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Background Following esophagectomy, esophageal cancer patients experience a clinically relevant deterioration of health-related quality of life, both on the short- and long-term. With the currently growing number of esophageal cancer survivors, the burden of disease- and treatment-related complaints and symptoms becomes more relevant. This emphasizes the need for interventions aimed at improving quality of life. Beneficial effects of post-operative physical exercise have been reported in several cancer types, but so far comparable evidence in esophageal cancer patients is lacking. The aim of this study is to investigate effects of physical exercise on health-related quality of life in esophageal cancer patients following surgery. Methods The Physical ExeRcise Following Esophageal Cancer Treatment (PERFECT) study is a multicenter randomized controlled trial including 150 esophageal cancer patients after surgery with curative intent. Patients are randomly allocated to an exercise group or usual care group. The exercise group participates in a 12-week combined aerobic and resistance exercise program, supervised by a physiotherapist near the patient’s home-address. In addition, participants in the exercise group are requested to be physically active for at least 30 min per day, every day of the week. Participants allocated to the usual care group are asked to maintain their habitual physical activity pattern. The primary outcome is health-related quality of life (EORTC-QLQ-C30). Secondary outcomes include esophageal cancer specific quality of life, fatigue, anxiety and depression, sleep quality, work-related factors, cardiorespiratory fitness (VO 2peak ), muscle strength, physical activity, malnutrition risk, anthropometry, blood markers, recurrence of disease and survival. All questionnaire outcomes, diaries and accelerometers are assessed at baseline, post-intervention (12 weeks post-baseline) and 24 weeks post-baseline. Physical fitness, anthropometry and blood markers are assessed at baseline and post-intervention. In addition, adherence and safety are monitored throughout the exercise program. Discussion This randomized controlled trial investigates effects of physical exercise versus usual care in esophageal cancer patients after surgery. As the design of the exercise program closely resembles daily practice, this study can contribute both to evidence on effects of exercise in esophageal cancer patients, and to potential implementation strategies. Trial registration Trial registration:Netherlands Trial Registry NTR5045 Date of trial registration: January 19th, 2015 Date and version study protocol: February 2017, version 1

Objective The aim of this study was to review the results and long-term outcome after total mesorectal excision (TME) for adenocarcinoma of the rectum in an unselected population in a community teaching hospital. Materials and methods Between 1996 and 2003, 210 patients with rectal cancer were identified in our prospective database, containing patient characteristics, radiotherapy plans, operation notes, histopathological reports, and follow-up details. An evaluation of prognostic factors for local recurrence, distant metastases, and overall survival was performed. Results The mean age at diagnosis was 69 years (range 40–91 years). A total of 145 patients were treated by anterior rectal resection; 65 patients had to undergo an abdominoperineal resection (APR). Anastomotic leakage rate was 5%. Postoperative mortality was 3%. After a median follow-up of 3.6 years, the local recurrence-free rate in patients with microscopically complete resections was 91%. The 5-year overall survival rate was 58%. An increased serum carcinoembryonic antigen, an APR, positive lymph nodes, and an incomplete resection all significantly influenced the 5-year overall survival and local recurrence rate. In a multivariate analysis, age was the most important prognostic factor for overall survival. Conclusions Patients with rectal cancer can safely be treated with TME in a community teaching hospital and leads to a good overall survival and an excellent local control. In patients aged above 80, treatment-related mortality is an important competitive risk factor, which obscures the positive effect of modern rectal cancer treatment.

The purpose of this study was to evaluate the pain experience of women during mammography for breast cancer screening. Possible associations with personal and medical history, sociodemographics and/or situational factors were studied. It was also investigated whether this pain influenced the intention to return for future breast cancer screening. In the Netherlands, women between 50-75 years are invited for screening every two years. A total of 1200 participants were asked to fill up a questionnaire. The response rate was 79.5% (n = 954), and 945 questionnaires contained adequate information for analyses. A total of 689 women (72.9%) described mammography as mild to severely painful. In this group, compared to the group that reported no pain, the following factors occurred significantly more often: sensitive breasts (P = 0.001), family history of breast diseases (P = 0.017); expected pain based on former mammography (P = 0.001), high education (P = 0.008), anxiety (P = 0.001), breast sensitivity in last three days (P = 0.001), insufficient attention of technologist (P = 0.001). Other factors like age, hormonal status, breast size and hormone use were not associated with the pain experienced. Thirty-two women (3.3%) indicated that they would not attend further screening, 25 (2.6%) reported that the pain might deter them, six women (0.6%) had other reasons, one woman (0.1%) was sure not to come because of severe pain. In conclusion, a large majority of women attending breast cancer screening describes mammography as painful (72.9%). Factors associated with pain were described. Relatively few women (2.7%) indicated that the pain might deter them from future mammography. Recommendations are given to reduce the pain experienced during screening mammography.

We know that screening for breast cancer leads to detection of smaller tumours with less lymph node metastases. Could it be possible that the decrease in mortality after screening is not only caused by this earlier stage, but also by a different mitotic activity index (MAI) of the tumours that are detected by screening? Is MAI a prognostic factor for recurrence-free survival? A retrospective study was carried out of 387 patients with breast cancer, treated at the University Hospital Nijmegen between January 1992 and September 1997. Ninety patients had screen-detected breast cancer, 297 patients had breast cancers detected outside the screening programme. The MAI, other prognostic factors and recurrence-free survival were determined. In non-screen-detected tumours the MAI is twice as high as in screen-detected tumours, even after correction for age took place. The MAI correlated well with other tumour characteristics. The MAI in itself is a prognostic factor for recurrence-free survival. Favourable outcome in screen detected breast cancer is not entirely caused by detecting cancer in early stages: quantitative features such as the MAI indicate a less malignant character of screen detected breast cancer. The MAI is an independent prognostic factor for recurrence-free survival. © 2000 Cancer Research Campaign

IntroductionIn daily practice large heterogeneity in the treatment of children with complex appendicitis exists. Complex appendicitis can be divided into two subtypes; complex appendicitis with and without appendiceal mass and/or abscess. As complex appendicitis is associated with high morbidity and costs, identification of the optimal treatment strategy is essential. In this article, we present the study protocol for the CAPP (Complex Appendicitis in the Pediatric Population) study.Methods and analysisThis nation-wide, multi-centre, comparative, non-randomised prospective cohort study includes all children <18 years old with a preoperative suspicion of complex appendicitis, which is based on imaging confirmed acute appendicitis and predefined criteria regarding the severity of appendicitis. Eligible patients are recruited in more than 30 hospitals. Open appendectomy will be compared with laparoscopic appendectomy for children without appendiceal mass and/or abscess and initial non-operative treatment (ie, intravenous antibiotics with or without percutaneous drainage) to direct appendectomy for children with appendiceal mass and/or abscess. Based on historical data supplied by the participating hospitals and an inclusion period of 2 years and 9 months, a sample size of 1308 patients is aimed. Primary outcome is the proportion of patients experiencing any complication at 3 months follow-up. Reported complications will be assessed by an independent adjudication committee. Secondary outcomes include, but are not limited to, quality of life, and (in)direct costs. To adjust for baseline differences and selection bias, outcomes will be compared after propensity score analysis (inverse probability weighting and stratification).Ethics and disseminationThe Medical Ethics Review Committee of the Amsterdam UMC, location AMC, declared that the Medical Research involving Human Subjects Act (WMO) did not apply to this study. Therefore, no official approval was required by national law. Study results will be presented in peer-reviewed scientific journals and at (inter)national conferences.Trial registration numbersNCT04755179; NL9371.

Results and experience with the treatmentof non‐palpable breast cancer are reported and related to the future ofless invasive treatment of small breast cancers. The retrospectivestudy included 102 patients treated between 1980 and 1993 at theUniversity Hospital of Nijmegen. Most cancers were screen‐detected.Tumor sizes on pathological examination proved 3 mm (SD 7.7 mm) largerthan on mammography (p = 0.0029). pT1 tumors wereencountered in 77 patients (75%); pT2 tumors in 17 patients (17%).Seventy‐five patients were free of lymph node metastases, 26 patientsshowed stage pN1 (25%). Most patients had invasive ductal cancers.Only two patients died of breast cancer. A 10‐year disease‐freesurvival of 94% was calculated, after excluding four patients withknown systemic disease (M1) at diagnosis. T1a,T1b, and T1c had a 10‐year survival of 100%,96%, and 96%, respectively. Early detection and multimodalitytreatment of breast cancer have significantly improved survival. Inpatients with small breast cancer tumors future developments intreatment must be aimed at the use of less invasive techniques,reducing morbidity while maintaining high levels of disease‐freesurvival.

Background There are several methods to read skin prick test results in type-I allergy testing. A commonly used method is to characterize the wheal size by its ‘average diameter’. A more accurate method is to scan the area of the wheal to calculate the actual size. In both methods, skin prick test (SPT) results can be corrected for histamine-sensitivity of the skin by dividing the results of the allergic reaction by the histamine control. The objectives of this study are to compare different techniques of quantifying SPT results, to determine a cut-off value for a positive SPT for histamine equivalent prick -index (HEP) area, and to study the accuracy of predicting cashew nut reactions in double-blind placebo-controlled food challenge (DBPCFC) tests with the different SPT methods. Methods Data of 172 children with cashew nut sensitisation were used for the analysis. All patients underwent a DBPCFC with cashew nut. Per patient, the average diameter and scanned area of the wheal size were recorded. In addition, the same data for the histamine-induced wheal were collected for each patient. The accuracy in predicting the outcome of the DBPCFC using four different SPT readings (i.e. average diameter, area, HEP-index diameter, HEP-index area) were compared in a Receiver-Operating Characteristic (ROC) plot. Results Characterizing the wheal size by the average diameter method is inaccurate compared to scanning method. A wheal average diameter of 3 mm is generally considered as a positive SPT cut-off value and an equivalent HEP-index area cut-off value of 0.4 was calculated. The four SPT methods yielded a comparable area under the curve (AUC) of 0.84, 0.85, 0.83 and 0.83, respectively. The four methods showed comparable accuracy in predicting cashew nut reactions in a DBPCFC. Conclusions The ‘scanned area method’ is theoretically more accurate in determining the wheal area than the ‘average diameter method’ and is recommended in academic research. A HEP-index area of 0.4 is determined as cut-off value for a positive SPT. However, in clinical practice, the ‘average diameter method’ is also useful, because this method provides similar accuracy in predicting cashew nut allergic reactions in the DBPCFC. Trial registration: Trial number NTR3572

Purpose Ongoing angiogenesis renders the tumor endothelium unresponsive to inflammatory cytokines and interferes with adhesion of leukocytes, resulting in escape from immunity. This process is referred to as tumor endothelial cell anergy. We aimed to investigate whether anti-angiogenic agents can overcome endothelial cell anergy and provide pro-inflammatory conditions. Experimental design Tissues of renal cell carcinoma (RCC) patients treated with VEGF pathway-targeted drugs and control tissues were subject to RNAseq and immunohistochemical profiling of the leukocyte infiltrate. Analysis of adhesion molecule regulation in cultured endothelial cells, in a preclinical model and in human tissues was performed and correlated to leukocyte infiltration. Results It is shown that treatment of RCC patients with the drugs sunitinib or bevacizumab overcomes tumor endothelial cell anergy. This treatment resulted in an augmented inflammatory state of the tumor, characterized by enhanced infiltration of all major leukocyte subsets, including T cells, regulatory T cells, macrophages of both M1- and M2-like phenotypes and activated dendritic cells. In vitro, exposure of angiogenic endothelial cells to anti-angiogenic drugs normalized ICAM-1 expression. In addition, a panel of tyrosine kinase inhibitors was shown to increase transendothelial migration of both non-adherent and monocytic leukocytes. In primary tumors of RCC patients, ICAM-1 expression was found to be significantly increased in both the sunitinib and bevacizumab-treated groups. Genomic analysis confirmed the correlation between increased immune cell infiltration and ICAM-1 expression upon VEGF-targeted treatment. Conclusion The results support the emerging concept that anti-angiogenic therapy can boost immunity and show how immunotherapy approaches can benefit from combination with anti-angiogenic compounds.

Increasing CO 2 concentrations are expected to increase plant growth and water efficiency. Tree-ring data covering 150 years from tropical forests show that water-use efficiency has increased with CO 2 concentrations but tree growth has not. The biomass of undisturbed tropical forests has likely increased in the past few decades 1 , 2 , probably as a result of accelerated tree growth. Higher CO 2 levels are expected to raise plant photosynthetic rates 3 and enhance water-use efficiency 4 , that is, the ratio of carbon assimilation through photosynthesis to water loss through transpiration. However, there is no evidence that these physiological responses do indeed stimulate tree growth in tropical forests. Here we present measurements of stable carbon isotopes and growth rings in the wood of 1,100 trees from Bolivia, Cameroon and Thailand. Measurements of carbon isotope fractions in the wood indicate that intrinsic water-use efficiency in both understorey and canopy trees increased by 30–35% over the past 150 years as atmospheric CO 2 concentrations increased. However, we found no evidence for the suggested concurrent acceleration of individual tree growth when analysing the width of growth rings. We conclude that the widespread assumption of a CO 2 -induced stimulation of tropical tree growth may not be valid.

The measurement of blood-plasma velocity distributions with spatial and temporal resolution in vivo is inevitable for the determination of shear stress distributions in complex geometries at unsteady flow conditions like in the beating heart. A non-intrusive, whole-field velocity measurement technique is required that is capable of measuring instantaneous flow fields at sub-millimeter scales in highly unsteady flows. Micro particle image velocimetry ( μ PIV ) meets these demands, but requires special consideration and methodologies in order to be utilized for in vivo studies in medical and biological research. We adapt μ PIV to measure the blood-plasma velocity in the beating heart of a chicken embryo. In the current work, bio-inert, fluorescent liposomes with a nominal diameter of 400 nm are added to the flow as a tracer. Because of their small dimension and neutral buoyancy the liposomes closely follow the movement of the blood-plasma and allow the determination of the velocity gradient close to the wall. The measurements quantitatively resolve the velocity distribution in the developing ventricle and atrium of the embryo at nine different stages within the cardiac cycle. Up to 400 velocity vectors per measurement give detailed insight into the fluid dynamics of the primitive beating heart. A rapid peristaltic contraction accelerates the flow to peak velocities of 26 mm/s, with the velocity distribution showing a distinct asymmetrical profile in the highly curved section of the outflow tract. In relation to earlier published gene-expression experiments, the results underline the significance of fluid forces for embryonic cardiogenesis. In general, the measurements demonstrate that μ PIV has the potential to develop into a general tool for instationary flow conditions in complex flow geometries encountered in cardiovascular research.