External validation of a lung cancer-based prediction model for two-year mortality in esophageal cancer patient cohorts.

PURPOSE/OBJECTIVE: Chemo-radiotherapy can improve the oncological outcome of esophageal cancer (EC) patients, but may cause long term radiation-induced toxicity, including an increased risk of non-cancer related death. For lung cancer patients, a model to predict 2-year total mortality using mean heart dose (MHD) and gross tumor volume (GTV) has previously been developed and validated. This project aimed to externally validate this model in EC patients. METHODS: Five EC patient cohorts from 3 different Dutch centres were used for model validation. External validity of the model was assessed separately in definitive (n = 170) and neo-adjuvant (n = 568) chemoradiotherapy (dCRT and nCRT) patients. External validity was assessed in terms of calibration by calibration plots, calibration-in-the-large (CITL) and calibration slope (CS), and discrimination by assessment of the c-statistic. If suboptimal model performance was observed, the model was further updated accordingly. RESULTS: For the dCRT patients, good calibration was found after adjustment of the intercept (CITL 0.00; CS 1.08). The c-statistic of the adjusted model was 0.67 (95%CI: 0.58 to 0.75). For nCRT patients the model needed adjustment of both the slope and the intercept because of initial miscalibration in the validation population (CITL 0.00; CS 1.72). After recalibration, the model showed perfect calibration (i.e., CITL 0, CS 1), as is common after recalibration. The c-statistic of the recalibrated model equaled 0.62 (95%CI: 0.57 to 0.67). CONCLUSION: The existing model for 2-year mortality prediction in lung cancer patients, based on the predictive factors MHD and GTV, showed good performance in EC patients after updating the intercept and/or slope of the original model.

Ultrasound-guided percutaneous cryoneurolysis for management of acute sternal fracture pain.

Background: Establishing adequate analgesia for rib and sternal fractures remains a challenge due to the prolonged nature of the associated pain. Historically, cryoneurolysis has demonstrated beneficial in treating chronic pain, and the recent development of hand-held devices has allowed its functionality to expand into the management of acute pain. Case: We present a polytrauma patient with sternal and multiple rib fractures that underwent ultrasound-guided intercostal cryoneurolysis at bedside, resulting in significant analgesia lasting several weeks and improving mobilization. This is the first report of the utilization of cryoneurolysis to treat acute sternal fracture pain. Conclusion: The most common sternal fracture pattern is transverse which only requires treatment of four intercostal nerves, making cryoneurolysis feasible in trauma centers. This portable, minimally invasive, and low risk technique has the added benefits of reducing opioid requirements, decreasing length of hospital stay, and improving mobility in polytrauma patients.

Priorities and preferences of advanced soft tissue sarcoma patients starting palliative chemotherapy: baseline results from the HOLISTIC study.

INTRODUCTION: Palliative chemotherapy is the principal treatment of patients with advanced soft tissue sarcomas (STS); however prognosis is limited (median overall survival 12-19 months). In this setting, patient values and priorities are central to personalised treatment decisions. PATIENTS AND METHODS: The prospective HOLISTIC study was conducted in the UK and the Netherlands assessing health-related quality of life in STS patients receiving palliative chemotherapy. Participants completed a questionnaire before starting chemotherapy, including attitudes towards quality of life (QoL) versus length of life (LoL), decisional control preferences, and decisional conflict. Chi-square and Fisher's exact tests were used to evaluate associations between patient characteristics and preferences. RESULTS: One hundred and thirty-seven patients with advanced STS participated (UK: n = 72, the Netherlands: n = 65). Median age was 62 (27-79) years. Preference for extended LoL (n = 66, 48%) was slightly more common than preference for QoL (n = 56, 41%); 12 patients (9%) valued LoL and QoL equally (missing: n = 3). Younger patients (age <40 years) prioritised LoL, whereas two-thirds of older patients (aged ≥65 years) felt that QoL was equally or more important than LoL (P = 0.020). Decisional conflict was most common in patients who prioritised QoL (P = 0.024). Most patients preferred an active (n = 45, 33%) or collaborative (n = 59, 44%) role in treatment decisions. Gender, performance status, and country were significantly associated with preferred role. Concordance between preferred and actual role in chemotherapy decision was high (n = 104, 76%). CONCLUSIONS: Heterogeneous priorities and preferences among advanced STS patients support personalised decisions about palliative treatment. Considering individual differences during treatment discussions may enhance communication and optimise patient-centred care.

Colorectal anastomotic leak: transcriptomic profile analysis.

BACKGROUND: Anastomotic leakage in patients undergoing colorectal surgery is associated with morbidity and mortality. Although multiple risk factors have been identified, the underlying mechanisms are mainly unknown. The aim of this study was to perform a transcriptome analysis of genes underlying the development of anastomotic leakage. METHODS: A set of human samples from the anastomotic site collected during stapled colorectal anastomosis were used in the study. Transcriptomic profiles were generated for patients who developing anastomotic leakage and case-matched controls with normal anastomotic healing to identify genes and biological processes associated with the development of anastomotic leakage. RESULTS: The analysis included 22 patients with and 69 without anastomotic leakage. Differential expression analysis showed that 44 genes had adjusted P < 0.050, consisting of two upregulated and 42 downregulated genes. Co-functionality analysis of the 150 most upregulated and 150 most downregulated genes using the GenetICA framework showed formation of clusters of genes with different enrichment for biological pathways. The enriched pathways for the downregulated genes are involved in immune response, angiogenesis, protein metabolism, and collagen cross-linking. The enriched pathways for upregulated genes are involved in cell division. CONCLUSION: These data indicate that patients who develop anastomotic leakage start the healing process with an error at the level of gene regulation at the time of surgery. Despite normal macroscopic appearance during surgery, the transcriptome data identified several differences in gene expression between patients who developed anastomotic leakage and those who did not. The expressed genes and enriched processes are involved in the different stages of wound healing. These provide therapeutic and diagnostic targets for patients at risk of anastomotic leakage.

[Taste and smell changes resulting from cancer therapies]. / Smaak- en reukverandering na oncologische behandeling.

Cancer therapies often cause changes in taste and smell. In this article, three patients treated with immunotherapy, chemotherapy and targeted therapy who experience changes in taste or smell are presented. These patients report lower quality of life and altered eating habits due to these changes. The prevalence and type of taste and smell changes is diverse among different cancer treatments and individual patients. In clinical practice, diagnosis is supported by questionnaires, taste strips or smell sticks. It is important to acknowledge the changes in taste and smell and inform the patient about these changes. More tools become available to provide patients with personalized advise to adjust their meals to their new sense of taste and smell at home. Furthermore, hospital cooks are implementing new strategies to adjust meals to taste and smell alterations and individual preferences. Smell training is an option for patients with severe smell disorders.

Management and outcome of colorectal cancer during pregnancy: report of 41 cases.

BACKGROUND: Colorectal cancer in pregnancy is rare, with an incidence of 0.8 per 100,000 pregnancies. Advanced disease (stage III or IV) is diagnosed more frequently in pregnant patients. We aimed to review all cases of colorectal cancer in pregnancy from the International Network on Cancer, Infertility and Pregnancy database in order to learn more about this rare disease and improve its management. METHODS: Data on the demographic features, symptoms, histopathology, diagnostic and therapeutic interventions and outcomes (obstetric, neonatal and maternal) were analysed. RESULTS: Twenty-seven colon and 14 rectal cancer cases were identified. Advanced disease was present in 30 patients (73.2%). During pregnancy, 21 patients (51.2%) received surgery and 12 patients (29.3%) received chemotherapy. Thirty-three patients (80.5%) delivered live babies: 21 by caesarean section and 12 vaginally. Prematurity rate was high (78.8%). Eight babies were small for gestational age (27.6%). Three patients (10.7%) developed recurrence of disease. Overall 2-year survival was 64.4%. CONCLUSION: Despite a more frequent presentation with advanced disease, colorectal cancer has a similar prognosis in pregnancy when compared with the general population. Diagnostic interventions and treatment should not be delayed due to the pregnancy but a balance between maternal and foetal wellbeing must always be kept in mind.

[Organ donation after circulatory death]. / Organspende nach Herz- und Kreislauftod.

Approximately 17 million inhabitants live in the Netherlands. The number of potential organ donors in 1999 was the lowest in Europe with only 10 donors per million inhabitants. Medical associations, public health services, health insurance companies and the government had to find common solutions in order to improve organ allocation, logistics of donations and to increase the number of transplantations. After a prolonged debate on medical ethical issues of organ transplantation, all participants were able to agree on socio-medico-legal regulations for organ donation and transplantation. In addition to improving the procedure for organ donation after brain death (DBD) the most important step was the introduction of organ donation after circulatory death (DCD). Measures such as the introduction of a national organ donor database, improved information to the public, further education on intensive care units (ICU), guidelines for end of life care on the ICU, establishment of transplantation coordinators on site, introduction of autonomous explantation teams and strict procedures on the course of organ donations, answered many practical issues about logistics and responsibilities for DBD and DCD. In 2014 the number of postmortem organ donations rose to 16.4 per million inhabitants. Meanwhile, up to 60 % of organ donations in the Netherlands originate from a DCD procedure compared to approximately 10 % in the USA. This overview article discusses the developments and processes of deceased donation in the Netherlands after 15 years of experience with DCD.

Difficulties with diagnosis of malignancies in pregnancy.

Diagnosis and staging of cancer during pregnancy may be difficult due to overlap in physical signs, uncertainties on safety and accuracy of diagnostic tests and histopathology in pregnant women. Tumour markers should be used with caution due to pregnancy-induced elevation. Ionizing imaging and staging techniques such as computed tomography (CT) or positron emission tomography (PET) scans and sentinel node procedures are safe during pregnancy when fetal radiation threshold of 100 mGy is maintained. Ionizing imaging techniques can increasingly be avoided with the technical devolvement of non-ionizing techniques such as magnetic resonance imaging (MRI), including whole body MRI and diffusion-weighted imaging, which hold potentially great opportunities for the diagnostic management of pregnant cancer patients. Pathological evaluation and establishing a diagnosis of malignancy can be difficult in pregnant women, and a note to the pathologist of the pregnant status is essential for accurate diagnosis. This chapter will give an overview of possibilities and difficulties in diagnosing pregnant women with cancer.

Management of ovarian cysts and cancer in pregnancy.

Adnexal masses during pregnancy are not uncommon. Ovarian cysts or masses during pregnancy should be accurately evaluated to identify the patients who need surgical interventions from those where a 'wait-and-see' strategy can be followed. Ultrasound and MRI are safe diagnostic tools to distinguish between benign and malignant lesions. Treatment options (surgical procedures) should be discussed for each patient individually. Both open surgery and laparoscopy can be performed considering the tumour diameter, gestational age and surgical expertise. A multidisciplinary approach is necessary in case of high suspicion of malignancy and preferably patients should be referred to centres with specialized experience.

Late-intervention study with ebselen in an experimental model of type 1 diabetic nephropathy.

BACKGROUND AND AIM: Previous studies have shown that preventive treatment with the antioxidant, ebselen, in experimental models of type 1 diabetic nephropathy resulted in an attenuation of structural and functional damage in the kidney. However, evidence for the effectiveness of ebselen in late-intervention studies is lacking. Thus, we aimed to investigate the effects of ebselen in attenuating established renal injury in type 1 diabetic nephropathy using the Akita mouse model. METHODS: Baseline blood glucose and albumin-to-creatinine ratio (ACR) were measured in wild-type (WT) and heterozygous Akita mice at 9 weeks of age. At 10 weeks of age, WT and Akita mice were randomized to receive either vehicle (5% carboxymethyl cellulose) or ebselen by oral gavage at 10mg/kg twice daily. Kidney and urine were collected after 16 weeks of treatment with ebselen for histological and functional analyses. RESULTS: At 9 weeks of age, Akita mice displayed well-established renal dysfunction with significant increases in ACR and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels when compared with WT controls. After 16 weeks of treatment with ebselen, oxidative stress, as measured by nitrotyrosine immunostaining and urinary 8-OHdG levels, was significantly reduced in the Akita mice. Furthermore, gene expression of the major reactive oxygen species-producing nicotinamide adenine dinucleotide phosphate enzyme, Nox4, was also reduced by ebselen. However, ebselen had no effect on ACR and glomerulosclerosis. CONCLUSION: Chronic treatment with ebselen significantly reduced oxidative stress in the Akita mice. However, ebselen failed to attenuate functional or structural kidney damage in this late-intervention study using the Akita mouse model.

Danger signals in the initiation of the inflammatory response after myocardial infarction.

During myocardial infarction, sterile inflammation occurs. The danger model is a solid theoretic framework that explains this inflammation as danger associated molecular patterns activate the immune system. The innate immune system can sense danger signals through different pathogen recognition receptors (PRR) such as toll-like receptors, nod-like receptors and receptors for advanced glycation endproducts. Activation of a PRR results in the production of cytokines and the recruitment of leukocytes to the site of injury. Due to tissue damage and necrosis of cardiac cells, danger signals such as extracellular matrix (ECM) breakdown products, mitochondrial DNA, heat shock proteins and high mobility box 1 are released. Matricellular proteins are non-structural proteins expressed in the ECM and are upregulated upon injury. Some members of the matricellular protein family (like tenascin-C, osteopontin, CCN1 and the galectins) have been implicated in the inflammatory and reparative responses following myocardial infarction and may function as danger signals. In a clinical setting, danger signals can function as prognostic and/or diagnostic biomarkers and for drug targeting. In this review we will provide an overview of the established knowledge on the role of danger signals in myocardial infarction and we will discuss areas of interest for future research.

Stability of the elbow joint: relevant anatomy and clinical implications of in vitro biomechanical studies.

The aim of this literature review is to describe the clinical anatomy of the elbow joint based on information from in vitro biomechanical studies. The clinical consequences of this literature review are described and recommendations are given for the treatment of elbow joint dislocation.The PubMed and EMBASE electronic databases and the Cochrane Central Register of Controlled Trials were searched. Studies were eligible for inclusion if they included observations of the anatomy and biomechanics of the elbow joint in human anatomic specimens.Numerous studies of the kinematics, kinesiology and anatomy of the elbow joint in human anatomic specimens yielded important and interesting implications for trauma and orthopaedic surgeons.

Simple elbow dislocations: a systematic review of the literature.

OBJECTIVE: To identify if functional treatment is the best available treatment for simple elbow dislocations. SEARCH STRATEGY: Electronic databases MEDLINE, EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials. SELECTION CRITERIA: Studies were eligible for inclusion if they were trials comparing different techniques for the treatment of simple elbow dislocations. DATA ANALYSIS: Results were expressed as relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes with 95% confidence intervals. MAIN RESULTS: This review has included data from two trials and three observational comparative studies. Important data were missing from three observational comparative studies and the results from these studies were extracted for this review. No difference was found between surgical treatment of the collateral ligaments and plaster immobilisation of the elbow joint. Better range of movement, less pain, better functional scores, shorter disability and shorter treatment time were seen after functional treatment versus plaster immobilisation.

Reactivation of ancient joint tuberculosis of the knee following total knee arthroplasty after 61 years: a case report.

The prevalence of pulmonary tuberculosis is increasing and is associated with a rise in skeletal tuberculosis. Even after appropriate anti-tuberculosis therapy, reactivation of the infection may occur, even after many years. In this case report we describe a patient who had a reactivation of tuberculosis in the knee after total knee arthroplasty. At the age of 14 years, the patient had isolated tuberculosis arthritis of the left knee. Reactivation occurred after total knee arthroplasty 61 years later, at the age of 75. The patient was treated with a combined therapy; first the joint was irrigated with povidine-iodine and saline solution, and gentamicin beads were left behind. When the cultures revealed Mycobacterium tuberculosis, drug therapy of isoniazid, rifampicin, ethambutol and pyrazinamide was started and was continued for 9 months postoperatively. At a recent follow-up, the patient is doing well, with good range of motion in the knee.

Interpretation of ANOVA models for microarray data using PCA.

MOTIVATION: ANOVA is a technique, which is frequently used in the analysis of microarray data, e.g. to assess the significance of treatment effects, and to select interesting genes based on P-values. However, it does not give information about what exactly is causing the effect. Our purpose is to improve the interpretation of the results from ANOVA on large microarray datasets, by applying PCA on the individual variance components. Interaction effects can be visualized by biplots, showing genes and variables in one plot, providing insight in the effect of e.g. treatment or time on gene expression. Because ANOVA has removed uninteresting sources of variance, the results are much more interpretable than without ANOVA. Moreover, the combination of ANOVA and PCA provides a simple way to select genes, based on the interactions of interest. RESULTS: It is shown that the components from an ANOVA model can be summarized and visualized with PCA, which improves the interpretability of the models. The method is applied to a real time-course gene expression dataset of mesenchymal stem cells. The dataset was designed to investigate the effect of different treatments on osteogenesis. The biplots generated with the algorithm give specific information about the effects of specific treatments on genes over time. These results are in agreement with the literature. The biological validation with GO annotation from the genes present in the selections shows that biologically relevant groups of genes are selected. AVAILABILITY: R code with the implementation of the method for this dataset is available from http://www.cac.science.ru.nl under the heading "Software".

Time-dependent hierarchical regulation analysis: deciphering cellular adaptation.

Cells adapt to changes in their environment by the concerted action of many different regulatory mechanisms. Examples of such mechanisms are feedback inhibition by intermediates of metabolism, covalent modification of enzymes and changes in the abundance of mRNAs and proteins. These mechanisms act in parallel at different levels in the cellular hierarchy while regulating a single process. Existing hierarchical regulation analysis determines the relative importance of these mechanisms when the cell regulates a transition from one steady-state to another. Here, the analysis is extended to the regulation of time-dependent phenomena, for which two methods are introduced and illustrated with a kinetic model incorporating transcription and translation of metabolic enzymes.