Comparative pharmacoscintigraphic and pharmacokinetic evaluation of two new formulations of inhaled insulin in type 1 diabetic patients.

In this open, single-dose study, we compared the lung deposition and bioavailability of two newly developed insulin formulations for pulmonary delivery. Twelve type 1 diabetic patients were administered the two insulin products (2 U/kg b.w.), which had been radiolabelled with (99m)Tc. The formulations were either microparticles of insulin without excipients (F1) or lipid-coated insulin microparticles (F2). Lung deposition was assessed by γ-scintigraphy imaging performed immediately after administration. Bioavailability was evaluated by quantifying serum insulin levels over a period of 6 h. Lung deposition was found to be 50 ± 9% and 24 ± 8% for the F1 and F2 formulations, respectively. The insulin AUC0₋360 ratio of F1/F2 was 188%, which was consistent with scintigraphic imaging. The concordance between imaging and biological results suggests that the lower bioavailability of F2 is due to its lower lung deposition and not to a reduced absorption into the blood stream. Additional in vitro experiments indicated that the lower performance of F2 was most probably related to a lower disaggregation efficiency of the powder when administered at a sub-optimal flow rate. The two formulations showed interesting pharmacokinetic profiles (T(max) of 26 and 16 min for F1 and F2, respectively) that mimic the physiological insulin secretion pattern. The bioavailability of the developed formulations was within the range of other DPI insulin formulations that have reached the final stages of clinical development.

Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa.

In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy. It was shown that the three formulations offered almost the same mean gastric residence time, which was about 240 min. Prolopa HBS 125 and Levo-Form 2 presented intragastric disintegration, which can lead to a more pronounced "peak & valley" effect on the plasma concentration-time profile of levodopa. In contrast, the plasma concentration-time profile of levodopa following the administration of Levo-Form 1 was more evenly distributed. Moreover, Levo-Form 1 provided the lowest variations between men and women in terms of AUC and C(max) values. Finally, when the same amount of inhibitors of extracerebral dopa decarboxylase--carbidopa and benserazide--had been administrated, the mean AUC, C(max) and T(max) values obtained for benserazide were lower than those obtained for carbidopa.

Skin biopsies in DC vaccines for stage III-IV melanoma patients: role of neutrophils?

Dendritic cell (DC) vaccines are used for the induction of anti-tumor T cell reaction in melanoma patients. DC are generated in vitro, pulsed with antigen and matured prior to injection. They are supposed to migrate to lymph nodes and to present the processed antigen to naive T cells allowing activation of tumor-specific lymphocytes. It has been suggested that intradermal injection allows a superior migration to the lymph node. Eight HLA-A2 positive patients with stage III or IV melanomas expressing NA 17 antigen were collected. They were included in a pilot trial of vaccination in which they received IL3/INFb DC presenting the NA17 A2 antigen. In each patient, a skin biopsy was performed at the injection site, 24 h after inoculation. The striking features of the biopsies were the presence of a perivascular CD3+/CD8+ T cell infiltrate with a slight population of CD4+ cells and the presence of a massive neutrophilic infiltrate associated with the injected DC still present, realizing a suppurative granuloma. The persistence of DC 24 h after the injection suggests that migration in the lymph node is not necessary for the induction of the immune response. The skin itself could be the location of a reaction starting with a massive recruitment of neutrophils.

Positive octreotide scintigraphy and determination of lanreotide activity in Paget's disease of bone associated with phosphate diabetes: a case report.

A patient with Paget's disease developed phosphate diabetes (phosphate: 1.6 mg/dl (2.5-4.4 mg/dl), with 29 ml/min phosphate clearance (Nl<15ml/min) and a 65% phosphate reabsorption rate (Nl>85%). As previously demonstrated in tumor-induced osteomalacia, we hypothesized that osteoblasts might manifest somatostatin receptor activity. The patient underwent an octreotide scan which demonstrated increased uptake localized in affected bone. Under lanreotide treatment (40 mg i.m.), the patient's bone pain improved with a concomitant decrease in phosphate alkaline level. Phosphate clearance and tubular readsorption rate of phosphate did not change significantly. We reviewed previously reported cases of associated Paget's bone disease and phosphate diabetes.

Possible association between deep infection and hypertrophic osteoarthropathy. Report of three cases and review of the literature.

Hypertrophic Osteoarthropathy is classically associated with chronic pulmonary disease, cancer or inflammatory bowel disease. However, deep infection such as vascular graft infection is an etiology important to recognize because of the risk of life-threatening complication (aorto-enteric fistula). In this study, we reported two cases of aortic graft infection and one case of para-anal abscess associated with hypertrophic osteoarthropathy. The previously reported cases are reviewed.

[The nuclear medicine department and the TEP/Biomedical Cyclotron unit]. / Le Service de Médecine Nucléaire et l'Unité TEP/Cyclotron Biomedical.

During the last 25 years, the clinical and experimental activity in nuclear medicine at Erasme hospital has been influenced by the implementation of positron emission tomography (PET) in 1990 as a method of brain functional investigation. The activity of the PET/biomedical cyclotron unit has been dedicated to various subjects in neurology, neurosciences, psychiatry, oncology and cardiology. This has been made possible by developments in radiochemistry. The radiochemistry laboratory has designed and produced original tracers such as 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)-methyl]guanine (FHPG), a tracer of viral thymidine kinase activity in gene therapy protocols. We have brought new applications of PET, such as its integration into stereotactic neurosurgical and radioneurosurgical techniques in order to improve their diagnostic and therapeutic performance in neurooncology. We have also conducted multiple studies on brain physiology and pathophysiology, in particular with the use of functional and metabolic brain mapping methods and the use of tracers of neurotransmission systems. The Department of nuclear medicine has also performed studies on bone metabolism and investigated in vivo imaging methods of infectious and immune processes.

180 degree pinhole SPET with a tilted detector and OS-EM reconstruction: phantom studies and potential clinical applications.

This study investigated the feasibility of ordered subsets expectation maximisation (OS-EM) reconstruction of pinhole single-photon emission tomography (SPET) acquired with a tilted detector head and a 180 degrees orbit. Phantom and patient data were recorded using a standard single-head camera. Reconstructions were performed using a dedicated OS-EM algorithm. Reconstructed images of line, uniformity and Picker's thyroid phantoms showed that the geometry, physical size and uniformity of the radioactive objects were preserved. For the range of radius corresponding to the patient studies, the measured full-widths at half-maximum lay between 4.90+/-0.25 mm and 6.05+/-0.25 mm. Finally, the gain in resolution associated with the use of the pinhole collimator instead of a parallel-hole collimator was highlighted in a parathyroid exploration and in a shoulder bone study.

Nondetection of sentinel lymph node with lymphoscintigraphy as a result of massive malignant invasion shown by positron emission tomography.

PURPOSE: The authors report the complementary roles of lymphoscintigraphy in sentinel node mapping and F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in a massively invaded sentinel node. MATERIALS AND METHODS: A 49-year-old woman was referred to the authors' institution after the resection of a malignant melanoma (Clark IV, Breslow 5.25) of the right buttock. No evidence of regional or distant organ metastases was observed on bone scintigraphy or thoracoabdominal or cerebral computed tomographs. Preoperative lymphoscintigraphy showed drainage around a circular structure, without any node detected. F-18 FDG PET imaging detected an area of focal, markedly hypermetabolic activity at the same location. RESULTS: The focal, markedly hypermetabolic activity detected by F-18 FDG PET corresponded to a massively invaded sentinel node not shown by lymphoscintigraphy but found and removed at the time of surgery. Radical regional lymphadenectomy showed only one small additional lymph node micrometastasis detected after immunohistochemical staining for S-100 protein and HMB45 antigen. CONCLUSIONS: This case emphasizes the complementary roles of lymphoscintigraphy sentinel node mapping and F-18 FDG PET. Indeed, a massively invaded sentinel node may be detected by PET but missed by lymphoscintigraphy.

Bone, bone marrow, and MIBI scintigraphic findings in Gaucher's disease "bone crisis".

PURPOSE: The authors report the utility of Tc-99m MIBI imaging in Gaucher's disease, which results in the accumulation of glucocerebroside in macrophages. Inflated macrophages, or Gaucher's cells, involve the reticuloendothelial organs. MATERIALS AND METHODS: A 38-year-old man with type I Gaucher's disease, splenectomy, and early bone involvement was examined for a low back "bone crisis." He had a history of total left hip replacement. Results of pelvic radiographs were normal. Magnetic resonance imaging showed complete infiltration of the bone marrow in the lumbar spine and the sacrum. The left iliac bone, the sacrum, and the adjacent part of L5 showed heterogeneously decreased uptake on bone scintigraphs. Hematopoietic bone marrow was absent in these regions and in the left femur. No infection of the prosthesis was revealed with labeled granulocytes. RESULTS: Avascular necrosis in the left iliac bone was diagnosed, which is a very unusual location. There was no uptake of MIBI in the iliac bones or the femurs. CONCLUSION: These findings suggest that MIBI may not be a good tool for the evaluation of medullary infiltration by Gaucher's cells.

Maximum-likelihood reconstruction with ordered subsets in bone SPECT.

UNLABELLED: This study was aimed at determining whether the ordered-subset expectation maximum (OSEM) is more effective than filtered backprojection (FBP) for bone SPECT in the routine clinical context. METHODS: Fifty-seven consecutive bone SPECT studies were analyzed. They included pelvic and lumbar spine, thoracolumbar spine, head and neck, feet and shoulders. A 64-projection SPECT study was acquired over 360 degrees by single-head cameras 2-3 h after the injection of 750 MBq 99mTc-methylene diphosphonate. Three observers compared the OSEM and FBP reconstructed images. RESULTS: Streak artifacts, always present with FBP, were rarely generated with the OSEM. When present (n = 24), artifacts associated with negative values near hyperactivities in FBP were not generated with the OSEM in 67% of the cases (n = 16), permitting a satisfactory interpretation of these regions. In half of the other cases (17%, n = 4/24), interpretation was precluded. In only one case did the three observers agree that more hyperactivities were seen with the OSEM. Ninety-six percent of the OSEM pictures were superior or equal to FBP for anatomic resolution and were clearly better in 12% of the cases. The extent of the lesion with the OSEM seemed better or equally defined in 96% and clearly better in 14% of the cases. The low-activity regions were better or equally visualized in all cases and were clearly better seen in 23% of the cases. The quality of the pictures was found to be better or superior with the OSEM in 98% of the cases and definitely better in 65% of the cases. CONCLUSION: Replacement of FBP by the OSEM in bone SPECT would be beneficial to clinical practice.

Sentinel lymph node mapping in the management of high risk malignant melanoma.

In patients with malignant melanoma, the selective biopsy of the first draining lymph node, so-called the sentinel lymph node, allows to identify, with a low morbidity, the patients with nodal metastasis that require radical lymphadenectomy and adjuvant systemic chemotherapy. Herein, we report our initial experience in sentinel lymph node biopsy in 16 patients with malignant melanoma. The sentinel lymph node was localised using preoperative lymphoscintigraphy and injection of dye blue. Intraoperatively, the dissection was guided with a gamma probe and by the recognition of the blue nodes. In the 16 cases the sentinel lymph node was localised. In 50% of the cases, multiple sentinel nodes were demonstrated at lymphoscintigraphy and found during surgery. A limited postoperative morbidity was observed in three cases. Three patients presented nodal metastasis and underwent further radical lymphadenectomy. We conclude that sentinel lymph node mapping is a feasible and reproductive procedure. The preoperative lymphoscintigraphy is essential to identify multiple sentinel nodes and guide surgical dissection. The impact of this approach on the overall survival of patients with high-risk melanoma has still to be demonstrated in studies with a long follow-up.

99mTc-sesta-(2-methoxy-isobutyl-isonitrile) uptake by pancreatic islets, parotid cells, and mammary carcinoma cells.

99mTc-sesta-(2-methoxy-isobutyl-isonitrile)(Tc-MIBI) is currently used for imaging of several organs. In the present study, its uptake by rat pancreatic islets, rat parotid cells, and human breast adenocarcinoma cells (MCF-7 cells) was found to be grossly proportional to its concentration (up to 0.1 microM), time-related (with a fractional turnover rate close to 2-3 10(-2).min(-1)), and stimulated by D-glucose. Comparable values for the fractional turnover rate were found in prelabeled islets and MCF-7 cells, D-glucose failing to affect Tc-MIBI efflux from prelabeled islets. In the islets, the uptake of Tc-MIBI was decreased at low temperature, in the presence of mitochondrial poisons and at high extracellular K+ concentration, unaffected by the absence of extracellular Ca2+, and increased by nutrient secretagogs, such as 2-ketoisocaproate and the association of L-leucine and L-glutamine. These findings are consistent with the view that Tc-MIBI uptake is ruled by its extracellular concentration, and the polarization of both plasma and mitochondrial membranes. It is proposed that this lipophilic cation may be useful to detect alteration of nutrient metabolism in pancreatic islets deprived of any exogenous fuel.