Molecular genetics improves the management of hereditary non-polyposis colorectal cancer.

BACKGROUND: The syndrome of hereditary non-polyposis colorectal cancer (HNPCC) can be diagnosed fairly accurately using clinical criteria and a family history. Identifying HNPCC helps to prevent large-bowel cancer, or allows cancer to be treated at an early stage. Once the syndrome has been diagnosed a family member's risk can be judged approximately from a family tree, or it can now be predicted accurately if the causative mutation is known. OBJECTIVE: This study involved attempts to improve the management of a family with HNPCC over a period of 10 years. Clinical diagnostic criteria, colonoscopic surveillance, surgical treatment, genetic counselling, molecular genetic research, and finally predictive genetic testing were applied as they evolved during this time. SUBJECTS AND METHODS: A rural general practitioner first noted inherited large-bowel cancer in the family and began screening subjects as they presented, using rigid sigmoidoscopy at the local hospital. At the time that the disorder was recognised as being HNPCC (1987), screening by means of colonoscopy at our university hospital was aimed primarily at first-degree relatives of affected individuals. After realising how many were at risk, screening was brought closer to the family. A team of clinicians and researchers visited the local hospital to identify and counsel those at risk and to perform screening colonoscopy. Family members were recruited for research to find the gene and its mutation that causes the disease, to develop an accurate predictive test and to reduce the number of subjects undergoing surveillance colonoscopies. RESULTS: There are approximately 500 individuals in this family. In the 10 years of this study the number of subjects who have been counselled for increased genetic risk or who have requested colonoscopic surveillance for HNPCC in this kindred has increased from 20 to 140. After the causative mutation was found in the hMLH1 gene on chromosome 3, a test for it has reduced the number of subjects who need screening colonoscopy by over 70%. A protocol has been devised to inform family members, to acquire material for research in order to provide genetic counselling for (pre-test and post-test) risk, and to test for the mutation. Eventually, identifying those with the mutation should focus surveillance accurately. CONCLUSIONS: The benefits of restricting screening to subjects with the mutation that causes colorectal cancer and of performing operations to prevent cancer are hard to measure accurately. However, it is likely that at least half the family members will be able to avoid colonoscopic screening, some deaths from cancer should be prevented, and the cost of preventing and treating cancer in the family should fall substantially.

In a resource-poor country, mutation identification has the potential to reduce the cost of family management for hereditary nonpolyposis colorectal cancer.

PURPOSE: Colonoscopic surveillance of family members at risk of hereditary nonpolyposis colorectal cancer is difficult in a resource-poor country because of its expense. For family members who live in remote areas, poor communication and limited access to sophisticated medical care make surveillance even more difficult. The identification of the mutation causing the disease will simplify surveillance. Our aim was to assess the impact of mutation analysis on the management of a South African family with more than 150 members at risk for hereditary nonpolyposis colorectal cancer. METHODS: We studied a family that met the Amsterdam criteria for hereditary nonpolyposis colorectal cancer. Colorectal cancer affected 27 members in three generations (evidence from histology in 12, barium enema in 1, and family statements in 14 family members). Leukocyte DNA from family members was tested for linkage to candidate loci for colorectal cancer, and DNA from formalin-fixed cancers from six family members was studied for microsatellite instability. DNA from all available family members was then screened for mutations in the hMLH1 gene. The number of individuals at 50 percent risk was calculated by family pedigree and compared with the number who have the mutation. RESULTS: A disease-causing mutation in exon 13 of hMLH1 segregated with the disorder in members of this kindred. Test results of 100 chromosomes from population-matched controls were negative. Sixty family members between the ages of 16 and 50 years are at 50 percent risk for colon cancer by pedigree analysis, but of these, only 26 (43 percent) have the mutation. CONCLUSION: A mutation in the DNA repair gene hMLH1 was found in family members with hereditary nonpolyposis colorectal cancer and in some unaffected relatives previously at 50 percent risk, but not in unrelated subjects. The blood test for the mutation will simplify management, counseling, and surveillance and help to establish prophylactic colectomy.

Presymptomatic diagnosis of familial adenomatous polyposis using intragenic polymorphisms and CA repeats flanking the APC gene.

To assess the value of DNA markers for the diagnosis of familial adenomatous polyposis (FAP) in South Africa, two highly informative CA-repeat polymorphisms (LNS CA-repeat in D5S346 and YN5.64c CA-repeat in D5S82) flanking the adenomatous polyposis coli (APC) gene, and three intragenic restriction fragment length polymorphisms (RFLPs) (exon 11/RsaI, exon 15.11/MspI, 3'UTR/SspI), were used for haplotype analysis in 13 South African families with the disease. The combination of these polymorphic markers proved to be highly informative and allowed an accurate diagnosis of FAP in 34/35 of the at-risk individuals analysed. Indirect molecular screening can therefore provide a comprehensive pre-clinical diagnostic test for FAP in South Africa. No predominant haplotype was found to be associated with FAP within the South African population. This suggests the absence of founder-type mutations in affected families and therefore marker studies remain important for the pre-clinical diagnosis of FAP in South Africa.

Non-operative management of breast masses diagnosed as fibroadenoma.

A 7-9-year study was undertaken in 99 female patients (median age 20 years), 56 of whom had single and 43 multiple fibroadenomas (total 279). Thirty-four women with 58 masses (21 per cent) were lost to follow-up. Twenty-eight women with 73 masses (26 per cent) subsequently underwent excision at a median of 10 (range 3-59) months for single and 38 (1-110) months for multiple fibroadenomas (P = 0.03), with histological confirmation in 71 and other benign disease in two cases. There was resolution of 107 masses (38 per cent of those entered into the study, 72 per cent of those not lost or excised), leaving 41 persisting masses (15 per cent of those entered into the study, 28 per cent of those not lost or excised). The actuarial probability of disappearance was 0.46 at 5 years and 0.69 at 9 years (Kaplan-Meier analysis). There was no difference in the rate of resolution when 56 single lesions were compared with 223 multiple lesions, or when 192 lesions measuring 2 cm or less in diameter were compared with 87 greater than 2 cm. Resolution was significantly more frequent in women aged 20 years or less than in those who were older (P < 0.01). Non-operative management remains a safe approach in selected women and should be followed by resolution of half of fibroadenomas at 5 years.

The use of DNA markers in the pre-clinical diagnosis of familial adenomatous polyposis in families in South Africa.

Haplotype association studies were performed in 10 unrelated South African families and 1 German immigrant family with familial adenomatous polyposis (FAP). Three DNA probes, recognising five restriction fragment length polymorphisms (RFLPs) around the gene locus for FAP on chromosome 5q, were used. The RFLP analysis was informative or partially informative in all the families studied. Five haplotypes were found to segregate with the disease locus. The predominant association of two of these haplotypes with FAP in the South African families suggests that two mutations may cause the disease in about 70% of families in this population. Meiotic recombination events were detected between the FAP gene and probe M4 (D5S6), but not probes Pi227 (D5S37) and C11p11 (D5S71). Haplotype analysis allowed the preclinical diagnosis of FAP in 5 subjects.

The outcome of familial adenomatous polyposis in the absence of a polyposis registry.

From 1964 to 1990, 70 patients with familial adenomatous polyposis were diagnosed at an institution without a polyposis registry. Those with symptoms at diagnosis were older (mean 34 v. 24 years) and more often had large-bowel cancer (7/30 v. 1/30, 23% v. 3%). The introduction of systematic screening significantly increased the number of cases diagnosed annually, from 2,3 to 5 per year, reduced the median age at diagnosis from 29 to 21 years and increased the proportion of cases diagnosed without symptoms from 52% to 90%. A colectomy with an ileorectal anastomosis achieved a low incidence of rectal cancer at 20 years (1/15, 7%) despite imperfect follow-up and annual sigmoidoscopy in only 40%. However, bowel cancer caused at least 35% of all deaths and 62% of deaths due to a known cause. A registry which maintained a screening programme should therefore prevent most large-bowel cancers and improve the life expectancy of patients with familial adenomatous polyposis who are managed at this institution. It might also refine the current method of screening by sigmoidoscopy alone, by facilitating the use of ophthalmoscopy and blood tests for DNA markers.

A study of a new osmotic purgative for colonoscopy. Is Golytely worth its salt?

An osmotic laxative containing polyethylene glycol and sodium sulfate (Golytely Braintree Laboratories, Inc., Braintree, MA) is widely used to clean the colon for colonoscopy. However, its salty taste makes the mixture unpalatable. We therefore tested the claim that a similar solution but without sodium sulfate (Golytely-RSS Braintree Laboratories, Inc., Braintree, MA) makes preparation of the colon more acceptable to patients in a double-blinded randomized controlled trial. Colonic preparation using polyethylene glycol with or without sodium sulfate was randomized in 100 patients due to undergo colonoscopy. The overall acceptability of the regimen was measured on a linear analogue scale and an estimate of symptoms was obtained. Body weight and serum electrolytes, urea, creatinine, hemoglobin and hematocrit were determined before and after preparation in order to assess fluid absorption. The efficacy of colonic cleansing was graded by the colonoscopist. Four patients did not complete the protocol, 47 received the regimen containing sodium sulfate and 49 received the regimen without it. The two groups did not differ in age or body mass. There was no statistical difference in the overall acceptability of the two regimens to the patients (median acceptability rating 74 for regimen with sodium sulfate, range 4-100 compared with 77 for regimen without, range 3-100, p = 0.32, Mann-Whitney test). Nor was there any difference in taste, nausea, vomiting, cramping or perianal discomfort or in the endoscopists' rating of the cleanliness of the colon. The serum sodium concentration rose slightly (mean 1.6 mmol/L) when the regimen with sodium sulfate was used.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased leukotriene B4 release from ileal pouch mucosa in ulcerative colitis compared with familial adenomatous polyposis.

Pouchitis may complicate the construction of an ileal pouch after colectomy for ulcerative colitis (UC) but not familial adenomatous polyposis (FAP). To examine whether differences in eicosanoid metabolism might explain why pouchitis is largely confined to UC patients, this study compared arachidonic acid stimulated release of immunoreactive leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) from macroscopically uninflamed pouch mucosal biopsy specimens incubated in vitro from patients with UC and FAP. The study also compared eicosanoid release from inflamed and uninflamed pouches in patients with UC. In uninflamed pouches, median LTB4 release was nearly twice as high in UC as in FAP (p = 0.001), but there was no significant difference in PGE2 production. In UC, stimulated eicosanoid release from uninflamed functioning pouch mucosa was not significantly different from that from either ileostomy or defunctioned pouch mucosa. LTB4 and PGE2 release were significantly greater from inflamed than uninflamed pouch mucosa in UC (p = 0.001 and 0.01, respectively). Leukotriene synthesis inhibition or receptor antagonism, or both merit therapeutic evaluation in pouchitis. Increased release of LTB4 from endoscopically normal pouch mucosa suggests increased 5-lipoxygenase activity in patients with UC and could contribute to their predisposition to pouchitis.

Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis.

Metronidazole has been used to treat pouchitis, but there are no controlled data that show it is effective. Chronic unremitting pouchitis is a form of the disorder particularly difficult to manage. Diarrhea is the main symptom of pouchitis, which results from acute inflammation of the mucosa of an ileal reservoir. To test the hypothesis that metronidazole (400 mg thrice daily for seven days) is no better than placebo at reducing stool frequency in chronic unremitting pouchitis, a double-blind placebo-controlled crossover study has been performed. Thirteen patients who had undergone restorative proctocolectomy for ulcerative colitis were studied. The diagnosis of pouchitis was based on clinical, endoscopic, and histological criteria. At entry all patients had symptomatic pouchitis and were passing more than six stools/24 hr or had consistently bloody stools with at least four of six endoscopic criteria of mucosal inflammation. The median frequency of defecation decreased by 3 bowel actions/24 hr (conservative 95% confidence intervals 0-4/24 hr) on metronidazole but increased by a median of 1/24 hr on placebo. The difference between the median number of bowel motions, when treatment with metronidazole was compared to placebo, was 4 motions/24 hr (P < 0.05) in favor of metronidazole. There was no significant change in the endoscopic or histological grade of inflammation, in the serum C-reactive protein level, or symptomatic scores. In a parallel study, metronidazole did not alter stool frequency in asymptomatic patients without pouchitis who had endoscopically normal reservoirs (six polyposis, six colitis).(ABSTRACT TRUNCATED AT 250 WORDS)

Randomised trial of targeted chemotherapy with lipiodol and 5-epidoxorubicin compared with symptomatic treatment for hepatoma.

Lipiodol injected into the hepatic artery is selectively retained in hepatomas so has been used as a vehicle for cytotoxic drugs. This study compared treatment with 5-epidoxorubicin emulsified in lipiodol and infused into the hepatic artery with symptomatic treatment alone in a randomised trial. Of 136 patients with hepatoma 78 (57%) were not eligible, eight (6%) refused to take part, and 50 entered the trial (chemotherapy: n = 25, symptomatic treatment: n = 25). The two groups had similar prognostic indices. Seven of 25 patients allocated to chemotherapy were unable to receive it. The slight survival disadvantage associated with chemotherapy was not significant (median survival 48 days compared with 51 days, log rank chi 2 = 0.07, p > 0.05). Patients given chemotherapy spent significantly longer in hospital, however (median three days compared with one, p = 0.0008). Changes in symptoms and indices of tumour growth did not differ significantly between the two groups. It is concluded that infusion of 5-epidoxorubicin emulsified in lipiodol for hepatoma increased morbidity but did not affect survival. In addition, most patients were unsuitable for this treatment because of advanced disease. The patients in the trial had a short median survival time so the conclusions may not be valid for other patients with hepatoma.

Abdominal rectopexy for complete prolapse: prospective study evaluating changes in symptoms and anorectal function.

The effect of abdominal rectopexy on bowel function is difficult to assess in retrospective studies because preoperative bowel habit cannot be determined accurately. This study examined bowel symptoms and physiologic tests of anorectal function prospectively in 23 patients before and at three months after rectopexy. Rectopexy eliminated complete prolapse in all and stopped bleeding in 16 of 18 patients. Incontinence improved significantly. Constipation (less than 3 bowel actions per week or straining for more than 25 percent of defecation time) was relieved in 4 of 11 affected patients but developed in 5 of the 12 who were not constipated preoperatively. Since the median bowel frequency was 21 motions per week before surgery and 17 afterward, the main determinant of constipation was straining. Abdominal pain was relieved after rectopexy in 6 of 12 patients but developed in 3 of 13 who were pain-free before surgery. Three patients (13 percent) had a first-degree relative with rectal prolapse. Perineal descent decreased significantly. Maximal anal resting pressure increased significantly, but this did not correlate significantly with improved continence. Twenty-one patients (91 percent) could expel a 50-ml balloon preoperatively; 18 of those 21 could still do so postoperatively. The two patients who could not expel the balloon preoperatively were able to do so postoperative. This study shows that rectal prolapse is associated with profoundly abnormal defecation and abdominal pain. While abdominal rectopexy improved continence, it may improve or worsen other bowel symptoms, including constipation.

Lateral ligament division during rectopexy causes constipation but prevents recurrence: results of a prospective randomized study.

Denervation of the rectum during rectopexy has been suggested as a reason for postoperative constipation. Bowel symptoms and anorectal function have been examined in a prospective randomized study of rectopexy with (n = 14) or without (n = 12) division of the lateral ligaments. Incontinence improved in both groups of patients. Division of the lateral ligaments increased the number of patients with constipation (three before operation, ten after operation, P less than 0.01). Mean and canal pressures were higher after operation in all patients. Rectal electrical sensory threshold increased significantly in those in whom the ligaments had been divided (preoperative 27.6 mA versus postoperative 56.7 mA; P less than 0.01) but not in those in whom they were preserved (39.0 versus 34.9 mA; P greater than 0.05). Prolapse recurred in six patients who did not undergo division of the lateral ligaments, but in none of the group in whom the ligaments were divided.

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.

Hereditary non-polyposis colorectal cancer in a Namaqualand kindred.

A family with hereditary non-polyposis colonic cancer affecting 16 males over three generations is described. Autosomal dominant inheritance with male predominance is demonstrated. The clinical features of this condition and methods for screening family members are discussed.

Bacteremia after injection of esophageal varices.

Elective sclerotherapy for esophageal varices produces bacteremia in 4% to 53% of patients. The clinical importance of this phenomenon is uncertain. This study was undertaken to re-assess the incidence and clinical relevance of post-sclerotherapy bacteremia. Blood cultures were taken prior to and at 5 min and 4 h after endoscopy in 50 patients for whom sclerotherapy was planned. In the 41 patients in whom varices were injected, positive cultures were obtained 5 min after sclerotherapy in only 4 patients (10%) and all but 1 patient had other possible causes of bacteremia. After 4 h, all blood cultures were sterile. No infective complications were identified. Bacteremia appears to be an infrequent and transient event after elective sclerotherapy. Only patients with prosthetic heart valves or endocardial abnormalities require antibiotic prophylaxis.