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Background Skeletal muscle mass (SMM) loss is common in metastatic colorectal cancer (mCRC) patients and associated with poor clinical outcomes, including increased treatment‐related toxicities and reduced survival. Muscle loss may contribute to reduced health‐related quality of life (HRQoL), including fatigue. Our aim was to study associations between changes in SMM and concomitant changes in patient‐reported HRQoL. Methods This was a secondary analysis of mCRC patients in the CAIRO3 randomized clinical trial who were—after initial treatment—randomized between maintenance treatment with capecitabine plus bevacizumab (CAP‐B) and observation until first disease progression (PD1). Included patients had computed tomography images for SMM quantification, together with HRQoL assessments available at randomization and PD1. Changes in SMM (categorized as >2% loss, stable, and >2% gain) and HRQoL were computed between randomization and PD1. Changes in HRQoL score >10 points were considered clinically relevant. Associations between SMM and HRQoL changes were studied by multiple linear regression models. We also investigated whether associations differed by treatment arm for global health and the 13 other HRQoL subscales. Results Of 221 patients included (mean age 63.5 ± 8.4 years), 24% lost, 27% remained stable, and 49% gained SMM. At randomization, mean global health status was 73.5 ± 15.9 in the CAP‐B arm and 75.1 ± 17.5 in the observation arm (P = 0.48). A stable or gain in SMM was significantly associated with a clinically relevant improvement in global health status (9.9 and 14.7 points, respectively), compared with patients who lost SMM. From the subscales that did not show significant differences between the two treatment arms, we found significant and clinically relevant associations for stable or gain in SMM with improved role functioning (12.0 and 17.9, respectively) and with less fatigue (−10.0 and −15.0, respectively) and pain (−16.3 for SMM gain). From the subscales that did show significantly different associations with SMM between the two treatment arms, we only found significant results in the observation arm. Here, associations were found for stable or gain in SMM with clinically relevant improved physical (12.4 for SMM gain), cognitive (10.7 and 9.7, respectively), and social functioning (15.5 and 15.6, respectively) as well as reduced appetite loss (−28.5 and −30.7, respectively). Conclusions In mCRC, SMM preservation during CAP‐B and observation treatment is associated with significant and clinically relevant improvements in global health status and multiple functional and symptom scales. Studies are warranted to investigate whether interventions targeting SMM lead to improved HRQoL, fewer symptoms, and better functioning.

Aims People with psychotic disorders receive mental healthcare services mainly for their psychiatric care needs. However, patients often experience multiple physical or social wellbeing-related care needs as well. This study aims to identify care needs, investigate their changes over time and examine their association with mental healthcare consumption and evidence-based pharmacotherapy. Methods This study combined annually obtained routine outcome monitoring (ROM) data with care consumption data of people with a long-term psychotic illness receiving treatment in four Dutch mental healthcare institutes between 2012 and 2016. Existing treatment algorithms were used to determine psychiatric, physical and social wellbeing-related care needs based on self-report questionnaires, semi-structured interviews and physical parameters. Care consumption was measured in hours of outpatient mental healthcare consumption per year. Generalised estimating equation models were used to calculate odds ratios of care needs and their associations with time, mental healthcare consumption and medication use. Results Participants (n = 2054) had on average 7.4 care needs per measurement and received 25.4 h of care per year. Physical care needs are most prevalent and persistent and people with more care needs receive more mental healthcare. Care needs for psychotic symptoms and most social wellbeing-related care needs decreased, whereas the chance of being overweight significantly increased with subsequent years of care. Several positive associations were found between care needs and mental healthcare consumption as well as positive relations between care needs and evidence-based pharmacotherapy. Conclusions This longitudinal study present a novel approach in identifying care needs and their association with mental healthcare consumption and pharmacotherapy. Identification of care needs in this way based on ROM can assist daily clinical practice. A recovery-oriented view and a well-coordinated collaboration between clinicians and general practitioners together with shared decisions about which care needs to treat, can improve treatment delivery. Special attention is required for improving physical health in psychosis care which, despite appropriate pharmacotherapy and increasing care consumption, remains troublesome.

A novel wearable sensor device is proposed to ease the participation of farmers in data acquisition and labelling. This wearable device complies with artificial neural network approaches and can be used to develop supervised learning models based on the farmer’s cultural practices. This paper focuses on system design and development using open-source software and hardware. During field testing, the system GNSS-based location estimates showed an average error of 0.7±0.45 m and three fisheye cameras enable the system to image its surroundings at a maximum resolution of 2,592 by 1,939 pixels. Combined with the ability of the system to take user input, the experimental results demonstrate that it is a suitable tool for simultaneous data collection and labelling.

Background. In this study, we aimed to retrieve and operationalize the building blocks of the working alliance in multidisciplinary teams with shared caseloads, for use in daily practice and research to support (Flexible) Assertive Community Treatment teams.Methods. After reviewing literature, concept mapping with professionals and clients was used to define working alliance in (F)ACT. The resulting concept maps formed the basis for the instrument. The instrument was pilot tested with professionals and clients by means of cognitive interviews with a think-aloud procedure.Results. The study led to development of a twenty-five item instrument to assess Working Alliance in Multidisciplinary teams (WAM), comprised of three subscales: bond, task/goal and team, with a version for clients and professionals.Conclusions. The WAM was developed to determine the quality of the working alliance in ACT teams. Future research will focus on testing its psychometric properties and predictive value.

Key Points Question How useful is the neonatal Sequential Organ Failure Assessment for identification of preterm infants at high risk for late-onset, infection-associated mortality? Findings In this multicenter cohort study of 653 preterm infants with late-onset infection, the neonatal Sequential Organ Failure Assessment score was associated with infection-attributable mortality. Analyses stratified by sex or Gram stain of pathogen class or restricted to less than 25 weeks’ completed gestation did not reduce the association of the neonatal Sequential Organ Failure Assessment score with infection-related mortality. Meaning In a large, multicenter cohort, the single-center–validated neonatal Sequential Organ Failure Assessment score was associated with mortality risk with late-onset infection in preterm infants, implying generalizability., Importance Infection in neonates remains a substantial problem. Advances for this population are hindered by the absence of a consensus definition for sepsis. In adults, the Sequential Organ Failure Assessment (SOFA) operationalizes mortality risk with infection and defines sepsis. The generalizability of the neonatal SOFA (nSOFA) for neonatal late-onset infection-related mortality remains unknown. Objective To determine the generalizability of the nSOFA for neonatal late-onset infection-related mortality across multiple sites. Design, Setting, and Participants A multicenter retrospective cohort study was conducted at 7 academic neonatal intensive care units between January 1, 2010, and December 31, 2019. Participants included 653 preterm (72 hours of life) infection including bacteremia, fungemia, or surgical peritonitis. Main Outcomes and Measures The primary outcome was late-onset infection episode mortality. The nSOFA scores from survivors and nonsurvivors with confirmed late-onset infection were compared at 9 time points (T) preceding and following event onset. Results In the 653 infants who met inclusion criteria, median gestational age was 25.5 weeks (interquartile range, 24-27 weeks) and median birth weight was 780 g (interquartile range, 638-960 g). A total of 366 infants (56%) were male. Late-onset infection episode mortality occurred in 97 infants (15%). Area under the receiver operating characteristic curves for mortality in the total cohort ranged across study centers from 0.71 to 0.95 (T0 hours), 0.77 to 0.96 (T6 hours), and 0.78 to 0.96 (T12 hours), with utility noted at all centers and in aggregate. Using the maximum nSOFA score at T0 or T6, the area under the receiver operating characteristic curve for mortality was 0.88 (95% CI, 0.84-0.91). Analyses stratified by sex or Gram-stain identification of pathogen class or restricted to infants born at less than 25 weeks’ completed gestation did not reduce the association of the nSOFA score with infection-related mortality. Conclusions and Relevance The nSOFA score was associated with late-onset infection mortality in preterm infants at the time of evaluation both in aggregate and in each center. These findings suggest that the nSOFA may serve as the foundation for a consensus definition of sepsis in this population., This cohort study assesses the generalizability of the neonatal Sequential Organ Failure Assessment metric for defining sepsis in neonates and estimating risk of infection-related mortality.

A status overview of 4MOST is presented, a new high-multiplex, wide-field spectroscopic survey facility under construction for ESO's VISTA telescope at Paranal. Its key specifications are: a large field of view of 4.4 deg2 and a high multiplex capability, with 1624 fibres feeding two low-resolution spectrographs (R = λ/Δλ ~ 6500), and 812 fibres transferring light to the high-resolution spectrograph (R ~ 20 000). The 4MOST system integration has commenced and the selection process for ESO community survey programmes has been started. This overview presents the expected performance of the instrument, the science the consortium expects to carry out, and the unique operational scheme of 4MOST.

The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential.

Introduction Pulmonary vein isolation (PVI) has become a cornerstone of the treatment of atrial fibrillation (AF). Several technologies have been developed to improve procedural and long-term outcomes. Depending on type of AF and rhythm recording used, 1-year freedom of AF varies between 55–82%. However, severe complications are reported in 1–3%. Purpose To describe procedural complications of PVI with either single tip radiofrequency ablation (STRF), multi electrode phased RF ablation (PVAC) or cryoballoon (CB). Methods Data was extracted from the Netherlands Heart Registry in which 14 Dutch heart centres participate. Procedural complications in patients treated with the 3 different ablation modalities (STRF, PVAC and CB ablation) were compared. Complications included: pericardial tamponade, persistent phrenic nerve palsy (PNP) beyond 24hrs, thromboembolic events, vascular- and bleeding complications. Patient characteristics: gender, age, BMI, CHA2DS2 -VASc, type of AF and previous left atrium ablation were assessed in a univariate and multivariate regression model. Results In total, 12,430 patients were included (STRF n=5,106, PVAC n=2,341, CB n=4,983) between January 2013 and December 2017, of whom, 69% were male, 74% had a history of paroxysmal AF, 24% persistent AF and 2% longstanding persistent AF. The incidence of complications within 30 days was 3.6%. Pericardial tamponade requiring intervention, occurred more frequently in the STRF group (STRF: 0.8% vs PVAC 0.3% vs CB 0.3% p= Univariate analysis Conclusion PVI was associated with a complication rate of 3.6%. Compared to PVAC and CB ablation, patients treated with STRF ablation more often developed a pericardial tamponade and vascular- and bleeding complications. PNP occurred most frequent in patients undergoing CB ablation. Female gender and CHA2DS2-VASc were independent predictors for pericardial tamponade, vascular- and bleeding complications.

Objectives To compare the performance of dual immunostaining of p16INK4a and Ki-67 proteins performed on self-collected vaginal specimens and clinician-collected cervical specimens, and to evaluate the performance of this technique in predicting high-grade disease. Methods Women aged 30–59 years (n = 1005) were recruited at two well-women clinics in Papua New Guinea. Each woman provided both cervical and vaginal specimens that were tested for high-risk human papillomavirus (hrHPV) DNA using the Xpert HPV Test (Cepheid) at point of care. A subset of paired cervical and vaginal specimens (n = 243) were selected to undergo CINTec® PLUS (Roche) p16/Ki-67 dual-stain cytology and liquid-based cytology (LBC). Results Fifty-five pairs (22%) were excluded from further analysis because the smears were not assessable. Of the 189 remaining paired specimens, 74 pairs (39.1%) were positive for one or more hrHPV genotypes. When comparing results of the dual stain, the overall percent agreement, positive and negative percent agreements and κ value between the cervical and vaginal specimens were 87.8% (CI 82.3–92.1%), 64.6% (CI 49.5–77.8%), 95.7% (CI 91.0–98.0%) and 0.65 (CI 0.51–0.79%) respectively. The sensitivity of the dual stain performed on the cervical specimen to predict high-grade disease, determined by LBC, was superior to that of the dual stain performed on the vaginal specimen: 100% (CI 84.6–100%) versus 68.2% (CI 45.1–86.1%). Conclusion Although further evaluation may be warranted, these findings indicate that dual-stain testing of vaginal specimens cannot be advocated as part of cervical screening programmes in low- and middle-income countries. However, dual-stain cytology performed on cervical specimens may have a role in quality assurance in such settings.

Background:Previous analysis of the REWARD study reported that patients with limited joint involvement have a considerable burden of disease1. Recent data suggest that patients with moderately active psoriatic arthritis (PsA) and a limited joint involvement have a high likelihood of achieving treatment goals when treated with apremilast2. According to EULAR recommendations a PDE4 inhibitor may be considered in patients with mild disease and an inadequate response to at least one csDMARD, in whom neither a bDMARD nor a JAK inhibitor is appropriate and the value of apremilast may be found in treating patients with relatively mild disease (oligoarticular)3.Objectives:The objective of this prospective, multicentre, non-interventional study is to describe patient reported outcomes, effectiveness and real-life use of apremilast in patients with PsA. Patients will be followed up for a maximum of 12 months. This interim analysis compared the baseline characteristics and experience on apremilast for two subgroups of patients, those remaining on apremilast versus the ones that discontinued.Methods:In this interim analysis we included patients with data available at cut-off date of 03 November 2020. Patient enrollment and follow up of current subjects is ongoing. Descriptive statistics (n’s and percents for categorical data, means for continuous data) were used to summarize the baseline data by subgroup. Kaplan Meier plots are presented to show patients’ experience on apremilast by subgroup.Results:85 patients were included in the analysis. 30 patients have completed the study, 39 patients have discontinued and 16 are ongoing. At baseline 22 (26%) patients were biologic experienced and 62 (74%) were biologic naïve. Both groups had a comparable disease activity measured with clinical disease activity in psoriatic arthritis (cDAPSA) scores. Biologic experienced patients had a longer disease duration compared to biologic naïve patients (mean 9.7 vs 6.2 years). Inefficacy of previous medication was the main reason for starting apremilast in both subgroups. Overall, 86% (n=69) of patients were still receiving apremilast at month 3, 60% (n=46) at month 6, and 41% (n=26) at month 12 (Figure 1). Drug survival (length of time until discontinuation of apremilast) for biologic naïve patients was 93% at month 3, 73% at month 6 and 58% at month 12. Drug survival of biologic experienced patients was 67%, 20%, and 0% at months 3, 6, and 12, respectively. At baseline mean values of body mass index (BMI), swollen joint count (SJC), tender joint count (TJC), psoriatic arthritis impact of disease (PsAID) were comparable between both groups (Table 1). Reasons for discontinuation were mainly lack of efficacy (49%) and adverse events (44%). In this analysis the nature and frequency of adverse events is in line with the known profile of apremilast.Conclusion:In this interim analysis, patients who were biologic naïve had a better probability to remain on treatment than those who were biologic experienced. Baseline characteristics were similar between the two groups, apart from disease duration that was longer in the biologic experienced group. Best drug survival is achieved when apremilast is prescribed earlier in the PsA treatment course, before biologics and after csDMARDs, as per apremilast EU label.References:[1]Jansen TL, et al. Ann Rheum Dis. 2019;78:913 [abstract FRI0442][2]Mease PJ, et al. Arthritis Care Res 2020 72 6 814–821[3]Gossec L, et al. Ann Rheum Dis 2020;79:700–712Disclosure of Interests:Reinhard Bos Consultant of: AbbVie BV, Genzyme Europe, Janssen-Cilag, Novartis, Pfizer, Grant/research support from: Galapagos, Tim Jansen Consultant of: AbbVie, Celgene Corporation – consultant, Speakers bureau: Grunenthal, Sobi – speakers bureau, Grant/research support from: ReumaNederland, Olatec, Grunenthal – grant/research support, Sylvia de Jong Shareholder of: Employee of Amgen Inc, Employee of: Employee of Amgen Inc, Antonio Castiglia Shareholder of: Employee of Amgen Inc, Employee of: Employee of Amgen Inc, Marijn Vis Consultant of: AbbVie, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Grant/research support from: Novartis, Pfizer, AbbVie, Celgene Corporation, Eli Lilly, Novartis, Pfizer.

BACKGROUND: Optimum cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is essential for the curative treatment of peritoneal carcinomatosis of colorectal origin. At present, surgeons depend on visual inspection and palpation for tumour detection. Improved detection of tumour tissue using molecular fluorescence-guided surgery could not only help attain a complete cytoreduction of metastatic lesions, but might also prevent overtreatment by avoiding resection of benign lesions.METHODS: For this non-randomised, single-centre feasibility study, we enrolled patients with colorectal peritoneal metastases scheduled for cytoreductive surgery and HIPEC. 2 days before surgery, 4·5 mg of the near-infrared fluorescent tracer bevacizumab-IRDye800CW was administered intravenously. The primary objectives were to determine the safety and feasibility of molecular fluorescence-guided surgery using bevacizumab-IRDye800CW. Molecular fluorescence-guided surgery was deemed safe if no allergic or anaphylactic reactions were recorded and no serious adverse events were attributed to bevacizumab-IRDye800CW. The technique was deemed feasible if bevacizumab-IRDye800CW enabled detection of fluorescence signals intraoperatively. Secondary objectives were correlation of fluorescence with histopathology by back-table imaging of the fresh surgical specimen and semi-quantitative ex-vivo analyses of formalin-fixed paraffin embedded (FFPE) tissue on all peritoneal lesions. Additionally, VEGF-α staining and fluorescence microscopy was done. This study is registered with the Netherlands Trial Registry, number NTR4632.FINDINGS: Between July 3, 2014, and March 2, 2015, seven patients were enrolled in the study. One patient developed an abdominal sepsis 5 days postoperatively and another died from an asystole 4 days postoperatively, most probably due to a cardiovascular thromboembolic event. However, both serious adverse events were attributed to the surgical cytoreductive surgery and HIPEC procedure. No serious adverse events related to bevacizumab-IRDye800CW occurred in any of the patients. Intraoperatively, fluorescence was seen in all patients. In two patients, additional tumour tissue was detected by molecular fluorescence-guided surgery that was initially missed by the surgeons. During back-table imaging of fresh surgical specimens, a total of 80 areas were imaged, marked, and analysed. All of the 29 non-fluorescent areas were found to contain only benign tissue, whereas tumour tissue was detected in 27 of 51 fluorescent areas (53%). Ex-vivo semi-quantification of 79 FFPE peritoneal lesions showed a tumour-to-normal ratio of 6·92 (SD 2·47).INTERPRETATION: Molecular fluorescence-guided surgery using the near-infrared fluorescent tracer bevacizumab-IRDye800CW is safe and feasible. This technique might be of added value for the treatment of patients with colorectal peritoneal metastases through improved patient selection and optimisation of cytoreductive surgery. A subsequent multicentre phase 2 trial is needed to make a definitive assessment of the diagnostic accuracy and the effect on clinical decision making of molecular fluorescence-guided surgery.FUNDING: FP-7 Framework Programme BetaCure and SurgVision BV.

Background: Eight-mm ablation catheters are widely used in cavotricuspid isthmus ablation (CTI) for treatment of right sided atrial flutter. However a high success rate, these large ablation tips comes with adisadvantage of lower resolution of fractionated signals. Purpose:The aim of this study was to evaluate the additional diagnostic value of the electrograms recorded from mini electrodes (MEs) in an 8-mm ablation catheter tip during CTI. Methods: CTI-Ablation procedures were compared retrospectively in two groups, namely, group A: The Abbott Safire 8-mm tip with a 3D mapping system (n =37) and group B: The Boston Scientific MiFi IntellaTip XP 8-mm tip without a 3D mapping system (n=13). We analyzed acute procedural success, ablation characteristics and recurrence rate at one-year follow-up. Electrograms from MEs were analyzed right before the onset of the critical ablation application that resulted in acute CTI-block. We determined whether these ME electrograms had additional diagnostic value in addition to of the 8-mm tip derivedelectrogram. Results: At the onset of the critical ablation application, the MEs had an important additional value in 3 out of 13 cases as local signals were sensed on the MEs that were not recorded by the 8-mm tip electrode. In 2cases the ME did not show local electrograms although the ablation was still effective. Acute procedural and long-Term success were observed in all patients. No differences were found in time to bidirectional block, procedure time or fluoroscopic exposure. Conclusions: Our data show that signals recorded from the MEs had additional diagnostic value, but only in a small percentage of the patients. We did not observe, although omitting 3D-mapping in the ME group, any difference between groups with regard to procedural or ablation characteristics during CTI-Ablation.

Background With two million patients, RMDs are one of the most common chronic diseases in the Netherlands. A 2016 Nivel survey showed that 50% of all RMD patients deal with people who know too little about RMDs in order to understand their situation. RMDs are not always visible, and symptoms may vary from day to day. This often leads to friends, colleagues, neighbours and even relatives showing incomprehension. For RMD patients this can lead to loneliness, insecurity and a sense of not being accepted. Understanding RMDs and being able to show compassion starts with knowing about RMDs. Objectives By launching a national creative campaign about incomprehension, the Dutch Arthritis Foundation aims to raise general awareness of RMDs to promote understanding of people with a RMD and to reduce their sense of loneliness. Methods The Dutch Arthritis Foundation started its campaign on World Arthritis Day: ‘Grow awareness, plant a bulb!’. To ‘grow understanding’, we created two special tulip bulb fields, one online and one offline, for participants to plant the special ‘Anita Witzier’ tulip bulb. Anita Witzier is a well-known Dutch television host who suffers from rheumatoid arthritis. She has been ambassador for the Dutch Arthritis Foundation since 2001. With the help from 70% of all local RMD patient organisations and a number of garden centres, we handed out a total of 15 000 bags of tulip bulbs across the Netherlands. The campaign kick-off was on World Arthritis Day. The event, held on a tulip breeder’s field, hosted presentations about incomprehension, and served to share real-life stories. We also developed a website where people could plant bulbs digitally. Every week, participants receive a video, cartoon, update or article with information about RMDs. The campaign will run until 21 May 2018 when the (real-life) tulips will bloom in our RMD field. All participants can then visit the field to pick a bunch of flowers. Results The campaign received a great deal of national media attention on WorldArthritisDay, and featured on television programmes, in newspapers and on online platforms. 8000 people have since signed up for the online tulip field, sharing the information with others in their network. The campaign site drew 68 000 visitors between 12Oc and 31Oc tober. The campaign also resonated with people on Facebook. In October, our campaign posts reached 1,869,000 visitors, with more than 65 000 interactions (respond, share, like, watch video, conversion to campaign site). Conclusions Raising awareness for incomprehension can be difficult. A creative approach can help to kickstart a public debate. Responses generally show that people with RMDs appreciate this complicated subject being put on the map. Disclosure of Interest None declared

Background The Dutch Arthritis Foundation (DAF) commissioned a large-scale survey to gain a broad insight into the various aspects of living with RMDs in the Netherlands. The results offer an insight into the prevalence of RMDs, as well as into living with RMDs and the use and standard of relevant healthcare and social care in our country. This was the first survey of this scale in the Netherlands. Objectives The survey aimed to generate data about the prevalence and the impact of RMDs on people’s every-day lives in the Netherlands. The DAF will use the results to better inform parties involved in caring for people with RMDs and to help them with policy drafting, such as authorities, healthcare insurers and healthcare providers. Methods The bulk of all data consists of statistical data from the NIVEL Healthcare Registrations (from 355 GP clinics, which register 1.1 million RMD patients). The survey also built on statistical and qualitative data from Vektis (business intelligence centre for the healthcare industry) and the National Institute of Public Health and Environmental Protection. Patients were contacted through the National Panel for Chronical Patients and asked to score their quality of life, the impact RMD has on their lives, and the standard of care. Rheumatologists, health professionals in rheumatology and orthopaedics were also represented in the monitoring group. The survey was carried out for four key disorders – chronic inflammatory rheumatism, osteoarthritis, gout and osteoporosis. These disorders are registered by both GPs and specialists. Fibromyalgia is not registered as a specific disorder by GPs and was therefore outside the scope of the survey. Results: The report generated the following results for the more than two million people with RMDs in the Netherlands: 1 in 9 people have a RMD; More than 2 million people have a RMD; Every day, 700 people are diagnosed with a form of RMD; There are 1.3 million people with osteoarthritis; 400,000 people with osteoporosis; 370,000 people with gout; 220,000 people with inflammatory rheumatism such as RA, ax-SpA, SLE, Sjogren syndrome and scleroderma. 69% of people with RMD are restricted by their symptoms in their day to day life; 50% of people with RMD between the ages of 40 and 65 are not in paid employment; 54% of people with RMD indicate they suffer from loneliness; 50% of people with RMD deal with incomprehension; 65% uses medication, 37% physiotherapy. Conclusions The report shows the extent of the impact of RMDs, not only medically, but also with regard to social effects. This was the first study to adequately reveal the sense of loneliness among RMD patients, laying bare the incomprehension they face in others. It also studied the impact of RMDs on employment, the great reliance on voluntary carers, and the fact that many people with a RMD also suffer other symptoms. The report was able to pinpoint the most vulnerable patients, and therefore provides a clear indication as to where improvements can be made. It also clearly shows that there is room for improvement when it comes to the registration of specific disorders such as fibromyalgia, but also disorders classed as a form of inflammatory arthritis, to enable the generation of objective data from the registration systems. Disclosure of Interest None declared

In-vivo fluorescently labelled drug (bevacizumab) breast cancer specimen where obtained from patients. We propose a new structured method to determine the optimal classification threshold in targeted fluorescence intra-operative imaging.

Background In the Netherlands, the peer-guided self-management training “Challenging Arthritis” exists for over 15 years and is being organized by the Dutch Arthritis Foundation and the University Medical Center Utrecht. The training is based on the “Arthritis Self-Management Program”1 but has recently gone through several updates, improvements and extensions2. The goal of the training is to improve self-management skills of patients and thereby improving their physical and emotional health and quality of life. Evaluations show that participants highly appreciate the training, but some of them have suggested that they would like to have an extra moment of training, (i.e., a booster session) after the ending of the regular program. Research shows that self-management programs are effective but mostly in the short term3. The effects of “Challenging Arthritis” may be enhanced and prolonged by organizing booster sessions. Objectives Aim of this research is to make recommendations about organizing booster sessions based on 1) a literature search and 2) a needs assessment among former participants and peer trainers. Methods A literature search was performed in databases like Google Scholar, PubMed and Science Direct, focusing on articles about the use of boosters in self-management interventions, limited to the years 2000–2016. Next to that, a needs assessment was conducted among participants and trainers on needs and preferences, using two separate online surveys. The survey for the participants, who followed a live training between 2012 and 2015, included items on the need for a booster and on preferences regarding its form, content and frequency. The survey for peer trainers addressed the perceived usefulness and the trainers9 willingness to provide booster sessions. The resulting data were analyzed using SPSS and thematic analysis. Results The literature search yielded 27 articles describing health interventions with aspects of self-management, including one or more booster sessions. From a theoretical perspective, boosters are a way to maintain new behavior over an extended period of time. As of yet, there is little evidence that the use of boosters lead to better outcomes in terms of health or health behavior, but it has been suggested that tailoring may lead to better results4,5. Regarding the needs assessment, 124 participants and 34 trainers completed the survey. Results showed that almost half of the participants (47,5%) expressed a need for a booster, while the other half (52,5%) expressed little or no need. Participants who prefer a booster want to share experiences, learn how to stay active with self-management and how to cope with setbacks. Trainers think boosters are very useful for the participants to stay active with self-management and maintain behavior and they are unanimously willing to provide booster sessions. Conclusions Boosters may contribute to the maintenance of newly acquired health behavior, although more research is needed on this subject. A substantial part of the participants expresses the need for a booster and trainers are highly motivated to provide it. Therefore, we think it9s worthwhile to start experimenting with organizing booster sessions on a small scale and, depending on the outcomes, consider further implementation. References References can be obtained from the first author. Disclosure of Interest None declared

Theater, as one of the oldest mass media, is often considered as the privileged place to discern the historically variable ways of how social identities are constructed and distributed. The social agency or performativity of theater is mostly studied from its representational aspects, focusing on the relation between what is performed on stage and the recipient of the performance, the spectator. However, it is equally important to include the place of performance as well. The location of the performance within the public space, its specific architecture and decorations, and its spatial structuring of the relation between performers and spectators, all contribute to theater's social agency. The importance of the performance place in the construction and distribution of social identities especially holds true for French eighteenth‐century architectural theory and practice. In a reaction to the dreadful spatial conditions of most French playhouses until deep in the eighteenth century, numerous architects and theorists proposed new ideas concerning theater architecture and the way they structured new modes of spectatorship.

Objective. Platinum-based chemotherapy is the standard treatment in advanced stage high grade serous ovarian cancer (HGSOC), but the majority of patients will relapse with drug-resistant disease. Platinum induces double-strand DNA breaks and subsequently activation of the DNA damage response (DDR). Drugs targeting DDR pathway components have gained major interest to be combined with chemotherapy as they could increase the therapeutic window. In the present study, we investigated the activation status of the Ataxia Telangiectasia Mutated (ATM) signaling axis within the DDR in a large, well-defined cohort of advanced stage HGSOC patients.Methods. Pre-therapy activation status of the ATM signaling axis of the DDR was determined by immunohistochemistry in 125 chemo-naive advanced stage HGSOC patients. Ovarian cancer cell lines with stable checkpoint kinase 2 (Chk2) knock down were used to study cell cycle distribution and survival in long-term clonogenic survival assays.Results. All ATM signaling axis components showed high expression levels. In two well-defined groups with the largest contrast in treatment response, high expression of Chk2 was related to good response (OR = 0.132; P = 0.014). Chk2 depletion abrogated the cisplatin-induced S-phase cell cycle arrest and caused increased resistance to cisplatin in long-term clonogenic survival assays.Conclusions. Chk2 is related to good response to platinum-based chemotherapy in advanced stage HGSOC patients. Chk2-depleted ovarian cancer cell lines have diminished platinum sensitivity, suggesting that Chk2 should not be considered a therapeutic target along with platinum-based treatment in HGSOC patients. (C) 2014 Elsevier Inc. All rights reserved.

The 4-metre Multi-Object Spectroscopic Telescope (4MOST) is a versatile optical survey instrument that will be installed on the VISTA telescope in 2022, offering medium- and high-resolution spectra and an innovative operations mode, explains Principal Investigator Roelof de Jong on behalf of the 4MOST Consortium.

There is an undisputed need for employment and improvement of robust technology for real-time analyses of therapeutic delivery and responses in clinical translation of gene and cell therapies. Over the past decade, optical imaging has become the in vivo imaging modality of choice for many preclinical laboratories due to its efficiency, practicality and affordability, while more recently, the clinical potential for this technology is becoming apparent. This review provides an update on the current state of the art in in vivo optical imaging and discusses this rapidly improving technology in the context of it representing a translation enabler or indeed a future clinical imaging modality in its own right. (C) 2013 Elsevier B.V. All rights reserved.

Item does not contain fulltext During September and October 2010, the Dutch Public Health Institute detected an enterovirus (EV) 68 (EV68) epidemic in the Netherlands through general practitioner-based surveillance of acute respiratory infections. EV68 shares phenotypic and genotypic properties with human rhinovirus (HRV). Despite increased EV and HRV detections, Dutch clinical laboratories did not identify EV68. To assess the capability of Dutch clinical laboratories to detect EV68, ten laboratories with more than eight detected EV and HRV cases in September and October 2010 provided information about their detection algorithms and testing results for a 2010 Dutch EV68 strain. For EV detection mostly stool specimens (median 49%), respiratory specimens (median 27%) and cerebrospinal fluid (median 22%) were used. For HRV detection only respiratory specimens were used. Except for the Seeplex(R) RV15ACE EV-specific assay, all EV and 73% of HRV assays, including those of the Public Health Institute, were able to detect EV68. Two-step EV RT-PCR protocols were the most sensitive. Thus, laboratories might have misidentified EV68 as HRV. In addition, EV68 cases might have also been missed because patients with respiratory diseases are usually not tested for EV infection. Therefore, clinical laboratories should include EV detection in the differential diagnosis of patients presenting with respiratory symptoms. 01 juni 2013

Summary: Objective To investigate the efficacy of bevacizumab and trastuzumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOCT) as first-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Methods In this multicentre, single-arm, phase II study, tumor HER2 status was determined centrally prior to treatment. Patients with advanced HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (immunohistochemistry 3+ or immunohistochemistry 2+/silver in-situ hybridization positive) were treated with six cycles of bevacizumab 7.5 mg/kg (day 1), docetaxel 50 mg/m2 (day 1), oxaliplatin 100 mg/m2 (day 1), capecitabine 850 mg/m2 b.i.d. (days 1–14), and trastuzumab 6 mg/kg (day 1) every three weeks, followed by maintenance with bevacizumab, capecitabine, and trastuzumab until disease progression. The primary objective was to demonstrate an improvement of progression-free survival (PFS) to >7.6 months (observed in the ToGA trial) determined according to the lower limit of the 95 % confidence interval (CI). Secondary endpoints were safety, objective response rate (ORR), and overall survival (OS). Results Twenty-five patients with HER2-positive tumors were treated with B-DOCT between March 2011 and September 2014. At a median follow-up of 17 months, median PFS was 10.8 months (95%CI: 9.0–NA), OS was 17.9 months (95%CI: 12.4–NA). One-year PFS and OS were 52 % and 79 %, respectively. The ORR was 74 % (95%CI: 52–90 %). Two patients became resectable during treatment with B-DOCT and achieved a pathological complete response. The most common treatment-related grade ≥ 3 adverse events were: neutropenia (16 %), diarrhoea (16 %), and hypertension (16 %). Conclusions B-DOCT is a safe and active combination in HER2-positive GC, supporting further investigations of DOC with HER2/vascular endothelial growth factor (VEGF) inhibition in HER2-positive GC.

The breaks and truncations in the luminosity profile of face-on spiral galaxies offer valuable insights in their formation history. The traditional method of deriving the surface photometry profile for face-on galaxies is to use elliptical averaging. In this paper, we explore the question whether elliptical averaging is the best way to do this. We apply two additional surface photometry methods, one new: principle axis summation, and one old that has become seldom used: equivalent profiles. These are compared to elliptically averaged profiles using a set of 29 face-on galaxies. We find that the equivalent profiles match extremely well with elliptically averaged profiles, confirming the validity of using elliptical averaging. The principle axis summation offers a better comparison to edge-on galaxies., Comment: Accepted for publication by Monthly Notices of the R.A.S. A hi-res version is available at http://www.astro.rug.nl/~vdkruit/Petersetal-VI.pdf

BackgroundThe effectiveness of open and endovascular aneurysm repair of aortic abdominal aneurysms (AAAs) can be jeopardised by deterioration of the residual infrarenal neck of the aneurysm.ObjectiveThe study aims to determine the length of the residual infrarenal aortic segment after endovascular and open aneurysm repair.MethodsIn a multicentre randomised controlled trial comparing open and endovascular AAA repair, 165 patients were discharged after open AAA repair (OR) and 169 after endovascular repair (EVAR). Immediately after the operation, surgeons were asked to enter in the case record form whether the level of their anastomosis after open repair was within or beyond 10 mm of the caudal renal artery. Postoperative computed tomography (CT) scans that were obtained within 6 months after surgery were used for comparative analysis. The distance between the caudal renal artery and the proximal anastomosis of the (endo-) graft was measured using axial CT slices and a standardised protocol. CT images were available and suitable for analysis in 156 (95%) of 165 OR patients and in 160 (95%) of 169 EVAR patients. Data are presented as median (range). Differences were analysed using the Mann–Whitney test.ResultsThe distance from the caudal renal artery to the proximal anastomosis was 24 mm (16–30 mm) in the OR group versus 0 mm (0–6 mm) in the EVAR group (p

Purpose: Breast-conserving surgery (BCS) results in tumour-positive surgical margins in up to 40% of the patients. Therefore, new imaging techniques are needed that support the surgeon with real-time feedback on tumour location and margin status. In this study, the potential of near-infrared fluorescence (NIRF) imaging in BCS for pre- and intraoperative tumour localization, margin status assessment and detection of residual disease was assessed in tissue-simulating breast phantoms.Methods: Breast-shaped phantoms were produced with optical properties that closely match those of normal breast tissue. Fluorescent tumour-like inclusions containing indocyanine green (ICG) were positioned at predefined locations in the phantoms to allow for simulation of (i) preoperative tumour localization, (ii) real-time NIRF-guided tumour resection, and (iii) intraoperative margin assessment. Optical imaging was performed using a custom-made clinical prototype NIRF intraoperative camera.Results: Tumour-like inclusions in breast phantoms could be detected up to a depth of 21 mm using a NIRF intraoperative camera system. Real-time NIRF-guided resection of tumour-like inclusions proved feasible. Moreover, intraoperative NIRF imaging reliably detected residual disease in case of inadequate resection.Conclusion: We evaluated the potential of NIRF imaging applications for BCS. The clinical setting was simulated by exploiting tissue-like breast phantoms with fluorescent tumour-like agarose inclusions. From this evaluation, we conclude that intraoperative NIRF imaging is feasible and may improve BCS by providing the surgeon with imaging information on tumour location, margin status, and presence of residual disease in real-time. Clinical studies are needed to further validate these results.

In spite of our recent insight into nasobronchial interaction mechanisms in allergic airway disease, the association between allergic rhinitis and voice complaints remains obscure. To evaluate the effects of nasal allergen provocation and seasonal grass pollen exposure on subjective and objective laryngeal parameters in singers with and without allergic rhinitis, an observational case control study was conducted. Prior to the pollen season, six grass pollen allergic and six non-allergic semiprofessional singers were exposed to nebulized sham solution and grass pollen extract (HAL°) in rising concentrations. After 3 min, 60 min and 24 h, nasal and laryngeal complaints were evaluated by the use of a visual analog scale (VAS). Laryngeal parameters like voice appearance (video stroboscopic images), voice range profile and subjective (GRBAS) and objective (jitter, shimmer, H/N, DSI) voice quality were evaluated before provocation, after 60 min and 24 h. During the pollen season, the allergic singers were re-evaluated. Results showed that in allergic singers both nasal (TNS of 4.0 ± 2.4 vs. 0.0 ± 0.0, p < 0.05) and laryngeal complaints (TLS of 1.4 ± 1.1 vs. 0.0 ± 0.2, p < 0.05) were induced at 3 min after the provocation. The induced laryngeal complaints were the feeling of laryngeal irritation, secretions and globus. No change in voice quality or stroboscopy score was measured. During the pollen season, laryngeal complaints were present (TLS of 2.4 ± 2.4) in allergic singers, without evidence for objective voice and laryngeal changes. In conclusion, we here demonstrate the rapid induction of laryngeal complaints in allergic singers by nasal allergen provocation and during the pollen season. There was no subject reported or investigator measured change in voice quality. No change in stroboscopy score was measured.

Aim: Tumor marker based recurrences of previously treated testicular cancer are generally detected with CT scan. They sometimes cannot be visualized with conventional morphologic imaging. FDG-PET has the ability to detect these recurrences. PET probe-guided surgery, may facilitate the extent of surgery and optimize the surgical resection.Methods: Three patients with resectable 2nd or 3rd recurrent testicular cancer based on elevated tumor markers after previous various chemotherapy schedules and resections of residual retroperitoneal tumor masses were included in this study. A diagnostic FDG-PET was performed and a hotspot in previously operated area of the retroperitoneal space in all three patients was visualized. PET probe-guided surgery was performed using a high-energy gamma probe 3 h post-injection of 500 MBq FDG.Results: All patients showed extended adhesions and scar tissue in the retroperitoneal area due to the previous surgeries. Pre-operative PET/CT scan showed a good correlation with intra-operative PET probe-guided detection of recurrent lesions. There was a high target to background ratio (TGB) of 5:1 during the procedure. In one patient, a 2 cm large lesion, which did not show on pre-operative FDG-PET scan, was detected with the PET probe. Histopathologic tissue evaluation demonstrated recurrent vital tumor in all PET probe positive lesions.Conclusions: PET probe-guided surgery seems to be a promising tool to localize FDG-PET positive lesion in recurrent testicular cancer in hardly accessible surgical locations. PET probe-guided surgery might be a useful technique in surgical oncology for recurrent testicular cancer and has the potential to be applied in surgery of other malignant diseases. (C) 2010 Elsevier Ltd. All rights reserved.

BACKGROUND: The occurrence of the retrovirus xenotropic murine leukemia virus (MLV)-related virus (XMRV) has been reported in prostate tissue of patients with prostate cancer (PrCa). Considering the potential great medical and social relevance of this discovery, we investigated whether this finding could be confirmed in an independent group of Dutch sporadic PrCa cases. METHODS: We investigated the occurrence of XMRV in fresh-frozen PrCa specimens of 74 PrCa patients from The Netherlands. Total RNA and DNA were isolated, subjected to cDNA synthesis, and analyzed by real-time PCR targeting conserved XMRV sequences. RESULTS: Spiking experiments showed that we were able to detect at least 10 copies of XMRV sequences in 100,000 cells by real-time PCR, demonstrating high sensitivity of the assay. XMRV sequences were detected in 3 out of 74 (i.e., 4%) PrCa specimens. The number of XMRV containing cells was extremely low (1 in 600-7,000 cells). This was corroborated by the fact that XMRV could not be detected in consecutive tissue sections of the initial XMRV-positive cases. CONCLUSIONS: XMRV was rarely detected, and at extremely low levels, in sporadic PrCa samples from Dutch patients. When XMRV would play a causal role in prostate carcinogenesis, integration of the provirus could be expected to be present in, at least, a proportion of tumor cells. Therefore, our data do not support the claim that there is an association between XMRV infection and PrCa in Dutch PrCa patients.

For decades, the decision-making process for water management in the Netherlands makes full utilisation of state of the art models. For rivers, two-dimensional hydrodynamic models are considered essential for a wide range of questions. Every five years, there is a major model revision that includes software updates, improved physical processes, new modelling strategy, and a new calibration. 2017 marked the setup and calibration of the first river model in the sixth generation of these models. In this paper, we discuss the most recent developments in two-dimensional hydrodynamic modelling of rivers. We give an overview of the process followed to agree on the functional design of the model and address the use of the recently developed Delft3D Flexible Mesh suite. We address, in some details: i) a mesh independent approach for model setup; ii) the utilisation of a new calibration technique, which is automated using data assimilation and includes spatial and discharge dependencies; and iii) the use of a novel operational module to control hydraulic structures. The first river model within the 6th generation of models is that of the Meuse River, where the new approaches are being successfully applied. In conclusion: the mesh independent modelling approach offers great flexibility and facilitates that the same data set can be used for multiple versions of the model (e.g. different grid resolution; or different model extent). The automated calibration approach makes it possible to utilise a comprehensive calibration data set for a large-scale model in a reproducible way. The increased complexity of modelling has become possible over the last decade due to the availability of large datasets and increased computational power. This paper is particularly relevant for modellers and decision makers alike.

Background: The outcome of cytoreductive surgery in patients with peritoneal carcinomatosis is influenced by incomplete resection as a result of inadequate detection of a tumor, i.e. residual disease. The future perspective of complete resection, made possible by application of intraoperative near-infrared fluorescence imaging (NIRF), led to the development and validation of a bioluminescent colorectal peritoneal carcinomatosis xenograft rat model to act as the gold standard for the evaluation of new optical imaging modalities. Methods: Twenty nude rats were inoculated intraperitoneally with 2 × 106 luciferase-labeled human colorectal tumor cells (HT-29-luc-D6). The peritoneal carcinomatosis index (PCI) was estimated using visual observation (PCI-VO) and VO combined with bioluminescence imaging (PCI-BLI). Subsequently, the BL images were presented, and residual tumor tissue was localized by PCI-BLI scoring and compared with the PCI-VO. Results: BLI revealed additional tumor tissue, confirmed by HE staining, compared to VO alone in 7 out of 8 rats (p < 0.02). Conclusion: The developed model turned out to be suitable. The use of BLI for tumor detection was more sensitive compared to VO alone. In this model, BLI significantly detected residual disease, and therefore, BLI can be denominated as the gold standard for the evaluation of optical imaging modalities like NIRF.

Inadequate surgical margins represent a high risk for adverse clinical outcome in breast-conserving therapy (BCT) for early-stage breast cancer. The majority of studies report positive resection margins in 20% to 40% of the patients who underwent BCT. This may result in an increased local recurrence (LR) rate or additional surgery and, consequently, adverse affects on cosmesis, psychological distress, and health costs. In the literature, various risk factors are reported to be associated with positive margin status after lumpectomy, which may allow the surgeon to distinguish those patients with a higher a priori risk for re-excision. However, most risk factors are related to tumor biology and patient characteristics, which cannot be modified as such. Therefore, efforts to reduce the number of positive margins should focus on optimizing the surgical procedure itself, because the surgeon lacks real-time intraoperative information on the presence of positive resection margins during breast-conserving surgery. This review presents the status of pre- and intraoperative modalities currently used in BCT. Furthermore, innovative intraoperative approaches, such as positron emission tomography, radioguided occult lesion localization, and near-infrared fluorescence optical imaging, are addressed, which have to prove their potential value in improving surgical outcome and reducing the need for re-excision in BCT.

Purpose Breast cancer patients with treatment-induced menopause experience frequent and severe hot flashes (HF). We compared venlafaxine and clonidine for the treatment of HF with regard to side effects, efficacy, quality of life and sexual functioning. Methods In a double-blind, cross-over study, 60 breast cancer patients experiencing HF were randomized to 8 weeks venlafaxine followed by 2 weeks wash-out, and 8 weeks clonidine or vice versa. HF frequency and severity, side effects, quality of life and sexuality were assessed. Results Thirty patients started with venlafaxine and 30 with clonidine. Premature discontinuation for toxicity occurred in 14/59 during venlafaxine and 5/53 during clonidine (P = .038). Venlafaxine induced more side effects. Median reduction in HF score was 49% for venlafaxine and 55% for clonidine (ns). Conclusion Venlafaxine and clonidine are equally, but moderately effective in HF reduction. Side effects are the main reason for drug discontinuation, occurring more often with venlafaxine.

Myocardial infarction (MI) induces an inflammatory response in which neutrophils fulfill a prominent role. Mean neutrophil volume (MNV) represents the average size of the circulating neutrophil population. Our goal was to determine the effect of MI on MNV and investigate the mechanisms behind MNV elevation. MNV of 84 MI patients was compared with the MNV of 209 stable angina patients and correlated to simultaneously measured CK levels. Fourteen pigs were subjected to temporary coronary balloon occlusion and blood was sampled at multiple time points to measure MNV. Echocardiography was performed followed by ex vivo infarct size assessment after 72 h. MNV was higher in MI patients compared to stable angina patients (602 SD26 AU vs. 580 SD20 AU, p

The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by β-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH.

Background: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer.Patients and methods: 302 patients were randomised and received bolus 5-FU 425 mg/m(2) day 1-5, FA 20 mg/m(2) day 1-5, q 4 wk or oxaliplatin 85 mg/m(2), 2 h-infusion, FA 200 mg/m(2), 1-h infusion. 5-FU 2600 mg/m(2), 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR).Results: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade 3/4 toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%.Conclusions: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.

In ovarian cancer the ceiling seems to be reached with chemotherapeutic drugs. Therefore a paradigm shift is needed. Instead of treating all patients according to standard guidelines, individualized molecular targeted treatment should be aimed for. This means that molecular profiles of the distinct ovarian cancer subtypes should be established. Until recently, most studies trying to identify molecular targets were single-marker studies. The prognostic role of key components of apoptotic and prosurvival pathways such as p53, EGFR, and HER2 has been extensively studied because resistance to chemotherapy is often caused by failure of tumor cells to go into apoptosis. However, it is more than likely that different ovarian cancer subtypes with extensive molecular heterogeneity exist. Therefore, exploration of the potential of specific tumor-targeted therapy, based on expression of a prognostic tumor profile, may be of interest. Recently, new profiling techniques, such as DNA and protein microarrays, have enabled high-throughput screening of tumors. In this review an overview of the current status of prognostic marker and molecular targeting research in ovarian cancer, including microarray studies, is presented.

Background: Accurate control of heparin anticoagulation is necessary during all stages of cardiopulmonary bypass (CPB). The activated clotting time, first described by Hattersley in 1966, is mostly used for determination of anticoagulation. Either celite or kaolin are used as activators. An ACT value of 480 sec is proposed to be the safe minimum level for anticoagulation during CPB. This study was designed to determine if the activated coagulation time (ACT) values of each analyser separately are repeatable, and to determine whether there exists a significant difference in ACT values measured by three different analysers: the GEM PCL (Instrumentation Laboratory), the Hemochron 801 (International Techni-dyne Corporation) and the ACT II Automated Coagulation Timer (Medtronic).Methods: All patients underwent cardiovascular surgical procedures requiring heparinisation (200 - 300 IU/kg). Blood samples for the measurement of the ACT were taken from all patients before and after heparinisation, during CPB, and after protamine administration. All samples were measured in duplicate with the three different analysers. To compare the activated clotting time data, the method described by Bland and Altman was used. The Pearson correlation coefficient was used to determine whether the differences were related to the average ACTs. p-Values < 0.05 were considered statistically significant.Results: The results showed that the three tested ACT analysers met the requirements of repeatability. The mean differences and standard deviations of the ACT values measured with the GEM PCL, the Hemochron 801, and the ACT II analyser were, respectively, -8.789 ± 37.61, -19.779±68.82, and -6.239±39.21, with p-values=0.177, 0.081 and 0.384, respectively. The Pearson correlation coefficients were too low (-0.012, -0.221 and -0.241, respectively) to show any correlation between the differences and the means. The ACT values measured with the Hemochron 801 were not significantly different from the ACT values measured with the ACT II analyser: ΔACT=-34.09 ± 146.68, with p=0.132. However, the GEM PCL did not agree with the Hemochron 801: ΔACT=-80.29 ± 143.06, with p=0.001, or the ACT II analyser: ΔACT=-119.139 ± 138.51, with pConclusions: All analysers used celite or kaolin as activator. However, it was evident that the ACT measurements depended also on the analyser that had been chosen. A precaution that ACT values could not always be interpreted in the same way seems to be necessary.

Advanced adenocarcinoma of the pancreas has a very poor prognosis. The aim of this study was to assess the efficacy and tolerability of a combination of the chemotherapeutic agents gemcitabine and raltitrexed. Chemonaive patients with advanced adenocarcinoma of the pancreas were treated with a combination of raltitrexed (3.5 mg m(-2) on day 1 of a 21-day treatment cycle) and gemcitabine (800 mg m(-2) intravenously ( i. v.) on days 1 and 8 of a 21-day cycle). Between April 2000 and February 2003, 27 patients were enrolled onto the study. The mean duration of treatment was 11 weeks. Four of 27 patients experienced at least one episode of grade 3 or 4 neutropenia. One patient with grade 4 neutropenia died due to sepsis. Four of 27 patients experienced grade 4 diarrhoea. There was one partial remission (4%) and 12 patients experienced disease stabilisation (44%). The 6-month and 1-year survival rates were 37 and 11%, respectively. Symptomatic benefit occurred in seven (26%) patients. We conclude that a combination of raltitrexed and gemcitabine, using the schedule and doses in this study, cannot be recommended for patients with advanced pancreatic cancer.

Non-steroidal anti-inflammatory drugs are chemopreventive agents in colorectal cancer. Non-steroidal anti-inflammatory drugs do not, however, offer complete protection against adenoma and carcinoma development. There is increasing interest in combining non-steroidal anti-inflammatory drugs with agents that target specific cell signalling pathways in malignant and premalignant cells. This review aims to describe the current knowledge regarding the efficacy of peroxisome proliferator-activated receptor-gamma ligands, cholesterol synthesis inhibitors (statins), epidermal growth factor signalling inhibitors and tumour necrosis factor-related apoptosis-inducing ligand against colorectal neoplasms and the rationale for combining these drugs with non-steroidal anti-inflammatory drugs to improve efficacy in the chemoprevention of colorectal cancer, a PUBMED computer search of the English language literature was conducted to identify relevant papers published before July 2004. Peroxisome proliferator-activated receptor-gamma ligands and statins, both in clinical use, reduce the growth rate of human colon cancer cells in vitro and in rodents models. In vitro, preclinical in vivo and clinical studies have shown efficacy of epidermal growth factor signalling inhibition in colorectal cancer. In vitro, tumour necrosis factor-related apoptosis-inducing ligand induces apoptosis in human colon cancer cells, but not in normal cells. These drugs have all been shown to interact with non-steroidal anti-inflammatory drugs in colorectal cancer cells and/or in rodent models. Combinational regimen are a promising strategy for the chemoprevention of colorectal cancer and should be further explored.

Automatic alignment (matching) of two-dimensional gel electrophoresis images is of primary interest in the field of proteomics. The proposed method of 2D gel image matching is based on fuzzy alignment of features, extracted from gels' images, and it allows both global and local interpolation of image grid, followed by brightness interpolation. Method performance is tested on simulated images and gel images available via the Internet databases.

Aim: To examine whether the detection of either telomerase and its components or high risk human papillomavirus (HPV) are of value in predicting the presence of cervical intraepithelial neoplasia (CIN) grade II/III in women referred because of cervical cytology reports showing at most moderate dyskaryosis. Methods: Cervical scrapings of 50 women referred with cytological borderline, mild, or moderate dyskaryosis were analysed. Telomerase activity was assessed by a commercially available telomere repeat amplification protocol assay and its components human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) were assessed by reverse transcriptase polymerase chain reaction (PCR). HPV was detected by GP5+/6+ PCR enzyme immunosassay. Histological findings on colposcopy guided biopsies or excised cervical tissue were regarded as the final pathological diagnosis. The sensitivity and specificity for detecting CIN II/III were calculated. Results: Twenty eight women were diagnosed with CIN II/III. Telomerase activity was detected in none, hTR in 88%, hTERT in 23%, and high risk HPV was detected in 79% of these women. As a diagnostic test none of the described analyses combined a sensitivity of at least 90% with a specificity ≥ 90%. Despite the small numbers, calculation of the 95% confidence intervals excluded a combined sensitivity and specificity of at least 90% for all of the evaluated parameters. Conclusions: Neither detection of telomerase or its components, nor detection of high risk HPV seem suitable for the triage of women with borderline, mild, and moderate cytological dyskaryosis.

Different preprocessing methods (direct orthogonal signal correction (DOSC), standard normal variate (SNV), multiple scatter correction (MSC), first and second derivation, offset correction and detrend correction) are applied to two sets of NIR spectra of a dermatological cream with different concentrations of an active compound. The influence of these preprocessing methods on the classification of the samples into the right concentration class is evaluated using 1 and 3 nearest neighbour method (with Euclidean distance and correlation coefficient as distance parameters) as classification method. PLS and PCR modelling are also used to make a prediction of the concentration of the active compound. The direct orthogonal signal correction gives best results in most of the classification methods.

Feature selection is a valuable technique in data analysis for information-preserving data reduction. This paper describes a feature selection approach for hierarchical clustering based on genetic algorithms using a fitness function that tries to minimize the difference between the dissimilarity matrix of the original feature set and the one of the reduced feature sets. Clustering trees based on reduced feature sets are comparable with those based on the complete feature set. Special measures to favor small reduced feature sets are discussed.

Epidemiological and experimental evidence strongly suggests an association between type 2 diabetes mellitus and cancer. Insulin resistance, causing hyperinsulinaemia and eventually hyperglycaemia, appears to increase cancer incidence and disease progression. In addition, insulin resistance seems to reduce the efficacy of cancer therapy. Treatment with cancer therapeutics such as glucocorticoids, chemotherapy, hormonal therapies and targeted drugs can actually induce insulin resistance. The question arises whether cancer-therapy induced insulin resistance impairs anticancer treatment efficacy and disease outcome. Here, we review current literature regarding the incidence of cancer-therapy induced insulin resistance and describe the systemic and extra- and intracellular changes that occur in insulin signalling pathways and glucose metabolism. Subsequently, clinical and preclinical evidence for consequences of insulin resistance in terms of cancer progression and survival is presented. Finally, potential interventions including diabetes medication and limiting energy availability through diets and exercise are discussed. (C) 2015 Elsevier Ltd. All rights reserved.

We present a new type of R-θ fiber actuator named PotsPos for multi-object astronomical spectroscopy. It was initially intended to use as an alternative positioner design for the 4-meter Multi-Object Spectroscopic Telescope (4MOST). Although another tilting spine technology developed by the Australian Astronomical Observatory (AAO) is currently chosen for the 4MOST, PotsPos design has some technical advantages over other positioning technologies and might therefore be an attractive choice for future spectrographs. The design would be similar in positioning capabilities to the tilting spine design but would not suffer from telecentricity and defocus errors. The mechanical design, suitable motors, computational results from dynamic simulations and finite element analyses are presented.

4MOST, the 4m Multi-Object Spectroscopic Telescope, features a 2.5 degree diameter field-of-view with ~2400 fibers in the focal plane that are configured by a fiber positioner based on the tilting spine principle (Echidna/FMOS) arranged in a hexagonal pattern. The fibers feed two types of spectrographs; ~1600 fibers go to two spectrographs with resolution R>5000 and ~800 fibers to a spectrograph with R>18,000. Part of the ongoing optimization of the fiber feed subsystem design includes early prototyping and testing of key components such as fiber connectors and fiber cable management. Performance data from this testing will be used in the 4MOST instrument simulator (TOAD) and 4MOST system design optimization. In this paper we give an overview of the current fiber feed subsystem design, simulations and prototyping plans.

There is a clear synergy possible in geothermal and hydrocarbon exploration if wells are targeted in a double play concept. In the Netherlands, clastic aquifers which have been explored extensively by the hydrocarbon industry and are now targeted for geothermal energy qualify well for a double play. Through a simple example we demonstrate quantitatively the benefit of the double play in monetary risk and reward of an exploration project. Furthermore, we evaluated the potential effects of synergy for a synthetic portfolio of gas prospects in the Netherlands. It is shown that the potential benefits may be considerable and can lead to approximately 7 BCM additional gas being produced, and in the order of 10 geothermal doublets being developed