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- Elgqvist, Jörgen, 1963, et al.
(författare)
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Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: Outcome related to measured tumor size and mean absorbed dose.
- 2006
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 47:8, s. 1342-50
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this work was to (a) investigate the efficacy of radioimmunotherapy using 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2 (nonspecific antibody) against differently advanced ovarian cancer in mice; (b) image the tumor growth on the peritoneum; and (c) calculate the specific energy and mean absorbed dose to tumors and critical organs. METHODS: Two experiments with 5-wk-old nude mice (n = 100 + 93), intraperitoneally inoculated with approximately 1 x 10(7) NIH:OVCAR-3 cells, were done. At either 1, 3, 4, 5, or 7 wk after inoculation animals were intraperitoneally treated with approximately 400 kBq 211At-MX35 F(ab')2 (n = 50 + 45), approximately 400 kBq 211At-Rituximab F(ab')2 (n = 25 + 24), or unlabeled Rituximab F(ab')2 (n = 25 + 24). At the time of treatment 29 animals were sacrificed and biopsies were taken for determination of tumor sizes using scanning electron microscopy (SEM). Eight weeks after each treatment the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined. The specific energy and mean absorbed dose to tumors were calculated. The activity concentration was measured in critical organs and abdominal fluid. RESULTS: When given treatment 1, 3, 4, 5, or 7 wk after cell inoculation the tumor-free fraction (TFF) was 95%, 68%, 58%, 47%, 26%, and 100%, 80%, 20%, 20%, and 0% when treated with 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2, respectively. The SEM images revealed maximum tumor radius of approximately 30 mum 1 wk after cell inoculation, increasing to approximately 340 mum at 7 wk. Specific energy to cell nuclei varied between 0 and approximately 540 Gy, depending on assumptions regarding activity distribution and tumor size. The mean absorbed dose to thyroid, kidneys, and bone marrow was approximately 35, approximately 4, and approximately 0.3 Gy, respectively. CONCLUSION: Treatment with 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2 resulted in a TFF of 95%-100% when the tumor radius was < or =30 microm. The TFF was decreased (TFF < or = 20%) for 211At-Rituximab F(ab')2 when the tumor radius exceeded the range of the alpha-particles. The specific antibody gave for these tumor sizes a significantly better TFF, explained by a high mean absorbed dose (>22 Gy) from the activity bound to the tumor surface and probably some contribution from penetrating activity.
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- Langen, Britta, et al.
(författare)
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Comparative Analysis of Transcriptional Gene Regulation Indicates Similar Physiologic Response in Mouse Tissues at Low Absorbed Doses from Intravenously Administered At-211
- 2013
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 54:6, s. 990-998
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Tidskriftsartikel (refereegranskat)abstract
- (211)At is a promising therapeutic radionuclide because of the nearly optimal biological effectiveness of emitted α-particles. Unbound (211)At accumulates in the thyroid gland and in other vital normal tissues. However, few studies have been performed that assess the (211)At-induced normal-tissue damage in vivo. Knowledge about the extent and quality of resulting responses in various organs offers a new venue for reducing risks and side effects and increasing the overall well-being of the patient during and after therapy. METHODS: Female BALB/c nude mice were injected intravenously with 0.064-42 kBq of (211)At or mock-treated, and the kidneys, liver, lungs, and spleen were excised 24 h after injection. A transcriptional gene expression analysis was performed in triplicate using RNA microarray technology. Biological processes associated with regulated transcripts were grouped into 8 main categories with 31 subcategories according to gene ontology terms for comparison of regulatory profiles. RESULTS: A substantial decrease in the total number of regulated transcripts was observed between 0.64 and 1.8 kBq of (211)At for all investigated tissues. Few genes were differentially regulated in each tissue at all absorbed doses. In all tissues, most of these genes showed a nonmonotonous dependence on absorbed dose. However, the direction of regulation generally remained uniform for a given gene. Few known radiation-associated genes were regulated on the transcriptional level, and their expression profile generally appeared to be dose-independent and tissue-specific. The regulatory profiles of categorized biological processes were tissue-specific and reflected the shift in regulatory intensity between 0.64 and 1.8 kBq of (211)At. The profiles revealed strongly regulated and nonregulated subcategories. CONCLUSION: The strong regulatory change observed between 0.64 and 1.8 kBq is hypothesized to result not only from low-dose effects in each tissue but also from physiologic responses to ionizing radiation-induced damage to, for example, the (211)At-accumulating thyroid gland. The presented results demonstrate the complexity of responses to radionuclides in vivo and highlight the need for further research to also consider physiology in ionizing radiation-induced responses.
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- Langen, Britta, et al.
(författare)
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Microarray Studies on 211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Non-Thyroid Tissues
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:2, s. 346-353
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Targeted α-therapy is a promising treatment option for various types of malignant tumors. Radiolabeled cancer-seeking agents, however, undergo degradation resulting in a certain percentage of free radionuclide in the body. The radiohalogen 211At accumulates in various tissues with specifically high uptake in the thyroid. When normal thyroid function is disturbed due to ionizing radiation (IR) exposure, deleterious effects can occur in tissues that depend on thyroid hormone (TH) regulation for normal physiological function. However, knowledge of systemic effects is still rudimentary. We previously reported similarities in transcriptomic regulation between the thyroid and other tissues despite large differences in absorbed dose from 211At (Langen et al. JNM, 2013). Here, we present supportive evidence on systemic effects after 211At administration. Methods: Expression microarray data from kidney cortex and medulla, liver, lungs, and spleen were used from previous studies where mice were i.v. injected with 0.064–42 kBq 211At and killed after 24 h, or injected with 1.7 kBq 211At and killed after 1, 6, or 168 h. Controls were mock-treated and killed after 24 h. Literature-based gene signatures were used to evaluate the relative impact from IR- or TH-induced regulation. Thyroid- and TH-associated upstream regulators as well as thyroid-related diseases and functions were generated using functional analysis software. Results: Responses in IR- or TH-associated gene signatures were tissue-specific, varied over time, and the relative impact of each gene signature differed between the investigated tissues. The liver showed a clear dominance of TH-responding genes. In the kidney cortex, kidney medulla, and lungs, the TH-associated signature was detected to at least similar extent as the IR-associated signature. The spleen was the single tissue showing regulation of only IR-associated signature genes. Various thyroid-associated diseases and functions were inferred from the data: L-triiodothyronine, TH, TH receptor, and triiodothyronine (reverse) were inferred as upstream-regulators with differences in incidence and strength of regulation depending on tissue type. Conclusion: These findings indicate that transcriptional regulation in various non-thyroid tissues was–in part–induced by thyroid (hormone)-dependent signaling. Consideration of the systemic context between tissues could contribute to normal tissue risk assessment and planning of remedial measures.
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- Minarik, David, et al.
(författare)
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Denoising of Scintillation Camera Images Using a Deep Convolutional Neural Network: A Monte Carlo Simulation Approach
- 2020
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 61:2, s. 298-303
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Tidskriftsartikel (refereegranskat)abstract
- Scintillation camera images contain a large amount of Poisson noise. We have investigated whether noise can be removed in whole-body bone scans using convolutional neural networks (CNNs) trained with sets of noisy and noiseless images obtained by Monte Carlo simulation. Methods: Three CNNs were generated using 3 different sets of training images: simulated bone scan images, images of a cylindric phantom with hot and cold spots, and a mix of the first two. Each training set consisted of 40,000 noiseless and noisy image pairs. The CNNs were evaluated with simulated images of a cylindric phantom and simulated bone scan images. The mean squared error between filtered and true images was used as difference metric, and the coefficient of variation was used to estimate noise reduction. The CNNs were compared with gaussian and median filters. A clinical evaluation was performed in which the ability to detect metastases for CNN- and gaussian-filtered bone scans with half the number of counts was compared with standard bone scans. Results: The best CNN reduced the coefficient of variation by, on average, 92%, and the best standard filter reduced the coefficient of variation by 88%. The best CNN gave a mean squared error that was on average 68% and 20% better than the best standard filters, for the cylindric and bone scan images, respectively. The best CNNs for the cylindric phantom and bone scans were the dedicated CNNs. No significant differences in the ability to detect metastases were found between standard, CNN-, and gaussian-filtered bone scans. Conclusion: Noise can be removed efficiently regardless of noise level with little or no resolution loss. The CNN filter enables reducing the scanning time by half and still obtaining good accuracy for bone metastasis assessment.
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- Sadik, May, 1970, et al.
(författare)
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3D prostate gland uptake of 18F-choline - association with overall survival in patients with hormone-naïve prostate cancer
- 2017
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Ingår i: Journal of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:supplement 1, s. 544-
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Tidskriftsartikel (refereegranskat)abstract
- Objectives : To develop a completely automated method to quantify prostate gland uptake of 18F-choline in PET/CT images and to study the relationship between this measure, clinical data and overall survival in patients with prostate cancer. Methods : An automated method for segmentation of the prostate gland in CT images was developed using a training group of 100 patients who had undergone PET/CT scanning. The algorithms were trained based on the manual segmentations of the prostate gland in the 100 CT scans performed by a single radiologist. A multi-atlas-based method was used applied for automated segmentation of the prostate gland. Each of a subset of the training images was registered separately to the test image. By applying the resulting transformations to the manual delineations a rough segmentation of the test image was obtained. This segmentation was refined using a random-forest classifier and the final segmentation was obtained with graph cuts. Voxels in the 18F-choline PET scans having a standard uptake value (SUV) >2.65 and localized in the prostate gland in the corresponding CT scan were defined as abnormal. Automated calculation of the following five PET measurements was performed: The maximal SUV within the prostate gland - SUVmax The average SUV within the abnormal part of the prostate gland - SUVmean The volume of abnormal uptake within the prostate gland - VOL The product SUVmean x VOL defined as Total Lesion Uptake - TLU The fraction of the prostate with abnormal uptake related to the whole volume of the prostate gland - FRAC The automated quantification method was retrospectively applied to a separate test group of 46 prostate cancer patients, aged 53-94 years, who had undergone 18F-choline PET/CT. These patients have previously been selected for a study aiming to compare whole-body bone scans, 18F-choline-PET/CT and 18F-NaF PET/CT with magnetic resonance imaging. The study entry criteria were biopsy-proven prostate cancer, a positive whole-body bone scan consistent with bone metastases, and no history of androgen deprivation. The association between the automated PET measurements, age, PSA, Gleason score and overall survival was evaluated using a univariate Cox proportional hazards regression model. Kaplan-Meier estimates were used to estimate the survival difference between patients with values above and below the median value for all variables analyzed. Results : The fraction of the prostate with abnormal uptake related to the whole volume of the prostate gland - FRAC and age were significantly associated with overall survival (Table) while PSA, Gleason score and other PET measurements were not. The patients with a FRAC above the median value (58.2%) had a significantly shorter median survival time than patients with a value below the median value (2.8 years vs. 5.5 years; p=0.04), see Figure. Conclusion : A completely automated method of quantifying 18F-choline PET uptake in the prostate gland yielded a measure of disease extent that was significantly associated with overall survival in patients with hormone-naïve prostate cancer. The method can also be applied to PET/CT scans with other tracers such as FDG or PSMA-targeted agents. It is our hope that these preliminary data will inspire further evaluation of this type of objective quantification of PET/CT scans.
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