Exploration of information and support needs in relation to health concerns, diet and physical activity in colorectal cancer survivors.

The purpose of the current study was to explore colorectal cancer survivors' information and support needs in relation to health concerns and health behaviour change. Face-to-face interviews were conducted with participants who had completed active treatment for cancer within the previous 2 years. Participants were colorectal cancer survivors (N = 24, men = 11, women = 13 M, age = 69.38 years, SD = 4.19) recruited from a hospital in Perth, Australia on the basis that they had existing morbidities that put them at increased risk of cardiovascular disease. Interview transcripts were analysed using thematic analysis. RESULTS: Five main themes emerged: bowel changes; Lack of knowledge concerning healthy eating and physical activity; conflicting information; desire for support; and, need for simple messages and strategies to stay healthy. Where dietary recommendations were provided, these were to resolve bowel problems rather than to promote healthy eating. The provision of lifestyle advice from the oncologists is limited and patients' lack knowledge of guidelines for diet and physical activity. Oncologists could provide patients with clear messages from the World Cancer Research Fund (); that is to increase physical activity and dietary fibre and reduce consumption of red meat, processed meat, alcohol and body fatness.

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.

Long-term survival following laparoscopic and open colectomy for colon cancer: a meta-analysis of randomized controlled trials.

AIM: Large randomized clinical trials comparing long-term survival after laparoscopic and open colectomy for large bowel cancer show equivalence, but meaningful analysis of data by stage has not been possible due to the small numbers of patients in individual trials. The aim of this meta-analysis was to improve statistical power by combining data to enable assessment of survival for individual stages. METHOD: A systematic review and meta-analysis was conducted through a computerized search of all randomized controlled trials comparing open and laparoscopic surgery for large bowel cancer. Overall survival data were analysed and subgroup analysis was performed for cancer of Stages I-III. RESULTS: Five trials (3152 patients) were included. Overall survival was equivalent (hazard ration 0.93; 95% confidence interval 0.80-1.07). With each of the cancer stages, I-III, there was no difference in 5-year survival. There was, however, a nonsignificant trend in favour of open surgery in the subgroup analysis of Stage II patients. CONCLUSION: Laparoscopic-assisted surgery for colon cancer is equivalent to open surgery with respect to long-term survival although there may be a difference for Stage II cancer.

Lifestyle factors associated with survival after colorectal cancer diagnosis.

BACKGROUND: Aside from tumour stage and treatment, little is known about potential factors that may influence survival in colorectal cancer patients. The aim of this study was to investigate the associations between physical activity, obesity and smoking and disease-specific and overall mortality after a colorectal cancer diagnosis. METHODS: A cohort of 879 colorectal cancer patients, diagnosed in Western Australia between 2005 and 2007, were followed up to 30 June 2012. Cox's regression models were used to estimate the hazard ratios (HR) for colorectal cancer-specific and overall mortality associated with self-reported pre-diagnosis physical activity, body mass index (BMI) and smoking. RESULTS: Significantly lower overall and colorectal cancer-specific mortality was seen in females who reported any level of recent physical activity than in females reporting no activity. The colorectal cancer-specific mortality HR for increasing levels of physical activity in females were 0.34 (95% CI=0.15, 0.75), 0.37 (95% CI=0.17, 0.81) and 0.41 (95% CI=0.18, 0.90). Overweight and obese women had almost twice the risk of dying from any cause or colorectal cancer compared with women of normal weight. Females who were current smokers had worse overall and colorectal cancer-specific mortality than never smokers (overall HR=2.64, 95% CI=1.18, 5.93; colorectal cancer-specific HR=2.70, 95% CI=1.16, 6.29). No significant associations were found in males. CONCLUSION: Physical activity, BMI and smoking may influence survival after a diagnosis of colorectal cancer, with more pronounced results found for females than for males.

Can population differences in chemotherapy outcomes be inferred from differences in pharmacogenetic frequencies?

Inter-ethnic differences in drug handling and frequencies of pharmacogenetic variants are increasingly being characterized. In this study, we systematically assessed the feasibility of inferring ethnic trends in chemotherapy outcomes from inter-ethnic differences in pharmacogenetic variant frequencies. Frequencies of 51 variants and chemotherapy outcomes of East Asian and Caucasian colorectal cancer patients on standard chemotherapy regimens were summarized by meta-analyses, and variant frequencies were validated by MassARRAY analysis. Inferences of relative chemotherapy outcomes were made by considering minor allele function and population differences in their frequency. Significant population differences in genotype distributions were observed for 13/23 (60%) and 27/35 (77%) variants in the meta-analyses and validation series, respectively. Across chemotherapy regimens, East Asians had lower rates of grade 3/4 toxicity for diarrhea and stomatitis/mucositis than Caucasians, which was correctly inferred from 13/18 (72%, P=0.018) informative genetic variants. With appropriate variant selection, inferring relative population toxicity rates from population genotype differences may be relevant.

Cancer auditing - how accurate are your data?

AIM: Human involvement in the collection and entering of information into a database leads to a degree of error. The aim of this study was to assess the concordance between two individuals blinded from each other who independently collected information on the same set of patients and entered it into a colorectal neoplasia database. METHOD: A colorectal research nurse and a surgeon independently maintained an electronic database on all new patients admitted with colorectal neoplasia under the surgeon over a 5-year period. Twenty-three key endpoints were selected from the database in order to determine the agreement between the two observers. The κ statistic (for nominal and ordinal data) and the concordance correlation coefficient (for interval data) were used to determine the level of agreement between the two data sets. RESULTS: Both observers recorded 432 new referrals during this period. There was only complete concordance between the two databases with respect to the number of new patients and returns to theatre within 30 days. Nonetheless, there was almost perfect concordance between the two data sets for a majority of the endpoints. The most important areas of variance were in the length of stay (κ=0.78), the American Society of Anesthesiology grade (κ=0.41), emergency surgery (κ=0.36), nodal staging (κ=0.54) and time to recurrence (κ=0.77). CONCLUSION: This study highlights a number of important areas of data inaccuracy in a prospective colorectal database. The inaccuracies were due to observer bias, issues of data interpretation, or just difficulty in collecting the information accurately.

Australasian ACPGBI risk prediction model for 30-day mortality after colorectal cancer surgery.

BACKGROUND: Postoperative mortality after colorectal cancer surgery varies across hospitals and countries. The aim of this study was to test the Association of Coloproctologists of Great Britain and Ireland (ACPGBI) models as predictors of 30-day mortality in an Australian cohort. METHODS: Data from patients who underwent surgery in six hospitals between 1996 and 2015 (CRC data set) were reviewed to test ACPGBI models, and patients from 79 hospitals in the Bi-National Colorectal Cancer Audit between 2007 and 2016 (BCCA data set) were analysed to validate model performance. Recalibrated models based on ACPGBI risk models were developed, tested and validated on a data set of Australasian patients. RESULTS: Of 18 752 patients observed during the study, 6727 (CRC data set) and 3814 (BCCA data set) were analysed. The 30-day mortality rate was 1·1 and 3·5 per cent in the CRC and BCCA data sets respectively. Both the original and revised ACPGBI models overestimated 30-day mortality for the CRC data set (observed to expected (O/E) ratio 0·17 and 0·21 respectively). Their ability to correctly predict mortality risk was poor (P < 0·001, Hosmer-Lemeshow test); however, the area under the curve for both models was 0·88 (95 per cent c.i. 0·85 to 0·92) showing good discriminatory power to classify 30-day mortality. The recalibrated original model performed well for calibration and discrimination, whereas the recalibrated revised model performed well for discrimination but not for calibration. Risk prediction was good for both recalibrated models. On external validation using the BCCA data set, the recalibrated models underestimated mortality risk (O/E ratio 3·06 and 2·98 respectively), whereas both original and revised ACPGBI models overestimated the risk (O/E ratio 0·48 and 0·69). All models showed similar good discrimination. CONCLUSION: The original and revised ACPGBI models overpredicted risk of 30-day mortality. The new Australasian calibrated ACPGBI model needs to be tested further in clinical practice.

ANTECEDENTES: La mortalidad postoperatoria tras la cirugía del cancer colorrectal (colorectal cáncer, CRC) varía entre hospitales y países. El objetivo de este estudio era evaluar los modelos de la Asociación de Coloproctólogos de Gran Bretaña e Irlanda (Association of Coloproctologists of Great Britain and Ireland, ACPGBI) como predictores de mortalidad a los 30 días en una cohorte de pacientes de Australia. MÉTODOS: Se revisaron los datos de pacientes sometidos a cirugía en seis hospitales entre 1996-2015 (datos CRC) para evaluar los modelos ACPGBI, mientras que los datos recogidos en 79 hospitales en la auditoría bi-nacional de cáncer colorrectal (Bi-National Colorectal Cancer Audit) entre 2007-2016 (datos BCCA) se analizaron para validar el comportamiento del modelo. Se desarrollaron modelos recalibrados basados en los modelos de riesgo ACPGBI que fueron aplicados y validados en un conjunto de datos multi-institucionales de pacientes australianos. La mortalidad observada y estimada (tasa 0/E) a 30 días se calculó en los modelos ACPGBI original y revisados usando el test de Hosmer-Lemeshow y los análisis de la curva de las características operador-receptor (ROC) para evaluar la calibración y discriminación de los modelos. RESULTADOS: De un total de 18,752 pacientes observados durante el periodo de estudio, se analizaron 6.727 (datos CRC) y 3.814 (datos BCCA). La mortalidad en los pacientes del grupo de datos CRC fue del 1,1% y en los del grupo de datos BCCA del 3,5%. Para el grupo de datos CRC, los modelos ACPGBI sobreestimaron significativamente la mortalidad a los 30 días, tanto en el modelo original como en el modelo revisado (O/E 0,17 y 0,21). La capacidad de los modelos para predecir correctamente el riesgo de mortalidad también fue limitada (test de Hosmer-Lemeshow 23,1 y 22.9); sin embargo, el área bajo la curva ROC de ambos modelos fue de 0,88 (i.c. del 95% 0,85-0,92) con una buena capacidad discriminatoria para clasificar a los pacientes que fallecían durante los primeros 30 días tras la cirugía. El modelo original ACPGBI recalibrado presentó un buen comportamiento para la predicción de riesgo (tasa O/E 1,06), pero no fue así en el caso del modelo revisado ACPGBI recalibrado (tasa O/E 0,99). En la validación externa con los datos BCCA, los modelos recalibrados subestimaron el riesgo de mortalidad a los 30 días (tasa O/E 3,06 y 2,98), mientras que los modelos ACPGBI original y revisado sobreestimaron el riesgo (tasa O/E 0,48 y 0,69, respectivamente). Todos los modelos mostraron una buena discriminación en las curvas ROC. CONCLUSIÓN: Los modelos ACPGBI original y revisado sobreestimaron el riesgo de mortalidad a los 30 días. Se desarrolló un nuevo modelo, denominado modelo ACPGBI calibrado australiano o modelo ACACPGBI, cuya utilidad en la práctica clínica debe ser evaluada.

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.

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.

Impaired renal function due to raised intraabdominal pressure.

A 19-year-old male developed renal failure after a laparotomy for liver trauma (urinary output of 30 ml/h, plasma creatinine 220 mumol/l). Surgical decompression of the abdomen was performed without any attempt at correcting the underlying pathology. This reduced the intraabdominal pressure (IAP) from 40 to 24 cm H2O and resulted in a massive diuresis (530 ml/h). Twenty-four hours later the plasma creatinine peaked at 280 mumol/l and then returned to within the normal range. This case report confirms that there is a direct relationship between IAP and renal function.

Surgery on trial: an account of clinical trials evaluating operations.

BACKGROUND: The objective of this study was to review published clinical trials to determine the level of compliance with issues relevant to operations. METHODS: We evaluated 10 methodologic criteria in 186 trials that were published in 10 prestigious journals between January 1986 and December 1995. RESULTS: One quarter of the trials failed to provide a clear account of the operative technique, 34% of the trials did not adequately detail the adverse events that occurred after operation, and 40% of the trials neglected to declare the nature and success of the follow-up of patients after the operation. Only 35% of the trials indicated that there was an attempt to standardize either the surgical procedure or perioperative care. In addition, less than 20% of the trials declared a method for assessing compliance with the surgical protocol or commented on the use of resources during the perioperative period. CONCLUSIONS: Greater attention needs to be paid to the specific issues that arise when operations are evaluated in clinical trials.

The prevention of wound infection in patients undergoing colorectal surgery.

Colorectal operations are, at best, clean-contaminated procedures, and at times there is gross contamination of both the peritoneal cavity and the surfaces of the surgical wound. In addition, the diseases of the large bowel that require surgery tend to afflict elderly patients. Collectively, the combination of an unclean environment, major surgery and debilitated patients creates a situation that is associated with a very high incidence of wound infection. This review documents the considerable support from clinical trials and meta-analyses that exists for the prophylactic use of a single dose of a suitable parenteral antimicrobial agent. In addition, although the evidence is less clear cut, it does not appear that the use of mechanical bowel preparations reduces the incidence of wound infections after colorectal surgery.

The influence of a colorectal service on the outcome of patients with colorectal cancer.

OBJECTIVE: To perform a prospective audit of outcomes and survival of all patients presenting to a colorectal service with colorectal cancer, and to compare these results with an historical control group. PATIENTS AND METHODS: At a community based teaching hospital, a prospective audit of outcomes and survival of patients with colorectal cancer was compared with a historical control. The study included all patients referred to a colorectal service with colorectal cancer from 1996 to 2000 (5-year period). The control group was a retrospective review of patients presenting to the same hospital with colorectal cancer from 1989 to 1994 (6-year period). A Kaplan-Meier survival analysis compared the overall survival (all-cause mortality) between the two groups. RESULTS: When comparing the study periods 1989-95 (n = 477) to 1996-2000 (n = 323), there has been a significant reduction in postoperative stay (16.2 vs 8.0 days, P < 0.05), and a reduction in postoperative mortality (4.5%vs 2.7%, n.s.). There was a significant increase in the overall 2 years survival for patients with colorectal cancer (62% to 71%, P < 0.01). There was also a significant increase in the overall 2 years survival of patients with rectal cancer (66% to 74%, P < 0.01), patients with ACPS C colon cancers (64% to 83%, P < 0.05), and ACPS C rectal cancers (74% to 85%, P < 0.01). CONCLUSIONS: There have been significant gains in the survival of patients presenting to a community based teaching hospital with colorectal cancer. These improvements have been most notable in patients with nodal metastases at the time of diagnosis.

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.

Effects of glutamine infusion on colonic anastomotic strength in the rat.

Glutamine is one of the primary respiratory fuels of the colon. However, it is not included in commercial preparations of parenteral nutrients because of its short shelf life. It has been suggested that colonic atrophy induced by conventional parenteral nutrition can be reversed by the intravenous infusion of fresh solutions of glutamine. This study evaluated the hypothesis that glutamine-enriched parenteral nutrition would enhance the strength of a standard colonic anastomosis in undernourished rats. After surgery, the rats were randomized to receive 6 days of postoperative support with either rat chow, conventional parenteral nutrition, or parenteral nutrition containing 1.2% glutamine. Measurement of colonic bursting tension failed to demonstrate any significant differences between the groups under study. In conclusion, the administration of 1.2% glutamine-enriched parenteral nutrition failed to influence the healing of colonic anastomoses in undernourished rats.

Investigating chronic, bright red, rectal bleeding.

BACKGROUND: Chronic, bright red, rectal bleeding is a common symptom in our community and the aetiology is frequently benign anal disease. The aim of the present study was to determine the efficacy of performing a flexible sigmoidoscopy on patients with chronic, bright red, rectal bleeding who are at low risk for colorectal neoplasia and who, on rigid sigmoidoscopy, are found to have an identifiable anal cause (e.g. haemorrhoids, fissure) for their bleeding. METHODS: A prospective study was conducted on patients presenting with chronic, bright red, rectal bleeding. Patients were considered at low risk for colorectal neoplasia if they fulfilled the following criteria: (i) less than 55 years of age; (ii) no past or family history of colorectal neoplasia or inflammatory bowel disease; (iii) no symptoms of altered bowel habit or abdominal pain; and (iv) a source of bleeding identified (e.g. haemorrhoids, fissure) on rigid sigmoidoscopy. All patients underwent a flexible sigmoidoscopy. RESULTS: Eighty-two patients were entered into the trial, mean age 39 +/- 9 years (range: 22-55 years), and the ratio of men:women was 1.8:1. The anal cause of bleeding was haemorrhoids in 96%, and anal fissure in 4%. At flexible sigmoidoscopy, five patients were found to have adenomatous polyps. Rigid sigmoidoscopy missed diminutive neoplastic lesions in 6% of patients. CONCLUSIONS: Flexible sigmoidoscopy results in a low yield of colorectal neoplasia in patients presenting with chronic, bright red, rectal bleeding who are at low risk for colorectal neoplasia and who have an identifiable anal cause for their bleeding.

Bowel cancer. Positive expectations for improvements in outcomes.

BACKGROUND: Colorectal cancer continues to be a major cause of mortality and morbidity in people over 50 years of age in the Western world. Age standardised incidence and mortality rates are high in Australia and too many patients with colorectal cancers are first diagnosed with advanced stage disease. OBJECTIVE: The aim of this overview of colorectal cancer is to present the clinical epidemiology of colorectal cancer in Australia, review screening strategies and demonstrate the benefits of early diagnosis. DISCUSSION: While little change has been noted in the cure rate within Australia during the past two decades, there are now promising signs that more colorectal cancers are being detected in the early stage due to greater community awareness of the disease. The movement to establish an effective screening program for colorectal cancer will further add to the ability to detect colorectal cancers at the early stages. These developments, coupled with improvements in surgical technique and adjuvant therapy, will provide real scope to improve treatment, survival and quality of life outcomes.

Meat consumption and cooking practices and the risk of colorectal cancer.

BACKGROUND/OBJECTIVES: The association between meat consumption and the risk of colorectal cancer (CRC) has been controversial. One of the difficulties in determining this association has been measurement of different attributes of meat consumption, including cooking methods and level of doneness. SUBJECTS/METHODS: We investigated the association between meat consumption and cooking practices and the risk of CRC in a population-based case-control study in the Western Australian Bowel Health Study. From July 2005 to February 2007, 567 incident CRC cases and 713 controls, who were frequency matched to cases for age- and sex, completed questionnaires on lifestyle and meat consumption. Estimated odds ratios (ORs) comparing meat consumption quartile groups were obtained from multivariate logistic regression models. RESULTS: The amount of red baked meat consumed had a statistically significant inverse trend of association with CRC (Q4 OR=0.73 95% confidence interval 0.53-1.01). When frequency was multiplied by serving size and by doneness, the association remained protective but was no longer statistically significant. The protective trends for red pan-fried meat were also borderline statistically significant. There were no other statistically significant or meaningful associations with any of the types of meat cooked by any method and the risk of CRC. CONCLUSIONS: Our data do not support the hypothesis that meat consumption is a risk factor for CRC.