Comparisons of PNEC derivation logic flows under example regulatory schemes and implications for ecoTTC.

Derivation of Predicted No Effect Concentrations (PNECs) for aquatic systems is the primary deterministic form of hazard extrapolation used in environmental risk assessment. Depending on the data availability, different regulatory jurisdictions apply application factors (AFs) to the most sensitive measured endpoint to derive the PNEC for a chemical. To assess differences in estimated PNEC values, two PNEC determination methodologies were applied to a curated public database using the EnviroTox Platform (www.EnviroToxdatabase.org). PNECs were derived for 3647 compounds using derivation procedures based on example US EPA and a modified European Union chemical registration procedure to allow for comparisons. Ranked probability distributions of PNEC values were developed and 5th percentile values were calculated for the entire dataset and scenarios where full acute or full chronic data sets were available. The lowest PNEC values indicated categorization based on chemical attributes and modes of action would lead to improved extrapolations. Full acute or chronic datasets gave measurably higher 5th percentile PNEC values. Algae were under-represented in available ecotoxicity data but drove PNECs disproportionately. Including algal inhibition studies will be important in understanding chemical hazards. The PNEC derivation logic flows are embedded in the EnviroTox Platform providing transparent and consistent PNEC derivations and PNEC distribution calculations.

A clickable NHC-Au(i)-complex for the preparation of stimulus-responsive metallopeptide amphiphiles.

We report the synthesis of an alkyne functionalised NHC-Au(i)-complex which is conjugated with amphiphilic oligopeptides using a copper(i) catalysed cycloaddition. The resulting Au(i)-metalloamphiphiles are shown to self-assemble into charge-regulated stimulus-responsive supramolecular polymers in water via a weakly cooperative polymerisation mechanism.

Single ingestion of di-(2-propylheptyl) phthalate (DPHP) by male volunteers: DPHP in blood and its metabolites in blood and urine.

Di-(2-propylheptyl) phthalate (DPHP) is used as a plasticizer for polyvinyl chloride products. A tolerable daily intake of DPHP of 0.2 mg/kg body weight has been derived from rat data. Because toxicokinetic data of DPHP in humans were not available, it was the aim of the present work to monitor DPHP and selected metabolites in blood and urine of 6 male volunteers over time following ingestion of a single DPHP dose (0.7 mg/kg body weight). Concentration-time courses in blood were obtained up to 24 h for DPHP, mono-(2-propylheptyl) phthalate (MPHP), mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP), and mono-(2-propyl-6-oxoheptyl) phthalate (oxo-MPHP); amounts excreted in urine were determined up to 46 h for MPHP, OH-MPHP, oxo-MPHP, and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). All curves were characterized by an invasion and an elimination phase the kinetic parameters of which were determined together with the areas under the concentration-time curves in blood (AUCs). AUCs were: DPHP > MPHP > oxo-MPHP > OH-MPHP. The amounts excreted in urine were: oxo-MPHP > OH-MPHP> > cx-MPHP > MPHP. The AUCs of MPHP, oxo-MPHP, or OH-MPHP could be estimated well from the cumulative amounts of urinary OH-MPHP or oxo-MPHP excreted within 22 h after DPHP intake. Not considering possible differences in species-sensitivity towards unconjugated DPHP metabolites, it was concluded from a comparison of their AUCs in DPHP-exposed humans with corresponding earlier data in rats that there is no increased risk of adverse effects associated with the internal exposure of unconjugated DPHP metabolites in humans as compared to rats when receiving the same dose of DPHP per kg body weight.

[The use of the permanent sample (eps) to study the returnto- work after cancer. Challenges and opportunities for research]. / Utilisation de l'échantillon permanent (eps) pour l'étude du retour au travail après cancer. Défis et opportunités pour la recherche.

INTRODUCTION: The introduction of early cancer detection and the improvement in treatment efficacy have led to a significant increase in the survival and the prevalence of (ex) cancer patients. Approximately 40 % of new cancer cases are diagnosed every year in the working age population (20-64 years). Maintaining their quality of life results, among others, in their retain on the labour market. Even though it is necessary to realize the scale of the phenomenon and to plan interventions, no measure allows assessing the rate of return to work among of (ex) cancer patients in Belgium nowadays. METHODS: We observe during a five-year period the socio-professional status (inability, disability, unemployment or death) of 645 workers identified in the permanent sample (EPS), having had an oncological multidisciplinary consultation (MOC) in 2011. RESULTS: By the end of follow-up, 24 % of the workers were deceased. Among those who survived 26 % are unable to work, 12 % are unemployed and 63 % do not receive any social benefit. Women and young workers (20-44 years) seemed to have encountered difficulties the most. CONCLUSIONS: The results of this study allow giving a prudent first estimation of the return to work of socially insured Belgian citizens of almost 40 %, five years after the first MOC. Nevertheless, the structure of the EPS presents many limitations to the interpretation and reliability of results. We suggest some modifications of the EPS that might offer scientists better opportunities to improve the performance and reliability of such cohort studies.

INTRODUCTION: L'introduction de la détection précoce des cancers et l'amélioration de l'efficacité des traitements ont mené à une augmentation significative de la prévalence d'(ex) patients. A peu près 40 % des nouveaux cancers sont diagnostiqués chaque année dans la population active (20-64 ans). Le maintien de leur qualité de vie passe, notamment, par leur maintien sur le marché du travail. Bien que nécessaire pour évaluer l'ampleur du phénomène et planifier des interventions spécifiques, aucune mesure ne permet actuellement d'établir avec précision le taux de réinsertion professionnelle des travailleurs atteints de cancer en Belgique. Matériel et Méthodes : Nous observons durant cinq ans le statut socioprofessionnel (incapacité de travail, invalidité, chômage ou décès) de 645 travailleurs identifiés dans l'échantillon permanent (EPS) ayant eu une première consultation oncologique multidisciplinaire (COM) en 2011. Résultats : Au terme du suivi, 24 % des travailleurs sont décédés. Parmi les travailleurs ayant survécu, 26 % sont en incapacité de travail, 12 % sont au chômage et 63 % ne bénéficient d'aucun revenu de remplacement. Les femmes et les jeunes travailleurs (20-44 ans) semblent rencontrer le plus de difficultés pour le retour au travail. CONCLUSIONS: Les résultats de cette étude permettent d'avancer une première estimation du retour au travail des assurés sociaux belges atteints de cancer à un peu moins de 40 %, cinq ans après la première COM. Toutefois, la structure et les données de l'EPS présentent de nombreuses limites pour l'interprétation et la fiabilité des résultats. Nous suggérons quelques modifications des données de l'EPS qui offriront aux scientifiques des opportunités pour améliorer la réalisation et la fiabilité de telles études de cohorte.

Folding induced supramolecular assembly into pH-responsive nanorods with a protein repellent shell.

We report the synthesis of ABA' triblock peptide-polysarcosine-peptide conjugates featuring two complementary phenylalanine-histidine pentapeptide strands A/A'. These sequences encode for antiparallel ß-sheet formation into folded conjugates, which promote the self-assembly into polysarcosine-shielded core-shell nanorods. These do not cause aggregation of serum proteins in human blood plasma underlining an enhanced stability.

Di-(2-propylheptyl) phthalate (DPHP) and its metabolites in blood of rats upon single oral administration of DPHP.

Di-(2-propylheptyl) phthalate (DPHP) does not act as a reproductive toxicant or endocrine disruptor in contrast to other phthalates. Considering adverse effects of phthalates to be linked to their metabolism, it was the aim of the present study to investigate in the rat the blood burden of DPHP and its metabolites as a basis for understanding the toxicological behavior of DPHP. Rats were administered single oral doses of DPHP of 0.7 and 100mg/kg body weight. Concentration-time courses of DPHP and metabolites were monitored in blood. The areas under the concentration-time curves in blood (AUCs), normalized for the dose of DPHP, showed the following order: DPHP

A Negative Life Event Impairs Psychosocial Stress, Recovery and Running Economy of Runners.

The purpose was to investigate how a negative life event (NLE) affects perceived psychosocial stress, recovery and running economy (RE). Competitive runners were monitored in a prospective non-experimental cohort study over one full training season in which they experienced the same unplanned severe NLE. 16 runners recorded stress and recovery scores (RESTQ-Sport) every week. The average scores over 3 weeks before the NLE were used as a baseline and were compared to scores during the week of the NLE (week 0), week 1 and week 2. 7 runners completed a submaximal treadmill test before and after the NLE. Repeated measures ANOVAs revealed that most scores on general stress scales were increased in week 0 and 1. Of the general recovery scales, "general well-being" was decreased in week 0 and 1, "social" and "physical recovery" were decreased in week 0. No changes in the sport-specific stress scales were found. However, 2 of the sport-specific recovery scales were decreased in week 0. An impaired RE was shown 3 weeks after the NLE. Therefore, it is important to know what is going on in an athlete's life, because stressful life events alter RE after the stress and recovery already returned to normal levels.

Monitoring Perceived Stress and Recovery in Relation to Cycling Performance in Female Athletes.

The purpose was to investigate perceived stress and recovery related to cycling performance of female athletes over one full year. 20 female athletes (age, 27±8 years; ˙VO2max, 50.3±4.6 mL·kg(-1)·min(-1)) were measured 8 times in one year to determine perceived stress and recovery (RESTQ-Sport) in relation to cycling performance (Lamberts and Lambert Submaximal Cycle Test (LSCT)). All 19 RESTQ-Sport scales were calculated and scores of the 4 main categories were determined (i. e., general stress, general recovery, sport-specific stress and sport-specific recovery). A balance score of total stress and recovery was calculated by recovery-stress. Power at the second stage (P80), third stage (P90) and heart rate recovery (HRR60 s) of the LSCT were determined as performance parameters. 110 RESTQ-Sports and LSCTs were analysed using a multilevel approach (random intercepts model). Higher self-efficacy was related to improvement of all performance parameters. Higher total recovery stress, and lower emotional stress were related to improvement of P90 and HRR60 s. Higher sport-specific recovery was related to P80, higher general stress, fatigue and physical complaints were related to decreased P90 and higher social stress and injury were related to decreased HRR60 s. Improved perceived recovery and stress contributed to an improved performance. Relevant information could be provided by monitoring changes in perceived stress and recovery of female athletes.

Quality improvement by implementing an integrated oncological care pathway for breast cancer patients.

BACKGROUND AND AIM: In cancer care, more and more systemized approaches such as care pathways are used to reduce variation, reduce waiting- and throughput times and to improve quality of care. The aim of this study was to determine whether the implementation of a multidisciplinary breast cancer pathway in three hospitals has improved the care for breast cancer patients. METHODS: Retrospectively almost 800 patients with breast cancer were selected from the Netherlands Cancer Registry (NCR). The patients were divided in two groups: before implementation of the pathway in 2006-07 (baseline measurement) and those after implementation in 2009 (post measurement). Fourteen quality indicators were compared before and after the implementation of the care pathway. To estimate the impact of the care pathway relative to evidence based guidelines and profession-based norms, involved project leaders were interviewed. RESULTS: Seven out of eight indicators with medical information and four out of five indicators with information about waiting- and throughput times improved. With the multidisciplinary meeting as key in the breast cancer care, more compliance to national guidelines was observed. E.g. for more patients a HER2neu test was performed after implementation of the pathway (from 92% to 96%, ⤳ = 0.016) and more patients started with their first chemotherapy (from 33% to 45%) or their first radiotherapy (from 55% to 59%) within 4 weeks after surgery. CONCLUSION: Implementing a multidisciplinary breast cancer pathway leads to better compliance with the national guidelines and can improve breast cancer care.

The impact of organisational external peer review on colorectal cancer treatment and survival in the Netherlands.

BACKGROUND: Organisational external peer review was introduced in 1994 in the Netherlands to improve multidisciplinary cancer care. We examined the clinical impact of this programme on colorectal cancer care. METHODS: Patients with primary colorectal cancer were included from 23 participating hospitals and 7 controls. Hospitals from the intervention group were dichotomised by their implementation proportion (IP) of the recommendations from each peer review (high IP vs low IP). Outcome measures were the introduction of new multidisciplinary therapies and survival. RESULTS: In total, 45 705 patients were included (1990-2010). Patients from intervention hospitals more frequently received adjuvant chemotherapy for stage III colon cancer. T2-3/M0 rectal cancer patients from hospitals with a high IP had a higher chance of receiving preoperative radiotherapy (OR 1.31, 95% CI 1.11-1.55) compared with the controls and low IP group (OR 0.75, 95% CI 0.63-0.88). There were no differences in the use of preoperative chemoradiation for T4/M0 rectal cancer. Survival was slightly higher in colon cancer patients from intervention hospitals but unrelated to the phase of the programme in which the hospital was at the time of diagnosis. CONCLUSIONS: Some positive effects of external peer review on cancer care were found, but the results need to be interpreted cautiously due to the ambiguity of the outcomes and possible confounding factors.

Prognostic factors for locoregional recurrences in colon cancer.

BACKGROUND: There is increased interest in locoregional recurrences of rectal cancer. Despite comparable locoregional recurrence rates in colon cancer, only a few studies on locoregional recurrences among colon cancer patients have been published. This study was designed to identify prognostic factors for locoregional recurrences among patients with colon cancer in the Netherlands. METHODS: The study population was composed of patients who underwent radical surgical resections for invasive colon carcinoma, diagnosed in three regions of the Netherlands from 2000 to 2003. The Kaplan-Meier method was used to calculate 5-year locoregional recurrence rates (LRR). Conditional hazard rates were estimated by the life-table method. Multivariate Cox regression analyses were performed to identify prognostic factors and to calculate a Locoregional Recurrence Risk Score (LRRS). RESULTS: In total 127 of 2,282 patients developed locoregional recurrences within 5 years (LRR 6.4%). The risk of developing a locoregional recurrence was highest at 0.5-1 year after surgery. Patients with left-sided tumors, T3-T4 tumors, and positive lymph nodes and those who did not receive adjuvant chemotherapy were more likely to develop locoregional recurrences. Four risk groups based on the LRRS were defined. Five-year LRR was 2.5% for the very low-risk group and 25.1% for the high-risk group. CONCLUSIONS: Although the locoregional recurrence rate in this study was relatively low, it remains a considerable problem. Identifying individual patients who might benefit from adjuvant chemotherapy may reduce the locoregional recurrence rate.

Implementation of trastuzumab in conjunction with adjuvant chemotherapy in the treatment of non-metastatic breast cancer in the Netherlands.

Trastuzumab in conjunction with adjuvant chemotherapy markedly improves outcome. In the Netherlands, a national guideline was released in September 2005 stating that trastuzumab should be given in conjunction with adjuvant chemotherapy in women with HER2-positive breast cancer. Aim of this study was to identify the number of women with HER2-positive breast cancer and to evaluate the level of implementation of adjuvant trastuzumab in clinical practice nationwide. Women diagnosed with primary breast cancer between September 2005 and January 2007 were selected from the Netherlands Cancer Registry (NCR). HER2 status, adjuvant treatment and reasons to withhold trastuzumab were registered. 14,934 Breast cancer patients were diagnosed in this period of whom 1,928 (13%) had a HER2-positive tumour. Of all HER2-positive women receiving adjuvant chemotherapy, 66 (6%) did not receive trastuzumab. This percentage decreased from 10% at the time of introduction of the guideline to 4% in the study period September 2005-December 2006. Most common reasons to withhold trastuzumab were cardiovascular disease (29%) and patient refusal (21%). Of all HER2-positive patients who received adjuvant chemotherapy, 94% received trastuzumab. The implementation of trastuzumab in clinical practice was realized within 8 months after introduction of the new guideline.

Telephone consultations on palliative sedation therapy and euthanasia in general practice in The Netherlands in 2003: a report from inside.

BACKGROUND: GPs with a special interest and with specific training in palliative medicine (GP advisors) supported professional carers (mostly GPs) through a telephone advisory service. Each telephone call was formally documented on paper and subsequently evaluated. OBJECTIVE: Data from 2003 were analysed independently to reveal how often and in what way palliative sedation and euthanasia were discussed. METHODS: The telephone documentation forms and corresponding evaluation forms of two GP advisors were systematically analysed for problems relating to the role of sedation and/or euthanasia both quantitatively and qualitatively. RESULTS: In 87 (21%) of 415 analysed consultations, sedation and/or euthanasia were discussed either as the presenting question (sedation 26 times, euthanasia 37 times and both 10 times) or arising during discussion (sedation 11 times and euthanasia three times). Qualitative analysis revealed that GPs telephoned to explore therapeutic options and/or wanted specific information. Pressure on the GP (either internal or external) to relieve suffering (including shortening life by euthanasia) had often precipitated the call. On evaluation, 100% of the GPs reported that the advice received was of value in the patient's care. CONCLUSION: GPs caring for patients dying at home encountered complex clinical dilemmas in end-of-life care (including palliative sedation therapy and euthanasia). They valued practical advice from, and open discussion with, GP advisors. The advice often helped the GP find solutions to the patient's problems that did not require deliberately foreshortening life.

Cancer in adolescents and young adults in north Netherlands (1989-2003): increased incidence, stable survival and high incidence of second primary tumours.

BACKGROUND: Lack of survival improvement in adolescents and young adults (AYA) with cancer has led to increased awareness of this young population. DESIGN: We carried out a population-based study of incidence and survival of primary tumours and second primary tumours in patients aged 12-24 in north Netherlands. Age-specific incidence rates per 100,000 and 3-year moving means were calculated. Factors associated with incidence and survival were assessed using a Poisson model, log-rank test and multivariate Cox proportional hazards analysis. RESULTS: From 1989 to 2003 a total of 1118 patients were diagnosed. The total age-specific incidence rates per 100,000 were as follows: males: 13.4 (12-15 years), 26.9 (16-19 years) and 27.5 (20-24 years) and females: 13.9, 20.7 and 20.7. Male : female ratio was 1.32. The overall estimated annual percentage change (EAPC) in incidence was 2.15% (P < 0.01). Five-year survival was 80.8% and did not improve during the study period. With median follow-up of 5.5 years (range 0.0-16.0) in our cohort the standardized incidence ratio (SIR) of second primary tumours was 30.55 (95% confidence interval = 19.96-44.76, P < 0.05). CONCLUSIONS: The total incidence of cancer in AYA increased (EAPC = 2.15%). Survival was unchanged. The SIR of a second primary tumour in this young cohort increased 31-fold. Further research is needed to study this increasing incidence and optimise treatment outcome in these young patients.

Guideline adherence for early breast cancer before and after introduction of the sentinel node biopsy.

This population-based study aimed to analyse variations in surgical treatment and guideline compliance with respect to the application of radiotherapy and axillary lymph node dissection (ALND), for early breast cancer, before and after the sentinel node biopsy (SNB) introduction. The study included 13 532 consecutive surgically treated stage I-IIIA breast cancer patients diagnosed in 1989-2002. Hospitals showed large variation in breast-conserving surgery (BCS) rates, ranging between 27 and 72% for T1 and 14 and 42% for T2 tumours. In multivariate analysis marked inter-hospital and time-dependent variation in the BCS rate remained after correction for case-mix. The guideline adherence was markedly lower for elderly patients. In 25.2% of the patients aged > or = 75 years either ALND or radiotherapy were omitted. The proportion of patients with no ALND after an SNB increased from 1.8% in 1999 to 37.8% in 2002. However, in 2002 also 12.2% of the patients with a positive SNB did not have an ALND. Guideline compliance for BCS, with respect to radiotherapy and ALND, fell since the SNB introduction, from 96.1% before 2000 to 91.4% in 2002 (P < 0.001). Noncompliance may however reflect patient-tailored medicine, as for elderly patients with small, radically resected primary tumours. The considerable variation in BCS-rates is more consistent with variations in surgeon preferences than patient's choice.

Soft tissue sarcoma: why not treated?

BACKGROUND: Soft tissue sarcomas (STS) are uncommon malignancies and elderly STS patients have been reported to receive less definitive treatment compared to young STS patients. The present study was performed to investigate whether withholding treatment was based on disease specific aspects, patients' general health condition, comorbidity or a combination of these. METHODS: Patients with primary STS, registered by the Comprehensive Cancer Center North-Netherlands (CCCN) from 1989 to 1999, were analyzed retrospectively with regard to the inclusion-criteria: no primary anti-tumor treatment. RESULTS: From 1989 to 1999, 620 patients (including 56 Kaposi sarcoma) were registered with primary STS. Seventy-six patients (13%) were registered as untreated. Nineteen patients were excluded. Records of 57 patients, median age 71 years (range 23-92, 40 patients > or =65 years, 17 patients < 65 years) were examined. The reasons for no treatment were irresectability of the sarcoma (65%), metastatic disease (11%), comorbidity (4%), poor general health (5%), death prior to therapy (7%) and refusal of therapy (3%) (motivation not documented in 5%). CONCLUSIONS: Thirteen percent of all STS patients within the CCCN region were not treated, 70% of these patients were elderly. Withholding treatment was mostly disease-related (76%), e.g. irresectable retroperitoneal STS or metastatic disease; for 19% of the patients, it was related to their poor general health. The decision to refrain from cancer treatment was justifiable in all these STS patients.

Physical functioning and quality of life after cancer rehabilitation.

In order to overcome cancer-related problems and to improve quality of life, an intensive multi-focus rehabilitation programme for cancer patients was developed. We hypothesised that this six-week intensive rehabilitation programme would result in physiological improvements and improvement in quality of life. Thirty-four patients with cancer-related physical and psychosocial problems were the subjects of a prospective observational study. A six-week intensive multi-focus rehabilitation programme consisted of four components: individual exercise, sports, psycho-education, and information. Measurements (symptom-limited bicycle ergometry performance, muscle force and quality of life [RAND-36, RSCL, MFI]) were performed before (T0) and after six weeks of rehabilitation (T1). After the intensive rehabilitation programme, statistically significant improvements were found in symptom-limited bicycle ergometry performance, muscle force, and several domains of the RAND-36, RSCL and MFI. The six-week intensive multi-focus rehabilitation programme had immediate beneficial effects on physiological variables, on quality of life and on fatigue.

Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study.

PURPOSE: To determine the radiosensitizing effect of prolonged exposure of carboplatin in patients with locally unresectable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with histologically proven NSCLC, performance score <2, weight loss <10%, and normal organ functions were randomized between carboplatin 840 mg/m2 administered continuously during 6 weeks of radiotherapy or thoracic radiotherapy alone (both 60 Gy). Toxicity was evaluated with National Cancer Institute Common Toxicity Criteria (NCI CTC) and the Radiation Therapy Oncology Group (RTOG) criteria. Quality of life was measured with European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/LC13 questionnaires. RESULTS: One-hundred and sixty patients were included. Pathologically confirmed persistent tumor was present in 53% of patients in the combination arm versus 58% in the radiotherapy alone arm (P=0.5). Median survival in the combination arm was 11.8 [95% confidence interval (CI) 9.3-14.2] months and in the radiotherapy alone arm 11.7 (95% CI 8.1-15.5) months; progression-free survival was not different between arms [6.8 and 7.5 months, respectively (P=0.28)]. Acute toxicity was mild, late toxicity was radiation-induced cardiomyopathy (three patients) and pulmonary fibrosis (five patients). Quality of life was not different between arms, but in all measured patients cough and dyspnea improved, pain became less, and slight paresthesia developed 3 months after treatment. CONCLUSION: Addition of continuously administered carboplatin as radiosensitizer for locally unresectable NSCLC does not improve local tumor control or overall survival.