177Lu-octreotate in Neuroendocrine Tumors: Treatment Effects

Neuroendocriene tumoren (NETs) zijn zeer zeldzame tumoren, die ontstaan vanuit neuroendocriene cellen in het lichaam. Deze tumoren produceren vaak hormonen en hormoonachtige stoffen. NETs ontstaan meestal in het maag-darm kanaal, in de alvleesklier, of in de longen. Jaarlijks komen er in Nederland ongeveer 700 nieuwe NET-patiënten bij. De enige mogelijkheid om deze patiënten te genezen is om hen te opereren. Vaak kan dit echter niet meer, omdat de tumor al uitgezaaid is, of te groot is om geopereerd te kunnen worden. Een behandeling die dan gegeven kan worden, is zogenaamde peptide receptor radionuclide therapie (PRRT). Een voorbeeld hiervan is behandeling met Lutetium-octreotaat, een radioactief gemerkt eiwit waarmee NETs inwendig en lokaal bestraald kunnen worden. Dit proefschrift beschrijft verschillende therapie effecten na behandeling van NETs met Lutetium-octreotaat. Een eerste bevinding was dat botuitzaaiingen op de CT scan anders reageerden op behandeling met Lutetium-octreotaat dan andere uitzaaiingen. Terwijl andere uitzaaiingen (met name leveruitzaaiingen) gemiddeld kleiner werden na behandeling, namen botuitzaaiingen in grootte toe. Omdat de botuitzaaiingen op de zogenaamde indium-octreotide scan (Octreoscan) (een nucleaire scan die NETs zichtbaar kan maken) in intensiteit of aantal afnamen, en omdat tumormarkers in het bloed ook afnamen, lijkt het erop dat de botuitzaaiingen wel reageren op de behandeling met Lutetium-octreotaat, maar dat een CT scan geen geschikte methode is om dit af te beelden. Om het effect van een behandeling te meten op een CT scan, zijn verschillende meetmethodes beschikbaar. In een analyse van 268 patiënten met een NET werd bekeken welke meetmethode het beste gebruikt kan worden. Uit deze analyse kwam naar voren, dat alle meetmethoden eenzelfde voorspelling qua overleving geven en dat er geen voordeel van de een boven de ander is. Een derde bevinding was dat als patiënten met zogenaamde niet-functionerende NETs van de alvleesklier die te groot waren om geopereerd te kunnen worden, een voorbehandeling met Lutetium-octreotaat kregen, deze behandeling ervoor kon zorgen, dat de tumor hierna wel geopereerd kon worden. Dit is een zeer veelbelovende toepassing van de behandeling met Lutetium-octreotaat, omdat een succesvolle operatie de enige kans op genezing is voor deze patiënten. Als laatste werd de toepassing van Lutetium-octreotaat bij patiënten met een insulinoom onderzocht. Een insulinoom is een tumor die een overmaat aan insuline produceert, waardoor mensen een zeer lage bloedsuikerspiegel kunnen krijgen, waardoor ze in een coma kunnen raken, of zelfs kunnen overlijden. Behandeling met Lutetium-octreotaat zorgde ervoor dat patiënten met een insulinoom geen klachten meer hadden van een lage bloedsuikerspiegel, en dat ze hierdoor niet meer voortdurend in het ziekenhuis opgenomen hoefden te zijn

Series: Public engagement with research. Part 3: Sharing power and building trust through partnering with communities in primary care research

Background : This article focuses on potential strategies to support primary care researchers in working in partnership with the public and healthcare professionals. Partnership working can potentially to improve the relevance and usefulness of research and ensure better research and health outcomes. Discussion : We describe what we mean by partnership working and the importance of reflecting on power and building trusting relationships. To share power in partnership working, it is essential to critically reflect on the multiple dimensions of power, their manifestations, and your own power. Power can influence relationships and therefore, it is essential to build trust with partners. Next, we outline how the context of primary care research and decisions about who you work with and how to work together, are vital considerations that are imbued with power. Lastly, we suggest different ways of working in partnership to address different dimensions of power. We provide examples from primary care research across Europe regarding how to recognise, tackle, and challenge, invisible, hidden and visible power. Conclusion : We conclude by proposing three calls to actions to encourage researchers working in primary care to consider the multiple dimensions of power and move towards partnership working. First is to use participatory methods to improve the inclusivity of your research. Second is to include patients and the public in decisions about the design, delivery and development of research and its outcomes. Third is to address various systemic and institutional barriers which hinder partnership working

Series: Public engagement with research. Part 1: The fundamentals of public engagement with research

BACKGROUND: In the first of a four-part series, we describe the fundamentals of public engagement in primary care research. OBJECTIVES: The article's purpose is to encourage, inform and improve the researcher's awareness about public engagement in research. For a growing number of researchers, funders and patient organisations in Europe, public engagement is a moral and ethical imperative for conducting high-quality research. DISCUSSION: Starting with an explanation of the role of public engagement in research, we highlight its diversity and benefits to research, researchers and the public members involved. We summarise principles of good practice and provide valuable resources for researchers to use in their public engagement activities. Finally, we discuss some of the issues encountered when researchers collaborate with members of the public and provide practical steps to address them. Case studies of real-life situations are used to illustrate and aid understanding. CONCLUSION: We hope this article and the other papers in this series will encourage researchers to better consider the role and practice of public engagement and the potential added value to research that collaborating with the public could provide

Dried blood spot versus venous blood sampling for phenylalanine and tyrosine

Background: This study investigated the agreement between various dried blood spot (DBS) and venous blood sample measurements of phenylalanine and tyrosine concentrations in Phenylketonuria (PKU) and Tyrosinemia type 1 (TT1) patients. Study design: Phenylalanine and tyrosine concentrations were studied in 45 PKU/TT1 patients in plasma from venous blood in lithium heparin (LH) and EDTA tubes; venous blood from LH and EDTA tubes on a DBS card; venous blood directly on a DBS card; and capillary blood on a DBS card. Plasma was analyzed with an amino acid analyzer and DBS were analyzed with liquid chromatography-mass spectrometry. Agreement between different methods was assessed using Passing and Bablok fit and Bland Altman analyses. Results: In general, phenylalanine concentrations in LH plasma were comparable to capillary DBS, whereas tyrosine concentrations were slightly higher in LH plasma (constant bias of 6.4 μmol/L). However, in the low phenylalanine range, most samples had higher phenylalanine concentrations in DBS compared to LH plasma. Remarkably, phenylalanine and tyrosine in EDTA plasma were higher compared to all other samples (slopes ranging from 7 to 12%). No differences were observed when comparing capillary DBS to other DBS. Conclusions: Overall agreement between plasma and DBS is good. However, bias is specimen-(LH vs EDTA), and possibly concentration-(low phenylalanine) dependent. Because of the overall good agreement, we recommend the use of a DBS-plasma correction factor for DBS measurement. Each laboratory should determine their own factor dependent on filter card type, extraction and calibration protocols taking the LH plasma values as gold standard

Series: Public engagement with research. Part 2:GPs and primary care researchers working inclusively with minoritised communities in health research to help address inequalities

Public engagement in health research is vital for addressing health disparities and promoting inclusivity among minoritised communities who often face barriers to accessing healthcare. Minoritised communities are groups, which have been made minorities by a dominant culture, race, ethnic group and/or social class and may experience health inequalities as a result. By incorporating diverse perspectives and lived experiences of minoritised communities, this approach aims to achieve contextually relevant research outcomes that reduce health inequalities and improve overall well-being. However, underrepresentation and lack of inclusivity challenges persist, necessitating the establishment of inclusive partnerships and grassroots participatory methodologies. To foster inclusive public engagement, it is important to overcome structural and cultural barriers, address socioeconomic challenges, and build trust with minoritised communities. This can be achieved by promoting a cultural shift that values inclusivity, providing comprehensive training to researchers, and collecting rigorous data on engagement demographics for transparency and accountability. Involving minoritised communities in decision-making through participatory research approaches enhances trust and yields successful outcomes. Additionally, allocating sufficient resources, collaborating in co-production, and prioritising the diverse needs and perspectives of stakeholders contribute to fostering inclusive public engagement in research. Overall, inclusive engagement practices particularly in primary care research have the potential to reduce health inequalities and cater to the unique requirements of minoritised communities, thereby creating more impactful outcomes and promoting equitable healthcare access

Aspartame and Phe-Containing Degradation Products in Soft Drinks across Europe

Phenylketonuria and tyrosinemia type 1 are treated with dietary phenylalanine (Phe) restriction. Aspartame is a Phe-containing synthetic sweetener used in many products, including many 'regular' soft drinks. Its amount is (often) not declared; therefore, patients are advised not to consume aspartame-containing foods. This study aimed to determine the variation in aspartame concentrations and its Phe-containing degradation products in aspartame-containing soft drinks. For this, an LC-MS/MS method was developed for the analysis of aspartame, Phe, aspartylphenylalanine, and diketopiperazine in soft drinks. In total, 111 regularly used soft drinks from 10 European countries were analyzed. The method proved linear and had an inter-assay precision (CV%) below 5% for aspartame and higher CVs% of 4.4-49.6% for the degradation products, as many concentrations were at the limit of quantification. Aspartame and total Phe concentrations in the aspartame-containing soft drinks varied from 103 to 1790 µmol/L (30-527 mg/L) and from 119 to 2013 µmol/L (20-332 mg/L), respectively, and were highly variable among similar soft drinks bought in different countries. Since Phe concentrations between drinks and countries highly vary, we strongly advocate the declaration of the amount of aspartame on soft drink labels, as some drinks may be suitable for consumption by patients with Phe-restricted diets

Demographics and Functional Outcome of Toe Fractures

Toe fractures are common; however, there are few data on demographics and functional outcome. We studied outcomes in 339 consecutive patients with toe fractures treated between January 2006 and September 2008. Two hundred and sixty-four patients, aged 16 to 75, were mailed an outcome questionnaire, and overall subjective satisfaction with the outcome of treatment was measured using a visual analog scale (VAS). Most frequently affected were the first (38%) and fifth (30%) toes, and most (75.6%) of the fractures were caused by stubbing or crush injury. More than 95% of the fractures were displaced less than 2 mm, and all of the fractures were treated conservatively. The questionnaire was returned by 141 (53%) patients with a median follow-up of 27 months. Respondents were female in 57.4% of cases and had a median age of 45 years. The median AOFAS score was 100 (P25, P75= 93,100) points; the median VAS was 10 (P25, P75= 8, 10) points. Univariate regression analysis revealed no statistically significant associations between outcome and the particular toe or phalanx involved, number of fractured toes, fracture type and location, articular involvement, gender, age, body mass index, smoking habits, and the presence of diabetes mellitus. Satisfaction VAS was dependent on age (P = .047) and gender (P = .049) in the multivariate analysis. The AOFAS midfoot score was not influenced by any of the covariates. This is the first epidemiological investigation using 2 outcome-scoring systems to determine function and satisfaction following treatment of toe fractures

Empirische evidence voor de effectiviteit van routine outcome monitoring; een literatuuronderzoek

achtergrond Routine outcome monitoring (ROM) is een belangrijk kwaliteitsinstrument om effecten van behandeling zichtbaar te maken en wordt landelijk geïmplementeerd in de Nederlandse ggz. doel Evalueren van de wetenschappelijke stand van zaken betreffende de effectiviteit van ROM voor diagnostiek, behandeling en andere uitkomsten. methode Literatuuronderzoek in PubMed, Medline, Psycinfo en Embase Psychiatry (1975-2009) naar gerandomiseerde gecontroleerde trials (rct\u27s) van ROM bij alle leeftijdsgroepen patiënten (algemeen en ggz). De voornaamste zoektermen waren \u27routine outcome monitoring\u27 c.q. \u27routine outcome measurement\u27. resultaten Er werden 52 rct\u27s geïncludeerd betreffende ROM bij volwassen patiënten. Hiervan waren 45 rct\u27s gericht op psychische klachten, zij het niet altijd in een psychiatrische setting of als primaire uitkomstmaat. Er bleken positieve effecten van ROM op de diagnostiek en behandeling, en op de communicatie tussen patiënt en behandelaar. Andere uitkomsten waren minder eenduidig. conclusie ROM blijkt vooral effectief voor het monitoren van behandelingen die onvoldoende aanslaan. Nader onderzoek is nodig naar de klinische effectiviteit en de kosteneffectiviteit van ROM in zowel de volwassenen- als de kinder- en jeugdpsychiatrie

Apology after medical errors: a qualitative vignette study:Medical errors: impact of apology and admission on the resolution and compensation of claims

Studies investigating the impact of apologies and admission of responsibility for medical errors have been primarily observational, making it hard to attach a causal effect to the admission of responsibility and apologies. Second, most research on the settlement of medical malpractice cases were conducted in the US, with its particular litigation laws and culture. In this multi-jurisdictional study, we investigate the impact of apology and admission of responsibility on preferred resolution and compensation of claims. Employing a vignette design, we examine, among a sample of 327 respondents from 10 different countries, whether admission and apology by the doctor impact respondents' preference for resolution through a civil court case, mediation or a disciplinary board, as well as preferred damages for pain and suffering. Admission and apology by the physician in the vignette did not impact respondents' preference for settlement through a civil court case or mediation, nor did it affect the amount respondents found suitable compensation for pains and damages. We perceived the absence of an apology as particularly aggravating. Thematic analysis of open answers reveals that the impact of admission and apology differs for the three resolution modes and is often contextual and conditional. Future (vignette) studies should investigate whether different cases of medical errors yield similar results and whether more knowledgeable or experienced respondents (such as lawyers) would have other preferences and arguments. <br/

The prognostic and predictive value of Tregs and tumor immune subtypes in postmenopausal, hormone receptor-positive breast cancer patients treated with adjuvant endocrine therapy: a Dutch TEAM study analysis

Evidence exists for an immunomodulatory effect of endocrine therapy in hormone receptor-positive (HR+ve) breast cancer (BC). Therefore, the aim of this study was to define the prognostic and predictive value of tumor immune markers and the tumor immune profile in HR+ve BC, treated with different endocrine treatment regimens. 2,596 Dutch TEAM patients were treated with 5 years of adjuvant hormonal treatment, randomly assigned to different regimens: 5 years of exemestane or sequential treatment (2.5 years of tamoxifen–2.5 years of exemestane). Immunohistochemistry was performed for HLA class I, HLA-E, HLA-G, and FoxP3. Tumor immune subtypes (IS) (low, intermediate & high immune susceptible) were determined by the effect size of mono-immune markers on relapse rate. Patients on sequential treatment with high level of tumor-infiltrating FoxP3+ cells had significant (p = 0.019, HR 0.729, 95 % CI 0.560–0.949) better OS. Significant interaction for endocrine treatment and FoxP3+ presence was seen (OS p < 0.001). Tumor IS were only of prognostic value for the sequentially endocrine-treated patients (RFP: p = 0.035, HR intermediate IS 1.420, 95 % CI 0.878–2.297; HR low IS 1.657, 95 % CI 1.131–2.428; BCSS: p = 0.002, HR intermediate IS 2.486, 95 % CI 1.375–4.495; HR low IS 2.422, 95 % CI 1.439–4.076; and OS: p = 0.005, HR intermediate IS 1.509, 95 % CI 0.950–2.395; HR low IS 1.848, 95 % CI 1.277–2.675). Tregs and the tumor IS presented in this study harbor prognostic value for sequentially endocrine-treated HR+ve postmenopausal BC patients, but not for solely exemestane-treated patients. Therefore, these markers could be used as a clinical risk stratification tool to guide adjuvant treatment in this BC population