 99mTc via the hydrazinoni-cotinamid (= HYNIC) moiety to form 99mTc-HYNIC-c(RGDfK) and 99mTc-HYNIC-E-[c(RGDfK)]2. In vitro, the IC50 showed a 10-fold higher affinity of the dimer for the alpha v beta 3 integrin as compared to the monomer (0.1 vs. 1.0 nM). In athymic female BALB/c mice with subcutaneously growing OVCAR-3 ovarian carcinoma xenografts, tumor uptake peaked at 5.8 +/- 0.7% ID/g and 5.2 +/- 0.6% ID/g for the dimer and the monomer, respectively. At 1, 2, and 4 h postinjection (p.i.) uptake of the dimer in the tumor was significantly higher than that of the monomeric analogue. Tumor-to-blood ratios were highest at 24 h p.i. at a value of 63 for both compounds. At all timepoints kidney retention of the dimer was significantly higher as compared to kidney retention of the monomer. In conclusion, in this mouse model the dimeric RGD-peptide showed better retention in the tumor than the monomeric analogue, most likely due to the bivalent interaction with the target cell. Furthermore, kidney retention of the dimeric peptide was higher than that of the monomeric peptide.

Nuclear medicine's role in infection and inflammation

Nuclear medicine imaging techniques can help in patient evaluation where infectious and non-infectious inflammatory disorders are suspected. When selected and tailored to the clinical situation, most techniques already in use or available soon provide information with high sensitivity. However, almost all currently available techniques lack the specificity to discriminate between infectious and non-infectious inflammation. In undiagnosed fever, this non-specificity may be an advantage since fever of unknown origin is caused by infection in only about 25% of cases, but in the postoperative patient the reliable differentiation between infection and sterile inflammation is highly relevant to clinical management. The range of radiopharmceuticals to investigate infectious and non-microbial inflammatory disorders is expanding and developments in protein/peptide chemistry and in labelling technology should lead to agents with very high specific activities. Nuclear medicine has to add specificity to its already high sensitivity if it is to distinguish both categories of inflammatory disorder.

Predictive and prognostic value of FDG-PET in nonsmall-cell lung cancer : A Systematic Review

For several years, molecular imaging with 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) has become part of the standard of care in presurgical staging of patients with nonsmall‐cell lung cancer (NSCLC), focusing on the detection of malignant lesions at early stages, early detection of recurrence, and metastatic spread. Currently, there is an increasing interest in the role of FDG‐PET beyond staging, such as the evaluation of biological characteristics of the tumor and prediction of prognosis in the context of treatment stratification and the early assessment of tumor response to therapy. In this systematic review, the literature on the value of the evolving applications of FDG‐PET as a marker for prediction (ie, therapy response monitoring) and prognosis in NSCLC is addressed, divided in sections on the predictive value of FDG‐PET in locally advanced and advanced disease, the prognostic value of FDG‐PET at diagnosis, after induction treatment, and in recurrent disease. Furthermore, the background and recommendations for the application of FDG‐PET for these indications will be discussed. Cancer 2007.

Treatment with Vitamin D and Calcium Reduces Bone Loss after Renal Transplantation: A Randomized Study

A decrease in bone mineral density (BMD) is a major complication of renal transplantation (RTx), predominantly occurring within the first 6 mo after RTx. The most important causative factor is the use of corticosteroids, but persisting hyperparathyroidism and abnormalities in vitamin D metabolism play a role too. This study examines the effect of treatment with calcium and active vitamin D on the loss of BMD in the first 6 mo after RTx. A total of 111 renal transplant recipients (65 men, 46 women; age, 47 +/- 13 yr) were randomized to either treatment with active vitamin D (0.25 microg/d) plus calcium (1000 mg/d) (CaD group), or to no treatment (NoT group). Immunosuppressive therapy consisted of cyclosporine, prednisone, and mycophenolate mofetil. Laboratory parameters and BMD (lumbar spine and hip) were measured at 0, 1 (laboratory only), 3, and 6 mo after RTx. Lumbar BMD was nearly normal at the time of RTx. In both groups, a significant decrease in lumbar BMD was observed during the first 3 mo (CaD, -3.3 +/- 4.3%; P < 0.0001; NoT, -4.1 +/- 4.8%; P < 0.0001). Between the third day and sixth month, lumbar BMD slightly recovered in the CaD group, but it decreased further in the NoT group (total loss 0 to 6 mo: CaD, -2.6 +/- 5.0% [P < 0.001]; NoT, -5.0 +/- 4.7% [P < 0.0001]). As a result, the amount of bone loss at 6 mo was significantly lower in the CaD group (P = 0.02). Loss of BMD at the different femoral sites was also significantly reduced in the CaD group. Apart from a trend toward more frequent hypercalcemia in the CaD group, no clinical or biochemical differences existed between the groups. Treatment with a low dose of active vitamin D and calcium partially prevents bone loss at the lumbar spine and proximal femur during the first 6 mo after RTx.

Chemotherapy Response Evaluation with 18F-FDG PET in Patients with Non-Small Cell Lung Cancer

The aim of this prospective study was to evaluate the value of 18F-FDG PET for the assessment of chemotherapy response in patients with non–small cell lung cancer. Furthermore, part of the objective of this study was to compare 2 methods to quantify changes in glucose metabolism. Methods: In 51 patients, dynamic 18F-FDG PET was performed before and at 5–8 wk into treatment. Simplified methods to measure glucose metabolism (standardized uptake value [SUV]) and quantitative measures (metabolic rate of glucose [MRGlu]), derived from Patlak analysis, were evaluated. The overall survival and progression-free survival with respect to MRGlu and SUV were calculated using Kaplan–Meier estimates. Fractional changes in tumor glucose use were stratified by the median value and also the predefined EORTC (European Organization for Research and Treatment of Cancer) metabolic response criteria, and criteria applying cutoff levels similar to those of RECIST (Response Evaluation Criteria in Solid Tumors) were evaluated. Results: When stratifying at the median value of ΔMRGlu and ΔSUV, the difference in overall survival (P = 0.017 for ΔMRGlu, P = 0.018 for ΔSUV) and progression-free survival (P = 0.002 for ΔMRGlu, P = 0.0009 for ΔSUV) was highly significant. When applying the predefined criteria for metabolic response, the cutoff levels as also used for size measurement (RECIST) showed significant differences for ΔSUV between response categories in progression-free survival (P = 0.0003) as well as overall survival (P = 0.027). Conclusion: The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by 18F-FDG PET is highly predictive for patient outcome, stratifying patients into groups with widely differing overall survival and progression-free survival probabilities. The use of 18F-FDG PET for therapy monitoring seems clinically feasible, because simplified methods to measure tumor glucose use (SUV) are sufficiently reliable and can replace more complex, quantitative measures (MRGlu) in this patient population.

Pretreatment with a Single, Low Dose of Recombinant Human Thyrotropin Allows Dose Reduction of Radioiodine Therapy in Patients with Nodular Goiter

In patients with nodular goiter, radioiodine ((131)I) therapy results in a mean reduction in thyroid volume (TV) of approximately 40% after 1 yr. We have demonstrated that pretreatment with a single, low dose of recombinant human TSH (rhTSH) doubles 24-h radioactive iodine uptake (RAIU) in these patients. We have now studied the safety and efficacy of therapy with a reduced dose of (131)I after pretreatment with rhTSH. Twenty-two patients with nodular goiter received (131)I therapy, 24 h after im administration of 0.01 (n = 12) or 0.03 (n = 10) mg rhTSH. In preceding diagnostic studies using tracer doses of (131)I, 24-h RAIU without and with rhTSH pretreatment (either 0.01 or 0.03 mg) were compared. Therapeutic doses of (131)I were adjusted to the rhTSH-induced increases in 24-h RAIU and were aimed at 100 micro Ci/g thyroid tissue retained at 24 h. Pretreatment with rhTSH allowed dose reduction of (131)I therapy by a factor of 1.9 +/- 0.5 in the 0.01-mg and by a factor of 2.4 +/- 0.4 in the 0.03-mg rhTSH group (P < 0.05, 0.01 vs. 0.03 mg rhTSH). Before and 1 yr after therapy, TV and the smallest cross-sectional area of the tracheal lumen were measured with magnetic resonance imaging. During the year of follow-up, serum TSH, free T(4) (FT(4)), T(3), and TSH receptor antibodies were measured at regular intervals. TV before therapy was 143 +/- 54 ml in the 0.01-mg group and 103 +/- 44 ml in the 0.03-mg rhTSH group. One year after treatment, TV reduction was 35 +/- 14% (0.01 mg rhTSH) and 41 +/- 12% (0.03 mg rhTSH). In both groups, smallest cross-sectional area of the tracheal lumen increased significantly. In the 0.01-mg rhTSH group, serum FT(4) rose, after (131)I treatment, from 15.8 +/- 2.8 to 23.2 +/- 4.4 pM. In the 0.03-mg rhTSH group, serum FT(4) rose from 15.5 +/- 2.5 to 23.5 +/- 5.1 pM. Individual peak FT(4) levels, reached between 1 and 28 d after (131)I treatment, were above the normal range in 12 patients. TSH receptor antibodies were negative in all patients before therapy and became positive in 4 patients. Hyperthyroidism developed in 3 of these 4 patients between 23 and 25 wk after therapy. In conclusion, in patients with nodular goiter pretreatment with a single, low dose of rhTSH allowed approximately 50-60% reduction of the therapeutic dose of radioiodine without compromising the efficacy of TV reduction.