A heavy-ion production channel of 149Tb via 63Cu bombardment of 89Y.

The radionuclide 149Tb (t1/2 = 4.1 h) is a potential theranostic isotope which can simultaneously be used for targeted-alpha-particle therapy and positron-emission tomography. Feasibility experiments were performed to test a near-symmetric heavy-ion reaction of 63Cu bombardment on monoisotopic 89Y. The indirect reaction was studied to avoid isomer production. Offline gamma spectroscopy was used to quantify thick-target physical yields and experimental results show modest agreement to the fusion-evaporation code PACE4. A near-symmetric fission yield was also observed.

Radioligand Therapy of Prostate Cancer with a Long-Lasting Prostate-Specific Membrane Antigen Targeting Agent 90Y-DOTA-EB-MCG.

Several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of radiotheranostics for the treatment of prostate cancer. Among them, ((( R)-1-carboxy-2-mcercaptoethyl)carbamoyl)-l-glutamic acid (MCG) has been successfully labeled with radioisotopes for prostate cancer imaging. The aim of this study is to conjugate MCG with an albumin binding moiety to further improve the in vivo pharmacokinetics. MCG was conjugated with an Evans blue (EB) derivative for albumin binding and a DOTA chelator. PSMA positive (PC3-PIP) and PSMA negative (PC3) cells were used for both in vitro and in vivo studies. Longitudinal PET imaging was performed at 1, 4, 24, and 48 h post-injection to evaluate the biodistribution and tumor uptake of 86Y-DOTA-EB-MCG. DOTA-EB-MCG was also labeled with 90Y for radionuclide therapy. Besides tumor growth measurement, tumor response to escalating therapeutic doses were also evaluated by immunohistochemistry and fluorescence microscopy. Based on quantification from 86Y-DOTA-EB-MCG PET images, the tracer uptake in PC3-PIP tumors increased from 22.33 ± 2.39%ID/g at 1 h post-injection (p.i.), to the peak of 40.40 ± 4.79%ID/g at 24 h p.i. Administration of 7.4 MBq of 90Y-DOTA-EB-MCG resulted in significant regression of tumor growth in PSMA positive xenografts. No apparent toxicity or body weight loss was observed in all treated mice. Modification of MCG with an Evans blue derivative resulted in a highly efficient prostate cancer targeting agent (EB-MCG), which showed great potential in prostate cancer treatment after being labeled with therapeutic radioisotopes.

Long-Term Outcome After Liver Transplantation for Hepatocellular Carcinoma Following Yttrium-90 Radioembolization Bridging Treatment.

BACKGROUND Bridging treatments are employed in liver transplant waitlist patients with hepatocellular carcinoma (HCC) because of the risk of tumor progression during the waiting time. Radioembolization is mostly employed in the control of large or multifocal HCCs when other locoregional treatment modalities cannot be applied because of the number or size of lesions. The purpose of this study was to evaluate our experience with the use of radioembolization as a bridge to transplantation and its effect on tumor recurrence and survival after liver transplantation. MATERIAL AND METHODS A retrospective review of 40 consecutive patients with HCC who underwent liver transplantation after radioembolization bridging treatment between January 2007 and December 2015 at the University Hospital Essen, Germany, was performed. Patients' characteristics, alpha-fetoprotein (AFP) levels, pathologic tumor response, tumor recurrence rate, and survival rates were examined through chart review. RESULTS Histopathological examination of the explanted liver specimen revealed complete tumor necrosis in 17 specimens, partial necrosis in 18 specimens, and no significant necrosis in five specimens. Median overall survival was 46 months. Nine patients developed recurrent HCC. Median time from liver transplantation to diagnosis of tumor recurrence was 15 months. There was a trend towards a lower risk of tumor recurrence for patients with complete necrosis on explant specimens. Patients with tumor recurrence demonstrated statistically significantly higher pre- and post-treatment AFP levels (p=0.0234 and p=0.0236) and statistically significantly more frequently microvascular invasion (p=0.0163). CONCLUSIONS Histopathological assessment of explanted livers revealed at least partial necrosis in 87.5% of patients. Patients with successful bridging treatment, i.e. complete necrosis of explant specimens, demonstrate a trend towards a lower risk of tumor recurrence.

Radioembolización de tumores hepáticos con 90Y-microesferas / Radioembolization with 90Y-microspheres for liver tumors

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DNP by thermal mixing under optimized conditions yields >60,000-fold enhancement of 89Y NMR signal.

Hyperpolarized (89)Y complexes are attractive NMR spectroscopy and MR imaging probes due to the exceptionally long spin-lattice relaxation time (T(1) ≈ 10 min) of the (89)Y nucleus. However, in vivo imaging of (89)Y has not yet been realized because of the low NMR signal enhancement levels previously achieved for this ultra low-γ(n) nucleus. Here, we report liquid-state (89)Y NMR signal enhancements over 60,000 times the thermal signal at 298 K in a 9.4 T magnet, achieved after the dynamic nuclear polarization (DNP) of Y(III) complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) samples at 3.35 T and 1.4 K. The (89)Y DNP was shown to proceed by thermal mixing and the liquid state (89)Y NMR signal enhancement was maximized by (i) establishing the optimal microwave irradiation frequency, (ii) optimizing the glassing matrix, (iii) choosing a radical with negligible inhomogeneous line broadening contribution to the ESR linewidth, and (iv) addition of an electron T(1e) relaxation agent. The highest enhancements were achieved using a trityl OX063 radical combined with a gadolinium relaxation agent in water-glycerol matrix. Co-polarization of (89)YDOTA and sodium [1-(13)C]pyruvate showed that both (89)Y and (13)C nuclear species acquired the same spin temperature, consistent with thermal mixing theory of DNP. This methodology may be applicable for the optimization of DNP of other low-γ(n) nuclei.

Prediction of (89)Zr production using the Monte Carlo code FLUKA.

The widely used Monte Carlo simulation code FLUKA has been utilized to prototype a solid target for the production of (89)Zr by irradiation of a metallic (89)Y target foil in a 16.5MeV proton biomedical cyclotron, through the reaction (89)Y(p, n)(89)Zr. Simulations were performed with and without an Al energy degrader. In the setup of the geometry of the target, state of the art support tools, like SimpleGeo, were used for accurate, detailed modeling. The results permitted a quick assessment of all possible radionuclidic contaminants and confirmed that the use of an energy degrader avoids production of the most important impurity, (88)Zr. The estimated value for the activity produced in one hour of irradiation at 20µA is 384 ± 42MBq; this is encouraging, indicating possible production of clinically significant amounts of activity with the relatively simple target setup adopted. Initial experimental tests gave results in excellent agreement with simulations, confirming the usefulness and accuracy of FLUKA as a tool for the design and optimization of targets for the production of PET radionuclides.

Quantitative comparison of yttrium-90 (90Y)-microspheres and technetium-99m (99mTc)-macroaggregated albumin SPECT images for planning 90Y therapy of liver cancer.

Yttrium-90 ((90)Y)-microspheres administered via the hepatic artery has been used for the treatment of unresectable primary or metastatic cancer in the liver. Prior to (90)Y therapy, however, the (90)Y administered activity and the percent shunting to lungs must be determined, most commonly by gamma camera imaging of technetium-99m ((99m)Tc)-macroaggregated albumin (MAA). The purpose of the current study was to identify and evaluate an objective measure of the correlation of (90)Y and MAA activity distributions and thus assess the reliability of MAA imaging for evaluation of (90)Y administered activity and tumor and liver radiation doses. The MAA study consisted of two acquisitions. After administration of 185 MBq of MAA, a partial-body or so-called breakthrough scan was performed in order to determine the percent shunting to lungs. Immediately after a breakthrough scan, a combined single-photon emission computed tomography (SPECT)/transmission computed tomography (CT) scanner was used to image MAA distribution in order to derived the prescribed (90)Y administered activity based on tumor and liver dosimetry. (90)Y SPECT/CT was performed 2-4 weeks later and activities used were in the range of 777-2,442 MBq. In order to compare (90)Y and MAA SPECT images, first the respective CT image sets were registered using a transform based on normalized mutual information. The transform thus derived was used to align the 90Y and MAA SPECT image sets, and the Spearman's (rho) rank correlation as well as image distance (L2-norm) between the registered SPECT images were then calculated. The Spearman's rank correlation values ranged from 0.451 to 0.818 and the L2 distances from 0.626 to 2.889. Based on visual inspection, the registration of the (90)Y and MAA SPECT images appeared reasonably accurate. The regression coefficient (r) between visual scoring and the Spearman's rank correlation was 0.65 and between visual scoring and L2 distance 0.61. The Spearman's rank correlation thus appears to be more reliable than the image distance for assessing the correlation of the (90)Y and MAA images.

Effect of voxel size and computation method on Tc-99m MAA SPECT/CT-based dose estimation for Y-90 microsphere therapy.

The use of selective internal radiation therapy for treatment of hepatocellular carcinoma and liver metastases using Y-90 labeled microspheres has become an effective and widely used treatment regimen. However, dosimetric evaluations of this treatment are still primitive as uniform distribution models based only on injected activity are often used. This investigation attempts to quantify the effectiveness of several sophisticated patient-specific techniques which utilize the source distribution of Tc-99m MAA simulation studies to perform voxelized dosimetric computations. Among these techniques are complete Monte-Carlo radiation transport computation in patient-specific CT-based voxel phantoms, local energy deposition in patient specific phantoms and kernel transport techniques in water. Each technique was evaluated using three different phantom voxel dimensions and SPECT reconstruction matrix sizes. Dose evaluation results using all methods were compared to the exact solution, obtained using fully 3-D Monte-Carlo simulations with source distribution based not on SPECT data, but on the injected activity and exact boundaries of the anthropomorphic phantom used in the study. The results of this study show that at large voxel sizes and using SPECT reconstructions with a small matrix size (64 x 64), Monte-Carlo and local deposition methods are nearly equivalent. However, using a large SPECT reconstruction matrix (256 x 256) the local deposition method is significantly more accurate than full 3-D Monte-Carlo transport, and with a negligible computational burden.

Alpha-fetoprotein response after locoregional therapy for hepatocellular carcinoma: oncologic marker of radiologic response, progression, and survival.

PURPOSE: Alpha-fetoprotein (AFP) is considered to be an indicator of tumor activity in hepatocellular carcinoma (HCC). We present a novel correlation of AFP response to radiologic response, time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) in patients treated with locoregional therapies. PATIENTS AND METHODS: Four hundred sixty-three patients with HCC were treated with chemoembolization or radioembolization at our institution. One hundred twenty-five patients with baseline AFP higher than 200 ng/mL were studied for this analysis. AFP response was defined as more than 50% decrease from baseline. One hundred nineteen patients with follow-up imaging were studied for the AFP imaging correlation analysis. AFP response was correlated to radiologic response, TTP, PFS, and OS. Multivariate analyses were performed. RESULTS: Eighty-one patients (65%) showed AFP response. AFP response was seen in 26 (55%) of 47 and 55 (70%) of 78 of patients treated with chemoembolization and radioembolization, respectively (P = .12). WHO response was seen in 41 (53%) of 77 and 10 (24%) of 42 of AFP responders and nonresponders, respectively (P = .002). The hazard ratio (HR) for TTP in AFP nonresponders compared with responders was 2.8 (95% CI, 1.5 to 5.1). The HR for PFS was 4.2 (95% CI, 2.4 to 7.2) in AFP nonresponders compared with responders. The HR for OS in AFP nonresponders compared with responders was 5.5 (95% CI, 3.1 to 9.9) and 2.7 (95% CI, 1.6 to 4.6) on univariate and multivariate analyses, respectively. CONCLUSION: The data presented support the use of AFP response seen after locoregional therapy as an ancillary method of assessing tumor response and survival, as well as an early objective screening tool for progression by imaging.

Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy.

PURPOSE: Liver metastases are the principal cause of death in patients with advanced colorectal cancer (CRC). Irinotecan is a chemotherapeutic agent used in the treatment of CRC and has demonstrated synergistic potential when used with radiation. Radioembolization with yttrium-90 microspheres has demonstrated increased response and survival rates when given with fluorouracil chemotherapy. This study's goal was to evaluate the maximum-tolerated dose of concomitant irinotecan and radioembolization in fluorouracil-refractory patients with CRC hepatic metastases. PATIENTS AND METHODS: Twenty-five irinotecan-naive patients who had experienced relapse after previous chemotherapy were enrolled onto three dose-escalating groups. Irinotecan was administered at 50, 75, or 100 mg/m(2) on days 1 and 8 of a 3-week cycle for the first two cycles, and full irinotecan doses (ie, 100 mg/m(2)) were administered during cycles 3 to 9. Radioembolization was administered during the first chemotherapy cycle. RESULTS: Most patients experienced acute, self-limiting abdominal pain and nausea. Mild lethargy and anorexia were common. Grades 3 to 4 events were seen in three of six patients at 50 mg/m(2) (obstructive jaundice, thrombocytopenia, diarrhea), in five of 13 patients at 75 mg/m(2) (neutropenia, leukopenia, thrombocytopenia, elevated alkaline phosphatase, abdominal pain, ascites, fatigue) and in four of six patients at 100 mg/m(2) (diarrhea, deep vein thrombosis, constipation, leukopenia). Eleven (48%) of 23 patients had a partial response, and nine patients (39%) had stable disease. The median progression-free survival was 6.0 months; the median survival was 12.2 months. CONCLUSION: Concomitant use of radioembolization plus irinotecan did not reach a maximum-tolerated dose. The recommended dose of irinotecan in this setting is 100 mg/m(2) on days 1 and 8 of a 3-week cycle.

Hepatic intra-arterial injection of Yttrium-loaded microspheres for liver metastasis secondary to colorectal cancer: best soups are sometimes made from old recipies.

Colorectal cancer is a severe disease with a significant incidence in Western world. In the course of disease, about 40% of patients will eventually develop metastases to the liver. The majority of them will never be candidate for curative surgical management. For those patients, systemic or intra-hepatic chemotherapy is the treatment's cornerstone. Unfortunately, despite evident improvements and apparition of several active new agents, no hope of cure emerges on the agenda for now. Hepatic intra-arterial injections of radioactive devices have since a long time drawn interest from the medical community. An anti-tumoural activity has been demonstrated with Yttrium-loaded microspheres injected in the hepatic artery for several liver neoplasms including metastases from colorectal cancer. We lack however the results of large randomized phase III trials to define clearly the place of those interventional therapies in the management of colorectal cancer metastatic to the liver.

Biologic and immunologic therapies for ovarian cancer.

Biologic therapy of ovarian cancer has been conducted using nonspecific biologic response modifiers, cytokines, monoclonal antibodies (MAbs), vaccines, and gene therapy. Antibodies directed toward her2/neu have also been studied. Phase I and II gene therapy trials using adenoviral vectors containing a wild-type or modified p53 have shown that the treatment is well tolerated. Phase II and III trials are ongoing with MAbs directed against CA-125 (MAb B43.13) and an antibody directed against HMFG1 (anti-HMFG1-yttrium-90-labeled antibody). The trials have shown that these agents are well tolerated and that immunologic responses occur, although the ultimate clinical value of these agents remains to be determined. Prolonged survival after MAb B43.13 treatment has been correlated with changes in several immune parameters, including human antimurine antibody, Ab2, anti-CA-125 antibody development, and induced T-cell immunity. Clinical trials using a MAb directed toward the encoded products of her2/neu have shown minimal activity against ovarian cancer in a phase I and II trial conducted by the Gynecologic Oncology Group. Cytokine therapies have been administered systemically and intraperitoneally. Intracavitary interferon alfa, interferon gamma, and interleukin-2 alone or in combination with cytotoxic therapy in phase I and II trials demonstrated intraperitoneal lymphoid cell stimulation and produced antitumor responses. A randomized trial of chemotherapy with or without interferon gamma in primary treatment produced a response and a progression-free survival advantage in the arm that incorporated the interferon gamma, without a statistically significant benefit in overall survival. A phase III study of interferon gamma in combination with first-line chemotherapy is currently ongoing.

Comparative dosimetry of copper-64 and yttrium-90-labeled somatostatin analogs in a tumor-bearing rat model.

90Y-DOTA-tyrosine3-octreotide (90Y-DOTA-Y3-OC) is currently being evaluated as a radiotherapy agent for trials in patients with somatostatin-receptor positive cancer. In this study, we compared the estimated absorbed doses to human organs, as well as to a CA20948 rat tumor, of 90Y- and 64Cu-labeled DOTA-Y3-OC and DOTA-Y3-octreotate (DOTA-Y3-TATE). Assuming that the radiopharmaceutical biodistributions are the same in rodents and humans, human absorbed dose estimates were obtained from rat biodistribution data. The absorbed doses of 90Y-DOTA-Y3-TATE were determined from the biodistribution of the 88Y-labeled peptide, with and without co-injection of a therapeutic amount of the 90Y-labeled peptide. Additionally, the absorbed doses of 90Y-DOTA-Y3-TATE were determined from data using two different biodistribution endpoints, 48 h and 168 h. Human absorbed dose estimates were calculated using MIRD methodology assuming that rats and humans have the same biodistribution. The biodistribution of the radiolabeled somatostatin analogs was dependent on the peptide and the radiometal. For 90Y-DOTA-Y3-TATE, the tumor dose was dependent on both the administration of therapeutic 90Y-peptide and the biodistribution endpoint. Our data suggested that, for both radionuclides, the TATE derivatives imparted a higher absorbed dose to the tumor than the OC analogs. 90Y-DOTA-Y3-OC and 64Cu-DOTA-Y3-OC were comparable with respect to their tumor-to-normal tissue dose ratios, while 90Y-DOTA-Y3-TATE appeared to have distinct advantages over 64Cu-DOTA-Y3-TATE.

A clinical and prospective chromosomal study of yttrium-90 synovectomy.

Yttrium-90 synovectomy resulted in complete resolution of chronic knee synovitis in 40% of a group of 15 patients. These patients would have otherwise required surgical synovectomy. The number of chromosomal aberrations detected in 30 patients after yttrium-90 synovectomy showed a statistically significant increase over the pre-treatment analysis, and, following treatment, chromosomal damage was noted in nine patients who had no damage before treatment. The risk arising from this chromosomal damage is uncertain but, while the long-term implications of the chromosomal aberrations are investigated in those who have already been treated, this therapy should be reserved for the older patient.

Saturation corrections for plane-parallel ionization chambers.

Experiments described in the literature lead to different formulae for saturation corrections in ionization chambers. To elucidate the differences, saturation curves of an extrapolation chamber irradiated with beta particles from 90Sr+90Y sources have been studied experimentally. The results could be described by one formula which was a combination of known formulae for charge collection losses due to volume recombination, initial recombination and diffusion.