Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers

Time-dependent intestinal adaptation and GLP-2 alterations after small bowel resection in rats

Existing data on morphological adaptation after small bowel resection are obtained by potentially biased methods. Using stereological techniques, we examined segments of bowel on days 0, 4, 7, 14, and 28 after 80% jejunoileal resection or sham operation in rats and correlated intestinal growth with plasma levels of glucagon-like peptide-2 (GLP-2). In the jejunum and ileum of the resected rats, the mucosal weight increased by 120 and 115% during the first week, and the weight of muscular layer increased by 134 and 83%, compared with sham-operated controls. The luminal surface area increased by 190% in the jejunum and by 155% in the ileum after 28 days. The GLP-2 level was increased by 130% during the entire study period in the resected rats. Small bowel resection caused a pronounced and persistent transmural growth response in the remaining small bowel, with the most prominent growth occurring in the jejunal part. The significantly elevated GLP-2 level is consistent with an important role of GLP-2 in the adaptive response.</jats:p

Local recurrence rate in a national Danish patient cohort after curative treatment for rectal cancer

Aim: Several trials have shown that preoperative (chemo)radiotherapy (CRT) reduces local recurrence rates (LRRs) in rectal cancer (RC). The use of CRT varies greatly between countries. It is unknown whether the restrictive use of CRT in Denmark results in a higher LRR relative to other countries. The aim was to evaluate the LRR in a national Danish consecutive cohort of patients with RC. Methods: All data from patients with RC in Denmark in 2009–2010 who were operated on with curative intent were retrieved from the Danish Colorectal Cancer Group database. Patients with metastases at the time of diagnosis, patients with synchronous colon cancer, and patients, in whom only local surgical procedures were performed, were excluded. In total, 1633 patients met the inclusion criteria. Clinical follow-up was at least five years with a cut-off date of 31 December 2015. Results: Clinical follow-up was 5.4 years (median) with an interquartile range of 4.5–6.1 years. Of all included patients, 479 (29%) were treated with preoperative long-course CRT. Local recurrence was found in 68 patients, resulting in an LRR of 4.2%, and 182 (11%) patients developed distant metastases. Five-year overall survival was 74% (95% CI: 71.64–75.91). Conclusions: Five-year follow-up of curatively treated patients with RC in Denmark revealed a low LRR. This figure is identical to those reported in other Nordic countries, despite Denmark’s considerably stricter guidelines for CRT. The obtained results justify the currently adopted restrictive use of preoperative CRT in Denmark.</p

GH decreases hepatic amino acid degradation after small bowel resection in rats without enhancing bowel adaptation

Growth hormone (GH) treatment in short bowel syndrome is controversial, and the mechanisms of a possible positive effect remain to be elucidated. Rats were randomly subjected to either an 80% jejunoileal resection or sham operation and were given either placebo (NaCl) or biosynthetic rat GH (brGH). The in vivo capacity of urea nitrogen synthesis (CUNS) and the expression of urea cycle enzymes were measured and related to changes in body weight and adaptive growth in ileal segments on days 7and 14. Ileal segments were examined by unbiased stereological techniques. brGH treatment decreased CUNS among the resected rats by 19% ( P &lt; 0.05) and 36% ( P &lt; 0.05) on days 7 and 14, respectively. The mRNA levels of urea cycle enzyme genes were not influenced by brGH treatment. brGH treatment did not increase the adaptive growth in the ileal segments. In conclusion, we found that GH treatment decreased the accelerated postoperative hepatic amino acid degradation in experimental short bowel syndrome without enhancing the morphological intestinal adaptation.</jats:p