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BACKGROUND: The LIR!C trial showed that laparoscopic ileocaecal resection is a cost-effective treatment that has similar quality-of-life outcomes to treatment with infliximab, an anti-tumour necrosis factor (TNF) drug. We aimed to compare long-term outcomes of both interventions and identify baseline factors associated with the duration of treatment effect in each group.METHODS: In this retrospective follow-up study, we collected data from patients who participated in the LIR!C trial, a multicentre randomised controlled trial that compared quality of life after surgical resection versus infliximab in adult patients with non-stricturing and immunomodulator-refractory ileocaecal Crohn's disease. From Jan 1 to May 1, 2018, we collected follow-up data from the time from enrolment in the LIR!C trial until the last visit at either the gastrointestinal surgeon or gastroenterologist. In this study, outcomes of interest were need for surgery or repeat surgery or anti-TNF therapy, duration of treatment effect, and identification of factors associated with the duration of treatment effect. Duration of treatment effect was defined as the time without need for additional Crohn's disease-related treatment (corticosteroids, immunomodulators, biologics, or surgery).FINDINGS: We collected long-term follow-up data for 134 (94%) of 143 patients included in the LIR!C trial, of whom 69 were in the resection group and 65 were in the infliximab group. Median follow-up was 63·5 months (IQR 39·0-94·5). In the resection group, 18 (26%) of 69 patients started anti-TNF therapy and none required a second resection. 29 (42%) patients in the resection group did not require additional Crohn's disease-related medication, although 14 (48%) of these patients were given prophylactic immunomodulator therapy. In the infliximab group, 31 (48%) of 65 patients had a Crohn's disease-related resection, and the remaining 34 patients maintained, switched, or escalated their anti-TNF therapy. Duration of treatment effect was similar in both groups, with a median time without additional Crohn's disease-related treatment of 33·0 months (95% CI 15·1-50·9) in the resection group and 34·0 months (0·0-69·3) in the infliximab group (log-rank p=0·52). In both groups, therapy with an immunomodulator, in addition to the allocated treatment, was associated with duration of treatment effect (hazard ratio for resection group 0·34 [95% CI 0·16-0·69] and for infliximab group 0·49 [0·26-0·93]).INTERPRETATION: These findings further support laparoscopic ileocaecal resection as a treatment option in patients with Crohn's disease with limited (affected segment ≤40 cm) and predominantly inflammatory terminal ileitis for whom conventional treatment is not successful.FUNDING: None.

Background: This systematic review and meta-analysis aimed to give an overview on the postoperative outcome after a minimally invasive (ie, laparoscopic and robot-assisted) central pancreatectomy and open central pancreatectomy with a specific emphasis on the postoperative pancreatic fistula. For benign and low-grade malignant lesions in the pancreatic neck and body, central pancreatectomy may be an alternative to distal pancreatectomy. Exocrine and endocrine insufficiency occur less often after central pancreatectomy, but the rate of postoperative pancreatic fistula is higher. Methods: An electronic search was performed for studies on elective minimally invasive central pancreatectomy and open central pancreatectomy, which reported on major morbidity and postoperative pancreatic fistula in PubMed, Cochrane Register, Embase, and Google Scholar until June 1, 2021. A review protocol was developed a priori and registered in PROSPERO as CRD42021259738. A meta-regression was performed by using a random effects model. Results: Overall, 41 studies were included involving 1,004 patients, consisting of 158 laparoscopic minimally invasive central pancreatectomies, 80 robot-assisted minimally invasive central pancreatectomies, and 766 open central pancreatectomies. The overall rate of postoperative pancreatic fistula was 14%, major morbidity 14%, and 30-day mortality 1%. The rates of postoperative pancreatic fistula (17% vs 24%, P = .194), major morbidity (17% vs 14%, P = .672), and new-onset diabetes (3% vs 6%, P = .353) did not differ significantly between minimally invasive central pancreatectomy and open central pancreatectomy, respectively. Minimally invasive central pancreatectomy was associated with significantly fewer blood transfusions, less exocrine pancreatic insufficiency, and fewer readmissions compared with open central pancreatectomy. A meta-regression was performed with a random effects model between minimally invasive central pancreatectomy and open central pancreatectomy and showed no significant difference for postoperative pancreatic fistula (random effects model 0.16 [0.10; 0.24] with P = .789), major morbidity (random effects model 0.20 [0.15; 0.25] with P = .410), and new-onset diabetes mellitus (random effects model 0.04 [0.02; 0.07] with P = .651). Conclusion: In selected patients and in experienced hands, minimally invasive central pancreatectomy is a safe alternative to open central pancreatectomy for benign and low-grade malignant lesions of the neck and body. Ideally, further research should confirm this with the main focus on postoperative pancreatic fistula and endocrine and exocrine insufficiency.

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Early modern literary careers are generally perceived as progressive: inadequate young authors gradually develop their literary skills and knowledge while growing old. In this article, we analyse how young authorship and career development of early modern Dutch women writers was represented in front matter in their literary print-publications. We demonstrate that front matter’s praise of young women’s authorship was connected to both male and female flavoured qualities. These qualities turn out to be connected to the ways in which female careers were represented. When young female authorship was mainly legitimated by referring to intellectual capacities considered typically masculine, the women’s career is perceived as progressive. However: when this legitimation is rather based on qualities considered as typically feminine, such as virtuousness and handiwork skills, the women’s authorship at an early age is sometimes represented as already fully-grown and complete.

Background Patients suffering from inflammatory bowel diseases (IBD) and treated with originator infliximab are increasingly being switched to biosimilars. Some patients, however, are “reverse switched” to treatment with the originator. Here we assess the prevalence of reverse switching, including its indication and outcomes. Methods In this retrospective multicenter cohort study, data on patients with IBD from 9 hospitals in the Netherlands were collected. All adult patients with IBD were included if they previously had been switched from originator infliximab to the biosimilar CT-P13 and had a follow-up time of at least 52 weeks after the initial switch. The reasons for reverse switching were categorized into worsening gastrointestinal symptoms, adverse effects, or loss of response to CT-P13. Drug persistence was analyzed through survival analyses. Results A total of 758 patients with IBD were identified. Reverse switching was observed in 75 patients (9.9%). Patients with reverse switching were predominantly female (70.7%). Gastrointestinal symptoms (25.5%) and dermatological symptoms (21.8%) were the most commonly reported reasons for reverse switching. In 9 patients (12.0%), loss of response to CT-P13 was the reason for reverse switching. Improvement of reported symptoms was seen in 73.3% of patients after reverse switching and 7 out of 9 patients (77.8%) with loss of response regained response. Infliximab persistence was equal between patients who were reverse-switched and those who were maintained on CT-P13. Conclusions Reverse switching occurred in 9.9% of patients, predominantly for biosimilar-attributed adverse effects. Switching back to originator infliximab seems effective in patients who experience adverse effects, worsening gastrointestinal symptoms, or loss of response after switching from originator infliximab to CT-P13.

To compare the concentration of the active metabolites of azathioprine (AZA), 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine ribonucleotides (6-MMPR), in paediatric patients with quiescent inflammatory bowel disease (IBD) on AZA monotherapy and AZA in combination with anti-tumour necrosis factor (TNF) therapy (i.e. infliximab [IFX] or adalimumab [ADAD. Design and methods In this exploratory retrospective observational study we extracted the medical records of paediatric IBD patients treated with AZA, IFX or ADA between January 1st 2009 and December 31st 2019 in Zuyderland Medical Centre, Heerlen/Sittard-Geleen, the Netherlands. 6-TGN levels were compared between patients on AZA monotherapy and combination therapy. In the combination therapy group, the correlation between 6-TGN levels and anti-TNF-α trough levels was evaluated. Results Thirty-six paediatric patients with IBD were included (12 patients on combination therapy and 24 patients on AZA monotherapy). The mean 6-TGN level was 298 pmol/8*108 red blood cells (RBC) in the combination therapy group and 360 pmol/8*108 RBC in the AZA monotherapy group (P = 0.122). From the 12 patients on combination therapy, 9 IFX trough levels were available. There was no correlation between 6-TGN level and IFX trough level. In 5 out of 9 patients (55%) an IFX trough level of < 3 mg/L was found (mean 3.3 mg/L; standard deviation 1.6). Conclusion In this study, the 6-TGN and 6-MMPR levels in paediatric IBD patients treated with AZA in combination with IFX or ADA were comparable with those of patients on AZA monotherapy. Further (prospective) research in a larger paediatric patient population is needed to evaluate whether relatively low 6-TGN levels could be sufficient to maintain long term clinical remission in patients on azathioprine and anti-TNF combination therapy.

To compare the concentration of the active metabolites of azathioprine (AZA), 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine ribonucleotides (6-MMPR), in paediatric patients with quiescent inflammatory bowel disease (IBD) on AZA monotherapy and AZA in combination with anti-tumour necrosis factor (TNF) therapy (i.e. infliximab [IFX] or adalimumab [ADAD. Design and methods In this exploratory retrospective observational study we extracted the medical records of paediatric IBD patients treated with AZA, IFX or ADA between January 1st 2009 and December 31st 2019 in Zuyderland Medical Centre, Heerlen/Sittard-Geleen, the Netherlands. 6-TGN levels were compared between patients on AZA monotherapy and combination therapy. In the combination therapy group, the correlation between 6-TGN levels and anti-TNF-α trough levels was evaluated. Results Thirty-six paediatric patients with IBD were included (12 patients on combination therapy and 24 patients on AZA monotherapy). The mean 6-TGN level was 298 pmol/8*108 red blood cells (RBC) in the combination therapy group and 360 pmol/8*108 RBC in the AZA monotherapy group (P = 0.122). From the 12 patients on combination therapy, 9 IFX trough levels were available. There was no correlation between 6-TGN level and IFX trough level. In 5 out of 9 patients (55%) an IFX trough level of < 3 mg/L was found (mean 3.3 mg/L; standard deviation 1.6). Conclusion In this study, the 6-TGN and 6-MMPR levels in paediatric IBD patients treated with AZA in combination with IFX or ADA were comparable with those of patients on AZA monotherapy. Further (prospective) research in a larger paediatric patient population is needed to evaluate whether relatively low 6-TGN levels could be sufficient to maintain long term clinical remission in patients on azathioprine and anti-TNF combination therapy.

Scope: It has been proposed that endogenously form N‐nitroso compounds (NOCs) are partly responsible for the link between red meat consumption and colorectal cancer (CRC) risk. As nitrite has been indicated as critical factor in the formation of NOCs, the impact of replacing the additive sodium nitrite (E250) by botanical extracts in the PHYTOME project is evaluated. Method and Results: A human dietary intervention study is conducted in which healthy subjects consume 300 g of meat for 2 weeks, in subsequent order: conventional processed red meat, white meat, and processed red meat with standard or reduced levels of nitrite and added phytochemicals. Consumption of red meat products enriched with phytochemicals leads to a significant reduction in the faecal excretion of NOCs, as compared to traditionally processed red meat products. Gene expression changes identify cell proliferation as main affects molecular mechanism. High nitrate levels in drinking water in combination with processed red meat intake further stimulates NOC formation, an effect that could be mitigated by replacement of E250 by natural plant extracts. Conclusion: These findings suggest that addition of natural extracts to conventionally processed red meat products may help to reduce CRC risk, which is mechanistically support by gene expression analyses.

Prehabilitation has been postulated as an effective preventive intervention to reduce postoperative complications, particularly for elderly patients with a relatively high risk of complications. To date, it remains to be determined whether prehabilitation increases physical capacity and reduces postoperative complications. The aim of this study was to assess the feasibility of a 4-week multimodal prehabilitation program consisting of a personalized, supervised training program and nutritional intervention with daily fresh protein-rich food for colorectal cancer patients aged over 64 years prior to surgery. The primary outcome was the feasibility of this prehabilitation program defined as ≥80% compliance with the exercise training program and nutritional intervention. The secondary outcomes were the organizational feasibility and acceptability of the prehabilitation program. A compliance rate of ≥80% to both the exercise and nutritional intervention was accomplished by 6 patients (66.7%). Attendance of ≥80% at all 12 training sessions was achieved by 7 patients (77.8%), all patients (100%) attended ≥80% of the available training sessions. Overall, compliance with the training was 91.7%. Six patients (66.7%) accomplished compliance of ≥80% with the nutritional program. The median protein intake was 1.2 (g/kg/d). No adverse events occurred. This multimodal prehabilitation program was feasible for the majority of patients.

SCOPE: It has been proposed that endogenously formed N-nitroso compounds (NOCs) are partly responsible for the link between red meat consumption and colorectal cancer (CRC) risk. As nitrite has been indicated as critical factor in the formation of NOCs, we evaluated the impact of replacing the additive sodium nitrite (E251) by botanical extracts in the PHYTOME project. METHOD AND RESULTS: A human dietary intervention study was conducted in which healthy subjects consumed 300 grams of meat for two weeks, in subsequent order: conventional processed red meat, white meat, and processed red meat with standard or reduced levels of nitrite and added phytochemicals. Consumption of red meat products enriched with phytochemicals leads to a significant reduction in the faecal excretion of NOCs, as compared to traditionally processed red meat products. Gene expression changes identify cell proliferation as main affected molecular mechanism. High nitrate levels in drinking water in combination with processed red meat intake further stimulates NOC formation, an effect that could be mitigated by replacement of E251 by natural plant extracts. CONCLUSION: These findings suggest that addition of natural extracts to conventionally processed red meat products may help to reduce CRC risk, which is mechanistically supported by gene expression analyses.