Susceptibility markers in colorectal cancer.

Many susceptibility factors contribute to an individual's risk of developing colorectal cancer. Family history of colorectal cancer (particularly with early age of onset), maleness and increasing age are all factors associated with increasing risk. About three quarters of colorectal cancers are thought to be due to somatic mutations, and both high- and low-penetrance predisposing genes contribute to the remaining quarter of cases. Many of the highly penetrant dominant genes are known, but others remain to be identified. Describing the contribution of individual genes is likely to be very complex, as some modify the impact of other genes and other environmental factors rather than incurring a direct, easily attributable effect. The two dominant predisposing syndromes are familial adenomatous polyposis and Lynch syndrome, the first due to a mutant tumour-suppressor gene APC, and the second due to mutations in a number of genes responsible for mismatch repair in DNA at cell division. Establishing genetic susceptibility for colorectal cancer will soon be possible, and could save lives by allowing targetting of screening and the encouragement of preventive behaviours. However, there will always be a risk of making healthy people "sick" through the identification of predisposing genes, and there are many potential ways by which a gene carrier may be stigmatized by society, insurance companies and employers.

Colonic crypt cell proliferation state assessed by whole crypt microdissection in sporadic neoplasia and familial adenomatous polyposis.

BACKGROUND: It has yet to be established whether proliferative activity in the macroscopically normal colonic mucosa is causally correlated with neoplastic risk. Measurement of proliferative activity in human subjects is of necessity usually undertaken using indirect methods with inherent limitations, and relatively little has been published on the effect of normal biological variables on such indices. AIMS: To establish the validity of mitosis counts following whole crypt microdissection as an index of the crypt cell proliferative state (CCPS) and to examine the effect of normal biological variables (age, sex, and colonic site) and colonic neoplasia on the mitotic index in macroscopically normal human colon. SUBJECTS: Mucosal samples were obtained at colectomy or colonoscopy from 107 individuals (24 controls, 23 sporadic adenoma patients, 31 sporadic carcinoma patients, and 29 patients with familial adenomatous polyposis (FAP)). METHODS: Mucosal specimens were hydrated, hydrolysed, and small groups of crypts separated from the main specimen under a dissecting microscope. The total number of mitoses/crypt were counted by one observer for each of 10 complete crypts. RESULTS: Validation work established that whole crypt mitoses counts were reliable and reproducible. There was no relation between age and mean mitoses/crypt (Pearson correlation coefficient -0.1). The CCPS count was higher for males than for females (difference in means 2.8 (95% confidence interval 0.80-4.66)) among controls but there was no gender difference in the three disease groups. For all disease groups and controls, the crypt mitotic count showed a significant linear increase (p=0.004) from the rectum to the caecum. Biopsies from within 5 cm of the macroscopic margin of a carcinoma (near) gave a mean mitosis count of 12.6 while those from more than 10 cm (far) were lower but not significantly so (p=0.12) with a count of 9.0. The mean mitoses/crypt were similar for the controls and adenomas (5.6 and 4.7, respectively) but greater for the cancers and especially for FAP (8.3 and 14.2, respectively). Statistical analysis confirmed that there were significant differences (p<0.05) between controls and all disease groups together, between sporadic disease and FAP, and between adenoma and carcinoma subjects at each of the four colonic sites. Post hoc comparison by t test showed significantly greater CCPS for FAP compared with controls (p<0.001) and for sporadic cancer versus controls (p=0.04). CONCLUSIONS: Whole crypt microdissection and mitosis counting is a reliable, reproducible, and robust technique for assessing CCPS in the human colon. CCPS is unaffected by age but increases from the distal to the proximal colon. CCPS is increased if a sporadic cancer is present and markedly increased in FAP. However, the precise relation of an increased CCPS to the neoplastic process remains uncertain.

Genetic predictive testing for bowel cancer predisposition: the impact on the individual.

When considering the impact of a genetic diagnosis of hereditary predisposition to colon cancer, there are many similarities to other predictive genetic tests, but also many differences. The development and availability of such genetic diagnoses, and the concept of testing being linked to effective prevention, have advanced rapidly, opening up not only unique opportunities but also unique psychosocial situations for the affected families-and unusual ethical issues for the professional. Compared to a diagnosis of sporadic colorectal cancer for a patient, hereditary colorectal cancer requires an understanding of genetics, heredity, and the attendant mathematics of risk calculation, but, most importantly, there must be a belief that it is possible to remain healthy whilst having an increased risk. This paper outlines the possible impact of a genetic diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP) on both the individual and the family and concludes that genetic testing should be accompanied by genetic counseling. Relevant ethical issues are also introduced, with the opinion presented suggesting that if primary considerations are always for the individual rather than the family or society, then unethical or eugenic decisions are likely to be avoided.

Endoscopic screening and surgery for familial adenomatous polyposis: dangerous delays.

BACKGROUND: Registries for patients with familial adenomatous polyposis (FAP) can improve patient management. However, in relation to colorectal cancer, a critical review has not previously been undertaken of the effectiveness of screening and surgical protocols within a registry. METHODS: A review was undertaken of 63 gene carriers who received primary treatment for FAP between 1987, when the Northern Region Polyposis Registry was formed, and 1995. RESULTS: In some gene carriers with colorectal cancer, surgery was delayed because of social factors or unpleasant surgical experiences in the family. Colonoscopy failed to detect five colorectal cancers. CONCLUSIONS: Delays in treatment still occur in patients with FAP and colorectal cancer, often because of complex social problems and patients' fear of surgery. If multiple colorectal polyps are present, colonoscopy is not a reliable screening test for malignancy and prophylactic surgery is indicated, preferably before the patient is 20 years old.

Clinical impact of colonoscopic screening in first-degree relatives of patients with hereditary non-polyposis colorectal cancer.

Sixty-one asymptomatic individuals with an affected first-degree relative from five large hereditary non-polyposis colorectal cancer (HNPCC) kindreds were screened by colonoscopy. Neoplasms were found in nine (15 per cent) of 61 individuals on the first screen. Five subjects had a single adenoma while two had two adenomas each. There were two patients (3 per cent) with malignant neoplasms: one with a Dukes B adenocarcinoma and one with synchronous Dukes C adenocarcinomas in the caecum and ascending colon. These findings support the hypothesis that adenomas do not occur in large numbers in HNPCC families but, because of the high malignant conversion rate, biennial colonoscopy with removal of polyps seen is recommended.

Colonic fermentation of complex carbohydrates in patients with familial adenomatous polyposis.

Decreased production of butyric acid by colonic carbohydrate fermentation may predispose to colonic carcinogenesis, with the implicit assumption that the decrease in faecal butyrate found predates the development of the tumour. The influence of the genetic predisposition to colonic tumours and the presence of colonic polyps on in vitro fermentation of carbohydrates was examined. Stool samples from 11 normal controls and 20 patients with familial adenomatous polyposis (FAP) were incubated anaerobically with a range of carbohydrates. Fermentation patterns were similar for glucose and raffinose. These sugars produced different short chain fatty acid (SCFA) patterns from the two polysaccharides, starch and arabinogalactan, which differed one from the other. The FAP gene carriers with polyps produced less butyrate than normal controls (p < 0.005) and gene carriers without polyps (p < 0.05). There were corresponding decreases in the molar ratios of butyrate. Gene carriers without polyps produced less absolute amounts of acetate than normal controls (p < 0.05) and slightly less total SCFAs (p < 0.05) but were otherwise not significantly different. The decreased production of butyrate noted by other workers may be secondary to the tumours rather than a contributory cause.

Comparison of morbidity and function after colectomy with ileorectal anastomosis or restorative proctocolectomy for familial adenomatous polyposis.

Restorative proctocolectomy with an ileal reservoir (RPC) should prevent colorectal cancer in patients with familial adenomatous polyposis. Until this is confirmed its role compared with total colectomy and ileorectal anastomosis (IRA) will depend on the relative morbidity and postoperative bowel function after the two procedures. This was analysed in 99 patients (37 RPC, 62 IRA) operated on between 1977 and 1989. Morbidity was greater after RPC with subsequent ileostomy closure (median hospital stay, 24 versus 11 days; complications, 60 versus 21 per cent; reoperation, 29 versus 3 per cent; return to normal activity; 31 versus 14 weeks). There was little difference in bowel function; after IRA median frequency was 3/24 h and urgency (unable to wait 15 min) occurred in 50 per cent, compared with 4.5/24h and 17 per cent after RPC. Night evacuation occurred in 10 and 43 per cent respectively. IRA was performed in younger patients (median 19 versus 31 years) who had fewer bowel motions before operation (2 versus 5/24 h). The greater morbidity of RPC suggests that it should be restricted to patients at higher risk of developing later rectal cancer, including those unavailable for follow-up and those with large or confluent rectal polyps or with curable colon cancer at the initial colectomy.

Role of a regional register for familial adenomatous polyposis: experience in the northern region.

Within 36 months of its formation the Northern Region Polyposis Registry had increased the number of identified gene carriers of familial adenomatous polyposis from 56 to 65 in a population of 3.1 million and had achieved a 15-fold increase in the number of at-risk relatives being regularly screened. Review of the surgical records at the outset of the registry revealed that the mean age at diagnosis of those patients detected by screening was 24.7 years, whereas it was 36.6 years for those detected by symptoms. Ten of the 31 in the latter group had colorectal carcinomas whilst only one of those detected by screening had a cancer and a significantly higher proportion had sphincter-saving surgery. A regional registry can provide an effective screening and counselling service to surgeons treating patients with familial adenomatous polyposis. At-risk relatives are best assessed by combining results of the different screening procedures now available but the prime requirement of a successful registry is dedicated domiciliary counselling.

Prehospital prophylactic lidocaine does not favorably affect outcome in patients with chest pain.

STUDY OBJECTIVES: The purpose of our study was to determine the morbidity and mortality in initially stable patients presenting to paramedics with chest pain; to examine possible beneficial effects of its use, including reduction of sudden death syndrome in the prehospital and emergency department setting; and to determine if prophylactic lidocaine is associated with adverse effects in this patient population. DESIGN AND SETTING: This was a randomized, prospective study using prophylactic lidocaine in patients complaining of chest pain who presented to our paramedic system between January 1984 and January 1988. TYPE OF PARTICIPANTS: All patients aged 18 years or older with chest pain of suspected cardiac origin who presented to paramedics during the study period were included. Excluded were patients presenting with warning arrhythmias, second- or third-degree heart block, bradycardias of less than 50, hypotension of less than 90 mm Hg systolic, or known allergy to lidocaine. INTERVENTIONS: Patients were randomized into two groups, the lidocaine-treated group and the control group. An initial bolus of 1 mg/kg IV lidocaine was administered to the lidocaine-treated group. A simultaneous 2 mg/min IV drip was established. Ten minutes after the first dose of lidocaine, a second bolus of 0.5 mg/kg was administered. MEASUREMENTS AND MAIN RESULTS: During the study period, 1,427 patients were entered; 704 received lidocaine, and 723 did not. Discharge diagnoses included acute myocardial infarction (31%), unstable angina (33%), other cardiac problems (7%), and noncardiac problems (29%); overall mortality rate was 7.4%. There was an equal distribution of deaths between the lidocaine-treated group (57) and the control group (48). Six patients had a cardiac arrest in the prehospital setting, and 15 had a cardiac arrest in the ED. Malignant ventricular arrhythmias as the precipitating arrest rhythm in patients with acute myocardial infarctions were similar for the lidocaine-treated and control groups. The incidence of adverse effects, including hypotension, bradycardias, second- or third-degree heart blocks, tinnitus, and altered mental status, was similar in both groups. CONCLUSION: There are no benefits from the administration of prehospital prophylactic lidocaine in stable patients with chest pain; therefore, routine use in this setting appears unwarranted.

Long-term internal cardiac defibrillation threshold stability.

The automatic implantable cardioverter-defibrillator is tested intraoperatively with defibrillation trials to ensure effectiveness. It is unknown if the energy requirement for internal defibrillation remains stable and that once demonstrated effective, if the device will continue to be effective in terminating lethal ventricular arrhythmias. In this study, the defibrillation energy requirement was compared in 56 patients at the time of lead implantation to that obtained at the time of generator replacement. Mean time to generator replacement was 17. +/- 6.6 months. The defibrillation threshold was stable over that time (11.9 +/- 6.7 joules compared to 12.7 +/- 8.4 joules, NS). There was no relation between transmyocardial impedance and defibrillation threshold. In addition, no effect on defibrillation threshold was demonstrated by the use of various cardiac medications, concomitant surgery or the occurrence of clinical shocks during follow-up.

Complications of automatic implantable cardioverter defibrillators: radiographic, CT, and echocardiographic evaluation.

Automatic implantable cardioverter defibrillators (AICDs) were studied in three groups: (a) Serial radiographs were reviewed in 51 clinic patients. Twenty of 96 (21%) AICD patches distorted with time. (b) Thirty-six postoperative computed tomographic (CT) scans of asymptomatic patients revealed that pericardial fluid collections were frequent during the month after surgery but rare beyond that. Echocardiography was insensitive for these collections. CT also demonstrated dense fibrosis around some distorted patches, months after surgery. (c) Five other patients with pericardial infection had distorted patches, and the four studied with CT had fluid beneath their patches. (d) A case of constrictive pericarditis had distorted patches but was not diagnosed with CT. The authors conclude that distorted patches may indicate postoperative complications and that CT is the imaging modality of choice.

Congenital hypertrophy of retinal pigment epithelium: a sign of familial adenomatous polyposis.

Families of people known to have familial adenomatous polyposis are screened for signs of the disease by yearly examination of the bowel. Multiple areas of congenital hypertrophy of the retinal pigment epithelium have been described in patients with familial adenomatous polyposis. To assess the reliability of this marker 40 patients with familial adenomatous polyposis, representing all 25 pedigrees with living affected members in the Northern region's polyposis registry, were examined for hypertrophy of the retinal pigment epithelium. All had multiple lesions, ranging in number from two to over 40. None of the 35 controls had more than two lesions. Ocular examination is valuable for detecting carriers of the gene for familial adenomatous polyposis before their symptoms develop.

Stratified application of the automatic implantable cardioverter defibrillator.

Since June 1983 we have developed a stratified regimen for staged implantation of the automatic implantable cardioverter defibrillator system. The protocol for management in patients who have fully recovered from sudden cardiac death is initiated with the use of standard electrophysiologic evaluation. Treatment in order of application has consisted of drugs followed by implantation of the device for patients with drug-refractory arrhythmias in whom direct cardiac surgical intervention for anatomic substrates for sudden death are absent. In surgical candidates, combinations of coronary revascularization and ablative therapy have been used to mitigrate the potential for lethal arrhythmia. Sensing and defibrillator lead systems have been placed at corrective operations to be followed later by implantation of the cardioverter defibrillator generator for either inducible or spontaneous tachyarrhythmia. This staged application has been effective in markedly reducing actual sudden cardiac death while at the same time saving on unnecessary device implantation. Morbidity of lead implantation alone remains a concern, particularly for infective complications. Additional follow-up is required to assess the validity of this approach.

Delayed infection of the automatic implantable cardioverter-defibrillator. Current recognition and management.

Three cases of delayed infection of automatic implantable cardioverter-defibrillator devices without systemic manifestations are reported. Computed tomographic scan of the heart revealed fluid deep to the patch in each case. Sonication of explanted automatic implantable cardioverter-defibrillator patches facilitated the recovery of adherent microorganisms in one case. Management of this previously unrecognized problem is outlined.