Yttrium-90 radioembolization for colorectal cancer liver metastases: a prospective cohort study on circulating angiogenic factors and treatment response.

BACKGROUND: Yttrium-90 radioembolization (90Y-RE) as a treatment for liver tumours induces radiation damage and hypoxia in liver tissue, which is also a trigger for systemic release of angiogenic factors, potentially stimulating tumour growth. We examined changes in circulating angiogenic factors following 90Y-RE and investigated the association between response and angiogenic factors. In this prospective study, 42 patients with unresectable, chemorefractory metastatic colorectal cancer (CRCLM) were treated with 90Y-RE. Blood samples were collected pre-treatment and at 0, 1, 3, 7 and 30 days of follow-up. Response was measured with MRI according to RECIST 1.1 at 1 month and subsequently 3-month interval until progressive disease (PD) occurred. Associations between circulating angiogenic factors and response were examined with linear mixed model analysis. RESULTS: Following 90Y-RE, three angiogenic factors demonstrated an increase in plasma levels, i.e., vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and angiopoietin-2 (Ang-2). Non-responders (= PD at 1-month follow-up, n = 10) had a significant increase of Ang-2 and HGF at 3 and 7 days post treatment compared to responders (= stable disease or better, n = 32), who showed little to no changes in plasma levels (respectively p = 0.01 and p = 0.007). Median overall survival was 9.2 months (95% confidence interval 6.1-12.4). CONCLUSIONS: Significant increases in plasma levels of Ang-2 and HGF in the first week after treatment were associated with rapid progressive disease of liver lesions at 1 month after 90Y-RE. Combination of 90Y-RE with anti-angiogenic therapy may reduce these effects and result in better response.

Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex.

AIM: To determine the gender-specific prevalence of pulmonary cysts typical for lymphangioleiomyomatosis (LAM) in adult patients with known tuberous sclerosis complex (TSC). MATERIALS AND METHODS: A retrospective, cross-sectional study in a cohort of 206 adult TSC patients was performed. Institutional review board approval was obtained, and patient informed consent was waived. Patients had routinely undergone abdominal CT scanning between 1996 and 2006. All 186 patients (mean age 38 years; range 19-72 years; 91 (49%) male patients) in whom at least the lung bases were depicted on computed tomography (CT) were included. Images were reviewed for the presence of pulmonary thin-walled cysts. Descriptive statistics, two sample t-test to compare means, and χ(2)-test to compare proportions were applied. RESULTS: CT demonstrated pulmonary thin-walled cysts in the lung bases in 52 (28%) of 186 patients. Size varied from 2mm in diameter to more than 2 cm. Pulmonary cysts were detected in 40 (42%) of 95 female patients and in 12 (13%) of 91 male patients (p<0.001). In general, cysts were larger and more numerous in women than in men. Only minimal cystic changes were found in four women and two men, moderate cystic changes were seen in three women and seven men, but considerable cystic changes were seen almost exclusively in women (33 women versus three men). CONCLUSION: CT demonstrated thin-walled pulmonary cysts in the lung bases in 28% of 186 included patients with tuberous sclerosis complex. Female patients were more affected than male patients.

Technical solutions to ensure safe yttrium-90 radioembolization in patients with initial extrahepatic deposition of (99m)technetium-albumin macroaggregates.

PURPOSE: To evaluate the incidence of extrahepatic deposition of technetium-99m-labeled albumin macroaggregates ((99m)Tc-MAA) after pretreatment angiography, before yttrium-90 radioembolizaton ((90)Y-RE), and to report on technical solutions that can be used to ensure safe delivery of (90)Y-microspheres in patients with initial extrahepatic deposition. MATERIALS AND METHODS: A retrospective analysis of 26 patients with primary and secondary liver malignancies, who were scheduled for treatment with (90)Y-RE in our institution in 2009, was performed. The angiograms and single-photon emission computed tomography images of all patients were reviewed by an interventional radiologist and a nuclear medicine physician, respectively, to identify and localize extrahepatic deposition of (99m)Tc-MAA when present. Subsequently, the technical solutions were used to successfully perform (90)Y-RE in these patients were evaluated and described. RESULTS: Extrahepatic deposition of (99m)Tc-MAA was observed in 8 of 26 patients (31%). In 7 of 8 patients, a second pretreatment angiography was performed to detect the cause of extrahepatic deposition. The technical solutions to enable safe (90)Y microspheres delivery included more distal placement of the microcatheter in the proper/right hepatic artery in 4 of 7 (57%) patients; (super)selective catheterization of multiple segmental branches in 2 of 7 (29%); and additional coiling of a newly detected branch in the remaining patient (14%). This was confirmed by a second MAA procedure. (90)Y-RE was eventually performed in 25 of 26 (96%) patients. No procedure-related complications (<30 days) were observed. CONCLUSION: Extrahepatic deposition of (99m)Tc-MAA after pretreatment angiography did occur in 8 of 26 (31%) patients. The technical solutions as presented allowed safe (90)Y-RE delivery in 25 of 26 (96%) patients.

Holmium-166 poly(L-lactic acid) microsphere radioembolisation of the liver: technical aspects studied in a large animal model.

OBJECTIVE: To assess the accuracy of a scout dose of holmium-166 poly(L-lactic acid) microspheres ((166)Ho-PLLA-MS) in predicting the distribution of a treatment dose of (166)Ho-PLLA-MS, using single photon emission tomography (SPECT). METHODS: A scout dose (60 mg) was injected into the hepatic artery of five pigs and SPECT acquired. Subsequently, a 'treatment dose' was administered (540 mg) and SPECT, computed tomography (CT) and magnetic resonance imaging (MRI) of the total dose performed. The two SPECT images of each animal were compared. To validate quantitative SPECT an ex vivo liver was instilled with (166)Ho-PLLA-MS and SPECT acquired. The liver was cut into slices and planar images were acquired, which were registered to the SPECT image. RESULTS: Qualitatively, the scout dose and total dose images were similar, except in one animal because of catheter displacement. Quantitative analysis, feasible in two animals, tended to confirm this similarity (r(2) = 0.34); in the other animal the relation was significantly better (r(2) = 0.66). The relation between the SPECT and planar images acquired from the ex vivo liver was strong (r(2) = 0.90). CONCLUSION: In the porcine model a scout dose of (166)Ho-PLLA-MS can accurately predict the biodistribution of a treatment dose. Quantitative (166)Ho SPECT was validated for clinical application.

IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have been implicated in tumorigenesis of gliomas. Patients with high-grade astrocytomas with IDH1 or IDH2 mutations were reported to have a better survival, but it is unknown if this improved survival also holds for low-grade astrocytoma and whether these mutations predict outcome to specific treatment. METHODS: We retrospectively investigated the correlation of IDH1 and IDH2 mutations with overall survival and response to temozolomide in a cohort of patients with dedifferentiated low-grade astrocytomas treated with temozolomide at the time of progression after radiotherapy. RESULTS: IDH1 mutations were present in 86% of the 49 progressive astrocytomas. No mutations in IDH2 were found. Presence of IDH1 mutations were early events and significantly improved overall survival (median survival 48 vs 98 months), but did not affect outcome of temozolomide treatment. CONCLUSION: These results indicate that IDH1 mutations identify a subgroup of gliomas with an improved survival, but are unrelated to the temozolomide response.

Microsphere radioembolization of liver malignancies: current developments.

The worldwide incidence of hepatic malignancies, both primary and secondary, exceeds 1 000 000 new cases each year. The poor prognosis of patients suffering from hepatic malignancies has lead to the development of a liver directed therapy which consists of intra-arterial administration of radioactive particles through a catheter. Yttrium-90 ((90)Y) microspheres are increasingly applied for this purpose, and up to now nearly all clinical experience with radioembolization has been obtained with these microspheres. The response rate is very promising in both patients with primary and metastatic liver malignancies. Currently, two commercially available (90)Y microsphere devices are in use clinically, both as a first-line treatment and in a salvage setting. Unfortunately, the use of a pure beta-emitter like (90)Y hampers acquisition of high quality nuclear images for pre-treatment work-up and follow-up. This issue was addressed by the development of holmium-166 ((166)Ho) and rhenium-188 ((188)Re) microspheres, which emit both beta-particles for therapeutic purposes and gamma-photons for nuclear imaging. Moreover, since holmium is paramagnetic it allows for magnetic resonance imaging. (166)Ho loaded poly(L-lactic acid) microspheres have been thoroughly investigated in a preclinical setting, and recently the first clinical results for (188)Re microspheres were reported. This review provides an overview of the current status and (pre-)clinical developments of radioactive microspheres for treatment of liver malignancies.

Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature.

BACKGROUND AND PURPOSE: To investigate the prevalence of subependymal giant cell ependymomas (SEGA) in patients with tuberous sclerosis complex (TSC). METHODS: We performed a retrospective cross-sectional study in a cohort of 285 patients with known TSC. Institutional review board approval was obtained. We included all 214 TSC-patients who had received a contrast-enhanced computed tomography (CT) scan of the brain. The most recent scan was evaluated for SEGA and presence of hydrocephalus. Additionally, a literature search was performed, and pooled estimates of SEGA prevalence in TSC were calculated. We used descriptive statistics, two sample t-test, chi-squared-test, and meta-analysis as appropriate. RESULTS: Computed tomography showed radiological evidence of SEGA in 43 of the 214 TSC-patients (20%); 23 of 105 men (22%) and 20 of 109 women (18%; P = .52). Average maximum tumor size was 11.4 mm (range, 4-29 mm). Patients with SEGA (mean, 31 years; range, 16-58 years) were on average younger than patients without SEGA (mean, 37 years; range, 10-72 years; P = 0.007). No association between tumor size and patient age was detected. Nine patients had bilateral SEGA. Hydrocephalus was present in six of the 43 patients (14%). Meta-analysis of reported prevalence and our current study showed that studies using radiological evidence to diagnose SEGA gave a higher pooled estimate of the prevalence of SEGA in TSC (0.16; 95% CI: 0.12, 0.21) than studies using mainly histopathological evidence of SEGA (0.09; 95% CI: 0.07, 0.12). CONCLUSIONS: In our cohort, CT demonstrated evidence of SEGA in 20% of TSC-patients. Prevalence of SEGA in TSC is higher in studies using radiological evidence to diagnose SEGA than in studies using histopathological evidence.

Radiation safety considerations for the bone seeking radiopharmaceuticals. 89SrCl2, 186Re-HEDP and 153Sm-EDTMP.

UNLABELLED: The radiation exposure to bystanders from 89SrCl2, 186Re-HEDP and 153Sm-EDTMP, is generally thought to be caused by "bremsstrahlung" and gamma-radiation, with negligible contribution from beta-radiation. The latter assumption may be erroneous. The aim of this prospective study was the investigation of radiation safety after treatment with these radiopharmaceuticals. The radiation field around treated patients was characterized and the magnitude estimated. PATIENTS, METHODS: 33 patients (30 prostate carcinoma, 3 breast carcinoma) were treated with 150 MBq 89SrCl2 (9 patients), 1295 MBq 186Re-HEDP (12 patients) or 37 MBq/kg 153Sm-EDTMP (12 patients). External exposure rates at 30 cm from the patient were measured at times 0 to 72 h post-injection. To evaluate the respective contribution of Bremsstrahlung, beta- and gamma-radiation, a calibrated survey meter was used, equipped with a shutter. For each patient, the measured exposure rate-versus-time data were fit to a curve and the curve integrated (area under the curve) to estimate the total exposure. RESULTS: For 29/33 patients the total ambient equivalent doses (mean+/-1 standard deviation [SD]) based on the integral of the fitted curve were 2.1+/-1.2 mSv for 89SrCl2, 3.3+/-0.6 mSv for 186Re-HEDP and 2.8+/-0.6 mSv for 153Sm-EDTMP. Beta-radiation contributes significantly to these doses (>99% for 89SrCl2, 87% for 186Re-HEDP and 27% for 153Sm-EDTMP). The effective doses (at 30 cm) are <0.1 mSv for 89SrCl2, 0.3 mSv for 186Re-HEDP and 1.6 mSv for 153Sm-EDTMP. CONCLUSION: Patients treated with 89SrCl2, 186Re-HEDP or 153Sm-EDTMP emit a spectrum of radiation, including non-negligible beta-radiation. With specific instructions effective doses to bystanders are acceptable.

Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis.

Radioembolization with yttrium-90 microspheres ((90)Y-RE), either glass- or resin-based, is increasingly applied in patients with unresectable liver malignancies. Clinical results are promising but overall response and survival are not yet known. Therefore a meta-analysis on tumor response and survival in patients who underwent (90)Y-RE was conducted. Based on an extensive literature search, six groups were formed. Determinants were cancer type, microsphere type, chemotherapy protocol used, and stage (deployment in first-line or as salvage therapy). For colorectal liver metastases (mCRC), in a salvage setting, response was 79% for (90)Y-RE combined with 5-fluorouracil/leucovorin (5-FU/LV), and 79% when combined with 5-FU/LV/oxaliplatin or 5-FU/LV/irinotecan, and in a first-line setting 91% and 91%, respectively. For hepatocellular carcinoma (HCC), response was 89% for resin microspheres and 78% for glass microspheres. No statistical method is available to assess median survival based on data presented in the literature. In mCRC, (90)Y-RE delivers high response rates, especially if used neoadjuvant to chemotherapy. In HCC, (90)Y-RE with resin microspheres is significantly more effective than (90)Y-RE with glass microspheres. The impact on survival will become known only when the results of phase III studies are published.

Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome.

OBJECTIVE: Effect of genetic screening on outcome in multiple endocrine neoplasia type 1 (MEN1) remains unclear. Expression of MEN1 is described using currently available diagnostic techniques. Manifestations and outcome are compared in patients diagnosed because of clinical expression with those diagnosed by genetic screening. DESIGN: Retrospective cohort study. Patients are divided into two groups: patients with a (i) clinical MEN1 diagnosis and (ii) MEN1 diagnosis by genetic screening. PATIENTS AND MEASUREMENTS: Demographic and clinical data were collected on MEN1 patients treated in the UMCU up to 1 January 2008. Results of mutation analysis were obtained from the Department of Medical Genetics. RESULTS: A total of 74 patients was included (median follow-up 5.5 year); 78% had hyperparathyroidism, 46% a pancreatic neuro-endocrine tumour (NET), 38% a pituitary abnormality, 8% a NET of other origin and 16% an adrenal adenoma at the end of follow-up. Of the patients 18% had no manifestation. All five MEN1-related tumours were seen as first manifestation. Compared with patients identified by genetic screening, patients with a clinical MEN1 diagnosis had significantly more manifestations at diagnosis (P < 0.001) and at end of follow-up (P = 0.002). Eleven of 30 patients with a genetic MEN1 diagnosis (mean age at diagnosis 30.0 years) already had manifestations at diagnosis. No malignancy or death was seen in genetically diagnosed patients. CONCLUSIONS: MEN1 is a syndrome with high morbidity. Genetic diagnosis is associated with less morbidity at diagnosis and at follow-up. Early genetic diagnosis might therefore lead to improvement of long-term outcome.

Clinical effects of transcatheter hepatic arterial embolization with holmium-166 poly(L-lactic acid) microspheres in healthy pigs.

PURPOSE: The aim of this study is to evaluate the toxicity of holmium-166 poly(L-lactic acid) microspheres administered into the hepatic artery in pigs. METHODS: Healthy pigs (20-30 kg) were injected into the hepatic artery with holmium-165-loaded microspheres ((165)HoMS; n=5) or with holmium-166-loaded microspheres ((166)HoMS; n=13). The microspheres' biodistribution was assessed by single-photon emission computed tomography and/or MRI. The animals were monitored clinically, biochemically, and ((166)HoMS group only) hematologically over a period of 1 month ((165)HoMS group) or over 1 or 2 months ((166)HoMS group). Finally, a pathological examination was undertaken. RESULTS: After microsphere administration, some animals exhibited a slightly diminished level of consciousness and a dip in appetite, both of which were transient. Four lethal adverse events occurred in the (166)HoMS group due either to incorrect administration or comorbidity: inadvertent delivery of microspheres into the gastric wall (n=2), preexisting gastric ulceration (n=1), and endocarditis (n=1). AST levels were transitorily elevated post-(166)HoMS administration. In the other blood parameters, no abnormalities were observed. Nuclear scans were acquired from all animals from the (166)HoMS group, and MRI scans were performed if available. In pigs from the (166)HoMS group, atrophy of one or more liver lobes was frequently observed. The actual radioactivity distribution was assessed through ex vivo (166m)Ho measurements. CONCLUSION: It can be concluded that the toxicity profile of HoMS is low. In pigs, hepatic arterial embolization with (166)HoMS in amounts corresponding with liver-absorbed doses of over 100 Gy, if correctly administered, is not associated with clinically relevant side effects. This result offers a good perspective for upcoming patient trials.

Cognitive impairment in tuberous sclerosis complex is a multifactorial condition.

OBJECTIVE: In patients with tuberous sclerosis complex (TSC), associations between tuber number, infantile spasms, and cognitive impairment have been proposed. We hypothesized that the tuber/brain proportion (TBP), the proportion of the total brain volume occupied by tubers, would be a better determinant of seizures and cognitive function than the number of tubers. We investigated tuber load, seizures, and cognitive function and their relationships. METHODS: Tuber number and TBP were characterized on three-dimensional fluid-attenuated inversion recovery MRI with an automated tuber segmentation program. Seizure histories and EEG recordings were obtained. Intelligence equivalents were determined and an individual cognition index (a marker of cognition that incorporated multiple cognitive domains) was calculated. RESULTS: In our sample of 61 patients with TSC, TBP was inversely related to the age at seizure onset and to the intelligence equivalent and tended to be inversely related to the cognition index. Further, a younger age at seizure onset or a history of infantile spasms was related to lower intelligence and lower cognition index. In a multivariable analysis, only age at seizure onset and cognition index were related. CONCLUSIONS: Our systematic analysis confirms proposed relationships between tuber load, epilepsy and cognitive function in tuberous sclerosis complex (TSC), but also indicates that tuber/brain proportion is a better predictor of cognitive function than tuber number and that age at seizure onset is the only independent determinant of cognitive function. Seizure control should be the principal neurointervention in patients with TSC.

Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations.

OBJECTIVE: The purpose of this study was to systematically analyze the associations between different TSC1 and TSC2 mutations and the neurologic and cognitive phenotype in patients with tuberous sclerosis complex (TSC). METHODS: Mutation analysis was performed in 58 patients with TSC. Epilepsy variables, including EEG, were classified. A cognition index was determined based on a comprehensive neuropsychological assessment. On three-dimensional fluid-attenuated inversion recovery MR images, an automated tuber segmentation program detected and calculated the number of tubers and the proportion of total brain volume occupied by tubers (tuber/brain proportion [TBP]). RESULTS: As a group, patients with a TSC2 mutation had earlier age at seizure onset, lower cognition index, more tubers, and a greater TBP than those with a TSC1 mutation, but the ranges overlapped considerably. Familial cases were older at seizure onset and had a higher cognition index than nonfamilial cases. Patients with a mutation deleting or directly inactivating the tuberin GTPase activating protein (GAP) domain had more tubers and a greater TBP than those with an intact GAP domain. Patients with a truncating TSC1 or TSC2 mutation differed from those with nontruncating mutations in seizure types only. CONCLUSIONS: Although patients with a TSC1 mutation are more likely to have a less severe neurologic and cognitive phenotype than those with a TSC2 mutation, the considerable overlap between both aspects of the phenotype implies that prediction of the neurologic and cognitive phenotypes in individuals with tuberous sclerosis complex should not be based on their particular TSC1 or TSC2 mutation.

Bone seeking radiopharmaceuticals for palliation of pain in cancer patients with osseous metastases.

Many patients with cancer develop symptomatic skeletal metastases at an advanced stage of their disease. Skeletal metastases are often complicated by pain. They cause considerable morbidity and mortality. Besides analgesics, treatment options include external beam radiotherapy, bisphosphonates, chemotherapy, surgery and bone seeking radiopharmaceuticals. Pain palliation with bone seeking radiopharmaceuticals has proved to be an effective treatment modality in patients with metastatic bone pain. Radiopharmaceuticals bind to the bone matrix in areas of increased bone turnover, due to a metastatic response. Beta rays from the specific radionuclide, bound to its carrier ligand, result in the therapeutic effect. Various radiopharmaceuticals have been developed for this purpose. All have their own characteristics. The radiopharmaceuticals Samarium-153-ethylenediaminetetramethylenephosphonic acid ((153)Sm-EDTMP) and Strontium-89-Chloride, which are approved in the USA and Europe, as well as the not universally approved Rhenium-186-hydroxyethylidenediphosphonic acid ((186)Re-HEDP), will be discussed in greater detail. Depending on the half-life and radiation energy of the specific radionuclide, they exert a different effect and toxicity profile. In most cases, bone marrow toxicity is limited and reversible, which makes repetitive treatment relatively safe. Several studies have shown encouraging clinical results of palliative therapy using bone seeking radiopharmaceuticals, with an overall reported pain response rate in the order of +/- 70-80% of patients. This systemic form of radionuclide therapy is simple to administer and complements other treatment options. It has been associated with marked pain reduction, improved mobility in many patients, reduced dependence on analgesics, and improved performance status and quality of life. Additionally, new therapeutic strategies hold the promise of enhancement of the palliative and anticancer effects of this form of therapy.

A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma.

CONTEXT: Medullary thyroid carcinoma (MTC) metastasizes early in its clinical course. No effective systemic therapy is available. Generally (somatic or germline), mutations in the rearranged during transfection gene are considered essential in the pathogenesis of MTC. OBJECTIVE: We investigated imatinib, a tyrosine kinase inhibitor, as a potential treatment in patients with disseminated MTC. DESIGN: A phase II study was initiated using 600 mg imatinib daily with a possible dose increase to 800 mg in case of progression. Standard Response Evaluation Criteria in Solid Tumors were used using computed tomography or magnetic resonance imaging every 2 months. RESULTS: There were 15 patients with disseminated MTC treated for up to 12 months. No objective responses were observed. Four patients had stable disease over 24 months. Three patients stopped treatment due to toxic effects [fatigue (n = 2) and nausea (n = 1)]. In four cases the dose of imatinib was decreased because of toxicity [rash and malaise (n = 2) and laryngeal swelling (n = 2)]. Emergency tracheotomy was performed in two cases due to mucosal swelling of the larynx in patients with recurrent nerve palsy and a narrow vocal cleft. In nine patients with a history of a thyroidectomy, the dose of supplemental thyroid hormone was increased because of serious hypothyroidism. CONCLUSIONS: Imatinib therapy yielded no objective responses and induced considerable toxicity in patients with MTC. A minority of patients had stable disease. Patients with supplemented hypothyroidism or with recurrent nerve palsy are specifically at risk for serious adverse events and need special attention when treated with imatinib.

Characterization of holmium loaded alginate microspheres for multimodality imaging and therapeutic applications.

In this paper the preparation and characterization of holmium-loaded alginate microspheres is described. The rapid development of medical imaging techniques offers new opportunities for the visualisation of (drug-loaded) microparticles. Therefore, suitable imaging agents have to be incorporated into these particles. For this reason, the element holmium was used in this study in order to utilize its unique imaging characteristics. The paramagnetic behaviour of this element allows visualisation with MRI and holmium can also be neutron-activated resulting in the emission of gamma-radiation, allowing visualisation with gamma cameras, and beta-radiation, suitable for therapeutic applications. Almost monodisperse alginate microspheres were obtained by JetCutter technology where alginate droplets of a uniform size were hardened in an aqueous holmium chloride solution. Ho(3+) binds via electrostatic interactions to the carboxylate groups of the alginate polymer and as a result alginate microspheres loaded with holmium were obtained. The microspheres had a mean size of 159 microm and a holmium loading of 1.3 +/- 0.1% (w/w) (corresponding with a holmium content based on dry alginate of 18.3 +/- 0.3% (w/w)). The binding capacity of the alginate polymer for Ho(3+) (expressed in molar amounts) is equal to that for Ca(2+), which is commonly used for the hardening of alginate. This indicates that Ho(3+) has the same binding affinity as Ca(2+). In line herewith, dynamic mechanical analyses demonstrated that alginate gels hardened with Ca(2+) or Ho(3+) had similar viscoelastic properties. The MRI relaxation properties of the microspheres were determined by a MRI phantom experiment, demonstrating a strong R(2)* effect of the particles. Alginate microspheres could also be labelled with radioactive holmium by adding holmium-166 to alginate microspheres, previously hardened with calcium (labelling efficiency 96%). The labelled microspheres had a high radiochemical stability (94% after 48 h incubation in human serum), allowing therapeutic applications for treatment of cancer. The potential in vivo application of the microspheres for a MR-guided renal embolization procedure was illustrated by selective administration of microspheres to the left kidney of a pig. Anatomic MR-imaging showed the presence of holmium-loaded microspheres in the kidney. In conclusion, this study demonstrates that the incorporation of holmium into alginate microspheres allows their visualisation with a gamma camera and MRI. Holmium-loaded alginate microspheres can be used therapeutically for embolization and, when radioactive, for local radiotherapy of tumours.

Lanthanide bearing microparticulate systems for multi-modality imaging and targeted therapy of cancer.

The rapid developments of high-resolution imaging techniques are offering unique possibilities for the guidance and follow up of recently developed sophisticated anticancer therapies. Advanced biodegradable drug delivery systems, e.g. based on liposomes and polymeric nanoparticles or microparticles, are very effective tools to carry these anticancer agents to their site of action. Elements from the group of lanthanides have very interesting physical characteristics for imaging applications and are the ideal candidates to be co-loaded either in their non-radioactive or radioactive form into these advanced drug delivery systems because of the following reasons: Firstly, they can be used both as magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents and for single photon emission computed tomography (SPECT). Secondly, they can be used for radionuclide therapies which, importantly, can be monitored with SPECT, CT, and MRI. Thirdly, they have a relatively low toxicity, especially when they are complexed to ligands. This review gives a survey of the currently developed lanthanide-loaded microparticulate systems that are under investigation for cancer imaging and/or cancer therapy.

Increased levels of viable circulating endothelial cells are an indicator of progressive disease in cancer patients.

BACKGROUND: There is accumulating evidence from preclinical studies that circulating endothelial cells (CECs) play an important role in neovascularization and tumor growth. The role of CECs in human cancer progression is sparsely investigated. We therefore analyzed CECs in peripheral blood of cancer patients. In addition, we correlated CEC levels in these patients with plasma levels of cytokines that are known to mobilize CECs in experimental models. PATIENTS AND METHODS: Viable CECs were isolated, quantified and cultured from cancer patients' whole blood by using magnetic beads coupled to an antibody directed against CD146, a pan-endothelial marker. Viable cells were visualized by calceinAM staining. Positive staining for specific endothelial cell markers [i.e. von Willebrand factor, CD31, vascular endothelial cell growth factor (VEGF) receptor-2] was used to confirm the endothelial phenotype. RESULTS: Cancer patients with progressive disease (95 patients) had on average 3.6-fold more CECs than healthy subjects (46 patients, P <0.001). Patients (17) with stable disease had CEC numbers equal to that circulating in healthy subjects (P = 0.69). A subset of in vitro cultured CECs incorporated into endothelial layers and formed colonies. Plasma levels of cytokines that are thought to mobilize CECs from the bone marrow [VEGF, placental growth factor, stromal cell derived factor 1alpha and stem cell factor (71 patients)] did not correlate with CEC amounts. The levels of viable CECs in cancer patients were modified by granulocyte colony-stimulating factor treatment and chemotherapy. CONCLUSION: In progressive cancer patients, the amount of CECs is increased. These CECs are viable and may contribute to vessel formation. The number of CECs is influenced by anticancer treatment.

186Re-etidronate. Efficacy of palliative radionuclide therapy for painful bone metastases.

Pain palliation with bone-seeking radiopharmaceuticals is an effective treatment modality in patients with advanced metastatic bone cancer. Several studies have shown encouraging clinical results of palliative therapy using 186Re-HEDP, with an overall reported response rate of +/-71% for painful osseous metastasized prostate and breast cancer patients. 186Re-HEDP is a very potential isotope with numerous advantageous characteristics for this purpose. Myelosuppressive toxicity is limited and reversible, which makes repetitive treatment safe. However, individual studies are difficult to compare, and are hampered by the numerous and different methods used to assess clinical response. Standardized clinical response assessment using the objective multi-dimensional pain evaluation model should therefore be implemented.