| 1. |
- Andersson, Ellinor, et al.
(författare)
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Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets.
- 2016
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 29:6, s. 616-629
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Tidskriftsartikel (refereegranskat)abstract
- We wanted to define the transcriptome of small intestinal neuroendocrine tumors in order to identify clinically relevant subgroups of tumors, prognostic markers and novel targets for treatment. Genome-wide expression profiling was conducted on tumor biopsies from 33 patients with well-differentiated neuroendocrine tumors of the distal ileum and metastatic disease at the time of diagnosis. Unsupervised hierarchical clustering analysis identified three groups of tumors. The largest group, comprising half of the tumors, was characterized by longer patient survival and higher expression of neuroendocrine markers, including SSTR2. Tumors with higher grade (G2/3) or gain of chromosome 14 were associated with shorter patient survival and increased expression of cell cycle-promoting genes. Pathway analysis predicted the prostaglandin E receptor 2 (PTGER2) as the most significantly activated regulator in tumors of higher grade, whereas Forkhead box M1 (FOXM1) was the most significantly activated regulator in tumors with gain of chromosome 14. Druggable genes identified from expression profiles included clinically proven SSTR2 and also novel targets, for example, receptor tyrosine kinases (RET, FGFR1/3, PDGFRB and FLT1), epigenetic regulators, molecular chaperones and signal transduction molecules. Evaluation of candidate drug targets on neuroendocrine tumors cells (GOT1) showed significant inhibition of tumor cell growth after treatment with tyrosine kinase inhibitors or inhibitors of HDAC, HSP90 and AKT. In conclusion, we have defined the transcriptome of small intestinal neuroendocrine tumors and identified novel subgroups with clinical relevance. We found specific gene expression patterns associated with tumor grade and chromosomal alterations. Our data also suggest novel prognostic biomarkers and therapies for these patients.
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| 2. |
- Andersson, Ellinor, et al.
(författare)
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High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids.
- 2009
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Ingår i: Endocrine-related cancer. - 1479-6821. ; 16:3, s. 953-66
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Tidskriftsartikel (refereegranskat)abstract
- Ileal carcinoids are malignant neuroendocrine tumours of the small intestine. The aim of this study was to obtain a high-resolution genomic profile of ileal carcinoids in order to define genetic changes important for tumour initiation, progression and survival. Forty-three patients with ileal carcinoids were investigated by high-resolution array-based comparative genomic hybridization. The average number of copy number alterations (CNAs) per tumour was 7.1 (range 1-22), with losses being more common than gains (ratio 1.4). The most frequent CNA was loss of chromosome 18 (74%). Other frequent CNAs were gain of chromosome 4, 5, 14 and 20, and loss of 11q22.1-q22.2, 11q22.3-q23.1 and 11q23.3, and loss of 16q12.2-q22.1 and 16q23.2-qter. Two distinct patterns of CNAs were found; the majority of tumours was characterized by loss of chromosome 18 while a subgroup of tumours had intact chromosome 18, but gain of chromosome 14. Survival analysis, using a series of Poisson regressions including recurrent CNAs, demonstrated that gain of chromosome 14 was a strong predictor of poor survival. In conclusion, high-resolution profiling demonstrated two separate patterns of CNAs in ileal carcinoids. The majority of tumours showed loss of chromosome 18, which most likely represents a primary event in the development and pathogenesis of tumours. A different genetic pathway is operative in a subgroup of tumours; this is characterized by gain of chromosome 14 and is strongly associated with poor prognosis. Predictive fluorescence in situ hybridization analysis of chromosome 14 status in patients with ileal carcinoids is suggested.
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| 3. |
- Arvidsson, Yvonne, 1960, et al.
(författare)
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miRNA profiling of small intestinal neuroendocrine tumors defines novel molecular subtypes and identifies miR-375 as a biomarker of patient survival
- 2018
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 31, s. 1302-1317
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Tidskriftsartikel (refereegranskat)abstract
- © 2018, United States & Canadian Academy of Pathology. The aim of this study was to define the miRNA profile of small intestinal neuroendocrine tumors and to search for novel molecular subgroups and prognostic biomarkers. miRNA profiling was conducted on 42 tumors from 37 patients who underwent surgery for small intestinal neuroendocrine tumors. Unsupervised hierarchical clustering analysis of miRNA profiles identified two groups of tumor metastases, denoted cluster M1 and M2. The smaller cluster M1 was associated with shorter overall survival and contained tumors with higher grade (WHO grade G2/3) and multiple chromosomal gains including gain of chromosome 14. Tumors of cluster M1 had elevated expression of miR-1246 and miR-663a, and reduced levels of miR-488-3p. Pathway analysis predicted Wnt signaling to be the most significantly altered signaling pathway between clusters M1 and M2. Analysis of miRNA expression in relation to tumor proliferation rate showed significant alterations including downregulation of miR-137 and miR-204-5p in tumors with Ki67 index above 3%. Similarly, tumor progression was associated with significant alterations in miRNA expression, e.g. higher expression of miR-95 and miR-210, and lower expression of miR-378a-3p in metastases. Pathway analysis predicted Wnt signaling to be altered during tumor progression, which was supported by decreased nuclear translocation of β-catenin in metastases. Survival analysis revealed that downregulation of miR-375 was associated with shorter overall survival. We performed in situ hybridization on biopsies from an independent cohort of small intestinal neuroendocrine tumors using tissue microarrays. Expression of miR-375 was found in 578/635 (91%) biopsies and survival analysis confirmed that there was a correlation between downregulation of miR-375 in tumor metastases and shorter patient survival. We conclude that miRNA profiling defines novel molecular subgroups of metastatic small intestinal neuroendocrine tumors and identifies miRNAs associated with tumor proliferation rate and progression. miR-375 is highly expressed in small intestinal neuroendocrine tumors and may be used as a prognostic biomarker.
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| 4. |
- Johanson, Viktor, 1958, et al.
(författare)
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A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis
- 2007
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 14:2, s. 433-444
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations in the RET proto-oncogene, resulting in constitutive activation of the RET tyrosine kinase. A substantial proportion of sporadic MTCs also have RET mutations, making the RET tyrosine kinase a potential therapeutic target in MTC. We have established a transplantable MTC in nude mice from a sporadic human MTC carrying a RET C634R mutation. Transplanted tumors had an exponential growth rate with an approximate doubling time of about 3 weeks, and expressed a neuroendocrine phenotype characteristic of MTC, e.g., expression of calcitonin, chromogranin A (CgA), synaptophysin, synaptic vesicle protein 2 (SV2), vesicular monoamine transporter-1 and -2, carcinoembryonic antigen, cytokeratin 8/18, epithelial cadherin, and neural cell adhesion molecule. Plasma calcitonin and CgA levels were elevated in tumor-bearing mice and correlated with tumor size. Cytogenetic analysis, including spectral karyotyping, confirmed the human origin of the xenografted tumors and demonstrated an abnormal, near triploid karyotype. Treatment of tumor-bearing nude mice with the tyrosine kinase inhibitor ZD6474, which specifically inhibits RET, epidermal growth factor receptor (EGFR), and vascular endothelium growth factor receptor (VEGFR) tyrosine kinases, resulted in a dose-dependent inhibition of tumor growth. Oral ZD6474 given once daily (250 mg/kg, 5 days/week) reduced tumor volume to 11% when compared with controls after 4 weeks. Our results show that this transplantable MTC, designated GOT2, represents a novel and useful model for studies of MTC and RET tyrosine kinase-dependent tumor growth.
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| 5. |
- Johanson, Viktor, 1958, et al.
(författare)
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Antitumoural effects of the pyridyl cyanoguanidine CHS 828 on three different types of neuroendocrine tumours xenografted to nude mice
- 2005
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 82:3-4, s. 171-6
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828, a cyanoguanidine with potent experimental antitumoural activity, inhibits activation of nuclear factor-kappaB. In the present study, marked antitumoural activity of peroral CHS 828 was shown against three different human neuroendocrine tumours, midgut carcinoid (GOT1), pancreatic carcinoid (BON), and medullary thyroid carcinoma (GOT2), transplanted in nude mice. Our results indicate that CHS 828 can be a candidate drug for treatment of neuroendocrine tumours.
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| 6. |
- Kölby, Lars, 1963, et al.
(författare)
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Chromogranin A as a determinant of midgut carcinoid tumour volume
- 2004
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Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 120:1-3, s. 269-73
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine (NE) tumours are characterized by their capacity to synthesize, store and release hormonal products. These substances are stored in neurosecretory vesicles together with chromogranin A (CgA). The concentration of plasma CgA in patients with NE tumours is thought to reflect the degree of NE differentiation, total tumour burden and effect of medical treatment. The aim of this study was to analyse the correlation between tumour weight and plasma CgA levels as well as the influence of treatment with a long-acting somatostatin analogue (octreotide) using nude mice with xenografted human ileal carcinoid tumours. There was a correlation between tumour weight and plasma CgA levels in all animals (p < 0.00001). In octreotide-treated mice, plasma CgA levels were significantly reduced versus untreated animals (p = 0.037). In conclusion, this study demonstrates that plasma CgA levels are closely correlated to tumour burden, and that plasma CgA is well suited for monitoring the clinical course and outcome of treatment in patients with NE tumours.
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| 7. |
- Swärd, Christina, 1967, et al.
(författare)
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[(177)Lu-DOTA(0)-Tyr (3)]-Octreotate Treatment in Patients with Disseminated Gastroenteropancreatic Neuroendocrine Tumors: The Value of Measuring Absorbed Dose to the Kidney.
- 2010
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Ingår i: World journal of surgery. - : Springer Science and Business Media LLC. - 1432-2323 .- 0364-2313. ; 34, s. 1368-1372
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Peptide receptor radiation therapy (PRRT) using [(177)Lu-DOTA(0)-Tyr(3)]-octreotate is a new, promising option for treatment of disseminated gastroenteropancreatic neuroendocrine tumors (GEPNETs). METHODS: During 2006-2008, 26 patients with disseminated GEPNETs were treated with (177)Lu-octreotate. Radiologic response (RECIST), biochemical response [plasma chromogranin-A (P-CgA)], hematologic toxicity [Common Toxicity Criteria (CTC)], absorbed dose to the kidneys (conjugate view method), and glomerular filtration rate (GFR) were analyzed. RESULTS: (177)Lu-octreotate (8 GBq) was given one to five times (median = 3) with a 6-week interval between each. Sixteen of the 26 patients were evaluated radiologically; 6 (38%) had partial response (PR), 8 (50%) had stable disease (SD), and 2 (13%) had progressive disease (PD). Seventeen of the 26 patients were evaluated biochemically; 6 (35%) showed a >/=30% decrease, 8 (47%) showed a >/=20% increase, and 3 (18%) showed neither a >/=30% decrease nor a >/=20% increase. The mean absorbed dose to the kidneys was 24 Gy. With a dose limit of 27 Gy to the kidneys, 10 patients did not receive the planned four treatments, while four patients had the potential to receive additional treatment. A significant reduction (p = 0.0013) of GFR was observed at follow-up. Three patients experienced CTC grade 3 hematologic toxicity. CONCLUSIONS: By using the absorbed dose to the kidneys as a limiting factor, treatment with (177)Lu-octreotate can be individualized, e.g., overtreatment can be avoided and patients with the potential to receive additional treatment can be identified. Further studies are needed to define tolerance doses to the kidneys so that treatment can be optimized.
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| 8. |
- Swärd, Christina, 1967
(författare)
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Aspects on Diagnosis and Treatment of Gastrointestinal Neuroendocrine Tumours
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aspects on Diagnosis and Treatment of Gastrointestinal Neuroendocrine Tumours Background. Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) originate from endocrine cells of the intestinal mucosa and pancreas. The tumour cells contain chromogranin A (CgA) and usually have a high expression of somatostatin receptors (SSTR), which can be used for diagnosis and treatment. The treatment alternatives in patients with disseminated GEP-NETs include debulking surgery, hepatic arterial embolization (HAE), in selected cases orthotopic liver transplantation (OLT), or somatostatin receptor (SSTR)-mediated radiation therapy besides medical treatment with somatostatin analogues, interferon, or combination of cytotoxic drugs. Material & Methods. A xenograft model with a transplantable midgut carcinoid tumour (GOT 1) was used to study the correlation between tumour weight and the tumour marker chromogranin A (CgA) in plasma as well as the therapeutic effects of the somatostatin analogue octreotide. The uptake and biodistribution of the radiopharmaceuticals 177Lu-octreotide and 177Lu-octreotate in GOT 1-bearing nude mice were studied. A consecutive series of 107 patients treated with HAE was analyzed regarding biochemical response and survival. The effect of SSTR-mediated radiation therapy was analysed in a consecutive series of 26 patients with disseminated GEP-NETs as well as in 6 patients with non-resectable recurrence of tumour after OLT. The absorbed dose to the kidney as a tool for optimization of radiotherapy was evaluated. Results. In GOT 1-bearing nude mice there was a strong correlation between tumour weight and P-CgA (P<0.00001). The P-CgA/tumour weight ratio was significantly lowered by octreotide (P<0.037). The uptake of 177Lu-octreotate was twice that of 177Lu-octreotide (P=0.00061) and the reduction of tumour volume was significantly higher in animals given 177Lu-octreotate (P=0.003). The tumour volume correlated significantly with P-CgA, which served as a marker of treatment effect. A good biochemical response with decreased tumour markers correlated with prolonged survival in patients after HAE (P=0.003). There was also a significant correlation between the responses to primary and repeat HAE. SSTR-mediated radiation therapy resulted in 38% partial tumour reduction according to RECIST-criteria. By using the absorbed dose to the kidney as a limiting factor for therapy we found that 10 patients received fewer than 4 treatments but 4 patients were identified as candidates for additional treatment. There was a significant reduction of glomerular filtration rate (GFR) after radiotherapy (P=0.0013). Also in transplanted patients SSTR-mediated radiation therapy could be used to treat tumour recurrence. Conclusions. 1. P-CgA was well suited for monitoring of the tumour burden and tumour response in GOT 1-bearing nude mice. 2. 177Lu-octreotate was a more suitable radiopharmaceutical than 177Lu-octreotide and the in vivo data allowed accurate determination of absorbed dose. 3. HAE provided prolonged survival in biochemically responsive patients. Repeat HAE can be considered in patients with favourable response to the first procedure. 4. Calculation of the accumulated dose to the kidneys during SSTR-mediated radiotherapy was valuable to optimize the treatment. 5. SSTR-mediated radiotherapy was a treatment option also for patients with non-resectable recurrence of SSTR-expressing tumours, previously treated with OLT. Key words: Carcinoid, endocrine pancreatic tumour, neuroendocrine, octreotide, somatostatin receptor, peptide receptor radionuclide therapy, absorbed dose, chromogranin A, liver transplantation.
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| 9. |
- Swärd, Christina, 1967, et al.
(författare)
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Comparison of [177Lu-DOTA0,Tyr3]-octreotate and [177Lu-DOTA0,Tyr3]-octreotide for receptor-mediated radiation therapy of the xenografted human midgut carcinoid tumor GOT1.
- 2008
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 23:1, s. 114-20
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare the tumor uptake versus time and the tumor response in nude mice transplanted with a human midgut carcinoid (GOT1), when treated with either [(177)Lu-DOTA(0),Tyr(3)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate and to evaluate if plasma chromogranin A (P-CgA) was a reliable marker of tumor response. The tumor uptake and retention of activity of a single intravenous (i.v.) dose (15 MBq) of [(177)Lu-DOTA(0),Tyr(3)]-octreotate or [(177)Lu-DOTA(0),Tyr(3)]-octreotide were compared in nude mice xenografted with GOT1. The activity concentration 24 hours after injection was significantly higher in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate versus [(177)Lu-DOTA(0),Tyr(3)]-octreotide (16%+/-1.4% of injected activity per gram [%IA/g] vs. 8.1%+/-2.1% IA/g, mean +/- standard error of the mean) (p=0.00061). The mean absorbed dose was higher in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate (46+/-4.3 vs. 17 +/- 3.4 Gy). The reduction of tumor volume was accordingly more prominent in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate than in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotide (p=0.003). The mean tumor volume for animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate was reduced to 3% of its initial value. P-CgA values were strongly correlated with tumor volume. Octreotate seems to be a more suitable somatostatin analog than octreotide for receptor-mediated radiation therapy. P-CgA is a simple, accurate method for the estimation of tumor response in this animal model.
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| 10. |
- Swärd, Christina, 1967, et al.
(författare)
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Prolonged survival after hepatic artery embolization in patients with midgut carcinoid syndrome.
- 2009
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 96:5, s. 517-21
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hepatic artery embolization (HAE) is a palliative treatment for patients with liver metastases from neuroendocrine tumours. HAE reduces hormonal symptoms, but its impact on survival has been questioned. METHODS: Biochemical responses and survival in consecutive patients with disseminated liver metastases from midgut carcinoid tumours were studied after HAE. Repeat HAE was performed in selected patients with radiological and biochemical signs of progression. RESULTS: Of 107 patients who had HAE, the median survival from the first procedure was 56 (range 1-204) months. Prolonged survival showed a strong correlation with reduction of urinary 5-hydroxyindoleacetic acid (P = 0.003) and plasma chromogranin A (P = 0.001) levels. The biochemical response to repeat HAE was similar to that for the first procedure (P = 0.002). The complication rate was low (7.5 per cent), as was the mortality rate (1.9 per cent) within 1 month of HAE. CONCLUSION: HAE is safe, provides good control of hormonal symptoms, and prolongs survival in biochemically responsive patients. It is a valuable palliative option for patients with midgut carcinoid syndrome due to liver metastases and can be repeated in patients with a favourable response to the first procedure.
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