The prognostic value of cancer stem-like cell markers SOX2 and CD133 in stage III colon cancer is modified by expression of the immune-related markers FoxP3, PD-L1 and CD3.

Cancer stem-like cells are highly tumourigenic cells that can repopulate entire tumours after apparent successful treatment. Recent evidence suggests they interact with other cells in the tumour microenvironment, including immune cell subsets, to enhance their survival. The aim of this study was to determine whether the expression of immune cell markers in primary colon cancer impacts the prognostic significance of cancer stem-like cell marker expression. Immunohistochemistry was used to assess the expression of putative stem cell markers (ALDH1, CD44v6, CD133, Lgr5, SOX2) and immune cell related markers (CD3, CD8, FoxP3, PD-L1) in 104 patients with stage III colon cancer. Associations of marker expression with overall and cancer-specific survival were determined using Kaplan-Meier analysis. High SOX2 expression in the central tumour area was found to be an independent factor for poor cancer-specific survival [hazard ratio (HR) 6.19; 95% confidence interval (CI) 2.24-17.14; p=0.001]. When immune-related factors were taken into account, patients categorised as SOX2low/FoxP3high had good outcome (HR 0.164; 95%CI 0.066-0.406; p<0.0001) whereas patients categorised as SOX2high/PD-L1low had poor outcome (HR 8.992; 95%CI 3.397-23.803; p<0.0001). The prognostic value of the SOX2 cancer stem-like cell marker in colon cancer is modified by expression of immune-cell related factors FoxP3 and PD-L1.

Objective analysis of cancer stem cell marker expression using immunohistochemistry.

Analysis of immunohistochemical expression is often a subjective and semiquantitative process that can lead to the inconsistent reporting of results. To assess the effect that region selection and quantification method have on results, five different cancer stem cell markers were used in this study to compare tissue scoring with digital analysis methods that used three different tissue annotation methods. Samples of tumour and normal mucosa were used from 10 consecutive stage II colon cancer patients and stained for the putative cancer stem cell markers ALDH1, CD44v6, CD133, Lgr5 and SOX2. Tissue scoring was found to have considerably different results to digital analysis with the three different digital methods harbouring concordant results overall. However, SOX2 on normal tissue and CD133 on tumour and normal tissue produced discordant results which could be attributed to the different regions of tissue that were analysed. It is important that quantification method and selection of analysis areas are considered as part of study design to ensure that reproducible and consistent results are reported in the literature.

Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer.

BACKGROUND: Foxp3+ regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown. METHODS: Foxp3+, CD3+, CD4+, CD8+ and IL-17+ cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated. RESULTS: Stromal Foxp3+ cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3+ cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3+ cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade. CONCLUSIONS: Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer.

Sexual health in women following pelvic surgery for rectal cancer.

BACKGROUND: 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. METHODS: The study group included women who underwent pelvic surgery for rectal cancer at the Colorectal Surgical Unit, Fremantle Hospital between 1996 and 2002. The patients were contacted by telephone and invited to complete an anonymized questionnaire on sexual health. A control group comprised women who had undergone surgery for colonic cancer during the same interval. RESULTS: Fifty women in the study group were contacted, of whom 22 completed questionnaires. Sixty-two women in the control group were contacted and 19 completed questionnaires. Women in the study group were significantly younger than those in the control group. Compared with those in the control group, women who had undergone pelvic surgery were significantly more likely to feel less attractive, feel that the vagina was either too short or less elastic during intercourse, experience superficial pain during intercourse, and complain of faecal soiling during intercourse. Women in the study group were concerned that these limitations would persist for the rest of their lives. There were no differences between the two groups in relationship to sexual arousal or libido. CONCLUSION: Pelvic surgery for rectal cancer has a significant influence on sexual health in women.

Fecal occult blood and flexible sigmoidoscopy screening for colorectal cancer: modeling the impact on colonoscopy requirements and cancer detection rates.

AIM: The aim of this study was to estimate the colonoscopy requirements and the likely impact of fecal occult blood and flexible sigmoidoscopy screening on the detection of colorectal cancer by using previously published data. METHODS: Fecal occult blood and flexible sigmoidoscopy screening programs were applied to the 2.04 million subjects aged 50-65 years, at a participation rate of 40%. The following strategies were evaluated: Fecal occult blood testing with colonoscopy follow up of all positive tests; flexible sigmoidoscopy with colonoscopy follow up of all adenomatous polyps; and flexible sigmoidoscopy with colonoscopy follow up of all adenomatous polyps > 10 mm in size. RESULTS: The fecal occult blood program detected 5.6% of all colorectal cancer cases at a rate of 2,914 colonoscopies/percentage of detection of colorectal cancer. The flexible sigmoidoscopy program detected 14% of all colorectal cancer cases at a rate of 8,160 colonoscopies/percentage of detection of colorectal cancer. The flexible sigmoidoscopy program with follow up of adenomatous polyps > 10 mm in size detected 13% of all colorectal cancer cases at a rate of 1,230 colonoscopies/percentage of detection of colorectal cancer. CONCLUSIONS: Flexible sigmoidoscopy screening followed by colonoscopic follow up of adenomatous polyps > 10 mm in size is the most efficient screening strategy in terms of colonoscopies generated and cases of colorectal cancer detected.

Flexible sigmoidoscopy screening for colorectal cancer in average-risk people: update of a community-based project.

OBJECTIVES: To analyse results of a screening program for colorectal cancer using flexible sigmoidoscopy. DESIGN: Survey of results of screening program and follow-up colonoscopies and identification of missed cases from State cancer registry data. PARTICIPANTS: Asymptomatic, average-risk people aged 55-64 years who were either mailed invitations after random selection from the electoral roll or volunteered after hearing about the program. SETTING: Fremantle Hospital, Western Australia (a public teaching hospital), July 1995 to November 1999 (first 4.5 years of the screening program). MAIN OUTCOME MEASURES: Participation rates; lesions detected; stage of colorectal cancers diagnosed at the hospital before and after the screening program began (1989-1995 versus 1996-1999); and diagnoses of colorectal cancer in previously screened individuals (from State cancer registry data). RESULTS: 6446 people were mailed invitations, and 1483 were screened (23% participation rate). Another 1122 people volunteered, giving 2605 people screened overall. Flexible sigmoidoscopy showed adenomatous polyps in 352 people (14%), and colonoscopy was recommended in 399 (15%) on the basis of clinically suspicious lesions. Colonoscopy was performed in 302 (76% participation rate). Screening and follow-up colonoscopy detected 14 colorectal cancers (10 invasive, with eight of these Dukes stage A). One participant was diagnosed with colorectal cancer 12 months after sigmoidoscopy gave normal results. Incidence of colorectal cancer was 119 per 100000 per year, and prevalence was 0.5%. Before the screening program, 12% of cancers diagnosed at our hospital were Dukes stage A, compared with 28% after (P<0.001). CONCLUSIONS: Flexible sigmoidoscopy screening is an acceptable strategy in asymptomatic, average-risk people which detects colorectal cancer and adenomatous polyps. Screening has been associated with a trend to earlier presentation of cancer in our institution.

Colorectal cancer screening by general practitioners: comparison with national guidelines.

OBJECTIVE: To determine whether general practitioners (GPs) had received Australian guidelines on early detection, screening and surveillance for colorectal cancer or rectal bleeding, and whether their reported practice conformed with these guidelines. DESIGN: Cross-sectional postal survey of self-reported practice. PARTICIPANTS AND SETTING: 213 GPs in practice in the southern metropolitan area of Perth, Western Australia, were randomly selected from the Fremantle Regional Division of General Practice database and surveyed in March 1997. RESULTS: Replies were received from 155 (73%) of the GPs, and 110 reported receiving guidelines (from the Australian Gastroenterology Institute [AGI], 44; Gut Foundation of Australia [GFA], 40; others, 6; and not specified, 20). GPs who reported receiving guidelines were significantly more likely to screen for colorectal cancer (99/110; 90%) than those who reported not receiving guidelines (33/45; 73%) (P = 0.008). The commonest method to investigate people with identifiable risk factors for colorectal cancer was colonoscopy. Reported screening frequencies in asymptomatic patients with above-average risk (family history of colorectal cancer or past history of adenomatous polyps or colorectal cancer) were significantly higher than recommended by AGI and GFA guidelines (P < 0.05). Up to 24% of GPs investigated altered bowel habit or bleeding per rectum with faecal occult blood testing. CONCLUSIONS: Most GPs report having received guidelines. Reported screening frequency was higher than recommended for most above-average-risk patients, which will result in excessive consumption of resources without benefits for cancer prevention.

Intra-abdominal pressure and renal function after surgery to the abdominal aorta.

It has been suggested that an elevated intra-abdominal pressure (IAP) can impair renal function. In a prospective longitudinal study, the IAP of 42 patients admitted to an intensive care unit after abdominal aortic surgery was monitored. When compared with the other patients, the 22 patients (53%) who developed renal impairment had higher IAP (17.8 +/- 6.0 mmHg versus 14.1 +/- 4.8 mmHg; P less than 0.01) and APACHE II scores (15.6 +/- 6.0 versus 9.8 +/- 4.6; P less than 0.01). Each of the 10 patients who were re-explored because of haemodynamic instability and oliguria had an IAP of greater than 18 mmHg (positive predictive value = 85%, negative predictive value = 62%). Following re-exploration, the urinary output increased by 115 +/- 40 mL/h (P less than 0.01), and the IAP decreased by 10 +/- 3 mmHg (P less than 0.01). Although it is concluded that an IAP greater than 18 mmHg is a significant risk factor for the development of impaired renal function, it was not possible to prove a causal relationship between these events. Nevertheless, such a relationship has been demonstrated in animal and human models.

Hypersensitivity reactions to heparin: delayed onset thrombocytopenia and necrotizing skin lesions.

Significant hypersensitivity reactions to heparin may manifest as either delayed onset thrombocytopenia or as necrotizing skin lesions. Such hypersensitivity reactions are uncommonly recognized, partly because of their rarity and partly because their existence is not widely appreciated. Both adverse reactions may be readily diagnosed. In the presence of these reactions, continuing heparin therapy may lead to serious thrombo-embolic complications and death of the patient. In this study, two patients who highlight the clinical settings of these reactions are discussed with reference to their pathogenesis and clinical significance.