[Hyperthermic Isolated Limb Perfusion Combined with Tasonermin - a Perfusion Leakage Monitoring Technique]. / Hypertermická izolovaná perfuze koncetin v kombinaci s tasonerminem - technika monitorování úniku perfuzátu.

BACKGROUND: Hyperthermic isolated limb perfusion is used to treat irresectable extremity malignancies. It is based on the following principle - the perfusion of the extremity is isolated from systemic circulation and connected to an extra-corporal circuit via which a very high concentration of a chemotherapeutic agent is administered into the blood compartment of the extremity. In some cases, treatment efficiency can be improved using tasonermin (a TNF-α agent). By itself, tasonermin can cause severe health complications in patients if leakage into systemic circulation results in a level that exceeds the maximally tolerated dose. Therefore, it is important to monitor for leakage during the whole operation. METHOD: Leakage monitoring was performed by a nuclear medicine method based on the measurement of activity of a gamma-emitting radiotracer detected by a scintillation probe located over the heart. An amount of radiotracer that resulted in a basal level of measured signal was first administered into the systemic circuit followed by the administration of a second, one order of magnitude higher amount of radiotracer into the perfusion circuit. Leakage, when it occurred, increased the count rate detected over the heart, and the mathematical relation between leakage level and count rate increase was derived. RESULTS: In our department, the method was tested and optimized during isolated limb perfusion without using a TNF-α agent. Then, accreditation for the use of TNF-α was granted. Since then, the method has been used to monitor leakage in all cases of isolated limb perfusion with TNF-α. All isolated limb perfusion operations with TNF-α passed without complications. The radiation burden was almost negligible for both the patient and medical staff. CONCLUSION: The method described in this report represents a reliable method for perfusion leakage monitoring when using TNF-α in our department.Key words: perfusion - isolated limb - TNF-α - leakage - monitoring - nuclear medicine - radiopharmaceuticalsThe authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 16. 6. 2016Accepted: 21. 6. 2016.

Rapid-Steady-State-T1 signal modeling during contrast agent extravasation: toward tumor blood volume quantification without requiring the arterial input function.

PURPOSE: This study demonstrates how to quantify the tumor blood volume fraction (BVf) using the dynamic Rapid-Steady-State-T1 (RSST1 )-MRI method despite contrast agent (CA) leakage and without arterial input function (AIF) determination. METHODS: For vasculature impermeable to CAs, the BVf is directly quantified from the RSST1 signal amplitude. In case of CA extravasation, we propose a two-compartment model to describe the dynamic RSST1 signal increase. We applied the mathematical model in a pilot-study on a RG2-glioma model to compare extravasation of two Gd-based CAs. The BVf quantification using the mathematical model in a C6-glioma model (n = 8) with the clinical CA Gd-DOTA was validated using a ΔR2 *-steady-state MRI method with an USPIO and by immunohistochemical staining of perfused vessels labeled with Hoechst-33342 dye in the same rats. RESULTS: BVf in tumor and in healthy brain tissues (0.034 ± 0.005 and 0.026 ± 0.004, respectively) derived from the dynamic RSST1 signal were confirmed by ΔR2 *-steady-state MRI (0.036 ± 0.003 and 0.027 ± 0.002, respectively, correlation coefficient rS = 0.74) and by histology (0.036 ± 0.003 and 0.025 ± 0.004 respectively, rS = 0.87). CONCLUSION: Straightforward tumor BVf quantification without AIF determination is demonstrated in presence of CA leakage. The method will facilitate angiogenesis assessment in longitudinal neuro-oncologic studies in particular when monitoring the response to antiangiogenic therapies.

An efficient computational approach to characterize DSC-MRI signals arising from three-dimensional heterogeneous tissue structures.

The systematic investigation of susceptibility-induced contrast in MRI is important to better interpret the influence of microvascular and microcellular morphology on DSC-MRI derived perfusion data. Recently, a novel computational approach called the Finite Perturber Method (FPM), which enables the study of susceptibility-induced contrast in MRI arising from arbitrary microvascular morphologies in 3D has been developed. However, the FPM has lower efficiency in simulating water diffusion especially for complex tissues. In this work, an improved computational approach that combines the FPM with a matrix-based finite difference method (FDM), which we call the Finite Perturber the Finite Difference Method (FPFDM), has been developed in order to efficiently investigate the influence of vascular and extravascular morphological features on susceptibility-induced transverse relaxation. The current work provides a framework for better interpreting how DSC-MRI data depend on various phenomena, including contrast agent leakage in cancerous tissues and water diffusion rates. In addition, we illustrate using simulated and micro-CT extracted tissue structures the improved FPFDM along with its potential applications and limitations.

Cooperative role of endogenous leucotrienes and platelet-activating factor in ischaemia-reperfusion-mediated tissue injury.

Insufficient oxygen delivery to organs leads to tissue dysfunction and cell death. Reperfusion, although vital to organ survival, initiates an inflammatory response that may both aggravate local tissue injury and elicit remote organ damage. Polymorphonuclear neutrophil (PMN) trafficking to remote organs following ischaemia/reperfusion (I/R) is associated with the release of lipid mediators, including leucotriene (LT) B4 , cysteinyl-LTs (CysLTs) and platelet-activating factor (PAF). Yet, their potentially cooperative role in regulating I/R-mediated inflammation has not been thoroughly assessed. The present study aimed to determine the cooperative role of lipid mediators in regulating PMN migration, tissue oedema and injury using selective receptor antagonists in selected models of I/R and dermal inflammation. Our results show that rabbits, pre-treated orally with BIIL 284 and/or WEB 2086 and MK-0571, were protected from remote tissue injury following I/R or dermal inflammation in an additive or synergistic manner when the animals were pre-treated with two drugs concomitantly. The functional selectivity of the antagonists towards their respective agonists was assessed in vitro, showing that neither BIIL 284 nor WEB 2086 prevented the inflammatory response to IL-8, C5a and zymosan-activated plasma stimulation. However, these agonists elicited LTB4 biosynthesis in isolated rabbit PMNs. Similarly, a cardioprotective effect of PAF and LTB4 receptor antagonists was shown following myocardial I/R in mice. Taken together, these results underscore the intricate involvement of LTB4 and PAF in each other's responses and provide further evidence that targeting both LTs and PAF receptors provides a much stronger anti-inflammatory effect, regulating PMN migration and oedema formation.

Dexrazoxane for the prevention of cardiac toxicity and treatment of extravasation injury from the anthracycline antibiotics.

The cumulative cardiac toxicity of the anthracycline antibiotics and their propensity to produce severe tissue injury following extravasation from a peripheral vein during intravenous administration remain significant problems in clinical oncologic practice. Understanding of the free radical metabolism of these drugs and their interactions with iron proteins led to the development of dexrazoxane, an analogue of EDTA with intrinsic antineoplastic activity as well as strong iron binding properties, as both a prospective cardioprotective therapy for patients receiving anthracyclines and as an effective treatment for anthracycline extravasations. In this review, the molecular mechanisms by which the anthracyclines generate reactive oxygen species and interact with intracellular iron are examined to understand the cardioprotective mechanism of action of dexrazoxane and its ability to protect the subcutaneous tissues from anthracycline-induced tissue necrosis.

Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery.

A polymer ultrasound contrast agent (UCA) developed in our lab has been shown to greatly reduce in size when exposed to ultrasound, resulting in nanoparticles less than 400 nm in diameter capable of escaping the leaky vasculature of a tumor to provide a sustained release of drug. Previous studies with the hydrophilic drug doxorubicin (DOX) demonstrated enhanced drug delivery to tumors when triggered with ultrasound. However the therapeutic potential has been limited due to the relatively low payload of DOX. This study compares the effects of loading the hydrophobic drug paclitaxel (PTX) on the agent's acoustic properties, drug payload, tumoricidal activity, and the ability to deliver drugs through 400 nm pores. A maximum payload of 129.46 ± 1.80 µg PTX/mg UCA (encapsulation efficiency 71.92 ± 0.99%) was achieved, 20 times greater than the maximum payload of DOX (6.2 µg/mg), while maintaining the acoustic properties. In vitro, the tumoricidal activity of paclitaxel loaded UCA exposed to ultrasound was significantly greater than controls not exposed to ultrasound (p<0.0016). This study has shown that PTX loaded UCA triggered with focused ultrasound have the potential to provide a targeted and sustained delivery of drug to tumors.

A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma.

Gene and nucleic acid therapy are expected to play a major role in the next generation of medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel non-viral gene delivery system. Poly(ethylene glycol) (PEG)ylation is a useful method for achieving a longer circulation time for delivery of the MEND to a tumour via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity for the delivery system. For successful gene delivery for cancer treatment, the crucial issue associated with the use of PEG, the 'PEG dilemma' must be addressed. In this review, we describe the development and applications of MEND, and discuss strategies for overcoming the PEG dilemma, based on the manipulation of intracellular trafficking of cellular uptake and endosomal release using functional devices such as specific ligands, cleavable PEG systems and endosomal fusogenic/disruptic peptides.

Tumor delivery of macromolecular drugs based on the EPR effect.

Enhanced permeability and retention (EPR) effect is the physiology-based principal mechanism of tumor accumulation of large molecules and small particles. This specific issue of Advanced Drug Delivery Reviews is summing up multiple data on the EPR effect-based drug design and clinical outcome. In this commentary, the role of the EPR effect in the intratumoral delivery of protein and peptide drugs, macromolecular drugs and drug-loaded long-circulating pharmaceutical nanocarriers is briefly discussed together with some additional opportunities for drug delivery arising from the initial EPR effect-mediated accumulation of drug-containing macromolecular systems in tumors.

The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect.

The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors related to their anatomical and pathophysiological differences from normal tissues. For example, angiogenesis leads to high vascular density in solid tumors, large gaps exist between endothelial cells in tumor blood vessels, and tumor tissues show selective extravasation and retention of macromolecular drugs. This EPR effect served as a basis for development of macromolecular anticancer therapy. We demonstrated methods to enhance this effect artificially in clinical settings. Of great importance was increasing systolic blood pressure via slow angiotensin II infusion. Another strategy involved utilization of NO-releasing agents such as topical nitroglycerin, which releases nitrite. Nitrite is converted to NO more selectively in the tumor tissues, which leads to a significantly increased EPR effect and enhanced antitumor drug effects as well. This review discusses molecular mechanisms of factors related to the EPR effect, the unique anatomy of tumor vessels, limitations and techniques to avoid such limitations, augmenting tumor drug delivery, and experimental and clinical findings.

Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects.

The success of an effective drug delivery system using liposomes for solid tumor targeting based on EPR effects is highly dependent on both size ranging from 100-200 nm in diameter and prolonged circulation half-life in the blood. A major development was the synthesis of PEG-liposomes with a prolonged circulation time in the blood. Active targeting of immunoliposomes to the solid tumor tissue can be achieved by the Fab' fragment which is better than whole IgG in terms of designing PEG-immunoliposomes with prolonged circulation. For intracellular targeting delivery to solid tumors based on EPR effects, transferrin-PEG-liposomes can stay in blood circulation for a long time and extravasate into the extravascular of tumor tissue by the EPR effect as PEG-liposomes. The extravasated transferrin-PEG-liposomes can maintain anti cancer drugs in interstitial space for a longer period, and deliver them into the cytoplasm of tumor cells via transferrin receptor-mediated endocytosis. Transferrin-PEG-liposomes improve the safety and efficacy of anti cancer drug by both passive targeting by prolonged circulation and active targeting by transferrin.

PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect.

As mortality due to cancer continues to rise, advances in nanotechnology have significantly become an effective approach for achieving efficient drug targeting to tumour tissues by circumventing all the shortcomings of conventional chemotherapy. During the past decade, the importance of polymeric drug-delivery systems in oncology has grown exponentially. In this context, poly(lactic-co-glycolic acid) (PLGA) is a widely used polymer for fabricating 'nanoparticles' because of biocompatibility, long-standing track record in biomedical applications and well-documented utility for sustained drug release, and hence has been the centre of focus for developing drug-loaded nanoparticles for cancer therapy. Such PLGA nanoparticles have also been used to develop proteins and peptides for nanomedicine, and nanovaccines, as well as a nanoparticle-based drug- and gene-delivery system for cancer therapy, and nanoantigens and growth factors. These drug-loaded nanoparticles extravasate through the tumour vasculature, delivering their payload into the cells by the enhanced permeability and retention (EPR) effect, thereby increasing their therapeutic effect. Ongoing research about drug-loaded nanoparticles and their delivery by the EPR effect to the tumour tissues has been elucidated in this review with clarity.

A murine experimental anthracycline extravasation model: pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage.

The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe(2+) complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a(Y165S/+)), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.

Pharmacological characterization of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), a novel selective 5-lipoxygenase-activating protein inhibitor that reduces acute and chronic inflammation.

Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.

[Effects of aloe gel on doxorubicin-induced extravasation injury in rats].

BACKGROUND AND OBJECTIVE: Aloe has preventive effects on some chemotherapy-induced extravasation injuries. This study was to investigate the effect and mechanism of aloe gel on doxorubicin-induced extravasation injury. METHODS: Sprague-Dawley (SD) rats were used to establish the extravasation injury model induced by doxorubicin. Thirty SD rats were randomly divided into three groups: control group, aloe gel group (1 g/L) and 50% magnesium sulfate group. The area of extravasation was measured and the degree of injury was observed. The injured tissues were resected from two randomly selected rats in each group on the 1st, 4th, 7th, 11th, and 18th day after treatments. Pathological morphology of the resected tissues was observed under an optical microscope after hematoxylin and eosin (HE) staining. The exosmosis skin and subcutaneous tissues of rats were resected five days after treatments. Then the wounds were interruptedly sutured. When sutures were removed on the 7th day after operation, the condition of primary wound healing and the healing time were recorded. Expressions of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in the exosmosis skin and subcutaneous tissues were detected by immunohistochemistry. RESULTS: The area and the degree of extravasation injury were smaller and less severe in the aloe gel and magnesium sulfate groups than in the control group (P<0.01). The rates of primary wound healing were significantly higher in the aloe gel (60.0%) and magnesium sulfate (66.7%) groups than in the control group (20.0%); while the healing time was significantly shorter in the aloe gel (9.6+/-1.64 d) and magnesium sulfate (9.33+/-1.40 d) groups than in the control group (12.13+/-2.06 d) (both P<0.01). Moreover, the expression levels of VEGF and EGFR were higher in the aloe gel group than in the control group. CONCLUSION: The preventive and therapeutic effects of aloe gel on doxorubicin-induced extravasation injury are satisfactory, which may be in relation to the up-regulation of VEGF and EGFR.

First-pass dynamic contrast-enhanced MRI with extravasating contrast reagent: evidence for human myocardial capillary recruitment in adenosine-induced hyperemia.

Human myocardial (1)H(2)O T(1)-weighted dynamic contrast-enhanced MRI data were acquired during the brief first-pass period after injection of a very small gadolinium diethylenetriaminepenta-acetate (GdDTPA(2-)) dose. The shutter-speed pharmacokinetic effects of both transendothelial and transcytolemmal equilibrium water exchange processes were investigated. Our results indicate that even for such a short acquisition window and relatively large pseudo-first-order rate constant (K(trans)) for plasma/interstitium contrast reagent (CR) transfer the kinetics of these water exchange processes cannot be treated as infinitely fast or slow. However, neither the intracellular water molecule lifetime (tau(i)) nor its intravascular counterpart (tau(b)) are among the parameters most influential in analysis of the noisy data typically associated with the cardiac perfusion application. Thus, the actual values of water exchange kinetic rate constants are relatively indeterminate as this experiment is usually conducted. Combining the K(trans) evaluations with independently determined flow (F) values allows us to estimate CR permeability coefficient surface area product (P(CR)S) values. The fact that the P(CR)S magnitudes almost equal the K(trans) values confirms that GdDTPA(2-) extravasation in resting human myocardial muscle is indeed permeation-limited and supports the validity of the K(trans) and P(CR)S estimations. Nevertheless the model analysis is most consistent with the results if P(CR)S is not assumed to be constant with changing flow. The capillary blood volume fraction (v(b)) is a sensitive parameter in the analysis. We also compared resting and hyperemic cardiac conditions, the latter resulting from the volume flow increase induced by adenosine arteriolar vasodilation. We found that the P(CR)S value increases with flow probably mostly because of an S increase associated with capillary recruitment. The v(b) values also increased in hyperemia and showed a flow-dependence with a clearly identifiable component due to capillary recruitment.

Non-invasive imaging of barriers to drug delivery in tumors.

Solid tumors often develop high interstitial fluid pressure (IFP) as a result of increased water leakage and impaired lymphatic drainage, as well as changes in the extracellular matrix composition and elasticity. This high fluid pressure forms a barrier to drug delivery and hence, resistance to therapy. We have developed techniques based on contrast enhanced magnetic resonance imaging for mapping in tumors the vascular and transport parameters determining the delivery efficiency of blood borne substances. Sequential images are recorded during continuous infusion of a Gd-based contrast agent and analyzed according to a new physiological model, yielding maps of microvascular transfer constants, as well as outward convective interstitial transfer constants and steady state interstitial contrast agent concentrations both reflecting IFP distribution. We further demonstrated in non small cell human lung cancer xenografts the capability of our techniques to monitor in vivo collagenase induced increase in contrast agent delivery as a result of decreased IFP. These techniques can be applied to test drugs that affect angiogenesis and modulate interstitial fluid pressure and has the potential to be extended to cancer patients for assessing resistance to drug delivery.

Management of anthracycline extravasation injuries.

OBJECTIVE: To review the evidence for the management of anthracycline extravasation and determine the optimal treatment of such injuries. DATA SOURCES: A search of MEDLINE (1966-February 2007) and International Pharmaceutical Abstracts (1970-February 2007) was performed using the search terms anthracyclines and extravasation. DATA SYNTHESIS: Extravasation of anthracyclines can have devastating effects. After infiltration of these drugs into the interstitial tissue, damage may range from mild erythema and pain to severe tissue necrosis. Many agents have been studied in the management of these injuries; however, few have demonstrated efficacy and treatment remains controversial. Nonpharmacologic modalities shown to limit extravasation injuries include local tissue cooling and elevation of the affected area. Corticosteroids, sodium bicarbonate, hyaluronidase, hyperbaric oxygen, heparin fractions, alpha-tocopherol, N-acetylcysteine, and granulocyte macrophage-colony stimulating factor have all either been shown to be ineffective or have limited data supporting their use. Topical dimethyl sulfoxide (DMSO) has been shown in prospective studies to limit the course of extravasation injuries. Dexrazoxane has been shown in animal models and case reports to be useful in the management of anthracycline extravasation. Two recent prospective clinical trials examining intravenous dexrazoxane 1000 mg/m2 within 6 hours of extravasation, 1000 mg/m2 24 hours after extravasation, and 500 mg/m2 48 hours after extravasation injuries add to the data supporting the use of this agent in such injuries. Of the 54 patients enrolled, surgery-requiring necrosis was avoided in 98.2%. CONCLUSIONS: The optimal treatment of anthracycline extravasation includes local tissue cooling, elevation of the afflicted extremity, dexrazoxane administration, and possibly topical DMSO. Many other drugs have been investigated; however, due to a lack of data, they cannot be recommended for the management of anthracycline extravasation.

Comparison of extraarticular leakage values of radiopharmaceuticals used for radionuclide synovectomy.

OBJECTIVES: Radionuclide synovectomy is a reliable therapy in patients with chronic synovitis. However, radiation doses delivered to non-target organ systems due to leakage of radioactive material from the articular cavity are an important disadvantage of this procedure. In this study we compared extraarticular leakage values of the 3 commonly used radiopharmaceuticals; 90Y-citrate, 90Y-silicate and 186Re-sulfide colloid. MATERIALS AND METHODS: Thirty-five patients with persistent synovitis were enrolled in the study. Twenty-two hemophilic, 8 rheumatoid arthritis and 5 patients with pigmented villonodular synovitis were studied. 90Y labeled silicate and citrate were used for knee joints and 186Re-sulfide for intermediate sized joints. Radiocolloid leakage values were evaluated using a gamma camera with 20% window centered over the bremsstrahlung photopeak of 90Y and a respective window over the 137 keV photopeak of 186Re. Regions of interest were drawn over the injection site, the regional lymph nodes and the background areas. Leakage of radiocolloid was calculated by dividing the counts/pixel in the regional lymph node area to the counts/pixel in the injection site. RESULTS: No visible leakage was observed. The median leakage values calculated for 90Y-citrate, 90Y-silicate and 186Re-sulfide were found as 1.9%, 2.4% and 2.7%, respectively. The difference between the variability of leakage values was not statistically significant (p > 0.05). CONCLUSION: There was no significant difference in terms of extraarticular leakage between 9Y-citrate, 9Y-silicate and 186Re-sulfide radiocolloids.

A pitfall of FDG-PET image interpretation: accumulation of FDG in the dependent area of the urinary bladder after bladder irrigation--the usefulness of the prone position.

In F-18 FDG PET studies, retrograde irrigation of the urinary bladder is usually used to reduce the interference with physiological urinary accumulation of F-18 FDG in patients with possible pelvic lesions. A 34-year-old female who had recently been diagnosed with cervical cancer had an F-18 FDG-PET scan performed for whole-body evaluation. The bladder was irrigated with physiological saline and filled with 200 mL of irrigation fluid through a 3-way balloon catheter inserted before the scan. Two areas with high FDG accumulation were noted in the posterior pelvis. Tumor invasion or metastasis could not be ruled out. Additional focal imaging of the pelvis was performed with the patient in the prone position. The lesion on the left side of the patient was still noted, whereas the lesion on the right had disappeared, which proved that it was a false-positive lesion. Great caution is required when assessing imaging results to avoid misdiagnosis in patients after bladder irrigation.

Characterizing extravascular fluid transport of macromolecules in the tumor interstitium by magnetic resonance imaging.

Noninvasive imaging techniques to image and characterize delivery and transport of macromolecules through the extracellular matrix (ECM) and supporting stroma of a tumor are necessary to develop treatments that alter the porosity and integrity of the ECM for improved delivery of therapeutic agents and to understand factors which influence and control delivery, movement, and clearance of macromolecules. In this study, a noninvasive imaging technique was developed to characterize the delivery as well as interstitial transport of a macromolecular agent, albumin-GdDTPA, in the MCF-7 human breast cancer model in vivo, using magnetic resonance imaging. The transport parameters derived included vascular volume, permeability surface area product, macromolecular fluid exudate volume, and drainage and pooling rates. Immunohistochemical staining for the lymphatic endothelial marker LYVE-1 was done to determine the contribution of lymphatics to the macromolecular drainage. Distinct pooling and draining regions were detected in the tumors using magnetic resonance imaging. A few lymphatic vessels positively stained for LYVE-1 were also detected although these were primarily collapsed and tenuous suggesting that lymphatic drainage played a minimal role, and that the bulk of drainage was due to convective transport through the ECM in this tumor model.