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.

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.

Relationships between self-reported health related quality of life and measures of standardized exercise capacity and metabolic efficiency in a middle-aged and aged healthy population.

BACKGROUND: The purpose of this study was to evaluate to what extent self-reported health related quality of life (HRQL), assessed by the Swedish standard version of the Medical Outcome Study Short-Form 36 (SF-36), is related to measured exercise capacity and metabolic efficiency in a cohort of healthy subjects from the Gothenburg area of Sweden. MATERIAL AND METHODS: Individuals were invited to take part in the evaluation where HRQL was compared with the maximal power output expressed in Watts assessed during a standardized treadmill test with incremental work loads. Whole body respiratory gas exchanges (CO2/O2) were simultaneously measured. Estimate of metabolic efficiency was derived from oxygen uptake per Watt produced (ml O2/min/W) near maximal work. RESULTS: The health status profile in the current population largely agreed with normative data from an age- and gender-matched reference group, although some measured scores were slightly better than reference scores. Males and females had a similar relationship between energy cost (ml O2/min) for production of maximal work (W), while the regressions for maximal exercise power and age were significantly different between males and females (p < 0.01). The overall metabolic efficiency was the same in individuals between 40 and 74 years of age (10.4 +/- 0.07 ml O2/min/ Watt). Maximal exercise power was only related to the SF-36 subscale physical functioning (PF), but unrelated to other physical subscales such as role limitations due to physical problems, good general health and vitality. There was also a discrepancy between measured maximal power and PF in many subjects, particularly in males who experienced either intact or severely reduced PF. CONCLUSIONS: Our results demonstrate that simultaneous measurements of self-reported and objective measures of PF should add a more integrated view for evaluation of therapeutic effectiveness, since the overall correlation was poor between objective and subjective scores among individuals.

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.

Induction and distribution of intestinal immune responses after administration of recombinant cholera toxin B subunit in the ileal pouches of colectomized patients.

The induction and dissemination of mucosal immune responses to recombinant cholera toxin B subunit (rCTB) administered into the ileal pouches of patients, who had been colectomized because of ulcerative colitis, was analyzed. Biopsies from the duodenum and ileal pouch were collected, along with peripheral blood and ileostomy fluids. Two immunizations induced strong CTB-specific immunoglobulin A (IgA) antibody-secreting cell (ASC) responses in the duodenum in five of five patients, whereas weaker and less-frequent ASC responses were noted in the ileal pouch. Intestine-derived CTB-specific IgA ASCs were found in peripheral blood in three of the five patients. The vaccination also induced significant IgA antitoxin titer rises in ileostomy fluid in all of the patients. Increased production of gamma interferon in cell cultures from the ileal pouch was found in four of five patients after the vaccination. These results clearly indicate that rCTB administered into the distal ileum is capable of inducing B-cell responses in the "entire" small intestine and that homing of immunocompetent cells occurs preferentially to the duodenum.

P53 mutations in primary tumors and subsequent liver metastases are related to survival in patients with colorectal carcinoma who undergo liver resection.

BACKGROUND: The appearance of p53 mutations in colorectal carcinoma was determined, independent of differentiation and tumor stage of the primary tumors, in relation to the survival of patients who were scheduled to undergo liver resection. METHODS: Tumor material was analyzed for p53 mutations in primary colorectal tumors and subsequent liver metastases from 41 consecutive patients who were scheduled to undergo surgical liver resection. DNA sequencing and immunohistochemical staining of p53 protein within tumor nuclei were performed. RESULTS: Primary tumors displayed p53 mutations within exons 5-9 in 41% of patients. No mutations were found in exons 4, 10, or 11. Forty-one percent of metastatic lesions had the same single mutation that was found in the primary tumor, whereas 11% of metastatic lesions had one additional mutation within exons 5-9; 22% had mutations only in their liver metastases, whereas corresponding primary tumors displayed wild-type p53. None of the patients had mutated p53 in their primary tumor and wild type in their metastases. Survival after undergoing liver resection was correlated negatively (P < 0.05-0.01) with Duke Stages A-D classification of the primary tumors, tumor differentiation, and radicality (> 0.7-0.8 mm) of resected liver metastases. CONCLUSIONS: The presence of p53 mutations in patients with metastatic lesions was related significantly (P < 0.003) to better survival after the patients underwent liver resection compared with patients with wild type p53 in their metastatic lesions. This finding was not related to covariates, such as Duke classification, tumor differentiation, type of liver metastasis, or metastatic radicality during resections. Explanations for this unexpected finding remain unclear, although the authors speculate that occult tumor cells with p53 mutations may be less responsive to growth factor(s) exposure during hepatic regeneration after resection.

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.

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.

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.

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.

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.

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.

The effect of recombinant human IGF-I on protein metabolism in post-operative patients without nutrition compared to effects in experimental animals.

This study has evaluated the effects of recombinant human insulin-like growth factor I (rhIGF-I) to moderately stressed post-operative patients provided with dextrose as the only exogeneous substrate. Thirty patients who underwent elective colorectal surgery were randomized to receive either rhIGF-I (80 micrograms kg-1 bw) subcutaneously twice daily or placebo injections in a double-blind parallel group design. Nitrogen balance, urinary 3-methyl-histidine excretion plasma growth hormone (GH), serum cortisol, IGF-I binding proteins (IGFBP-1,3), glomerular filtration rate, plasma amino acid concentrations and whole-body energy expenditures were measured as effector variables during days 1-5 post-operatively. Animal and isolated tissue experiments were performed as additional control experiments to confirm cellular effectiveness of the recombinant material. rhIGF-I increased significantly the glomerular filtration rate and prevented the adaptive decrease in whole-body energy expenditure in response to partial starvation in the postoperative period. Serum and plasma concentrations of IGFBP-1,3 cortisol, blood glucose and amino acids were not significantly influenced by rhIGF-I administration, while plasma GH levels decreased significantly as expected. rhIGF-I had no effect on either nitrogen balance or protein breakdown (3-methylhistidine excretion) in post-operative patients on dextrose supplementation only, although plasma concentrations of IGF-I increased from 130-140 ng mL-1 to a range of 300-450 ng mL-1. In contrast, IGF-I stimulated the synthesis of both globular and myofibrillar proteins (+50%, P < 0.01), when given as a single dose (100 micrograms kg-1) 2 h before measurements of protein synthesis in skeletal muscles of overnight fasted adult mice. This stimulatory effect by IGF-I (1 microgram mL-1) was also confirmed by measurements of skeletal muscle protein synthesis in vitro (+40%, P < 0.05). Orally re-fed mice had a normal transcription of IGF-I mRNA in skeletal muscle cells, while overnight fasted mice showed a trend to down-regulated transcription. Our results demonstrate that rhIGF-I has several significant physiological effects, without major side-effects, when supplied to partially starved patients in the post-operative phase. The lack of a whole-body nitrogen sparing effect by rhIGF-I alone to post-operative patients is not clear, but was most likely explained by subnormal plasma concentrations of amino acids.

Exercise capacity in patients undergoing proctocolectomy and small bowel resection for Crohn's disease.

The effect of proctocolectomy and small bowel resection on working capacity has not been assessed objectively in previous research. Twenty-nine patients with Crohn's disease were investigated with cycle ergometry and a questionnaire, following proctocolectomy with and without small bowel resection. Maximal exercise load is known to correspond well with working capacity, particularly when account is taken of body composition and metabolic variables. Maximal exercise load was reduced marginally (by 9 per cent) in patients without small bowel resection and by 22 per cent in patients with moderate small bowel resection (15-30 per cent resection). Patients with extensive bowel resection (more than 50 per cent) had a 40 per cent reduction in the maximal exercise load. This reduction in maximal exercise load was greater than predicted when accounting for reduction in muscle mass. All patients had a normal oxygen uptake including resting energy expenditure. Urinary sodium and magnesium excretion was low in the group with moderate bowel resection, whereas the extensively resected patients were malnourished and had a reduced body cell mass. The authors conclude that the significantly reduced working capacity was of multifactorial origin secondary to malabsorption. However, the patients seemed unaware of the degree of their diminished working capacity. This reduced capacity makes it unlikely that they would be able to perform any labour involving high energy consumption at the level of 500-700 W, and this inability was reflected by a high rate of unemployment among the patients.

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.

Results of screening, rescreening, and follow-up in a prospective randomized study for detection of colorectal cancer by fecal occult blood testing. Results for 68,308 subjects.

All 68,308 inhabitants of Göteborg born between 1918 and 1931 were randomly divided into a test and a control group. The subjects in the test group were invited to perform Hemoccult II fecal occult blood testing on 3 days and to repeat the test after 16 to 24 months. In the prevalence screening 21,347 (63%) performed the test, and in the rescreening 19,991 (60%). Investigation of the 942 (4.4%) with positive tests in the prevalence screening showed 47 cancers and 129 subjects with adenomas > or = 1.0 cm. In the rescreening 5.1% had a positive test, and 34 cancers and 122 subjects with adenomas (> or = 1.0 cm) were found among those. Cancer had also been diagnosed in 19 subjects in the interval between the two screening occasions and in 15 subjects among the non-responders. Forty-four cancers had been diagnosed in the control group during the same period. Cancers detected by screening were at a less advanced stage than in the control group. It is too early to show any effect of screening on mortality from colorectal cancer.

Follow-up after screening for colorectal neoplasms with fecal occult blood testing in a controlled trial.

PURPOSE: The aim of this study was to investigate the number of new colorectal neoplasms during the first seven years after the end of rescreening in a prospective randomized screening study. METHODS: 27,700 inhabitants of Göteborg born between 1918 and 1922 (60-64 years old) who were randomly allocated to a control or a test group in 1982 were followed up. All people in the latter group were offered six fecal occult blood tests and rescreening 16 to 22 months later. RESULTS: One hundred one carcinomas were diagnosed in the screened group and 128 in the control group during the seven years of follow-up. The number of carcinomas in the test group was half that in the control group during the first two years of follow-up, but equal during the rest of the follow-up period. The distribution of carcinomas according to Dukes classification was significantly better among the participants compared with the refusers (P < 0.02) but there was no difference in the Dukes distribution when the test and control groups as a whole were compared. The number of adenomas in the two groups during seven years of follow-up was the same. CONCLUSION: The results indicate that screening and rescreening of a population has little influence upon the stage of the carcinomas in the test group compared with a control group during the first seven years of follow-up. The number of carcinomas was higher in the control than in the test group during the follow-up, probably because of a lead time effect during the screening.