| 1. |
- Crona, Joakim, et al.
(author)
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Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors
- 2015
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In: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 22, s. 1428-1435
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Journal article (peer-reviewed)abstract
- BACKGROUND: Until recently, the genetic landscape of small intestinal neuroendocrine tumors (SI-NETs) was limited to recurrent copy number alterations, most commonly a loss on chromosome 18. Intertumor heterogeneity with nonconcordant genotype in paired primary and metastatic lesions also is described, further contributing to the difficulty of unraveling the genetic enigma of SI-NETs. A recent study analyzing 55 SI-NET exomes nominated CDKN1B (p27) as a haploinsufficient tumor suppressor gene.METHODS: This study aimed to determine the frequency of CDKN1B inactivation and to investigate genotype-phenotype correlations. It investigated 362 tumors from 200 patients. All samples were resequenced for mutations in CDKN1B using automated Sanger sequencing. The expression of p27 was investigated in 12 CDKN1B mutant and nine wild type tumors.RESULTS: Some 8.5 % (17/200) of patients had tumors with pathogenic mutations in CDKN1B including 13 insertion deletions, four nonsense variants, and one stop-loss variant. All variants with available nontumoral DNA were classified as somatic. Inter- and intratumor heterogeneity at the CDKN1B locus was detected respectively in six of ten and two of ten patients. Patients with CDKN1B mutated tumors had both heterogeneous disease presentation and diverse prognosis. Expression of the p27 protein did not correlate with CDKN1B mutation status, and no differences in the clinical characteristics between CDKN1B mutated and CDKN1B wild type tumor carriers were found.CONCLUSION: This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.
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| 2. |
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| 3. |
- Edfeldt, Katarina, 1979-, et al.
(author)
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A Plausible Role for Actin Gamma Smooth Muscle 2 (ACTG2) in Small Intestinal Neuroendocrine Tumorgenesis
- 2016
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In: BMC Endocrine Disorders. - : BioMed Central (BMC). - 1472-6823. ; 16
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Journal article (peer-reviewed)abstract
- BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) originate from the enterochromaffin cells in the ileum and jejunum. The knowledge about genetic and epigenetic abnormalities is limited. Low mRNA expression levels of actin gamma smooth muscle 2 (ACTG2) have been demonstrated in metastases relative to primary SI-NETs. ACTG2 and microRNA-145 (miR-145) are aberrantly expressed in other cancers and ACTG2 can be induced by miR-145. The aim of this study was to investigate the role of ACTG2 in small intestinal neuroendocrine tumorigenesis.METHODS: Protein expression was analyzed in SI-NETs (n = 24) and in enterochromaffin cells by immunohistochemistry. The cell line CNDT2.5 was treated with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep), the selective EZH2 inhibitor EPZ-6438, or 5-aza-2'-deoxycytidine, a DNA hypomethylating agent. Cells were transfected with ACTG2 expression plasmid or miR-145. Western blotting analysis, quantitative RT-PCR, colony formation- and viability assays were performed. miR-145 expression levels were measured in tumors.RESULTS: Eight primary tumors and two lymph node metastases displayed variable levels of positive staining. Fourteen SI-NETs and normal enterochromaffin cells stained negatively. Overexpression of ACTG2 significantly inhibited CNDT2.5 cell growth. Treatment with DZNep or transfection with miR-145 induced ACTG2 expression (>10-fold), but no effects were detected after treatment with EPZ-6438 or 5-aza-2'-deoxycytidine. DZNep also induced miR-145 expression. SI-NETs expressed relatively low levels of miR-145, with reduced expression in metastases compared to primary tumors.CONCLUSIONS: ACTG2 is expressed in a fraction of SI-NETs, can inhibit cell growth in vitro, and is positively regulated by miR-145. Theoretical therapeutic strategies based on these results are discussed.
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| 7. |
- Edfeldt, Katarina, 1979-, et al.
(author)
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DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors
- 2017
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In: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 105:2, s. 170-181
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Journal article (peer-reviewed)abstract
- Small intestinal neuroendocrine tumors (SI-NETs) are amine- and peptide producing neoplasms. Most patients display metastases at the time of diagnosis, they have an unpredictable individual disease course and the tumors are often therapy resistant. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are the clinically most used biomarkers today, but there is a great need for novel diagnostic and prognostic biomarkers and new therapeutic targets. Sixty-nine biomarkers were screened in serum from 23 SI-NET patients and 23 healthy controls using multiplex PLA (proximity ligation assay). A refined method, PEA (proximity extension assay), was used to analyze 76 additional biomarkers. Statistical testing and multivariate classification were performed. Immunohistochemistry and ELISA assays were performed in an extended cohort. Using PLA, 19 biomarkers showed a significant difference in serum concentrations between patients and controls, and PEA revealed difference in concentrations in 13 proteins. Multivariate classification analysis revealed decoy receptor 3 (DcR3), trefoil factor 3 (TFF3) and Midkine to be good biomarkers for disease, which was confirmed by ELISA analysis. All three biomarkers were expressed in tumor tissue. DcR3 concentrations were elevated in patients with stage IV disease. High concentrations of DcR3 and TFF3 were correlated to poor survival. DcR3, TFF3 and Midkine exhibited elevated serum concentrations in SI-NET patients compared to healthy controls, and DcR3 and TFF3 were associated with poor survival. DcR3 seems to be a marker for liver metastases while TFF3 and Midkine may be new diagnostic biomarkers for SI-NETs.
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| 8. |
- Edfeldt, Katarina, et al.
(author)
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Different gene expression profiles in metastasizing midgut carcinoid tumors
- 2011
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In: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 18:4, s. 479-489
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Journal article (peer-reviewed)abstract
- The genetic events leading the progression of midgut carcinoid tumors are largely unknown. The disease course varies from patient to patient, and there is a lack of reliable prognostic markers. In order to identify genes involved in tumor progression, gene expression profiling was performed on tumor specimens. Samples comprised 18 primary tumors, 17 lymph node (LN) metastases, and seven liver metastases from a total of 19 patients. Patients were grouped according to clinical data and histopathology into indolent or progressive course. RNA was subjected to a spotted oligo microarray and B-statistics were performed. Differentially expressed genes were verified using quantitative real-time PCR. Self-organizing maps demonstrated three clusters: 11 primary tumors separated in one cluster, five LN metastases in another cluster, whereas all seven liver metastases, seven primary, and 12 LN metastases formed a third cluster. There was no correlation between indolent and progressive behavior. The primary tumors with Ki67>5%, with low frequency of the carcinoid syndrome, and a tendency toward shorter survival grouped together. Primary tumors differed in expression profile from their associated LN metastases; thus, there is evidence for genetic changes from primary tumors to metastases. ACTG2, GREM2, REG3A, TUSC2, RUNX1, TPH1, TGFBR2, and CDH6 were differentially expressed between clusters and subgroups of tumors. The expression profile that assembles tumors as being genetically similar on the RNA expression level may not be concordant with the clinical disease course. This study reveals differences in gene expression profiles and novel genes that may be of importance in midgut carcinoid tumor progression.
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| 9. |
- Edfeldt, Katarina, 1979-, et al.
(author)
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Improved health‐related quality of life during peptide receptor radionuclide therapy in patients with neuroendocrine tumours
- 2023
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In: Journal of neuroendocrinology. - : John Wiley & Sons. - 0953-8194 .- 1365-2826. ; 35:10
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Journal article (peer-reviewed)abstract
- Neuroendocrine tumours (NETs) can arise in different locations in the body, and may give rise to hormonal symptoms, which amongst other factors may affect patients' health-related quality of life (HRQoL). Up to four cycles of peptide receptor radionuclide therapy (PRRT) have been shown effective for symptom alleviation and prolonging progression-free survival. The aim of this study was to assess the patient's perspective regarding changes in their HRQoL during PRRT. HRQoL was assessed using the questionnaires for cancer in general, EORTC QLQ-C30, and the gastrointestinal NET-specifically EORTC QLQ-GINET21. Patients with NET (n = 204) rated their HRQoL before PRRT cycles one and four. The medical records of patients were reviewed and their HRQoL was compared to a matched reference population (n = 4910). HRQoL was found to improve during PRRT in aspects of global quality of life; role, social, and emotional functioning, and multiple symptom relief. Potential risk groups for worse HRQoL during PRRT were patients with overweight (BMI >25) who completed four cycles of PRRT and older patients (>65 years old). In conclusion, we found that PRRT improves HRQoL in patients with NETs. The results of this study may be used to improve person-centred care.
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| 13. |
- Edfeldt, Katarina, 1979-, et al.
(author)
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Oral health and oral care in patients in a surgical context : A quantitative study comparing patients' and nurses' assessments
- 2023
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In: Journal of Clinical Nursing. - : John Wiley & Sons. - 0962-1067 .- 1365-2702. ; 33:6, s. 2201-2208
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Journal article (peer-reviewed)abstract
- AimsTo investigate fundamental care delivery regarding oral care in a surgical context, and to compare patients' self-reported oral health with registered nurse assessments.DesignA descriptive and comparative study, with a consecutive selection.MethodsA patient oral health rating tool, including questions about performed oral care, was distributed to patients (n = 50), at four surgical wards in Sweden. The response rate was 72%. Oral health status was assessed by a registered nurse using the Revised Oral Assessment Guide (ROAG), and a comparison between patient and registered nurse assessment was performed by calculating Cohen's kappa coefficient and percentage agreement.ResultsPatients (38%) reported severe oral symptoms, mostly dry lips and not an adequate amount of saliva, and 80% were not offered help with oral care. ROAG assessments revealed that 74% had problems with oral health. Almost half of the patients (48%) needed assistance with oral care but only 10% received help. Registered nurses assessed the patient's oral health as worse than the patient's self-assessment did.ConclusionThere are deficiencies in fundamental care delivery regarding oral care in a surgical care context. Oral health assessments need to be performed by registered nurses. Routines for systematic oral assessments and for oral care need to be implemented by nurse managers to ensure that patients' fundamental care needs are fulfilled.Implications for the Profession and Patient CareOral health assessments need to be performed regularly by registered nurses since it is insufficient that patients self-assess their oral health. Nurse managers needto provide and implement routines for nurse assessments and oral care in surgical care contexts.ImpactThere are deficiencies in patients' oral health and oral care, and registered nurses need to perform oral health assessments. Nurse managers need to implement routines for registered nurse assessments and oral care.Patient ContributionPatients admitted to a surgical ward were included in the study after being screened for inclusion criteria. After participants signed informed consent, they filled in a questionnaire about oral health and oral care, and a registered nurse performed an oral health assessment.Reporting MethodThis study was carried out according to the STROBE checklist.
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| 14. |
- Edfeldt, Katarina, 1979-
(author)
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Small Intestinal Neuroendocrine Tumours : Genetic and Epigenetic Studies and Novel Serum Biomarkers
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Small intestinal neuroendocrine tumours (SI-NETs) are rare, hormone producing and proliferate slowly. Patients usually display metastases at time of diagnosis, the tumours are difficult to cure, and the disease course is unpredictable.The gene expression pattern was investigated in paper I, with emphasis on aggressive disease and tumour progression. Expression microarrays were performed on 42 tumours. Unsupervised hierarchal clustering revealed three clusters that were correlated to clinical features, and expression changes from primary tumour to metastasis. Eight novel genes, ACTG2, GREM2, REG3A, TUSC2, RUNX1, TGFBR2, TPH1 and CDH6 may be of importance for tumour progression.In paper II, expression of ACTG2 was detected in a fraction of SI-NETs, but not in normal enterochromaffin cells. Inhibition of histone methyltransferase and transfection of miR-145 induced expression and no effect was seen after DNA methylation or selective EZH2 inhibition in vitro. miR-145 expression was reduced in metastases compared to primary tumours. Overexpression of ACTG2 inhibited cell growth, and inducing ACTG2 may have therapeutic effects.TCEB3C (Elongin A3) is located on chromosome 18 and is imprinted in some tissues. In paper III a reduced protein expression was detected. The gene was epigenetically repressed by both DNA and histone methylation in a tumour tissue specific context. The expression was also induced in primary cell cultures after DNA demethylation and pyrosequencing revealed promoter region hypermethylation. Overexpression of TCEB3C inhibited cell growth by 50%, suggesting TCEB3C to be a tumour suppressor gene.In paper IV, 69 biomarkers were analysed in blood serum using multiplex proximity ligation assay. Nineteen markers displayed different levels between patients and controls. In an extended cohort, ELISA analysis showed elevated serum levels of Mindin, DcR3 and TFF3 in patients and protein expression in tumour cells. High levels of DcR3 and TFF3 were associated with poor survival, and DcR3 may be a marker for liver metastases. Mindin, DcR3, and TFF3 are potential novel diagnostic biomarkers for SI-NETs.
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| 15. |
- Edfeldt, Katarina, et al.
(author)
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TCEB3C a putative tumor suppressor gene of small intestine neuroendocrine tumors
- 2014
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In: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 21:2, s. 275-284
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Journal article (peer-reviewed)abstract
- Small intestinal neuroendocrine tumors (SI-NETs), formerly midgut carcinoids, are rare and slow-growing neoplasms. Frequent loss of one copy of chromosome 18 in primary tumors and metastases has been observed. The aim of the study was to investigate a possible role of TCEB3C (Elongin A3), currently the only imprinted gene on chromosome 18, as a tumor suppressor gene in SI-NETs, and whether its expression is epigenetically regulated. Primary tumors, metastases, the human SI-NET cell line CNDT2.5, and two other cell lines were included. Immunohistochemistry, gene copy number determination by PCR, colony formation assay, Western blotting, real-time quantitative RT-PCR, RNA interference, and quantitative CpG methylation analysis by pyrosequencing were performed. The large majority of tumors (33/43) showed very low to undetectable Elongin A3 expression and as expected 89% (40/45) displayed one TCEB3C gene copy. The DNA hypomethylating agent 5-aza-2'-deoxycytidine induced TCEB3C expression in CNDT2.5 cells, in primary SI-NET cells prepared directly after surgery, but not in two other cell lines. Also siRNA to DNMT1 and treatment with the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in a cell type-specific way. CpG methylation at the TCEB3C promoter was observed in all analyzed tissues and thus not related to expression. Overexpression of TCEB3C resulted in a 50% decrease of clonogenic survival of CNDT2.5 cells, but not of control cells. The results support a putative role of TCEB3C as a tumor suppressor gene in SI-NETs. Epigenetic repression of TCEB3C seems to be tumor cell type-specific and involves both DNA and histone methylation.
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| 18. |
- Hultin, Hella, et al.
(author)
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Left-Shifted Relation between Calcium and Parathyroid Hormone in Obesity
- 2010
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:8, s. 3973-3981
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Journal article (peer-reviewed)abstract
- Background: A condition resembling secondary hyperparathyroidism (HPT), including raised levels of PTH and normal levels of serum calcium, has been reported in obesity. A plausible reason may be vitamin D deficiency, but conflicting data have been reported. Objective: Our objective was to investigate calcium homeostasis in obese individuals with emphasis on the function of the parathyroid glands. Design and Intervention: Morbidly obese patients (mean body mass index = 46.6 +/- 6) were examined for their status of calcium homeostasis. A subset was thoroughly investigated with calcium-citrate (CiCa) clamping. Patients: Of 108 morbidly obese patients, 11 underwent CiCa clamping as well as 21 healthy volunteers of normal weight and 15 with primary HPT (pHPT). Large patient cohorts of normal individuals and pHPT patients were also used as comparisons. Outcome Measures and Results: All obese individuals had normal serum calcium and creatinine levels. Mean levels of 25-OH-vitamin D-3 in serum were low, 53 nmol/liter (reference range 75-250 nmol/liter). Mean intact plasma PTH was 5.1 pmol/liter (reference range 1.1-6.9 pmol/liter). There was a significant positive correlation between PTH and duration of obesity. CiCa clamping in obese subjects revealed a remarkably high sensitivity for calcium and a left-shifted relation between plasma calcium and PTH (set point) compared with the normal population. CiCa clamping in pHPT patients demonstrated a right-shifted PTH-Ca curve. Conclusion: Although vitamin D levels in the obese individuals were low, few displayed overt signs of secondary HPT. The CiCa clamping implied a disturbance in the calcium homeostasis comparable to early renal insufficiency, with a left-shifted Ca-PTH curve and a lower set point compared with the normal population.
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| 19. |
- Jangland, Eva, Docent, et al.
(author)
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Effective learning activity to facilitate post-graduate nursing students' utilization of nursing theories : Using the fundamentals of care framework
- 2023
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In: Journal of Advanced Nursing. - : John Wiley & Sons. - 0309-2402 .- 1365-2648. ; 79:3, s. 1082-1093
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Journal article (peer-reviewed)abstract
- AIMS: To explore how postgraduate nursing students used the Fundamentals of Care framework in a written assignment based on a clinical situation, and describe their learning process in using the framework.DESIGN: A qualitative descriptive study design applying the Fundamentals of Care framework.METHODS: Postgraduate nursing students' theoretical written assignments (n = 35) based on self-experienced clinical cases were included. The data were collected in 2021 in five specialties in a postgraduate nursing programme in Sweden. The data were analysed using content analysis.RESULTS: Applying the framework to a self-experienced clinical case illuminated the importance of nurse-patient relationships and clarified the meaning of person-centred care. The students assessed the framework as easy-to-use bedside as a guide to providing nursing care. By using the framework, the students were aided in reasoning about the fundamental values of care such as ethics, equality in healthcare and patient rights. When students reflected on their learning process, they stated that the assignment taught them how to use the framework, as well as paving the way for finding and applying other theories of nursing.CONCLUSION: Learning activities with an opportunity to practice analysing nursing care guided by a theory, combined with a self-evaluating element, are conducive to deepening students' learning and improving their ability to use theories in clinical practice.IMPACT: The framework illuminated the importance of the nurse-patient relationship in nursing care to the students and made them recognize and value the clinical use of theories. It is the responsibility of leaders in nurse education and healthcare to provide the next generation of specialist nurses-future nursing leaders-with regular opportunities to analyse nursing care through theories and frameworks. Nurses call for continuous learning on theories; leaders in nurse education and healthcare must meet these needs.
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| 20. |
- Lejonklou, Margareta Halin, et al.
(author)
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Neurogenin 3 and neurogenic differentiation 1 are retained in the cytoplasm of multiple endocrine neoplasia type 1 islet and pancreatic endocrine tumor cells
- 2009
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In: Pancreas. - 0885-3177 .- 1536-4828. ; 38:3, s. 259-266
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Journal article (peer-reviewed)abstract
- OBJECTIVES:To investigate if transcription factors involved in pancreatic differentiation and regeneration are present in pancreatic endocrine tumors and if they are differentially expressed in normal pancreas compared with multiple endocrine neoplasia type 1 (MEN1) nontumorous pancreas.METHODS:The expression of neurogenin 3 (NEUROG3), neurogenic differentiation 1 (NEUROD1), POU class 3 homeobox 4 (POU3F4), pancreatic duodenal homeobox factor 1 (PDX1), ribosomal protein L10 (RPL10), delta-like 1 homolog (Drosophila; DLK1), and menin was analyzed by immunohistochemistry in normal pancreas and pancreatic endocrine tumors from 6 patients with MEN1 and 16 patients with sporadic tumors, as well as pancreatic specimens from Men1 heterozygous and wild type mice. Quantitative polymerase chain reaction was performed in a subset of human tumors.RESULTS:Tumors and MEN1 nontumorous endocrine cells showed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression. These factors were significantly more expressed in the cytoplasm of Men1 heterozygous mouse islet cells compared with wild type islets; the latter showed an exclusively nuclear reactivity. The degree of Pou3f4, Rpl10, and Dlk1 immunoreactivities differed significantly between islets of heterozygous and wild type mice. The expressions of RPL10 and NEUROD1 were prominent in the MEN1 human and heterozygous mouse exocrine pancreas. Insulinomas had significantly higher PDX1 and DLK1 messenger RNA levels compared with other tumor types.CONCLUSIONS: Transcription factors involved in pancreatic development show altered expression and subcellular localization in MEN1 nontumorous pancreas and pancreatic endocrine tumors.
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| 21. |
- Norlén, Olov, et al.
(author)
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Peritoneal carcinomatosis from small intestinal neuroendocrine tumors : Clinical course and genetic profiling
- 2014
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In: Surgery. - : Elsevier BV. - 0039-6060 .- 1532-7361. ; 156:6, s. 1512-1522
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Journal article (peer-reviewed)abstract
- Background. One-fifth of all patients with small-intestinal neuroendocrine tumors (SI-NETs) present with or develop peritoneal carcinomatosis (PC). Our aim was to determine the prognosis and genetic profiles of tumors in patients with PC compared with tumors in patients without PC. Methods. We included SI-NET patients (cases with PC, n = 73, and controls without PC, n = 468) who underwent operation between 1985 and 2012. The Lyon prognostic index was used to correlate the amount of PC to survival. DNA samples from patients with (n = 8) and without (n = 7) PC were analyzed with a single-nucleotide polymorphism array (HumanOmni2.5 BeadChip, Illumina) to investigate genetic disparities between groups. Results. Patients with PC had poorer survival (median 5.1 years) than controls (11.1 years). An advanced postoperative Lyon prognostic index was a negative prognostic marker for survival by multivariable analysis (P = .042). Patients with and without PC clustered differently based on loss of heterozygosity and copy number variation data from single-nucleotide polymorphism array of the primary tumors (P = .042). Conclusion. SI-NET patients with PC have poor survival, which diminishes with increasing PC load after surgery. Clustering based on copy number variation and loss of heterozygosity data suggests different genotypes in primary tumors comparing patients with and without PC.
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| 22. |
- Åkerström, Göran, et al.
(author)
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A review on management discussions of small intestinal neuroendocrine tumors 'midgut carcinoids'
- 2015
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In: INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY. - : Future Medicine Ltd. - 2045-0869 .- 2045-0877. ; 2:2, s. 119-128
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Research review (peer-reviewed)abstract
- European Neuroendocrine Tumor Society staging, together with the Ki67 grading system, has appeared as superior for classification of neuroendocrine tumors (NET). The management of small intestinal NET (SI-NET) has been overall controversial. Mesenteric metastases occur also with the smallest SI-NET, and the majority of patients risk to ultimately progress with liver metastases. 68Gallium (somatostatin receptor)/PET/CT has appeared as most sensitive for imaging, and fluorodeoxyglucose-PET is recommended to identify lesions with high proliferation. Our treatment policy for SINET is to initiate somatostatin analog treatment, and in order to prevent abdominal complications we recommend early intestinal resection for removal of primary tumors and clearance of lymph node metastases. Liver metastases are liberally treated by resection (or ablation), as this can efficiently palliate carcinoid syndrome-associated symptoms.
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