Small Intestinal Neuroendocrine Tumours : Genetic and Epigenetic Studies and Novel Serum Biomarkers

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

A plausible role for actin gamma smooth muscle 2 (ACTG2) in small intestinal neuroendocrine tumorigenesis

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

Effective learning activity to facilitate post-graduate nursing students' utilization of nursing theories - Using the fundamentals of care framework

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

Additional file 1: Table S1. of A plausible role for actin gamma smooth muscle 2 (ACTG2) in small intestinal neuroendocrine tumorigenesis

Patient characteristics, immunohistochemistry analysis of ACTG2 and miR-145 analysis in SI-NETs (XLSX 49 kb

Missed nursing care in surgical care– a hazard to patient safety : a quantitative study within the inCHARGE programme

Background Missed nursing care occurs globally, and the consequences are severe for the patients when fundamental care needs are not fulfilled, nor delivered in a person-centred way. This study aimed to investigate the occurrence and cause of missed nursing care, and the relationship between registered nurses’ and nursing assistants’ perceptions of missed nursing care, in a surgical care context. Methods A quantitative study was performed using the MISSCARE survey, measuring missed nursing care and associated reasons, in three surgical wards with registered nurses and nursing assistants as the participants (n = 118), during May-November in 2022. The MISSCARE survey also covers background data such as job satisfaction and intention to leave. The survey was distributed paper-based and the response rate was 88%. Results Aspects of nursing care rated to be missed the most were ‘attending interdisciplinary care conferences’, ‘turning patient every 2 h’, ‘ambulation 3 times per day or as ordered’, and ‘mouth care’. Differences between registered nurse and nursing assistant ratings were detected for eight out of 24 items, where registered nurses rated more missed nursing care. The uppermost reasons for missed nursing care were ‘inadequate number of staff’ and ‘unexpected rise in patient volume and/or acuity on the unit’. Registered nurses and nursing assistants rated differently regarding six of 17 items. Almost every fourth staff member (24.6%, n = 29) had the intention to leave within a year in the present department. Conclusions The occurrence of missed nursing care is frequent in the surgical context, and in combination with a high number of staff members intending to leave their employment, poses a hazard to patient safety. Registered nurses, holding higher educational levels, reported more missed care compared with the nursing assistants. The main reason for missed nursing care was an inadequate number of staff. These findings support a warranted investment in nursing within the organisation. The results can be used to form strategies and interventions, to reduce nurse attrition and optimise competence utilisation, and to achieve safe person-centered fundamental care

Improved health‐related quality of life during peptide receptor radionuclide therapy in patients with neuroendocrine tumours

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

Oral health and oral care in patients in a surgical context : A quantitative study comparing patients' and nurses' assessments

  Aims To investigate fundamental care delivery regarding oral care in a surgical context, and to compare patients' self-reported oral health with registered nurse assessments. Design A descriptive and comparative study, with a consecutive selection. Methods A 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. Results Patients (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. Conclusion There 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 Care Oral health assessments need to be performed regularly by registered nurses since it is insufficient that patients self-assess their oral health. Nurse managers need to provide and implement routines for nurse assessments and oral care in surgical care contexts. Impact There 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 Contribution Patients 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 Method This study was carried out according to the STROBE checklist

Additional file 1 of Missed nursing care in surgical care– a hazard to patient safety: a quantitative study within the inCHARGE programme

Supplementary Material