| 1. |
- Druid, Malin, et al.
(författare)
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Late age- and dose-related effects on the proteome of thyroid tissue in rats after 131I exposure.
- 2024
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Ingår i: Radiation. - 2673-592X. ; 4:2, s. 149-166
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Tidskriftsartikel (refereegranskat)abstract
- The physiological process of iodine uptake in the thyroid is used for 131I treatment of thyroid diseases. Children are more sensitive to radiation compared to adults and may react differently to 131I exposure. The aims of this study were to evaluate the effects on thyroid protein expression in young and adult rats one year after 131I injection and identify potential biomarkers related to 131I exposure, absorbed dose, and age. Twelve Sprague Dawley rats (young and adults) were i.v. injected with 50 kBq or 500 kBq 131I and killed twelve months later. Twelve untreated rats were used as age-matched controls. Quantitative proteomics, statistical analysis, and evaluation of biological effects were performed. The effects of irradiation were most prominent in young rats. Protein biomarker candidates were proposed related to age, absorbed dose, thyroid function, and cancer, and a panel was proposed for 131I exposure. In conclusion, the proteome of rat thyroid was differentially regulated twelve months after low-intermediate dose exposure to 131I in both young and adult rats. Several biomarker candidates are proposed for 131I exposure, age, and many of them are known to be related to thyroid function or thyroid cancer. Further research on human samples is needed for validation. Data are avaiable via ProteomeXchange with identifier PXD024786.
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| 2. |
- Larsson, Malin, et al.
(författare)
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Long-term transcriptomic and proteomic effects in Sprague Dawley rat thyroid and plasma after internal low dose 131I exposure.
- 2020
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- Radioiodide (131I) is commonly used to treat thyroid cancer and hyperthyroidis.131I released during nuclear accidents, have resulted in increased incidence of thyroid cancer in children. Therefore, a better understanding of underlying cellular mechanisms behind 131I exposure is of great clinical and radiation protection interest. The aim of this work was to study the long-term dose-related effects of 131I exposure in thyroid tissue and plasma in young rats and identify potential biomarkers.Male Sprague Dawley rats (5-week-old) were i.v. injected with 0.5, 5.0, 50 or 500 kBq 131I (Dthyroid ca 1-1000 mGy), and killed after nine months at which time the thyroid and blood samples were collected. Gene expression microarray analysis (thyroid samples) and LC-MS/MS analysis (thyroid and plasma samples) were performed to assess differential gene and protein expression profiles in treated and corresponding untreated control samples. Bioinformatics analyses were performed using the DAVID functional annotation tool and Ingenuity Pathway Analysis (IPA). The gene expression microarray data and LC-MS/MS data were validated using qRT-PCR and ELISA, respectively.Nine 131I exposure-related candidate biomarkers (transcripts: Afp and RT1-Bb, and proteins: ARF3, DLD, IKBKB, NONO, RAB6A, RPN2, and SLC25A5) were identified in thyroid tissue. Two dose-related protein candidate biomarkers were identified in thyroid (APRT and LDHA) and two in plasma (DSG4 and TGM3). Candidate biomarkers for thyroid function included the ACADL and SORBS2 (all activities), TPO and TG proteins (low activities). 131I exposure was shown to have a profound effect on metabolism, immune system, apoptosis and cell death. Furthermore, several signalling pathways essential for normal cellular function (actin cytoskeleton signalling, HGF signalling, NRF2-mediated oxidative stress, integrin signalling, calcium signalling) were also significantly regulated.Exposure-related and dose-related effects on gene and protein expression generated few expression patterns useful as biomarkers for thyroid function and cancer.
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| 3. |
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| 4. |
- Romiani, Arman, 1991, et al.
(författare)
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Better therapeutic results after fractionated administration of Lu-177-octreotate in mice bearing human neuroblastoma
- 2018
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Ingår i: The European Association of Nuclear Medicine (EANM).
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Neuroblastoma (NB) is a neuroendocrine tumor and one of the most common cancer types in infants. NB is a heterogeneous cancer form, meaning that it has various characteristics and features, with diverse outcomes. High-risk NB has a 5-year survival rate of only 40-50%, demonstrating the need for new and improved treatment options for this patient group. Since NB overexpresses somatostatin receptors Lu-177-octreotate has the potential to be a treatment option. Our previous in vitro studies indicated high and specific uptake of Lu-177-octreotate in the human NB cell lines CLB-Bar and IMR-32. Furthermore, biodistribution studies of Lu-177-octreotate in NB-xenografted mice showed high uptake in tumor tissue in comparison with risk organs. These promising results encouraged studies on the anti-tumor effects of Lu-177-octreotate therapy. The aim of this work was to study the anti-tumor effects after fractionated administration of Lu-177-octreotate in nude mice bearing CLB-Bar. Methods: Nude BALB/c mice aged 5-6 weeks were injected with 2x10^6 CLB-Bar cells on the flank of the mice. Mice with tumors between 250 and 1100 mm^3 were included in the study. Three groups of mice were i.v injected with totally 15 MBq Lu-177-octreotate: given as 15 MBq x1, 7.5 MBq x2 with a 2-h interval or 5 MBq x3 with 1-h interval. The tumor volume was measured with a caliper twice a week after injection and the mice were killed when the tumor mass exceeded 10 % of the body weight. Results: The relative tumor volume 7 days post injection was 2.0, 1.7 and 1.3 for the 15 MBq x1, 7.5 MBq x2 and 5 MBq x3 group, respectively, corresponding mean survival time after study start was of 9.6, 14 and 16 days, respectively. Conclusion: The fractionated administration of Lu-177-octreotate resulted in a better anti-tumor effect, with the most prominent results from 3x5 MBq. These results might be due to saturation of the somatostatin receptors for the higher amounts of Lu-177-octreotate or upregulation of receptors from previous fractions. Further studies are needed to optimize the fractionation scheme and to evaluate the mechanisms behind the results.
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| 5. |
- Romiani, Arman, 1991, et al.
(författare)
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Neuroblastoma xenograft models demonstrate the therapeutic potential of Lu-177-octreotate
- 2021
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Neuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40-50%, indicating the need for novel and improved treatment options. Lu-177-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of Lu-177-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of Lu-177-octreotate for treatment of NB. Methods BALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5-7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq Lu-177-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1-5, and Ki67 were carried out for tumor xenografts from the three cell lines. Results High Lu-177 concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq Lu-177-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq Lu-177-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32. Conclusion T/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of Lu-177-octreotate as a therapeutic alternative for metastatic NB.
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| 6. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Combination therapy of medullary thyroid cancer using radiation and vandetanib
- 2017
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. Annual Congress of the European Association of Nuclear Medicine October 21 – 25, 2017 Vienna, Austria. Vol. 44, Suppl. 2. EP-0792. - : Springer. - 1619-7070 .- 1619-7089.
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Konferensbidrag (refereegranskat)abstract
- INTRODUCTION Most patients diagnosed with medullary thyroid cancer (MTC) present with metastatic disease. MTC are rare neuroendocrine tumours that occur either sporadically or in a hereditary form. Surgical resection of the thyroid gland followed by external beam radiotherapy (EBRT) or the use of tyrosine kinase inhibitors are current clinical methods for management of MTC. Unfortunately, the 10-year survival for patients with metastatic disease is only about 40%. However, many MTC tumours overexpress somatostatin receptors as molecular targets. Therefore, one option for patients with MTC is systemic treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) that bind with high affinity and specificity to somatostatin receptors on the tumour cells. In addition, the tyrosine kinase inhibitor vandetanib has recently been approved for single-agent treatment of MTC by the U.S. Food and Drug Administration (FDA). The aim of this study was to investigate the potential synergistic effect of combining irradiation and vandetanib for treatment of MTC. SUBJECTS & METHODS BALB/c nude mice were transplanted with patient-derived MTC cells (GOT2). When developed tumours reached a volume of about 500 mm3, the mice were treated with EBRT, vandetanib or a combination of both. The radiation dose and the amount of vandetanib were chosen to give moderate effect as single treatment to enable detection of any increased effect from the combination. Tumour volume was followed and compared with that in untreated mice. RESULTS We found that the largest treatment effect over time was seen for the animals receiving a combination of both EBRT and vandetanib. Given as single-agent treatment, EBRT and vandetanib resulted in a reduction in tumour size or in tumour growth arrest. For example, at two weeks after start of treatment, the tumour volume was reduced by 64%, 52%, and 73% compared with the untreated control group, for the animals treated with single EBRT, single vandetanib, and the combination, respectively. CONCLUSION The results indicate that an additive or even synergistic effect could be achieved when combining irradiation with vandetanib for treatment of patients with MTC. Further studies are needed to investigate the possibility of using 177Lu-octreotate for treatment of MTC, both as single-agent treatment or in combination with vandetanib.
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| 7. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer.
- 2019
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Ingår i: PloS One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.
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| 8. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Increased therapeutic effect on medullary thyroid cancer using a combination of radiation and tyrosine kinase inhibitors : Increased effect on medullary thyroid cancer by combining radiation with tyrosine kinase inhibitors
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.
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| 9. |
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| 10. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Tyrosinkinashämmare kan öka effekten från strålbehandling av medullär tyreoideacancer
- 2019
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Ingår i: Nationellt möte om sjukhusfysik.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- SYFTE Medullär tyreoideacancer (MTC) är en neuroendokrin cancertyp som har sitt ursprung i sköldkörtelns hormonproducerande C-celler. Många MTC överuttrycker receptorer för somatostatin vilket möjliggör radionuklidterapi med exempelvis 177Lu-oktreotat. Få patienter botas dock helt och optimering av behandlingen behövs. Ett sätt att optimera behandlingen är att kombinera 177Lu-oktreotat med ett annat läkemedel i syfte att öka effekten från strålningen. Nyligen godkändes två tyrosinkinashämmare (vandetanib och cabozantinib) för behandling av MTC. Syftet med denna studie var att undersöka ifall en ökad effekt kan fås då strålbehandling kombineras med tyrosinkinashämmare för behandling av MTC. METOD Nakna möss (BALB/c) transplanterades med humana MTC-celler (GOT2) och behandlades med extern strålbehandling och/eller tyrosinkinashämmare. Behandlings-effekten, som tumörvolym efter behandling, jämfördes med den hos obehandlade möss. För att möjliggöra detektion av en eventuellt ökad behandlingseffekt hos de möss som fick kombinationsbehandling (både strålbehandling och tyrosinkinas¬hämmare) valdes den absorberade dosen och mängden läkemedel så att en suboptimal effekt erhölls då respektive behandling gavs som singelbehandling. RESULTAT Kombinationsbehandling resulterade i störst minskning av tumörvolym och längst tid till progression. Exempelvis hade tumörvolymen hos de möss som fick kombinationsbehandling minskat med ca 70-75% efter två veckor jämfört med obehandlade möss. Även som singelbehandling resulterade båda behandlingar i en tydlig effekt på tumörvolymen, med en minskning på ca 50-65% efter två veckor. KONKLUSIONER Effekten från strålbehandling av möss med MTC-tumörer kan ökas genom kombinationsbehandling med tyrosinkinashämmare. Framtida studier bör utvärdera möjligheten att använda en kombination av 177Lu-oktreotat och tyrosinkinashämmare för behandling av patienter med MTC.
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