Cameron Platell

Tumor-Infiltrating FOXP3+ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer

PURPOSE To determine the prognostic significance of FOXP3(+) lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8(+) and CD45RO(+) lymphocyte densities. PATIENTS AND METHODS Tissue microarrays and immunohistochemistry were used to assess the densities of CD8(+), CD45RO(+), and FOXP3(+) lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. RESULTS FOXP3(+) Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8(+) and CD45RO(+) cell densities were lower. FOXP3(+) Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3(+) Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8(+) and CD45RO(+). High FOXP3(+) Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3(+) Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). CONCLUSION FOXP3(+) Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8(+) and CD45RO(+) lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3(+) Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3(+) Treg density may help to improve the prognostication of early-stage colorectal cancer.

The incidence of anastomotic leaks in patients undergoing colorectal surgery

Background  There is evolving interest in auditing and credentialling the performance of surgeons. The incidence of anastomotic leakage has been proposed as a measure of performance following colorectal surgery. The aim of this study was to evaluate the incidence and risk factors associated with anastomotic leakage in patients undergoing resections of the colon and rectum.

Cost-effectiveness of colorectal cancer screening: comparison of community-based flexible sigmoidoscopy with fecal occult blood testing and colonoscopy.

Background and Aims:  To determine the cost‐effectiveness of screening for colorectal cancer using flexible sigmoidoscopy once every 10 years, compared with annual and biennial rehydrated Hemoccult fecal occult blood testing and colonoscopy once every 10 years, or no screening.

Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features

BackgroundMost previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites. In the present study we performed comprehensive DNA methylation profiling of CRC with the aim of characterizing CIMP subgroups.MethodsDNA methylation at 1,505 CpG sites in 807 cancer-related genes was evaluated using the Illumina GoldenGate® methylation array in 28 normal colonic mucosa and 91 consecutive CRC samples. Methylation data was analyzed using unsupervised hierarchical clustering. CIMP subgroups were compared for various clinicopathological and molecular features including patient age, tumor site, microsatellite instability (MSI), methylation at a consensus panel of CpG islands and mutations in BRAF and KRAS.ResultsA total of 202 CpG sites were differentially methylated between tumor and normal tissue. Unsupervised hierarchical clustering of methylation data from these sites revealed the existence of three CRC subgroups referred to as CIMP-low (CIMP-L, 21% of cases), CIMP-mid (CIMP-M, 14%) and CIMP-high (CIMP-H, 65%). In comparison to CIMP-L tumors, CIMP-H tumors were more often located in the proximal colon and showed more frequent mutation of KRAS and BRAF (P < 0.001).ConclusionsComprehensive DNA methylation profiling identified three CRC subgroups with distinctive clinicopathological and molecular features. This study suggests that both KRAS and BRAF mutations are involved with the CIMP-H pathway of CRC rather than with distinct CIMP subgroups.

Tumor-Infiltrating Lymphocytes and Perforation in Colon Cancer Predict Positive Response to 5-Fluorouracil Chemotherapy

Purpose: The major pathologic markers of prognosis in colorectal cancer include vascular invasion by tumor cells, invasion of adjacent lymph nodes, and perforation of the serosal wall. Recent work suggests that a high density of tumor-infiltrating lymphocytes (TIL) is associated with good outcome independently of these established prognostic markers. The aim of the present study was to investigate the prognostic significance of TILs and other routinely reported pathologic features in colon cancer, particularly in relation to the use of adjuvant chemotherapy. Experimental Design: Pathologic markers, disease-specific survival, and the use of adjuvant chemotherapy were recorded in a retrospective, population-based series of 1,156 stage III colon cancer patients with a median follow-up time of 52 months. Results: In patients treated by surgery alone (n = 851), markers with significant prognostic value included poor histologic grade, T4 stage, N2 nodal status, vascular invasion, and perforation, but not the presence of TILs. In patients treated with 5-fluorouracil–based chemotherapy (n = 305), TILs were associated with significantly improved survival [hazard ratio (HR), 0.52; 95% confidence interval, 0.30-0.91; P = 0.02] and perforation with a trend for improved survival (HR, 0.67; 95% confidence interval, 0.27-1.05; P = 0.16). Patients with TILs or perforation seemed to gain more survival benefit from chemotherapy (HR, 0.22 and 0.21, respectively) than patients without these features (HR, 0.84 and 0.82, respectively). Conclusion: The apparent survival advantage from 5-fluorouracil associated with TILs and perforation requires confirmation in prospective studies. Because the presence of TILs reflects an adaptive immune response and perforation is associated with inflammatory response, these results suggest that there may be interactions between the immune system and chemotherapy leading to improved survival of colon cancer patients.

Population-based study of prognostic factors in stage II colonic cancer.

Adjuvant chemotherapy in stage II colorectal cancer may be considered for patients whose tumours have poor prognostic features. The aim of this study was to evaluate the prognostic significance of commonly reported clinical and pathological features of stage II colonic cancer.

The influence of lavage on peritonitis.

Lavage was adopted by surgeons around the turn of the century for managing patients with peritonitis. In 1906, Franz Torek from the New York PostGraduate Medical School described how “the salt water is poured into all recesses” and “the hand, by some gentle to-and-fro motions, assists it in washing all parts” and pus was “dipped out, rather than wiped out, as the latter procedure would be more likely to injure the peritoneum.” Over the years, support for its use has fluctuated, depending largely on opinions rather than evidence. Lavage is currently widely used in the treatment of patients with peritonitis either from bowel perforation or from acute pancreatitis. Early opponents of the use of lavage claimed that it served to spread infection. In the first half of this century, Rodney Maingot commented that, “Irrigation of the peritoneal cavity for cleansing purposes is, in my opinion, never justified, even in the presence of gross fecal contamination.” Burnett and coworkers in 1957 reintroduced peritoneal lavage as a treatment option in patients with peritonitis in association with high concentrations of antibiotics. He commented that “lavage removes large quantities of toxins from a great absorptive area and many bacteria which would have otherwise have to be dealt with by the body’s defenses.” The primary role of the surgeon in managing patients with peritonitis is to control the source of contamination. Failure to do so results in septicemia and a universally poor prognosis. Secondary treatment aims include reducing the bacterial load in the peritoneal cavity by lavage, antibiotics, or both. Lavage is claimed to remove not only bacteria but also material that may promote bacterial proliferation (eg, blood) and proinflammatory cytokines that may enhance local inflammation. The objective of this article is, first, to give an overview of peritoneal defense mechanisms and how lavage may influence the resolution of peritonitis; and second, to review the relevant surgical literature and to perform a combined analysis of available randomized prospective clinical trials, to evaluate whether lavage influences mortality and morbidity in patients with bacterial peritonitis.

The Influence of Parenteral Glutamine and Branched-Chain Amino Acids on Total Parenteral Nutrition—Induced Atrophy of the Gut

We tested the hypothesis that the provision of glutamine and branched-chain amino acids would reverse the gut atrophy that accompanies parenteral nutrition. Three hundred seventy-five rats were randomized into 15 groups to receive either conventional parenteral nutrition, rat food, glutamine-enriched parenteral nutrition (0.5% to 2.5%), branched-chain amino acid-enriched parenteral nutrition (0.8% to 2.0%), or glutamine plus branched-chain amino acid-enriched parenteral nutrition (0.5%/0.4% to 1.25%/1/0%). When compared with effects of conventional parenteral nutrition, the infusion of either glutamine or branched-chain amino acids partially reversed, in a dose-dependent manner, atrophy of the small bowel as assessed by gut weight (p < .05), mucosal weight (p < .05), villous height (p < .05), crypt cell production rate (p < .05), and mucosal protein concentration (p < .05). There was no effect on the large bowel. These results suggest that the parenteral infusion of either glutamine or branched-chain amino acids partially reverses the small-bowel atrophy that is associated with the infusion of solutions of conventional parenteral nutrients.

Sexual health in women following pelvic surgery for rectal cancer

Sexual dysfunction is a recognized complication in men undergoing pelvic surgery for rectal cancer. There is, however, little information on the influence of such surgery on sexual health in women. The aim of this study was to evaluate sexual health in women undergoing pelvic surgery for rectal cancer.

Half-life of truth in surgical literature.

The hypothetico-deductive model of Karl Popper contends that “An assertion is true if it corresponds to, or agrees with, the facts”. Because “the facts” change over time, truth is relative. In this view of events, science progresses via a series of theories (paradigms) that are held to be true until they are replaced by a better approximation of reality. It follows that some “truths” will last longer than others. We decided to estimate the half-life of dogma relating to the practice of surgery. The journal Surgery Gynecology and Obstetrics had a section entitled International Surgical Abstracts that concluded at the end of 1994. We obtained copies of all of the abstracts for the even numbered months for each fifth year after 1935. The first 20 abstracts about general surgery from each of the 13 review periods were selected for study. The one sentence from each abstract that best summarised the conclusion was copied to a database. Editing of these sentences was restricted to the rephrasing of outdated terminology and the elimination of redundant words. The form, which contained the 260 selected sentences in a random order, was assessed by seven general surgeons. They were asked to mark each question as being either true or false. We explored the relation between time and the number of positive responses from the questionnaire using scatter plots and regression analyses. The linear model detailed in the figure was found to be most appropriate (R=0·86, p<0·001). It suggests that the rate of loss of truth is 0·75% per year and that the estimated half-life of truth for clinical statements in the surgical literature is 45 years. This seems appropriate; 45 years ago it was suggested that: prefrontal lobotomy usefully altered patients’ reactions so that “no anxiety, fear, or concern over their impending death from cancer was manifest”; “in primary malignant hypertension the malignant phase may disappear” after lumbodorsal sympathectomy; and, the detection of a gastric ulcer was “a strong indication for immediate operation”. Extrapolation of the regression line can be used to hypothesise that the current era of surgery extends between 1904 and 2038. From an historical perspective, 1904 is a reasonable estimate of the commencement of the era of “open” surgery. Gauze masks and rubber gloves had just been introduced into operating theatres and abdominal surgery gained public respectability in the UK in 1902 when Edward VII’s coronation was delayed by the need to drain his appendiceal abscess. More contentious is extrapolation of the regression line to predict the future. However, a nexus point for the present era of surgery in the second quartile of the next century is consistent with the current trend towards the ascendancy of minimally invasive procedures and medical treatments over open surgery.