No abstract

High macrophage infiltration has been correlated to improved survival in colorectal cancer (CRC). Tumor associated macrophages (TAMs) play complex roles in tumorigenesis since they are believed to hold both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we have applied an immunohistochemical approach to determine the degree of infiltrating macrophages with a M1 or M2 phenotype in clinical specimens of CRC in relation to prognosis, both in CRC in general but also in subgroups of CRC defined by microsatellite instability (MSI) screening status and the CpG island methylator phenotype (CIMP). A total of 485 consecutive CRC specimens were stained for nitric oxide synthase 2 (NOS2) (also denoted iNOS) as a marker for the M1 macrophage phenotype and the scavenger receptor CD163 as a marker for the M2 macrophage phenotype. The average infiltration of NOS2 and CD163 expressing macrophages along the invasive tumor front was semi-quantitatively evaluated using a four-graded scale. Two subtypes of macrophages, displaying M1 (NOS2+) or M2 (CD163+) phenotypes, were recognized. We observed a significant correlation between the amount of NOS2+ and CD163+ cells (P<0.0001). A strong inverse correlation to tumor stage was found for both NOS2 (P<0.0001) and CD163 (P<0.0001) infiltration. Furthermore, patients harbouring tumors highly infiltrated by NOS2+ cells had a significantly better prognosis than those infiltrated by few NOS2+ cells, and this was found to be independent of MSI screening status and CIMP status. No significant difference was found on cancer-specific survival in groups of CRC with different NOS2/CD163 ratios. In conclusion, an increased infiltration of macrophages with a M1 phenotype at the tumor front is accompanied by a concomitant increase in macrophages with a M2 phenotype, and in a stage dependent manner correlated to a better prognosis in patients with CRC.

In this population based study, 12% of the patients had symptomatic anastomotic leakage after anterior resection of the rectum. Postoperative 30-day mortality was 2.1%. Low anastomosis, pre-operative radiation, presence of intra-operative adverse events and male gender were independent risk factors for symptomatic anastomotic leakage in the multivariate analysis. There was no difference in the use of temporary stoma in patients with or without anastomotic leakage.

Objective: The aim of this randomized multicenter trial was to assess the rate of symptomatic anastomotic leakage in patients operated on with low anterior resection for rectal cancer and who were intraoperatively randomized to a defunctioning stoma or not. Summary Background Data: The introduction of total mesorectal excision surgery as the surgical technique of choice for carcinoma in the lower and mid rectum has led to decreased local recurrence and improved oncological results. Despite these advances, perioperative morbidity remains a major issue, and the most feared complication is symptomatic anastomotic leakage. The role of the defunctioning stoma in regard to anastomotic leakage is controversial and has not been assessed in any randomized trial of sufficient size. Methods: From December 1999 to June 2005, a total of 234 patients were randomized to a defunctioning loop stoma or no loop stoma. Loop ileostomy or loop transverse colostomy was at the choice of the surgeon. Inclusion criteria for randomization were expected survival Ͼ6 months, informed consent, anastomosis Յ7 cm above the anal verge, negative air leakage test, intact anastomotic rings, and absence of major intraoperative adverse events. Results: The overall rate of symptomatic leakage was 19.2% (45 of 234). Patients randomized to a defunctioning stoma (n ϭ 116) had leakage in 10.3% (12 of 116) and those without stoma (n ϭ 118) in 28.0% (33 of 118) (odds ratio ϭ 3.4; 95% confidence interval, 1.6 -6.9; P Ͻ 0.001). The need for urgent abdominal reoperation was 8.6% (10 of 116) in those randomized to stoma and 25.4% (30 of 118) in those without (P Ͻ 0.001). After a follow-up of median 42 months (range, 6 -72 months), 13.8% (16 of 116) of the initially defunctioned patients still had a stoma of any kind, compared with 16.9% (20 of 118) those not defunctioned (not significant). The 30-day mortality after anterior resection was 0.4% (1 of 234) and after elective reversal a defunctioning stoma 0.9% (1 of 111). Median age was 68 years (range, 32-86 years), 45.3% (106 of 234) were females, 79.1% (185 of 234) had preoperative radiotherapy, the level of anastomosis was median 5 cm, and intraoperative blood loss 550 mL, without differences between the groups. Conclusion: Defunctioning loop stoma decreased the rate of symptomatic anastomotic leakage and is therefore recommended in low anterior resection for rectal cancer.

One patient of 5 ended up with a permanent stoma after low anterior resection of the rectum for cancer, and half of the patients with a permanent stoma had previous symptomatic anastomotic leakage.

The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eightgene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score Z7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score r4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P ¼ 0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear.

Purpose: The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation.Experimental Design: Archival tumor samples from 190 patients from the Northern Sweden Health and Disease Study (NSHDS) and 414 patients from the Colorectal Cancer in Umeå Study (CRUMS), including 574 with cancer-specific survival data, were analyzed for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). MSI screening status was assessed by immunohistochemistry.Results: CIMP-low patients had a shorter cancer-specific survival compared with CIMP-negative patients (multivariate hazard ratio in NSHDS, 2.01; 95% confidence interval, 1.20-3.37; multivariate hazard ratio in CRUMS, 1.48; 95% confidence interval, 1.00-2.22). This result was similar in subgroups based on MSI screening status and was statistically significant in microsatellite stable (MSS) tumors in NSHDS. For CIMP-high patients, a shorter cancer-specific survival compared with CIMPnegative patients was observed in the MSS subgroup. Statistical significance was lost after adjusting for the BRAF mutation, but the main findings were generally unaffected.Conclusions: In this study, we found a poor prognosis in CIMP-low patients regardless of MSI screening status, and in CIMP-high patients with MSS. Although not consistently statistically significant, these results were consistent in two separate patient groups and emphasize the potential importance of CIMP and MSI status in colorectal cancer research. Clin Cancer Res; 16(6); 1845-55. ©2010 AACR.

AimHealth-related quality of life (HRQoL) assessment is important in understanding the patient’s perspective and for decision-making in health care. HRQoL is often impaired in patients with stoma. The aim was to evaluate HRQoL in rectal cancer patients with permanent stoma compared to patients without stoma.Methods711 patients operated for rectal cancer with abdomino-perineal resection or Hartman’s procedure and a control group (n = 275) operated with anterior resection were eligible. Four QoL questionnaires were sent by mail. Comparisons of mean values between groups were made by Student´s independent t test. Comparison was made to a Swedish background population.Results336 patients with a stoma and 117 without stoma replied (453/986; 46 %). A bulging or a hernia around the stoma was present in 31.5 %. Operation due to parastomal hernia had been performed in 11.7 % in the stoma group. Mental health (p = 0.007), body image (p < 0.001), and physical (p = 0.016) and emotional function (p = 0.003) were inferior in patients with stoma. Fatigue (p = 0.019) and loss of appetite (p = 0.027) were also more prominent in the stoma group. Sexual function was impaired in the non-stoma group (p = 0.034). However in the stoma group, patients with a bulge/hernia had more sexual problems (p = 0.004). Pain was associated with bulge/hernia (p < 0.001) and fear for leakage decreased QoL (p < 0.001). HRQoL was impaired compared to the Swedish background population.ConclusionOverall HRQoL in patients operated for rectal cancer with permanent stoma was inferior compared to patients without stoma. In the stoma group, a bulge or a hernia around the stoma further impaired HRQoL.