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The Prospective Dutch Colorectal Cancer (PLCRC) cohort: real-world data facilitating research and clinical care
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Jeroen W. G. Derksen1,2,
Geraldine R. Vink1,3,
Marloes A. G. Elferink3,
Jeanine M. L. Roodhart1,
Helena M. Verkooijen4,
Wilhelmina M. U. van Grevenstein5,
Peter D. Siersema6,7,
Anne M. May2 na1,
Miriam Koopman1 na1 &
The PLCRC Study Group
Scientific Reports volume 11, Article number: 3923 (2021) Cite this article
Real-world data (RWD) sources are important to advance clinical oncology research and evaluate treatments in daily practice. Since 2013, the Prospective Dutch Colorectal Cancer (PLCRC) cohort, linked to the Netherlands Cancer Registry, serves as an infrastructure for scientific research collecting additional patient-reported outcomes (PRO) and biospecimens. Here we report on cohort developments and investigate to what extent PLCRC reflects the "real-world". Clinical and demographic characteristics of PLCRC participants were compared with the general Dutch CRC population (n = 74,692, Dutch-ref). To study representativeness, standardized differences between PLCRC and Dutch-ref were calculated, and logistic regression models were evaluated on their ability to distinguish cohort participants from the Dutch-ref (AU-ROC 0.5 = preferred, implying participation independent of patient characteristics). Stratified analyses by stage and time-period (2013–2016 and 2017–Aug 2019) were performed to study the evolution towards RWD. In August 2019, 5744 patients were enrolled. Enrollment increased steeply, from 129 participants (1 hospital) in 2013 to 2136 (50 of 75 Dutch hospitals) in 2018. Low AU-ROC (0.65, 95% CI: 0.64–0.65) indicates limited ability to distinguish cohort participants from the Dutch-ref. Characteristics that remained imbalanced in the period 2017–Aug'19 compared with the Dutch-ref were age (65.0 years in PLCRC, 69.3 in the Dutch-ref) and tumor stage (40% stage-III in PLCRC, 30% in the Dutch-ref). PLCRC approaches to represent the Dutch CRC population and will ultimately meet the current demand for high-quality RWD. Efforts are ongoing to improve multidisciplinary recruitment which will further enhance PLCRC's representativeness and its contribution to a learning healthcare system.
Global colorectal cancer (CRC) incidence is expected to increase in the coming decades1, which emphasizes the need to fulfill current knowledge gaps and improve clinical outcomes. In the current era of precision medicine, smaller treatment‐eligible target populations are both an advancement as well as a challenge in cancer research2,3. Due to the large amount of CRC subgroups defined by clinical characteristics in combination with the many (low-frequency) molecular markers4,5,6, the enrollment of sufficiently large sample sizes in studies evaluating the safety and efficacy of new therapeutic agents is a growing challenge. In addition, selective enrollment in most phase III randomized clinical trials (RCTs) may affect the generalizability of trial results and limits our understanding of the "true" treatment's benefit-risk profile in the broader patient population. This is a constraint in clinical cancer research, given that international clinical guidelines are often based on results from strongly selected trial populations.
As advocated by both the research community and regulators such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the development of high quality population-based studies in cancer patients that provide real-world data (RWD) is a major research priority to overcome challenges in research methodologies, complement RCT data, and ultimately improve patient outcomes7,8. A learning healthcare system approach, defined as a circular system in which "science, informatics, incentives, and culture are aligned for continuous improvement and innovation, with best practices seamlessly embedded in the delivery process and new knowledge captured as an integral by-product of the delivery experience"9, uses RWD to accelerate knowledge generation and its translation into clinical practice. RWD mainly distinguishes itself from trial-based evidence by being population-level data originating from sources outside of the typical clinical research setting, such as electronic health records (EHRs) or cancer registries, with the potential to efficiently answer research questions relevant to the broader patient population10. To warrant high quality RWD, ascertaining a high quality of primary data (i.e. completeness and accuracy of EHRs), linkage of data sources, and quality of derived variables, is paramount11,12. Altogether, a prospective "real-world" cohort requires longitudinal patient, treatment (sequences), and outcome data from an unselected and representative patient population.
Since 2013, the Prospective Dutch Colorectal Cancer (PLCRC) cohort collects extensive longitudinal clinical data, together with blood, (tumor) tissue, and repeated patient-reported outcomes (PROs) in patients with stage I to IV CRC that are prospectively followed from primary diagnosis until death13. PLCRC serves as an infrastructure for a wide variety of research projects including etiological, biomarker, basic, (epi)genetic, and interventional [according to the Trials within Cohorts (TwiCs) design14], as well as health-care policy and cost-effectiveness studies. In order for results to be generalizable, and for accurate evaluation of cancer treatments, it is important to obtain a cohort that consists of a demographically and clinically representative patient population. Therefore, the aims of this manuscript are to (1) describe developments towards a nationwide cohort, (2) provide baseline characteristics, including PROs, of the first 5722 participants, and (3) investigate to what extent PLCRC reflects the "real-world"—over time and by tumor stage—by comparing PLCRC cohort participants with the general Dutch CRC population as registered in the Netherlands Cancer Registry (NCR).
PLCRC is an initiative coordinated by the Dutch Colorectal Cancer Group (DCCG) and is registered at Clinicaltrials.gov (NCT02070146). The 'Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)' guidelines were taken into account when the cohort was designed15. We here describe the cohort briefly since the detailed design is published elsewhere13.
The PLCRC population
PLCRC consists of patients diagnosed with a malignancy of the colon and/or rectum (ICD-10, C18-20) in the Netherlands. Each patient with histologically proven, or a strong suspicion of CRC without pathological confirmation, who is ≥ 18 years of age is eligible. The informed consent procedure is preferably performed shortly after diagnosis and before treatment starts. However, patients can also be enrolled during treatment or follow-up. Consent for longitudinal clinical data collection is mandatory for participation. In addition, patients can choose to consent to other optional items as shown in Box 1. Patients enrolled before August 1, 2019 of whom complete clinical data of the initial diagnosis and treatment period were available—to ascertain correct classification of tumor stage—were included in the analyses. Of these patients, baseline demographic and clinical data were retrieved and reported, as well as self-reported physical activity, fatigue, quality of life, BMI, presence of chronic comorbidities, smoking behavior, alcohol consumption, education level, and living situation at baseline.
Box 1 Informed consent options and main objectives of PLCRC.
The Netherlands Cancer Registry (NCR)
The Netherlands Cancer Registry (NCR) contains an extensive set of clinical data—from diagnosis onwards—of individuals diagnosed with cancer in the Netherlands and has a national coverage of over 95%16. Clinical data of the complete treatment trajectory are retrieved from EHRs and entered into the NCR. Importantly, the completeness of the NCR therefore depends on the completeness of EHRs. Overall, the NCR's high quality is assured by thorough training of data managers and computerized consistency checks. PLCRC's informed consent allows for linkage with the NCR and thus ensures the availability of clinical data over the complete cancer trajectory.
For the current analysis, only data of the initial data registration phase, i.e. at diagnosis, were used. We compared characteristics of PLCRC participants with the general Dutch CRC population (Dutch-ref) from the NCR with incidences between January 1, 2013 and December 31, 2017.
Descriptive statistics were used to describe baseline patient characteristics, including baseline PROs. Standardized differences (d) were calculated to quantify the magnitude of differences in patient characteristics between PLCRC participants and the Dutch-ref. Values greater than 0.20 indicate a large imbalance, while values between 0.10 and 0.20 indicate a small imbalance, and standardized differences less than 0.10 indicate a negligible imbalance17,18. Results are shown for the total group and stratified by tumor stage and time of enrollment. Two time-periods (enrolled between 2013–'16 and 2017–August '19) were evaluated to assess whether PLCRC participants became more representative of the Dutch-ref over time. Logistic regression models were used to investigate to what extent, based on the available a priori selected patient characteristics (i.e. age, sex, primary tumor location and tumor stage), cohort participation could be predicted19. Model performance was assessed based on calibration and discrimination20. Calibration—the goodness of fit—was evaluated using the Hosmer–Lemeshow test21. Discrimination refers to the ability to distinguish cohort participants from non-participants, and was quantified by the area under the receiver operating characteristic curve (AU-ROC)20. The AU-ROC ranges from 1, corresponding to perfect discrimination, to 0.5, corresponding to a model with no discrimination ability, here preferred and defined as cohort participation independent of patient characteristics (0.5 = random chance, 0.5–0.7 = poor, 0.7–0.8 = good, 0.8–1.0 = strong, 1.0 = perfect prediction)22. Statistical analyses were performed using STATA (Release 15, Stata Corp LLC, College Station, TX) and SPSS (version 25.0, IBM Corp, Armonk, NY).
The study protocol was approved by the Institutional Review Board of the University Medical Center Utrecht (The Netherlands). All procedures performed that involved human participants were in accordance with the institutional and/or national ethical standards and guidelines as well as with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent to participate
Informed consent was obtained from all individual participants included in the study.
The flowchart for the selection of individuals for the current analyses is shown in Fig. 1. On August 1, 2019, a total of 5744 patients were enrolled. A complete TNM tumor stage could not be retrieved for 22 patients, who were therefore not included in the analyses.
Flow diagram of the selection of individuals for the current analyses. aInsufficient data in patient's EHRs for the NCR to collect a complete TNM stage. bMissing due to time-lag in NCR clinical data collection. This number is higher than presented in Table 1, as for some cases sufficient staging information was available to classify into TNM stage.
Developments towards a nationwide cohort
PLCRC has continuously strengthened its infrastructure to improve the enrollment rate. In August 2019, patients were enrolled in 50 of 75 Dutch hospitals including 7 (of 8) academic hospitals, 22 (of 26) top clinical hospitals that focus on education and research, and 21 (of 41) regular hospitals (Fig. 2). This led to an improved annual enrollment-rate, from 129 participants from 1 recruiting hospital in 2013 to 2136 from 50 recruiting hospitals in 2018 (note that there are approx. 14,000 incident cases annually). At enrollment, 100% of patients consented for using their clinical data obtained from the NCR, which was mandatory, 81% consented to receive repeated PRO questionnaires, 83% for blood withdrawals, 95% for use of tissue for scientific research, 83% for contact when relevant DNA abnormalities are found, and 78% for future research and trials according to the TwiCs design (Fig. 3). Once consented to receive questionnaires for PROs, 77% of patients returned their baseline questionnaire, and completion rates remained above 60% in the first three years after enrollment (Fig. 4). Interestingly, patients who received paper-based questionnaires had consistently higher completion rates compared to electronic questionnaires (85% vs. 72% at baseline, respectively).
PLCRC recruiting hospitals (academic, non-academic, and top clinical hospitals) over time. Note: In The Netherlands there is a total of 75 hospitals, of which 8 academic hospitals and 26 top-clinical hospitals.
Baseline informed consent percentages per item. The use of clinical NCR data is 100% since this item is mandatory for participation. NCR Netherlands Cancer Registry, PROs patient-reported outcomes, TwiCs Trials within Cohorts.
Completion rates of questionnaires until three years after enrollment. Overall completion rates are presented in the bars, and electronic and paper-based percentages at the dashed lines. Time-points (T) are months since enrollment.
Baseline patient characteristics
The cohort contained 851 patients with stage I CRC, 1079 with stage II, 1960 with stage III, 946 with stage IV, and 886 patients of whom data on tumor stage is still being collected (Table 1). The median number of days from diagnosis until enrollment was 18 (IQR: 1 to 131) for the total cohort, and was similar for all stages except for stage IV patients, who were enrolled much later in the cancer trajectory (188 [IQR: 23 to 670] days). The percentage of males was higher than females for all stages, and 61% of the patients had a primary tumor located in the colon, and 39% in the rectum. Of the 946 stage IV patients, 79% had synchronous liver, 22% lung, and 17% peritoneal metastases. Regarding molecular diagnostics at diagnosis, RAS status was available in 596 (10%) patients, BRAF in 570 (10%), and microsatellite instability (MSI) in 2600 (45%). In terms of physical and psychological wellbeing at enrollment (supplementary Table 1), patients reported to experience impaired psychosocial functioning, and high levels of fatigue, appetite loss and diarrhea as compared to reference populations (refs).
Table 1 Baseline descriptive demographic and clinical characteristics at PLCRC enrollment, stratified by tumor stage.
PLCRC versus the general Dutch CRC population
While the logistic regression model including age, sex, primary tumor location, and tumor stage overestimates the probability of participation (p < 0.001), the low discriminative power (AU-ROC 0.65, 95% CI: 0.64–0.65) indicates limited ability to distinguish cohort participants from the Dutch-ref, based on available data (full ROC curves in supplementary Fig. 1). This discrimination decreased over time from an AU-ROC of 0.70 (95% CI: 0.68–0.71) in PLCRC's initial phase (2013–'16) to 0.64 (95% CI: 0.63–0.64) in the most recent phase (2017–Aug '19).
Between PLCRC participants (n = 4759) and the Dutch-ref (n = 72,685), large imbalances were found for age at diagnosis (64.9 years in PLCRC, 69.3 in the Dutch-ref, dage 0.41), primary tumor location (43% rectum in PLCRC and 31% in the Dutch-ref, dpr.tumor 0.24) and TNM stage (41% stage III in PLCRC and 30% in the Dutch-ref, dtnm 0.24), a small imbalance in sex (62% male in PLCRC and 57% in the Dutch-ref, dsex 0.11), and negligible imbalances in BMI at diagnosis (26.6 in PLCRC and 26.6 in the Dutch-ref, dbmi 0.01) and in location of synchronous metastasis (15% liver in PLCRC and 15% in the Dutch-ref, dmeta between 0.01 and 0.08), Table 2.
Table 2 Characteristics of PLCRC participants at diagnosis (2013-Aug'19), compared with the general Dutch CRC population (2013–'17), and stratified by time-period (2013–'16, and 2017–Aug'19).
When the two time-periods were compared with the Dutch-ref to study PLCRC's evolution, a large imbalance remained for age at diagnosis and tumor stage (dage from 0.45 to 0.40, dtnm from 0.33 to 0.22). The distribution of sex, BMI at diagnosis, and primary tumor location improved to imbalances classified as small or negligible (dsex from 0.17 to 0.09, dbmi from 0.16 to 0.03, dpr.tumor from 0.53 to 0.16). For location of synchronous metastases, e.g. liver metastasis, the imbalance compared with the Dutch-ref was negligible in both time periods (dliver from 0.08 to 0.04).
Table 3 shows stratified analyses in which PLCRC participants were compared with the Dutch-ref by tumor stage. Age at diagnosis was lower for PLCRC participants in all stages, and discrepancies increased by stage (dage from 0.28 in stage I to 0.55 in stage IV). For all disease stages, PLCRC contained relatively more patients with a primary tumor in the rectum and fewer patients with a primary tumor in the colon, compared with the Dutch-ref (dpr.tumor between 0.14 and 0.25). The proportions of sex and BMI at diagnosis were comparable to the ref. population in all stages (dsex between 0.08 and 0.19, dbmi between 0.01 and 0.08).
Table 3 Characteristics of the PLCRC participants at diagnosis (2013–Aug'19), compared with the general Dutch CRC population (2013–'17), stratified by tumor stage.
Over the past six years, the increased number of PLCRC recruiting centers has resulted in a steep increase in participating patients, with excellent consent rates for PROs, blood and tissue biobanking, and participation in future research within PLCRC. Although we found an overall shift towards the Dutch-ref for patients enrolled between 2017–Aug 2019, regular hospitals remain underrepresented as participating centers to enroll patients and PLCRC participants were still younger and more often had stage III disease, as compared to the total Dutch CRC population.
Besides common discrepancies such as performance status and number of comorbidities, clinical trial participants are notably younger than the real-world population, which for now might hamper the applicability of trial results in daily clinical practice. It was recently shown that phase-III RCT patients were on average seven years younger than the general CRC population23. Similarly, patients within PLCRC are younger compared to the Dutch-ref, however, this difference only is 4 years (mean age 65 years). Standardized differences for age increased by tumor stage, with stage IV patients showing a mean age comparable to phase-III clinical trials in metastatic CRC24. This emphasizes the need to focus on the enrollment of (stage IV) patients that are diagnosed at older age. Although important factors such as comorbidities and performance status are currently unknown, we believe that PLCRC has the potential to serve as a research platform that fulfills the current demand for RWD as advocated for by regulators and research community. The additional advantage of PLCRC is the large collection of biospecimen, which is intertwined with routine clinical care, and longitudinal PROs from diagnosis onwards. Moreover, the incorporation of PROs that describe the impact of treatment on quality of life, daily activities and symptoms is increasingly recognized as an essential component of real-world evidence and has the potential to improve cancer care, shared decision making, and clinical outcomes25,26,27.
Dutch CRC guidelines recommend, in line with the European guidelines, to determine both mismatch repair status in stage II-IV tumors, and RAS and BRAF mutation status in tumor of patients with metastatic CRC prior to the start of systemic treatment28,29,30. Although our percentages may be an underestimation as mutation status could become available during NCR updates after the initial data registration, the amount of missing data on molecular diagnostics is noteworthy. A limitation that is currently inevitable within PLCRC is that completeness of the NCR depends on daily clinical practices. In contrast to the above mentioned national guidelines, molecular markers are not routinely measured in all patients in the clinic. This means that currently, PLCRC is missing opportunities to optimally use tumor mutation status for research purposes. Efforts are ongoing to perform retrospective molecular profiling within PLCRC to supplement existing molecular pathology data with the aim to be able to tailor treatment options to the individual patient in the future. Next to the identification of predictors for treatment response and clinical outcomes, this will also contribute to the development of a unique cohort that could provide "external" controls for future single arm clinical trials in uncommon CRC subtypes with high unmet medical need31,32.
Given the large variety of available data, PLCRC will allow for comprehensive analyses on CRC. However, future improvements are required to optimize two fundamental elements of RWD sources: completeness of cases and completeness of clinical data. Based on our experience, over 90% of patients provide informed consent once the study aim is explained. Enhanced integration of research into daily clinical practice and the development of local infrastructures that lead to increased willingness and availability of personnel to inform the patient about PLCRC, especially in regular hospitals, are crucial to further improve the completeness of cases and create a true RWD cohort. Second, completeness of clinical data mainly depends on how well clinicians document clinical data in EHRs. Regardless of the list of items to be collected in the NCR, unmeasured or undocumented data will never become available to the research community. Moreover, EHR data are often unstructured and inconsistent due to large variation between clinicians and differences in EHR software systems. Bertagnolli and colleagues33 recently stated that the use of data obtained during routine clinical care as "real-world" data to fuel a learning healthcare system is currently still in its infancy. Prior to utilizing EHRs to facilitate a learning health system, EHRs must contain readily exchangeable and clinically meaningful structured data elements of adequate quality to draw valid inferences33. Therefore, we emphasize that nationwide harmonization and standardization of clinical data entries in EHRs and subsequent implementation of electronic data-capture systems to enable real-time data transfer from EHRs to the NCR, will significantly enhance the completeness and quality of clinical data.
Future focus should be given to reaching and enrolling older patients and to enhance involvement of the gastroenterology departments to enroll patients with early stage tumors. Moreover, especially stage IV patients should be enrolled closer to diagnosis to standardize time points for PROs and avoid potential survivor bias. This can be achieved by an optimal research-focused infrastructure and implementation of research-specific consultations for all cancer patients shortly after diagnosis. During this consultation, the patient is informed about the specific components of PLCRC (Box 1), as well as on the main aim to optimally evaluate treatments, accelerate innovation, and learn from each individual patient. Such an infrastructure will also contribute to enrolling patients with the least hospital visits, e.g. patients with a polypectomy only, or extensively metastasized disease with rapid progression and best supportive care only. Besides the aforementioned suggestions, we need to create a societal change with respect to clinical research. All stakeholders should be aware that, in order to improve oncology practice, research needs to become an integrated part of clinical care and that contributions to clinical research are self-evident. Lastly, PLCRC is a platform to centralize national CRC research to maximize its potential and minimize patient burden. Access to cohort resources for collaborative research projects may be requested through the Scientific Committee [https://plcrc.nl/for-international-visitors] that reviews all research projects for approval.
To conclude, PLCRC is establishing a unique and steeply growing national RWD cohort that allows for a wide range of research. Data from the general patient population enables a learning healthcare system that provides insight into the care and outcomes of patients that are usually underrepresented in RCTs, e.g. the very young and older patients and the ones with multiple comorbidities. Comprehensive analyses within PLCRC are facilitated by the extensive amount of clinical data covering the complete treatment trajectory and additional patient-reported outcomes. Further improvements in recruitment methodologies and multidisciplinary enrollment of patients will contribute to the aim of enrolling all newly diagnosed CRC patients in the Netherlands. This will continue to enhance PLCRC's representation of the real-world and its ability to improve both scientific research and daily clinical practice.
Access to cohort resources for collaborative research projects may be requested through the Scientific Committee [https://plcrc.nl/for-international-visitors] that reviews all research projects for approval.
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We thank all patients and staff at each of the participating hospitals. The authors would like to acknowledge Dr. S.G. (Sjoerd) Elias who provided statistical advice.
The Prospective Dutch Colorectal Cancer (PLCRC) cohort is an initiative of the Dutch Colorectal Cancer Group (DCCG). PLCRC is supported by the Dutch Cancer Society; Stand Up to Cancer; ZonMw; Health Holland; Maag Lever Darm Stichting; Lilly (unrestricted grant); Merck (unrestricted grant); Bristol-Myers Squibb (unrestricted grant); Bayer (unrestricted grant); and Servier (unrestricted grant). The current work is supported by the Province of Utrecht, the Netherlands.
These authors jointly supervised this work: Anne M. May and Miriam Koopman.
A comprehensive list of consortium members appears at the end of the paper.
Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, PO Box 85500, 3508 GA, Utrecht, The Netherlands
Jeroen W. G. Derksen, Geraldine R. Vink, Jeanine M. L. Roodhart & Miriam Koopman
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, PO Box 85500, 3508 GA, Utrecht, The Netherlands
Jeroen W. G. Derksen & Anne M. May
Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), PO Box 19079, 3501 DB, Utrecht, The Netherlands
Geraldine R. Vink & Marloes A. G. Elferink
Imaging Division, University Medical Center Utrecht, Utrecht University, PO Box 85500, 3508 GA, Utrecht, The Netherlands
Helena M. Verkooijen
Department of Surgical Oncology, University Medical Center Utrecht, Utrecht University, PO Box 85500, 3508 GA, Utrecht, The Netherlands
Wilhelmina M. U. van Grevenstein
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, PO Box 85500, 3508 GA, Utrecht, The Netherlands
Peter D. Siersema
Department of Gastroenterology and Hepatology, Radboud UMC, Radboud University, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Surgery, Nederlands Kanker Instituut - Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Geerard L. Beets
Department of Surgery, Albert Schweitzer Hospital, Dordrecht, The Netherlands
Eric J. Th. Belt
Department of Radiotherapy, Maastro Clinic, Maastricht, The Netherlands
Maaike Berbée
Department of Surgery, Franciscus Gasthuis and Vlietland Hospital, Schiedam, The Netherlands
Frederique H. Beverdam
Department of Medical Oncology, Saxenburgh Hospital, Hardenberg, The Netherlands
Ruud Blankenburgh
Department of Surgery, Maasstad Hospital, Rotterdam, The Netherlands
Peter Paul L. O. Coene
Department of Medical Oncology, Antonius Hospital, Sneek, The Netherlands
Hester van Cruijsen
Department of Surgery, Reinier de Graaf Hospital, Delft, The Netherlands
Jan Willem T. Dekker
Department of Medical Oncology, Meander Medical Center, Amersfoort, The Netherlands
Joyce M. van Dodewaard-de Jong
Department of Medical Oncology, Zuyderland Hospital, Heerlen, The Netherlands
Frans L. G. Erdkamp
Department of Medical Oncology, Isala Oncology Center, Zwolle, The Netherlands
Jan Willem B. de Groot
Department of Medical Oncology, Ziekenhuis Gelderse Vallei, Ede, The Netherlands
Annebeth W. Haringhuizen
Department of Medical Oncology, Haaglanden Medical Center, Den Haag, The Netherlands
Helgi H. Helgason
Department of Medical Oncology, Northwest Clinics, Alkmaar, The Netherlands
Mathijs P. Hendriks
Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
Ignace H. J. T. de Hingh
Department of Medical Oncology, Ziekenhuisgroep Twente, Hengelo, The Netherlands
Ronald Hoekstra
Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Jan N. M. Ijzermans
Department of Surgery, Admiraal de Ruyter Hospital, Goes, The Netherlands
Jan Jansen
Department of Surgery, Treant Hospital, Emmen, The Netherlands
Frank W. H. Kloppenberg
Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Hospital, Amsterdam, The Netherlands
Anja U. G. van Lent
Department of Medical Oncology, St. Antonius Hospital, Nieuwegein, The Netherlands
Maartje Los
Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center - Loc. VU, University of Amsterdam, Amsterdam, The Netherlands
Martijn R. Meijerink
Department of Medical Oncology, Medisch Spectrum Twente, Enschede, The Netherlands
Leonie J. M. Mekenkamp
Department of Medical Oncology, Wilhelmina Hospital, Assen, The Netherlands
Peter Nieboer
Department of Surgery, Leiden University Medical Center, University of Leiden, Leiden, The Netherlands
Koen C. M. J. Peeters
Department of Medical Oncology, Sint Jans Hospital, Weert, The Netherlands
Natascha A. J. B. Peters
Department of Medical Oncology, Medical Center Leeuwarden, Leeuwarden, The Netherlands
Marco B. Polée
Department of Medical Oncology, Jeroen Bosch Hospital, Den Bosch, The Netherlands
Johannes F. M. Pruijt
Department of Medical Oncology, Amsterdam University Medical Center - Loc. AMC, University of Amsterdam, Amsterdam, The Netherlands
Cornelis J. A. Punt & Dirkje W. Sommeijer
Department of Medical Oncology, Haga Hospital, Den Haag, The Netherlands
Patricia Quarles van Ufford-Mannesse
Department of Medical Oncology, Rode Kruis Hospital, Beverwijk, The Netherlands
Ron C. Rietbroek
Department of Surgery, Diakonessenhuis Hospital, Utrecht, The Netherlands
Anandi H. W. Schiphorst
Department of Surgery, St Jansdal Hospital, Harderwijk, The Netherlands
Arjan Schouten van der Velden
Department of Gastroenterology and Hepatology, Bernhoven Hospital, Uden, The Netherlands
Ruud W. M. Schrauwen
Department of Medical Oncology, ZorgSaam Hospital, Terneuzen, The Netherlands
Mark P. S. Sie
Department of Medical Oncology, Maxima Medical Center, Eindhoven, The Netherlands
Lieke Simkens
Department of Medical Oncology, Flevo Hospital, Almere, The Netherlands
Dirkje W. Sommeijer
Department of Surgery, Dijklander Hospital, Purmerend, The Netherlands
Dirk J. A. Sonneveld
Department of Medical Oncology, Alrijne Hospital, Leiderdorp, The Netherlands
Leontine E. A. Spierings
Department of Surgery, Spaarne Hospital, Haarlem, The Netherlands
Hein B. A. C. Stockmann
Department of Surgery, Deventer Hospital, Deventer, The Netherlands
Koen Talsma
Department of Medical Oncology, Bravis Hospital, Roosendaal, The Netherlands
Frederiek Terheggen
Department of Medical Oncology, Amphia Hospital, Breda, The Netherlands
Albert J. ten Tije
Department of Medical Oncology, Rivierenland Hospital, Tiel, The Netherlands
Manuel L. R. Tjin-A-Ton
Department of Medical Oncology, Maastricht University Medical Center, Maastricht, The Netherlands
Liselot B. J. Valkenburg-van Iersel
Department of Gastroenterology and Hepatology, Martini Hospital, Groningen, The Netherlands
Renzo P. Veenstra
Department of Medical Oncology, Tergooi Hospital, Hilversum, The Netherlands
Ankie M. T. van der Velden
Department of Surgery, Ijsselland Hospital, Capelle Aan Den Ijssel, The Netherlands
Maarten Vermaas
Department of Surgery, Ikazia Hospital, Rotterdam, The Netherlands
Wouter J. Vles
Department of Surgery, Viecuri Hospital, Venlo, The Netherlands
Jeroen F. J. Vogelaar
Department of Medical Oncology, Rijnstate Hospital, Arnhem, The Netherlands
Theo van Voorthuizen
Department of Medical Oncology, Van Weel-Bethesda Hospital, Dirksland, The Netherlands
Aad I. de Vos
Department of Surgery, Elkerliek Hospital, Helmond, The Netherlands
Johannes A. Wegdam
Department of Surgery, Radboud University Medical Center, University of Nijmegen, Nijmegen, The Netherlands
Johannes H. W. de Wilt
Department of Surgery, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands
David D. E. Zimmerman
Jeroen W. G. Derksen
Geraldine R. Vink
Marloes A. G. Elferink
Jeanine M. L. Roodhart
Anne M. May
Miriam Koopman
, Eric J. Th. Belt
, Maaike Berbée
, Frederique H. Beverdam
, Ruud Blankenburgh
, Peter Paul L. O. Coene
, Hester van Cruijsen
, Jan Willem T. Dekker
, Joyce M. van Dodewaard-de Jong
, Frans L. G. Erdkamp
, Jan Willem B. de Groot
, Annebeth W. Haringhuizen
, Helgi H. Helgason
, Mathijs P. Hendriks
, Ignace H. J. T. de Hingh
, Ronald Hoekstra
, Jan N. M. Ijzermans
, Jan Jansen
, Frank W. H. Kloppenberg
, Anja U. G. van Lent
, Maartje Los
, Martijn R. Meijerink
, Leonie J. M. Mekenkamp
, Peter Nieboer
, Koen C. M. J. Peeters
, Natascha A. J. B. Peters
, Marco B. Polée
, Johannes F. M. Pruijt
, Cornelis J. A. Punt
, Patricia Quarles van Ufford-Mannesse
, Ron C. Rietbroek
, Anandi H. W. Schiphorst
, Arjan Schouten van der Velden
, Ruud W. M. Schrauwen
, Mark P. S. Sie
, Lieke Simkens
, Dirkje W. Sommeijer
, Dirk J. A. Sonneveld
, Leontine E. A. Spierings
, Hein B. A. C. Stockmann
, Koen Talsma
, Frederiek Terheggen
, Albert J. ten Tije
, Manuel L. R. Tjin-A-Ton
, Liselot B. J. Valkenburg-van Iersel
, Renzo P. Veenstra
, Ankie M. T. van der Velden
, Maarten Vermaas
, Wouter J. Vles
, Jeroen F. J. Vogelaar
, Theo van Voorthuizen
, Aad I. de Vos
, Johannes A. Wegdam
, Johannes H. W. de Wilt
& David D. E. Zimmerman
J.D: Conceptualization, Methodology, Data curation, Formal analysis, Visualization, Writing—original draft. G.V. Funding acquisition, Writing—review and editing. M.E.: Data curation, Formal analysis, Writing—review and editing. J.R.: Conceptualization, Supervision, Writing—review and editing. H.V.: Funding acquisition, Writing—review and editing. W.G.: Writing—review and editing. P.S.: Funding acquisition, Writing—review and editing. A.M.: Conceptualization, Methodology, Supervision, Writing—review and editing. M.K.: Funding acquisition, Conceptualization, Supervision, Writing—review and editing.
Correspondence to Miriam Koopman.
MK reports institutional financial interests with Amgen, Bayer, BMS, Merck-Serono, Nordic Pharma, Roche, Servier, Sirtex, and Sanofi-Aventis. MK reports the following non-financial interests: an advisory role for ZON-MW, membership of the scientific board of the Dutch Cancer Society (KWF), chairmanship of the Dutch Colorectal Cancer Group (DCCG), principal investigator (PI) of the Prospective Dutch Colorectal Cancer (PLCRC) cohort. GRV reports institutional financial interests with Servier, Merck, Bayer, Sirtex, BMS, and Lilly. JMLR reports institutional financial interests with Servier, Merck, and Bayer. PDS reports institutional financial interests with The eNose Company, Norgine, and Motus GI. JWGD, MAGE, HMV, WMUG, and AMM report no competing interests.
Supplementary Information.
Derksen, J.W.G., Vink, G.R., Elferink, M.A.G. et al. The Prospective Dutch Colorectal Cancer (PLCRC) cohort: real-world data facilitating research and clinical care. Sci Rep 11, 3923 (2021). https://doi.org/10.1038/s41598-020-79890-y
DOI: https://doi.org/10.1038/s41598-020-79890-y
Real-world-Daten in der Arzneimittelregulation – aktuelle Entwicklungen und Ausblick
Julia Wicherski
Katharina Schneider
Karl Broich
Prävention und Gesundheitsförderung (2023)


After much deliberation, I think I have chosen this image for my kitchen wall…………..
Its going to be 3.2m high x 3.8m wide, very large, but oh so magnificent. I don't want to go for your stereotypical foody, flower image that kitchens usually suffer from, but something magical and I suppose a talking point. With white gloss kitchen and plenty of colourful ceramics on my open shelves I think I am going to love it.
Well, it certainly does give one an appetite! Such a picture in the kitchen would certainly encourage one to get throught the main meal and on to dessert! Love it! Bet Baba Yaga would approve!


text:
Quaker Youth Pilgrimage 2010 Epistle
by micahin Uncategorizedon Posted on August 13, 2010
2010 Quaker Youth Pilgrimage
To Friends Everywhere:
Thirty-two pilgrims
From Friends to friends we became
With these words we part
An image of QYP begins to formulate, as fuzzy as it is, with twenty-eight youth and four adults sending in applications that will, over time, be reviewed and accepted. These thirty-two pilgrims are to gather together for a month in the summer of 2010, exploring Quakerism while journeying through parts of the Pacific Northwest. What brought us individuals together was our titles as Friends, and yet we were worlds apart in our definitions of Quakerism, as well as our expectations of what this pilgrimage would bring:
"I think QYP will give me a better idea of what all Quakers have in common, because I wonder 'what makes a Quaker?"- Emmie Touwen
"Through sharing and learning about other people and their way of life I feel I will gain something no other experience will allow me to gain."- Simon Rolph
Of course, the time between applications and the beginning of our trip allowed our expectations and levels of preparation to develop, in some cases dramatically. Nevertheless, we universally entered this journey with less than concrete ideas of what was to come.
Perhaps the most significant factor to set QYP apart from any other experience, Quaker or otherwise, is the sense of immersion which comes from living in a close-knit and, in many respects, isolated community for as long as we have. Our use of music as well as our introduction to compassionate listening added strength to the foundation of our connection.
However, so strong a sense of community takes time and effort to build, mistakes are made, allowing for knowledge to be gained. Structuring and organizing our community was a particular challenge, as we were not all accustomed to Quaker business practice, and (naturally for an international group) there was variation in the practices with which we were familiar.
Exposure is unavoidable, both in terms of how well we have gotten to know each other and how honest we are forced to be with ourselves. With a lack of privacy, we could not hide our true traits and emotions from others; we were stripped bare and left vulnerable. We were forced to examine ourselves both socially and spiritually and, immersed in our secure environment, allowed to address our faults and develop as individuals. Our identity as Quakers was frequently called into question, both through intimate discussion as well as whole-group activities deliberately formulated for self-exploration. For some people even calling themselves Quakers became discomforting when faced with the spectrum of belief which exists within the Religious Society of Friends. Since the majority of our group were previously unexposed to Programmed and Evangelical Friends, such experiences caught us off guard and again challenged our ideas on what unites us as Quakers.
Through some of these foreign experiences, we were forced to realize how limited our own knowledge of Quakerism was, and thus educating ourselves became an integral part of our shared experience. Among these, we gained a new idea of hospitality. We were the cause of genuine excitement not only in Quaker Churches, but also in the homes of Seattle, Portland, and Camas Friends. Contrary to our fears, Friends across branches were willing to hear our voices and our beliefs, not with the intention to convert but with the intention to listen with love. This in particular is among the most significant lessons we hope to bring home. Many of us also leave having unearthed an unanticipated respect for the teachings of the Bible and their relationship to the core values of Quakerism. Our growth and exploration throughout the pilgrimage also highlighted many difficulties. These included exploring the differences in our faith with other pilgrims and the limited time for exploring our spirituality as a group. This has left many of us with a desire to maintain and extend this interest beyond QYP.
As a gathered youth, we are empowered to speak of one final, lasting concern. Throughout the pilgrimage we were reminded of the saddening truth that we are not a complete gathering of Friends. We will not be a complete gathering until there is a fair representation of all sections of the Religious Society of Friends. In this pilgrimage there was only one youth from a pastoral background. Overall, there were four Friends—out of the thirty-two total—that consider themselves evangelical or conservative Friends. For those members of the community, it was difficult at times to feel safe in expressing their beliefs. With this in mind, we as Quakers call for a greater commitment to improving the diversity of this pilgrimage. While we cannot deny the power of the Spirit's presence in the group, it is important to realize that a greater learning experience could have been achieved from a more representative community.
Our journey has finally reached its end; as a community we are readying to leave. We have written our words of reflection, hoping that those outside of the community will not only understand the essence of this pilgrimage but also that those within will be able to look back at this with the willingness to return to being vulnerable and honest, even in the presence of conflict.
"In the past, I couldn't bring Quakerism home with me. It was a week every year and then a couple of weekends when I could be a Quaker. Now I'm going to be a Quaker all of the time" – Mason George
"This trip has taught me that it's our actions that make us Quaker just as much as our beliefs. I definitely have more drive to 'put faith into action'" – Naomi Garnault
npym,nwym,qyp

redpajama_set_name: RedPajamaCommonCrawl


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text:
Поліканов Володимир Олексійович (1940—1994) — радянський російський футболіст, нападник.
 Поліканов Герасим Павлович (1907—1972) — старший сержант РА, учасник Другої світової війни, Герой Радянського Союзу.
 Поліканов Олександр Миколайович — підполковник Збройних сил України; миротворець.
 Поліканов Сергій Михайлович (1926—1994) — фізик, член-кореспондент АН СРСР з 1974 року, член Московської Гельсінської групи. Лауреат Ленінської премії.

redpajama_set_name: RedPajamaWikipedia


text:
Home 6 future Qualcomm wifi Qualcomm Announces Wi-Fi 6 For Automotive, Bringing Greater Capacity for Premium In-Vehicle Experiences
Qualcomm Announces Wi-Fi 6 For Automotive, Bringing Greater Capacity for Premium In-Vehicle Experiences
Qualcomm Technologies, Inc., a subsidiary of Qualcomm Incorporated (NASDAQ: QCOM), today introduced the new Qualcomm® Automotive Wi-Fi 6 chip, the QCA6696, bringing the next generation of Wi-Fi and Bluetooth® connectivity to the automotive industry. Complementing the Qualcomm® SnapdragonTM Automotive 4G and 5G Platforms, the QCA6696 is Qualcomm Technologies' most advanced Wi-Fi solution designed to offer fast, secure and efficient Wi-Fi connectivity, to meet consumer demands for greater robustness and reduced latency when operating in congested and dense environments.
The QCA6696 features dual Wi-Fi 6 multiple-input multiple output (MIMO) access points designed to support Gigabit in-car hotspot and to deliver efficient Wi-Fi connectivity throughout the vehicle, supporting ultra-high definition (ultra-HD) video streaming on multiple displays, screen mirroring from compatible devices and wireless back-up cameras, as well as Bluetooth 5.1 support and Qualcomm® aptXTM Adaptive audio to deliver high fidelity voice and streaming audio support. The QCA6696 chip also features full MIMO client capability designed to extend range at high data rates for connecting to external access points for automotive services, such as vehicle diagnostics, software updates and automatic check-ins when pulling up to dealerships.
"Qualcomm Technologies has a track-record of excellence in Wi-Fi, bringing our expertise to deliver solutions like the QCA6696 to support improved connectivity and enhanced in-vehicle experiences," said Nakul Duggal, senior vice president of product management, Qualcomm Technologies. "As vehicle connectivity continues to advance from 4G to 5G, Wi-Fi 6 is an integral part of the connectivity evolution, as it enables seamless connections, across multiple devices, and in congested environments. The QCA6696 builds on our leadership in the automotive industry, proving yet again how we are in an unparalleled position to meet the demands of the industry."
Key QCA6696 features include:
Increased user throughput in crowded networks, designed to reach rates of nearly
1.8 Gbps, featuring Dual-Band Simultaneous (DBS) and Higher Order Modulation (1024
QAM) in both 2.4 GHz and 5 GHz bands
8-Stream Sounding, designed to allow connected vehicles to leverage the growing base
of 8x8 MU-MIMO Wi-Fi 6 access points being commercially deployed and benefit from faster throughput and longer range, for car-to-Cloud connections and automotive dealer services
Improved security utilizing WPA3, the latest Wi-Fi security protocol, to support WPA- 3-Personal, WPA3-Enterprise, WPA3-Enhanced Open, WPA3-Easy Connect
Intelligent interference handling using BSS Color designed to allow the vehicle-to-device connection to be more resilient to outside interference
• Target Wakeup Time (TWT) to facilitate in-vehicle phones to use up to 33% lower
power when streaming or using Wi-Fi calling
"As vehicle connectivity continues to advance from 4G to 5G, Wi-Fi 6 is an integral part of the connectivity evolution, as it enables seamless connections, across multiple devices, and in congested environments. The QCA6696 builds on our leadership in the automotive industry, proving yet again how we are in an unparalleled position to meet the demands of the industry."said Nakul Duggal, senior vice president of product management, Qualcomm Technologies, Inc
Qualcomm® Bluetooth 5.1:
• aptX-Adaptive audio for ultra-HD quality voice and low latency audio, ideal for enhanced in-vehicle experiences
The QCA6696 is now sampling and is expected to appear in commercial vehicles in 2021. It is also included as a part of Qualcomm Technologies' 2nd generation Qualcomm® Connected Car Reference Design (CCRD), which also features the Snapdragon Automotive 4G or 5G Platform with integrated RF Front-End (RFFE) solutions, C-V2X and HP-GNSS support, as well as a Qualcomm Technologies application processor and Qualcomm® Vision Enhanced Precise Positioning (VEPP). As a comprehensive telematics/V2X reference design, automakers and Tier-1 suppliers can develop on the 2nd generation CCRD for rapid prototyping for accelerating their time to commercialization.
About Qualcomm
Qualcomm invents breakthrough technologies that transform how the world connects, computes and communicates. When we connected the phone to the Internet, the mobile revolution was born. Today, our inventions are the foundation for life-changing products, experiences, and industries. As we lead the world to 5G, we envision this next big change in cellular technology spurring a new era of intelligent, connected devices and enabling new opportunities in connected
cars, remote delivery of health care services, and the IoT — including smart cities, smart homes, and wearables. Qualcomm Incorporated includes our licensing business, QTL, and the vast majority of our patent portfolio. Qualcomm Technologies, Inc., a subsidiary of Qualcomm Incorporated, operates, along with its subsidiaries, all of our engineering, research and development functions, and all of our products and services businesses, including, the QCT semiconductor business.
Qualcomm Announces Wi-Fi 6 For Automotive, Bringing Greater Capacity for Premium In-Vehicle Experiences Reviewed by Bhakti Dua on 8:46 PM Rating: 5
Tags : 6 future Qualcomm wifi


text:
Q: How to find available times in work schedule using bits? In reference to an answer already given to another question:
https://stackoverflow.com/a/1609686/1183608
I am working with this answer, however I am confused on the meaningfulness of calculating the acceptable_times array. I want to find out at what times of the day (schedule) are available for the specific time slot length, but the function for doing so in the above answer does not seem to satisfy that, unless I have missed something.

A: grioja, the answer you linked to does give you the times of day which are available for your desired slot length. The busy/available times are represented by bits, for example:
1100001110
(This would be 30 available minutes, followed by 60 busy minutes, followed by 45 available, followed by 15 busy.) Then you get a binary number which represents the length of the available time slot you want to find, say:
111
(This would mean you want to find a slot of 45 available minutes.) Then you try shifting the 2 numbers against each other:
1100001110
0000000111
1100001110
0000001110
1100001110
0000011100
...and so on, for every possible relative shift length. The AND operation he shows in that answer determines whether the 1's in the "desired slot length" number are matching all 1's in the "available times" number. If they are, you have found an acceptable time.
By the way, you could do the same thing in other ways. For example, you could represent busy/available times by characters in a string, and use a regular expression to find an available slot of the desired length.
Note that this general approach (which is basically just "linear search") will not scale if the list of available/busy time slots is very long. There are other approaches which will be much faster in that case.

redpajama_set_name: RedPajamaStackExchange


Each Bijou gives 75 Zandalar Tribe reputation for being destroyed, and the resulting Zandalar Honor Token gives 50. It is advisable to not use up Honor Tokens for rep and instead save them for the shoulder enchants or other prizes.
Where can u delivery this Hakkari Bijou...?
These actually could sell pretty well depending on your server. On Daggerspine I can usually sell these Bijou's for 25g each. Combined with Runecloth, Coins, Illusion Dust and Greater Eternal Essence you can pull in 700g an hour + in ZG It's pretty sweet. For videos of boss kills and me farming ZG Check out my youtube channel and my website.
If you're looking to make some extra change the Zul'Gurub might be the place for you! In Zul'Gurub you'll get Runecloth, and greens which you can DE into Greater Eternal Essences and Illusion dust. On top of that you can also get a ton of Bijous and coins which might also sell on your server. I average 650-700g an hour in here. Below are videos of the path I use to farm ZG.
Bear in mind that you can get 1000 of one particular coin, but none of the others.
Each Bijou awards 125 reputation, every 3 coins award 75 reputation. Each kill is worth approximately 7 pure reputation taking boss kills into account. With the drop rates 2% for Bijous, and 5% for coins, each kill awards 10.75 reputation in total.
Edit: Note that rogues and mages need more kills because they can't kill most bosses.
This item can still be used to gain reputation with the Zandalar Tribe. If you can't find your stockpile, which most people don't have, this item can be bought. With some luck and really really REALLY big pockets you could get exalted using these items.
I was on the PTR, testing out the new zone-scaling in the old world (specifically in dungeons).
I decided to test Zul-Farak, to see what would happen to the BoE's that would drop from the instance (would they be as before, or scale to the max level etc... turns out they stay exactly as is on live right now).
I ran the dg again afterwards, and he dropped another one (a purple one this time though).
A third run, he didn't drop any, but the end boss did instead (yellow one).
I'm wondering/hoping that with the zandalari returning in BFA, that maybe we'll finally be able to gain rep with this faction again, and maybe this is the first step to that goal?
Am also hoping that it's not just horde that gets this (give them a new zandalari faction instead, and allow everyone to get the old rep).
Also to add, I went to Yojamba isle afterwards to see if that had changed (and to see if I could hand them in)... unfortunately it is still empty .... mostly. There's now a basilisk there, which seems to be a hunter tame as well as part of a questline.
2nd thing to add, as before, on logging out they still disappear :( (so presumably they still require being kept in a guild bank and/or the post to be able to be kept for now, assuming this goes to live).
"[A significant Paragon of Power from the Gurubashi Empire.]"