Development of a quality of life questionnaire for patients with pancreatic neuroendocrine tumours (the PANNET module)

Gastrinoma; Insulinoma; Pancreatic neuroendocrine tumourGastrinoma; Insulinoma; Tumor neuroendocrino pancreáticoGastrinoma; Insulinoma; Tumor neuroendocrí pancreàticPancreatic neuroendocrine tumours (panNET) are heterogeneous neoplasms usually characterised by slow growth and secretion of hormones, which often cause symptoms. The effect of these symptoms on quality of life (QoL) has not previously been examined in detail. EORTC (European Organisation for Research and Treatment of Cancer) guidelines were followed in phases 1–3 to produce a potential module of questions usable for trials in panNET, focusing on three common types of panNET. For two less common types, a list of symptoms was constructed. Following an extensive literature search and phase 1a interviews with patients and healthcare workers, a long list of potential issues (169) was obtained. This list was shown to 12 patients from three countries in phase 1b interviews to check that no items were missed. The list was reduced to 57 issues. The list of issues was converted to questions, mainly from existing validated questions within the EORTC item library. The list of questions was then used in a phase 3 international study in eight countries using seven languages. A provisional module of 24 items is presented for use in nonfunctioning panNET, gastrinoma and insulinoma. This module increases knowledge concerning QoL in this condition and may be a useful adjunct in clinical trials. A phase 4 trial is being considered for validation of this questionnaire

The inflammatory potential of diet is related to incident frailty and slow walking in older adults

Background: Certain foods and dietary patterns have been associated with both inflammation and frailty. As chronic inflammation may play a role in frailty and disability, we examined the association of the inflammatory potential of diet with these outcomes. Methods: Data were taken from 1948 community-dwelling individuals =60 years old from the Seniors-ENRICA cohort, who were recruited in 2008–2010 and followed-up through 2012. Baseline diet data, obtained with a validated diet history, was used to calculate Shivappa's Dietary Inflammatory Index (DII), an “a priori” pattern score which is based on known associations of foods and nutrients with inflammation, and Tabung's Empirical Dietary Inflammatory Index (EDII), an “a posteriori” pattern score which was statistically derived from an epidemiological study. At follow-up, incident frailty was assessed with Fried's criteria, and incident limitation in instrumental activities of daily living (IADL) with the Lawton-Brody index. Statistical analyses were performed with logistic regression, and adjusted for the main confounders. Results: Compared with individuals in the lowest tertile of DII, those in the highest tertile showed higher risk of frailty (odds ratio [OR] 2.48; 95% confidence interval [CI]: 1.42, 4.44, p-trend = 0.001) and IADL disability (OR: 1.96; 95% CI: 1.03, 3.86, p-trend = 0.035). By contrast, EDII did not show an association with these outcomes. The DII score was associated with slow gait speed, both as a low score in the Short Physical Performance Battery test (OR: 1.82; 95% CI: 1.27, 2.62, p-trend = 0.001) and as a positive Fried's criterion (OR: 1.64; 95% CI: 1.08, 2.51, p-trend = 0.021), which use different thresholds. Conclusions: DII predicted frailty and IADL while EDII did not. DII is able to measure diet healthiness in terms of physical decline in addition to avoidance of inflammation

Cabozantinib for the treatment of solid tumors: a systematic review

Cabozantinib; Hepatocellular carcinoma; Solid tumorCabozantinib; Carcinoma hepatocel·lular; Tumor sòlidCabozantinib; Carcinoma hepatocelular; Tumor sólidoBackground: Cabozantinib is approved, in various settings, for the treatment of renal cell carcinoma, medullary thyroid cancer, and hepatocellular carcinoma, and it has been investigated for the treatment of other cancers. With the available evidence and the real-world performance of cabozantinib compared with clinical trial data, we performed a systematic review of cabozantinib monotherapy as treatment for solid tumors in adults. Methods: This study was designed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with PROSPERO (CRD42020144680). We searched for clinical and observational studies of cabozantinib monotherapy for solid tumors using Embase, MEDLINE, and Cochrane databases (October 2020), and screened relevant congress abstracts. Eligible studies reported clinical or safety outcomes, or biomarker data. Small studies (n < 25) and studies of cabozantinib combination therapies were excluded. Quality was assessed using National Institute for Health and Care Excellence methodology, and study characteristics were described qualitatively. Results: Of 2888 citations, 114 were included (52 randomized studies, 29 observational studies, 32 nonrandomized phase I or II studies or pilot trials, and 1 analysis of data from a randomized study and a nonrandomized study). Beyond approved indications, other tumors studied were castration-resistant prostate cancer, urothelial carcinoma, Ewing sarcoma, osteosarcoma, uveal melanoma, non-small-cell lung cancer, Merkel cell carcinoma, glioblastoma, pheochromocytomas and paragangliomas, cholangiocarcinoma, gastrointestinal stromal tumor, colorectal cancer, salivary gland cancer, carcinoid and pancreatic neuroendocrine tumors, and breast, endometrial and ovarian cancers. The most common adverse events were hypertension, diarrhea, and fatigue. Conclusion: The identified evidence demonstrates the positive efficacy/effectiveness of cabozantinib monotherapy in various solid tumor types, with safety findings being consistent with those observed with other VEGFR-targeting tyrosine kinase inhibitors. When available, real-world findings were consistent with the data reported from clinical trials. A limitation of this review is the high proportion of abstracts; however, this allowed us to capture the most up-to-date findings.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Ipsen

The Southern European Atlantic Diet is associated with lower concentrations of markers of coronary risk

Objective: The Southern European Atlantic Diet (SEAD) is the traditional diet of Northern Portugal and Galicia, a region in northwest Spain. The SEAD has been associated with a lower risk of non-fatal acute myocardial infarction, but the mechanisms of this association have not yet been investigated. Thus, we examined the association between the SEAD and numerous biomarkers of coronary risk, blood pressure and anthropometrics. Methods: Cross-sectional study conducted in 2008–2010 among 10,231 individuals representative of the population aged 18 years and older in Spain. Diet was assessed with a validated computerized diet history. SEAD adherence was measured with an index including 9 food components (fresh fish, cod, red meat and pork products, dairy products, legumes and vegetables, vegetable soup, potatoes, whole-grain bread, and wine), which ranges from 0 (lowest adherence) to 9 (highest adherence). C-reactive protein, uric acid, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, glucose, glycated hemoglobin, insulin, leptin, fibrinogen, were determined in 12-h fasting blood samples, while creatinine and urine albumin were determined in urine. Results: Mean SEAD score was 2.9 points (inter-quartile range 2–4 points). Higher SEAD adherence was associated with a lower level of plasma C-reactive protein (adjusted difference in geometric means between the highest and lowest SEAD quartiles −0.2 mg/l; p for trend <0.001), plasma triglycerides (−3.4 mg/dl; p for trend 0.012), insulin (−0.5 mU/l; p for trend <0.001), HOMA-IR (−0.12; p for trend <0.001), urine albumin (−0.8 mg/l; p for trend <0.001), urine albumin-creatinine ratio (−0.3 mg/g creatinine; p for trend <0.034), and systolic blood pressure (−1.6 mm Hg; p for trend <0.001). Conclusions: This study identifies possible mediators of the effect of SEAD on myocardial infarction, because SEAD is associated with a lower concentration of markers of inflammation and with reduced triglycerides, insulin, insulin resistance, and systolic blood pressure

Patient Registries: An Underused Resource for Medicines Evaluation: Operational proposals for increasing the use of patient registries in regulatory assessments

IntroductionPatient registries, 'organised systems that use observational methods to collect uniform data on a population defined by a particular disease, condition, or exposure, and that is followed over time', are potentially valuable sources of data for supporting regulatory decision-making, especially for products to treat rare diseases. Nevertheless, patient registries are greatly underused in regulatory assessments. Reasons include heterogeneity in registry design and in the data collected, even across registries for the same disease, as well as unreliable data quality and data sharing impediments. The Patient Registries Initiative was established by the European Medicines Agency in 2015 to support registries in collecting data suitable to contribute to regulatory assessments, especially post-authorisation safety and effectiveness studies.MethodsWe conducted a qualitative synthesis of the published observations and recommendations from an initiative-led multi-stakeholder consultation and four disease-specific patient registry workshops. We identified the primary factors facilitating the use of registry data in regulatory assessments. We generated proposals on operational measures needed from stakeholders including registry holders, patients, healthcare professionals, regulators, marketing authorisation applicants and holders, and health technology assessment bodies for implementing these.ResultsTen factors were identified as facilitating registry use for supporting regulatory assessments of medicinal products. Proposals on operational measures needed for implementation were categorised according to three themes: (1) nature of the data collected and registry quality assurance processes; (2) registry governance, informed consent, data protection and sharing; and (3) stakeholder communication and planning of benefit-risk assessments.ConclusionsThese are the first explicit proposals, from a regulatory perspective, on operational methods for increasing the use of patient registries in medicines regulation. They apply to registry holders, patients, regulators, marketing authorisation holders/applicants and healthcare stakeholders broadly, and their implementation would greatly facilitate the use of these valuable data sources in regulatory decision-making

Rationale of the association between Mediterranean diet and the risk of frailty in older adults and systematic review and meta-analysis

Frailty is a geriatric syndrome whose frequency is increasing in parallel with population aging and is of great interest due to its dire consequences: increased disability, hospitalizations, falls and fractures, institutionalization, and mortality. Frailty is multifactorial but nutritional factors, which are modifiable, play a crucial role in its pathogenesis. Epidemiologic evidence supports that high-quality dietary patterns can prevent, delay or even reverse the occurrence of frailty. In order to add new knowledge bridging the gap as the main purpose of the present article we performed a comprehensive review of the rationale behind the association of MedDiet with frailty and a systematic review and meta-analysis updating the latest ones published in 2018 specifically examining the relationship of Mediterranean diet (MedDiet) and incident frailty. Adding the updated information, our results confirmed a robust association of a higher adherence to MedDiet with reduced incident frailty. Key components of the MedDiet, i.e., abundant consumption of vegetables and fruit as well as the use of olive oil as the main source of fat, all of which have been associated with a lower incidence of frailty, may help explain the observed benefit. Future well-designed and sufficiently large intervention studies are needed to confirm the encouraging findings of the current observational evidence. Meanwhile, based on the existing evidence, the promotion of MedDiet, a high-quality dietary pattern, adapted to the conditions and traditions of each region, and considering lifelong and person-tailored strategies, is an open opportunity to reduced incident frailty. This could also help counteract the worrying trend towards the spread of unhealthy eating and lifestyle models such as those of Western diets that greatly contribute to the genesis of chronic non-communicable diseases and disability

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

Bronchial epithelial spheroids: an alternative culture model to investigate epithelium inflammation-mediated COPD

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) is characterized by abnormal lung inflammation that exceeds the protective response. Various culture models using epithelial cell lines or primary cells have been used to investigate the contribution of bronchial epithelium in the exaggerated inflammation of COPD. However, these models do not mimic <it>in vivo </it>situations for several reasons (e.g, transformed epithelial cells, protease-mediated dissociation of primary cells, etc.). To circumvent these concerns, we developed a new epithelial cell culture model.</p> <p>Methods</p> <p>Using non transformed non dissociated bronchial epithelium obtained by bronchial brushings from COPD and non-COPD smokers, we developed a 3-dimensional culture model, bronchial epithelial spheroids (BES). BES were analyzed by videomicroscopy, light microscopy, immunofluorescence, and transmission electron microscopy. We also compared the inflammatory responses of COPD and non-COPD BES. In our study, we chose to stimulate BES with lipopolycaccharide (LPS) and measured the release of the pro-inflammatory mediators interleukin-8 (IL-8) and leukotriene B4 (LTB4) and the anti-inflammatory mediator prostaglandin E2 (PGE2).</p> <p>Results</p> <p>BES obtained from both COPD and non-COPD patients were characterized by a polarized bronchial epithelium with tight junctions and ciliary beating, composed of basal cells, secretory cells and ciliated cells. The ciliary beat frequency of ciliated cells was not significantly different between the two groups. Of interest, BES retained their characteristic features in culture up to 8 days. BES released the inflammatory mediators IL-8, PGE2 and LTB4 constitutively and following exposure to LPS. Interestingly, LPS induced a higher release of IL-8, but not PGE2 and LTB4 in COPD BES (p < 0.001) which correlated with lung function changes.</p> <p>Conclusion</p> <p>This study provides for the first time a compelling evidence that the BES model provides an unaltered bronchial surface epithelium. More importantly, BES represent an attractive culture model to investigate the mechanisms of injuring agents that mediate epithelial cell inflammation and its contribution to COPD pathogenesis.</p

Exploring cut-off values for large waist circumference in older adults: a new methodological approach

BACKGROUND: There is an ongoing debate about the applicability of current criteria for large waist circumference (WC) in older adults. OBJECTIVES: Our aim was to explore cut-off values for large WC in adults aged 70 years and older, using previously used and new methods. DESIGN: Prospective cohort study. PARTICIPANTS: Data of 1049 participants of the Longitudinal Aging Study Amsterdam (LASA) (1995-1996), aged 70-88y, were used. MEASUREMENTS: Measured BMI and WC, and self-reported mobility limitations. RESULTS: Linear regression analyses showed that the values of WC corresponding to BMI of 25kg/m2 and 30kg/m2 were higher than the current cut-offs. Cut-offs found in men were 97 and 110cm, whereas 88 and 98cm represented the cut-offs in women. Areas under the Receiver Operating Characteristic (ROC) curves showed that the accuracy to predict mobility limitations improved when the higher cut-offs were applied. Spline regression curves showed that the relationship of WC with mobility limitations was U-shaped in men, while in women, the risk for mobility limitations increased gradually with increasing WC. However, at the level of current cut-off values for WC the odds for mobility limitations were not increased. CONCLUSION: Based on results of extensive analyses, this study suggests that the cut-offs for large WC should be higher when applied to older adults. The association of WC with other negative health outcomes needs to be investigated to establish the final cut-points