Predicting keratinocyte carcinoma in patients with actinic keratosis: development and internal validation of a multivariable risk-prediction model

Background: Patients with actinic keratosis (AK) are at increased risk for developing keratinocyte carcinoma (KC) but predictive factors and their risk rates are unknown. Objectives: To develop and internally validate a prediction model to calculate the absolute risk of a first KC in patients with AK. Methods: The risk-prediction model was based on the prospective population-based Rotterdam Study cohort. We hereto analysed the data of participants with at least one AK lesion at cohort baseline using a multivariable Cox proportional hazards model and included 13 a priori defined candidate predictor variables considering phenotypic, genetic and lifestyle risk factors. KCs were identified by linkage of the data with the Dutch Pathology Registry. Results: Of the 1169 AK participants at baseline, 176 (15·1%) developed a KC after a median follow-up of 1·8 years. The final model with significant predictors was obtained after backward stepwise selection and comprised the presence of four to nine AKs [hazard ratio (HR) 1·68, 95% confidence interval (CI) 1·17–2·42], 10 or more AKs (HR 2·44, 95% CI 1·65–3·61), AK localization on the upper extremities (HR 0·75, 95% CI 0·52–1·08) or elsewhere except the head (HR 1·40, 95% CI 0·98–2·01) and coffee consumption (HR 0·92, 95% CI 0·84–1·01). Evaluat

Development of a stratification tool to identify pancreatic intraductal papillary mucinous neoplasms at lowest risk of progression

Background: Because most pancreatic intraductal papillary mucinous neoplasms (IPMNs) will never become malignant, currently advocated long-term surveillance is low-yield for most individuals. Aim: To develop a score chart identifying IPMNs at lowest risk of developing worrisome features or high-risk stigmata. Methods: We combined prospectively maintained pancreatic cyst surveillance databases of three academic institutions. Patients were included if they had a presumed side-branch IPMN, without worrisome features or high-risk stigmata at baseline (as defined by the 2012 international Fukuoka guidelines), and were followed ≥ 12 months. The endpoint was development of one or more worrisome features or high-risk stigmata during follow-up. We created a multivariable prediction model using Cox-proportional logistic regression analysis and performed an internal-external validation. Results: 875 patients were included. After a mean follow-up of 50 months (range 12-157), 116 (13%) patients developed worrisome features or high-risk stigmata. The final model included cyst size (HR 1.12, 95% CI 1.09-1.15), cyst multifocality (HR 1.49, 95% CI 1.01-2.18), ever having smoked (HR 1.40, 95% CI 0.95-2.04), history of acute pancreatitis (HR 2.07, 95% CI 1.21-3.55), and history of extrapancreatic malignancy (HR 1.34, 95% CI 0.91-1.97). After validation, the model had good discriminative ability (C-statistic 0.72 in the Mayo cohort, 0.71 in the Columbia cohort, 0.64 in the Erasmus cohort). Conclusion: In presumed side branch IPMNs without worrisome features or high-risk stigmata at baseline, the Dutch-American Risk stratification Tool (DART-1) successfully identifies pancreatic lesions at low risk of developing worrisome features or high-risk stigmata

Autonomy Challenges in Epigenetic Risk-Stratified Cancer Screening: How Can Patient Decision Aids Support Informed Consent?

Information of an individual’s epigenome can be useful in cancer screening to enable personalised decision making on participation, treatment options and further screening strategies. However, adding this information might result in complex risk predictions on multiple diseases, unsolicited findings and information on (past) environmental exposure and behaviour. This complicates informed consent procedures and may impede autonomous decision-making. In this article we investigate and identify the specific features of epigenetic risk-stratified cancer screening that challenge the current informed consent doctrine. Subsequently we describe current and new informed consent models and the principle of respect for autonomy and argue for a specific informed consent model for epigenetic risk-stratified screening programmes. Next, we propose a framework that guides the development of Patient Decision Aids (PDAs) to support informed consent and promote autonomous choices in the specific context of epigenetic cancer screening programmes

Kartor för blodbussarna i mobila enheter : Samla information från HTML-kod med Java

Examensarbetets mål är en färdig mobilapplikation som snabbast möjligast avgör avstånd och väg till blodbussar genom olika informationssamlare och som visar upp resultatet i Google Maps. Målet med själva applikationen är att den ska underlätta för användare att ge blod och därmed i förlängningen att den brist på blod som idag råder i Sverige minskar. Att samla information genom att välja och formatera information är ett väldigt smidigt sätt om man är säker på att hemsidan du samlar ifrån inte kommer förändras inom den närmaste framtiden. Möjligheterna för informationssamlande är helt beroende på hur sidan du hämtar informationen ifrån ser ut. Jag har använt Java och Android när jag hämtat information från Blodbussens hemsida. Undersökningen som har gjorts mellan olika informationssamlare hade även den ett mål i sig och det var att jämföra två bibliotek som väljs genom en förstudie för att senare göra själva html-informationssamlingen och så har jag använt en egen klass som använder några utav Android positionsmetoder för att komma från adress till koordinater. Mitt fokus har varit på jämförelsen mellan de olika html-informationssamlarna och jag har utvärderat det i rapporten under resultat. De aspekter jag har haft i åtanke är korrekthet och hastighet. Detta projekt resulterade i en "proof-of-concept"-applikation som visar var de olika bussarna befinner sig relativt till en individs position. Resultatet av förstudien kring de olika informationssamlarna har lett till ökad kunskap inom parsning och bland de två jag jämförde mer grundligt har jag fått större inblick i deras styrkor och svagheter.The goal of this degree project is to give a complete Native Mobile application which determines the range and route to the bloodmobiles through different information collectors and show the result in Google Maps as fast as possible. The goal with the application is that it should make it easier to donate blood and in the long run terminate the shortage of blood that reign in Sweden. To get information through selecting and formatting information is a very flexible way of getting information if you are certain that the page won’t change anything in a near future. The possibilities of getting information are totally dependent on how the homepage is looking. I have used Java and Android when I have been gathering information from the Blood Bus homepage. The study of the different information collectors also had a goal in itself and that was to examine two libraries which are chosen by a pre-study for the html-information-collector and then I have made a class of my own to go from address to coordinates which are using a few of the location methods from Android. My main focus is on the comparison between the html-information-collector and I have evaluated that in the report under results. The main aspects I have had in mind for my evaluation are correctness and speed. This project resulted in a "proof-of-concept"-application that shows where the different buses are relative to your position. The result of the pre-study about the different information collectors has given me increased knowledge in parsing and insight of the up- and downsides of the two libraries that I compared more thorough

Liposomal drug delivery in an in vitro 3D bone marrow model for multiple myeloma

Purpose: Liposomal drug delivery can improve the therapeutic index of treatments for multiple myeloma. However, an appropriate 3D model for the in vitro evaluation of liposomal drug delivery is lacking. In this study, we applied a previously developed 3D bone marrow (BM) myeloma model to examine liposomal drug therapy. Material and methods: Liposomes of different sizes (~75-200 nm) were tested in a 3D BM myeloma model, based on multipotent mesenchymal stromal cells, endothelial progenitor cells, and myeloma cells cocultured in hydrogel. The behavior and efficacy of liposomal drug therapy was investigated, evaluating the feasibility of testing liposomal drug delivery in 3D in vitro. Intracellular uptake of untargeted and integrin α4β1 (very late antigen-4) targeted liposomes was compared in myeloma and supporting cells, as well as the effectivity of free and liposome-encapsulated chemotherapy (bortezomib, doxorubicin). Either cocultured myeloma cell lines or primary CD138+ myeloma cells received the treatments. Results: Liposomes (~75-110 nm) passively diffused throughout the heterogeneously porous (~80-850 nm) 3D hydrogel model after insertion. Cellular uptake of liposomes was observed and was increased by targeting very late antigen-4. Liposomal bortezomib and doxorubicin showed increased cytotoxic effects toward myeloma cells compared with the free drugs, using either a cell line or primary myeloma cells. Cytotoxicity toward supporting BM cells was reduced using liposomes. Conclusion: The 3D model allows the study of liposome-encapsulated molecules on multiple myeloma and supporting BM cells, looking at cellular targeting, and general efficacy of the given therapy. The advantages of liposomal drug delivery were demonstrated in a primary myeloma model, enabling the study of patient-to-patient responses to potential drugs and treatment regimes

Cellular immunotherapy on primary multiple myeloma expanded in a 3D bone marrow niche model

Bone marrow niches support multiple myeloma, providing signals and cell-cell interactions essential for disease progression. A 3D bone marrow niche model was developed, in which supportive multipotent mesenchymal stromal cells and their osteogenic derivatives were co-cultured with endothelial progenitor cells. These co-cultured cells formed networks within the 3D culture, facilitating the survival and proliferation of primary CD138+ myeloma cells for up to 28 days. During this culture, no genetic drift was observed within the genomic profile of the primary myeloma cells, indicating a stable outgrowth of the cultured CD138+ population. The 3D bone marrow niche model enabled testing of a novel class of engineered immune cells, so called TEGs (αβT cells engineered to express a defined γδTCR) on primary myeloma cells. TEGs were engineered and tested from both healthy donors and myeloma patients. The added TEGs were capable of migrating through the 3D culture, exerting a killing response towards the primary myeloma cells in 6 out of 8 donor samples after both 24 and 48 hours. Such a killing response was not observed when adding mock transduced T cells. No differences were observed comparing allogeneic and autologous therapy. The supporting stromal microenvironment was unaffected in all conditions after 48 hours. When adding TEG therapy, the 3D model surpassed 2D models in many aspects by enabling analyses of specific homing, and both on- and off-target effects, preparing the ground for the clinical testing of TEGs. The model allows studying novel immunotherapies, therapy resistance mechanisms and possible side-effects for this incurable disease

Cellular immunotherapy on primary multiple myeloma expanded in a 3D bone marrow niche model

Bone marrow niches support multiple myeloma, providing signals and cell-cell interactions essential for disease progression. A 3D bone marrow niche model was developed, in which supportive multipotent mesenchymal stromal cells and their osteogenic derivatives were co-cultured with endothelial progenitor cells. These co-cultured cells formed networks within the 3D culture, facilitating the survival and proliferation of primary CD138+ myeloma cells for up to 28 days. During this culture, no genetic drift was observed within the genomic profile of the primary myeloma cells, indicating a stable outgrowth of the cultured CD138+ population. The 3D bone marrow niche model enabled testing of a novel class of engineered immune cells, so called TEGs (αβT cells engineered to express a defined γδTCR) on primary myeloma cells. TEGs were engineered and tested from both healthy donors and myeloma patients. The added TEGs were capable of migrating through the 3D culture, exerting a killing response towards the primary myeloma cells in 6 out of 8 donor samples after both 24 and 48 hours. Such a killing response was not observed when adding mock transduced T cells. No differences were observed comparing allogeneic and autologous therapy. The supporting stromal microenvironment was unaffected in all conditions after 48 hours. When adding TEG therapy, the 3D model surpassed 2D models in many aspects by enabling analyses of specific homing, and both on- and off-target effects, preparing the ground for the clinical testing of TEGs. The model allows studying novel immunotherapies, therapy resistance mechanisms and possible side-effects for this incurable disease

Endosteal and Perivascular Subniches in a 3D Bone Marrow Model for Multiple Myeloma

The bone marrow microenvironment is the preferred location of multiple myeloma, supporting tumor growth and development. It is composed of a collection of interacting subniches, including the endosteal and perivascular niche. Current in vitro models mimic either of these subniches. By developing a model combining both niches, this study aims to further enhance the ability to culture primary myeloma cells in vitro. Also, the dependency of myeloma cells on each niche was studied. A 3D bone marrow model containing two subniches was created using 3D bioprinting technology. We used a bioprintable pasty calcium phosphate cement (CPC) scaffold with seeded osteogenic multipotent mesenchymal stromal cells (O-MSCs) to model the endosteal niche, and Matrigel containing both endothelial progenitor cells (EPCs) and MSCs to model the perivascular niche. Within the model containing one or both of the niches, primary CD138+ myeloma cells were cultured and analyzed for both survival and proliferation. The 3D bone marrow model with combined subniches significantly increasing the proliferation of CD138+ myeloma cells compared to both environments separately. The developed model showed an essential role of the perivascular niche over the endosteal niche in supporting myeloma cells. The developed model can be used to study the expansion of primary myeloma cells and their interactions with varying bone marrow subniches