1.
Dalmo, Johanna, et al.
(författare)
Potential renal toxicity biomarkers indicating radiation injury after 177Lu-octreotate treatment
2013
Ingår i: Annual congress of the European association of nuclear medicine, october 19-23, 2013, Lyon, France. Posterwalk.
Konferensbidrag (övrigt vetenskapligt/konstnärligt) abstract
The kidneys are one of the most exposed non-tumor tissues and regarded as one of the main dose-limiting organs in peptide receptor radionuclide therapy (PRRT). [177Lu-DOTA0, Tyr3]-octreotate (177Lu-octreotate) has shown promising results in the treatment of somatostatin receptor overexpressing neuroendocrine tumors, but optimization is still needed. The ability to give each patient as much 177Lu-octreotate as possible without inducing nephrotoxicity is necessary for an efficient treatment. However, due to large inter-individual differences in uptake and retention in the kidneys, there is a need for efficient Methods that early can indicate renal injury. A possible way is to identify biomarkers for high risk of radiation nephrotoxicity. The aim of this study was to investigate the potential of using urinary retinol binding protein (RBP), and blood valinhydantoin (VH) as biomarkers of nephrotoxicity on adult mice after 177Lu-octreotate treatment. BALB/c nude mice (n=6/group) were i.v. injected with 60 MBq or 120 MBq of 177Lu-octreotate. The control group was mock treated with saline. Spot urine samples were collected before injection, and 14, 30, 60 and 90 days after injection. Analysis of RBP4 and creatinine was performed using Mouse RBP4 ELISA kit and Creatinine kit from R&D Systems, respectively. Erythrocytes were separated from whole blood samples collected 90 days after injection, and analysed for VH by LC-MS/MS. The ratio between VH and a volumetric standard was calculated. The RBP/creatinine level increased with time in both groups given 177Lu-octreotate, with earlier and higher response for the 120 MBq group. No clear change in VH level between the different groups was observed. The result show that RBP may be a promising new biomarker for radiation induced kidney toxicity. The presently used method based on VH was not sensitive enough to be used as kidney toxicity marker. Further studies on mice are ongoing to validate if RBP4 may be efficient in predicting late nephrotoxicity. In patients, RBP/creatinine levels are followed in urine samples after treatment with 177Lu-octreotate.
2.
Langen, Britta, et al.
(författare)
Transcriptional gene regulation in abdominal organs and the lung after i.v. injection of 211At in mouse
2012
Ingår i: Radiation research society. San Juan, Puerto Rico. 2012.
Konferensbidrag (övrigt vetenskapligt/konstnärligt) abstract
Astatine-211 (211At) is a promising radionuclide for radiation therapy with a nearly optimal biological effectiveness of emitted α-particles. Despite its potential, few studies have analysed 211At-induced normal tissue responses in vivo. In order to determine the quality and extent of 211At-induced cellular responses in vivo, the transcriptional gene regulation was analysed in the kidney cortex and medulla, liver, lung, and spleen. Female BALB/c nude mice were i.v. injected with 0.064, 0.64, 1.8, 14, and 42 kBq 211At and killed after 24h. Respective organs were excised and stored at -80°C until further analysis. Extracted total RNA was analysed with the Illumina MouseRef-8 Whole Genome Beadchip platform and data processing was performed with Nexus Expression 2.0. A common strong decrease in the total number of regulated transcripts was seen between 0.64 and 1.8 kBq 211At corresponding to absorbed doses between 2 and 50 mGy for all investigated tissues. Only minor responses in previously identified radiation-associated transcripts could be observed at any exposure. Among tissues at similar absorbed dose levels, the similarity in transcript up- and down-regulation decreased with increased absorbed dose. This phenomenon was more pronounced when the increase in absorbed dose corresponded also to an increase between 0.64 and 1.8 kBq 211At. Biological processes associated with regulated transcripts were categorised to assess the regulatory profiles in each tissue at a given exposure. These profiles showed distinct patterns which mirrored the threshold behaviour on the categorical and sub-categorical level of biological processes. The strong regulatory change demonstrated at the low absorbed doses in the tissues studied might be due to both radiation-induced effects of each tissue and physiological response from radiation-induced effects on the 211At-accumulating thyroid gland. These findings demonstrate the complexity of responses in vivo and highlight the need for a better understanding of the physiology when studying effects of ionizing radiation exposure.
3.
Schüler, Emil, et al.
(författare)
Biological effects of 177Lu-octreotate therapy in mouse: in vivo normal kidney tissue response evaluated with gene expression microarray
2012
Ingår i: 58th Annual Meeting of the Radiation Research Society. San Juan, Puerto Rico. 2012.
Konferensbidrag (övrigt vetenskapligt/konstnärligt) abstract
The kidneys are the dose limiting organ when patients undergo 177Lu-octreotate therapy. The purpose of the present study was to investigate alterations in gene expression levels in the kidney following exposure to various absorbed doses of 177Lu. Female Balb/c mice were i.v. injected with 1.3-140 MBq 177Lu-octreotate, corresponding to an absorbed dose to the kidneys of 0.13-13 Gy. Control animals did not receive any 177Lu-octreotate. The animals were killed 24 hours after injection and the kidneys were removed, followed by dissection of the kidney medulla and cortex. Total RNA was extracted and processed using the Illumina Mouse-Ref-8 Whole-Genome Expression Beadchips to identify differentially expressed transcripts between irradiated and non-irradiated kidney tissues. The total number of differentially regulated transcripts was 480 and 281 in the kidney medulla and cortex, respectively. Of these, 39 and 32 transcripts were regulated at all absorbed doses in the two renal tissues. Of the affected biological processes, three and five processes were affected at all absorbed dose levels in the medulla and cortex, respectively; glycerol metabolism, immune response, and defense response in the medulla, and immune response, amino acid transport, circadian rhythm, rhythmic processes, and regulation of lipoprotein lipase activity in the cortex. In general, metabolic processes were strongly expressed at all absorbed dose levels studied, however, inversely related to increasing absorbed dose. Furthermore, cellular and developmental processes were strongly associated with kidney medulla, while a strong association with transport and immune response was seen in kidney cortex. The results demonstrate distinct differences in the response seen after 177Lu exposure to different absorbed doses. Effects on metabolism and stress responses were frequently seen, while no processes associated with maintaining DNA integrity were found, which indicates a very diverse response following 177Lu exposure.
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6.
Arne, Gabriella, et al.
(författare)
Gastrointestinal stromal tumors (GISTs) express somatostatin receptors and bind radiolabeled somatostatin analogs.
2013
Ingår i: Acta oncologica (Stockholm, Sweden). - 1651-226X .- 0284-186X. ; 52:4, s. 783-792
Tidskriftsartikel (refereegranskat) abstract
Background. Gastrointestinal stromal tumors (GISTs) can be effectively treated with tyrosine kinase inhibitors (TKIs). However, some patients with GIST develop drug resistance, and alternative treatment strategies are therefore needed. The aim of this study was to analyze the expression of somatostatin receptors (SSTR) in GIST as a target for peptide receptor-mediated radiotherapy (PRRT). Material and methods. Expression profiling of SSTR1-5 was performed on biopsies from 34 GISTs (16 gastric tumors, 15 small intestinal tumors, and three rectal tumors). SSTR scintigraphy ((111)In-octreotide) and measurement of (111)In activity in tumor specimens was performed in seven patients. Uptake and internalization of (177)Lu- octreotate was studied in primary cell cultures from two patients. Results. Quantitative PCR analysis showed expression of SSTR1 and SSTR2 in the majority of tumors, while SSTR3-5 were expressed at low levels. Immunohistochemical analysis confirmed the presence of SSTR1 and SSTR2 proteins in all GISTs, and SSTR3-5 in a subset of tumors. Diagnostic imaging by SSTR scintigraphy, using (111)In-octreotide, demonstrated tumor uptake of (111)In in three of six GIST patients. Measurement of (111)In activity in excised tumor specimens from five patients gave tumor-to-blood (T/B) activity ratios of between eight and 96. Tumor cells in primary culture (gastric and small intestinal GIST) specifically bound and internalized (177)Lu when incubated with the therapeutic compound (177)Lu-octreotate for 4-48 hours (p < 0.05). Conclusion. Peptide receptor-mediated radiotherapy via SSTR may provide a novel treatment strategy in carefully selected GIST patients with TKI-resistant tumors.
7.
Ljungberg, Maria, et al.
(författare)
31P MR spectroscopy to evaluate the efficacy of hepatic artery embolization in the treatment of neuroendocrine liver metastases.
2012
Ingår i: Acta radiologica (Stockholm, Sweden : 1987). - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 53:10, s. 1118-1126
Tidskriftsartikel (refereegranskat) abstract
BackgroundIt is common to treat patients with metastatic disease from gastrointestinal neuroendocrine (NE) tumors with surgical reduction to prolong survival. This can be combined with hepatic arterial embolization (HAE) and medical treatment to reduce hormonal symptoms. Today there are no rapid and reliable methods to evaluate the efficacy of HAE in the treatment of neuroendocrine liver metastasis.PurposeTo investigate metabolic changes in hepatic metastases of NE tumors following HAE, and to establish if there are any early spectral patterns that might indicate therapeutic efficacy based on in vivo (31)P MRS data.Material and MethodsVolume selective (31)P MRS was used to study 11 patients with disseminated NE tumors with regional lymph nodes and bilobar liver metastases. Measurements were performed before and 1 and 3 days after HAE.ResultsNon-responders had significantly higher PME/Pi and αNTP/ΣNTP ratios than the responders before HAE (P < 0.05). Three days after HAE, non-responders still had significantly higher αNTP/ΣNTP than the responders did (P < 0.05). We also observed trends for increased PME ratios 3 days after HAE, decreased ATP-levels, and liberated Pi in responders.ConclusionThis (31)P-MRS study showed significant differences in PME/Pi and αNTP/ΣP ratios between responders and non-responders on the day before HAE, which is an interesting finding that may reflect intrinsic properties of the tumor tissue. We also observed trends for cell membrane renewal and increased energy consumption in responders after HAE. These results demonstrate potentials for (31)P-MRS to predict individual responsiveness prior to HAE.
8.
Sandblom, Viktor, 1987, et al.
(författare)
Radiolabelled pharmaceuticals MIBG and octreotate for treatment of metastatic pheochromocytoma and paraganglioma
2014
Ingår i: SweRays Workshop, Malmö, Sweden, Aug 20-22, 2014.
Konferensbidrag (övrigt vetenskapligt/konstnärligt) abstract
Background: The 5-year survival for patients with metastatic pheochromocytoma (PC) and paraganglioma (PGL) is less than 50%. There is a clear need for development of better diagnostic and therapeutic options for these patients. Radionuclide therapy offers the possibility to treat spread PC/PGL. The norepinephrine (NE) analogue metaiodobenzylguanidine (MIBG) and the somatostatin (SST) analogues octreotate or octreotide are possible molecules that could be used for this purpose. These analogues have different biodistribution and different organs at risk, when used for therapy. Thus, combined therapy, using both radiolabelled NE and SST analogues, might be beneficial for these patients. Aim: The aim of this study was to evaluate the possibility of using 177Lu-octreotate and/or 131I-MIBG for treatment of patients with metastatic PC/PGL. Materials and Methods: Three patients with metastatic PC/PGL were injected with 131I-MIBG and 111In-octreotide, and four patients with metastatic PC/PGL were injected with 111In-octreotide, before surgical removal of the primary tumour. During surgery, tissue samples of tumour, blood, fat and muscle were collected and weighed, and the radioactivity was measured in a gamma counter. The activity concentration in these tissue samples was then calculated for each radionuclide. Additionally, tumour-to-blood activity concentration ratios (T/B) were calculated. Results: The activity concentrations and T/B values showed large variations between patients. For 111In-octreotide, T/B values were 25-590 and for 131I-MIBG, the corresponding values were 0-1600. Conclusion: The sometimes high T/B values show a clear possibility of using 177Lu-octreotate and 131I-MIBG for treatment of some patients with metastatic PC/PGL. However, due to the large variation between patients, individual investigation of tumour uptake prior to treatment is required.
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10.
Spetz, Johan, et al.
(författare)
Specific binding and uptake of 131I-MIBG and 111In-octreotide in malignant paraganglioma - tools for choice of radionuclide therapy
2012
Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 44:5, s. 400-404
Tidskriftsartikel (refereegranskat) abstract
Tumor-specific uptake of the radiolabeled nor-epinephrine analogue meta-iodobenzylguanidine via norepinephrine transporter or radiolabeled somatostatin analogues octreotide/octreotate via somatostatin receptors offers possibilities to diagnose and treat metastatic pheochromocytoma/paraganglioma. High uptake of 123I-meta-iodobenzylguanidine is dependent on high expression of vesicular monoamine transporters responsible for mediating uptake of biogenic amines into dense core granules. A patient with metastatic paraganglioma (liver and bone metastases) underwent surgical removal of the primary after injection of 131I-meta-iodobenzylguanidine and 111In-octreotide. Radioactivity was determined in biopsies from tumor and normal tissue biopsies. The tumor/blood concentration value was high: 180 for 131I-meta-iodobenzylguanidine 3 h after injection and 590 for 111In-octreotide 27 h after injection. Studies of primary tumor cell cultures demonstrated increased cell membrane binding and internalization over time for 131I-meta-iodobenzylguanidine. The vesicular monoamine transporter antagonist reserpine and the norepinephrine transporter inhibitor clomipramine reduced internalization by 90% and 70%, respectively, after 46 h of incubation. The results demonstrated increased cell membrane binding and internalization over time also for 111In-octreotide. Internalization was highest for a low concentration of 111In-octreotide. Excess of octreotide reduced internalization of 111In-octreotide with 75% after 46 h of incubation. In conclusion, uptake and tumor/blood concentration values of radiolabeled meta-iodobenzylguanidine and somatostatin analogues can be determined for metastatic pheochromocytoma/paraganglioma to evaluate the possibility to use one or both agents for therapy. For this patient, the high tumor/blood values clearly demonstrated that therapy using both radiopharmaceuticals would be most beneficial. In vitro studies verified specific cell-membrane binding and internalization in tumor cells of both radiopharmaceuticals.
