| 1. |
- Hofving, Tobias, 1989, et al.
(författare)
-
177 Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition
- 2019
-
Ingår i: Endocrine-Related Cancer. - 1479-6821 .- 1351-0088. ; 26:4, s. 437-449
-
Tidskriftsartikel (refereegranskat)abstract
- Lu-177-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The Lu-177-octreotate therapy has shown promising results in clinical trials by prolonging progression-free survival, but complete responses are still uncommon. The aim of this study was to improve the Lu-177-octreotate therapy by means of combination therapy. To identify radiosensitising inhibitors, two cell lines, GOT1 and P-STS, derived from small intestinal neuroendocrine tumours (SINETs), were screened with 1224 inhibitors alone or in combination with external radiation. The screening revealed that inhibitors of Hsp90 can potentiate the tumour cell-killing effect of radiation in a synergistic fashion (GOT1; false discovery rate < 3.2 x 10(-11)). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of Lu-177-octreotate in an in vivo setting was studied in the somatostatin receptor-expressing GOT1 xenograft model. The combination led to a larger decrease in tumour volume relative to monotherapies and the tumour-reducing effect was shown to be synergistic. Using patient-derived tumour cells from eight metastatic SINETs, we could show that ganetespib enhanced the effect of Lu-177-octreotate therapy for all investigated patient tumours. Levels of Hsp90 protein expression were evaluated in 767 SINETs from 379 patients. We found that Hsp90 expression was upregulated in tumour cells relative to tumour stroma in the vast majority of SINETs. We conclude that Hsp90 inhibitors enhance the tumour-killing effect of Lu-177-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.
|
|
| 2. |
- Arvidsson, Yvonne, 1960, et al.
(författare)
-
Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells.
- 2016
-
Ingår i: Neuroendocrinology. - : S. Karger AG. - 1423-0194 .- 0028-3835. ; 103:5, s. 578-591
-
Tidskriftsartikel (refereegranskat)abstract
- Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class-I and class-IIa HDACs, on neuroendocrine tumour (NET) cell growth.
|
|
| 3. |
- Elf, Anna-Karin, et al.
(författare)
-
NAMPT inhibitor GMX1778 enhances the efficacy of 177Lu-DOTATATE treatment of neuroendocrine tumors.
- 2017
-
Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:2, s. 288-292
-
Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine tumors (NETs) can be treated by peptide receptor radionuclide therapy using radiolabeled somatostatin analogs. However, the efficacy of such treatment is low and needs to be optimized.To evaluate the potential radiosensitizing effects of NAMPT inhibition on (177)Lu-DOTATATE treatment in a NET model.Nude mice xenografted with the human NET cell line GOT1 were treated with semi-efficient doses of (177)Lu-DOTATATE (7,5 MBq, i.v.) and/or GMX1778 (100 mg/kg/week, p.o.).Median time to tumor progression (tumor volume larger than at day 0) was 3 days for controls, 7 days for single dose GMX1778, 28 days for single dose (177)Lu-DOTATATE and 35 days for 3 weekly doses of GMX1778. Combined treatment with (177)Lu-DOTATATE and GMX1778 x1 resulted in a median time to progression of 98 days. After (177)Lu-DOTATATE and 3 weekly doses of GMX1778 none of the tumors progressed within 120 days.The NAMPT inhibitor GMX1778 enhances the efficacy of (177)Lu-DOTATATE treatment and induces a prolonged antitumor response. Combinations of radiolabeled somatostatin analogs and radiosensitizing drugs should be further evaluated to optimize the efficacy of peptide receptor radionuclide therapy in NETs.
|
|
| 4. |
- Elf, Anna-Karin, et al.
(författare)
-
Radioembolization Versus Bland Embolization for Hepatic Metastases from Small Intestinal Neuroendocrine Tumors: Short-Term Results of a Randomized Clinical Trial.
- 2018
-
Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 42:2, s. 506-513
-
Tidskriftsartikel (refereegranskat)abstract
- Radioembolization (RE) with intra-arterial administration of 90Y microspheres is a promising technique for the treatment of liver metastases from small intestinal neuroendocrine tumors (SI-NET) not amenable to surgery or local ablation. However, studies comparing RE to other loco-regional therapies are lacking. The aim of this randomized study was to compare the therapeutic response and safety after RE and bland hepatic arterial embolization (HAE), and to investigate early therapy-induced changes with diffusion-weighted MRI (DWI-MRI).Eleven patients were included in a prospective randomized controlled pilot study, six assigned to RE and five to HAE. Response according to RECIST 1.1 using MRI or CT at 3 and 6months post-treatment was recorded as well as changes in DWI-MRI parameters after 1month. Data on biochemical tumor response, toxicity, and side effects were also collected.Three months after treatment, all patients in the HAE group showed partial response according to RECIST while none in the RE group did (p=0.0022). After 6months, the response rates were 4/5 (80%) and 2/6 (33%) in the HAE and RE groups, respectively (NS). DWI-MRI metrics could not predict RECIST response, but lower pretreatment ADC(120-800) and larger ADC(0-800) increase at 1month were related to larger decrease in tumor diameter when all tumors were counted.HAE resulted in significantly higher RECIST response after 3months, but no difference compared to RE remained after 6months. These preliminary findings indicate that HAE remains a safe option for the treatment of liver metastases from SI-NET, and further studies are needed to establish the role of RE and the predictive value of MR-DWI.
|
|
| 5. |
- Hofving, Tobias, 1989, et al.
(författare)
-
The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines
- 2018
-
Ingår i: Endocrine-Related Cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 25:3, s. 367-380
-
Tidskriftsartikel (refereegranskat)abstract
- Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.
|
|
| 6. |
- Hofving, Tobias, et al.
(författare)
-
The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines
- 2018
-
Ingår i: Endocrine-Related Cancer. - 1479-6821 .- 1351-0088. ; 25:3, s. 367-380
-
Tidskriftsartikel (refereegranskat)abstract
- Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number rofiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.
|
|
| 7. |
- Jalnefjord, Oscar, 1989, et al.
(författare)
-
Comparison of methods for estimation of the intravoxel incoherent motion (IVIM) diffusion coefficient (D) and perfusion fraction (f)
- 2018
-
Ingår i: Magnetic Resonance Materials in Physics, Biology and Medicine. - : Springer Science and Business Media LLC. - 0968-5243 .- 1352-8661. ; 31:6, s. 715-723
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Intravoxel incoherent motion (IVIM) shows great potential in many applications, e.g., tumor tissue characterization. To reduce image-quality demands, various IVIM analysis approaches restricted to the diffusion coefficient (D) and the perfusion fraction (f) are increasingly being employed. In this work, the impact of estimation approach for D and f is studied. Materials and methods: Four approaches for estimating D and f were studied: segmented IVIM fitting, least-squares fitting of a simplified IVIM model (sIVIM), and Bayesian fitting of the sIVIM model using marginal posterior modes or posterior means. The estimation approaches were evaluated in terms of bias and variability as well as ability for differentiation between tumor and healthy liver tissue using simulated and in vivo data. Results: All estimation approaches had similar variability and ability for differentiation and negligible bias, except for the Bayesian posterior mean of f, which was substantially biased. Combined use of D and f improved tumor-to-liver tissue differentiation compared with using D or f separately. Discussion: The similar performance between estimation approaches renders the segmented one preferable due to lower numerical complexity and shorter computational time. Superior tissue differentiation when combining D and f suggests complementary biologically relevant information.
|
|
| 8. |
|
|
| 9. |
- Lesén, Eva, et al.
(författare)
-
Real-world treatment patterns, resource use and costs of treating uncontrolled carcinoid syndrome and carcinoid heart disease : a retrospective Swedish study
- 2018
-
Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 53:12, s. 1509-1518
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: To quantify healthcare resource use (HRU) and costs in relation to carcinoid syndrome (CS) and carcinoid heart disease (CHD) in a real-world setting, and to provide perspective on treatment patterns.Materials and methods: Patient data and HRU were collected retrospectively from three Swedish healthcare registers. Adult patients diagnosed with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) grade 1 or 2 and CS who purchased somatostatin analogs (SSAs), and experienced controlled (defined by SSAs use) and uncontrolled (defined by SSAs dose escalation) CS for ≥8 months during the study period were included. Patients diagnosed with CHD from the date of the GEP-NET diagnosis were included in the CHD study group.Results: Overall, total HRU cost increased with uncontrolled CS and CHD. Total resource cost was 15,500€/patient during controlled CS (8 months), rising to 21,700€/patient during uncontrolled CS (8 months), representing an increase of ∼40% (6200€/patient). Costs/patient were driven mainly by SSA use, tumor-related medical interventions and examinations. The total mean cost/year of disease was 1100€/patient without CHD, compared to 4600€/patient with CHD, a difference of 3500€/patient. Excluding SSA cost burden, the main drivers of increased cost in CHD patients were surgical interventions and echocardiography.Conclusions: This study provides a comprehensive overview of the treatment patterns and burden of uncontrolled CS symptoms and CHD using Swedish national register data. Increases in medical interventions and examinations HRU and increased SSA use suggest that SSA dose escalation alone may not effectively control the symptoms associated with uncontrolled CS, highlighting an unmet treatment need in this patient group.
|
|
| 10. |
|
|
