Targeted therapy using EGFR inhibitors cetuximab and panitumumab has anti-tumor efficacy in colorectal cancer, though only in patients without a KRAS mutation in their tumor. This thesis aims to... Show moreTargeted therapy using EGFR inhibitors cetuximab and panitumumab has anti-tumor efficacy in colorectal cancer, though only in patients without a KRAS mutation in their tumor. This thesis aims to give insight on several aspects of EGFR inhibitors en RAS mutations in colorectal cancer. It reviews aspects of mutational analysis, aims to find ways to restore sensitivity to EGFR inhibitors in patients with KRAS mutated colorectal cancer and discusses the distinctive skin toxicity of cetuximab en pantiumumab. Show less
Deursen, L. van; Aardoom, J.J.; Alblas, E.E.; Struijs, J.N.; Chavannes, N.H.; Vaart, R. van der 2023
PurposeThe purpose of this study was to gather insights from colorectal cancer (CRC) survivors on how to improve care for CRC survivors and how e-health technology could be utilized to improve CRC... Show morePurposeThe purpose of this study was to gather insights from colorectal cancer (CRC) survivors on how to improve care for CRC survivors and how e-health technology could be utilized to improve CRC care delivery.MethodsThree semi-structured focus groups were held with sixteen CRC survivors. To initiate the discussion, an online registration form and two vignettes were used. The data was analyzed using the framework method.ResultsBased on survivors' experiences, five themes were identified as opportunities for improving CRC care delivery. These themes include better recognition of complaints and faster referrals, more information as part of the care delivery, more guidance and monitoring of health outcomes, more collaboration between practitioners, and more attention for partners and relatives. In addition, survivors expressed opportunities for using e-health to facilitate information provision, improve communication, and monitor survivors' health conditions.ConclusionSeveral suggestions for improvement of CRC care delivery were identified. These often translated into possibilities for e-health to support or improve CRC care delivery. The ideas of survivors align with the vast array of existing e-health resources that can be utilized to enhance CRC care delivery. Therefore, the next step involves addressing the implementation gap between the needs of stakeholders, such as CRC survivors and healthcare providers, and the e-health tools currently available in clinical practice. Show less
Deursen, L. van; Aardoom, J.J.; Alblas, E.E.; Struijs, J.N.; Chavannes, N.H.; Vaart, R. van der 2023
PurposeThe purpose of this study was to gather insights from colorectal cancer (CRC) survivors on how to improve care for CRC survivors and how e-health technology could be utilized to improve CRC... Show morePurposeThe purpose of this study was to gather insights from colorectal cancer (CRC) survivors on how to improve care for CRC survivors and how e-health technology could be utilized to improve CRC care delivery.MethodsThree semi-structured focus groups were held with sixteen CRC survivors. To initiate the discussion, an online registration form and two vignettes were used. The data was analyzed using the framework method.ResultsBased on survivors’ experiences, five themes were identified as opportunities for improving CRC care delivery. These themes include better recognition of complaints and faster referrals, more information as part of the care delivery, more guidance and monitoring of health outcomes, more collaboration between practitioners, and more attention for partners and relatives. In addition, survivors expressed opportunities for using e-health to facilitate information provision, improve communication, and monitor survivors’ health conditions.ConclusionSeveral suggestions for improvement of CRC care delivery were identified. These often translated into possibilities for e-health to support or improve CRC care delivery. The ideas of survivors align with the vast array of existing e-health resources that can be utilized to enhance CRC care delivery. Therefore, the next step involves addressing the implementation gap between the needs of stakeholders, such as CRC survivors and healthcare providers, and the e-health tools currently available in clinical practice. Show less
Deursen, L. van; Aardoom, J.J.; Alblas, E.E.; Struijs, J.N.; Chavannes, N.H.; Vaart, R. van der 2023
PurposeThe purpose of this study was to gather insights from colorectal cancer (CRC) survivors on how to improve care for CRC survivors and how e-health technology could be utilized to improve CRC... Show morePurposeThe purpose of this study was to gather insights from colorectal cancer (CRC) survivors on how to improve care for CRC survivors and how e-health technology could be utilized to improve CRC care delivery.MethodsThree semi-structured focus groups were held with sixteen CRC survivors. To initiate the discussion, an online registration form and two vignettes were used. The data was analyzed using the framework method.ResultsBased on survivors’ experiences, five themes were identified as opportunities for improving CRC care delivery. These themes include better recognition of complaints and faster referrals, more information as part of the care delivery, more guidance and monitoring of health outcomes, more collaboration between practitioners, and more attention for partners and relatives. In addition, survivors expressed opportunities for using e-health to facilitate information provision, improve communication, and monitor survivors’ health conditions.ConclusionSeveral suggestions for improvement of CRC care delivery were identified. These often translated into possibilities for e-health to support or improve CRC care delivery. The ideas of survivors align with the vast array of existing e-health resources that can be utilized to enhance CRC care delivery. Therefore, the next step involves addressing the implementation gap between the needs of stakeholders, such as CRC survivors and healthcare providers, and the e-health tools currently available in clinical practice. Show less
Background and study aims Overcoming logistical obstacles for the implementation of colorectal endoscopic submucosal dissection (ESD) requires accurate prediction of procedure times. We aimed to... Show moreBackground and study aims Overcoming logistical obstacles for the implementation of colorectal endoscopic submucosal dissection (ESD) requires accurate prediction of procedure times. We aimed to evaluate existing and new prediction models for ESD duration.Patients and methods Records of all consecutive patients who underwent single, non-hybrid colorectal ESDs before 2020 at three Dutch centers were reviewed. The performance of an Eastern prediction model [GIE 2021;94(1):133-144] was assessed in the Dutch cohort. A prediction model for procedure duration was built using multivariable linear regression. The model's performance was validated using internal validation by bootstrap resampling, internal-external cross-validation and external validation in an independent Swedish ESD cohort.Results A total of 435 colorectal ESDs were analyzed (92% en bloc resections, mean duration 139 minutes, mean tumor size 39 mm). The performance of current unstandardized time scheduling practice was suboptimal (explained variance: R-2 =27%). We successfully validated the Eastern prediction model for colorectal ESD duration <60 minutes (c-statistic 0.70, 95% CI 0.62-0.77), but this model was limited due to dichotomization of the outcome and a relatively low frequency (14%) of ESDs completed <60 minutes in the Dutch centers. The model was more useful with a dichotomization cut-off of 120 minutes (c-statistic: 0.75; 88% and 17% of "easy" and "very difficult" ESDs completed <120 minutes, respectively). To predict ESD duration as continuous outcome, we developed and validated the six-variable cESD-TIME formula ( https://cesdtimeformula.shinyapps.io/calculator/ ; optimism-corrected R-2 =61%; R-2 =66% after recalibration of the slope).Conclusions We provided two useful tools for predicting colorectal ESD duration at Western centers. Further improvements and validations are encouraged with potential local adaptation to optimize time planning. Show less
Colorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of... Show moreColorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of quality of life, treatment discontinuation and sometimes even death. Moreover, chances for curation in the metastatic setting are low. Therefore, a large window of opportunity to improve both safety as well as efficacy of chemotherapeutic treatment for the individual patient exists. A possible approach to improve chemotherapeutic treatment for CRC patients could be the discovery, validation and implementation of new genetic biomarkers. The use of genetic biomarkers allows to identify patients that are at higher risk for severe adverse drug events and to select patients which will benefit the most from chemotherapy. The aim of this thesis was therefore to improve the safety and efficacy of chemotherapeutic drugs in patients with colorectal cancer by individualising drug dosing and choice of drug based on germline genetic biomarkers. The described studies in this thesis brought us a few steps closer to safe and effective use of chemotherapeutic drugs in the individual colorectal cancer patient. Irinotecan should no longer be administered without a UGT1A1 genotype test and a start has been made towards personalised medicine for colorectal cancer patients with peritoneal metastases. Show less
For part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and... Show moreFor part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and decreased with age. Also, 30-day and one-year excess mortality decreased over the years for colon and rectal cancer. After surviving the first postoperative year, the survival of surgically treated older patients aligned with their younger counterparts, except for patients with stage III disease. Part II describes the results of the analyses of the RAPIDO trial. DRTF decreased from 30% in the standard-care group to 24% in the experimental group at 3 years after randomisation, mainly due to a decrease in DM, which is probably due to better compliance preoperatively and perhaps due the earlier treatment of micrometastases in the treatment process. Although patients with DM in the experimental group had worse survival compared to patients in the standard-care group, the cumulative probability of overall survival remained comparable for both treatment groups. If the patients with a complete response can be identified during reassessment after neoadjuvant therapy, surgery may be omitted, a W&W after a cCR with an appropriate follow-up has no additional oncological risk in young patients compared to older patients (part III). This opens the door for potential organ preservation. Show less
Glycosylation is a widely occurring and complex modification found on lipids and proteins and is involved in the recognition, signaling and interaction events within the cell and between cells.... Show moreGlycosylation is a widely occurring and complex modification found on lipids and proteins and is involved in the recognition, signaling and interaction events within the cell and between cells. These events based on glycan structures result in adhesion, cell-matrix interaction and immune recognition. Alterations in the glycomic profile are considered a hallmark of various diseases, including cancer where it contributes to the development and progression of cancer, affecting cell-cell communication, cell-matrix interactions, tumor angiogenesis, invasion and metastasis. These functions are governed by different glycans and their terminal structures. In order to further explore these structures with regard to their potential as biomarkers and specific targets for diagnostic applications and therapeutical strategies for various diseases, in-depth glycomic analysis is needed. It is further noted that aberrant glycosylation not only results from the altered expression of glycosyltransferases (GTs) but also from the changed activity of GTs and glycosidases as well as the availability and abundance of sugar nucleotide donors. The aim of the research described in this thesis was to explore the glycomic signatures of colorectal cancer (CRC) in cell lines and tissues as well as of acute myeloid leukemia (AML) cell lines. Show less
Colorectal cancer is one of the most diagnosed cancer types worldwide and incidence remains on the rise, especially in patients under 50. The prognosis for patients with CRC differs greatly and... Show moreColorectal cancer is one of the most diagnosed cancer types worldwide and incidence remains on the rise, especially in patients under 50. The prognosis for patients with CRC differs greatly and although immunotherapy has shown promising results in a number of cancer types, not all CRC patients respond well to these treatments. This can in part be attributed to the differences in T cell infiltration between cancers but does not one on one translate to clinical response. Moreover, the activity of specific immune cells can directly influence other immune cells, both in an activating and inhibitory manner. This highlights the complexity of the tumour immune microenvironment and requires an comprehensive multiplex approach to simultaneously investigate all the players of the tumour immune microenvironment. Furthermore, the interaction between different immune cells and between those and cancer cells is essential to take into account, hence the need for an approach that combines multiplex immunophenotyping with spatial cell context. This will provide hints into the behaviour of the players of the tumour immune microenvironment and aid the understanding of CRC, but potentially of other cancer types as well. In this work we developed and applied multispectral immunophenotyping methodologies to strengthen our understanding of CRC Show less
Background and aims: From 2014, the Dutch colorectal cancer (CRC) faecal immunochemical testing-based screening programme was gradually rolled out by birth cohort. We evaluated changes in advanced... Show moreBackground and aims: From 2014, the Dutch colorectal cancer (CRC) faecal immunochemical testing-based screening programme was gradually rolled out by birth cohort. We evaluated changes in advanced-stage CRC incidence by timing of invitation to further strengthen the evidence for the effectiveness of CRC screening. Methods: Data on advanced-stage CRC incidence in the period 2010-2019 by invitation cohort were collected through the Netherlands Cancer Registry. Crude rates of advanced -stage CRC incidence and cumulative advanced-stage CRC incidence were calculated. Observed advanced-stage CRC incidence and cumulative advanced-stage CRC incidence were compared with expected advanced-stage CRC incidence and cumulative advanced-stage CRC incidence by invitation cohort using trend lines extrapolating data prior to the introduction of screening. Results: For the invitation cohort that was first invited for screening in 2014, advanced-stage CRC incidence increased before the introduction of screening from 94.1 to 124.7 per 100,000 individuals in the period 2010-2013. In 2014, the observed increase was higher than in preceding years, to 184.9 per 100,000 individuals. Hereafter, a decrease in incidence was observed to levels below expected incidence based on trends before the introduction of screening. A similar pattern was observed for invitation cohorts in subsequent years, coinciding with the first invitation to the screening pro-gramme. In 2019, the observed incidence for all invitation cohorts remained below expected inci-dence. The cumulative advanced-stage CRC incidence in the 2014-2016 invitation cohorts was significantly lower than the expected cumulative CRC incidence in the period 2010-2019. Conclusions: In the period 2014-2019, an increase in advanced-stage CRC incidence was observed for all invitation cohorts first invited for screening, followed by a decrease below expected incidence, following the pattern of the phased implementation. The cumulative advanced-stage CRC inci-dence in invitation cohorts invited for screening multiple times was lower than expected based on trends from the pre-screening era. These findings support a causal relationship between the intro-duction of the Dutch screening programme and a decrease in advanced-stage CRC incidence.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Zwager, L.W.; Moons, L.M.G.; Sarasqueta, A.F.; Lacle, M.M.; Albers, S.C.; Hompes, R.; ... ; Dutch eFTR Working Group 2022
Background: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with... Show moreBackground: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. Methods/design: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. Discussion: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Show less
BackgroundT1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly... Show moreBackgroundT1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization.Methods/designIn this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate.DiscussionSince the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Show less
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the western world and an improved understanding of the molecular pathways involved in CRC could potentially allow... Show moreColorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the western world and an improved understanding of the molecular pathways involved in CRC could potentially allow improved prediction and personalized therapy. The BMP pathway is known to be crucial for the maintenance of intestinal homeostasis and deregulation of this pathway is known to contribute to colorectal cancer formation. The studies presented in this thesis provide evidence that the BMP pathway is an important homeostatic pathway and that, both in normal tissue and in cancer, BMP signaling is influenced by (cancer-associated) fibroblasts. The outcome of BMP signaling on the epithelial cells appears to be dependent on the bioavailability of BMPs and, importantly, on the presence of a functional intracellular BMP pathway. Show less
Mutations in Bone Morphogenetic Protein (BMP) Receptor (BMPR)1A and SMAD4 are detected in 50% of juvenile polyposis syndrome (JPS) patients, who develop stroma-rich hamartomatous polyps. The... Show moreMutations in Bone Morphogenetic Protein (BMP) Receptor (BMPR)1A and SMAD4 are detected in 50% of juvenile polyposis syndrome (JPS) patients, who develop stroma-rich hamartomatous polyps. The established role of stromal cells in regulating BMP activity in the intestine implies a role for stromal cells in polyp development. We used conditional Cre-LoxP mice to investigate how specific loss of BMPR1A in endothelial cells, fibroblasts, or myofibroblasts/smooth muscle cells affects intestinal homeostasis. Selective loss of BMPR1A in fibroblasts causes severe histological changes in the intestines with a significant increase in stromal cell content and epithelial cell hyperproliferation, leading to numerous serrated polyps. This phenotype suggests that crucial changes occur in the fibroblast secretome that influences polyp development. Analyses of publicly available RNA expression databases identified CXCL12 as a potential candidate. RNAscope in situ hybridization showed an evident increase of Cxcl12-expressing fibroblasts. In vitro, stimulation of fibroblasts with BMPs resulted in downregulation of CXCL12, while inhibition of the BMP pathway resulted in gradual upregulation of CXCL12 over time. Moreover, neutralization of CXCL12 in vivo in the fibroblast-specific BMPR1A KO mice resulted in a significant decrease in polyp formation. Finally, in CRC patient specimens, mRNA-expression data showed that patients with high GREMLIN1 and CXCL12 expression had a significantly poorer overall survival. Significantly higher GREMLIN1, NOGGIN, and CXCL12 expression were detected in the Consensus Molecular Subtype 4 (CMS4) colorectal cancers, which are thought to arise from serrated polyps. Taken together, these data imply that fibroblast-specific BMP signaling-CXCL12 interaction could have a role in the etiology of serrated polyp formation. Show less
Unterrainer, M.; Deroose, C.M.; Herrmann, K.; Moehler, M.; Blomqvist, L.; Cannella, R.; ... ; European Soc Gastrointestinal Abdominal Radiology (ESGAR) 2022
Background: Treatment monitoring in metastatic colorectal cancer (mCRC) relies on imaging to evaluate the tumour burden. Response Evaluation Criteria in Solid Tumors provide a framework on... Show moreBackground: Treatment monitoring in metastatic colorectal cancer (mCRC) relies on imaging to evaluate the tumour burden. Response Evaluation Criteria in Solid Tumors provide a framework on reporting and interpretation of imaging findings yet offer no guidance on a standardised imaging protocol tailored to patients with mCRC. Imaging protocol hetero-geneity remains a challenge for the reproducibility of conventional imaging end-points and is an obstacle for research on novel imaging end-points. Patients and methods: Acknowledging the recently highlighted potential of radiomics and arti-ficial intelligence tools as decision support for patient care in mCRC, a multidisciplinary, international and expert panel of imaging specialists was formed to find consensus on mCRC imaging protocols using the Delphi method. Results: Under the guidance of the European Organisation for Research and Treatment of Cancer (EORTC) Imaging and Gastrointestinal Tract Cancer Groups, the European Society of Oncologic Imaging (ESOI) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), the EORTC-ESOI-ESGAR core imaging protocol was identified. Conclusion: This consensus protocol attempts to promote standardisation and to diminish variations in patient preparation, scan acquisition and scan reconstruction. We anticipate that this standardisation will increase reproducibility of radiomics and artificial intelligence studies and serve as a catalyst for future research on imaging end-points. For ongoing and future mCRC trials, we encourage principal investigators to support the dissemination of these im-aging standards across recruiting centres. (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Immunotherapy is a highly promising treatment option for cancer. At present, only a small proportion of cancer patients benefits from immunotherapeutic interventions. There is an unmet need to... Show moreImmunotherapy is a highly promising treatment option for cancer. At present, only a small proportion of cancer patients benefits from immunotherapeutic interventions. There is an unmet need to understand which factors determine a patient’s response to immunotherapy as well as to develop novel immunotherapeutic approaches that address shortcomings of current immunotherapies.In this thesis, we have performed an unprecedented characterization of immune cell subsets participating in anti-tumor responses in colorectal cancer and pancreatic ductal adenocarcinoma with different single-cell technologies. Most cancer immunology research studied the role of cytotoxic T cells in both cancer types, while a comprehensive analysis of both innate and adaptive components of cancer immunity was largely lacking. With such an approach, we demonstrated an important involvement of understudied unconventional (γδ T cells) and innate (innate lymphoid cells (ILCs)) immune effector cells in anti-tumor immunity. These immune subsets displayed cytotoxic activity and showed potential for therapeutic exploitation. Further studies will focus on their functional characterization and potential reconversion into a therapeutic agent.This thesis resulted from the collaboration between research groups led by Noel de Miranda (Pathology, LUMC) and Frits Koning (Immunology, LUMC), and underscores the relevance of applying single-cell technologies for the study of complex biological systems. Show less
Hulst, H.C.V.; Dekker, J.W.T.; Bastiaannet, E.; Bol, J.M. van der; Bos, F. van den; Hamaker, M.E.; ... ; Souwer, E.T.D. 2022
Background: For clinical decision making it is important to identify patients at risk for adverse outcomes after co-lorectal cancer (CRC) surgery, especially in the older population. Because the... Show moreBackground: For clinical decision making it is important to identify patients at risk for adverse outcomes after co-lorectal cancer (CRC) surgery, especially in the older population. Because the American College of Surgeons Na-tional Surgical Quality Improvement Program (ACS NSQIP) surgical risk calculator is potentially useful in clinical practice, we performed an external validation in a Dutch multicenter cohort of patients >= 70 years undergoing elective non-metastatic CRC surgery.Methods: We compared the ACS NSQIP calculator mean predicted risk to the overall observed rate of anastomotic leakage, return to operation room, pneumonia, discharge not to home, and readmission in our cohort using a one-sample Z-test. Calibration plots and receiver operating characteristic (ROC) curves were used to determine the calculator's performance.Results: Six hundred eighty-two patients were included. Median age was 76.2 years. The ACS NSQIP calculator ac-curately predicted the overall readmission rate (predicted: 8.6% vs. observed: 7.8%, p = 0.456), overestimated the rate of discharge not to home (predicted:11.2% vs. observed: 7.0% p = 0.005) and underestimated the observed rate of all other outcomes. The calibration plots showed poor calibration for all outcomes. The ROC-curve showed an area under the curve (AUC) of 0.75 (95% confidence interval [CI] 0.67-0.83) for pneumonia and 0.70 (0.62-0.78) for discharge not to home. The AUC for all other outcomes was poor.Conclusions: The ACS NSQIP surgical risk calculator had a poor individual risk prediction (calibration) for all out-comes and only a fair discriminative ability (discrimination) to predict pneumonia and discharge not to home. The calculator might be considered to identify patients at high risk of pneumonia and discharge not to home to initiate additional preoperative interventions. (c) 2022 Elsevier Ltd. All rights reserved. Show less
This thesis focused on risk factors and outcomes based on colorectal cancer auditing and aimed to provide new insights into outcome indicators, treatment modalities, and outcomes in high-risk... Show moreThis thesis focused on risk factors and outcomes based on colorectal cancer auditing and aimed to provide new insights into outcome indicators, treatment modalities, and outcomes in high-risk patients, and to monitor outcomes after implementation of minimally invasive surgery. Nationwide population-based studies with data of the Dutch ColoRectal Audit (DCRA) were used to provide information regarding colorectal cancer care on different levels (hospital, national, and international level) and in specific high-risk subpopulations. Show less
This thesis highlights, firstly, the importance of early CRC detection by presenting results of a CRC diagnostic proteomic biomarker signature with high discriminative power. Secondly, a strong... Show moreThis thesis highlights, firstly, the importance of early CRC detection by presenting results of a CRC diagnostic proteomic biomarker signature with high discriminative power. Secondly, a strong robust, independent prognostic tumor stroma ratio (TSR) biomarker, which confirms to be of important clinical value. The TSR has the ability to stratify colon cancer patients according to their prognostic outcome in a highly reproducible and low-cost manner. It has shown to link patients with a high intra tumor stromal content and a worse prognosis. Literature shows a wealth of evidence that supports this prognostic value in CRC as well as in other cancers. This PhD research therefore concludes that it should be implemented in the official guidelines of the TNM classification to improve stratification for CRC patients in daily routine pathological evaluation. The prospective, international, multicentre UNITED study will hopefully overcome the last hurdle for this clinical implementation. Lastly, this thesis offers more insight in the elusiveness of the tumor microenvironment and stromatogenesis that contributes to the aggressiveness of some CRC tumors. The biological differences, interconnections and changes in the microenvironment presented give multiple leads for further research and new personalized treatment possibilities. Show less
Purpose: The recently developed fibroblast activation protein inhibitor (FAPI) tracer for PET/CT, binding tumour-stromal cancer-associated fibroblasts, is a promising tool for detection of positive... Show morePurpose: The recently developed fibroblast activation protein inhibitor (FAPI) tracer for PET/CT, binding tumour-stromal cancer-associated fibroblasts, is a promising tool for detection of positive lymph nodes. This study provides an overview of features, including sizes and tumour-stromal content, of lymph nodes and their respective lymph node metastases (LNM) in colorectal cancer (CRC), since literature lacks on whether LNMs contain sufficient stroma to potentially allow FAPI-based tumour detection. Methods: Haematoxylin and eosin-stained tissue slides from 73 stage III colon cancer patients were included. Diameters and areas of all lymph nodes and their LNMs were assessed, the amount of stroma by measuring the stromal compartment area, the conventional and total tumour-stroma ratios (TSR-c and TSR-t, respectively), as well as correlations between these parameters. Also, subgroup analysis using a minimal diameter cut off of 5.0 mm was performed. Results: In total, 126 lymph nodes were analysed. Although positive correlations were observed between node and LNM for diameter and area (r = 0.852, p < 0.001 and r = 0.960, p < 0.001, respectively), and also between the LNM stromal compartment area and nodal diameter (r = 0.612, p < 0.001), nodal area (r = 0.747, p < 0.001) and LNM area (r = 0.746, p < 0.001), novel insight was that nearly all (98%) LNMs contained stroma, with median TSR-c scores of 35% (IQR 20-60%) and TSR-t of 20% (IQR 10-30%). Moreover, a total of 32 (25%) positive lymph nodes had a diameter of < 5.0 mm. Conclusion: In LNMs, stroma is abundantly present, independent of size, suggesting a role for FAPI PET/CT in improved lymph node detection in CRC. Show less
