T1 colorectal cancers (T1CRC) are increasingly being treated by endoscopic submucosal dissection (ESD). After ESD of a T1CRC, completion surgery is indicated in a subgroup of patients. Currently,... Show moreT1 colorectal cancers (T1CRC) are increasingly being treated by endoscopic submucosal dissection (ESD). After ESD of a T1CRC, completion surgery is indicated in a subgroup of patients. Currently, the influence of ESD on surgical morbidity and mortality is unknown. The aim of this study was to compare 90-day morbidity and mortality of completion surgery after ESD to primary surgery. The completion surgery group consisted of suspected T1CRC patients from a multicenter prospective ESD database (2014–2020). The primary surgery group consisted of pT1CRC patients from a nationwide surgical registry (2017–2019). Patients with rectal or sigmoidal cancers were selected. Patients receiving neoadjuvant therapy were excluded. Propensity score adjustment was used to correct for confounders. In total, 411 patients were included: 54 in the completion surgery group (39 pT1, 15 pT2) and 357 in the primary surgery group with pT1CRC. Adverse event rate was 24.1% after completion surgery and 21.3% after primary surgery. After completion surgery 90-day mortality did not occur, though one patient died in the primary surgery group. After propensity score adjustment, lymph node yield did not differ significantly between the groups. Among other morbidity-related outcomes, stoma rate (OR 1.298 95%-CI 0.587-2.872, p = 0.519) and adverse event rate (OR 1.162; 95%-CI 0.570-2.370, p = 0.679) also did not differ significantly. A subgroup analysis was performed in patients undergoing rectal surgery. In this subgroup (37 completion and 136 primary surgery), these morbidity outcomes also did not differ significantly. In conclusion, this study suggests that ESD does not compromise morbidity or 90-day mortality of completion surgery. Show less
Background. Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of... Show moreBackground. Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of surgical treatment for suspicious LLNs is lacking. This study evaluated the surgical treatment of LLNs in an untrained setting at a national level.Methods. Patients who underwent additional LLN surgery were selected from a national cross-sectional cohort study regarding patients undergoing rectal cancer surgery in 69 Dutch hospitals in 2016. LLN surgery consisted of either 'node-picking' (the removal of an individual LLN) or 'partial regional node dissection' (PRND; an incomplete resection of the LLN area). For all patients with primarily enlarged (=7 mm) LLNs, those undergoing rectal surgery with an additional LLN procedure were compared to those undergoing only rectal resection.Results. Out of 3057 patients, 64 underwent additional LLN surgery, with 4-year LR and LLR rates of 26% and 15%, respectively. Forty-eight patients (75%) had enlarged LLNs, with corresponding recurrence rates of 26% and 19%, respectively. Node-picking (n = 40) resulted in a 20% 4-year LLR, and a 14% LLR after PRND (n = 8; p = 0.677). Multivariable analysis of 158 patients with enlarged LLNs undergoing additional LLN surgery (n = 48) or rectal resection alone (n = 110) showed no significant association of LLN surgery with 4-year LR or LLR, but suggested higher recurrence risks after LLN surgery (LR: hazard ratio [HR] 1.5, 95% confidence interval [CI] 0.7-3.2, p = 0.264; LLR: HR 1.9, 95% CI 0.2-2.5, p = 0.874).Conclusion. Evaluation of Dutch practice in 2016 revealed that approximately one-third of patients with primarily enlarged LLNs underwent surgical treatment, mostly consisting of node-picking. Recurrence rates were not significantly affected by LLN surgery, but did suggest worse outcomes. Outcomes of LLN surgery after adequate training requires further research. Show less
Warps, A.K.; Saraste, D.; Westerterp, M.; Detering, R.; Sjovall, A.; Martling, A.; ... ; Swedish Colorectal Canc Registry 2022
Background: The timing and degree of implementation of minimally invasive surgery (MIS) for colorectal cancer vary among countries. Insights in national differences regarding implementation of new... Show moreBackground: The timing and degree of implementation of minimally invasive surgery (MIS) for colorectal cancer vary among countries. Insights in national differences regarding implementation of new surgical techniques and the effect on postoperative outcomes are important for quality assurance, can show potential areas for country-specific improvement, and might be illustrative and supportive for similar implementation programs in other countries. Therefore, this study aimed to evaluate differences in patient selection, applied techniques, and results of minimal invasive surgery for colorectal cancer between the Netherlands and Sweden. Methods: Patients who underwent elective minimally invasive surgery for T1-3 colon or rectal cancer (2012-2018) registered in the Dutch ColoRectal Audit or Swedish ColoRectal Cancer Registry were included. Time trends in the application of MIS were determined. Outcomes were compared for time periods with a similar level of MIS implementation (Netherlands 2012-2013 versus Sweden 2017-2018). Multilevel analyses were performed to identify factors associated with adverse short-term outcomes.Results: A total of 46,095 Dutch and 8,819 Swedish patients undergoing MIS for colorectal cancer were included. In Sweden, MIS implementation was approximately 5 years later than in the Netherlands, with more robotic surgery and lower volumes per hospital. Although conversion rates were higher in Sweden, oncological and surgical outcomes were comparable. MIS in the Netherlands for the years 2012- 2013 resulted in a higher reoperation rate for colon cancer and a higher readmission rate but lower non- surgical complication rates for rectal cancer if compared with MIS in Sweden during 2017-2018.Conclusion: This study showed that the implementation of MIS for colorectal cancer occurred later in Sweden than the Netherlands, with comparable outcomes despite lower volumes. Our study demonstrates that new surgical techniques can be implemented at a national level in a controlled and safe way, with thorough quality assurance. Show less
Background In the recent years two innovative approaches have become available for minimally invasiveen blocresections of large non-pedunculated rectal lesions (polyps and early cancers). One is... Show moreBackground In the recent years two innovative approaches have become available for minimally invasiveen blocresections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden. Methods Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior. Discussion This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for theen blocresection of large non-pedunculated rectal lesions. This is important as the detection rate of these adenomas is expected to further increase with the introduction of colorectal screening programs throughout Europe. This study will therefore support an optimal use of healthcare resources in the future. Show less
Groningen, J.T. van; Ceyisakar, I.E.; Gietelink, L.; Henneman, D.; Harst, E. van der; Westerterp, M.; ... ; Dutch Surg Colorectal Audit Grp 2020
Background: Comparing outcomes across hospitals to learn from best performing hospitals can be valuable. However, reliably identifying best performance is challenging. This study assesses the... Show moreBackground: Comparing outcomes across hospitals to learn from best performing hospitals can be valuable. However, reliably identifying best performance is challenging. This study assesses the possibility to distinguish best performing hospitals on single outcomes and consistency of performance on different outcomes.Methods: Data were derived from the Dutch ColoRectal Audit 2013-2015. Outcomes considered were textbook outcome (colon), (circumferential) resection margins, (serious) complications, mortality, and 'failure to rescue'. To include uncertainty in rankings, random effect logistic regression models were used to calculate expected ranks (ERs), for each hospital and outcome. Rankability was calculated for each outcome, as a measure of reliability of ranking. Furthermore, correlation between ERs on different outcomes was assessed. Correlation was considered weak <0.40, moderate between 0.40 - 0.59 and strong >0.60.Results: The study included 32 143 patients; of whom 11 373 were treated in 2015 across 84 hospitals, 8181 colon and 3192 rectal cancer patients. In this one-year period 'Postoperative complications' had the highest rankability for colon (57%) and rectal (41%) surgery. No (group of) hospital(s) had the highest ER(s) on all outcomes. Correlation between ERs of outcomes was moderate in 2 (of 25) and strong in 4 (of 25) combinations. Rankability of colorectal mortality increased from 14% in 2015 to 35% when data over 2013-2015 were used.Conclusion: The highest reliability of identifying best performance based on an outcome was 57%. However, the balance between reliability and relevance of outcomes is vulnerable. No (group of) hospital(s) could be identified as best performer on all outcomes. Performance was not consistent on outcomes. (C) 2020 Published by Elsevier Ltd. Show less
Aim This study aimed to determine predictive factors for the circumferential resection margin (CRM) within two northern European countries with supposed similarity in providing rectal cancer care.... Show moreAim This study aimed to determine predictive factors for the circumferential resection margin (CRM) within two northern European countries with supposed similarity in providing rectal cancer care. Method Data for all patients undergoing rectal resection for clinical tumour node metastasis (TNM) stage I-III rectal cancer were extracted from the Swedish ColoRectal Cancer Registry and the Dutch ColoRectal Audit (2011-2015). Separate analyses were performed for cT1-3 and cT4 stage. Predictive factors for the CRM were determined using univariable and multivariable logistic regression analyses. Results A total of 6444 Swedish and 12 089 Dutch patients were analysed. Over time the number of hospitals treating rectal cancer decreased from 52 to 42 in Sweden, and 82 to 79 in the Netherlands. In the Swedish population, proportions of cT4 stage (17% vs 8%), multivisceral resection (14% vs 7%) and abdominoperineal excision (APR) (37% vs 31%) were higher. The overall proportion of patients with a positive CRM (CRM+) was 7.8% in Sweden and 5.4% in the Netherlands. In both populations with cT1-3 stage disease, common independent risk factors for CRM+ were cT3, APR and multivisceral resection. No common risk factors for CRM+ in cT4 stage disease were found. An independent impact of hospital volume on CRM+ could be demonstrated for the cT1-3 Dutch population. Conclusion Within two northern European countries with implemented clinical auditing, rectal cancer care might potentially be improved by further optimizing the treatment of distal and locally advanced rectal cancer. Show less
Amelung, F.J.; Borstlap, W.A.A.; Consten, E.C.J.; Veld, J.V.; Halsema, E.E. van; Bemelman, W.A.; ... ; Dutch Snapshot Res Grp 2019
Background: Although self-expandable metal stent (SEMS) placement as bridge to surgery (BTS) in patients with left-sided obstructing colonic cancer has shown promising short-term results, it is... Show moreBackground: Although self-expandable metal stent (SEMS) placement as bridge to surgery (BTS) in patients with left-sided obstructing colonic cancer has shown promising short-term results, it is used infrequently owing to uncertainty about its oncological safety. This population study compared long-term oncological outcomes between emergency resection and SEMS placement as BTS.Methods: Through a national collaborative research project, long-term outcome data were collected for all patients who underwent resection for left-sided obstructing colonic cancer between 2009 and 2016 in 75 Dutch hospitals. Patients were identified from the Dutch Colorectal Audit database. SEMS as BTS was compared with emergency resection in the curative setting after 1: 2 propensity score matching.Results: Some 222 patients who had a stent placed were matched to 444 who underwent emergency resection. The overall SEMS-related perforation rate was 7.7 per cent (17 of 222). Three-year locoregional recurrence rates after SEMS insertion and emergency resection were 11-4 and 13.6 per cent (P= 0-457), disease-free survival rates were 58-8 and 52.6 per cent (P= 0-175), and overall survival rates were 74-0 and 68-3 per cent (P= 0.231), respectively. SEMS placement resulted in significantly fewer permanent stomas (23.9 versus 45.3 per cent; P < 0-001), especially in elderly patients (29.0 versus 57.9 per cent; P < 0-001). For patients in the SEMS group with or without perforation, 3-year locoregional recurrence rates were 18 and 11.0 per cent (P= 0.432), disease-free survival rates were 49 and 59.6 per cent (P= 0-717), and overall survival rates 61 and 75.1 per cent (P= 0.529), respectively.Conclusion: Overall, SEMS as BTS seems an oncologically safe alternative to emergency resection with fewer permanent stomas. Nevertheless, the risk of SEMS-related perforation, as well as permanent stoma, might influence shared decision-making for individual patients. Show less
Timely sensing of lipopolysaccharide (LPS) is critical for the host to fight invading Gram-negative bacteria. We recently showed that apolipoprotein CI (apoCI) (apoCI(1-57)) avidly binds to LPS,... Show moreTimely sensing of lipopolysaccharide (LPS) is critical for the host to fight invading Gram-negative bacteria. We recently showed that apolipoprotein CI (apoCI) (apoCI(1-57)) avidly binds to LPS, involving an LPS-binding motif (apoCI(48-54)), and thereby enhances the LPS-induced inflammatory response. Our current aim was to further elucidate the structure and function relationship of apoCI with respect to its LPS-modulating characteristics and to unravel the mechanism by which apoCI enhances the biological activity of LPS. We designed and generated N- and C-terminal apoCI-derived peptides containing varying numbers of alternating cationic/hydrophobic motifs. ApoCI(1-38), apoCI(1-30), and apoCI(35-57) were able to bind LPS, whereas apoCI(1-23) and apoCI(46-57) did not bind LPS. In line with their LPS-binding characteristics, apoCI(1-38), apoCI(1-30), and apoCI(35-57) prolonged the serum residence of I-125-LPS by reducing its association with the liver. Accordingly, both apoCI(1-30) and apoCI(35-57) enhanced the LPS-induced TNF alpha response in vitro (RAW 264.7 macrophages) and in vivo (C57Bl/6 mice). Additional in vitro studies showed that the stimulating effect of apoCI on the LPS response resembles that of LPS-binding protein (LBP) and depends on CD14/ Toll-like receptor 4 signaling.(jlr) We conclude that apoCI contains structural elements in both its N-terminal and C-terminal helix to bind LPS and to enhance the proinflammatory response toward LPS via a mechanism similar to LBP.-Berbee, J. F. P., C. P. Coomans, M. Westerterp, J. A. Romijn, L. M. Havekes, and P. C. N. Rensen. Apolipoprotein CI enhances the biological response to LPS via the CD14/TLR4 pathway by LPS-binding elements in both its N- and C-terminal helix. J. Lipid Res. 2010. 51: 1943-1952 Show less
Boer, M.A.M. den; Westerterp, M.; Vries-van der Weij, J. de; Wang, Y.A.; Hu, L.H.; Santo, S.M.S.E.; ... ; Rensen, P.C.N. 2010
Objective: The use of the HIV-protease inhibitor ritonavir (RTV) is associated with induction of hypertriglyceridemia, which is a cardiovascular risk factor. Therefore, we investigated the effect... Show moreObjective: The use of the HIV-protease inhibitor ritonavir (RTV) is associated with induction of hypertriglyceridemia, which is a cardiovascular risk factor. Therefore, we investigated the effect of RTV on atherosclerosis development in APOE*3-Leiden transgenic mice, a model for human-like lipoprotein metabolism and atherosclerosis. Methods and results: APOE*3-Leiden mice were fed a Western-type diet without or with RTV (35 mg/kg/day) for 19 weeks. RTV increased plasma TG levels throughout the study (similar to 2-fold; P < 0.05). Despite these increased TG levels, RTV decreased the atherosclerotic lesion area in the aortic root (-57%; P < 0.05), concomitant with reduced macrophage area (-72%; P < 0.01) and decreased lesion severity. This could not be explained by reduced inflammatory markers in plasma (i.e. serum amyloid A, E-selectin and fibrinogen), nor by decreased lipid accumulation in macrophages or increased cholesterol efflux from macrophages, as assessed using peritoneal macrophages in vitro. Rather, whereas RTV did not affect plasma total cholesterol levels, RTV decreased (V) LDL-cholesterol and increased cholesterol in apoE-rich large HDL. Conclusion: Despite inducing hypertriglyceridemia, RTV decreases atherosclerotic lesion area and severity, associated with decreased (V) LDL-cholesterol and increased atheroprotective apoE-rich large HDL. (C) 2009 Elsevier Ireland Ltd. All rights reserved. Show less
The main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e.... Show moreThe main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e. transgenic and knock-out mouse models). Many of these genes exert their role in atherosclerosis development as a result of effects on lipoprotein metabolism and inflammation. Transgenic mouse models have also been proven to be suitable for evaluating the mechanisms underlying the anti-atherosclerotic action of experimental drugs aimed to reduce atherogenic lipoprotein levels. However, thus far no suitable animal model was present to evaluate the mechanism of action of anti-atherosclerotic effect of HDL-raising therapeutic strategies. In this thesis, we further explored the role of apolipoprotein CI (apoCI) and cholesteryl ester transfer protein (CETP) in lipoprotein metabolism, inflammation, and atherosclerosis. Furthermore, we developed a mouse model that will be suitable for testing potential high-density-lipoprotein (HDL) raising therapies as a novel strategy to treat CVD. Show less
