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Abstract Background High-level evidence regarding the technique of abdominal wall closure for patients undergoing emergency midline laparotomy is sparse. Therefore, we conducted a randomized controlled trial (RCT) to evaluate the efficacy and safety of two commonly applied abdominal wall closure strategies after primary emergency midline laparotomy. Methods/design CONTINT was a multi-center pragmatic open-label exploratory randomized controlled parallel trial. Two different abdominal wall closure strategies in patients undergoing primary midline laparotomy for an emergency surgical intervention with a suspected septic focus in the abdominal cavity were compared: the continuous, all-layer suture and the interrupted suture technique. The primary composite endpoint was burst abdomen within 30 days after surgery or incisional hernia within 12 months. As reliable data on this composite primary endpoint were not available for patients undergoing emergency surgery, it was planned to initially recruit 80 patients and conduct an interim analysis after these had completed the 12 months follow-up. Results From August 31, 2009, to June 28, 2012, 124 patients were randomized of whom 119 underwent surgery and were analyzed according to the intention-to-treat (ITT) principal. The primary composite endpoint did not differ between the continuous suture (C: 27.1%) and the interrupted suture group (I: 30.0%). None of the individual components of the primary endpoint (reoperation due to burst abdomen after 30 days (C: 13.5%, I: 15.1%) and reoperation due to incisional hernia (C: 3.0%, I:11.1%)) differed between groups. Time needed for fascial closure was longer in the interrupted suture group (C: 12.8 ± 4.5 min, I: 17.4 ± 6.1 min). BMI was associated with burst abdomen during the first 30 days with an OR of 1.17 (95% CI 1.04–1.32). Conclusion This RCT showed no difference between continuous suture with slowly absorbable suture versus interrupted rapidly absorbable sutures after primary emergency midline laparotomy in rates of postoperative burst abdomen and incisional hernia after one year. However, the trial was stopped after the interim analysis due to futility as there was no chance to show superiority of one suture technique.

Abstract Background The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. Methods We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways. Results In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies. Conclusions Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.