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Abdominoperineal resection (APR) is associated with considerable morbidity, particularly regarding the perineal wound.1 Reported incidences of perineal wound problems vary widely, but have been observed in up to 47% of patients following APR,2 leading to intensive wound care, prolonged hospital stay, and a diminished quality of life. Some patients may experience chronic perineal complications for many years. As a means of preventing these complications, a variety of techniques using autologous tissue transfer have been proposed. One of the rationales is related to obliterating the pelvic dead space, thereby preventing presacral abscess formation. Furthermore, well-vascularized tissue might have a positive influence on wound healing, especially after radiotherapy. This might reduce perineal wound infection and dehiscence and other complications associated with non-healing. Options for perineal reconstruction following APR include musculocutaneous, fasciocutaneous, subcutaneous, or greater omentum flaps.3–5 However, the reconstructive procedures are complex, increase operating time, and are associated with a risk of added donor- and recipient-site morbidity (e.g. infection, flap loss). Despite several techniques currently employed for perineal closure after APR, it still remains unclear as to which strategy is superior. In The Netherlands, the perineal wound after APR for non-locally advanced rectal cancer is most often closed using primary layered suturing of the subcutaneous fat and skin, even in cases of an extralevator approach.

As a means of preventing these complications, a variety of techniques using autologous tissue transfer have been proposed. One of the rationales is related to obliterating the pelvic dead space, thereby preventing presacral abscess formation. Furthermore, well-vascularized tissue might have a positive influence on wound healing, especially after radiotherapy. This might reduce perineal wound infection and dehiscence and other complications associated with non-healing. Options for perineal reconstruction following APR include musculocutaneous, fasciocutaneous, subcutaneous, or greater omentum flaps.3–5 However, the reconstructive procedures are complex, increase operating time, and are associated with a risk of added donor- and recipient-site morbidity (e.g. infection, flap loss). Despite several techniques currently employed for perineal closure after APR, it still remains unclear as to which strategy is superior. In The Netherlands, the perineal wound after APR for non-locally advanced rectal cancer is most often closed using primary layered suturing of the subcutaneous fat and skin, even in cases of an extralevator approach. There is no uniformity in the use of omentoplasty (OP), which is performed by approximately one-third of Dutch surgeons. It is hypothesized by surgeons who perform OP that this will improve perineal wound healing and prevent presacral abscess formation by adding well-vascularized and non-irradiated tissue. Although it is primarily intended to obliterate dead space, it has been suggested that an OP might also prevent perineal herniation and small bowel obstruction by preventing descent of bowel loops in the narrow pelvic cavity. Therefore, the aim of this multicenter snapshot study was to evaluate the impact of OP on perineal wound healing, presacral abscess formation, prevention of small bowel obstruction, and development of a perineal hernia in patients undergoing APR with primary perineal wound closure for rectal cancer.

rrow pelvic cavity. Therefore, the aim of this multicenter snapshot study was to evaluate the impact of OP on perineal wound healing, presacral abscess formation, prevention of small bowel obstruction, and development of a perineal hernia in patients undergoing APR with primary perineal wound closure for rectal cancer. Patients and Methods A retrospective cross-sectional snapshot study was performed by the Dutch Snapshot Research Group, evaluating all rectal cancer resections performed in 2011 in 71 hospitals in The Netherlands. This collaborative, resident-led research project has been extensively described in a previous paper from the Dutch Snapshot Research Group.6 Using a web-based application, relevant data until the last registered follow-up were collected in 2015. Data entry was performed by one or two residents or research nurses per participating hospital, supervised by a staff member. Since the present study was retrospectively completed based on electronic patient files with anonymized data analysis, the Medical Ethical Committee of the Academic Medical Centre in Amsterdam, The Netherlands, concluded that written informed consent was not required.

Patients and Methods A retrospective cross-sectional snapshot study was performed by the Dutch Snapshot Research Group, evaluating all rectal cancer resections performed in 2011 in 71 hospitals in The Netherlands. This collaborative, resident-led research project has been extensively described in a previous paper from the Dutch Snapshot Research Group.6 Using a web-based application, relevant data until the last registered follow-up were collected in 2015. Data entry was performed by one or two residents or research nurses per participating hospital, supervised by a staff member. Since the present study was retrospectively completed based on electronic patient files with anonymized data analysis, the Medical Ethical Committee of the Academic Medical Centre in Amsterdam, The Netherlands, concluded that written informed consent was not required. Patients Patients were included if the index procedure was an APR for rectal cancer. For the purpose of the present study, only patients in whom primary perineal closure (PPC) was performed, with or without OP, were included for analyses. Patients with locally advanced disease (pT4 stage and/or those who underwent additional visceral resection), autologous tissue flaps, or pelvic floor reconstruction using a mesh were excluded in order to decrease heterogeneity of the cohort and facilitate analysis and interpretation of the data. Patients were also excluded if data on perineal closure were not available.

d/or those who underwent additional visceral resection), autologous tissue flaps, or pelvic floor reconstruction using a mesh were excluded in order to decrease heterogeneity of the cohort and facilitate analysis and interpretation of the data. Patients were also excluded if data on perineal closure were not available. Outcome Primary endpoints were non-healing of the perineal wound at 1, 3, 6, 12 and 18 months and at the end of follow-up, overall incidence of presacral abscess, re-intervention for ileus, and perineal hernia development, irrespective of symptoms. Non-healing of the perineal wound was defined as an open perineal wound. Secondary study endpoints were 30-day mortality, 30-day overall complication rate, need for re-admissions or re-interventions related to the index procedure, local recurrence rate, disease-free survival and overall survival.

espective of symptoms. Non-healing of the perineal wound was defined as an open perineal wound. Secondary study endpoints were 30-day mortality, 30-day overall complication rate, need for re-admissions or re-interventions related to the index procedure, local recurrence rate, disease-free survival and overall survival. Statistical Analysis Proportions were expressed as a percentage of the total number of cases in the group. According to distribution, continuous data were reported as mean ± standard deviation (SD) or median with interquartile range (IQR). Numerical data were analyzed using either the t test or Mann–Whitney U test, while categorical data were analyzed using the χ 2 test or Fisher’s exact test. Perineal hernia incidence and survival rates were calculated using Kaplan–Meier analysis, and subgroups were compared using the log-rank test. Patients with missing data on perineal hernia status were not included in the Kaplan–Meier analysis. Univariable and multivariable analyses for primary endpoints were performed by binary logistic regression, with separate analyses using Bonferroni correction. Predictors identified in the univariable analysis were candidates for multivariable regression if p < 0.2. Significance was set at p < 0.05. All analyses were performed using IBM SPSS statistics, version 23.0.0 (IBM Corporation, Armonk, NY, USA).

logistic regression, with separate analyses using Bonferroni correction. Predictors identified in the univariable analysis were candidates for multivariable regression if p < 0.2. Significance was set at p < 0.05. All analyses were performed using IBM SPSS statistics, version 23.0.0 (IBM Corporation, Armonk, NY, USA). Results Patient Characteristics Of the total snapshot cohort of 2102 patients who underwent resection of rectal cancer in 71 Dutch hospitals in 2011, 639 underwent an APR procedure. After excluding locally advanced disease, extended resection and/or additional reconstructive procedures (i.e. flaps/biomesh), a total of 477 patients (172 OP and 305 non-OP) were included in the analyses. Patient baseline characteristics are displayed in Table 1. The mean age was 67 years (± 10.8) and 70% were male. A total of 96% of patients received neoadjuvant radiotherapy and 8% received adjuvant chemotherapy, with no significant differences between the groups. The proportion of OP at hospital level was 0% in 17 hospitals (27%), between 1 and 25% in 14 hospitals (22%), between 26 and 75% in 18 hospitals (29%), and between 76 and 100% in 14 hospitals (22%). Patients who underwent OP more often had diabetes mellitus, a higher percentage underwent extralevator APR, and a laparoscopic approach was used less often (Table 1). Total follow-up after OP was 42 months (IQR 25–46), which was similar to a follow-up of 40 months (IQR 22–47) in the non-OP group.Table 1 Baseline characteristics

who underwent OP more often had diabetes mellitus, a higher percentage underwent extralevator APR, and a laparoscopic approach was used less often (Table 1). Total follow-up after OP was 42 months (IQR 25–46), which was similar to a follow-up of 40 months (IQR 22–47) in the non-OP group.Table 1 Baseline characteristics Group A Group B No omentoplasty [n = 305] Omentoplasty (n = 172) p value Hospital Non-teaching hospital 59 (19) 26 (15) 0.001 Teaching hospital 231 (76) 120 (70) University hospital 15 (5) 26 (15) Sex Male 203 (67) 129 (75) 0.054 Age, years Mean ± SD 68 ± 11 66 ± 11 0.131 Body mass index, kg/m2 Mean ± SD 26 ± 4 27 ± 4 0.007 ASA classification 1 86 (29) 41 (24) 0.526 2 166 (55) 100 (59) 3 47 (16) 26 (15) 4 1 (0.3) 2 (1.2) Comorbidity Diabetes mellitus 25 (8) 32 (19) 0.001 Vascular 110 (37) 57 (34) 0.540 Previous operations Abdominal surgery 101 (34) 51 (30) 0.453 Pelvic surgery 34 (12) 16 (10) 0.530 Distance to anorectal junction, cm Median (IQR) 2 (1–4) 2 (0–4) 0.782 Relation tumor to MRF on MRI < 1 mm 107 (42) 75 (53) 0.035 Neoadjuvant radiotherapy Total 278 (96) 150 (94) 0.363 Surgery prior to resection Stoma 22 (7) 7 (4) 0.168 Type of surgery iAPR 23 (8) 11 (7) 0.641 cAPR 227 (78) 100 (61) < 0.001 eAPR 41 (14) 53 (32) < 0.001 Approach Laparoscopic 164 (55) 56 (33) < 0.001 Conversion Total 16 (10) 3 (6) 0.288 Intraoperative complicationa Total 15 (5) 10 (6) 0.686 Adjuvant chemotherapy Total 25 (8) 15 (9) 0.859 Data are expressed as n (%) unless otherwise specified

Mean ± SD 26 ± 4 27 ± 4 0.007 ASA classification 1 86 (29) 41 (24) 0.526 2 166 (55) 100 (59) 3 47 (16) 26 (15) 4 1 (0.3) 2 (1.2) Comorbidity Diabetes mellitus 25 (8) 32 (19) 0.001 Vascular 110 (37) 57 (34) 0.540 Previous operations Abdominal surgery 101 (34) 51 (30) 0.453 Pelvic surgery 34 (12) 16 (10) 0.530 Distance to anorectal junction, cm Median (IQR) 2 (1–4) 2 (0–4) 0.782 Relation tumor to MRF on MRI < 1 mm 107 (42) 75 (53) 0.035 Neoadjuvant radiotherapy Total 278 (96) 150 (94) 0.363 Surgery prior to resection Stoma 22 (7) 7 (4) 0.168 Type of surgery iAPR 23 (8) 11 (7) 0.641 cAPR 227 (78) 100 (61) < 0.001 eAPR 41 (14) 53 (32) < 0.001 Approach Laparoscopic 164 (55) 56 (33) < 0.001 Conversion Total 16 (10) 3 (6) 0.288 Intraoperative complicationa Total 15 (5) 10 (6) 0.686 Adjuvant chemotherapy Total 25 (8) 15 (9) 0.859 Data are expressed as n (%) unless otherwise specified ASA American Society of Anesthesiologists, MRF mesorectal fascia, MRI magnetic resonance imaging, i/c/eAPR intersphincteric/conventional/extralevator abdominoperineal resection, SD standard deviation, IQR interquartile range aIncludes injury to spleen, intestine, ureter/urethra, bladder and vagina, and bleeding for which transfusion was required

ASA American Society of Anesthesiologists, MRF mesorectal fascia, MRI magnetic resonance imaging, i/c/eAPR intersphincteric/conventional/extralevator abdominoperineal resection, SD standard deviation, IQR interquartile range aIncludes injury to spleen, intestine, ureter/urethra, bladder and vagina, and bleeding for which transfusion was required Primary Endpoints There were no significant differences between groups in proportions with a primary healed perineal wound, at any time point during follow-up (Fig. 1). After 30 days, the non-healing rate was 47% (72/152) after OP and 48% (132/272) without OP (p = 0.819). At the end of follow-up, the rate of chronic non-healing of the perineal wound was 9% (13/152) and 5% (13/272) in the OP and non-OP groups, respectively (p = 0.120). By univariable logistic regression, the following variables reached p < 0.2: age, diabetes mellitus, OP, and type of APR (electronic supplementary Table S1). Using a multivariable model, non-healing of the perineal wound at 30 days and 3 months postoperatively occurred significantly less often after an intersphincteric approach if compared with a conventional APR (Table 2). Age was also independently associated with non-healing at 30 days, with an OR of 1.03 [95% confidence interval (CI) 1.010–1.049] for increasing age of 1 year each (p = 0.003).Fig. 1 Perineal wound healing over time with and without omentoplasty. APR abdominoperineal resection, FU follow-up Table 2 Multivariable logistic regression analysis

Primary Endpoints There were no significant differences between groups in proportions with a primary healed perineal wound, at any time point during follow-up (Fig. 1). After 30 days, the non-healing rate was 47% (72/152) after OP and 48% (132/272) without OP (p = 0.819). At the end of follow-up, the rate of chronic non-healing of the perineal wound was 9% (13/152) and 5% (13/272) in the OP and non-OP groups, respectively (p = 0.120). By univariable logistic regression, the following variables reached p < 0.2: age, diabetes mellitus, OP, and type of APR (electronic supplementary Table S1). Using a multivariable model, non-healing of the perineal wound at 30 days and 3 months postoperatively occurred significantly less often after an intersphincteric approach if compared with a conventional APR (Table 2). Age was also independently associated with non-healing at 30 days, with an OR of 1.03 [95% confidence interval (CI) 1.010–1.049] for increasing age of 1 year each (p = 0.003).Fig. 1 Perineal wound healing over time with and without omentoplasty. APR abdominoperineal resection, FU follow-up Table 2 Multivariable logistic regression analysis Parameter Perineal hernia Open wound, 30 days Open wound, 3 months Open wound, 12 months Open wound, end of follow-up OR p value OR p value OR p value OR p value OR p value Omentoplasty 2.61 0.009 NI NI NI NI 1.46 0.324 1.59 0.279 eAPRa NI NI 1.03 0.910 1.06 0.846 NI NI NI NI iAPRa NI NI 0.40 0.024 0.25 0.027 NI NI NI NI Open approachb NI NI – – – – – – – – Female sex 2.42 0.021 NI NI NI NI NI NI NI NI Agec NI NI 1.03 0.003 1.02 0.093 1.02 0.192 1.03 0.181 Diabetes mellitus – – NI NI NI NI 1.64 0.319 2.14 0.139 Vascular disease – – NI NI NI NI NI NI NI NI Previous pelvic surgeryd 1.18 0.760 – – – – – – – – Neoadjuvant radiotherapy 0.29 0.038 NI NI NI NI NI NI NI NI

– – – Female sex 2.42 0.021 NI NI NI NI NI NI NI NI Agec NI NI 1.03 0.003 1.02 0.093 1.02 0.192 1.03 0.181 Diabetes mellitus – – NI NI NI NI 1.64 0.319 2.14 0.139 Vascular disease – – NI NI NI NI NI NI NI NI Previous pelvic surgeryd 1.18 0.760 – – – – – – – – Neoadjuvant radiotherapy 0.29 0.038 NI NI NI NI NI NI NI NI OR odds ratio, APR abdominoperineal resection, e/iAPR extralevator/intersphincteric abdominoperineal resection, NI not included based on univariate analysis aConventional APR as a reference bCompared with the transabdominal laparoscopic procedure cIncluded as a continuous variable dIncludes hysterectomy, prostatectomy, cystectomy, and ovariectomy During complete follow-up, a presacral abscess developed in 12% (21/170) of patients after OP, which did not significantly differ from the 13% (39/300) of patients without OP (p = 0.840). Univariable logistic regression analysis showed no significant influence of baseline characteristics on abscess formation (electronic supplementary Table S1). The re-admission rate for ileus was 5% (8/172) in the OP group and 7% (21/305) in the non-OP group (p = 0.327). The re-intervention rate pertaining to small bowel obstruction was also equivalent between groups [5% (8/172) OP vs. 3% (9/305) non-OP; p = 0.336].

During complete follow-up, a presacral abscess developed in 12% (21/170) of patients after OP, which did not significantly differ from the 13% (39/300) of patients without OP (p = 0.840). Univariable logistic regression analysis showed no significant influence of baseline characteristics on abscess formation (electronic supplementary Table S1). The re-admission rate for ileus was 5% (8/172) in the OP group and 7% (21/305) in the non-OP group (p = 0.327). The re-intervention rate pertaining to small bowel obstruction was also equivalent between groups [5% (8/172) OP vs. 3% (9/305) non-OP; p = 0.336]. The median duration between APR and perineal hernia development was 9 months (IQR 6–21). Perineal herniation occurred significantly more often after APR with OP compared with APR without OP (13% vs. 7%; OR 2.61, 95% CI 1.271–5.364; p = 0.009) [Table 2, and electronic supplementary Table S1], and also after Bonferroni correction (electronic supplementary Table S3). Over time, perineal herniation appeared to stabilize in the non-OP group after 24 months, while perineal hernias continued to occur beyond 2 years in the OP group (Fig. 2; p = 0.032 [log-rank test]). Females also had an increased risk of developing a perineal hernia after APR compared with men (OR 2.42, 95% CI 1.141–5.135; p = 0.021). Neoadjuvant radiotherapy was associated with a lower risk of perineal herniation (OR 0.29, 95% CI 0.088–0.934; p = 0.038). An extralevator approach was not significantly associated with perineal hernia development in univariable analysis (p > 0.2) and was therefore not included in the multivariable model (Table 2).Fig. 2 Kaplan–Meier curve for developing a perineal hernia over time

ineal herniation (OR 0.29, 95% CI 0.088–0.934; p = 0.038). An extralevator approach was not significantly associated with perineal hernia development in univariable analysis (p > 0.2) and was therefore not included in the multivariable model (Table 2).Fig. 2 Kaplan–Meier curve for developing a perineal hernia over time Secondary Endpoints At 30 days postoperatively, the overall complication rate was 37% (174/465). Surgical complications, re-intervention for a surgical complication, and 30-day mortality rate did not significantly differ between groups (electronic supplementary Table S2). In the period after 30 days postoperatively, the re-admission rate was not decreased by use of an OP compared with no OP (20% vs. 23%, respectively; p = 0.499), and neither was the need for reoperations (16% vs. 13%, respectively; p = 0.329). Three-year local recurrence (6% vs. 3%), disease-free survival (66% vs. 67%), and overall survival (80% vs. 80%) did not differ between groups (electronic supplementary Table S4). Discussion This snapshot study is the largest reported comparative cohort study to date on the effect of OP on perineal wound complications after APR in a homogenous patient population. Performing an OP in combination with primary wound closure appeared not to improve perineal wound healing. Filling of the pelvic dead space by OP was also not associated with fewer pelvic abscesses or re-interventions for ileus. Moreover, OP was an independent risk factor for perineal hernia formation, besides female sex.

forming an OP in combination with primary wound closure appeared not to improve perineal wound healing. Filling of the pelvic dead space by OP was also not associated with fewer pelvic abscesses or re-interventions for ileus. Moreover, OP was an independent risk factor for perineal hernia formation, besides female sex. Despite its frequent use and clinical implications, there are only very limited data on OP for filling of the pelvic cavity after APR. A counterintuitive finding was the higher perineal hernia rate after OP, while the extralevator approach was not associated with perineal hernia development. The incidence of perineal hernia was based on documentation in the patient files, without predefined definition. The 13 and 7% hernia rates in the two groups are higher than the rates mostly reported in the literature, but are even likely to be underestimated (small asymptomatic hernias are probably not documented). An OP is often considered to be a perineal reconstruction technique, but the omental fat is actually frequently the content of the hernia sac if a perineal hernia occurs. A plausible explanation may be that a fully mobilized OP with a long vascular pedicle allows for more herniation than descending small bowel loops that are restricted by mesenteric length (Fig. 3). After removal of the rectum, the bladder and internal genital organs move posteriorly and reduce the presacral space towards the pelvic outlet. This sometimes even prevents the small bowel to fully descend to the closed perineum, or it is only a single loop that fills the presacral space. In contrast, an OP will prevent the bladder and internal genital organs from displacing and a large bulk of omental fat will give downward pressure on the perineal wound in a standing position. That the extralevator approach was not associated with perineal hernia formation might be explained by the fact that surgeons performing a ‘conventional’ APR have already adopted elements of cylindrical resection without changing the name of their surgical technique. The protective effect of radiotherapy for developing a perineal hernia was also remarkable, but might be explained by inducing fibrosis,7 which in turn might strengthen the perineal scar. However, these results should be interpreted with caution since 96% of patients received radiotherapy.Fig. 3 Two male patients after abdominoperineal resection with primary perineal closure for rectal cancer.

lso remarkable, but might be explained by inducing fibrosis,7 which in turn might strengthen the perineal scar. However, these results should be interpreted with caution since 96% of patients received radiotherapy.Fig. 3 Two male patients after abdominoperineal resection with primary perineal closure for rectal cancer. a Computed tomography image, sagittal plane, showing descent of a small bowel loop with restricted mesenteric length. b Magnetic resonance image, sagittal plane, showing a large perineal hernia in which the hernia sac is filled with fully mobilized bulky omentum It has been proposed that an OP would lower infectious complications after APR by obliterating the perineal dead space, which reduces the formation of fluid collections with secondary infection. Furthermore, OP might promote angiogenesis and might enhance local immunity and antibiotic delivery.8–10 Given the often irradiated fibrotic pelvic tissues, adding well-vascularized tissue might enhance the local wound healing. Besides its potential role in reducing infectious complications, it has been suggested that OP might prevent small bowel descent with the risk of ileus. However, none of these potential advantages of OP could be demonstrated in the present study.

s, adding well-vascularized tissue might enhance the local wound healing. Besides its potential role in reducing infectious complications, it has been suggested that OP might prevent small bowel descent with the risk of ileus. However, none of these potential advantages of OP could be demonstrated in the present study. In a randomized controlled trial on biomesh repair after APR, we have already demonstrated that OP did not improve wound healing, based on a post hoc analysis.11 OP was performed in 61 of the 101 included patients, with no impact of OP on perineal wound complications (RR 1.111, 95% CI 0.651–1.897). This snapshot study confirms this observation in a large observational cohort. Killeen et al. published a systematic review in which they included all APR cohort series mentioning the use of OP, regardless of indication.12 They found an improved primary wound healing rate, more rapid healing, and fewer infectious complications after OP. These contradictory findings, compared with the present study, are likely to be related to several methodological shortcomings of the studies included in the review. These consisted of heterogeneous and mostly historical patient populations with confounded comparisons. Half of the studies did not include a control, with only three small comparative series since 2000. Furthermore, data were pooled from studies containing inflammatory bowel disease together with series only describing cancers. Cancer patients received neoadjuvant radiotherapy in a wide range, between 14 and 75%, which is one of the major determinants for perineal wound complications. The extent of the resection and use of myocutaneous flaps was not evenly distributed among groups, without the ability to correct for these confounders. Finally, the pooled median follow-up was only 13.5 months, with merely two studies exceeding 24 months. This underlines the importance of the present study in which the impact of OP is evaluated in a large homogeneous patient cohort with a median follow-up of 41 months.

out the ability to correct for these confounders. Finally, the pooled median follow-up was only 13.5 months, with merely two studies exceeding 24 months. This underlines the importance of the present study in which the impact of OP is evaluated in a large homogeneous patient cohort with a median follow-up of 41 months. A possible explanation for not finding an impact of OP on abscess formation and perineal wound healing may be related to insufficient bulk of tissue because of low body mass index or inadequate mobilization. There is no consensus on the technical aspects of detachment of the omentum, whether to create a vascular pedicle on the right or left gastroepiploic artery, and the route along which the OP is positioned in the pelvic cavity (i.e. left paracolic gutter or via a mesenteric window). An insufficient OP leads to a small residual cavity, providing an opportunity for abscess formation. Another possibility is that the larger perineal defects were selected for OP, thus leading to an underestimation of the added effect of OP in the prevention of perineal wound complications. However, the observed perineal non-healing and abscess rates do not indicate any trend favoring OP, and extensive resections for locally advanced disease were excluded.

perineal defects were selected for OP, thus leading to an underestimation of the added effect of OP in the prevention of perineal wound complications. However, the observed perineal non-healing and abscess rates do not indicate any trend favoring OP, and extensive resections for locally advanced disease were excluded. There are some limitations to this study, inherent to its retrospective and non-randomized design. Selection of participating centers could have introduced bias; however, the study included a relatively large number of hospitals and cases of APR. We also recognize limitations due to the unavailability of some relevant variables such as indication for OP, technical details of the OP, i.e. type of vascular pedicle, postoperative drain use, or the extent of the perineal wound, and technical details on perineal closure (e.g. layered suturing, leaving the skin open). Finally, the results might have been biased by allocation. However, the divergent proportions of OP applied per center indicate that the decision of using OP was mainly surgeon- or hospital-related, rather than patient-related.

d, and technical details on perineal closure (e.g. layered suturing, leaving the skin open). Finally, the results might have been biased by allocation. However, the divergent proportions of OP applied per center indicate that the decision of using OP was mainly surgeon- or hospital-related, rather than patient-related. Although the physiological properties of the omentum make it an excellent hypothetical candidate for routine use following APR, the present study found no evidence to support an OP for improvement of perineal wound healing or reducing the risk of postoperative ileus. On the contrary, OP seemed to be associated with a higher incidence of perineal hernia. Furthermore, OP results in a longer operating time and has a reported risk of necrosis and prolonged postoperative ileus, although incidences seem to be low.12, 13 The only potential improvement by performing an OP might be regarding preservation of bladder and sexual function by preventing posterior displacement, which was not investigated in the present study. Considering the implications for current daily practice, the present study, as well as the low-quality available literature, do not support routine use of an OP. Conclusions In the absence of randomized controlled trials, this large, comparative cohort study provides the best available evidence on the additional value of OP in patients undergoing APR for rectal cancer with PPC and almost routine use of radiotherapy. OP did not have any impact on abscess formation, postoperative ileus, or (time to) perineal wound healing.

trolled trials, this large, comparative cohort study provides the best available evidence on the additional value of OP in patients undergoing APR for rectal cancer with PPC and almost routine use of radiotherapy. OP did not have any impact on abscess formation, postoperative ileus, or (time to) perineal wound healing. Electronic Supplementary Material Below is the link to the electronic supplementary material. Supplementary material 1 (DOC 118 kb) Supplementary material 2 (XLS 47 kb) Collaborators of the Dutch Snapshot Research Group are listed in “Acknowledgment”. Electronic supplementary material The online version of this article (10.1245/s10434-017-6273-9) contains supplementary material, which is available to authorized users.

Electronic Supplementary Material Below is the link to the electronic supplementary material. Supplementary material 1 (DOC 118 kb) Supplementary material 2 (XLS 47 kb) Collaborators of the Dutch Snapshot Research Group are listed in “Acknowledgment”. Electronic supplementary material The online version of this article (10.1245/s10434-017-6273-9) contains supplementary material, which is available to authorized users. Acknowledgement Collaborators Dutch Snapshot Research Group A. Aalbers , Y. Acherman, G.D. Algie, B. Alting von Geusau, F. Amelung, T.S. Aukema, I.S. Bakker, S.A. Bartels, S. Basha, A.J.N.M. Bastiaansen, E. Belgers, W. Bleeker, J. Blok, R.J.I. Bosker, J.W. Bosmans, M.C. Boute, N.D. Bouvy, H. Bouwman, A. Brandt-Kerkhof, D.J. Brinkman, S. Bruin, E.R.J. Bruns, J.P.M. Burbach, J.W.A. Burger, S. Clermonts, P.P.L.O. Coene, C. Compaan, E.C.J. Consten, T. Darbyshire, S.M.L. de Mik , E.J.R. de Graaf, I. de Groot, R.J.L. de Vos tot Nederveen Cappel, J.H.W. de Wilt, J. van der Wolde, F.C. den Boer, J.W.T. Dekker, A. Demirkiran, M. Derkx-Hendriksen, F.R. Dijkstra, P. van Duijvendijk, M.S. Dunker, Q.E. Eijsbouts, H. Fabry, F. Ferenschild, J.W. Foppen, E.J.B. Furnée, M.F. Gerhards, P. Gerven, J.A.H. Gooszen, J.A. Govaert, W.M.U. van Grevenstein, R. Haen, J.J. Harlaar, E. Harst, K. Havenga, J. Heemskerk, J.F. Heeren, B. Heijnen, P. Heres, C. Hoff, W. Hogendoorn, P. Hoogland, A. Huijbers, P. Janssen, A.C. Jongen, F.H. Jonker, E.G. Karthaus, A. Keijzer, J.M.A. Ketel, J. Klaase, F.W.H. Kloppenberg, M.E. Kool, R. Kortekaas, P.M. Kruyt, J.T. Kuiper, B. Lamme, J.F. Lange, T. Lettinga, D.J. Lips, F. Logeman, M.F. Lutke Holzik, E. Madsen, A. Mamound, C.C. Marres, I. Masselink, M. Meerdink, A.G. Menon, J.S. Mieog, D. Mierlo, G.D. Musters, P.A. Neijenhuis, J. Nonner, M. Oostdijk, S.J. Oosterling, P.M.P. Paul, K.C.M.J.C. Peeters, I.T.A. Pereboom, F. Polat, P. Poortman, M. Raber, B.M.M. Reiber, R.J. Renger, C.C. van Rossem, H.J. Rutten, A. Rutten, R. Schaapman, M. Scheer, L. Schoonderwoerd, N. Schouten, A.M. Schreuder, W.H. Schreurs, G.A. Simkens, G.D. Slooter, H.C.E. Sluijmer, N. Smakman, R. Smeenk, H.S. Snijders, D.J.A. Sonneveld, B. Spaansen, E.J. Spillenaar Bilgen, E. Steller, W.H. Steup, C. Steur, E. Stortelder, J. Straatman, M. Stuijvenberg, H.A. Swank, C. Sietses, H.A. ten Berge, H.G. ten hoeve, W.W. ter Riele, I.M. Thorensen, B. Tip-Pluijm, B.R. Toorenvliet, L. Tseng, J.B. Tuynman, J. van Bastelaar, S.C. van beek, A.W.H. van de Ven, M.A.J. van de Weijer, C. van den Berg, I. van den Bosch, J.D.W. van der Bilt, S.J. van der Hagen, R. van der Hul, G. van der Schelling, A.

Sietses, H.A. ten Berge, H.G. ten hoeve, W.W. ter Riele, I.M. Thorensen, B. Tip-Pluijm, B.R. Toorenvliet, L. Tseng, J.B. Tuynman, J. van Bastelaar, S.C. van beek, A.W.H. van de Ven, M.A.J. van de Weijer, C. van den Berg, I. van den Bosch, J.D.W. van der Bilt, S.J. van der Hagen, R. van der Hul, G. van der Schelling, A. van der Spek, N. van der Wielen, E. van Duyn, C. van Eekelen, J.A. Van Essen, K. Van Gangelt, A.A.W. Van Geloven, C. Van Kessel, Y.T. van Loon, A. van Rijswijk, S.J. van Rooijen, T. van Sprundel, L. van Steensel, W.F. van Tets, H.L. van Westreenen, C.J. van de Velde, S. Veltkamp, T. Verhaak, P.M. Verheijen, L. Versluis-Ossenwaarde, S. Vijfhuize, W.J. Vles, S. Voeten, F.J. Vogelaar, W.W. Vrijland, E. Westerduin, M.E. Westerterp, M. Wetzel, M. Wevers, B. Wiering, A.C. Witjes, M.W. Wouters, S.T.K. Yauw, E.C. Zeestraten, D.D. Zimmerman, T. Zwieten. Financial Support Financial support for this snapshot research was provided by the Dutch Cancer Society (KWF) and the Dutch Surgical Colorectal Audit. Disclosure Robin D. Blok, Gijsbert D. Musters, Wernard A.A. Borstlap, Christianne J. Buskens, Wilhelmus A. Bemelman, and Pieter J. Tanis have no conflicts of interest to declare.

In the treatment of patients with locally advanced rectal cancer, preoperative chemoradiotherapy (CRT) has proven to reduce the local recurrence (LR) rate significantly and has become the standard of care.1 A pathological complete response (pCR) following CRT was found in 15–20% of patients, and this is associated with a favorable oncological outcome.2 Furthermore, there is a recent trend towards rectal-preserving treatment in patients with a good response.3 One of the unresolved issues regarding preoperative CRT is the optimal time interval to total mesorectal excision (TME) surgery and the role of re-staging in determining this interval. A recent systematic review including 13 studies with a total of 19,652 patients concluded that an interval of ≥ 8 weeks from the end of CRT is safe and efficacious because of higher pCR rates, without increasing complication rates;4 however, reasons for delaying surgery in the mostly non-randomized comparisons were not provided, and data on the use and outcome of restaging were lacking. Furthermore, no impact on survival was observed. The GRECCAR-6 trial recently reported contradictory findings.5 In this trial, 265 patients from 24 French centers were randomized to between 7 and 11 weeks waiting after the end of CRT. No difference in the pCR rate was observed, but the authors did find a higher morbidity rate and worse quality of the mesorectal resection after a prolonged interval. Restaging was not systematically performed in this trial. It is likely the time interval to surgery has to be tailored to the individual patient, rather than a ‘one size fits all’ approach. Non-responders should continue with further treatment (e.g. surgery or further chemotherapy), and those having a good response might benefit from additional waiting time or consolidation chemotherapy to maximize tumor shrinkage with the highest change of negative resection margins.6 However, the role of MRI and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in assessing tumor downstaging after CRT, and its value for clinical decision making, is still unclear.7,8

on chemotherapy to maximize tumor shrinkage with the highest change of negative resection margins.6 However, the role of MRI and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in assessing tumor downstaging after CRT, and its value for clinical decision making, is still unclear.7,8 The aim of this multicenter, cross-sectional study of patients who underwent CRT for rectal cancer in 71 Dutch centers in 2011 was to first evaluate variation in practice with respect to MRI restaging and its impact on time interval to surgery, and, second, to evaluate the impact of timing of surgery on pathological, surgical, and long-term oncological outcomes. Patients and methods A retrospective, resident-led, collaborative research project with a cross-sectional study design was conducted in 71 of 94 hospitals in The Netherlands by the Dutch Snapshot Research Group (DSRG) in 2015. All patients who underwent resection for primary rectal cancer in these hospitals in 2011 were identified from the Dutch ColoRectal Audit (DCRA).9 Additional diagnostic and treatment characteristics, as well as long-term surgical and oncological outcomes, were retrospectively added to the DCRA dataset for the year 2011. Details of this cross-sectional study cohort have been published previously.10

s in 2011 were identified from the Dutch ColoRectal Audit (DCRA).9 Additional diagnostic and treatment characteristics, as well as long-term surgical and oncological outcomes, were retrospectively added to the DCRA dataset for the year 2011. Details of this cross-sectional study cohort have been published previously.10 Patients and Definitions All patients who underwent rectal cancer resection after preoperative CRT between 1 January and 31 December 2011 were selected from the initial cohort. The CRT schedule was not registered in the database but consisted of either 25 fractions of 2 Gy or 28 fractions of 1.8 Gy, with concomitant capecitabine as a radiosensitizer. Only the start date of radiotherapy was available in the dataset. Patients were divided into two interval groups based on the observed median time interval: surgery < 14 weeks from the start of CRT (short interval), and surgery after 14 weeks or more (long interval). Patients with metastasis, patients who received additional neoadjuvant chemotherapy preceding or following CRT, and patients with an unknown start date for CRT were excluded. To evaluate the timing of MRI restaging, the interval between the start of CRT and the date of MRI was categorized into four groups: < 6, 6–8, 8–10, and > 10 weeks (electronic supplementary Fig. 1). The MRI restaging result was classified by the study collaborators as ‘progressive disease’, ‘stable disease’, ‘partial response’ and ‘complete response’ based on the radiology reports. To evaluate the subsequent time interval between MRI restaging and surgery, three groups of < 2, 2–4, and > 4 weeks were defined.

1). The MRI restaging result was classified by the study collaborators as ‘progressive disease’, ‘stable disease’, ‘partial response’ and ‘complete response’ based on the radiology reports. To evaluate the subsequent time interval between MRI restaging and surgery, three groups of < 2, 2–4, and > 4 weeks were defined. Outcome Parameters Pathological outcome parameters included pCR (ypT0N0), near pCR (ypT1N0), and circumferential resection margin (CRM) involvement (tumor-free resection margin ≤ 1 mm). Surgical outcome parameters were 30-day overall and surgical complication rate, postoperative blood transfusion, perineal wound problems after abdominoperineal resection (APR), anastomotic leakage after (low) anterior resection (LAR), chronic presacral sinus, length of stay, and re-intervention- and re-admission rate within 30-days. For long-term oncological outcome, 3-year LR, distant recurrence (DR), disease-free survival (DFS), and overall survival (OS) rates were analyzed.

esection (APR), anastomotic leakage after (low) anterior resection (LAR), chronic presacral sinus, length of stay, and re-intervention- and re-admission rate within 30-days. For long-term oncological outcome, 3-year LR, distant recurrence (DR), disease-free survival (DFS), and overall survival (OS) rates were analyzed. Statistical Analysis Categorical or dichotomous outcomes were expressed as absolute numbers with percentages. Statistical analysis of categorical outcomes between groups was performed using the Pearson Chi square test or Fisher’s exact test, where appropriate. Continuous outcomes were expressed as median with interquartile range (IQR). For intergroup variation, the Mann–Whitney U test was used following their distribution, otherwise Student’s t test was used for independent samples. To determine the 3-year LR, DR, DFS, and OS rates, the Kaplan–Meier method was used and the log-rank test was used for comparison between the two interval groups. Univariable and multivariable analyses were performed to identify independent predictors for CRM, LR, DR, DFS, and OS. Variables with a p value < 0.10 in the univariable analysis were included in the multivariable model. Results of the multivariable analyses were reported as odds ratios (OR) with 95% confidence intervals (CIs). A p value < 0.05 was considered statistically significant. Statistical analyses were performed in PASW Statistics version 24 (IBM Corporation, Armonk, NY, USA).

analysis were included in the multivariable model. Results of the multivariable analyses were reported as odds ratios (OR) with 95% confidence intervals (CIs). A p value < 0.05 was considered statistically significant. Statistical analyses were performed in PASW Statistics version 24 (IBM Corporation, Armonk, NY, USA). Results Patient Characteristics Within the total cohort of 2095 patients, 684 patients underwent preoperative CRT. After exclusion of patients with metastasis (n = 92), patients who received additional preoperative chemotherapy (n = 3) and patients with unknown start date of CRT (n = 114), 475 patients remained for inclusion in the present analysis.

Within the total cohort of 2095 patients, 684 patients underwent preoperative CRT. After exclusion of patients with metastasis (n = 92), patients who received additional preoperative chemotherapy (n = 3) and patients with unknown start date of CRT (n = 114), 475 patients remained for inclusion in the present analysis. The median time interval between the start of CRT and surgery was 14 weeks (IQR 12–16) (Fig. 1). Based on this median time interval, patients were subdivided into two groups: 224 patients with a short interval and 251 patients with a long interval. Patient and tumor characteristics of the two groups are reported in Table 1. Significant differences between the interval groups were found for American Society of Anesthesiologists (ASA) score, distance to the anorectal junction on MRI, and clinical tumor stage. Regarding treatment characteristics, the proportion of open approaches (45.5% vs. 58.6%, p = 0.011) and multivisceral resections (8.7% vs. 16.5%, p = 0.012) was significantly different between the short- and long-interval groups. The proportion of patients receiving adjuvant chemotherapy in the short-interval group was lower in comparison with the long-interval group, however was not statistically significant (n = 16 [7.1%] vs. n = 31 [12.4%], p = 0.058)Fig. 1 Number of patients for each chemoradiotherapy-surgery time interval in weeks from start of chemoradiotherapy Table 1 Patient, tumor, and treatment characteristics, and pathological, surgical, and long-term oncologic outcomes for the short- and long-interval groups

The median time interval between the start of CRT and surgery was 14 weeks (IQR 12–16) (Fig. 1). Based on this median time interval, patients were subdivided into two groups: 224 patients with a short interval and 251 patients with a long interval. Patient and tumor characteristics of the two groups are reported in Table 1. Significant differences between the interval groups were found for American Society of Anesthesiologists (ASA) score, distance to the anorectal junction on MRI, and clinical tumor stage. Regarding treatment characteristics, the proportion of open approaches (45.5% vs. 58.6%, p = 0.011) and multivisceral resections (8.7% vs. 16.5%, p = 0.012) was significantly different between the short- and long-interval groups. The proportion of patients receiving adjuvant chemotherapy in the short-interval group was lower in comparison with the long-interval group, however was not statistically significant (n = 16 [7.1%] vs. n = 31 [12.4%], p = 0.058)Fig. 1 Number of patients for each chemoradiotherapy-surgery time interval in weeks from start of chemoradiotherapy Table 1 Patient, tumor, and treatment characteristics, and pathological, surgical, and long-term oncologic outcomes for the short- and long-interval groups Overall [n = 475] (%) <14 weeks interval [n = 224] (%) ≥ 14 weeks interval [n = 251] (%) p value Sex Male 300/475 (63.2) 140/224 (62.5) 160/251 (63.7) 0.779 Age, years 0.169 <60 159/475 (33.5) 84/224 (37.5) 75/251 (29.9) 61–70 192/475 (40.4) 91/224 (40.6) 101/251 (40.2) 71–80 110/475 (23.2) 43/224 (19.2) 67/251 (26.7) > 80 14/475 (2.9) 6/224 (2.7) 8/251 (3.2) ASA score

Overall [n = 475] (%) <14 weeks interval [n = 224] (%) ≥ 14 weeks interval [n = 251] (%) p value Sex Male 300/475 (63.2) 140/224 (62.5) 160/251 (63.7) 0.779 Age, years 0.169 <60 159/475 (33.5) 84/224 (37.5) 75/251 (29.9) 61–70 192/475 (40.4) 91/224 (40.6) 101/251 (40.2) 71–80 110/475 (23.2) 43/224 (19.2) 67/251 (26.7) > 80 14/475 (2.9) 6/224 (2.7) 8/251 (3.2) ASA score 0.026 I–II 418/475 (88.0) 205/224 (91.5) 213/251 (84.9) III–IV 57/475 (12.0) 19/224 (8.5) 38/251 (15.1) Preoperative imaging a 0.061 MRI 446/465 (96.0) 215/220 (97.7) 231/245 (94.3) CT 19/465 (4.0) 5/220 (2.3) 14/245 (5.7) Distance to the anorectal junction, cm 0.043 < 3 143/475 (30.1) 72/224 (32.1) 71/251 (28.2) 3.1–7.0 129/475 (27.2) 57/224 (25.4) 72/251 (28.7) > 7 108/475 (22.7) 60/224 (26.8) 48/251 (19.1) Unknown 95/475 (20.0) 35/224 (15.6) 60/251 (23.9) MRF Positive 99/475 (20.8) 47/224 (21.0) 52/251 (20.7) 0.943 Clinical tumor stage cT3N0M0 59/475 (12.4) 29/224 (12.9) 30/251 (12.0) 0.743 cT4N0M0 15/475 (3.2) 7/224 (3.1) 8/251 (3.2) 0.969 cT1-3N1-2M0 269/475 (56.6) 134/224 (59.8) 135/251 (53.8) 0.185 cT4N1-2M0 49/475 (10.3) 16/224 (7.1) 33/251 (13.1) 0.032 Unknown 20/475 (4.2) 13/224 (5.8) 7/251 (2.8) 0.102 Procedure LAR with primary anastomosis 192/475 (40.4) 100/224 (44.6) 92/251 (36.7) 0.289 APR 202/475 (42.5) 89/224 (39.7) 113/251 (45.0) Hartmann 76/475 (16.0) 32/224 (14.3) 44/251 (17.5) Other 5/475 (1.1) 3/224 (1.3) 2/251 (0.8) Approach 0.011 Open 249/475 (52.4) 102/224 (45.5) 147/251 (58.6) Laparoscopic 220/475 (46.3) 120/224 (53.6) 100/251 (39.8) Laparoscopic conversion 6/475 (1.3) 2/224 (0.9) 4/301 (1.6) Multivisceral resection (additional) b

LAR with primary anastomosis 192/475 (40.4) 100/224 (44.6) 92/251 (36.7) 0.289 APR 202/475 (42.5) 89/224 (39.7) 113/251 (45.0) Hartmann 76/475 (16.0) 32/224 (14.3) 44/251 (17.5) Other 5/475 (1.1) 3/224 (1.3) 2/251 (0.8) Approach 0.011 Open 249/475 (52.4) 102/224 (45.5) 147/251 (58.6) Laparoscopic 220/475 (46.3) 120/224 (53.6) 100/251 (39.8) Laparoscopic conversion 6/475 (1.3) 2/224 (0.9) 4/301 (1.6) Multivisceral resection (additional) b Yes 60/466 (12.9) 19/218 (8.7) 41/248 (16.5) 0.012 No 406/466 (87.1) 199/218 (91.3) 207/248 (83.5) Adjuvant chemotherapy Yes 47/475 (9.9) 16/224 (7.1) 31/251 (12.4) 0.058 MRI restaging after CRT c 0.002 Yes 366/461 (79.4) 158/216 (73.1) 208/245 (84.9) No 95/461 (20.6) 58/216 (26.9) 37/245 (15.1) MRI restaging results d 0.244 Progression 7/361 (1.9) 1/7 (14.3) 6/7 (85.7) Stable 45/361 (12.5) 19/45 (42.2) 26/45 (57.8) Partial response 194/361 (53.7) 130/294 (44.2) 164/294 (55.8) Complete response 15/361 (4.2) 4/15 (26.7) 11/15 (73.3) Interval CRT–MRI (weeks) e < 0.001 <6 7/341 (2.0) 5/146 (3.4) 2/195 (1.0) 6–8 21/341 (6.2) 14/146 (9.6) 7/195 (3.6) 8–10 114/341 (33.4) 73/146 (50.0) 41/195 (21.0) 10–12 117/341 (34.3) 47/146 (32.2) 70/195 (35.9) 12–14 50/341 (14.7) 7/146 (4.8) 43/195 (22.1) 14–16 21/341 (6.2) – 21/195 (10.8) > 16 13/341 (3.8) – 11/195 (5.6) Interval MRI–surgery (weeks) f < 0.001

<6 7/341 (2.0) 5/146 (3.4) 2/195 (1.0) 6–8 21/341 (6.2) 14/146 (9.6) 7/195 (3.6) 8–10 114/341 (33.4) 73/146 (50.0) 41/195 (21.0) 10–12 117/341 (34.3) 47/146 (32.2) 70/195 (35.9) 12–14 50/341 (14.7) 7/146 (4.8) 43/195 (22.1) 14–16 21/341 (6.2) – 21/195 (10.8) > 16 13/341 (3.8) – 11/195 (5.6) Interval MRI–surgery (weeks) f < 0.001 < 1 9/340 (2.6) 6/146 (4.1) 3/194 (1.5) 1–2 28/340 (8.2) 21/146 (14.4) 7/194 (3.6) 2–3 63/340 (18.5) 43/146 (29.5) 20/194 (10.3) 3–4 69/340 (20.3) 36/146 (24.7) 33/194 (17.0) 4–5 62/340 (18.2) 24/146 (16.4) 38/194 (19.6) 5–6 41/340 (12.0) 13/146 (8.9) 28/194 (14.4) 6–7 25/340 (7.4) 3/146 (2.1) 22/194 (11.3) 7–8 17/340 (5.0) – 17/194 (8.8) 8–9 8/340 (2.4) – 8/194 (4.1) > 9 18/340 (0.3) – 18/194 (9.3) Pathological, surgical and long-term oncologic outcomes Histological type tumorg Adenocarcinoma 431/461 (93.5) 206/219 (94.1) 225/242 (93.0) 0.087 Mucinous 10/461 (2.2) 7/219 (3.2) 3/242 (1.2) Signet ring cell 15/461 (0.2) 1/19 (0.5) 14/242 (5.8) Other 5/461 (4.1) 5/219 (2.2) 0/242 (0.0) CRMh 0.145 Positive 47/365(12.9) 17/176 (9.7) 30/189 (15.9) Negative 318/365 (87.1) 159/176 (90.3) 159/189 (84.1) Unknown 29/365 (8.0) 14/176 (8.0) 15/189 (7.9) ypTN classification ypT0N0 (pCR) 81/475 (17.0) 34/224 (15.2) 47/251 (18.7) 0.305 ypT1N0 (near pCR) 30/475 (6.3) 17/224 (7.6) 13/251 (5.2) 0.281 ypT0N1-2 9/475 (1.9) 1/224 (0.4) 8/251 (3.2) 0.029 Postoperative transfusioni Yes 59/475 (12.4) 19/222 (8.6) 40/245 (16.3) 0.021

Histological type tumorg Adenocarcinoma 431/461 (93.5) 206/219 (94.1) 225/242 (93.0) 0.087 Mucinous 10/461 (2.2) 7/219 (3.2) 3/242 (1.2) Signet ring cell 15/461 (0.2) 1/19 (0.5) 14/242 (5.8) Other 5/461 (4.1) 5/219 (2.2) 0/242 (0.0) CRMh 0.145 Positive 47/365(12.9) 17/176 (9.7) 30/189 (15.9) Negative 318/365 (87.1) 159/176 (90.3) 159/189 (84.1) Unknown 29/365 (8.0) 14/176 (8.0) 15/189 (7.9) ypTN classification ypT0N0 (pCR) 81/475 (17.0) 34/224 (15.2) 47/251 (18.7) 0.305 ypT1N0 (near pCR) 30/475 (6.3) 17/224 (7.6) 13/251 (5.2) 0.281 ypT0N1-2 9/475 (1.9) 1/224 (0.4) 8/251 (3.2) 0.029 Postoperative transfusioni Yes 59/475 (12.4) 19/222 (8.6) 40/245 (16.3) 0.021 Any perineal wound problems <1 year (APR) 64/202 (31.7) 33/89 (37.1) 31/113 (27.4) 0.144 Overall leak rate (LAR)j 42/192 (21.9) 19/100 (19.0) 23/92 (25.0) 0.329 Chronic sinus rate (LAR)k 25/192 (13.0) 11/100 (11.0) 14/92 (15.2) 0.366 30-day overall complication ratel 166/471 (35.2) 74/222 (33.3) 92/249 (36.9) 0.445 30-day surgical complication rate 103/475 (21.7) 45/224 (20.1) 58/251 (23.1) 0.943 Length of stay (median [IQR])m 8 [6–14] 7 [6–12] 9 [7–15] 0.131 Re-intervention < 30 days 64/475 (13.5) 28/224 (12.5) 36/251 (14.3) 0.557 Re-admission < 30 days 2/475 (0.4) 1/224 (0.5) 1/251 (0.4) 0.211 Follow-up months (median [IQR])n 43 [35–47] 43 [36–47] 42 [32–47] 0.349 3-year local recurrence (Kaplan–Meier) 26/475 (5.5) 9/224 (4.0) 17/251 (6.8) 0.169 3-year distant recurrence (Kaplan–Meier) 90/475 (18.9) 45/224 (20.1) 45/251 (17.9 0.769 3-year disease-free survival (Kaplan–Meier) 343/475 (72.2) 167/223 (74.6) 176/251 (70.1) 0.267 3-year overall survival (Kaplan–Meier)o 404/474 (85.2) 196/223 (87.9) 208/251 (82.9) 0.178 A p value of less than 0.05 was considered statistically significant and it is highlighted in bold

9) 45/224 (20.1) 45/251 (17.9 0.769 3-year disease-free survival (Kaplan–Meier) 343/475 (72.2) 167/223 (74.6) 176/251 (70.1) 0.267 3-year overall survival (Kaplan–Meier)o 404/474 (85.2) 196/223 (87.9) 208/251 (82.9) 0.178 A p value of less than 0.05 was considered statistically significant and it is highlighted in bold ASA American Society of Anesthesiologists, MRI magnetic resonance imaging, CT computed tomography, MRF mesorectal fascia, LAR low anterior resection, APR abdominoperineal resection, CRT chemoradiotherapy, CRM circumferential resection margin, pCR pathological complete response, IQR interquartile range aPreoperative imaging was not reported in 10 patients bMultivisceral resection was not reported in 9 patients cMRI restaging after CRT was not reported in 14 patients dMRI restaging results were not reported in 114 patients eInterval CRT–MRI restaging was not reported in 134 patients fInterval CRT–MRI restaging was not reported in 135 patients gNot reported in 14 patients hCRM involvement is calculated by subtraction of unknown CRM and pCR iTransfusion was not reported in 8 patients jOverall leak rate was not reported in 5 patients kChronic sinus rate was not reported in 5 patients l30-day overall complication rate was not reported in 4 patients mLength of stay was not reported in 5 patients nMedian follow-up was not reported in 3 patients o3-year overall survival was not reported in 1 patient

iTransfusion was not reported in 8 patients jOverall leak rate was not reported in 5 patients kChronic sinus rate was not reported in 5 patients l30-day overall complication rate was not reported in 4 patients mLength of stay was not reported in 5 patients nMedian follow-up was not reported in 3 patients o3-year overall survival was not reported in 1 patient Magnetic Resonance Imaging Restaging Results MRI restaging was performed in 366 patients (79.4%), with a significant difference between the short- and long-interval groups (73.1% and 84.9%, p = 0.002). The median interval between the start of CRT and MRI restaging was 10 weeks (IQR 8–11), and the median interval between MRI restaging and surgery was 4 weeks (IQR 2–5). The CRT–MRI and MRI–surgery intervals are displayed in Table 1 for each of the interval groups, and the MRI restaging results are displayed in Table 2 for the different CRT–MRI and MRI–surgery intervals. With regard to MRI restaging results and pCR rate, a significant association was found for patients with a complete response in comparison with the other MRI restaging results (n = 7 [46.7%], p = 0.022). No significant association between the restaging result and the timing of MRI restaging was found.Table 2 Interval between start of CRT and MRI restaging, and interval between MRI restaging and surgery

Short Ref Long 1.65 (0.89–3.09) 0.115 Variables with a p value less than 0.10 in the univariable analysis were included in the multivariable model. A p value of less than 0.05 was considered statistically significant and it is highlighted in bold OR odds ratio, CI confidence interval, CRM circumferential resection margin, BMI body mass index Discussion This large cross-sectional study including 71 Dutch centers reflects daily practice in The Netherlands in 2011 with regard to clinical management of locally advanced rectal cancer. MRI restaging after CRT was performed in 79% of patients, with substantial variability in timing. In addition, substantial variability in the time interval between the start of CRT and surgery was observed, with a median of 14 weeks. Using the median interval as the cut-off, similar postoperative and long-term surgical and oncological outcomes were found for the two interval groups. The median of 14 weeks after the start of CRT corresponds with approximately 9 weeks after the end of CRT, which is between the two intervals to which patients were randomized in the GRECCAR-6 trial (7 vs. 11 weeks). Despite the methodological shortcomings in this comparison, we could not confirm the unfavorable results after longer waiting times in the GRECCAR-6 trial.

d for patients with a complete response in comparison with the other MRI restaging results (n = 7 [46.7%], p = 0.022). No significant association between the restaging result and the timing of MRI restaging was found.Table 2 Interval between start of CRT and MRI restaging, and interval between MRI restaging and surgery MRI restaging results Progression (%) Stable (%) Partial response (%) Complete response (%) p value CRT–MRI restaging intervala < 6 weeks 0 0 2/2 (100) 0 0.447 6–8 weeks 0 5/32 (15.6) 27/32 (84.4) 0 8–10 weeks 1/121 (0.8) 18/121 (14.9) 99/121 (81.8) 3/121 (2.5) > 10 weeks 6/183 (3.3) 18/183 (9.8) 148/183 (80.9) 11/183 (6.0) Overall 7/338 (2.1) 41/338 (12.1) 276/338 (81.7) 14/338 (4.1) MRI restaging—surgery intervalb Time interval, weeks (median [IQR]) 3 [2–4] 4.5 [3–6] 3 [2–5] 3.5 [2–4] 0.598 < 2 weeks 1/7 (14.3) 4/40 (10) 29/276 (10.5) 2/14 (14.2) 2–4 weeks 3/7 (42.9) 10/40 (25) 113/276 (40.9) 5/14 (35.7) > 4 weeks 3/7 (42.9) 26/40 (65) 134/276 (48.6) 7/14 (50.0) pCR 1/7 (14.3) 6/40 (15) 49/276 (17.8) 7/14 (50.0) 0.022 p values were calculated for the total study group CRT chemoradiotherapy, MRI magnetic resonance imaging, IQR interquartile range, pCR pathological complete response aCRT–MRI restaging interval results were not reported in 137 patients bMRI restaging-surgery interval results were not reported in 138 patients

MRI restaging results Progression (%) Stable (%) Partial response (%) Complete response (%) p value CRT–MRI restaging intervala < 6 weeks 0 0 2/2 (100) 0 0.447 6–8 weeks 0 5/32 (15.6) 27/32 (84.4) 0 8–10 weeks 1/121 (0.8) 18/121 (14.9) 99/121 (81.8) 3/121 (2.5) > 10 weeks 6/183 (3.3) 18/183 (9.8) 148/183 (80.9) 11/183 (6.0) Overall 7/338 (2.1) 41/338 (12.1) 276/338 (81.7) 14/338 (4.1) MRI restaging—surgery intervalb Time interval, weeks (median [IQR]) 3 [2–4] 4.5 [3–6] 3 [2–5] 3.5 [2–4] 0.598 < 2 weeks 1/7 (14.3) 4/40 (10) 29/276 (10.5) 2/14 (14.2) 2–4 weeks 3/7 (42.9) 10/40 (25) 113/276 (40.9) 5/14 (35.7) > 4 weeks 3/7 (42.9) 26/40 (65) 134/276 (48.6) 7/14 (50.0) pCR 1/7 (14.3) 6/40 (15) 49/276 (17.8) 7/14 (50.0) 0.022 p values were calculated for the total study group CRT chemoradiotherapy, MRI magnetic resonance imaging, IQR interquartile range, pCR pathological complete response aCRT–MRI restaging interval results were not reported in 137 patients bMRI restaging-surgery interval results were not reported in 138 patients Pathological and Surgical Outcomes No statistically significant differences were found in the pCR rate (n = 34 [15.2%] vs. n = 47 [18.7%], p = 0.305) and near pCR rate (n = 17 [7.6%] vs. n = 13 [5.2%], p = 0.373) between the short- and long-interval groups (Table 1). Significantly less-isolated residual nodal disease (ypT0N1-2) was found in the short-interval group (n = 1 [0.4%] vs. n = 8 [3.2%], p = 0.029). The proportion of CRM involvement was lower after a short interval, but did not reach statistical significance (n = 17 [9.7%] vs. n = 30 [15.9%], p = 0.145). With regard to postoperative outcomes, significantly less patients received postoperative transfusion in the short-interval group (n = 19 [8.6%] vs. n = 40 [16.3%], p = 0.021). No significant differences were found between the two interval groups in regard to length of stay (median 7 vs. 9 days, p = 0.131), perineal wound problems < 1 year following APR (n = 33 [37.1%] vs. n = 31 [27.4%], p = 0.144), overall anastomotic leakage rate following LAR (n = 19 [19.0%] vs. n = 23 [25.0%], p = 0.329), and chronic sinus rate (n = 11 [11.0%], n = 14 [15.2%], p = 0.366).

in regard to length of stay (median 7 vs. 9 days, p = 0.131), perineal wound problems < 1 year following APR (n = 33 [37.1%] vs. n = 31 [27.4%], p = 0.144), overall anastomotic leakage rate following LAR (n = 19 [19.0%] vs. n = 23 [25.0%], p = 0.329), and chronic sinus rate (n = 11 [11.0%], n = 14 [15.2%], p = 0.366). Long-Term Oncologic Outcomes The median long-term follow-up was 43 months (IQR 35–47) and was similar between the two interval groups (Table 1). With regard to LR rates (n = 9 [4.0%] vs. n = 17 [6.8%], p = 0.169) (Fig. 2a) and DR rates (n = 45 [20.1%] vs. n = 45 [17.9%], p = 0.769) (Fig. 2b), no significant differences were found between the short- and long-interval groups, respectively. Similarly, no significant differences were found for DFS (n = 167 [74.6%] vs. 176 [70.1%] p = 0.267) (Fig. 2c) and OS (n = 196 [87.9%] vs. n = 208 [82.9%], p = 0.178) (Fig. 2d).Fig. 2 Kaplan–Meier of local recurrence, distant recurrence, disease-free survival and overall survival in short- and long interval group

vely. Similarly, no significant differences were found for DFS (n = 167 [74.6%] vs. 176 [70.1%] p = 0.267) (Fig. 2c) and OS (n = 196 [87.9%] vs. n = 208 [82.9%], p = 0.178) (Fig. 2d).Fig. 2 Kaplan–Meier of local recurrence, distant recurrence, disease-free survival and overall survival in short- and long interval group Predictors of Circumferential Resection Margin Involvement, Recurrence, and Survival The results of univariable and multivariable analyses for CRM involvement are shown in Table 3. In multivariable analysis, laparoscopic conversion, intraoperative complications, and nodal stage were identified as independent predictors for CRM involvement. Five of the six patients in whom a laparoscopic resection was converted to an open approach had a positive CRM (one patient and four patients for the short- and long-interval groups, respectively). The results of the univariable and multivariable analysis for LR, DR, DFS, and OS are provided in electronic supplementary Tables 1 and 2. The time interval between the start of CRT and surgery was not associated with any of these outcome parameters.Table 3 Univariable and multivariable analyses for CRM Variable Univariable analysis Multivariable analysis OR (95% CI) p value OR (95% CI) p value Sex Male 1.15 (0.61–2.16) 0.675 Female Ref BMI, kg/m 2 < 25 0.72 (0.37–1.38) 0.319 25–30 Ref > 30 0.85 (0.35–2.08) 0.724 Distance to the anorectal junction, cm < 3 0.82 (0.33–2.00) 0.658 3.1–7 1.10 (0.46–2.61) 0.832 > 7 Ref Approach Open Ref Ref Laparoscopic 0.54 (0.28–1.05) 0.068 0.56 (0.27–1.15) 0.113 Laparoscopic conversion 39.46 (4.45–350) 0.001 39.1 (3.87–395) 0.002

Male 1.15 (0.61–2.16) 0.675 Female Ref BMI, kg/m 2 < 25 0.72 (0.37–1.38) 0.319 25–30 Ref > 30 0.85 (0.35–2.08) 0.724 Distance to the anorectal junction, cm < 3 0.82 (0.33–2.00) 0.658 3.1–7 1.10 (0.46–2.61) 0.832 > 7 Ref Approach Open Ref Ref Laparoscopic 0.54 (0.28–1.05) 0.068 0.56 (0.27–1.15) 0.113 Laparoscopic conversion 39.46 (4.45–350) 0.001 39.1 (3.87–395) 0.002 Intraoperative complication Yes 3.65 (1.11–11.97) 0.033 5.22 (1.43–19.11) 0.013 Multiple visceral resection Yes 2.31 (1.10–4.83) 0.026 1.98 (0.75–5.26) 0.170 Tumor stage ypT0 Ref Ref ypT1-3 3.40 (1.02–11.28) 0.046 2.62 (0.74–9.27) 0.135 ypT4 8.46 (2.03–35.20) 0.003 2.14 (0.39–11.79) 0.381 Nodal stage ypN0 Ref Ref ypN1-2 3.47 (1.87–6.41) < 0.001 3.13 (1.60–6.16) 0.001 Interval group Short Ref Long 1.65 (0.89–3.09) 0.115 Variables with a p value less than 0.10 in the univariable analysis were included in the multivariable model. A p value of less than 0.05 was considered statistically significant and it is highlighted in bold OR odds ratio, CI confidence interval, CRM circumferential resection margin, BMI body mass index

ponds with approximately 9 weeks after the end of CRT, which is between the two intervals to which patients were randomized in the GRECCAR-6 trial (7 vs. 11 weeks). Despite the methodological shortcomings in this comparison, we could not confirm the unfavorable results after longer waiting times in the GRECCAR-6 trial. The Dutch rectal cancer guideline from 2008, still being used in 2011, did not include a statement on the use and interpretation of restaging MRI after CRT for rectal cancer, nor did it recommend a certain time interval for response evaluation or surgery following CRT. This likely explains the large observed variability in practice. A significantly lower proportion of MRI restaging in the short-interval group (73% vs. 85%) was likely related to some hospitals that routinely planned surgery after 6–8 weeks from the end of radiotherapy without any response assessment, thereby following the guideline at that time.

ge observed variability in practice. A significantly lower proportion of MRI restaging in the short-interval group (73% vs. 85%) was likely related to some hospitals that routinely planned surgery after 6–8 weeks from the end of radiotherapy without any response assessment, thereby following the guideline at that time. Standardized MRI assessment regarding tumor regression grade (mrTRG) has been proposed, and good interobserver agreement can be achieved after interactive case-based learning.11 Although mrTRG correlates with oncological outcome, the role of MRI in restaging rectal cancer after CRT as a single diagnostic modality, and its clinical implications, are still the subject of debate.12 When restaging MRI suggested complete tumor response in the present study, pathology revealed cancer in 50% of patients in the present study, confirming the reported inaccuracy of restaging MRI.13 Nowadays, the impact of restaging MRI is likely to be different. The European Society of Gastrointestinal and Abdominal Radiology (ESGAR) recently published their updated recommendations.14 Routinely adding diffusion-weighted MRI for the purpose of yT restaging reached consensus, especially due to improved differentiation between partial and complete response. Structured MRI reporting was unanimously recommended and a template for both primary and restaging was published. Following such consensus guidelines will likely reduce hospital variation and increase the clinical impact of MRI restaging.

especially due to improved differentiation between partial and complete response. Structured MRI reporting was unanimously recommended and a template for both primary and restaging was published. Following such consensus guidelines will likely reduce hospital variation and increase the clinical impact of MRI restaging. Nowadays, response evaluation and timing of subsequent treatment after CRT is often aimed at identifying clinical complete responders who are candidates for a watch-and-wait policy. Digital examination and endoscopy are also important modalities, besides MRI restaging, in this clinical scenario. However, patients included in the present study were treated at the time a watch-and-wait strategy was considered experimental, with only a single institution in The Netherlands publishing their initial experience.15 Other implications of restaging MRI might be limiting the extent of the resection in order to refrain from multivisceral resection or enable sphincter preservation. Unfortunately, the dataset did not include variables to analyze these outcomes.

ingle institution in The Netherlands publishing their initial experience.15 Other implications of restaging MRI might be limiting the extent of the resection in order to refrain from multivisceral resection or enable sphincter preservation. Unfortunately, the dataset did not include variables to analyze these outcomes. The optimal length of the interval between neoadjuvant CRT and surgery has frequently been analyzed, but with conflicting results regarding pathological response.16–24 It has been suggested that tumor response to CRT can take up to several months, depending on tumor volume and characteristics.25,26 Only a few randomized controlled trials compared short and long intervals between CRT and surgery, with conflicting results in relation to pCR rates.27,28 Most recently, the GRECCAR-6 trial showed no differences in pCR rates between 7- and 11-week interval.5 Similarly, pCR rates did not differ between the two intervals in the present study (15.2% vs. 18.7%); however, even with a higher clinical stage at baseline, pCR rates were slightly higher in the long-interval group. The significantly higher proportion of patients with cT4N1-2 stage in the long-interval group (13% vs. 7%) was likely the reason for a higher proportion of multivisceral resections (17% vs. 9%). As a consequence, this probably also explains the higher proportion of CRM positivity (16% vs. 10%) and isolated residual nodal disease (ypT0N1-2) in the long-interval group, as well as more postoperative blood transfusions (16% vs. 9%). The GRECCAR-6 trial suggested that longer waiting times after radiotherapy increase the difficulty of surgery due to more radiation-induced fibrosis, probably explaining the observed higher morbidity rates and worse quality of the specimen in that study. This might have also been an explanation for the higher CRM positivity and blood transfusion rates after longer waiting times in the present study.

e the difficulty of surgery due to more radiation-induced fibrosis, probably explaining the observed higher morbidity rates and worse quality of the specimen in that study. This might have also been an explanation for the higher CRM positivity and blood transfusion rates after longer waiting times in the present study. Previous studies comparing the long-term oncologic outcomes for different time intervals between CRT and surgery have shown conflicting results.29–31 In the follow-up of the Lyon R90-01 trial, the study group found no significant differences between the two intervals regarding LR rates and OS (5-, 10-, 15-, and 17-year follow-up).32 Some studies demonstrated improved prognosis after longer intervals.33,34 We could not find any impact on the oncological outcome of waiting times between CRT and surgery, which is consistent with other retrospective studies.35 Pathological tumor and nodal status, CRM involvement, and multivisceral resection were identified as significant predictors of long-term oncological outcomes in this cohort of locally advanced rectal cancer patients with neoadjuvant CRT, whereas adjuvant chemotherapy was not associated with DFS and OS. The Dutch rectal cancer guideline from 2008 did not recommend adjuvant chemotherapy for stage 3 rectal cancer, and this has not been changed in the guideline revision of 2014 because this is still not considered to prolong survival.36,37 This explains the low number of patients in both study groups who received adjuvant chemotherapy.

l cancer guideline from 2008 did not recommend adjuvant chemotherapy for stage 3 rectal cancer, and this has not been changed in the guideline revision of 2014 because this is still not considered to prolong survival.36,37 This explains the low number of patients in both study groups who received adjuvant chemotherapy. The strength of this cross-sectional study is the large population-based data with short- and long-term intervals to surgery, reflecting daily practice. However, limitations of this study design are related to the retrospective data collection, with, for example, missing information on patient-tailored approaches or institutional protocols. Excluding patients without a reported start date for CRT could have resulted in selection bias. MRI restaging results were pragmatically categorized into four options for retrospective interpretation of the MRI reports, while central review using standardized criteria, as recently published by ESGAR, would have been more informative. Furthermore, not all Dutch hospitals participated in this voluntary cross-sectional study, in contrast to the mandatory DCRA, which might limit the representativeness of the results. Finally, patients who did not proceed to surgery after CRT because of a watch-and-wait policy, treatment-related toxicity, or other reasons are not recorded in this cross-sectional study as only patients who underwent resection were included.

the mandatory DCRA, which might limit the representativeness of the results. Finally, patients who did not proceed to surgery after CRT because of a watch-and-wait policy, treatment-related toxicity, or other reasons are not recorded in this cross-sectional study as only patients who underwent resection were included. Conclusions This large cross-sectional study on CRT followed by TME surgery for locally advanced rectal cancer, reflecting daily practice in The Netherlands in 2011, showed high usage of restaging MRI not supported by guideline recommendations at that time. Timing of surgery after preoperative CRT was highly variable, partially related to the variable impact of MRI-based response assessment and differences in patient and tumor characteristics, however this did not significantly influence short- and long-term outcomes. Electronic supplementary material Below is the link to the electronic supplementary material. Supplementary material 1 (DOCX 1851 kb) Supplementary material 2 (DOCX 49 kb) Appendix Definitions Low anterior resection with primary anastomosis (LAR) was defined as a TME, with or without diverting stoma. APR was defined, according to the TME principles, as a rectal resection including the anal sphincter complex with a definitive colostomy. The low Hartmann’s procedure was defined as an LAR with rectal stump closure and a definitive colostomy.

mary anastomosis (LAR) was defined as a TME, with or without diverting stoma. APR was defined, according to the TME principles, as a rectal resection including the anal sphincter complex with a definitive colostomy. The low Hartmann’s procedure was defined as an LAR with rectal stump closure and a definitive colostomy. LR was defined as the recurrent disease at the anastomotic site, in the pelvis, or in the perineal wound. DR was defined as metastatic localizations, not present at primary rectal cancer surgery. DFS was defined as all patients without recurrent disease, excluding the patients lost to follow-up. OS was defined as all patients alive after the end of follow-up, excluding the patients lost to follow-up.

in the perineal wound. DR was defined as metastatic localizations, not present at primary rectal cancer surgery. DFS was defined as all patients without recurrent disease, excluding the patients lost to follow-up. OS was defined as all patients alive after the end of follow-up, excluding the patients lost to follow-up. Acknowledgment Collaborators of the Dutch Snapshot Research Group: A. Aalbers, Y. Acherman, G. D. Algie, B. Alting von Geusau, F. Amelung, S. A. Bartels, S. Basha, A. J. N. M. Bastiaansen, E. Belgers, W. Bleeker, J. Blok, R. J. I. Bosker, J. W. Bosmans, M. C. Boute, N. D. Bouvy, H. Bouwman, A. Brandt-Kerkhof, D. J. Brinkman, S. Bruin, E. R. J. Bruns, J. P. M. Burbach, J. W. A. Burger, C. J. Buskens, S. Clermonts, P. P. L. O. Coene, C. Compaan, E. C. J. Consten, T. Darbyshire, S. M. L. de Mik, E. J. R. de Graaf, I. de Groot, R. J. L. de vos tot Nederveen Cappel, J. H. W. de Wilt, J. van der Wolde, F. C. den Boer, J. W. T. Dekker, A. Demirkiran, M. Derkx-Hendriksen, F. R. Dijkstra, P. van Duijvendijk, M. S. Dunker, Q. E. Eijsbouts, H. Fabry, F. Ferenschild, J. W. Foppen, M. F. Gerhards, P. Gerven, J. A. H. Gooszen, J. A. Govaert, W. M. U. Van Grevenstein, R. Haen, J. J. Harlaar, E. Harst, K. Havenga, J. Heemskerk, J. F. Heeren, B. Heijnen, P. Heres, C. Hoff, W. Hogendoorn, P. Hoogland, A. Huijbers, P. Janssen, A. C. Jongen, F. H. Jonker, E. G. Karthaus, A. Keijzer, J. M. A. Ketel, J. Klaase, F. W. H. Kloppenberg, M. E. Kool, R. Kortekaas, P. M. Kruyt, J. T. Kuiper, B. Lamme, J. F. Lange, T. Lettinga, D. J. Lips, F. Logeman, M. F. Lutke Holzik, E. Madsen, A. Mamound, C. C. Marres, I. Masselink, M. Meerdink, A. G. Menon, J. S. Mieog, D. Mierlo, G. D. Musters, G. A. P. Nieuwenhuijzen, P. A. Neijenhuis, J. Nonner, M. Oostdijk, P. M. P. Paul, K. C. M. J. Peeters, I. T. A. Pereboom, F. Polat, P. Poortman, M. Raber, B. M. M. Reiber, R. J. Renger, C. C. van Rossem, H. J. Rutten, A. Rutten, R. Schaapman, M. Scheer, L. Schoonderwoerd, N. Schouten, A. M. Schreuder, W. H. Schreurs, G. A. Simkens, G. D. Slooter, H. C. E. Sluijmer, N. Smakman, R. Smeenk, H. S. Snijders, D. J. A. Sonneveld, B. Spaansen, E. J. Spillenaar Bilgen, E. Steller, W. H. Steup, C. Steur, E. Stortelder, J. Straatman, H. A. Swank, C. Sietses, H. A. ten Berge, H. G. ten hoeve, W. W. ter Riele, I. M. Thorensen, B. Tip-Pluijm, B. R. Toorenvliet, L. Tseng, J. B. Tuynman, J. van Bastelaar, S. C. van Beek, A. W. H. van de Ven, M. A. J. van de Weijer, C. van den Berg, I. van den Bosch, J. D. W. van der Bilt, S.

E. Stortelder, J. Straatman, H. A. Swank, C. Sietses, H. A. ten Berge, H. G. ten hoeve, W. W. ter Riele, I. M. Thorensen, B. Tip-Pluijm, B. R. Toorenvliet, L. Tseng, J. B. Tuynman, J. van Bastelaar, S. C. van Beek, A. W. H. van de Ven, M. A. J. van de Weijer, C. van den Berg, I. van den Bosch, J. D. W. van der Bilt, S. J. van der Hagen, R. van der hul, G. van der Schelling, A. van der Spek, N. van der Wielen, E. van duyn, C. van Eekelen, J. A. van Essen, K. van Gangelt, A. A. W. van Geloven, C. van Kessel, Y. T. van Loon, A. van Rijswijk, S. J. van Rooijen, T. van Sprundel, L. van Steensel, W. F. van Tets, H. L. van Westreenen, S. Veltkamp, T. Verhaak, P. M. Verheijen, L. Versluis-Ossenwaarde, S. Vijfhuize, W. J. Vles, S. C. Voeten, F. J. Vogelaar, W. W. Vrijland, E. Westerduin, M. E. Westerterp, M. Wetzel, K. P. Wevers, B. Wiering, C. D. M. Witjes, M. W. Wouters, S. T. K. Yauw, E. S. van der Zaag, E. C. Zeestraten, D. D. Zimmerman, T. Zwieten Availability of data and material The data that support the findings of this study are available from the DSRG but are not publicly available; however, data are available from the authors upon reasonable request and with permission from the DSRG. Disclosures Robin Detering, Wernard A. A. Borstlap, Lisa Broeders, Linda Hermus, Corrie A. M. Marijnen, Regina G. H. Beets-Tan, Willem A. Bemelman, Henderik L. van Westreenen and Pieter J. Tanis have no conflicts of interest to declare.