Years of Life Lost for Older Patients After Colorectal Cancer Diagnosis.

BACKGROUND: An aging population combined with an increased colorectal cancer (CRC) incidence in the older population will increase its prevalence in the elderly, questioning how many years of life are lost (YLLs) in these patients. PATIENTS AND METHODS: Data from 32,568 Dutch CRC patients ≥ 80 years were used to estimate the number of YLLs after diagnosis, using a reference age-, sex- and year-of-onset-matched cohort derived from national life tables. YLLs were additionally adjusted by comorbidities. Number needed to treat (NNT) was used as measure of surgical effect size. RESULTS: Surgery was applied in 74.9% of patients leading to 1.3 YLLs, being superior in 86.1% of cases with respect to alternative therapies (YLLs 4.8 years) and resulting in a number of two patients needed to operate to achieve one positive outcome. YLLs and NNTs depended on CRC stage, patient' age and comorbidities. For Stage I-II patients in the best clinical conditions (80-85 years without comorbidities), YLLs increased up to 4.1 years after surgery and up to 8.8 years without surgery (NNT 3). For Stage III patients, the NNT of surgery varied between 2 when they were in the best clinical conditions and 4 when they were older with high comorbidities. In Stage IV patients, the NNT ranged between 6 and 31. CONCLUSIONS: YLLs represents a novel approach to evaluate CRC prognosis. Stage I-III surgical patients can have a life expectancy similar to that of general population, being the NNT of surgery reasonably small compared with alternatives. Personalized comorbidity data are needed to confirm present findings.

Short-term effect of preoperative intravenous iron therapy in colorectal cancer patients with anemia: results of a cohort study.

BACKGROUND: In the treatment of preoperative anemia, which is associated with increased postoperative morbidity, iron supplementation can replace blood transfusion and erythropoiesis-stimulating agents. The aim of this study was to assess the efficacy of preoperative intravenous (IV) iron infusion in optimizing hemoglobin (Hb) levels in anemic colorectal cancer patients. STUDY DESIGN AND METHODS: A retrospective cohort study was performed on patients who underwent surgery for colorectal cancer between 2010 and 2016 in a single teaching hospital. The primary outcome measure, the change in Hb level, was assessed by comparing anemic patients receiving usual care (UC; i.e. no iron therapy and no blood transfusion) with anemic patients receiving IV iron therapy (no blood transfusion). RESULTS: A total of 758 patients with colorectal cancer were eligible, of whom 318 (41.9%) had anemia. The IV and the UC groups included 52 and 153 patients with mean Hb levels at diagnosis of 6.3 and 6.9 mmol/L, respectively. In the IV group, preoperative Hb level was significantly increased compared to the UC group (0.65 mmol/L vs. 0.10 mmol/L, p < 0.001). High increase in Hb level after iron infusion was associated with initial higher transferrin and lower ferritin levels (high vs. poor responders: median transferrin 2.9 g/L vs. 2.7 g/L, median ferritin 12 µg/L vs. 27 µg/L). CONCLUSION: Implementation of IV iron therapy in anemic colorectal cancer patients leads to a distinct increase of preoperative Hb level. IV iron therapy is most effective in patients presenting with more severe anemia, and with higher transferrin and lower ferritin levels, markers for an absolute iron deficiency (ID), compared to functional ID.

Capsaicin-induced satiety is associated with gastrointestinal distress but not with the release of satiety hormones.

BACKGROUND: Capsaicin, which is the major pungent principle in chili peppers, is able to induce satiety and reduce caloric intake. The exact mechanism behind this satiating effect is still unknown. We hypothesized that capsaicin induces satiety through the release of gastrointestinal peptides, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), from enteroendocrine cells in the small intestine. OBJECTIVE: We investigate the effects of an intraduodenal capsaicin infusion (1.5 mg pure capsaicin) in healthy volunteers on hunger, satiety, and gastrointestinal symptoms and the release of GLP-1 and PYY. DESIGN: Thirteen participants (7 women) [mean ± SEM age: 21.5 ± 0.6 y; body mass index (in kg/m(2)): 22.8 ± 0.6] participated in this single-blind, randomized, placebo-controlled crossover study with 2 different treatments. During test days, an intraduodenal infusion of either capsaicin or a placebo (physiologic saline) was performed with the use of a nasoduodenal catheter over a period of 30 min. Visual analog scale scores were used to measure hunger, satiety, and gastrointestinal symptoms. Blood samples were drawn at regular intervals for GLP-1 and PYY. Gallbladder volumes were measured with the use of real-time ultrasonography. RESULTS: The intraduodenal capsaicin infusion significantly increased satiety (P-treatment effect < 0.05) but also resulted in an increase in the gastrointestinal symptoms pain (P-treatment × time interaction < 0.0005), burning sensation (P-treatment × time interaction < 0.0001), nausea (P-treatment × time interaction < 0.05), and bloating (P-treatment × time interaction < 0.001) compared with the effects of the placebo infusion. Satiety scores had a positive correlation with all gastrointestinal symptoms. No differences in GLP-1 and PYY concentrations and gallbladder volumes were observed after the capsaicin infusion compared with after the placebo infusion. CONCLUSIONS: An intraduodenal infusion of capsaicin significantly increases satiety but does not affect plasma concentrations of GLP-1 and PYY. Rather, the effect on satiety seems related to gastrointestinal stress as shown by the associations with pain, burning sensation, nausea, and bloating scores. This trial was registered at clinicaltrials.gov as NCT01667523.

Dietary heme induces acute oxidative stress, but delayed cytotoxicity and compensatory hyperproliferation in mouse colon.

Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by generating cytotoxic and oxidative stress. Recently, we found that this surface injury is compensated by hyperproliferation and hyperplasia of crypt cells, which was induced by a changed surface to crypt signaling. It is unknown whether this changed signaling is caused by cytotoxic stress and/or oxidative stress, as these processes were never studied separately. The aim of this study was to determine the possible differential effects of dietary heme on these luminal stressors and their impact on the colonic mucosa after 2, 4, 7 and 14 days of heme feeding. Mice received a purified, humanized, control diet or the diet supplemented with 0.2 µmol heme/g. Oxidative and cytotoxic stress were measured in fecal water. Proliferation was determined by Ki67-immunohistochemistry and mucosal responses by whole-genome transcriptomics. After heme ingestion, there was an acute increase in reactive oxygen species (ROS) leading to increased levels of lipid peroxidation products. Mucosal gene expression showed an acute antioxidant response, but no change in cell turnover. After day 4, cytotoxicity of the colonic contents was increased and this coincided with differential signaling and hyperproliferation, indicating that cytotoxicity was the causal factor. Simultaneously, several oncogenes were activated, whereas the tumor suppressor p53 was inhibited. In conclusion, luminal cytotoxicity, but not ROS, caused differential surface to crypt signaling resulting in mucosal hyperproliferation and the differential expression of oncogenes and tumor suppressor genes.

Dietary haem stimulates epithelial cell turnover by downregulating feedback inhibitors of proliferation in murine colon.

OBJECTIVE: Colon cancer is a leading cause of cancer deaths in Western countries and is associated with diets high in red meat. Haem, the iron-porphyrin pigment of red meat, induces cytotoxicity of gut contents and damages the colon surface epithelium. Compensatory hyperproliferation leads to epithelial hyperplasia which increases the risk of colon cancer. The aim of this study was to identify molecules signalling from the surface epithelium to the crypt to initiate hyperproliferation upon stress induced by haem. METHODS: C57Bl6/J mice (n=9/group) received a 'westernised' control diet (40 en% fat) with or without 0.5 µmol/g haem for 14 days. Colon mucosa was used to quantify cell proliferation and for microarray transcriptome analysis. Gene expression profiles of surface and crypt cells were compared using laser capture microdissection. Protein levels of potential signalling molecules were quantified. RESULTS: Haem-fed mice showed epithelial hyperproliferation and decreased apoptosis, resulting in hyperplasia. Microarray analysis of the colon mucosa showed 3710 differentially expressed genes (false discovery rate (q) <0.01), with many involved in the cell cycle. Expression levels of haem- and stress-related genes showed that haem affected surface cells but did not directly affect crypt cells. Injured surface cells should therefore signal to crypt cells to induce compensatory hyperproliferation. Haem downregulated the inhibitors of proliferation, Wnt inhibitory factor 1, Indian Hedgehog and bone morphogenetic protein 2. Interleukin-15 was also downregulated. Haem upregulated amphiregulin, epiregulin and cyclo-oxygenase-2 mRNA in surface cells. Their protein/metabolite levels were, however, not increased as haem induced surface-specific inhibition of translation by increasing 4E-BP1. CONCLUSIONS: Haem induces colonic hyperproliferation and hyperplasia by inhibiting the surface to crypt signalling of feedback inhibitors of proliferation.

[The quality indicator 'tumour positive surgical margin following breast-conserving surgery' does not provide transparent insight into care]. / De prestatie-indicator 'irradicaliteit na borstsparende operatie': geen zuiver zicht op goede zorg.

OBJECTIVE: To determine whether the quality indicator 'tumour positive surgical margin following breast-conserving surgery, consistently measured the quality of breast-cancer surgery independently of the different definitions used and differences in case mix, taking statistical random variation into account. DESIGN: Descriptive study. METHODS: Data was collected from 762 patients who underwent breast-conserving surgery for invasive or in situ carcinoma of the breast, in the period 1 July 2007 - 30 June 2008 in 1 of the 9 hospitals in the region of the Comprehensive Cancer Centre West in the Netherlands. We compared 3 definitions for 'tumour positive surgical margin': the one used by the Health Care Inspectorate, the one used by the organisation 'Zichtbare Zorg' ('transparent care') and the percentage of re-resection. For case mix correction we identified risk factors for tumour margin positivity with logistic regression. The results were presented in a funnel plot, using 95% confidence interval (CI) around the national standard of 20%. RESULTS: Depending on the definition used, the tumour positive surgical margin rate of the total group varied from 11 to 21%. Individual hospital rates varied by up to 19%. In situ carcinoma was associated with higher tumour positive surgical margin rates. Results differed significantly between hospitals for all 3 definitions. However, the funnel plot showed that results for most hospitals fell within the 95% CI of the standard. Whether a hospital fell within the 95% CI of the standard depended upon on the definition used and case mix correction. CONCLUSION: The lack of a single definition for the quality indicator 'tumour positive surgical margin following breast-conserving surgery' and the lack of case-mix correction undermine the validity of the indicator. Standardisation of definitions, uniform registration and the use of funnel plots can provide a more transparent insight into the quality of care.