Survival benefit in a randomized clinical trial of faecal occult blood screening for colorectal cancer.

BACKGROUND: Early detection of colorectal cancer could reduce cancer-specific mortality. The aim of this trial was to evaluate the effect of faecal occult blood test (FOBT) screening on colorectal cancer mortality in a Swedish population. METHODS: All 68,308 citizens in Göteborg born between 1918 and 1931 were randomized to a screening or a control group at the age of 60-64 years. All were screened two to three times with rehydrated Hemoccult-II. Compliance was 70.0 per cent (23,916 individuals). Those with a positive test result were offered sigmoidoscopy and a double-contrast enema. The primary endpoint was death from colorectal cancer. RESULTS: After a mean of 9 years from the last screening, there was a significant reduction in colorectal cancer mortality in the screening group compared with the control group. The overall risk ratio of death from colorectal cancer was 0.84 (95 per cent confidence interval 0.71 to 0.99). The groups did not differ in incidence of colorectal cancer or in overall mortality. CONCLUSION: FOBT screening significantly reduces colorectal cancer mortality.

Protection of metabolic and exercise capacity in unselected weight-losing cancer patients following treatment with recombinant erythropoietin: a randomized prospective study.

This study was aimed at evaluating whether anemia could be prevented in unselected weight-losing cancer patients on anti-inflammatory treatment by early and prophylactic treatment with recombinant human erythropoietin (rhEPO) and whether such a benefit could be translated into improved physical function and metabolic efficiency. One hundred eight cancer patients who experienced progressive cachexia due to solid, mainly gastrointestinal tumors were randomized to receive twice daily a cyclo-oxygenase inhibitor (controls; indomethacin, 50 mg twice a day) or indomethacin and erythropoietin, provided on individual basis to prevent development of progressive anemia (study patients; indomethacin, 50 mg twice a day plus rhEPO; range, 12,000-30,000 units per week). All patients were treated and followed up until death or to preterminal stage. Biochemical tests (blood, liver, kidney, and thyroid), nutritional state assessment (food intake and body composition), and exercise testing with simultaneous measurements of respiratory gas exchanges before and during exercise were performed before institution of treatments and then at regular intervals during the treatment period (2-30 months after start). Study and control patients did not differ in survival. rhEPO prevented development of anemia during the entire observation period. This was associated with a significantly more preserved maximum exercise capacity in study patients compared to control patients during the follow-up period (101 +/- 10 versus 66 +/- 6 W; P < 0.0001), based on more effective ventilation and whole-body respiratory gas exchanges. These improvements were also evident when exercise performance was normalized to lean body mass, an indirect measure of the skeletal muscle mass. The metabolic efficiency, expressed as oxygen uptake per watt produced, was also significantly preserved in rhEPO-treated patients compared to controls (14.1 +/- 1.1 versus 16.3 +/- 0.9 ml O2/W, P < 0.05). Our results demonstrate that institution of early and prophylactic rhEPO treatment to patients with progressive cancer prevents development of tumor-induced anemia. This achievement was associated with a better preserved exercise capacity, which is explained in part by improved whole-body metabolic and energy efficiency during work load.

Mutations and allelic loss of p53 in primary tumor DNA from potentially cured patients with colorectal carcinoma.

PURPOSE: To compare p53 alterations in survivors and nonsurvivors after surgery for colorectal cancer. PATIENTS AND METHODS: Twenty-nine potentially cured patients with colorectal carcinoma, without recurrent disease for more than 6 years after their primary surgery, were selected to match a group of 41 colorectal cancer patients with early metastatic spread to the liver. All patients were screened for mutations in the p53 gene, exons 5 to 9, by denaturing gradient gel electrophoresis and subsequent sequencing. RESULTS: The frequency of p53 mutations was significantly different in cured patients (60%) compared with patients with early relapse (41%, P <.05). A significant difference was found in the distribution of mutations, indicating that potentially cured patients had a different proportion of mutations in conserved regions of p53 (P =.02). This difference was explained by a significantly different frequency of mutations in exon 8 (40% v 15%, P =.03), which is part of the conserved region V. All mutations in region V were codon 273 mutations in cured patients, whereas three of four mutations were located in codon 273 in patients with metastatic disease. Allelic loss of p53 (loss of heterozygosity [LOH]) was demonstrated in 26% of the cured patients and in 39% of patients with metastatic disease (P =.36). The combination of mutation and LOH of p53 was the same (17%) in both groups. CONCLUSION: A large number of p53 mutations in colorectal cancer do not promote disease progression. Some mutations, particularly within conserved regions, may even counteract negative functional effects of other p53 structural alterations. A complete loss of p53 function was not related to survival or progression after curative operation of colorectal carcinoma.

The place for colectomy and ileorectal anastomosis: a valid surgical option for ulcerative colitis?

BACKGROUND: Conflicting views regarding the use of ileorectal anastomosis (IRA) in ulcerative colitis (UC) exist and this controversy prompted us to review our experience, especially against the background of the current tendency to choose the ileal pouch-anal procedure (IPAA). METHODS: Thirty-two consecutive patients with IRA were studied. Complications, failure rate, reasons for failure and functional results were assessed. The median follow-up time was 3.5 years. RESULTS: The overall complication rate was 28%. The rectum was excised in 4 patients, indicating a failure rate of 12%. The mean daily evacuation frequency was 5.6. Despite urgency occurring in one-third of the patients, continence function was well preserved. CONCLUSIONS: Employed on a selective basis, IRA is a safe procedure with low mortality and morbidity and good prospects for success in many patients with UC. The patients must be prepared to submit to life-long rectoscopy surveillance.

Endoscopic and surgical complications of work-up in screening for colorectal cancer.

BACKGROUND AND PURPOSE: In an ongoing randomized screening study of 68,306 patients for early detection of colorectal neoplasm, those with positive Hemoccult II tests (Smith Kline Diagnostic, Sunnyvale, CA) were examined with a flexible sigmoidoscope (FS; 60 cm) and double-contrast barium enema (DCE). The aim of this study was to determine the rate of complications to the work-up. METHODS: A total of 2,108 FS, 1,987 DCE, 190 colonoscopies, and 104 laparotomies were performed because of a positive Hemoccult. RESULTS: One patient's large bowel was perforated during diagnostic endoscopy. Four perforations of the large bowel occurred during endoscopic polypectomy (0.8 percent of 513 adenomas removed), and one case of bleeding occurred 12 days after polypectomy. No complications occurred in connection with the 1,987 DCE. Five of 104 laparotomized patients underwent relaparotomy, 3 after removal of a colorectal carcinoma, and 2 of 4 patients with diverticular disease. All five patients healed but required a longer stay at the hospital. CONCLUSIONS: Complications occurred in 0.3 percent of the endoscopies, and 5 percent of patients had to undergo laparotomy again. No mortality occurred. If mortality attributable to colorectal cancer will decrease because of screening, we find the complication rate is acceptable.

Total exchangeable sodium related to body composition in patients with conventional or reservoir ileostomy.

Decreased exchangeable body sodium might be a consequence of proctocolectomy and construction of an ileal reservoir. To investigate this, 35 patients with ulcerative colitis and conventional ileostomy were studied before and after conversion to continent ileostomy and compared with 25 unoperated subjects as reference. The sodium urinary excretion varied between 7 and 229 and 1 and 217 mmol/24 h in patients with conventional and reservoir ileostomy, respectively. The total exchangeable sodium was measured and related to body composition estimated from body weight, total body water, and total body potassium. No effect on exchangeable sodium was observed after conversion: 3100 mmol and 2990 mmol, respectively. Patients with ileostomy, regardless of type, did not differ from reference subjects in their exchangeable sodium when related to total body water. A larger variation of total exchangeable sodium related to total body water suggests unstable sodium homeostasis in patients with ileal reservoir compared with reference subjects.

Altered erythrocyte transmembrane transport of sodium and potassium in patients with conventional or reservoir ileostomy.

After proctocolectomy, the loss of the colonic absorptive capacity of sodium is compensated for by increased small intestine sodium absorption and renal conservation of Na by enhanced tubular reabsorption. These processes entail increased cellular sodium transport in the enterocytes and in the renal tubular cells. In order to evaluate if there is a general increase in cellular transport of Na after proctocolectomy for inflammatory bowel diseases erythrocyte Na and K contents and the transmembrane Na fluxes were determined in 35 patients with conventional ileostomy, 23 of which were reinvestigated after conversion to continent reservoir ileostomy. A selected group of another 12 patients having high output from their reservoir ileostomy and low urinary Na were studied concomitantly and 33 healthy subjects served as controls. The intracellular Na content did not differ between the groups while the intracellular K levels were higher in patients with conventional or continent ileostomy compared to controls. In addition, the Na influx and the efflux rate constant of Na were both increased after conversion to reservoir ileostomy. Na influx correlated positively with intake and urinary excretion of Na in conventional ileostomy patients. The results suggest that patients with ileostomy have an increased cellular K uptake and that construction of a reservoir ileostomy further alters cell cation transport by increasing the transmembrane Na turnover.

Selected postoperative antibiotic prophylaxis in colo-rectal surgery on the basis of bacterial concentration in the operative field.

A new approach to antibiotic prophylaxis was tested in a prospective study of postoperative septic complications in elective colo-rectal surgery. The degree of contamination in the operative field in a nontreated group was estimated by dipslide technique. When the slide yielded greater than or equal to 5 CFU of a coliform bacterium or S. aureus the patient was judged to be contaminated. This trait was significantly correlated to the development of postoperative infection. All contaminated cases in another group of patients were subjects to prophylaxis within 24 hours after peritoneal closure, using an antibiotic with a favourable MIC concerning the current bacterium (-iae). This resulted in a significant reduction of the rate of infection. These findings challenge the current concept of a very limited effective period of prophylactic systemic antibiotics.

Screening for colorectal neoplasia with faecal occult blood testing compared with flexible sigmoidoscopy directly in a 55-56 years' old population.

Reduced mortality from colorectal cancer may be achieved by screening with faecal occult blood testing. Screening for neoplasia in the rectum and sigmoid colon with flexible sigmoidoscopy is suggested to be more effective, particular among persons between 50 and 60 years of age. A cohort of 6367 persons 55-56 years of age were randomised to screening with rehydrated Hemoccult II tests (HII group) or with flexible videosigmoidoscopy directly (FS group). In the HII group 59% (1893/3183) attended, compared to 49% (1353/3184) in the FS group. Of the 1893 persons who attended in the HII group, 4% had a positive HII test and in 13% (10/78) of them a neoplasm > or = 1 cm in the rectum or sigmoid colon was diagnosed by endoscopy. The corresponding rate in the FS group was 2.3%. Overall the number of persons with a neoplasm > or = 1 cm diagnosed in the HII group was 10 and in the FS group 31. A subgroup in the flexible sigmoidoscopy group, who also performed rehydrated HII tests, showed a sensitivity of the HII test for neoplasia > or = 1 cm of 26% and a specificity of 95.6%. To find a neoplasm > or = 1 cm in the rectum or sigmoid colon, 44 examinations were needed when using flexible sigmoidoscopy directly and 7 examinations when only those with positive HII tests were examined. In mass screening for neoplasia in the rectum and sigmoid colon, the relatively low prevalence of colorectal neoplasia at 55-56 years of age makes primary selection with rehydrated Hemoccult testing an alternative to the resource-consuming endoscopy of all invited persons.

Comparison of sialyl-Lewis a-carrying CD43 and MUC1 mucins secreted from a colon carcinoma cell line for E-selectin binding and inhibition of leukocyte adhesion.

The colon carcinoma cell line COLO 205 has earlier been shown to express and secrete two mucin-type glycoproteins, the leukocyte-associated sialoglycoprotein CD43 or leukosialin (named L-CanAg) and the MUC1 mucin (named H-CanAg). Both glycoproteins carry sialyl-Lewis a epitopes and could bind transfected COS cells expressing E-selectin in a Ca(2+)- and E-selectin-dependent way. Using the monoclonal antibodies C50, C241 (both against sialyl-Lewis a), and CSLEX1 (against sialyl-Lewis x), the MUC1 mucin was shown to express both sialyl-Lewis a and sialyl-Lewis x epitopes, while the CD43 mucin expressed sialyl-Lewis a and almost no sialyl-Lewis x epitopes. These two secreted glycoproteins could inhibit human polymorphonuclear leukocyte or HL-60 cell adhesion to E-selectin-transfected COS cells or IL-1 beta-stimulated human endothelial cells in vitro. The inhibitory efficiency of the MUC1 mucin was 5-10 times larger than that of the CD43 mucin, when studied on endothelial cells and comparable amounts of sample were used. Removing the sialic acids from the MUC1 or CD43 mucins by sialidase treatment abolished the inhibitory effect. Monoclonal antibodies against sialyl-Lewis a greatly and equally inhibited the binding of the MUC1 or CD43 mucins, whereas an antibody against sialyl-Lewis x (CSLEX1) showed almost no inhibitory effect. The result proposes that the sialyl-Lewis a epitope on at least some mucin-type molecules bind E-selectin better than sialyl-Lewis x and that the potency of tumor-secreted mucins to interfere with leukocyte attachment to E-selectin could be dependent on the apoprotein size or its presentation of the carbohydrate epitopes.

Ileostomy output of gas and feces before and after conversion from conventional to reservoir ileostomy.

In 28 patients who had previously had a proctocolectomy for ulcerative colitis, the ileostomy output of feces was determined before and after conversion to continent reservoir ileostomy, as was the output of gas in 20 of the patients. The median output of feces/24 hours collected in the hospital was 576 g before and 692 g after conversion (P less than 0.05); when collected at home the corresponding figures were 734 g and 740 g, respectively. In the majority of patients, the change in fecal ileostomy output after the conversion was not considerable, while in a few patients there was a marked increase. The fecal output was 24 percent (P less than 0.01) and 11 percent (P less than 0.01) larger at home than in hospital before and after conversion, respectively. The proportion dry weight of ileostomy discharge decreased after conversion (P less than 0.01). The median gas volume in the ileostomy output/24 hours was 1,664 ml before and 1,450 ml after conversion. The gas constituted 58 percent of the output and is significant with respect to the required reservoir capacity. Recording the emptying volumes and frequency in patients with reservoir ileostomy showed that, in general, patients with large output expand their reservoir capacity instead of increasing their emptying frequency.

Expansion of various types of ileal reservoirs in situ. An experimental study in rats.

In experiments on rats four types of ileal reservoirs were constructed and left to expand in situ. After 3 months the volumes and tissue weights of the various reservoirs were compared. The reservoir types were: two loops, isoperistaltic (type I), two loops, antiperistaltic (type II), three loops, S-shaped (type III) and "four loops', double-folded U loop (Kock pouch) (type IV). There was a considerable volume increase in all types of reservoir as well as a marked increase in their tissue weight. The expansion of the reservoirs in groups III and IV was significantly greater than that in groups I and II. The difference in expansion could possibly be explained by the greater radius in three- and four-loop reservoirs compared with two-loop reservoirs if Laplace's law is applied to this process. According to this law the tension in the wall of a tube increases with increasing radius.

Significance of the antireflux valve for upper urinary tract pressure. An experimental study in patients with urinary diversion via a continent ileal reservoir.

When bladder substitution is required, a low pressure receptacle and an antireflux valve with low resistance to flow is essential for preservation of the upper urinary tract. The aim of this study was to evaluate whether these criteria are attained in the continent ileal reservoir used for urinary diversion. The investigations were performed in six patients more than one year after supravesical urinary diversion via a continent ileal reservoir. The pressure was recorded simultaneously both in the afferent loop and in the reservoir during filling of the reservoir. There was a slow parallel increase in the basal pressure in the reservoir and the afferent loop. Pressure waves appeared sometimes simultaneously and sometimes in only one compartment at a time. Only during short periods of time did the pressure exceed 25 cm of water. The frequency of pressure waves increased with increased filling of the reservoir. The "total pressure" was larger in the reservoir than in the afferent loop. It is the antireflux valve which prevents pressure rises in the reservoir from being conveyed to the upper urinary tract. The resistance to urinary flow was moderate.

Secreted MUC1 mucins lacking their cytoplasmic part and carrying sialyl-Lewis a and x epitopes from a tumor cell line and sera of colon carcinoma patients can inhibit HL-60 leukocyte adhesion to E-selectin-expressing endothelial cells.

A secreted MUC1 mucin from the spent medium of the colon carcinoma cell line COLO 205 carrying sialyl-Lewis a and x epitopes (H-CanAg) was purified by trichloroacetic acid precipitation and Superose 6 gel filtration. The purified H-CanAg inhibited adhesion of the leukocyte cell line HL-60 to E-selectin transfected COS-1 cells or interleukin-1 beta (IL-1 beta)-activated human umbilical vein endothelial cells. Sera from two patients with advanced colon carcinoma containing high concentrations of sialyl-Lewis a and x activity inhibited HL-60 cell adhesion to E-selectin-expressing COS-1 cells and IL-1 beta-activated endothelial cells. After affinity column absorption of the sialyl-Lewis a activity, the sera also lost most of their sialyl-Lewis x activity and at the same time their adhesion inhibitory effect. A large part of the sialyl-Lewis a/x activity in the two patients was found in fractions containing mucins having a MUC1 apoprotein, as shown by its size, and reactivity with the two anti-MUC1 apoprotein monoclonal antibodies, Ma552 and HMFG-2. The cell-adhesion inhibitory effect of the purified sialyl-Lewis a-carrying MUC1 mucin fraction from the sera of the two patients was stronger than that of smaller sized sialyl-Lewis a-carrying mucin-type glycoproteins also found in the patient sera. The MUC1 mucin fraction secreted by the COLO 205 cells and from the two sera were all shown to lack their C-terminal portion, in contrast to the MUC1 mucin from cells. It is hypothesized that sialyl-Lewis a- and/or x-containing mucins, especially MUC1, secreted by tumors can interact with E-selectin on endothelial cells and thus inhibit leukocyte adhesion.

Immune responses in ileostomy fluid and serum after oral cholera vaccination of patients colectomized because of ulcerative colitis.

The capacity of an oral inactivated B-subunit-whole-cell cholera vaccine to induce immune responses in patients colectomized due to ulcerative colitis was studied. Two doses of vaccine induced significant mucosal immunoglobulin A (IgA) antibody responses in ileostomy fluid against cholera toxin in 14 of 15 (93%) patients and against whole vibrios in 9 of 15 (60%) cases. The serological responses were lower (but not significantly) than those observed in healthy Swedish volunteers. Increased IgA antitoxin levels were found in ileostomy fluid as late as 2 years after vaccination.

Sodium and potassium excretion before and after conversion from conventional to reservoir ileostomy.

Sodium and potassium in the ileostomy output and urine were determined in 28 patients with ulcerative colitis on a free diet and in eight patients on a defined constant diet, before and after conversion from a conventional ileostomy (CI) to a continent reservoir ileostomy (RI). Feces and urine were collected both in the hospital and at home. Patients with CI on free diet had a median intestinal loss of 62 mmol sodium and those with RI 74 mmol/24 h collected in the hospital (p < 0.05). The figures for at home was 79 and 81 mmol/24 respectively, and were larger than in the hospital (p < 0.01). Sodium loss in the urine (U-Na) and the intake of sodium did not change significantly after conversion. Patients with a low U-Na before conversion also had a low U-Na after, in a few almost nil, implying a need for increased intake of sodium. Patients with a CI and low urinary output of sodium should be carefully studied with respect to their sodium balance before accepting them for conversion to RI. The ileostomy output of potassium increased after conversion (4.3 vs. 6.8 mmol/24 h; p < 0.01) in the hospital (5.3 vs 7.1 mmol/24 h; p < 0.01) at home. Patients on a defined constant diet before and after conversion did not show any significant differences in absorption of sodium, potassium, magnesium or calcium after conversion, but did show a reduced dry weight of the ileostomy output, indicating an increased degradation of intestinal contents in RI patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The yield of flexible sigmoidoscopy and double-contrast barium enema in the diagnosis of neoplasms in the large bowel in patients with a positive Hemoccult test.

BACKGROUND AND STUDY AIMS: In an ongoing screening study of 68,306 patients for early detection of colorectal cancer, those with a positive Hemoccult II test (H2) were examined with a flexible sigmoidoscope (60 cm) (FS) and double-contrast barium enema (DCE). The aim of this study was to compare the results of FS and DCE examinations in the rectum and the sigmoid colon, and to evaluate the benefit of DCEs. PATIENTS AND METHODS: 1831 FS and DCE examinations were performed on the basis of positive H2 tests (90% acceptance rate for positive Hemoccult tests). The radiologists were unaware of the endoscopic findings. One hundred and thirty-five patients underwent total colonoscopy due to abnormalities found on FS or DCE, or both. All patients were followed-up through various Swedish cancer registers (range: 50-145 months). RESULTS: The sigmoidoscope was fully introduced in 71% of cases, and the mean time for the examination was 5 minutes. The combination of FS and DCE detected 235 adenomas of 1 cm and more, and 81 cancers which were in Dukes stages A (n = 29), B (n = 22), and C (n = 23). Twenty-one cancers (26%) and 24 adenomas (10%) identified on DCE were above the rectosigmoid area. The rate of overlooked adenomas (> or = 1.0 cm) and cancers was 22 and five for FS in the rectosigmoid area, and 55 and 15, respectively, for DCE. Adenomas found in the rectosigmoid area were only rarely associated with more proximal adenomas of 1 cm and more (1%). CONCLUSIONS: This approach-screening by FS and DCE, and selective use of colonoscopy in case of abnormalities-leads to the diagnosis of significant colonic tumors (larger adenomas and cancers) in 17.7% of cases; only two of eighty-three cancers (2.4%) were overlooked with this method.