Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced βCATENIN (βCAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH‐GLI pathway. Unexpectedly, they acquire a high HEDGEHOG‐GLI (HH‐GLI) signature coincident with the development of metastases. We show that the growth of CC xenografts, their recurrence and metastases require HH‐GLI function, which induces a robust epithelial‐to‐mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self‐renewal of CC stem cells in vivo relies on HH‐GLI activity. Our results indicate a key and essential role of the HH‐GLI1 pathway in promoting CC growth, stem cell self‐renewal and metastatic behavior in advanced cancers. Targeting HH‐GLI1, directly or indirectly, is thus predicted to decrease tumour bulk and eradicate CC stem cells and metastases.

The aim of this study was to compare open and laparoscopic sigmoid resection for diverticulitis with the patient and the nursing staff blinded to the surgical approach. A total of 113 patients scheduled for an elective sigmoidectomy were randomized to receive either a conventional open (54 patients) or a laparoscopic (59 patients) approach. Postoperatively, an opaque wound dressing was applied and left in place for 4 days, and patients from both groups were managed similarly. The primary endpoints for analysis were (1) postoperative pain; (2) duration of postoperative ileus; and (3) duration of hospital stay (ClinicalTrials.gov, number NCT 00453830). The median duration of procedure was 165 minutes (range, 90–285) in the laparoscopy group and 110 minutes (range, 70–210) in the open group (P < 0.0001). The median delay between surgery and first bowel movement was 76 (range, 31–163) hours in the laparoscopy group versus 105 (range, 53–175) hours in the open group (P < 0.0001). The median score for maximal pain (assessed by a visual analog scale) was 4 (range, 1–10) in the laparoscopy group and 5 (range, 1–10) in the open group (P = 0.05). Finally, the median duration of hospital stay was 5 days (range, 4–69) in the laparoscopy group versus 7 days (range, 5–17) in the open group (P < 0.0001). Laparoscopic sigmoid resection is associated with a 30% reduction in duration of postoperative ileus and hospital stay; by comparison, benefits in terms of postoperative pain appear less impressive, when the patient is blinded to the surgical technique.

Previous studies demonstrate the initiation of colon cancers through deregulation of WNT‐TCF signalling. An accepted but untested extension of this finding is that incurable metastatic colon carcinomas (CCs) universally remain WNT‐TCF‐dependent, prompting the search for WNT‐TCF inhibitors. CCs and their stem cells also require Hedgehog (HH)‐GLI1 activity, but how these pathways interact is unclear. Here we define coincident high‐to‐low WNT‐TCF and low‐to‐high HH‐GLI transitions in patient CCs, most strikingly in their CD133⁺ stem cells, that mark the development of metastases. We find that enhanced HH‐GLI mimics this transition, driving also an embryonic stem (ES)‐like stemness signature and that GLI1 can be regulated by multiple CC oncogenes. The data support a model in which the metastatic transition involves the acquisition or enhancement of a more primitive ES‐like phenotype, and the downregulation of the early WNT‐TCF programme, driven by oncogene‐regulated high GLI1 activity. Consistently, TCF blockade does not generally inhibit tumour growth; instead, it, like enhanced HH‐GLI, promotes metastatic growth in vivo. Treatments for metastatic disease should therefore block HH‐GLI1 but not WNT‐TCF activities.

Background: Intestinal ischaemia as a result of small bowel obstruction (SBO) requires prompt recognition and early intervention. A clinicoradiological score was sought to predict the risk of ischaemia in patients with SBO. Methods: A clinico-radiological protocol for the assessment of patients presenting with SBO was used. A logistic regression model was applied to identify determinant variables and construct a clinical score that would predict ischaemia requiring resection. Results: Of 233 consecutive patients with SBO, 138 required laparotomy of whom 45 underwent intestinal resection. In multivariable analysis, six variables correlated with small bowel resection and were given one point each towards the clinical score: history of pain lasting 4 days or more, guarding, C-reactive protein level at least 75 mg/l, leucocyte count 10 × 109/l or greater, free intraperitoneal fluid volume at least 500 ml on computed tomography (CT) and reduction of CT small bowel wall contrast enhancement. The risk of intestinal ischaemia was 6 per cent in patients with a score of 1 or less, whereas 21 of 29 patients with a score of 3 or more underwent small bowel resection. A positive score of 3 or more had a sensitivity of 67·7 per cent and specificity 90·8 per cent; the area under the receiver operating characteristic curve was 0·87 (95 per cent confidence interval 0·79 to 0·95). Conclusion: By combining clinical, laboratory and radiological parameters, the clinical score allowed early identification of strangulated SBO.