Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all common cancers. However, divergent outcomes exist between patients, suggesting distinct underlying tumor biology. Here, we ...delineated this heterogeneity, compared interconnectivity between classification systems, and experimentally addressed the tumor biology that drives poor outcome. RNA-sequencing of 90 resected specimens and unsupervised classification revealed four subgroups associated with distinct outcomes. The worst-prognosis subtype was characterized by mesenchymal gene signatures. Comparative (network) analysis showed high interconnectivity with previously identified classification schemes and high robustness of the mesenchymal subtype. From species-specific transcript analysis of matching patient-derived xenografts we constructed dedicated classifiers for experimental models. Detailed assessments of tumor growth in subtyped experimental models revealed that a highly invasive growth pattern of mesenchymal subtype tumor cells is responsible for its poor outcome. Concluding, by developing a classification system tailored to experimental models, we have uncovered subtype-specific biology that should be further explored to improve treatment of a group of PDAC patients that currently has little therapeutic benefit from surgical treatment.
Ankle sprains are common problems in acute medical care. The variation in treatment observed for the acutely injured lateral ankle ligament complex in the first week after the injury suggests a lack ...of evidence-based management strategies for this problem.
To analyze the effectiveness of applying rest, ice, compression, and elevation (RICE) therapy begun within 72 hours after trauma for patients in the initial period after ankle sprain.
Eligible studies were published original randomized or quasi-randomized controlled trials concerning at least 1 of the 4 subtreatments of RICE therapy in the treatment of acute ankle sprains in adults.
MEDLINE, Cochrane Clinical Trial Register, CINAHL, and EMBASE. The lists of references of retrieved publications also were checked manually.
We extracted relevant data on treatment outcome (pain, swelling, ankle mobility or range of motion, return to sports, return to work, complications, and patient satisfaction) and assessed the quality of included studies. If feasible, the results of comparable studies were pooled using fixed- or random-effects models.
After deduction of the overlaps among the different databases, evaluation of the abstracts, and contact with some authors, 24 potentially eligible trials remained. The full texts of these articles were retrieved and thoroughly assessed as described. This resulted in the inclusion of 11 trials involving 868 patients. The main reason for exclusion was that the authors did not describe a well-defined control group without the intervention of interest.
Insufficient evidence is available from randomized controlled trials to determine the relative effectiveness of RICE therapy for acute ankle sprains in adults. Treatment decisions must be made on an individual basis, carefully weighing the relative benefits and risks of each option, and must be based on expert opinions and national guidelines.
Abstract In a major incident, correct triage is crucial to emergency treatment and transportation priority. The aim of this study was to evaluate the triage process pursued at the site of the fire ...disaster in Volendam, the Netherlands on January 1, 2001. On-site (OS) and Emergency Department (ED) data regarding total body surface area burned (TBSA) and inhalation injury (INH) were compared with the final (FIN) assessment of these two parameters after hospital admission. Finally, the effect of OS intubation and the time of arrival at a hospital were evaluated. There were 245 injured. Mean age was 17.3 years. Final median TBSA was 12%; 96 patients (39%) had inhalation injury. Agreement between TBSA-OS (n = 46) and TBSA-FIN was poor (Pearson's correlations coefficient PCC = 0.77; R2 = 0.60). TBSA-ED (n = 78) was more accurate (PCC = 0.96; R2 = 0.93). INH-OS (n = 79, sensitivity 100%, specificity 24%) and INH-ED (n = 198, sensitivity 99%, specificity 36%) were sensitive but not specific. Eight patients were intubated on-site. No differences in outcome were found between this group and the patients who were intubated in the hospital. There was no difference in time of arrival at a hospital ( p = 0.55). TBSA was not estimated reliably in a non-clinical environment. The diagnosis of inhalation injury was adequate but resulted in over-triage on-site and at the ED. Triage did not lead to transport priorities for the severely wounded. In a major burn accident, a field triage protocol for rapid evaluation of burn injuries may be useful. Detailed assessment of injuries of burn casualties is practical only in a specialized clinical setting.
Patient decision aids (PtDAs) are structured clinical tools that facilitate shared decision-making. Two important treatment decisions for patients with differentiated thyroid cancer (DTC), which ...could benefit from PtDAs, are as follows (1): the extent of surgery decision in patients with low-risk DTC and (2) the decision to start or delay starting the treatment with tyrosine kinase inhibitors (TKIs) in patients with advanced tumors.
PtDAs for these two decisions were developed using the International Patient Decision Aids Standards (IPDAS) quality criteria in an iterative process of prototype development
alpha and beta testing by patients and physicians. The information content of the PtDAs was based on the available literature, current guidelines, and patient's needs, preferences, and values.
The web-based PtDAs underwent two rounds of alpha testing, revisions, and beta testing. The PtDAs have the same structure, consisting of six steps: a general introduction, information about the treatment options, comparing the treatment options, knowledge questions, a values clarification exercise, and saving the information. The alpha testing (
= 8 patients,
= 10 physicians) showed that the PtDAs were highly acceptable and usable for decision-making. Results of the beta testing in 20 patients showed that two patients did not use the PtDA; the other 18 patients found that the PtDAs were readable (
= 17) and helpful (
= 14) for decision-making. All patients recommend using the PtDAs.
Evidence-based PtDAs were created for patients with DTC for two different treatment decisions. Our final version was judged to be clear, balanced, and helpful in decision-making.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, being the fourth leading cause of cancer-related deaths. Long-term survival reaching 15% is achieved in less than 5% of ...patients who undergo surgery, and median survival is only 6 months in those with inoperable lesions. A deeper understanding of PDAC biologic characteristics as well as novel prognostic markers are therefore required to improve outcomes. Herein we report that BAG3, a protein with recognized anti-apoptotic activity, was expressed in 346 PDACs analyzed, but was not expressed in the surrounding nonneoplastic tissue. In a cohort of 66 patients who underwent radical resection (R0), survival was significantly shorter in patients with high BAG3 expression (median, 12 months) than in those with low BAG3 expression (median, 23 months) ( P = 0.001). Furthermore, we report that BAG3 expression in PDAC-derived cell lines protects from apoptosis and confers resistance to gemcitabine, offering a partial explanation for the survival data. Our results indicate that BAG3 has a relevant role in PDAC biology, and suggest that BAG3 expression level might be a potential marker for prediction of patient outcome.
The upper gastrointestinal tract is home to some of most notorious cancers like esophagogastric and pancreatic cancer. Several factors contribute to the lethality of these tumors, but one that stands ...out for both tumor types is the strong inter- as well as intratumor heterogeneity. Unfortunately, genetic tumor models do not match this heterogeneity, and for esophageal cancer no adequate genetic models exist. To allow for an improved understanding of these diseases, tissue banks with sufficient amount of samples to cover the extent of diversity of human cancers are required. Additionally, xenograft models that faithfully mimic and span the breadth of human disease are essential to perform meaningful functional experiments.
We describe here the establishment of a tissue biobank, patient derived xenografts (PDXs) and cell line models of esophagogastric and pancreatic cancer patients. Biopsy material was grafted into immunocompromised mice and PDXs were used to establish primary cell cultures to perform functional studies. Expression of Hedgehog ligands in patient tumor and matching PDX was assessed by immunohistochemical staining, and quantitative real-time PCR as well as flow cytometry was used for cultured cells. Cocultures with Hedgehog reporter cells were performed to study paracrine signaling potency. Furthermore, SHH expression was modulated in primary cultures using lentiviral mediated knockdown.
We have established a panel of 29 PDXs from esophagogastric and pancreatic cancers, and demonstrate that these PDXs mirror several of the (immuno)histological and biochemical characteristics of the original tumors. Derived cell lines can be genetically manipulated and used to further study tumor biology and signaling capacity. In addition, we demonstrate an active (paracrine) Hedgehog signaling mode by both tumor types, the magnitude of which has not been compared directly in previous studies.
Our established PDXs and their matching primary cell lines retain important characteristics seen in the original tumors, and this should enable future studies to address the responses of these tumors to different treatment modalities, but also help in gaining mechanistic insight in how some tumors respond to certain regimens and others do not.
In 3–5 % of all cases of pancreatic ductal adenocarcinoma (PDAC), hereditary factors influence etiology. While surveillance of high-risk individuals may improve the prognosis, this study describes ...two very different outcomes in patients with screen-detected lesions. In 2000, a surveillance program of carriers of a
CDKN2A/p16
-
Leiden
-mutation consisting of annual MRI was initiated. Patients with a suspected pancreatic lesion undergo CT-scan and Endoscopic Ultrasound, and surgery is offered when a lesion is confirmed. In 2015, two patients with a screen-detected solid lesion were identified. In both patients, lesions were visible on MRI and CT scan, while the EUS was unremarkable. Surgical resection of the head of the pancreas resulted in nearly fatal complications in the first patient. This patient was shown to have a benign lesion. In contrast, timely identification of an early cancer in the second patient was accompanied by an uneventful postoperative course. These cases underline the risks inherent to a PDAC prevention program. All patients should be fully informed about the possible outcomes before joining a surveillance program.
After the Volendam fire, a multidisciplinary, integral evaluation, called the Medical Evaluation of the Disaster in Volendam (MERV), was established. This article is a discussion of disaster research ...methodology. It describes the organizational framework of this project and the methodological problems.
A scientific steering group consisting of members from three hospitals prepared and guided the project. A research team wrote the final study protocol and performed the study. The project was funded by the Ministry of Health. The study protocol had a modular design in which each of the modules focused on one specific area or location. The main questions for each location were: (1) which treatment protocols were used; (2) what was the condition of the patient; and (3) was medical care provided according to existing protocols. After the fire, 241 victims were treated in hospitals; they all were included in the study. Most of the victims had burn injuries, and approximately one-third suffered from inhalation injury. All hospitals and ambulance services involved were visited in order to collect data, and interviewers obtained additional information. The government helped obtain permission for data-collection in three of the hospitals. Over 1,200 items of information about each patient and > 200,000 total items were collected. During data processing, the data were re-organized, categorized, and presented in a uniform and consistent style. A cross-sectional site analysis and a longitudinal patient analysis were conducted. This was facilitated by the use of several sub-databases. The modular approach made it possible to obtain a complete overview of the medical care provided. The project team was guided by a multidisciplinary steering group and the research was performed by a research team. This enabled the research team to focus on the scientific aspects.
The evaluation of the Volendam fire indicates that a project approach with a modular design is effective for the analysis of complex incidents. The use of several sub-databases makes it easy to combine findings and conduct cross-sectional and longitudinal analyses. The government played an important role in the funding and support of the project. To limit and structure data collection and analysis, a pilot study based on several predefined main questions should be conducted. The questions then can be specified further based on the availability of data.
To establish the level of medical care provided in the emergency department of general hospitals to the victims of the Volendam café fire on 1 January 2001.
A retrospective review was done based on a ...standardized chart, for all victims seen at the emergency departments of 19 hospitals. Diagnostic findings and logistic aspects were inventoried. Treatment described in the Emergency Management of Severe Burns protocol was used as a gold standard against which the care provided to the victims was assessed.
Data from 233 patients were included in the analysis. The documentation rate was low. Suspected inhalation injury and burns were the most frequently documented diagnoses. Most patients with suspected inhalation injury, for whom treatment records were available, received oxygen therapy (81%). Intubation was performed in 43% of patients with suspected inhalation injury and 14% of the remaining patients required intubation after admission to the intensive care unit. Most patients with circulatory problems (83%) and/or more than 15% of total body surface area burned (97%), for whom treatment records were available, received intravenous lines. Pain treatment seemed to have had low priority. Two patients (3%) were re-admitted after having been released earlier from the emergency department.
Treatment and triage of the burn casualties after the Volendam café fire was adequate. The documentation rate was low. Not all steps in diagnosis and treatment may be of equal importance in disaster circumstances.
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