Biomedical subjects

Christophe Van de Wiele

Publications and source records attributed to Christophe Van de Wiele.

At least 19 recordsLinked to original sources

PubMed2006

Valine-based biphenylsulphonamide matrix metalloproteinase inhibitors as tumor imaging agents.

Among matrix metalloproteinases (MMPs), the subfamily of gelatinases (MMP-2, MMP-9) is of particular interest due to their ability to degrade type IV collagen and other non-fibrillar collagen domains and proteins such as fibronectin and laminin. Whilst malignant cells often over-express various MMPs, the gelatinases have been most consistently detected in malignant tissues and associated with tumor growth, metastatic potential and angiogenesis. Radiosynthesis of carboxylic (1') and hydroxamic (2') MMPIs resulted in radiochemical yields of 70 +/- 5% (n = 6) and 60 +/- 5% (n = 4), respectively. Evaluation in A549-inoculated athymic mice showed a tumor uptake of 2. 0+/- 0.7%ID/g (3 h p.i.), a tumor/blood ratio of 0.5 and a tumor/muscle ratio of 4.6 at 48 h p.i. for 1'. For compound 2' a tumor uptake of 0.7 +/- 0.2%ID/g (3 h p.i.), a tumor/blood ratio of 1.2 and a tumor/muscle ratio of 1.8 at 24 h p.i. were observed. HPLC analysis of the blood (plasma) showed no dehalogenation or other metabolites of 1' 2 h p.i. For compound 2', 65.4% of intact compound was found in the blood (plasma) and one polar metabolite (31%) was detected whereas in the tumor 91.8% of the accumulated activity was caused by intact compound and only 8.1% by the metabolite. Planar imaging, using a Toshiba GCA-9300A/hg SPECT camera, showed that tumor tissue could be visualized and that image quality improved by decreasing specific activity resulting in lower liver uptake, indicating some degree of saturable binding in the liver. In vivo evaluation of these radioiodinated carboxylic and hydroxamic MMP inhibitor tracers revealed that MMP inhibitors could have potential as tumor imaging agents, but that further research is necessary.

Animals↗

PubMed2006

Formatted anti-tumor necrosis factor alpha VHH proteins derived from camelids show superior potency and targeting to inflamed joints in a murine model of collagen-induced arthritis.

OBJECTIVE: The advent of tumor necrosis factor (TNF)-blocking drugs has provided rheumatologists with an effective, but highly expensive, treatment for the management of established rheumatoid arthritis (RA). Our aim was to explore preclinically the application of camelid anti-TNF VHH proteins, which are single-domain antigen binding (VHH) proteins homologous to human immunoglobulin V(H) domains, as TNF antagonists in a mouse model of RA. METHODS: Llamas were immunized with human and mouse TNF, and antagonistic anti-TNF VHH proteins were isolated and cloned for bacterial production. The resulting anti-TNF VHH proteins were recombinantly linked to yield bivalent mouse and human TNF-specific molecules. To increase the serum half-life and targeting properties, an anti-serum albumin anti-TNF VHH domain was incorporated into the bivalent molecules. The TNF-neutralizing potential was analyzed in vitro. Mouse TNF-specific molecules were tested in a therapeutic protocol in murine collagen-induced arthritis (CIA). Disease progression was evaluated by clinical scoring and histologic evaluation. Targeting properties were evaluated by 99mTc labeling and gamma camera imaging. RESULTS: The bivalent molecules were up to 500 times more potent than the monovalent molecules. The antagonistic potency of the anti-human TNF VHH proteins exceeded even that of the anti-TNF antibodies infliximab and adalimumab that are used clinically in RA. Incorporation of binding affinity for albumin into the anti-TNF VHH protein significantly prolonged its serum half-life and promoted its targeting to inflamed joints in the murine CIA model of RA. This might explain the excellent therapeutic efficacy observed in vivo. CONCLUSION: These data suggest that because of the flexibility of their format, camelid anti-TNF VHH proteins can be converted into potent therapeutic agents that can be produced and purified cost-effectively.

Adalimumab↗

PubMed2006

Fasting blood glucose levels are related to exercise capacity in patients with coronary artery disease.

BACKGROUND AND AIM: Previous studies have demonstrated reduced exercise capacity in patients with diabetes mellitus. This study evaluated the relationship between fasting blood glucose (FBG) levels and exercise capacity in patients with coronary artery disease (CAD). METHODS: We evaluated 986 consecutive patients with CAD referred for bicycle spiroergometry combined with gated myocardial perfusion imaging. Maximum oxygen consumption (VO2max) and maximal watts were measured. Patients were divided into 4 FBG categories: < 100 mg/dL (n = 611), 100 to 109 mg/dL (n = 144), 110 to 125 mg/dL (n = 102), and > or = 126 mg/dL (n = 129). Differences in clinical characteristics, exercise hemodynamics, perfusion imaging, and univariate as well as multivariate predictors of exercise capacity were determined. RESULTS: Maximal watts and VO2max were significantly lower (P < .0001) in patients with higher FBG levels and were related to FBG values in univariate and multivariate analyses. Left ventricular volumes and ejection fractions did not differ between the FBG categories. Myocardial perfusion imaging showed a comparable degree of ischemia in the 4 FBG groups. However, patients with higher FBG levels had higher heart rate and blood pressure values at rest resulting in a higher rate-pressure product (values in the 4 FBG groups 8299 +/- 2051, 8733 +/- 2008, 9558 +/- 2583, and 9588 +/- 2468 beat/min x mm Hg, P < .0001), suggesting increased myocardial oxygen consumption per unit time at rest. CONCLUSION: Exercise capacity in patients with CAD is related to FBG levels. Patients with impaired fasting glucose or an FBG level > or = 126 mg/dL reached lower peak watts and lower VO2max values. This could be attributed to a higher myocardial oxygen consumption per unit time at rest and the inability to adapt their coronary flow adequately to higher metabolic demands during maximal exercise.

Aged↗

PubMed2006

Imaging probes targeting matrix metalloproteinases.

During the past few years, several imaging probes targeting matrix metalloproteinases (MMPs) have been developed. Most of these probes have been validated in animal models. Overall, results derived from most of these studies have been disappointing. Whether or not this relates to shortcomings of the imaging probes used or to the set-up of the reported studies is currently unclear. Firstly, MMPs targeted in these studies, MMP-1, -2 and -9, are cell secreted and their expression is known to vary extensively within one tumor type, depending on the stage of development of the tumor and on the presence of naturally occurring TIMPs. Given the lack of data on the levels of MMP expression by incoculated tumor tissue at the time of imaging in most studies reported, it cannot be excluded that the negative results reported are, in fact, false-negative imaging results. Secondly, given that most of the agents used for imaging are intrinsically broad-spectrum agents, their higher affinity for specific subsets of MMPs does not necessarily imply that a positive imaging result also corresponds to overexpression of specific subsets of MMPs, as suggested in some papers published. Accordingly, well-characterized tumor models need to be developed for the purpose of validating currently available, as well as future, MMP-imaging probes. So far, only 111In-DTPA-N-TIMP-2 has been injected in patients, respectively suffering from Kaposi Sarcoma. Imaging results obtained with this agent proved disappointing. Imaging results obtained with other MMP-targeting probes in patients are awaited.

Animals↗

PubMed2006

Assessment of supra-additive effects of cytotoxic drugs and low dose rate irradiation in an in vitro model for hepatocellular carcinoma.

The use of 5-fluorouracil, topotecan, or gemcitabine was tested for enhancement of the effects of low dose rate (LDR) irradiation in an in vitro model for hepatocellular carcinoma. For comparison, all drugs were tested in combination with high dose rate (HDR) gamma-irradiation as well. Multicellular spheroids of HepG2 cells were exposed to HDR or LDR irradiation by means of external beam cobalt-60 or rhenium-188 (188Re), respectively, dissolved in the culture medium. Secondly, exposure to irradiation was combined with the cytotoxic drug. Toxicity was evaluated by means of a quantitative spheroid outgrowth assay and histology. For 5-fluorouracil, supra-additive effects were observed in combination with HDR irradiation. With 188Re, the supra-additive toxicity was only transient. For topotecan and 188Re, no supra-additive effects were seen, whereas the addition of HDR irradiation at the end of the topotecan exposure yielded lasting supra-additive effects. Incubation with gemcitabine followed by exposure to HDR irradiation, induced a synergistic toxicity on the outgrowth. No supra-additive effects were observed when HDR irradiation was added at the start of the incubation with gemcitabine or combined with LDR irradiation. For all drugs tested, supra-additive effects were observed with HDR irradiation if the timing of the irradiation was appropriate. For 188Re, no lasting supra-additive effects were observed.

Antimetabolites, Antineoplastic↗

PubMed2006

Early prediction of endocrine therapy effect in advanced breast cancer patients using 99mTc-depreotide scintigraphy.

UNLABELLED: In vitro assessment of hormone receptor status using a ligand-binding assay or immunohistochemistry in breast cancer patients predicts endocrine responsiveness with an accuracy of only 60%-70%. Assessment of an end product of estrogen receptor stimulation, such as the progesterone receptor, is assumed to provide a measure of functional receptor content and has proven to increase predictive accuracy. In analogy with the estrogen-dependent regulation of somatostatin receptor (SSTR) expression in endocrine-responsive human breast cancer cell lines, efficient antiestrogen treatment in patients may result in a downregulation of SSTR at the cell surface in breast tumors. In vivo imaging of this molecular event by means of sequential (99m)Tc-depreotide scintigraphy could enable selection of breast cancer patients susceptible to endocrine therapy. METHODS: Twenty patients with a diagnosis of advanced breast cancer in whom first- or second-line hormonal therapy was going to be initiated were included. Patients underwent sequential (99m)Tc-depreotide scintigraphy before and 3 wk after initiating hormonal treatment. Follow-up data were retrieved from routine clinical evaluation by means of physical examination, imaging (e.g., bone scan, CT, MRI) and blood analysis. Lesion-to-background ratios (L/BGs) were calculated on planar and SPECT images and a change of >25% between the baseline and follow-up scan was considered significant. RESULTS: At 6 mo after initiation of treatment, 8 patients had stable disease and were considered to be responding to hormonal treatment, whereas 10 patients had progressive disease and were considered to be nonresponders. The positive and negative predictive values of baseline (99m)Tc-depreotide scintigraphy for endocrine responsiveness were 73% (8/11) and 100% (7/7), respectively. Sequential scans were always both positive or both negative. The relative change in (99m)Tc-depreotide uptake between sequential scans significantly differed in responders compared with nonresponders (P= 0.017)-uptake decreased in the first group and increased in the latter. As such, baseline (99m)Tc-depreotide scintigraphy combined with the changes in tracer uptake between the baseline and follow-up scan predicted endocrine responsiveness with an accuracy of 100%. CONCLUSION: Sequential (99m)Tc-depreotide scintigraphy could allow for separation of responders and nonresponders immediately or as early as 3 wk after initiation of treatment.

Aged↗

PubMed2006

Sequential 99mTc-hydrazinonicotinamide-annexin V imaging for predicting response to chemotherapy.

UNLABELLED: This study was undertaken to evaluate changes in relative (99m)Tc-hydrazinonicotinamide (HYNIC)-annexin V tumor uptake over time in patients undergoing chemotherapeutic treatment at baseline and at 5-7 h and 40-44 h after treatment initiation. Imaging results are related to clinical outcomes, as assessed with response evaluation criteria in solid tumors (RECIST). METHODS: We prospectively included 20 patients (11 men and 9 women; mean age, 59.8 y; range, 22-75 y) scheduled for chemotherapy (n = 19) or bisphosphonate treatment (n = 1). Curable disease was present in 5 patients. The other patients had metastatic disease and were treated in a palliative setting. Three of the 20 enrolled patients were excluded from analysis: 1 patient ultimately refused the proposed chemotherapy treatment; because of difficulties with the labeling procedure, 1 patient did not receive a pretreatment scan; and 1 patient presented with an allergic reaction (rash and nausea) to the (99m)Tc-HYNIC-annexin V formulation. The remaining 17 patients underwent 3 scintigraphic scans with (99m)Tc-HYNIC-annexin V: before treatment and 5-7 h and 40-44 h after treatment initiation. The tumor response was evaluated with RECIST and related to observed changes in the ratios of tumor activity to background activity for the largest known lesion; values exceeding 25% the baseline value on either the 5- to 7-h scan or the 40- to 44-h scan were considered significant. RESULTS: With the proposed sequential imaging protocol and a 25% change threshold, responders to treatment could be separated from nonresponders with a 94% accuracy (16/17 patients). CONCLUSION: Sequential (99m)Tc-HYNIC-annexin V imaging may allow for assessment of the response to chemotherapy within 3 d after treatment initiation.

Adult↗

PubMed2005

(188)Re-HDD/lipiodol therapy for hepatocellular carcinoma: an activity escalation study.

PURPOSE: The aim of this study was to investigate the feasibility of administering increasing activities of (188)Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ((188)Re-HDD/lipiodol) for the treatment of hepatocellular carcinoma (HCC) in patients with well-compensated cirrhosis. METHODS: The activity levels were increased by 1.1 GBq/step after a 6-week interval without unacceptable adverse events in at least five consecutive patients. Absorbed doses to the various organs were calculated according to the MIRD formalism, based on three gamma-scintigraphic studies. Response was assessed by means of MRI and alpha-fetoprotein (AFP) monitoring. RESULTS: Thirty-five treatments were carried out in 28 patients. Activities from 4.8 to 7.0 GBq (188)Re-HDD/lipiodol were administered via a transfemoral catheter. The mean absorbed dose to the liver (including tumour) was 7.6+/-2.2, 9.8+/-4.9 and 15.2+/-4.9 Gy for the 4.8-, 5.9- and 7.0-GBq groups, respectively. Treatment was well tolerated at all activity levels. Further escalation of the administered activity was not feasible owing to limitations related to the radiolabelling procedure. Response assessment on MRI showed partial response, stable disease and disease progression in 1, 28 and 2 assessable treatments, respectively. In 8 of 17 treatment sessions with an initially elevated AFP, a reduction ranging from 19% to 97% was observed 6 weeks later. CONCLUSION: Following the intra-arterial administration of 4.8-7.0 GBq (188)Re-HDD/lipiodol in patients with HCC and well-compensated liver cirrhosis, no severe adverse events occurred. Further escalation was not feasible owing to limitations in the radiolabelling procedure.

Aged↗

PubMed2005

Differences of cortical 5-HT2A receptor binding index with SPECT in subtypes of anorexia nervosa: relationship with personality traits?

OBJECTIVE: Using single photon emission computed tomography and the 5-HT2A receptor antagonist, 123I-5-I-R91150, we explored differences in 5-HT2A binding index in anorexia nervosa patients with and without bulimic features. We also searched for associations between temperament dimensions and cortical 5-HT2) binding. METHOD: About 9 restrictive and 7 bulimic anorexia nervosa patients were examined and cortical 123I-5-I-R91150 binding index values were compared between the two subgroups. Open explorative correlation analysis was used to examine any relationships between binding index values and temperament scores, as assessed with the Temperament and Character Inventory. RESULTS: 5-HT2A binding index was significantly reduced in the parietal cortex in bulimic anorexia nervosa patients in comparison with restrictive anorectics. Further, a positive correlation was documented between reward dependence and parietal 5-HT2A binding index across patients in the two subgroups. DISCUSSION: Restrictive anorexia nervosa patients differ from binging/purging anorexia nervosa patients on the basis of a reduced parietal 5-HT2A binding index in the latter. We speculate that the finding of a positive correlation between parietal 5-HT2A binding and reward dependence might reflect an association between these two variables, at least in anorexia nervosa patients.

Adolescent↗

PubMed2005

Blunted prefrontal perfusion in depressed patients performing the Tower of London task.

Impairment of cognition is common in depression, and many tasks on which depressed patients are impaired are sensitive to frontal lobe dysfunction. Performance on the Tower of London (TOL) task, which includes setting up and maintaining multiple subgoals at the same time, has been shown to depend on intact prefrontal cortices. Single photon emission computed tomography (SPECT) with 99mTc-ethyl cysteinate dimer was used to compare cognitive activation in nine depressed patients and nine normal controls during performance of the TOL task. Planning times and accuracy were measured as performance parameters, and functional imaging data were analysed with statistical parametric mapping (SPM99) to determine significant voxel-wise differences in activation between the two groups. During activation, depressed patients were as accurate as controls but differed in that they spent more thinking time. These findings agree with the results of neuropsychological studies. Compared with the normal controls, depressed patients were characterized by a blunted perfusion response in the right middle frontal cortex [Brodmann area (BA) 6] and the left superior frontal gyrus (BA 9), and by increased perfusion in the right superior temporal gyrus (BA 21) and the insular cortex (BA 13). This study shows that a SPECT activation procedure using the TOL task under classical test conditions is feasible in depressed patients.

Adult↗

PubMed2005

Treatment of hepatocellular carcinoma by means of radiopharmaceuticals.

Several techniques have been developed for radionuclide therapy of hepatocellular carcinoma (HCC). Medical literature databases (Pubmed, Medline) were screened for available literature and articles were critically analysed as to their scientific relevance. In a palliative setting, intra-arterial administration of 131I-Lipiodol yields responses in 17-92% of patients. According to a randomised study, 131I-Lipiodol was far better tolerated than classic chemo-embolisation. The additive value of a single 131I-Lipiodol administration following partial liver resection for HCC was evaluated and evidence is available that adjuvant radionuclide treatment reduces the recurrence rate. Data concerning the role of 131I-Lipiodol in bridging patient to liver transplantation are scarce but suggest a potential benefit in terms of reducing the drop-out rate while patients are listed for transplantation. 188Re- and 90Y-labelled conjugates are emerging and initial clinical data are promising. Treatment of HCC with 90Y-labelled microspheres is likely as efficacious as treatment with radiolabelled Lipiodol but pretreatment 99mTc-MAA scintigraphy is required in order to exclude patients with significant lung shunting. Several antibodies targeting antigens expressed on HCC have been radiolabelled, almost exclusively with 131I, and evaluated in a preclinical or clinical setting. The use of radiolabelled Lipiodol and microspheres allows for selective targeting of HCC with limited toxicity. Prospective, randomised controlled trials demonstrating that both treatment modalities may provide a survival benefit in a palliative setting are mandatory. In addition, future research should focus on the complementary role of radionuclide treatment in patients at risk for recurrent disease following partial liver resection or while awaiting liver transplantation.

Animals↗

PubMed2005

In vivo apoptosis detection with radioiodinated Annexin V in LoVo tumour-bearing mice following Tipifarnib (Zarnestra, R115777) farnesyltransferase inhibitor therapy.

In this paper, the use of (123)I-Annexin V for the detection of farnesyltransferase inhibitor (FTI)-induced apoptosis in tumour-bearing athymic mice is described. In vitro binding assays on LoVo cells show time- and dosage-dependent (125)I-Annexin V binding upon treatment with Tipifarnib (Zarnestra, R115777), a selective and potent FTI. In vivo experiments using planar gamma scintigraphy on LoVo inoculated mice show a 40% increased (123)I-Annexin V uptake 8 h after a single oral administration of 100 mg/kg Tipifarnib in 20% beta-cyclodextrin in 0.1 M HCl, as well as after 3 days of twice daily treatments with the same dose. Ex vivo TUNEL assays, detecting end-stage apoptotic cells, correlate significantly with both in vitro and in vivo results. The percentage of necrosis is also increased by Tipifarnib treatment, but is too low to interfere with the (123)I-Annexin V uptake. It can be concluded that (123)I-Annexin V can be used to monitor Tipifarnib-induced apoptosis in LoVo xenograft tumours in athymic mice. Future applications might include the early prediction of FTI response and the selection of FTI-sensitive patients very shortly after treatment initiation. Subsequently, such patients would greatly benefit from a noninvasive and fast therapy evaluation.

Adenocarcinoma↗

PubMed2005

Radiolabeled lipiodol therapy for hepatocellular carcinoma in patients awaiting liver transplantation: pathology of the explant livers and clinical outcome.

BACKGROUND: Liver transplantation has become an important curative treatment option for hepatocellular carcinoma (HCC). Criteria for transplantation are strict and, therefore, it is crucial that patients awaiting transplantation do not suffer disease progression. One of the therapeutic options to achieve disease stabilization is neoadjuvant radiolabeled lipiodol treatment. This study aimed to document the dropout rate on the waiting list, the pathological findings on the explant livers, and the long-term outcome of patients treated with radionuclide therapy while awaiting transplantation. METHODS: Patients eligible for transplantation were treated with 2.1 GBq (131)I-lipiodol or 4.1 GBq (188)Re-HDD/lipiodol by transfemoral catheterization of the hepatic arteries. Tumor necrosis was assessed in the explant livers and follow-up data, such as dropout from the waiting list, recurrence, and survival following transplantation were retrospectively documented. RESULTS: In 5 of 22 explants, necrosis exceeded 90%. Two patients died while on the waiting list (10%) and 4 of 20 transplanted patients (20%) suffered recurrent disease. The overall recurrence-free survival was 19.7 months (range, 1.75-56), with a mean follow-up of 20.1 months. CONCLUSION: Our data support the evaluation on larger patient numbers to confirm the benefit of radiolabeled lipiodol in candidates for liver transplantation who are suffering from HCC.

Carcinoma, Hepatocellular↗

PubMed2005

Tryptophane-based biphenylsulfonamide matrix metalloproteinase inhibitors as tumor imaging agents.

AIM: As a part of our efforts to use small organic matrix metalloproteinase (MMP) inhibitors with improved characteristics for the diagnosis and treatment of different kinds of tumor tissues, biphenylsulfonamide analogues were synthesized. This study reports on the in vivo biodistribution of iodine-123-labeled biphenylsulfonide and analogues in A549 lung carcinoma inoculated into athymic mice and the evaluation of their suitability as imaging agents using a single photon emission computed tomography (SPECT) camera. METHODS: The radioiodinated carboxylic and hydroxamic MMP inhibitors 2-(4'- [(123)I]iodobiphenyl-4-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid (1') and 2-(4'-[(123)I]iodobiphenyl-4- sulfonylamino)-3-(1H-indol-3-yl)-propionamide (2') were synthesized by electrophilic aromatic substitution of the tributylstannyl derivatives. Planar gamma camera imaging was performed in nu/nu athymic mice bearing an A549 tumor using a Toshiba GCA-9300A/hg SPECT camera in planar mode equipped with a high-resolution, parallel-hole collimator. RESULTS: Radiosynthesis of (1') and (2') resulted in radiochemical yields of 60 +/- 5% (n +/- 3) and 70 +/- 5% (n = 6), respectively. Evaluation of tumors induced in athymic mice by the inoculation of non-small cell lung A549 carcinoma cells, showed a tumor uptake of 0.27-0.01 percent injected dose per gram (%ID/g) (3 hours-48 hours p.i.), a tumor-blood ratio of 0.7, a tumor-muscle ratio of 1.6, and a tumor-fat ratio of 0.5 at 24 hours (p.i.) for compound 1'. For compound 2' a tumor uptake of 0.7-0.04 %ID/g (3 hours-48 hours p.i.), a postinjection tumor-blood ratio of 1.2, a tumor-muscle ratio of 3.2, and a tumor-fat ratio of 2.4 at 48 hours p.i. was observed. SPECT evaluation confirmed the results obtained from biodistribution. CONCLUSION: In vivo evaluation of these radioiodinated carboxylic and hydroxamic MMP inhibitor tracers revealed that they do not appear suitable as tumor-imaging agents.

Animals↗

PubMed2005

188Re-HDD/lipiodol therapy for hepatocellular carcinoma: a phase I clinical trial.

UNLABELLED: The aim of this study was to investigate the pharmacokinetics, organ dosimetry, and toxicity after the intraarterial administration of (188)Re-labeled 4-hexadecyl-1,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ((188)Re-HDD/lipiodol) for palliative treatment of hepatocellular carcinoma (HCC). A secondary objective was to document the response. METHODS: A mean activity of 3.60 GBq (188)Re-HDD/lipiodol (range, 1.86-4.14 GBq) was administered to 11 patients (16 treatment sessions) via a transfemoral catheter. The pharmacokinetic and dosimetric data were collected by means of venous blood samples, urine collections, and 4 or 5 gamma-scintigraphies over 76 h. Absorbed doses to the various organs were calculated according to the MIRD formalism, using the MIRDOSE3.1 software. The toxicity was assessed until 6 wk after administration by means of the Common Toxicity Criteria scale. The response was evaluated on MRI and by monitoring of the tumor marker. RESULTS: A fast blood clearance of the injected activity was observed with a calculated effective half-life of 7.6 +/- 2.2 h (+/-SD) in blood. The predominant elimination of the activity was through urinary excretion with a mean renal clearance of 44.1% +/- 11.7% (+/-SD) of the injected activity within the 76 h after administration. Fecal elimination was negligible. The calculated whole-body effective half-life was 14.3 +/- 0.9 h (+/-SD). The absorbed dose to the liver tissue, the lungs, the kidneys, and the thyroid was 4.5 +/- 1.9, 4.1 +/- 1.2, 0.9 +/- 0.7, and 0.3 +/- 0.1 Gy, respectively. Treatment was well tolerated, except in 2 patients. One Child B patient experienced a worsening of his liver dysfunction (hyperbilirubinemia) and another patient experienced dyspnea and coughing. Response assessment on MRI showed 1 case of partial response, disease stabilization in 11 treatments, and progressive disease in 1 treatment. In 5 of 8 treatment sessions with an initially elevated alpha-fetoprotein, a reduction (range, 19%-90%) was observed 6 wk later. CONCLUSION: After the intraarterial administration of 3.60 GBq (188)Re-HDD/lipiodol, a fast clearance of the activity appearing in the blood is observed and the predominant elimination is through urinary excretion. The tolerance as well as the preliminary response rates of the present phase I study are encouraging.

Aged↗

PubMed2005

188Re-HDD/lipiodol for treatment of hepatocellular carcinoma: a feasibility study in patients with advanced cirrhosis.

UNLABELLED: This study aimed to investigate the feasibility of the intraarterial administration of 3.7 GBq (188)Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ((188)Re-HDD/lipiodol) for treatment of hepatocellular carcinoma (HCC) in patients with moderately advanced cirrhosis. METHODS: Patients with HCC and underlying cirrhosis classified as Child-Pugh B in terms of severity were eligible. Whole-body scintigraphies were performed at 4 time points after injection. Absorbed doses to the various organs were calculated according to the MIRD formalism. Urine was collected for 52 h after injection. Toxicity was assessed until 6 wk after administration by means of the Common Toxicity Criteria for Adverse Events (version 3.0) scale. Responses were evaluated on MRI and by alpha-fetoprotein (AFP) monitoring. RESULTS: A mean activity +/- SD of 3.7 +/- 0.2 GBq (188)Re-HDD/lipiodol was administered in the hepatic artery to 12 patients; 36.2% +/- 5.7% of the activity was excreted in the urine 52 h after injection. The absorbed dose to the liver, lungs, kidney, and thyroid was 7.6 +/- 2.9, 4.8 +/- 2.6, 0.8 +/- 0.7, and 0.2 +/- 0.1 Gy (mean +/- SD), respectively. Two weeks after administration, 6 of 12 patients had adverse events consisting of aggravations of preexisting laboratory changes (3 patients), fatigue (2 patients), vomiting (1 patient), fever (1 patient), encephalopathy (1 patient), and ascites (1 patient). Toxicity assessment at week 6 revealed single cases of the worsening of hyperbilirubinemia, pleural effusion, thrombocytopenia, and dyspnea. Three patients dropped out of the study because of deterioration of their general condition. The response was assessable by MRI in 8 patients: 1 patient with a partial response and 7 patients with stable disease were reported. Nine patients with an initially elevated AFP were evaluated. Stable AFP was recorded in 1 patient and 3 showed a reduction, whereas a considerable increase was observed in 5 patients. CONCLUSION: After the administration of 3.7 GBq (188)Re-HDD/lipiodol, half of the Child-Pugh B patients in the present study had a worsening of their general condition or aggravation of preexisting symptoms. This was associated with a rise in AFP in a considerable number of patients. In the future, administration of the radiopharmaceutical as close to the tumor feeding arteries as possible might avoid further deterioration of the liver function and show enhanced antitumoral activity.

Adult↗

PubMed2004

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.

Humans↗

PubMed2004

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. (123)I-labelled, (124)I-labelled, (125)I-labelled, (18)F-labelled), (99m)Tc/(94m)Tc-labelled Annexin V derivatives using different chelators and co-ligands (i.e. BTAP, Hynic, iminothiolane, MAG(3), EDDA, EC, tricarbonyl, SDH) or direct (99m)Tc-labelling, (99m)Tc-labelled Annexin V mutants and (99m)Tc/(18)F-radiopeptide constructs (i.e. AFIM molecules), (111)In-DTPA-PEG-Annexin V, (11)C-Annexin V and (64)Cu-, (67)Ga- and (68)Ga-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 (99m)Tc-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.

Animals↗