Biokinetics and dosimetry in patients administered with (111)In-DOTA-Tyr(3)-octreotide: implications for internal radiotherapy with (90)Y-DOTATOC.

Recent advances in receptor-mediated tumour imaging have resulted in the development of a new somatostatin analogue, DOTA-dPhe(1)-Tyr(3)-octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, ease of labelling and stability with yttrium-90 and favourable biodistribution in animal models. The aim of this work was to evaluate the biodistribution and dosimetry of DOTATOC radiolabelled with indium-111, in anticipation of therapy trials with (90)Y-DOTATOC in patients. Eighteen patients were injected with DOTATOC (10 microg), labelled with 150-185 MBq of (111)In. Blood and urine samples were collected throughout the duration of the study (0-2 days). Planar and single-photon emission tomography images were acquired at 0.5, 3-4, 24 and 48 h and time-activity curves were obtained for organs and tumours. A compartmental model was used to determine the kinetic parameters for each organ. Dose calculations were performed according to the MIRD formalism. Specific activities of >37 GBq/ micromol were routinely achieved. Patients showed no acute or delayed adverse reactions. The residence time for (111)In-DOTATOC in blood was 0.9+/-0.4 h. The injected activity excreted in the urine in the first 24 h was 73%+/-11%. The agent localized primarily in spleen, kidneys and liver. The residence times in source organs were: 2.2+/-1.8 h in spleen, 1.7+/-1.2 h in kidneys, 2.4+/-1.9 h in liver, 1.5+/-0.3 h in urinary bladder and 9. 4+/-5.5 h in the remainder of the body; the mean residence time in tumour was 0.47 h (range: 0.03-6.50 h). Based on our findings, the predicted absorbed doses for (90)Y-DOTATOC would be 7.6+/-6.3 (spleen), 3.3+/-2.2 (kidneys), 0.7+/-0.6 (liver), 2.2+/-0.3 (bladder), 0.03+/-0.01 (red marrow) and 10.1 (range: 1.4-31.0) (tumour) mGy/MBq. These results indicate that high activities of (90)Y-DOTATOC can be administered with low risk of myelotoxicity, although with potentially high radiation doses to the spleen and kidneys. Tumour doses were high enough in most cases to make it likely that the desired therapeutic response desired would be obtained.     

(125)I liquid in an intracranial balloon: TG-43 formalism for an extended source

PURPOSE: To present a calculation formalism for spherical homogeneous liquid brachytherapy sources and to analyze the difficulties encountered in numerical integration over non-spherical source volumes. METHODS AND MATERIALS: TG-43 formalism provides a general definition of the geometric factor for distributed source distributions. Here the geometric factor and dose for a spherical source are computed for an (125)I balloon. The errors in numerical summation of dose from point sources are assessed by computing ratios of the geometric factors of point-source and extended-source voxel volumes. RESULTS: This sphere calculation agrees well with measured dose values, showing maximum and average differences of 4.8% and 0.5% at the balloon surface. Numerical integration gives errors greater than 1% within five voxel radii of a voxel source. CONCLUSIONS: A new spherical dose calculation technique is proposed for brachytherapy treatment planning systems. Numerical integration over point source voxels is not accurate near the balloon surface.     

Liquid Embolic Agents for Endovascular Embolization: Evaluation of an Established (Onyx) and a Novel (PHIL) Embolic Agent in an In Vitro AVM Model

BACKGROUND AND PURPOSE:Embolization plays a key role in the treatment of arteriovenous malformations. The aim of this study was to evaluate an established (Onyx) and a novel (precipitating hydrophobic injectable liquid [PHIL]) liquid embolic agent in an in vitro AVM model.MATERIALS AND METHODS:An AVM model was integrated into a circuit system. The artificial nidus (subdivided into 28 honeycomb-like sections) was embolized with Onyx 18 (group Onyx; n = 8) or PHIL 25 (group PHIL; n = 8) with different pause times between the injections (30 and 60 seconds, n = 4 per study group) by using a 1.3F microcatheter. Procedure times, number of injections, embolization success (defined as the number of filled sections of the artificial nidus), volume of embolic agent, and frequency and extent of reflux and draining vein embolization were assessed.RESULTS:Embolization success was comparable between Onyx and PHIL. Shorter pause times resulted in a significantly higher embolization success for PHIL (median embolization score, 28 versus 18; P = .011). Compared with Onyx, lower volumes of PHIL were required for the same extent of embolization (median volume per section of the artificial nidus, 15.5 versus 3.6 μL; P < .001).CONCLUSIONS:While the embolization success was comparable for Onyx and PHIL, pause time had a considerable effect on the embolization success in an in vitro AVM model. Compared with Onyx, lower volumes of PHIL were required for the same extent of embolization.

Arteriovenous malformations are complex vascular structures composed of feeding arteries, an intervening network of small pathologic blood vessels (the so-called nidus), and draining veins. The lack of an intervening capillary bed allows high-flow arteriovenous shunting of blood. While AVMs can occur throughout the entire body, cerebral AVMs are of particular relevance due to their ability to cause impairing neurologic symptoms and their considerable risk of hemorrhage.¹Alone or in combination with microneurosurgery and stereotactic radiation therapy, embolization plays an important role in the management of cerebral AVMs.² The aim of AVM embolization is complete filling of the nidus, while unwanted reflux into the feeding arteries should be minimized and premature embolization of the draining veins should be avoided.³A wide variety of embolic agents has been and is currently used for embolization of AVMs. At present, the liquid embolic agents (LEAs) ethylene-vinyl alcohol copolymer (EVOH) and n-butyl cyanoacrylate are used most frequently.⁴ Although the embolization results have improved since the introduction of EVOH-based LEAs with rates of complete obliteration ranging from 16% to 100%, the success rate of AVM embolization, especially for complex AVMs, is not yet satisfying.^2,3 Currently, new LEAs are being introduced to improve embolization features, such as embolization efficacy, intraprocedural handling, and control. Furthermore, their use should improve fluoroscopic visibility and reduce artifacts in postinterventional imaging.The aim of this study was to evaluate an established EVOH-based embolic agent and a novel copolymer-based embolic agent in an in vitro AVM model.     

Pharmacokinetics and Biodistribution of (86)Y-Trastuzumab for (90)Y dosimetry in an ovarian carcinoma model: correlative MicroPET and MRI.

Preclinical biodistribution and pharmacokinetics of investigational radiopharmaceuticals are typically obtained by longitudinal animal studies. These have required the sacrifice of multiple animals at each time point. Advances in small-animal imaging have made it possible to evaluate the biodistribution of radiopharmaceuticals across time in individual animals, in vivo. MicroPET and MRI-based preclinical biodistribution and localization data were obtained and used to assess the therapeutic potential of (90)Y-trastuzumab monoclonal antibody (mAb) (anti-HER2/neu) against ovarian carcinoma. METHODS: Female nude mice were inoculated intraperitoneally with 5.10(6) ovarian carcinoma cells (SKOV3). Fourteen days after inoculation, 12-18 MBq (86)Y-labeled trastuzumab mAb was injected intraperitoneally. Tumor-free mice, injected with (86)Y-trastuzumab, and tumor-bearing mice injected with labeled, irrelevant mAb or (86)Y-trastuzumab + 100-fold excess unlabeled trastuzumab were used as controls. Eight microPET studies per animal were collected over 72 h. Standard and background images were collected for calibration. MicroPET images were registered with MR images acquired on a 1.5-T whole-body MR scanner. For selected time points, 4.7-T small-animal MR images were also obtained. Images were analyzed and registered using software developed in-house. At completion of imaging, suspected tumor lesions were dissected for histopathologic confirmation. Blood, excised normal organs, and tumor nodules were measured by gamma-counting. Tissue uptake was expressed relative to the blood concentration (percentage of injected activity per gram of tissue [%IA/g]/%IA/g blood). (86)Y-Trastuzumab pharmacokinetics were used to perform (90)Y-trastuzumab dosimetry. RESULTS: Intraperitoneal injection of mAb led to rapid blood-pool uptake (5-9 h) followed by tumor localization (26-32 h), as confirmed by registered MR images. Tumor uptake was greatest for (86)Y-trastuzumab (7 +/- 1); excess unlabeled trastuzumab yielded a 70% reduction. Tumor uptake for the irrelevant mAb was 0.4 +/- 0.1. The concentration in normal organs relative to blood ranged from 0 to 1.4 across all studies, with maximum uptake in spleen. The absorbed dose to the kidneys was 0.31 Gy/MBq (90)Y-trastuzumab. The liver received 0.48 Gy/MBq, and the spleen received 0.56 Gy/MBq. Absorbed dose to tumors varied from 0.10 Gy/MBq for radius = 0.1 mm to 3.7 Gy/MBq for radius = 5 mm. CONCLUSION: For all injected compounds, the relative microPET image intensity of the tumor matched the subsequently determined (86)Y uptake. Coregistration with MR images confirmed the position of (86)Y uptake relative to various organs. Radiolabeled trastuzumab mAb was shown to localize to sites of disease with minimal normal organ uptake. Dosimetry calculations showed a strong dependence on tumor size. These results demonstrate the usefulness of combined microPET and MRI for the evaluation of novel therapeutics.     

Hypoxia-induced alteration of tracer accumulation in cultured cancer cells and xenografts in mice: implications for pre-therapeutic prediction of treatment outcomes with (99m)Tc-sestamibi, (201)Tl chloride and (99m)Tc-HL91

Weak visualization of tumours in pre-therapeutic scintigrams with technetium-99m sestamibi (MIBI) is likely a predictive sign of unfavourable tumour response to radiotherapy and chemotherapy. However, factors relating to this scintigraphic finding are not well understood. The presence of hypoxic tumour cells is one of the major reasons for therapeutic failure; consequently, we attempted to determine whether oxygenation status affects (99m)Tc-MIBI accumulation in tumour cells. LS180 human colon cancer and T24 human bladder cancer cells were incubated in air or N(2) gas at 37 degrees C. Cellular uptake of (99m)Tc-MIBI was subsequently determined at 15, 60 and 120 min. Uptake of thallium-201 chloride was also assessed. Uptake of (99m)Tc-HL91 was assessed as a hypoxic marker. Accumulation of the tracers in LS180 xenografts was observed in mice treated with 5 mg/kg hydralazine and compared with that in untreated mice. pO(2) in the medium and tumours was measured with O(2) microelectrodes. N(2) gas flow gradually reduced pO(2) in the cell suspension to 1-2 mmHg in 60 min. Cellular uptake of (99m)Tc-MIBI in LS180 cells decreased by approximately 30% in N(2) gas in comparison to that in air throughout the study. Hypoxia had a more prominent influence on (201)Tl uptake, which displayed a reduction of approximately 60% in N(2) gas at 120 min, than on (99m)Tc-MIBI uptake. On the other hand, N(2) gas induced an increase of 170% in (99m)Tc-HL91 uptake at 120 min, indicating the hypoxic condition of cells. The results of in vitro assays employing the T24 cell line were similar to those obtained with the LS180 cell line. Hydralazine treatment markedly reduced (99m)Tc-MIBI and (201)Tl accumulation in LS180 xenografts; moreover, intratumoural pO(2) decreased from 14.5 +/- 6.6 mmHg to 7.6 +/- 6.2 mmHg. (99m)Tc-HL91 accumulation in xenografts was markedly increased by hydralazine. In conclusion, hypoxia reduced accumulation of (99m)Tc-MIBI and (201)Tl in tumour cells. Accordingly, hypoxia may be an important factor in terms of the interpretation of scintigraphic findings obtained with these tracers for pre-therapeutic prediction of tumour response to treatment. Furthermore, the enhanced (99m)Tc-HL91 accumulation in hypoxic tumour cells indicates the usefulness of this tracer in this regard.     

Dissociation between respiratory burst activity and deoxyglucose uptake in human neutrophil granulocytes: implications for interpretation of (18)F-FDG PET images.

Neutrophil granulocytes play a key role in the pathogenesis of a wide variety of pulmonary diseases. In many such conditions, the injury observed reflects the activation status rather than the total number of inflammatory cells present. The metabolic activity of neutrophils can now be assessed noninvasively using PET to measure the regional uptake of (18)F-FDG after intravenous injection. METHODS: To understand the mechanism responsible for the increased (18)F-FDG signal, we have measured the uptake of tritiated deoxyglucose (DG) in neutrophils isolated from human peripheral blood and sought to determine which aspects of neutrophil function correlate with an increase in DG uptake. RESULTS: Our results show that formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated respiratory burst activity and (3)H-DG uptake are temporally dissociated, that neutrophil-priming agents such as tumor necrosis factor-alpha (TNFalpha) cause an identical increase in (3)H-DG uptake compared with fMLP without affecting respiratory burst activity, and that fMLP stimulation of TNFalpha-primed cells causes major upregulation of superoxide anion generation (O(2)(-)) yet no incremental increase in (3)H-DG uptake. Furthermore, direct activation of reduced nicotinamide adenine dinucleotide phosphate oxidase activity with the ester phorbol 12-myristate 13-acetate resulted in a concentration-dependent loss of cell-associated (3)H-DG, and preincubation of neutrophils with the phosphoinositide 3-kinase inhibitor wortmannin, which abolished both agonist-stimulated superoxide anion generation and degranulation, had no effect on TNFalpha- or fMLP-stimulated (3)H-DG uptake. In contrast, the fMLP-stimulated change in neutrophil shape was not influenced by priming or wortmannin, and of the functional responses examined, this appeared to correlate most closely with (3)H-DG uptake. CONCLUSION: DG uptake occurs in both primed and activated neutrophils. It does not correlate with respiratory burst or secretory activity but may reflect the polarization and migrational status of these cells. These data have important implications for the analysis of (18)F-FDG signals in vivo.     

Optimization of computed tomography (CT) arthrography of hip for the visualization of cartilage: an in vitro study

Objective

We sought to optimize the kilovoltage, tube current, and the radiation dose of computed tomographic arthrography of the hip joint using in vitro methods.

Materials and methods

A phantom was prepared using a left femoral head harvested from a patient undergoing total hip arthroplasty and packed in a condom filled with iodinated contrast. The right hip joint of a cadaver was also injected with iodinated contrast. The phantom and the cadaver were scanned using different values of peak kilovoltage (kVp) and tube current (milliamp seconds, mAs). Three different regions of interest (ROI) were drawn in the cartilage, subchondral bone plate, and intraarticular contrast. The attenuation values, contrast/noise ratio (CNR), and effective dose were calculated. Two independent observers classified the quality of the contrast-cartilage interface and the cartilage-subchondral bone plate interface as (1) diagnostic quality or (2) nondiagnostic quality.

Results

Contrast, cartilage, and subchondral bone plate attenuation values decreased at higher kVp. CNR increased with both kVp and mAs. The qualitative analysis showed that in both phantom and cadaver, at 120 kVp and 50 mAs, the contrast-cartilage and cartilage-subchondral bone plate interfaces were of diagnostic quality, with an effective dose decreased to 0.5 MSv.

Conclusions

The absolute effective dose is not directly related to the quality of images but to the specific combination of kVp and mAs used for image acquisition. The combination of 120 kVp and 50 mAs can be suggested to decrease the dose without adversely affect the visibility of cartilage and subchondral bone plate.     

Deaths within 12 months after (125)I implantation for brachytherapy of prostate cancer: an investigation of radiation safety issues in Japan (2003-2010)

PurposeThe International Commission on Radiological Protection recommends removing the prostate before cremation if death occurs within 12 months after ¹²⁵I brachytherapy. However, the incidence of death within this time frame has not been robustly investigated in any country. The purpose this study was to investigate the incidence and cause of death and actions taken when death has occurred within 12 months after ¹²⁵I brachytherapy for prostate cancer in Japan.Methods and MaterialsData were extracted from the Japan Radioisotope Association database to investigate the total number of implantation cases, number of early deaths after implantation, cause of death, and postmortem actions between September 2003 and the end of June 2010 in Japan. Early death was defined as occurring within 12 months after ¹²⁵I brachytherapy for prostate cancer.ResultsDuring the study period, 15,427 patients underwent ¹²⁵I brachytherapy and 43 (0.28%) died within 12 months after implantation. For 37 of the 43 patients (86%), the brachytherapy source was retrieved together with the prostate gland at autopsy; however, autopsy could not be performed in six (14%) of the deceased patients. The largest proportion of early deaths was because of cerebrovascular or cardiovascular disease (17/43, 40%), followed by malignant tumor (15/43, 35%), and respiratory disease or infection (7/43, 16%).ConclusionsThe incidence of early deaths within 12 months after ¹²⁵I brachytherapy in Japan was 0.28%. In almost all cases, the brachytherapy sources were removed in the intact prostate before the body was cremated and stored appropriately.     

Uptake in melanoma cells of N-(2-diethylaminoethyl)-2-iodobenzamide (BZA2), an imaging agent for melanoma staging: relation to pigmentation

N-(2-diethylaminoethyl)-2-iodobenzamide (BZA(2)) has been singled out as the most efficacious melanoma scintigraphy imaging agent. Our work was designed to assess the mechanisms of the specific affinity of the radioiodinated iodobenzamide for melanoma tissue. We studied the cellular uptake and retention of [(125)I]-BZA(2) on various cell lines. In vitro, cellular [(125)I]-BZA(2) uptake was related to the pigmentation status of the cells: higher in pigmented melanoma cell lines (M4 Beu, IPC 227, B 16) than in a nonpigmented one (M3 Dau) and nonmelanoma cell lines (MCF 7 and L 929). Two mechanisms were assessed: binding of the tracer to melanin or to sigma receptors of melanoma cells. First, the uptake of [(125)I]-BZA(2) after melanogenesis stimulation by alpha-melanocyte-stimulating hormone and l-tyrosine increased in the B 16 melanoma cell line both in vitro and in vivo according to melanin concentration. Moreover, the binding of [(125)I]-BZA(2) to synthetic melanin was dependent on melanin concentration and could be saturated. Second, no competition was evidenced on M4 Beu cells between [(125)I]-BZA(2) and haloperidol, a sigma ligand, at concentrations < or =10(-6) M. We show that the specificity and sensibility of BZA(2) as a melanoma scintigraphic imaging agent are mostly due to interactions with melanic pigments.     

Retention of mild asthmatics in the navy (REMAIN): a low-risk approach to giving mild asthmatics an opportunity for military service

OBJECTIVE: Rising U.S. asthma prevalence will be reflected in military applicants. We studied retaining mild asthmatics on active duty. METHODS: A cohort study at Great Lakes Naval Training Center from 2000 to 2002 compared recruits diagnosed during basic training with mild asthma to matched comparison recruits on outpatient visits, hospitalizations, and discharge through August 2003. RESULTS: A total of 136 asthmatic and 404 control subjects were enrolled. Overall attrition was greater among the asthma cohort (p < 0.01), largely during training. Asthmatics used more health care than controls during training (0.1 vs. 0.004 per person-month). No asthma-related hospitalizations or deaths occurred during the study. CONCLUSIONS: Although attrition during recruit training was higher in mild asthmatics, nearly 40% of recruits were retained on active duty without significant risk of hospitalization or excessive outpatient treatment after recruit training. These findings argue for consideration of a trial on active duty for recruits with mild asthma.     

SIC, an intracerebral beta(+)-range-sensitive probe for radiopharmacology investigations in small laboratory animals: binding studies with (11)C-raclopride.

Our aim was to show the ability of a recently developed beta(+)-range-sensitive intracerebral probe (SIC) to measure, in vivo, the binding of radioligands in small animals. METHODS: The potential of the device for pharmacokinetic studies was evaluated by measurement of the dynamic striatal binding of (11)C-raclopride, a well-documented D(2) dopaminergic receptor ligand, in rat brain after intravenous injection of the labeled compound. The effects of preinjection of the unlabeled ligand (raclopride, 2 mg/kg intravenously) and of increasing the synaptic dopamine level (amphetamine treatment, 1 mg/kg intravenously) or of depleting synaptic dopamine (reserpine pretreatment, 5 mg/kg intraperitoneally) on in vivo (11)C-raclopride binding were monitored by SIC. RESULTS: The radioactivity curves measured as a function of time were reproducible and consistent with previous studies using PET imaging (ratio of striatum to cerebellum, 2.6 +/- 0.3 after 20 min). Further studies showed significant displacement of (11)C-raclopride by its stable analog. Finally, the device proved its capacity to accurately detect changes in (11)C-raclopride binding after a sudden (amphetamine) or a gradual (reserpine) modulation of endogenous dopamine levels. CONCLUSION: These results show that the new device can monitor binding of PET ligands in anesthetized rodents in vivo, with high temporal resolution.