Tauroselcholic (Selenium-75 [Se-75]) acid 370kBq capsules

BACKGROUND: The principal diagnosis/indication for this assessment is chronic diarrhoea due to bile acid malabsorption (BAM). Diarrhoea can be defined as the abnormal passage of loose or liquid stools more than three times daily and/or a daily stool weight > 200 g per day and is considered to be chronic if it persists for more than 4 weeks. The cause of chronic diarrhoea in adults is often difficult to ascertain and patients may undergo several investigations without a definitive cause being identified. BAM is one of several causes of chronic diarrhoea and results from failure to absorb bile acids (which are required for the absorption of dietary fats and sterols in the intestine) in the distal ileum. OBJECTIVE: For people with chronic diarrhoea with unknown cause and in people with Crohn's disease and chronic diarrhoea with unknown cause (i.e. before resection): (1) What are the effects of selenium-75-homocholic acid taurine (SeHCAT) compared with no SeHCAT in terms of chronic diarrhoea, other health outcomes and costs? (2) What are the effects of bile acid sequestrants (BASs) compared with no BASs in people with a positive or negative SeHCAT test? (3) Does a positive or negative SeHCAT test predict improvement in terms of chronic diarrhoea, other health outcomes and costs? DATA SOURCES: A systematic review was conducted to summarise the evidence on the clinical effectiveness of SeHCAT for the assessment of BAM and the measurement of bile acid pool loss. Search strategies were based on target condition and intervention, as recommended in the Centre for Reviews and Dissemination (CRD) guidance for undertaking reviews in health care and the Cochrane Handbook for Diagnostic Test Accuracy Reviews. The following databases were searched up to April 2012: MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; the Cochrane Databases; Database of Abstracts of Reviews of Effects; Health Technology Assessment (HTA) Database; and Science Citation Index. Research registers and conference proceedings were also searched. REVIEW METHODS: Systematic review methods followed the principles outlined in the CRD guidance for undertaking reviews in health care and the National Institute for Health and Care Excellence (NICE) Diagnostic Assessment Programme interim methods statement. In the health economic analysis, the cost-effectiveness of SeHCAT for the assessment of BAM, in patients with chronic diarrhoea, was estimated in two different populations. The first is the population of patients with chronic diarrhoea with unknown cause and symptoms suggestive of diarrhoea-predominant irritable bowel syndrome (IBS-D) and the second population concerns patients with Crohn's disease without ileal resection with chronic diarrhoea. For each population, three models were combined: (1) a short-term decision tree that models the diagnostic pathway and initial response to treatment (first 6 months); (2) a long-term Markov model that estimates the lifetime costs and effects for patients initially receiving BAS; and (3) a long-term Markov model that estimates the lifetime costs and effects for patients initially receiving regular treatment (IBS-D treatment in the first population and Crohn's treatment in the second population). Incremental cost-effectiveness ratios were estimated as additional cost per additional responder in the short term (first 6 months) and per additional quality-adjusted life-year (QALY) in the long term (lifetime). RESULTS: We found three studies assessing the relationship between the SeHCAT test and response to treatment with cholestyramine. However, the studies had small numbers of patients with unknown cause chronic diarrhoea, and they used different cut-offs to define BAM. For the short term (first 6 months), when trial of treatment is not considered as a comparator, the optimal choice depends on the willingness to pay for an additional responder. For lower values (between £1500 and £4600) the choice will be no SeHCAT in all scenarios; for higher values either SeHCAT 10% or SeHCAT 15% becomes cost-effective. For the lifetime perspective, the various scenarios showed widely differing results: in the threshold range of £20,000-30,000 per QALY gained we found as optimal choice either no SeHCAT, SeHCAT 5% (only IBS-D) or SeHCAT 15%. When trial of treatment is considered a comparator, the analysis showed that for the short term, trial of treatment is the optimal choice across a range of scenarios. For the lifetime perspective with trial of treatment, again the various scenarios show widely differing results. Depending on the scenario, in the threshold range of £20,000-30,000 per QALY gained, we found as optimal choice either trial of treatment, no SeHCAT or SeHCAT 15%. CONCLUSIONS: In conclusion, the various analyses show that for both populations considerable decision uncertainty exists and that no firm conclusions can be formulated about which strategy is optimal. Standardisation of the definition of a positive SeHCAT test should be the first step in assessing the usefulness of this test. As there is no reference standard for the diagnosis of BAM and SeHCAT testing provides a continuous measure of metabolic function, diagnostic test accuracy (DTA) studies are not the most appropriate study design. However, in studies where all patients are tested with SeHCAT and all patients are treated with BASs, response to treatment can provide a surrogate reference standard; further DTA studies of this type may provide information on the ability of SeHCAT to predict response to BASs. A potentially more informative option would be multivariate regression modelling of treatment response (dependent variable), with SeHCAT result and other candidate clinical predictors as covariates. Such a study design could also inform the definition of a positive SeHCAT result. STUDY REGISTRATION: The study is registered as PROSPERO CRD42012001911. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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Data regarding the diagnosis, management, and follow-up of carcinoid syndrome (CS) and carcinoid heart disease (CHD) were identified by searches of the MEDLINE database using specific terms in human studies: CS; CHD; screening; epidemiology; diagnosis; treatment; prognosis. The search results were supplemented by manual searching of relevant journals, reference lists in key articles and other appropriate documents, and expert opinion. All recommendations are offered on the basis of the best available evidence, supplemented by the authors' experiences in managing CS and CHD. Each recommendation for treatment will have a level of evidence and grade of recommendation as per the GRADE system (adapted in Infectious Disease society of US Public Health Service grading system)1 (Tables 1 and 2). A list of abbreviations is provided at the end of the manuscript. Carcinoid syndrome (CS) is the most frequent hormonal complication accompanying neuroendocrine neoplasms (NENs) and is defined by chronic diarrhoea and/or flushing in the presence of systemic elevated levels of serotonin or its metabolite 5-hydroxyindolacetic acid (5-HIAA). Importantly, other causes of these symptoms should be considered and investigated depending on the clinical presentation. CS is predominantly encountered in patients with well-differentiated NENs (neuroendocrine tumours, NETs) of intestinal origin, followed by lung NETs, and only in a minority of patients with pancreatic, ovarian, thymic, or unknown origin (UKO) NETs. The main symptoms defining CS are skin flushing, secretory diarrhoea, bronchospasm, or abdominal pain (in some cases of advanced intestinal NETs) in the presence of systemically elevated levels of serotonin and/or other biologically active amins and peptides. Patients with CS suffer from an impaired quality of life (QoL), which is lower when compared to patients without CS or other types of cancer.2 Carcinoid heart disease (CHD) is a rare and complex cardiac complication occurring in patients with advanced NETs and CS, usually manifesting mainly as right-sided heart valves regurgitation/stenosis (see Section A. d.) and eventually leading to right heart failure (RHF). CS is caused by tumoural secretion of multiple hormonal amines and peptides. Serotonin (5-hydroxytryptamine, 5-HT) is the major secretagogue in CS, with a proposed pathophysiological role in diarrhoea and fibrotic complications; other hormones involved include histamine, tachykinins, kallikrein and prostaglandins.2 Because tumour-released active hormones are usually inactivated by the liver, CS indicates the presence of (metastatic) tumour sites outside of the portal venous drainage.3 Liver metastases are present in 87%–100% of patients with CS. However, in 5%–13% of cases, CS may develop in the absence of liver metastases, particularly if the primary tumour arises from the ovary, testis or very rarely lung, or if a large burden of retroperitoneal tumour disease is present.4, 5 CHD is characterised by plaque-like fibrous deposits on right-sided heart valves and endocardial surfaces, inducing tricuspid valve regurgitation/stenosis and pulmonary valve regurgitation/stenosis, ultimately leading to right ventricular volume overload and right heart failure. Elevated levels of hormones, particularly serotonin, in the right heart are deemed causative for CHD-associated plaque formation. Left-sided valve involvement may occur either in the presence of a patent foramen ovale (PFO), a functioning lung NET, and/or in cases with very high circulating levels of vasoactive substances, overwhelming the hepatic and pulmonary degradative capacity.6 The prevalence of CS among patients with NETs has varied widely, ranging from 3% to 74% in the past, to 19% to 35% to date, depending on world region and management.7 Median overall survival in patients with CS is significantly reduced at 4.7 years compared to 7.1 years in NET patients without CS. Tumour burden is a relevant contributor to CS-associated mortality.4 CHD is present in approximately 20%–50% of CS patients and is a major prognostic indicator, with reduced overall survival at 3 years of 31% in patients with CHD, compared to 69% in patients without CHD.8 Carcinoid crisis is a potentially life-threatening complication of uncontrolled CS caused by the sudden release of high levels of serotonin and other vasoactive substances from a NET, especially in patients with refractory CS (RCS; see Section C. b.). It can occur spontaneously, but more frequently as result of tumour biopsy, surgical manipulation, use of sympathomimetic drugs, anaesthesia or different cytolytic therapies (hepatic embolisation) and sometimes because of peptide receptor radionuclide therapy (PRRT). It is defined by abrupt flushing, severe shifts in blood pressure with haemodynamic instability, profuse diarrhoea, and distressing bronchospasm with wheezing2 (Table 3). Other specific complications of CS patients are summarised in Table 3.9 The presence of CS should be actively scrutinised by history taking, physical examination, and laboratory analysis. Flushing, a clinical hallmark of CS, is reported in over 90% of cases (either by the patient and/or by his/her family members); it is an intermittent or persistent sensation of warmth together with skin erythema, usually involving the head, neck, and upper part of the torso, with telangiectasia in longstanding disease. In CS, flushing is usually not associated with sweating (‘dry flushing’). It is the result of circulating vasoactive substances, inducing cardiovascular abnormalities (hypo-/hypertension, brady-/tachycardia). Specific flushing features depend on the primary tumour and four different types of flushing have been described in CS12: Serotonin or its main metabolite 5-HIAA should be measured at presentation in all patients with advanced intestinal NETs, in lung/ovary NETs of any stage, in unknown origin (UKO) NETs with liver metastases, and in every NET patient with suspected CS. 4A Serotonin is metabolised to 5-HIAA. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) should be evaluated as screening biomarker of CHD in all patients with increased u5-HIAA and/or suspicious symptoms, at baseline and follow-up (Figure 1). NT-pro-BNP belongs to a neurohormone family released by the atria and ventricles in response to the increase in wall stress as a result of volume and pressure overload.20, 21 4A For CHD detection, an NT-proBNP cut-off level of 235–260 pg mL–1 (31 pmoL L–1) had shown sensitivity and specificity of 87–92% and 80–91%, respectively (NT-proBNP normal range: men under 70 years: < 100 pg mL–1, women under 70 years: < 150 pg mL–1, 70 years and over: < 300 pg mL–1). Quantitative assessment of tumour growth rate on sequential cross sectional imaging studies can provide useful information on tumour activity and prognosis.25 3B Q2: What is the differential diagnosis of CS? Diarrhoea in CS is always secretory, persists with fasting, may occur during the night and is associated with abdominal discomfort and faecal urgency. Patients with CS treated with somatostatin analogues (SSA) may experience deterioration of previously controlled diarrhoea, or ongoing diarrhoea which never responded to SSA. Other causes of diarrhoea, NET-related (steatorrhoea secondary to SSA, small intestinal bacterial overgrowth, mesenteric ischaemia, bile salt malabsorption or short-bowel syndrome), or NEN-unrelated (colitis, gastroenteritis), need to be excluded. 5A Flushing in the context of CS has been described in Section B. Q3: Which tools are needed to characterise severity of CHD? CHD diagnosis and monitoring by severity quantification is challenging and focusses on functional imaging of the left and right chambers of the heart. Q4: Which are the principles/aims of treatment in a patient with CS?34, 35 Long-term adverse events include fibrotic nodules at injection sites, cholelithiasis and exocrine pancreatic insufficiency, occurring in 5%–15% of cases; diabetic patients need close follow-up, as anti-glycaemic treatment intensification may be needed. RCS is defined by recurring or persisting CS symptoms and increasing or persistently high u5-HIAA levels despite the use of maximum label doses of SSA. RCS may be divided into either non-aggressive or aggressive, based on symptoms burden (< or ≥ 4 BM/day, and/or < or ≥ 5 flushing episodes/day, respectively) together with disease stability (stable or progressive), hepatic burden (< or ≥ 50% liver involvement), and/or the presence of CHD. Differential diagnosis of RCS (Figure 2) includes problems with SSA administration, SSA tachyphylaxis, SSA-induced exocrine pancreatic insufficiency, infectious/inflammatory diarrhoea, mesenteric fibrosis, and worsening of diarrhoea in patients whose primary small bowel NET was surgically removed. Worsening of CS 2–3 weeks after SSA injection may imply tachyphylaxis; more frequent doses (octreotide LAR 30 mg/2–3 weeks or lanreotide Autogel® 120 mg/2 weeks), [2bA] increased octreotide LAR dosage to 60 mg every 4 weeks or switching to the alternative SSA can be considered. 3bA Overall, SSA dose-escalation offers symptom improvement in nearly 80% of cases, whereas only 29% of patients show further reduction in u5-HIAA levels.42 Treatment of RCS with radiologically stable NET or indolent progression and low symptom/tumour burden TACE/SIRT may be reserved for G2 intestinal or non-intestinal NET. 3bB In the absence of conclusive data on which trans-arterial treatment is most efficient, the selection should be made based on individual factors such as tumour load, topography of metastases, and arterial anatomy. Treatment of RCS with radiologically progressive NET and/ or high symptom burden We recommend prophylactic short-acting octreotide prior to and during invasive procedures—to be tapered down afterwards, or continuous infusions when major surgical/loco-regional interventions are considered or when there is concurrent CHD. 3b Ultimately, all patients develop symptomatic progression of CS when on an SSA. Therefore, once CS treatment is initiated, physicians should actively monitor the patient's status for a clinical, biochemical, and radiological response. Symptom relief should be monitored monthly in the first 2–3 months and, once achieved, at intervals of 4–6 months. Biochemical and imaging tests can be evaluated every 4–6 months. 4B. Q6: What are the general recommendations for the initial management of CHD?56 The two main goals of management are aggressive reduction of hormonal secretion by the tumour and management of CHD and RHF, when present. A holistic approach must be taken, with consideration of NET status, CHD severity/symptoms, and nutritional and general performance status of the patient.58, 59 Q7: Do's and don'ts in CS/severe CHD RV dilatation should not represent, per se, an indication for surgery in asymptomatic NET patients. Cardiac surgery, which primarily consists of valve replacement, is the most effective treatment option for advanced CHD. 3bA In a recent metanalysis74 consisting of 416 pre-operative patients, 97% had moderate or severe TR, 72% moderate or severe PR, and 33% with PS with or without regurgitation. Left heart characteristics included mitral valve regurgitation (MR) in 24% and aortic valve regurgitation (AR) in 18% of patients. Additional procedures include PFO closure and removal of intramyocardial metastasis. The use of mechanical valves should be discouraged having several disadvantages: Bioprosthetic valves are the recommended option73 because of the inherent increased risk of bleeding in patients with advanced high-volume liver disease and hepatic dysfunction from NET, the increased likelihood of invasive procedures requiring temporary discontinuation of anticoagulant agents, and, to a lesser extent, the risk of right-sided mechanical valve thrombosis. Post-operatively, following bioprosthetic valve replacement, either VKA or novel oral anticoagulants are recommended for 3–6 months, with a preference for VKA albeit not supported by randomised trials (Consensus opinion). 5B The experience with minimally invasive options (percutaneous catheter-based interventions, valve-in-valve replacements) is limited; however, this approach will play a growing role in the future, as: Valve-in-valve replacement is feasible in degenerated surgical bioprosthesis, and should be the first choice in CHD patients.79 Q10: What are the advantages of MDT approach in improving the overall management of CS and CHD patients? Decisions for optimal management of patients with moderate to severe CHD, as part of advanced NEN and CS, are complex and require a “holistic” approach as well as close collaboration between NEN Physicians and Cardiac Specialists. A dedicated CHD MDT will facilitate the optimal patient's medical treatment and define the appropriate type, as well as optimal timing for cardiac intervention (surgical/catheter based). The CHD MDT, which can run separately or be a part of the main NEN MDT, will discuss patients with significant (moderate/severe or progressing) CHD who have been assessed in the cardiology/CHD clinic and fulfil the echocardiogram and/or clinical criteria for cardiac intervention. If the CHD MDT runs separately, all referred patients need to have been previously discussed at the main NEN MDT meeting, where decisions about control of hormonal secretion and tumour growth should have been made. CHD MDT mandatory members include NEN physician(s), cardiologist(s) with expertise in CHD (preferable), cardio-thoracic surgeon(s), cardiac anesthetist, NEN and cardiology specialist nurses, and a dedicated nutritionist. Several factors associated to the heart, NEN disease and patient’ status and preferences need to be considered. Cardiovascular symptoms (NYHA class), RV function, tricuspid and left-sided cardiac valves (through echocardiography) and pulmonary valve (through TTE/TOE, CCT/CMRI) need to be thoroughly reviewed alongside NEN disease status (stable/progressing) and tumour burden, as well as patient-related factors including comorbidities, major organ function, and nutritional status. CS related unmet needs: CHD related unmet needs: This ENETS guidance paper, developed by a multidisciplinary consensus task force, provides up-to-date and practical advice on the diagnosis and management of CS and CHD, based on recent developments and using the recent ENETS Echo synoptic report in CHD patients.31 Hopefully, these recommendations will pave the road for more standardised care for our CS and CHD patients resulting in improved outcomes. Upcoming studies aimed to fulfill the gap will allow us to focus on many unmet needs in this field. Simona Grozinsky-Glasberg: Conceptualization; data curation; formal analysis; methodology; project administration; supervision; validation; writing – original draft; writing – review and editing. Joseph Davar: Conceptualization; data curation; resources; writing – original draft; writing – review and editing. Johannes Hofland: Data curation; investigation; writing – original draft; writing – review and editing. Rebecca Dobson: Data curation; formal analysis; writing – original draft; writing – review and editing. Vikas Prasad: Data curation; formal analysis; investigation; resources; writing – original draft; writing – review and editing. Andreas Pascher: Data curation; investigation; writing – original draft; writing – review and editing. Timm Denecke: Investigation; validation; writing – original draft; writing – review and editing. Margot E.T. Tesselaar: Data curation; investigation; writing – original draft; writing – review and editing. Francesco Panzuto: Data curation; investigation; writing – original draft; writing – review and editing. Anders Albage: Data curation; formal analysis; writing – original draft; writing – review and editing. Heidi Connolly: Data curation; validation; writing – original draft; writing – review and editing. Jean-Francois Obadia: Data curation; methodology; writing – original draft; writing – review and editing. Rachel Riechelmann: Data curation; formal analysis; investigation; supervision; writing – original draft; writing – review and editing. C. Toumpanakis: Conceptualization; methodology; supervision; visualization; writing – original draft; writing – review and editing. The authors of this ENETS guidance paper are grateful to the ENETS Advisory Board members for their useful suggestions and comments in a common effort to improve the quality of the present manuscript (the list of the participants appears in the Appendix S1). The peer review history for this article is available at https://publons.com/publon/10.1111/jne.13146. Data sharing is not applicable to this article as no new data were created or analyzed in this study. Appendix S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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Drought stress poses a significant obstacle to agricultural productivity, particularly in the case of oilseed crops such as sunflower ( Helianthus annuus L.). Selenium (Se) is a fundamental micronutrient that has been recognized for its ability to enhance plant resilience in the face of various environmental stresses. The FH-770 sunflower variety was cultivated in pots subjected to three stress levels (100% FC, 75% FC, and 50% FC) and four Se application rates (0 ppm, 30 ppm, 60 ppm, and 90 ppm). This research aimed to investigate the effect of exogenously applied Se on morpho-physiological and biochemical attributes of sunflower to improve the drought tolerance. Foliar Se application significantly lowered H 2 O 2 (hydrogen peroxide; ROS) (20.89%) accumulation that markedly improved glycine betaine (GB) (74.46%) and total soluble protein (Pro) (68.63%), improved the accumulation of ascorbic acid (AA) (25.51%), total phenolics (TP) (39.34%), flavonoids (Flv) (73.16%), and anthocyanin (Ant) (83.73%), and improved the activity of antioxidant system superoxide dismutase (SOD) (157.63%), peroxidase (POD) (100.20%), and catalase (CAT) (49.87%), which ultimately improved sunflower growth by 36.65% during drought stress. Supplemental Se significantly increased shoot Se content (93.86%) and improved calcium (Ca 2+ ), potassium (K + ), and sodium (Na + ) ions in roots by 36.16%, 42.68%, and 63.40%, respectively. Selenium supplements at lower concentrations (60 and 90 ppm) promoted the growth, development, and biochemical attributes of sunflowers in controlled and water-deficient circumstances. However, selenium treatment improved photosynthetic efficiency, plant growth, enzymatic activities, osmoregulation, biochemical characteristics, and nutrient balance. The mechanisms and molecular processes through which Se induces these modifications need further investigation to be properly identified.

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Cadmium (Cd) contamination has become a major environmental issue and has toxic effects on agricultural crops. Selenium (Se) is an essential trace element that plays an important role due to its impact on several physiological and biochemical processes in plants. This study addresses the mechanistic insights into the role of SeNPs in enhancing Cd stress tolerance, thereby contributing to sustainable nano-agronomic strategies for the soils contaminated with heavy metals (HMs). The current experimental approach involved a pot trial conducted in a greenhouse with two levels of cadmium stress (C1 = control; C2 = 20 mg kg−1 of soil w/w using CdCl2), and four levels of SeNPs (0, 25, 50, and 75 mg L−1) in mungbean plants. The findings indicated that cd stressed conditions significantly affected the productivity of mungbean plants. The optimal level of SeNPs significantly enhanced the growth, biomass, and photosynthetic traits of mungbean. This study also indicated that Cd-stressed conditions increased lipid peroxidation and membrane damage. Moreover, SeNPs application increased soluble protein (110.10%), and decreased the proline accumulation (64.45%) and malondialdehyde (MDA) contents (64.25%) in comparison with control (0 mg L−1 of SeNPs). Furthermore, the SeNPs also decreased the leaf Cd contents by 64.95% and grain Cd contents by 64.88% by reduced Cd uptake. An optimum level of SeNPs offers great potential as an eco-friendly and feasible method for mitigating the effects of Cd stress on mungbean plants. However, long-term environmental impact of Se NPs, including their bioavailability, accumulation, and potential toxicity, is crucial for ensuring their safe and sustainable use in agriculture.

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