Competing risks analysis of the association between perioperative blood transfusion and long-term outcomes after resection of colorectal cancer.

AIM: Despite numerous reports over three decades, the association between perioperative blood transfusion and long-term outcomes after resection of colorectal cancer remains controversial. This cohort study used competing risks statistical methods to examine the association between transfusion and recurrence and colorectal cancer-specific death after potentially curative and noncurative resection. METHOD: A hospital database provided prospectively recorded clinical, operative and follow-up information. All surviving patients were followed for at least 5 years. Data were analysed by multivariable competing risks regression. RESULTS: From 2575 patients in the period 1995-2010 inclusive, after exclusions, 2334 remained for analysis. Among 1941 who had a potentially curative resection and 393 who had a noncurative resection the transfusion rates were 24.9% and 33.6%, respectively. After potentially curative resection there was no significant bivariate association between transfusion and recurrence (HR 0.93, CI 0.74-1.16, P = 0.499) or between transfusion and colorectal cancer-specific death (HR 1.04, CI 0.82-1.33, P = 0.753). After noncurative resection there was no significant association between transfusion and cancer-specific death (HR 0.93, CI 0.73-1.19, P = 0.560). Multivariable models showed no material effect of potential confounder variables on these results. CONCLUSION: The competing risks findings in this study showed no significant association between perioperative transfusion and recurrence or colorectal cancer-specific death.

Recurrence and cancer-specific death after adjuvant chemotherapy for Stage III colon cancer.

AIM: The recommended standard of care for patients after resection of Stage III colon cancer is adjuvant 5-fluorouracil based chemotherapy - FOLFOX (fluorouracil, leucovorin with oxaliplatin) - or CAPOX (capecitabine, oxaliplatin). This may be modified in older patients or depending on comorbidity. This has been challenged recently as the apparent benefit of adjuvant chemotherapy may arise from improvements in surgery or preoperative imaging or pathology staging. This study compares recurrence and colon-cancer-specific death between patients who received postoperative adjuvant chemotherapy and those who did not. METHOD: Prospectively recorded data from 363 consecutive patients who had a resection for Stage III colonic adenocarcinoma between 1995 and 2010 inclusive were analysed. Surviving patients were followed for at least 5 years. The suitability of patients for chemotherapy was discussed routinely at multidisciplinary team meetings. The incidence of recurrence and colon-cancer-specific death was evaluated by competing risk methods. RESULTS: After adjustment for the competing risk of non-colorectal cancer death, there was no significant difference in recurrence between the 204 patients who received chemotherapy and the 159 who did not [hazard ratio (HR) 0.94, 95% CI 0.66-1.32, P = 0.700) and no significant difference in colon-cancer-specific death (HR 0.73, 95% CI 0.50-1.04, P = 0.084; HR 0.88, 95% CI 0.57-1.36, P = 0.577 after adjustment for relevant covariates). CONCLUSION: These findings question the routine use of chemotherapy after complete mesocolic excision for Stage III colon cancer. Recurrence and cancer-specific death, assessed by competing risk methods, should be the standard outcomes for evaluating the effectiveness of adjuvant chemotherapy after potentially curative resection.

Competing risks analysis of microsatellite instability as a prognostic factor in colorectal cancer.

BACKGROUND: Despite an extensive literature suggesting that high microsatellite instability (MSI-H) enhances survival and protects against recurrence after colorectal cancer resection, such effects remain controversial as many studies show only a weak bivariate association or no multivariable association with outcome. This study examined the relationship between MSI status and colorectal cancer outcomes with adjustment for death from other causes as a competing risk. METHODS: A hospital database of patients following colorectal cancer resection was interrogated for clinical, operative, pathology, adjuvant therapy and follow-up information. MSI-H status was determined by immunohistochemistry for mismatch repair protein deficiency. The cumulative incidence of recurrence and colorectal cancer-specific death was evaluated by competing risks methods. RESULTS: Among 1009 patients who had a resection between August 2002 and December 2008, and were followed to at least December 2013, there were 114 (11·3 per cent) with MSI-H (72·8 per cent aged at least 70 years; 63·2 per cent women). After potentially curative resection, with adjustment for non-colorectal cancer death as a competing risk and adjustment for 22 clinical, operative and pathological variables, there was no association between MSI-H and recurrence (hazard ratio (HR) 0·81, 95 per cent c.i. 0·42 to 1·57) or colorectal cancer-specific death (HR 0·73, 0·39 to 1·35) in this patient population. For palliative resections, there was no association between MSI-H and colorectal cancer-specific death (HR 0·65, 0·21 to 2·04). MSI-H was associated with non-colorectal cancer death after both curative (HR 1·55, 1·04 to 2·30) and palliative (HR 3·80, 1·32 to 11·00) resections. CONCLUSION: Microsatellite instability status was not an independent prognostic variable in these patients.

Long-term results following an anatomically based surgical technique for resection of colon cancer: a comparison with results from complete mesocolic excision.

AIM: Complete mesocolic excision (CME) has been advocated as likely to improve the long-term oncological outcome of colon cancer resection, although there is a paucity of long-term results in the literature. The aim of this study was to supplement our previously published results on colon cancer resection based on a standardized technique of precise dissection along anatomical planes with high vascular ligation and to compare our long-term results with those of recent European studies of CME. METHOD: Data were drawn from a prospective hospital registry of consecutive resections for colon cancer between 1996 and 2007, including follow-up to the end of 2012. The principal outcomes from potentially curative resections were 5-year Kaplan-Meier rates of local recurrence, systemic recurrence, overall survival and cancer-specific survival. Secondary outcomes for all resections were postoperative complications, number of lymph nodes retrieved and R0 status. RESULTS: For 779 potentially curative resections the local recurrence rate was 2.1% (95% CI 1.3-3.4), the systemic recurrence rate was 10.2% (95% CI 8.1-12.7), the 5-year overall survival rate was 76.2% (95% CI 73.0-79.0) and the cancer-specific survival rate was 89.8% (95% CI 87.3-91.9). For all 905 resections, rates of 14 surgical complications were low and not dissimilar to those in a comparable study. The median lymph node count was 15 (range 0-113). R0 status was confirmed in 883/905 patients (97.6%; 95% CI 96.4-98.5). CONCLUSION: For colon cancer, meticulous dissection along anatomical planes together with high vascular ligation results in few complications, a high R0 rate, low recurrence and high survival.

Impact of obesity on complications after resection for rectal cancer.

AIM: The prevalence of obesity in Australia is high and increasing, with associated serious negative effects on health. The technical complexity of rectal cancer surgery is exacerbated in obese patients, which may compromise outcomes. The aim of this study was to examine the association between obesity and complications after resection of rectal cancer. METHOD: Data were drawn from a comprehensive prospective registry of rectal cancer resections performed from 2007 to 2011 by members of the colorectal surgical unit in a tertiary referral hospital and in a single private hospital with which they were affiliated. RESULTS: Of 255 patients who had a resection for rectal cancer during the study period, 95 (37%) were classified as obese on the basis of a body mass index (BMI) ≥ 30 kg/m(2) . Among 24 postoperative complications the only significant differences for obese patients were higher rates of wound complications (16% vs 8%, P = 0.038), small bowel obstruction (4% vs 0%, P = 0.019) and prolonged ileus (18% vs 8%, P = 0.011). The total number of complications did not differ significantly between obese and nonobese patients, and there was no difference between obese and nonobese patients in the rates of reoperation and postoperative death. CONCLUSION: This study did not support an association between obesity and early postoperative complications after resection of rectal cancer.

A comparison of published rates of resection margin involvement and intra-operative perforation between standard and 'cylindrical' abdominoperineal excision for low rectal cancer.

AIM: The study aimed to compare recent reports on standard and alternative methods of abdominoperineal excision for low rectal cancer regarding the rates of circumferential resection margin involvement and intra-operative bowel perforation. METHOD: Data on rates of margin involvement and perforation were obtained from eight recently published reports and also from a prospective registry of resections at Concord Hospital. Rates of these outcomes and their 95% confidence intervals were evaluated. RESULTS: There was no evidence that extralevator abdominoperineal excision yielded significantly lower rates of resection margin involvement or intra-operative bowel perforation compared with standard abdominoperineal excision in six independent hospital- and population-based patient series. Abdominosacral resection of the rectum, on the other hand, did show significantly lower rates of these endpoints, albeit in selected patients. CONCLUSION: The role of extralevator abdominoperineal excision and abdominosacral resection of the rectum should be investigated further in randomized controlled trials.

Overexpression of protein S100A4 is independently associated with overall survival in stage C colonic cancer but only in cytoplasm at the advancing tumour front.

PURPOSE: S100A4, a multifunctional protein, has been linked to the invasive growth and metastases of several human cancers. This study investigated the association between S100A4 and overall survival and other clinicopathological features in patients with stage C colonic cancer. METHODS: Clinical and pathological data were obtained from a prospective hospital registry of 409 patients who had a resection for stage C colonic cancer. Tissue microarrays for immunohistochemistry were constructed from archived tissue. S100A4 staining intensity and percentage of stained cells were assessed in nuclei and cytoplasm for both the central part of the tumour and at the advancing front. Overall survival was analysed by the Kaplan-Meier method and Cox regression. RESULTS: Only a high percentage of cells with S100A4 cytoplasmic staining in frontal tissue was associated with poor survival (hazard ratio, 1.6; 95 % CI 1.1-2.2; p = 0.008) after adjustment for other prognostic variables. There was no association between frontal cytoplasmic S100A4 expression and any of 13 other clinicopathological variables. CONCLUSIONS: High expression of S100A4 in cytoplasm at the advancing front of stage C colonic tumours indicates a poor prognosis. Whether S100A4 can predict response to adjuvant chemotherapy remains to be investigated in a randomised clinical trial.

Magnetic resonance imaging cannot predict histological tumour involvement of a circumferential surgical margin in rectal cancer.

AIM: Several recent studies have attempted to evaluate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting the likelihood of tumour involvement of the postoperative circumferential resection margin (CRM) in rectal cancer with the intention of selecting patients who might benefit from neoadjuvant therapy and as a guide to surgery. The aim of this study was to assess whether such studies can provide a valid answer as to whether preoperative MRI can accurately predict CRM involvement by tumour. METHOD: The study design and methodology of studies on this topic were critically examined. RESULTS: Features identified as affecting the efficacy of these studies were: representativeness of patients, definition of the margin assessed by MRI and by histology, lack of blinding of surgeons and pathologists to MRI results, effect of neoadjuvant treatment, and number of patients studied. CONCLUSION: Because of methodological inadequacies in studies completed to date, there is insufficient evidence of the ability of a positive MRI result to predict an involved CRM. Although MRI may be able to identify a tumour that has extended to the mesorectal fascia and/or intersphincteric plane, logically, it cannot indicate where the surgical boundary of the resection will ultimately lie, and therefore cannot validly predict an involved CRM and should not be relied upon for this purpose.

Relative effects of direct spread, lymph node metastasis and venous invasion in relation to blood borne distant metastasis present at the time of resection of colorectal cancer.

Conventionally, lymphatic spread is regarded as the principal mechanism by which haematogenous metastasis occurs in colorectal cancer. The aim of this cross sectional study was to determine the relative strengths of direct tumour spread, the presence of lymph node metastasis and histologically demonstrated venous invasion as drivers of haematogenous metastasis diagnosed at the time of resection of colorectal cancer. The data were drawn from a hospital database of consecutive bowel cancer resections between 1995 and 2017 inclusive. The presence of haematogenous metastasis was determined at the time of surgery by imaging or other investigations or operative findings. Where possible, histological confirmation was obtained. Specimen dissection and reporting followed a standardised procedure. Tumour staging was according to the 7th edition of the UICC/AJCC pTNM system. Analysis was by multivariable logistic regression. After exclusions 3133 patients remained, among whom 380 (12.1%) had one or more haematogenous metastases. In bivariate analyses, the frequency of haematogenous metastasis was directly associated with increasing T status (p<0.001), increasing N status (p<0.001) and increasing extent of venous invasion (p<0.001) and with some other patient and tumour features. In a multivariable model, after adjustment for other features, associations with the occurrence of haematogenous metastasis were as follows: T3 odds ratio (OR) 4.41 (95% confidence interval 2.40-8.10), p<0.001; T4a OR 6.29 (3.27-12.10), p<0.001; T4b OR 5.50 (2.71-11.15), p<0.001; N1 OR 3.39 (2.47-4.64), p<0.001; N2 OR 4.59 (3.21-6.54), p<0.001; mural venous invasion OR 2.18 (1.14-4.16), p=0.018; extramural venous invasion OR 2.91 (2.21-3.83), p<0.001. Only three other features had significant, though weak effects in the model. These results led to the conclusion that venous invasion, demonstrated histologically and also inferred independently by the extent of direct tumour spread, made a greater contribution to the occurrence of haematogenous metastasis than did spread through lymphatics. Our approach and findings may have implications for other cancer sites apart from colorectal cancer.

Anastomotic leakage after resection of colorectal cancer generates prodigious use of hospital resources.

OBJECTIVE: The aim of this study was to determine the demand for hospital resources generated by anastomotic leakage, including surgical, medical, imaging, pathology, and other allied health consultations or services and length of postoperative hospital stay. METHOD: Data were obtained from a comprehensive, prospective hospital registry of all resections for colorectal cancer from January 1995 to December 2004 and from retrospective review of patients' notes. RESULTS: Forty-one patients with a leak spent 92 days in intensive care, required 129 days of total parenteral nutrition, 69 days of enteric feeding and 41 days on ventilation and had a median postoperative hospital stay of 28 days (range 11-104). These patients required 24 re-operations and 2273 separate medical consultations or allied services. CONCLUSION: Anastomotic leakage generates a very considerable demand for hospital resources and diverts these resources from the hospital population at large.

Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer.

The mutated in colorectal cancer (MCC) gene is in close linkage with the adenomatous polyposis coli (APC) gene on chromosome 5, in a region of frequent loss of heterozygosity in colorectal cancer. The role of MCC in carcinogenesis, however, has not been extensively analysed, and functional studies are emerging, which implicate it as a candidate tumor suppressor gene. The aim of this study was to examine loss of MCC expression due to promoter hypermethylation and its clinicopathologic significance in colorectal cancer. Correspondence of MCC methylation with gene silencing was demonstrated using bisulfite sequencing, reverse transcription-polymerase chain reaction and Western blotting. MCC methylation was detected in 45-52% of 187 primary colorectal cancers. There was a striking association with CDKN2A methylation (P<0.0001), the CpG island methylator phenotype (P<0.0001) and the BRAF V600E mutation (P<0.0001). MCC methylation was also more common (P=0.0084) in serrated polyps than in adenomas. In contrast, there was no association with APC methylation or KRAS mutations. This study demonstrates for the first time that MCC methylation is a frequent change during colorectal carcinogenesis. Furthermore, MCC methylation is significantly associated with a distinct spectrum of precursor lesions, which are suggested to give rise to cancers via the serrated neoplasia pathway.

Immunodiagnosis of colorectal cancer: clinical evaluation of Tennessee antigen (Tenagen).

Blood samples from 172 consecutive patients undergoing complete colon investigations to exclude colorectal cancer (CC) were examined for levels of Tennessee antigen, i.e., Tenagen (Tg), and carcinoembryonic antigen. Patients included 48 with CC, 34 with adenomatous polyps, 14 with colitis, and 76 with no organic mucosal disease. All patients were investigated by the one clinical and histopathology department. Laboratory estimations were performed blindly. Although there were some statistically significant differences among average values, the degree of overlap among the groups of patients precludes the practical application of Tg in the diagnosis of CC.

The psychological effects of being a prisoner of war: forty years after release.

Forty years after the end of World War II, the authors compared a random sample of former Japanese-held Australian prisoners of war (POWs) with a group of non-POW combatants of the same era. The POWs were significantly more depressed than were the control subjects, but the two groups did not differ in prevalence of anxiety symptoms or alcohol problems. Apart from a higher rate of postwar duodenal ulcer in the POWs, the two groups had similar degrees of medical morbidity.

Are malnutrition and stress risk factors for accelerated cognitive decline? A prisoner of war study.

We set out to test the hypothesis that severe malnutrition and stress experienced by prisoners of war (POWs) are associated with cognitive deficits later in life. We assessed 101 former Australian POWs of the Japanese and 108 veteran control subjects using a battery of neuropsychological tests, a depression scale, a clinical examination for dementia, and CT. We divided the POWs into high weight loss (>35%) and low weight loss groups (<35%). We found no significant differences in cognitive performance between the POWs and control subjects or between high and low weight loss groups on any of the tests or in the prevalence of dementia. Scores on the depression scale showed that the former POWs had more depressive symptoms than the control subjects a decade previous, but the difference had diminished over time. This study does not support the hypothesis that malnutrition is a risk factor for accelerated cognitive decline nor the theory that severe stress can lead to hippocampal neuronal loss and cognitive deficits. Cognitive deficits in earlier studies of former POWs may have been associated with concurrent depression.

Intrapleural bupivacaine in the control of postthoracotomy pain.

A randomized, double-blind trial was conducted to determine the effectiveness of intrapleural bupivacaine hydrochloride in the management of pain after thoracotomy. Thirty-three men and 7 women with a mean age of 62 years (range, 21 to 76 years) undergoing elective posterolateral thoracotomy were randomly allocated preoperatively to either a study group receiving 20 mL of 0.25% bupivacaine or a control group receiving 20 mL of 0.9% saline solution through a pleural catheter every 4 hours. Patients received supplementary doses of intramuscular papaveretum as required. Assessment of pain, somnolence, and breathing capacity was performed after the intrapleural injections at 4, 24, 48, and 72 hours postoperatively. Pain assessment, as measured by a linear analog scale, was lower in the bupivacaine group at all times, reaching significance at 4, 24, and 72 hours (p less than 0.05). The forced vital capacity and forced expiratory volume in 1 second at 6 weeks postoperatively remained significantly lower than preoperatively (p less than 0.05). The fall in forced vital capacity from this postoperative level was significantly less in the bupivacaine group at 4, 24, and 48 hours, and the fall in forced expiratory volume in 1 second was significantly less at 4 and 48 hours in the treated group. When used in conjunction with doses of parenteral narcotic, intrapleural bupivacaine gives better pain control with less respiratory depression than intermittent doses of narcotic alone.

Participation in faecal occult blood screening for colorectal cancer.

Chemical faecal occult blood testing has been proposed as a means of screening for colorectal cancer (C.C.) in populations or in identified high-risk groups. The level of public participation is a critical factor in the effectiveness of screening programmes. This study was conducted as a methodological pretest for an intended investigation of factors influencing screening participation. Faecal occult blood screening was offered to 728 employees of a teaching hospital in Sydney, New South Wales and 41% participation was obtained. Both participants and non-participants were questioned on demographic and social background factors, on their experience of C.C. in others, and on their reasons for participating or not participating. Major reasons for participation were: a general feeling of the importance of health checks and screening tests; a belief that it is important to diagnose C.C. early; and the fact that the test was simple and easy to do. Prominent self-acknowledged reasons for non-participation were indifference, procrastination, absence of previous bowel complaints, preference for one's own doctor to do such tests and inconvenience or lack of time. Those more likely to participate were: females; those of Australian or British origin; single, separated or divorced persons; those having two or more dependents and those with personal knowledge of a C.C. patient.

Alcohol consumption in a community sample of older people.

OBJECTIVE: To examine the prevalence and pattern of alcohol use among community-living elderly Australians. METHODS: A survey was conducted of randomly selected non-institutionalised people aged 75 years and older living in the inner western suburbs of Sydney. Personal interviews by trained interviewers covered background demographic information and self-reported alcohol use. RESULTS: 72% of men and 54% of women drank alcohol. The median usual daily volume of ethanol consumed by drinkers was 10 grams for men and 1.3 grams for women. However 11% of male drinkers and 6% of female drinkers consumed at defined hazardous or harmful levels. CONCLUSIONS AND IMPLICATIONS: Although a sizeable majority of these older people were either non-drinkers or very light drinkers, a small but important proportion drank in the hazardous to harmful range. Despite increasing evidence of the health benefits of alcohol consumption it remains important to be alert for potentially harmful alcohol use among older people.

Combined endoscopic laser and radiotherapy palliation of advanced rectal cancer.

BACKGROUND: In the palliative treatment of patients with advanced, inoperable rectal cancer, combined endoscopic laser and radiotherapy have been claimed to be more effective than laser therapy alone. The number of laser treatments, laser energy used, relapse rate, treatment of relapse, morbidity and survival in consecutive patients who were treated either by laser therapy alone or laser plus radiotherapy was compared. METHODS: Prospective data were analysed with regard to number of treatments, laser energy used, relapse rate, morbidity and survival for 56 consecutive patients. RESULTS: The crude relapse rate was significantly higher in the laser only group than in the laser plus radiotherapy group (58 and 15%, respectively; P = 0.002). There was no difference between the groups in the median total number of laser treatments or the mean total laser energy used. In patients experiencing a relapse, there was no difference in the median number of relapses, the number of laser treatments post-relapse or the total energy used post-relapse. Survival did not differ between the groups and there were no treatment-related deaths. CONCLUSIONS: These findings demonstrate a clear reduction in relapse after using combined laser and radiotherapy to palliate patients with advanced rectal cancer with no appreciable additional morbidity and have encouraged continuing use of this treatment.