F. T. McDermott

Cancer risk in relatives of patients with common colorectal cancer.

Screening for colorectal cancer continues to be controversial [1, 2]. The role of fecal occult blood tests is being evaluated [3-8], but definitive results are unlikely before 1995. One intervening strategy is to improve screening for people at high risk, for example, those with a family history of colorectal cancer. Secondary prevention of colorectal cancer (detection and resection of adenomas and early stage cancers to prevent fatal cancer) is already well accepted in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer (HNPCC) [9] and is somewhat accepted in ulcerative colitis [10-12]. Close relatives of patients with common (sporadic) colorectal cancer (those cancers not associated with familial adenomatous polyposis, HNPCC, or chronic inflammatory bowel disease) may have an increased risk for colorectal cancer [2], and selective screening has been suggested for these relatives [13-16]. Most of the evidence for increased risk is based on cancer mortality studies [17-19] and cancer incidence studies [20-27]. However, problems with study design have led to conflicting estimates of risk ranging from no increase [21] to 6.3-fold [22] and 8-fold [20] increases in risk for first-degree relatives. Pedigree analysis has suggested that an inherited susceptibility may be present in common colorectal cancer [28, 29], but the yield of neoplastic lesions in screened relatives has been low in most [30-32] but not all prevalence studies [15, 33]. Accordingly, we did a casecontrol family study to assess risk for colorectal cancer in relatives and to define possible markers for any increased risk. Methods The study used a matched casecontrol design [34] to compare the occurrence of cancer in relatives between patients with common colorectal cancer (case patients) and patients without cancer (control patients). Case and control patients were selected from one surgeons practice and were matched by gender, age (within 5 years and usually within 2 years), and country of birth or upbringing. Patients Case patients were selected from a series of more than 2400 patients with colorectal cancer treated between 1952 and 1985. All 576 patients alive at the time of the survey (June 1985 to May 1986) and residing in Australia were reviewed for eligibility. Detailed clinical, surgical, and pathologic information was available for every patient [35, 36]. Exclusion criteria were 1) colorectal cancer associated with ulcerative colitis, Crohn disease, familial adenomatous polyposis, or recognized HNPCC [37]; and 2) referral to the surgeon because he previously had treated a relative or spouse for colorectal cancer or adenoma. The minimum criteria for diagnosis of the HNPCC were three affected first-degree relatives with at least two relatives having colorectal cancer diagnosed before 50 years of age, or multiple primary cancers, or colorectal cancer plus another syndrome cancer [38]. Control patients were selected from patients who had surgery for nonmalignant disease during the same period and had no known history of neoplastic disease. Data Collection Questionnaires were mailed concurrently to case patients and their matched control patients. Accompanying letters made case and control patients equally aware that the study was about family history of colorectal cancer. The questionnaires covered personal information; information about first-degree relatives (parents, siblings, and children surviving to the age of 12 years), including year of birth, occurrence of colorectal cancer, age at diagnosis, occurrence of other types of cancer, age at death, and cause(s) of death when relevant; and information about second-degree relatives and spouses. Each case patient and control was contacted by telephone to review responses and to assess the degree of certainty about listed diagnoses. Care was taken to question case and control patients to the same degree. In many instances, responses were reviewed during a subsequent visit. Close relatives were encouraged to help collect information. All questionnaires were masked to prevent identification of their casecontrol status and were then assessed by an independent gastroenterologist to classify each relative as evaluable or nonevaluable according to whether information about his or her medical history was available up to the time of death or, in the case of living relatives, up to the time of completion of the questionnaire. Half-brothers and half-sisters were excluded. Many subjects were contacted again at this stage. Verification of diagnoses was sought for all reported cases of bowel cancer, other abdominal cancer, and abdominal surgery of unspecified type using hospital or physician records, Australian state cancer registries, and death registries. Colorectal cancers in relatives were classified as definite when confirmation of the diagnosis was obtained from a medical source; as probable when relatives were able to provide convincing information about the diagnosis (such as name of the surgeon and hospital as well as details about the surgical procedure) but where medical confirmation could not be obtained; and as possible when relatives were stated to have had colorectal cancer but when the evidence was less convincing. Final Selection of Patients for the Study Of the 576 patients with colorectal cancer alive at the time of the survey, 20 were excluded because cancer was associated with ulcerative colitis, Crohn disease, or familial adenomatous polyposis and 22 were excluded because of failure to complete questionnaires (15 had terminal illness, 5 refused, and 2 could not be contacted). Five potential control patients failed to complete questionnaires, and suitable replacements were recruited. Eleven case patients (and their respective control patients) were classified as ineligible and were excluded from the study; two proved to be members of families with recognized HNPCC, and the other nine had been referred to the surgeon because he previously had treated a relative or spouse for colorectal cancer. The research protocol was approved by the Ethics Review Advisory Committee at Alfred Hospital, Melbourne, Australia. Statistical Analysis Case-Control Analysis The data were first analyzed as a casecontrol study, with exposure defined by the presence of disease among (subsets of) relatives. The proportion of case patients with affected relatives was compared with the proportion of control patients, with the odds ratio and standard error calculated by standard methods using logistic regression [39]. Risk to Relatives of a Case Patient Compared with Relatives of a Control Patient A cohort analysis of disease in relatives, which takes into account the matching of casecontrol pairs and the number of relatives and allows for relatives to be dependent in their colorectal cancer status (as is the case if true familial aggregation exists for colorectal cancer), was also done [40]. For each case patient, i, let there be ni relatives of a predetermined type (for example, mother, parent, or sibling), of whom xi also have colorectal cancer. Let the matched control patient, i, have mi such relatives of whom yi have colorectal cancer. Let ti = xi + yi and Ni = ni + mi and the true odds ratio, ORi, for cancer in a relative of a case patient compared with cancer in a relative of a control patient be defined as (E[xi]E[mi yi])/(E[yi]E[ni xi]). Suppose a true common odds ratio exists; for example, ORi = OR for all i. The Mantel-Haenszel estimator is ORMH = Ri/Si, where Ri = xi(mi yi)/Ni and Si = yi(ni xi)/Ni. It is asymptotically normal, even if nonindependence exists within sets of relatives. A consistent and robust test statistic for Ho: OR = 1 is EQUATION OMITTED which has an approximate chi-square distribution with one degree of freedom, independent of the underlying true distribution for the {xi} and {yi}. Because log(ORMH) has more nearly a normal distribution than ORMH, an approximate test-based standard error, SE, for log(ORMH) was calculated by assuming (log[ORMH]/SE)2 = T. An approximate asymmetric 95% CI for ORMH is (elog[ORMH sup] 1.96SE, elog[ORMH sup] + 1.96SE). The same analysis was applied to subsets of casecontrol pairs selected according to a predetermined characteristic of the case patients (for example, age of onset less than 45 years). Analysis of Cumulative Incidence among Relatives of (Subsets of) Case and Control Patients Parents, siblings, and children were pooled. A Kaplan-Meier survival curve, S(t), was calculated for time free of colorectal cancer, t, based on age at diagnosis in relatives [41]. (Age at death was treated as a censoring time.) Cumulative incidence to age, a, was then defined as 1 S(a) and was plotted for 10-year increments in age. Comparison of survival, and therefore of cumulative incidence, between groups was evaluated by the two-tailed generalized Wilcoxon test according to Gehan [42]. Results Characteristics of Case and Control Patients The study group comprised 523 cases (250 men, 273 women; mean age, 71.2 years [SD, 10.3 years]), and 523 gender-matched control patients (mean age, 69.9 years [SD, 10.2 years]). Of the case patients, 426 (81%) were born in Australia. Thirteen (2.5%) case patients had been treated for synchronous cancers of the large bowel and 30 (5.7%) for metachronous cancers. The primary lesions were in the proximal colon (proximal to the splenic flexure) in 83 case patients, in the distal colon in 148, and in the rectum or at the rectosigmoid junction in 338. Colorectal cancer was diagnosed before age 45 years in 82 (16%) case patients, between ages 45 and 54 years in 147 (28%) patients, between ages 55 and 64 years in 173 (33%), and at 65 years in 121 (23%). A diagnosis of colorectal cancer was made at least 5 years before the survey in 436 (83%) case patients. Characteristics of Relatives The case and control patients reported a total of 7530 first-degree relatives, of whom all but 37 were evaluable. This left 3857 relati

Tumor recurrence in the abdominal wall scar tissue after large-bowel cancer surgery

In the Melbourne (Monash) series reviewed here the development of apparently isolated incisional scar tissue recurrences after curative excisions for large-bowel cancer proved unusual. Eleven patients with such a recurrence all died of disseminated disease within four years, and most within 12 months, of its development. This suggests that an incisional recurrence is a manifestation of disseminated cancer rather than isolated implantation.

Lung recurrence after curative surgery for colorectal cancer

A total of 1578 patients were treated with potentially curative surgical resection for colon and rectal cancer by one surgeon from 1950 to 1982. Follow-up revealed that 117 (11,5 percent) of 1013 patients with rectal carcinoma eventually presented with clinical evidence of pulmonary recurrence, with or without evidence of spread elsewhere; the corresponding figures for the colon were 20 (3.5 percent) of 565 (P<0.001). An analysis of the times to recurrence revealed that half of the lung recurrence, were clinically obvious within 32 months for rectal tumors and 34 months for colonic, compared to 22 and 21 months, respectively, for liver recurrences, excluding those with other distant metastases. The slower recurrence rate and the longer survival in patients with recurrences in the lung compared to the liver were statistically significant only for rectal primaties (P<0.02 andP=0.001, respectively). Sixteen patients underwent surgeery with curative intention for lung recurrences; four of these remain alive at two, six, 11, and 15 years, and one patient was free of recurrence when he died from other causes 15 months after surgery. The conditional probability survival rate for the 16 patients was 38±13 percent at five years after recurrence operation.

Evaluation of the medical management and preventability of death in 137 road traffic fatalities in Victoria, Australia: An overview

OBJECTIVES In 1992 a multidisciplinary committee was established to identify problems in the management of road fatalities in Victoria, Australia, to assess their contribution to death, and to identify preventable deaths (preventable: survival probability more than 75%; potentially preventable: 25 to 75%). METHODS For 1992 and 1993 all 137 fatality cases surviving until arrival of ambulance services were evaluated by analysis and discussion of their complete prehospital, hospital, and autopsy records. RESULTS 1,012 problems were identified in 509 admissions to the various areas of care. Six hundred eighty-five (68%) were management errors and 217 (21%) were system inadequacies. Technique errors (45 (4%)), diagnosis delays (25 (2%)), and diagnosis errors (40 (4%)) were less frequent. The emergency department (ED) accounted for 537 (53%) problems, followed by prehospital (200 (20%)) and intensive care unit (118 (12%)). Four hundred seventy (46%) problems were assessed as contributing to death. Two hundred twenty-eight (49%) occurred in the ED, 90 (19%) were prehospital problems, and 63 (13%) occurred in the intensive care unit. Management errors comprised 326 (69%) problems contributing to death, and system inadequacies 88 (19%). Resuscitation problems accounted for 82 (49%) of the 167 ED management errors contributing to death. Eighty-five (62%) deaths were assessed as nonpreventable, 7 (5%) as preventable, and 45 (33%) as potentially preventable. CONCLUSION Organizational and educational counter measures are required to reduce the high frequency of problems in emergency services and clinical management.

Adaptation of the gastric mucosa to repeated administration of aspirin in the rat

The effects of single and repeated doses of aspirin on the gastric mucosa of the rat were compared to determine whether the mucosal response alters after repeated aspirin. Aspirin (120 mg/kg) was administered by esophageal intubation either as a single dose or daily for 3, 14, 28 and 56 days. Mucosal damage was present in all treated rats but, on histologic quantitation, there was a highly significant reduction in the numbers of acute erosions in the groups receiving repeated daily aspirin. This apparent adaptation did not persist when aspirin administration was interrupted for 3 days. Repeated aspirin administration was not associated with any reduction in aspirin absorption or excretion, nor was there any significant change in hydrochloric acid or pepsin secretion. The investigation has shown an adaptation to repeated aspirin in the rat which appears to result from an alteration in the gastric mucosa. The precise mechanism of the adaptation remains uncertain.The effects of single and repeated doses of aspirin on the gastric mucosa of the rat were compared to determine whether the mucosal response alters after repeated aspirin. Aspirin (120 mg/kg) was administered by esophageal intubation either as a single dose or daily for 3, 14, 28 and 56 days. Mucosal damage was present in all treated rats but, on histologic quantitation, there was a highly significant reduction in the numbers of acute erosions in the groups receiving repeated daily aspirin. This apparent adaptation did not persist when aspirin administration was interrupted for 3 days. Repeated aspirin administration was not associated with any reduction in aspirin absorption or excretion, nor was there any significant change in hydrochloric acid or pepsin secretion. The investigation has shown an adaptation to repeated aspirin in the rat which appears to result from an alteration in the gastric mucosa. The precise mechanism of the adaptation remains uncertain.

I. Carcinoma of the rectum and rectosigmoid: Cancer specific long-term survival. A series of 1061 cases treated by one surgeon

The long‐term cancer specific survival based on individual follow‐up and analysis of prospectively collected data from 1061 patients undergoing resection for carcinoma of the rectum is presented. All patients were operated on and managed by one surgeon. Survival data for 978 cases were analyzed according to the methods of Kaplan and Meier,9 and Gehan.6 Results have been presented as cancer specific survival times in months and as percentage survivor rates at five‐year intervals. The median overall cancer specific survival time was 96 months. Five, ten, 15, and 20‐year survival rates were 56, 49, 47, and 46%, respectively. After a potentially curative resection of the tumor, the corresponding percentages were 69, 60, 57, and 56%. Age and sex were not significant prognostic factors. A death rate from recurrent cancer of nil was seen after 15.4 years. At this point, the cancer specific survival rates were 77% for patients in Stage A, 59% in Stage B, 37% in Stage C, and 9% for patients with tumors invading adjacent organs (D1), while no patient with macroscopic metastases to distant organs (Stage D2) survived beyond four and a half years (median, 11 months).

Palliative operative management in rectal carcinoma

The results of palliative operative management of 338 patients with rectal carcinoma managed by one of the authors are presented. Postoperative mortality was higher for patients undergoing palliative resection (11.7 per cent) than colostomy bypass (5.3 per cent) or diagnostic laparatomy (6.8 per cent). Cancer specific survival following palliative resection was significantly (P<0.001) longer than that following colostomy bypass or diagnostic laparotomy for tumor Stages D1 (local visceral involvement) and D2 (distant metastases). However, in patients with liver or peritoneal metastases alone, cancer specific survival did not differ significantly after the operations of resection or colostomy bypass. The failure to demonstrate improved survival after resection of the primary tumor in these latter two groups with distant metastases indicates the dominant role of volume of tumor tissue present in these situations. The results suggest that longer survival following pallitative resection reflects a bias of patient selection towards more favorable cases.

The risk of rectal carcinoma following colectomy in ulcerative colitis.

In a series of 1439 patients with ulcerative colitis, managed by one of the authors (E.S.R.H.), surgical resection was performed on 374 patients (26 per cent): colectomy, 273 (subtotal colectomy and mucous fistula, 172, colectomy and primary ileorectal anastomosis, 101); proctocolectomy, 61; and miscellaneous procedures, 40. Of the 172 patients undergoing subtotal colectomy and mucous fistula, 93 (54 per cent) subsequently required rectal excision, 33 (19 per cent) had ileorectal anastomosis performed as a second procedure, and in 46 (27 per cent) subsequently developed as a mucous fistula. Two hundred seventy-three patients were at risk for the development of rectal, cancer after subtotal colectomy; ten patients (3.6 per cent) subsequently developed rectal cancer. The cumulative probability of developing rectal cancer after subtotal colectomy reached 17 per cent at 27 years from disease onset. The tumors were more advanced in stage and of higher grade malignancy than those of a parallel general series of patients with rectal cancer uncomplicated by inflammatory bowel disease. Colectomy and ileorectal anastomosis has been successful for most patients. However, the experience of this series highlights the danger of carcinomatous transformation in the retained rectum, the requirement for regular long-term follow-up, the need for markers of precancerous change, and the value, where relevant, of prophylactic proctectomy.

Gender differences in outcome in patients with hypotension and severe traumatic brain injury

BACKGROUND Animal studies have identified hormonal influences on responses to injury and recovery, creating a potential gender effect on outcome. Progesterone and oestrogen are thought to afford protection in the immediate post-injury period, suggesting females have an advantage, although there has been limited evidence of this in human outcome studies. METHODS This study examined the influence of gender on outcome in 229 adults (151 males), aged >17 years, with severe blunt head trauma, initial GCS <9 and hypotension, recruited into a randomised controlled trial of pre-hospital hypertonic saline resuscitation versus conventional fluid management. Outcome was measured by survival and Glasgow Outcome Scale-Extended version (GOS-E) scores at 6 months post-injury. RESULTS Females recruited into the study had a higher mean age. Females were more likely to be injured as passengers and pedestrians and males as drivers or motorcyclists. There were no gender differences in GCS or injury severity scores, ICP, cerebral perfusion pressure, gas exchange (PaO2/FiO2 ratio), or duration of mechanical ventilation. After controlling for GCS, age and cause of injury, females had a lower rate of survival. They also showed a lower rate of good outcome (GOS-E score >4) at 6 months, but this appeared to reflect the lower rate of initial survival. Those females surviving had similar outcomes to males. CONCLUSIONS The study provides no evidence that females fare better than males following severe TBI, suggesting rather that females may fare worse.

Influence of achlorhydria on aspirin-induced occult gastrointestinal blood loss: studies in Addisonian pernicious anaemia.

The effect of aspirin (acetylsalicylic acid) ingestion on occult gastrointestinal blood loss has been studied in patients with treated Addisonian pernicious anaemia and proved achlorhydria and in control patients able to secrete hydrochloric acid. A highly significant increase in gastrointestinal blood loss (1·9 ml./day of treatment) occurred with aspirin ingestion in the achlorhydric patients. The control group had a significantly greater increase in blood loss (4·29 ml./day of treatment). Thus aspirin can produce occult gastrointestinal blood loss by a mechanism unrelated to hydrochloric acid. Half of the control patients had losses of similar magnitude to those in the pernicious anaemia group, and the degree of blood loss in individual control patients appeared unrelated to gastric acidity. Differences in gastric mucosal characteristics, in the rate of gastric emptying, or in systemic effects of aspirin may explain the variation between individuals in the degree of occult gastrointestinal blood loss after aspirin.