[Show abstract][Hide abstract] ABSTRACT: Purpose: Multidrug resistance (MDR) is a significant obstacle to successful chemotherapy and a major prognostic factor in osteosarcoma
(OS). We have previously observed that the chemosensitivity of OS cell lines to doxorubicin depends on P-glycoprotein (Pgp)
and can be predicted based on functional assays using 99mTc-Sestamibi (MIBI). These results prompted us to develop an orthotopic
model of OS for in vivo imaging of MDR and pharmacological inhibition with MIBI.
Methods: Sensitive (143B) and resistant (MNNG) OS cell lines expressing different levels of Pgp and carrying a luciferase reporter
gene were inoculated into the tibia of nude mice. Local tumor growth was monitored weekly by bioluminescence imaging and X-ray.
After primary tumor growth, the animals were imaged with MIBI during 60 min. A group of animals were pre-treated with a Pgp
inhibitor (PSC833). Images were analyzed for calculation of MIBI washout half-life (t1/2) and T/NT uptake ratios.
Results: A progressively increasing bioluminescent signal was detected at 1-2 weeks after cells inoculation. The t1/2 of MIBI in drug resistant MNNG-tumors (t1/2 = 87.3±15.7 min) was significantly (pt1/2 = 161.0±47.4 min). Administration of PSC833 increased significantly the retention of MIBI in MNNG-tumors (t1/2 = 173.0±24.5 min) and had no significant effects in 143Btumors. The T/NT ratio was significantly (p
[Show abstract][Hide abstract] ABSTRACT: The outcome of antifungal therapy depends on the progression of the infection at the start of therapy. Unfortunately, most patients are diagnosed once the fungal infection has progressed considerably as a result of the non-specific clinical signs of fungal infections in immunocompromised patients and the poor sensitivity of current mycological diagnostic tests. This review will highlight current fungal diagnostic techniques and will focus on scintigraphic methods for the specific detection of fungal infections in mice. For this purpose, antifungal components (e.g. fluconazole and antifungal peptides) are radiolabeled e.g. with technetium-99m ((99m)Tc) and their in vivo distribution is monitored in infected mice. It has been demonstrated that (99m)Tc-fluconazole is an excellent tracer to detect Candida albicans infections in mice as it distinguishes these infections from bacterial infections and sterile inflammations. However, this radiopharmaceutical only poorly detects infections with Aspergillus fumigatus in mice. (99m)Tc-peptides derived from antifungal peptides/proteins, such as human ubiquicidin and lactoferrin, can distinguish C. albicans and A. fumigatus infections from sterile inflammations, but not from bacterial infections, in mice. Furthermore, the efficacy of fluconazole in C. albicans-infected mice could be successfully monitored using (99m)Tc-ubiquicidin. In conclusion, neither (99m)Tc-fluconazole nor the (99m)Tc-peptides tested are optimal tracers for fungal infections. Nonetheless, since early initiation of antifungal therapy for candidemia reduces its high mortality rate, a positive result with (99m)Tc-fluconazole scintigraphy is of clinical relevance. Finally, the possibility that other (radiolabeled) antifungal agents, e.g. voriconazole, caspofungin, antifungal plant or insect defensins, can be useful for detection of fungal infections should be considered.
Current Drug Targets 01/2006; 6(8):945-54. DOI:10.2174/138945005774912753 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glomerular function of all long-term survivors who underwent hemopoietic stem cell transplantation (HSCT) from 1991 to 1998 (study I, n=121) was studied retrospectively. In addition, we prospectively analyzed glomerular and tubular function of all long-term surviving children who received an HSCT between 1998 and 2000 (study II, n=41). We found a lower prevalence of children with chronic renal failure (CRF) post-HSCT in our more recent cohort (study II: 10%) as compared to the older cohort (study I: 24%) 5.0 (0.7 s.d.) and 7.6 (2.4 s.d.) year's post-HSCT, respectively. Furthermore, it seems that renal function may stabilize after 1-year post-HSCT. None of the patients required dialysis or antihypertensive medication at long-term follow-up. The sole predictor of CRF in our study was high serum creatinine pre-HSCT (P=0.007), while acute renal failure within 3 months after HSCT (P=0.08) only showed a trend towards predicting CRF. We could not confirm a relation of conditioning with irradiation with CRF post-HSCT, as was shown in several other pediatric and adult studies. Proximal and distal tubular dysfunction only occurred in a minority of long-time survivors of HSCT (3-12 and 9-13%, respectively) and had no clinical consequences.
Bone Marrow Transplantation 11/2005; 36(7):605-10. DOI:10.1038/sj.bmt.1705110 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Technetium-99m (Tc-99m) is the radionuclide of choice for nuclear medicine imaging. However, some radiotracers are still labeled with radioiodine, which has various detrimental characteristics. Among these agents is the radioiodine-labeled guanethidine analogue MIBG (metaiodobenzylguanidine), which is used for the study of cardiac innervation. This scintigraphic depiction of the innervation patterns is of clinical importance to evaluate the function of the cardiac sympathetic nervous system. This paper reviews the possibilities of developing a Tc-99m-labeled radiotracer that has adrenergic specificity. This search has resulted in four agents which, with some effort, can be labeled with 99mTc and have the potential to be used for diagnostic purposes: epinephrine, metahydroxyepinephrine, desipramine and atomoxetine. In order to avoid pharmacological effects, the final product after labeling should be (nearly) carrier-free.
Drugs of the Future 10/2005; 30(10). DOI:10.1358/dof.2005.030.10.927378 · 0.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nuclear medicine is an important diagnostic tool in the evaluation of patients with a variety of diseases. This modality uses radiopharmaceuticals that target the area of interest due to functional rather than morphological abnormalities, adding important information to other imaging methods such as magnetic resonance imaging and computed tomography. One of the challenges for nuclear medicine is the evaluation of atherosclerosis. Atherosclerosis originates from increased endothelial permeability and enhanced endocytosis of LDL, which carries endogenous serum cholesterol. Plaque formation occurs when the LDL particles accumulate in the vessel wall. Of special interest is the identification of vulnerable plaque, which is weakened by apoptosis and inflammatory reactions. These vulnerable plaques represent a life-threatening danger, as rupture releases thrombogenic gruel with possible downstream occlusive thrombosis. Since vulnerable plaque is characterized by increased apoptosis, it is worthwhile to investigate the possible targeting of radiolabeled annexin V to the lesion. For patient studies, this agent would preferably be labeled with technetium-99m (Tc-99m). This radionuclide offers all the characteristics for adequate patient studies. Indeed, under experimental conditions, Tc-99m-annexin targets the plaque lesions prone to rupture.
Drugs of the Future 07/2004; 29(7). DOI:10.1358/dof.2004.029.07.854167 · 0.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This review presents the state of the art of imaging of bacterial and fungal infections in laboratory animals using antimicrobial peptides labelled with technetium-99m ((99m)Tc). The mechanistic basis of this approach is that these peptides accumulate at sites of infection, but not in sterile inflammatory lesions, because of their preferential binding to bacteria and fungi over mammalian cells. For practical reasons, such as production of large amounts of peptides under good laboratory practice conditions and favourable pharmacokinetics, synthetic peptides representing such binding domains of natural antimicrobial peptides are preferred. On the basis of their preferential in vitro and in vivo binding to microorganisms over human cells, fast and easy penetration into the target area, and rapid clearance from the circulation via the urinary tract, various (99m)Tc-antimicrobial peptides were identified. Next, it was determined whether these radiopharmaceuticals distinguish infectious foci from sites of sterile inflammation. Further experiments with (99m)Tc-ubiquicidin-derived peptides in infected laboratory animals have revealed that the radioactivity at the infectious site correlated well with the number of viable bacteria present, indicating that these (99m)Tc-labelled peptides may enable the monitoring of the efficacy of antimicrobial therapy. Together, (99m)Tc-labelled synthetic peptides derived from human ubiquicidin are promising candidates for imaging of bacterial and fungal infections in nuclear medicine.
The quarterly journal of nuclear medicine: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR) 01/2004; 47(4):238-45.
[Show abstract][Hide abstract] ABSTRACT: In patients with an osteosarcoma, the prognosis is still poor. The aim of the present study was to investigate whether routinely tested biochemical parameters or additional parameters on bone scintigraphy could be identified which can select prognostic subgroups at the time of diagnosis.
A retrospective study was performed in 115 consecutive patients (70 male, 45 female) (mean age: 25.6 years; range: 3.50-78.0 years) who were referred for bone scintigraphy prior to treatment from March 1986 to September 2000 because of a newly diagnosed osteosarcoma. All bone scans were reassessed for the intensity and pattern of uptake and a bone-scan index. All pre-treatment general, histological, biochemical, and scintigraphic data were correlated with clinical outcome during follow-up.
During follow-up 54 patients died. Tumour volume and GGT showed significance as independent variables for metastases. Patients with metastases demonstrated a significantly lower survival rate (23% 5-year survival) than patients without metastases (98% 5-year survival). Tumours of the humerus and femur had a significantly lower survival rate. With respect to significant biochemical parameters (ALP, GGT, ASAT), it was not possible to determine a cut-off value that could be used to differentiate between high- and low-risk patients. Additional parameters assessed on bone scintigraphy were not important for prognostic stratification.
The strongest predictor of survival in osteosarcoma is the presence or absence of metastasis. Some biochemical parameters have prognostic value, but they cannot be used for the unequivocal identification of subgroups. Additional scintigraphic parameters are irrelevant for prognostic stratification.
Journal of Cancer Research and Clinical Oncology 08/2002; 128(7):393-9. DOI:10.1007/s00432-002-0350-5 · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical oncologists have always shown great interest in circulating tumor markers. There are several markers that in the clinical routine are a signal of particular tumor types; some of them are strictly tissue-specific such as prostatic specific antigen (PSA) for prostatic cancer, AFP and HCG for germ cell tumors of the testis and ovary, others such as CA 15.3, CA125, CEA or cytokeratins are less specific since their elevations can be found in different varieties of cancers even if they are preferentially associated to a certain tumor type, thus are considered markers for breast, ovarian cancer and colon adenocarcinoma. The most useful clinical applications of these parameters is their determination during the follow-up of the treated patients, in order to detect the tumor recurrence early, and also to evaluate the evolution of the disease by monitoring the treatment responses. During follow-up, increasing levels of tumor markers can be observed even several months before the clinical demonstration of cancer recurrence. The association of tumor marker tests with imaging modalities can lead to several advantages: the first is to confirm the diagnosis of relapses, possibly before the appearence of the related clinical symptoms due to tumor growth; the second is to localize the sites of lesions, while tumor markers provide only a general indication of the existence of metastases; the third is to make possible a correct whole body restaging. In the assessment of cancer response tumor markers are often very reliable and their changes are faster than the morphological ones. Among all the imaging modalities, nuclear medicine plays an important role in detecting recurrences and metastatic localizations as it is able to investigate functional rather than morphological aspects of tumors, and provide different information in comparison to morphologic imaging. In addition, the scintigraphic techniques offer the possibility to evaluate treatment responses, confirming or not the information from biochemical changes. This review aims to show some examples (breast, prostate and ovarian cancer) in which the combination of nuclear medicine imaging modalities and tumor marker tests is proposed for clinical practice. The advantages and some critical aspects are discussed on the basis of the clinical findings and the most important clinical indications are described.
The quarterly journal of nuclear medicine: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR) 07/2002; 46(2):88-104.