Colorectal cancer screening with fecal immunochemical testing or primary colonoscopy: An analysis of health equity based on a randomised trial.

Background: We have addressed health equity attained by fecal immunochemical testing (FIT) and primary colonoscopy (PCOL), respectively, in the randomised controlled screening trial SCREESCO conducted in Sweden. Methods: We analysed data on the individuals recruited between March 2014, and March 2020, within the study registered with ClinicalTrials.gov, NCT02078804. Swedish population registry data on educational level, household income, country of birth, and marital status were linked to each 60-year-old man and woman who had been randomised to two rounds of FIT 2 years apart (n = 60,123) or once-only PCOL (n = 30,390). Furthermore, we geo-coded each study individual to his/her residential area and assessed neighbourhood-level data on deprivation, proportion of non-Western immigrants, population density, and average distance to healthcare center for colonoscopy. We estimated adjusted associations of each covariate with the colonoscopy attendance proportion out of all invited to respective arms; ie, the preferred outcome for addressing health equity. In the FIT arm, the test uptake and the colonoscopy uptake among the test positives were considered as the secondary outcomes. Findings: We found a marked socioeconomic gradient in the colonoscopy attendance proportion in the PCOL arm (adjusted odds ratio [95% credibility interval] between the groups categorised in the highest vs. lowest national quartile for household income: 2·20 [2·01-2·42]) in parallel with the gradient in the test uptake of the FIT × 2 screening (2·08 [1·96-2·20]). The corresponding gradient in the colonoscopy attendance proportion out of all invited to FIT was less pronounced (1·29 [1·16-1·42]), due to higher proportions of FIT positives in socioeconomically disadvantaged groups. Interpretation: The unintended risk of exacerbating inequalities in health by organised colorectal cancer screening may be higher with a PCOL strategy than a FIT strategy, despite parallel socioeconomic gradients in uptake. Funding: This work was supported by the Swedish Cancer Society under Grant 20 0719. CB and US provided economic support from the Swedish Research Council for Health, Working life, and Welfare under Grant 2020-00962.

Aspects of colorectal cancer screening, methods, age and gender.

Colorectal cancer (CRC) is, besides breast, prostate, lung and skin cancers, the most common cancer worldwide and is suitable for screening. The incidence of CRC varies considerably in different parts of the world: in well-developed countries, the incidence is between 30 and 70 per 100 000 inhabitants, whereas in less-developed countries such as sub-Saharan Africa, it is 10-20/100 000 inhabitants. Women have a lower incidence of CRC, which is usually one-third of total incidence. Several studies have shown that it is possible to decrease mortality from CRC with about 20%, which is evidenced through the data from countries with screening programmes. Though the method of choice to identify blood samples in faecal matter is under debate, the most feasible way is to perform colonoscopy. Other methods include more advanced faecal analyses, testing for mutations from CRC, sigmoidoscopy, CT colonoscopy or optical colonoscopy. Colonoscopy is in most countries not available in sufficient amount and has to be carried out with great accuracy; otherwise, lesions will be missed to identify, thus leading to complications. Gender is an issue in CRC screening, as women have about 20% fewer colorectal adenomas and CRCs, but they also have more right-sided lesions, which are more difficult to detect with tests for faecal blood since they create less blood in faeces. Thus, other strategies may have to be developed for women in order for screening to have the same effect. It is essential to introduce colorectal cancer screening in all countries together with other clinical pieces of advice such as information on smoking, obesity and exercise in order to reduce one of the most dangerous cancers.

Cost-effectiveness of high-sensitivity faecal immunochemical test and colonoscopy screening for colorectal cancer.

BACKGROUND: Colorectal cancer screening can decrease morbidity and mortality. However, there are widespread differences in the implementation of programmes and choice of strategy. The primary objective of this study was to estimate lifelong costs and health outcomes of two of the currently most preferred methods of screening for colorectal cancer: colonoscopy and sensitive faecal immunochemical test (FIT). METHODS: A cost-effectiveness analysis of colorectal cancer screening in a Swedish population was performed using a decision analysis model, based on the design of the Screening of Swedish Colons (SCREESCO) study, and data from the published literature and registries. Lifelong cost and effects of colonoscopy once, colonoscopy every 10 years, FIT twice, FIT biennially and no screening were estimated using simulations. RESULTS: For 1000 individuals invited to screening, it was estimated that screening once with colonoscopy yielded 49 more quality-adjusted life-years (QALYs) and a cost saving of €64 800 compared with no screening. Similarly, screening twice with FIT gave 26 more QALYs and a cost saving of €17 600. When the colonoscopic screening was repeated every tenth year, 7 additional QALYs were gained at a cost of €189 400 compared with a single colonoscopy. The additional gain with biennial FIT screening was 25 QALYs at a cost of €154 300 compared with two FITs. CONCLUSION: All screening strategies were cost-effective compared with no screening. Repeated and single screening strategies with colonoscopy were more cost-effective than FIT when lifelong effects and costs were considered. However, other factors such as patient acceptability of the test and availability of human resources also have to be taken into account.

High dose ursodeoxycholic acid in primary sclerosing cholangitis does not prevent colorectal neoplasia.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have a high risk of developing colorectal cancer and dysplasia. Ursodeoxycholic acid (UDCA) has been suggested to have chemopreventive effects on the development of colorectal cancer and dysplasia but long-term data and larger trials are lacking. AIM: To evaluate the effect of high dose (17-23 mg/kg/day) UDCA on colorectal neoplasia in a cohort of patients with PSC and IBD. METHODS: From our previous 5-year randomised controlled trial of UDCA vs. placebo in PSC, we performed a follow-up of 98 patients with concomitant IBD from entry of the trial 1996-1997 until 2009 for development of colorectal cancer or dysplasia. RESULTS: The total follow-up time was 760 person-years. Dysplasia/cancer-free survival was compared between placebo- (n = 50) and UDCA-treated (n = 48) patients. There was a similar frequency of dysplasia or cancer after 5 years between patients originally assigned to UDCA or placebo (13% vs. 16%) and no difference in dysplasia/cancer-free survival (P = 0.46, log rank test). At the end of 2009 no difference in cancer-free survival was detected, 30% of the placebo patients compared with 27% of UDCA patients had developed colorectal cancer or dysplasia. CONCLUSIONS: Long-term high dose ursodeoxycholic acid does not prevent colorectal cancer or dysplasia in patients with primary sclerosing cholangitis-associated inflammatory bowel disease.

Risk of ischaemic heart disease and cardiomyopathy in patients with haemochromatosis and in their first-degree relatives: a nationwide, population-based study.

BACKGROUND: Iron-loaded macrophages increase atherosclerosis formation. Genetic haemochromatosis (GH) is an autosomal recessive disease characterized by iron overload, for example in the myocardium, but the reticuloendothelial system is depleted of iron. In contrast to the elevated risk of cardiomyopathy in GH, the risk of ischaemic heart disease (IHD) may therefore not be increased. Little is known of these risks among heterozygotes also being first-degree relatives (FDRs), thus sharing other factors for phenotypic expression of GH. OBJECTIVE: To assess the risks of IHD and cardiomyopathy among haemochromatosis patients and their FDRs. DESIGN: Population-based cohort study. SETTING AND SUBJECTS: A total of 3531 haemochromatosis patients and 11 794 FDRs were identified using nationwide, population-based health and census registers. Matched (1:10) population controls were randomly selected. Individuals with a record of IHD and cardiomyopathy during 1997-2005 were identified through linkage with the National Patient Register. Relative risks were estimated using Cox proportional hazard regression. RESULTS: Of the 3531 patients, 259 were diagnosed with IHD compared with 3077 of the 37 369 controls [hazard ratio (HR) = 1.17; 95% CI, 1.03-1.33]. Based on 30 patients versus 115 controls, the HR for cardiomyopathy was 3.21 (95% CI, 2.15-4.81). Of 11 794 FDRs of haemochromatosis patients, 582 were registered with IHD compared with 6197 among FDRs of controls (HR = 1.05; 95% CI, 0.97-1.15). Based on 28 FDRs of patients versus 291 FDRs of controls registered with cardiomyopathy, the HR for cardiomyopathy was 1.06 (95% CI, 0.72-1.56). CONCLUSIONS: In patients with haemochromatosis, the increased risk of cardiomyopathy is much more pronounced than that of IHD, which is barely elevated. FDRs of haemochromatosis patients are not at increased risk of cardiomyopathy or IHD.

The burden of hepatitis C in Sweden: a national study of inpatient care.

The spread of hepatitis C virus (HCV) in Sweden in the 1970s indicated that serious liver complications (SLC) would increase in the 2000s. The aim of this study was to analyse the burden of HCV-associated inpatient care in Sweden, to demonstrate the changes over time and to compare the findings with a noninfected population. The HCV-cohort (n: 43,000) was identified from the national surveillance database 1990-2006, and then linked to national registers to produce an age-, sex-, and region-matched noninfected comparison population (n: 215,000) and to obtain information on demographics, cancers, inpatient care and prescriptions. Cox regression was used to estimate the likelihood (hazard ratios) for admission to hospital in the HCV compared with the noninfected cohort. The hazard ratios were 4.03 (95% CI: 3.98-4.08) for all care, 77.52 (71.02-84.60) for liver-related care and 40.74 (30.58-54.27) for liver cancer care. The admission rate in the HCV-cohort compared with the noninfected cohort, the rate ratio (age- and sex-adjusted) for all inpatient care was 5.91 (95% CI: 5.87-5.94), and the rate ratio for liver-related care was 70.05 (66.06-74.28). In the HCV-cohort, 45% of all episodes were for psychiatric, mostly drug-related, care. Inpatient care for SLC increased in the 2000s. To conclude, drug-related care was common in the HCV-infected cohort, the demand for liver-related care was very high, and SLC increased notably in the 2000s, indicating that the burden of inpatient care from serious liver disease in HCV-infected individuals in Sweden is an increasing problem.

Detection and characterization of focal liver lesions with contrast-enhanced ultrasonography in patients with hepatitis C-induced liver cirrhosis.

BACKGROUND: Hepatitis C virus (HCV)-associated liver cirrhosis provides a major preneoplastic condition for hepatocellular carcinoma (HCC). Ultrasonography (US) is usually used for screening of HCC, but needs improvement. PURPOSE: To assess whether use of a second-generation ultrasound contrast agent can improve characterization of focal liver lesions and detection of HCC in HCV-infected patients with liver cirrhosis. MATERIAL AND METHODS: In total, 96 US studies in 49 HCV-infected patients with liver cirrhosis were performed. The patients were first examined with a baseline US. After this, a diagnostic decision was made and recorded. The patients were then re-examined with contrast-enhanced ultrasound (CEUS), and the diagnostic triage was repeated. The patients were followed up for at least 1 year. RESULTS: On baseline US, indeterminate focal lesions were found in 27 examinations. After CEUS, a confident diagnosis of HCC was made in eight of these examinations. In an additional eight US examinations, diagnosis of regenerative/dysplastic noduli was established. In one patient with no detectable focal lesion at baseline examination, an indeterminate malignant lesion was detected with CEUS. This lesion was further investigated with computed tomography and diagnosed as HCC. CONCLUSION: Our study indicates that the use of CEUS significantly improves diagnostic confidence. CEUS improves the detection of HCC in patients with HCV-induced liver cirrhosis. Also, CEUS makes it possible to rule out malignancy in many cases where baseline US shows indeterminate focal lesions. In low-endemic countries, the use of CEUS in screening for HCC may be considered.

Sporadic adenomatous polyp regression with exisulind is effective but toxic: a randomised, double blind, placebo controlled, dose-response study.

BACKGROUND AND AIMS: A 12 month, multicentre, randomised, double blind, placebo controlled, phase 3, dose-response study was carried out. Exisulind inhibits tumour growth by induction of apoptosis. The aim of our study was to investigate if exisulind induces regression of sporadic colonic adenomas. PATIENTS AND METHODS: A 12 month multicentre randomised double blind placebo controlled phase 3 dose response study was carried out. At baseline colonoscopy, left sided polyps (3-10 mm) were tattooed, measured, and left in place. Subjects received exisulind 200 or 400 mg, or placebo daily. Follow up sigmoidoscopy was performed after six months, and removal of any remaining polyps at the 12 month colonoscopy. The primary efficacy variable was change in polyp size from baseline. RESULTS: A total of 281 patients were enrolled and randomised; 155 (55%) fulfilled the criteria for the intention to treat (ITT) analysis and 114 (41%) fulfilled the criteria for the efficacy evaluation analysis (patients who underwent the 12 month colonoscopy). The decrease in median polyp size was significantly greater (p=0.03) in patients who received exisulind 400 mg (-10 mm2) compared with those who received placebo (-4 mm2). Complete or partial response was significantly higher in the exisulind 400 mg group (54.6%) compared with the placebo group (30.2%), and disease progression was significantly lower (6.1% v 27.9%) (p=0.04 and 0.02, respectively). Increased liver enzymes (8.4%) and abdominal pain (14.7%) were also reported at a greater frequency in the exisulind 400 mg group. CONCLUSION: Exisulind caused significant regression of sporadic adenomatous polyps but was associated with more toxicity. This model of polyp regression, short in its term and involving a comparatively small patient sample size, may be the best available tool to assess a therapeutic regimen before launching into large preventive clinical studies.

Virtual reality colonoscopy simulation: a compulsory practice for the future colonoscopist?

BACKGROUND AND STUDY AIM: As for any manual procedure, the learning curves for medical interventions can have undesirable phases, occurring mostly in the early experience of applying a technique. There have been impressive advances in endoscopic procedures during recent years, and there is an emerging trend that the number of procedures is increasing in parallel with these. In addition, the introduction of screening programs for colorectal cancer will also increase the numbers of procedures needed. Recent developments in medical simulation seem promising with regard to the possibility of "training out" undesirable parts of the learning curve outside the operating room. The aim of this study was to investigate whether the use of the AccuTouch flexible endoscopy simulator improves the early part of the learning curve in colonoscopy training. METHOD: 12 endoscopy trainees, 10 surgeons and two medical gastroenterologists, all with experience in gastroscopy but with no specific colonoscopy experience, were randomly assigned to either simulator training or to a control group. They all received the same theoretical study package and the training group practiced with the AccuTouch colonoscopy simulator until a predefined expert level of performance was reached. All trainees performed their first ten individual colonoscopies described in detail in a separate protocol. RESULTS: Trainees in the simulator-trained group performed significantly better (P=0.0011) and managed to reach the cecum in 52% of their cases (vs. 19% in the control group), and were 4.53 times more likely to succeed compared with the controls. Additionally, there was a significantly shorter procedure time and less patient discomfort in the hands of the simulator-trained group. CONCLUSION: Skills acquired using the AccuTouch simulator transfer well into the clinical colonoscopy environment. The results of this trial clearly support the plan to integrate simulator training into endoscopic education curricula.

An open, randomized, controlled study of transdermal hormone replacement therapy on the rate of bone loss in primary biliary cirrhosis.

OBJECTIVES: The prevalence of osteoporosis amongst patients with primary biliary cirrhosis (PBC) is high and may be a serious clinical problem. Hormone replacement therapy (HRT) is effective in preventing bone loss but has not been evaluated in randomized trials in PBC. The primary aim was to study the effect of transdermal HRT in combination with daily vitamin D and calcium supplementation on bone loss compared with vitamin D and calcium supplementation only in postmenopausal women with PBC. The secondary aim was to study the safety of transdermal HRT. SUBJECTS/INTERVENTIONS: Eighteen females with PBC were randomized to receive 2 years therapy with either (i) transdermal oestradiol 50 microg 24 h(-1) two times per week + medroxyprogesterone 2.5 mg day(-1) + alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1) or (ii) alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1). Dual-energy X-ray absorptiometry for measurement of bone mineral density (BMD) and sampling of blood and serum for measurements of biochemical markers of liver function was performed before, during and at the end of treatment. RESULTS: BMD increased significantly at the lumbar spine (P < 0.05) and the femoral neck (P < 0.05) in the HRT group whereas no significant change was found in the control group. One oestrogen-treated patient was excluded after 1 year because of deteriorating, but reversible, aminotransferases. Dropout frequency because of nonliver-related causes was higher in the HRT group. Otherwise, no difference with respect to adverse liver reactions was found between the groups. CONCLUSION: Transdermal HRT increases BMD in PBC patients with few severe side effects related to the liver.

Tumour necrosis factor alpha and its promoter polymorphisms' role in the phenotypic expression of hemochromatosis.

BACKGROUND: The majority of hemochromatosis patients are homozygous for the HFE-C282Y mutation. However, less than half of C282Y homozygous subjects identified by population screening studies actually develop the disease. The cytokine TNF-alpha is implicated in the regulation of iron metabolism at different levels. Our aim was to study the role of TNF-alpha and its promoter polymorphisms in the phenotypic expression of hemochromatosis in individuals with and without the C282Y mutation. METHODS: We studied 4 groups of 10 subjects each: (1) C282Y homozygotes without clinical hemochromatosis; (2) C282Y homozygotes with hemochromatosis; (3) secondary hemochromatosis (without C282Y mutation); and (4) controls. Groups were age-matched and sex-matched. Peripheral blood mononuclear cells (PBMC) were stimulated with lipopolysaccharide (LPS) and the release of TNF-alpha was measured. Additionally, the G/A polymorphisms at position -238 and -308 of the TNF-alpha, gene were determined by PCR and RFLP analysis in 178 hemochromatosis patients and 41 controls. RESULTS: TNF-alpha production from PBMC at 8 and 24 h after increasing concentrations of LPS stimulation were similar in the four groups. The prevalence of TNF-alpha polymorphisms was similar in patients and controls. The prevalences of cirrhosis, siderosis, median s-ferritin and median ALT values were similar in patients with and without the TNF-alpha polymorphisms. CONCLUSIONS: Neither TNF-alpha, released from PBMC nor the presence of TNF-alpha polymorphisms seem to be associated with disease manifestation in hemochromatosis.

Psychological factors in irritable bowel syndrome: a population-based study of patients, non-patients and controls.

BACKGROUND: It has been suggested that psychopathology in irritable bowel syndrome (IBS) patients is a function of patient status rather than of the disease. Although there are many studies comparing IBS patients, IBS non-patients, and controls with each other, no previous study has recruited all three groups from a representative community sample and had all subjects diagnosed by a physician. In the present study we aimed to compare psychological factors in IBS patients, IBS non-patients, and normal controls in a sample recruited from the population. METHODS: Subjects aged 18-45 years were recruited from a random sample of the normal population. Seventeen (2 M and 15 F) IBS patients were matched by sex and age with IBS non-patients and normals. Measures of personality traits, interpersonal distress, and temporary psychological distress were used. A physician diagnosed all 51 subjects in order to exclude possible gastrointestinal diagnoses other than IBS. RESULTS: Controls often differed from IBS non-patients and patients on the personality, interpersonal, and psychological distress measures, while IBS non-patients and patients very rarely differed from each other. All three groups were non-alexithymic. CONCLUSIONS: The results indicate that there are psychopathological differences between normals and IBS persons (patients and non-patients), but they could not confirm that psychopathology was a function of patient status. Whether this psychopathology is a vulnerability factor for IBS, or a consequence of it, remains to be studied.

Psychological Factors in Irritable Bowel Syndrome: a Population-based Study of Patients, Non-patients and Controls.

BACKGROUND: It has been suggested that psychopathology in irritable bowel syndrome (IBS) patients is a function of patient status rather than of the disease. Although there are many studies comparing IBS patients, IBS non-patients, and controls with each other, no previous study has recruited all three groups from a representative community sample and had all subjects diagnosed by a physician. In the present study we aimed to compare psychological factors in IBS patients, IBS non-patients, and normal controls in a sample recruited from the population. METHODS: Subjects aged 18-45 years were recruited from a random sample of the normal population. Seventeen (2 M and 15 F) IBS patients were matched by sex and age with IBS non-patients and normals. Measures of personality traits, interpersonal distress, and temporary psychological distress were used. A physician diagnosed all 51 subjects in order to exclude possible gastrointestinal diagnoses other than IBS. RESULTS: Controls often differed from IBS non-patients and patients on the personality, interpersonal, and psychological distress measures, while IBS non-patients and patients very rarely differed from each other. All three groups were non-alexithymic. CONCLUSIONS: The results indicate that there are psychopathological differences between normals and IBS persons (patients and non-patients), but they could not confirm that psychopathology was a function of patient status. Whether this psychopathology is a vulnerability factor for IBS, or a consequence of it, remains to be studied.

Acquired platelet dysfunction may be an aetiologic factor in Heyde's syndrome--normalization of bleeding time after aortic valve replacement.

BACKGROUND: There is a well-documented relationship, with unknown aetiology, between aortic valve stenosis and occult gastrointestinal bleeding in elderly patients. Despite several studies attempting to determine the prevalence and to discuss the aetiology, there are still many unanswered questions. METHODS: A total of 288 consecutive patients with valvular aortic stenosis--mean age 73 +/- 9 years aortic stenosis group (ASG)--were compared with 129 pacemaker-treated patients, mean age 73 +/- 9 years control group (CG). Screening for occult blood in stools was performed in both groups. Those with a positive Hemocult test or a history of gastrointestinal bleeding were scheduled for further examination including upper endoscopy and colonoscopy. Template bleeding time was performed on patients in both groups and in patients with a prolonged bleeding time with an extended coagulation evaluation was carried out. Patients referred to aortic valve replacement and with a preoperatively prolonged bleeding time were re-examined after surgery. RESULTS: There was a significant difference in the number of subjects with prolonged bleeding time between groups (ASG 19; CG 2; P = 0.028). Re-examination of the bleeding time after aortic valve surgery revealed normalized values in nine of 12 (P = 0.0003). The number of patients with positive Hemocult test did not differ between groups (ASG 29; CG 12; NS). Comparison of the pressure gradient over the aortic valve demonstrated a significantly higher maximal gradient amongst patients with a preoperatively prolonged bleeding time (113 mm HG vs. 90 mmHG; P = 0.005). CONCLUSION: Prolonged bleeding time is related to valvular aortic stenosis and seems to be caused by acquired platelet dysfunction. The normalization of the bleeding time after valve surgery supports the hypothesis that the calcified cusps may interact with the platelet function.

Iron overload decreases the protective effect of tumour necrosis factor-alpha on rat hepatocytes exposed to oxidative stress.

BACKGROUND: Intracellular iron can participate in the formation of free radicals, leading to liver cell damage. This may be prevented by the ability of ferritin to oxidize and store iron. Tumour necrosis factor alpha (TNF-alpha) has been shown to increase the ferritin synthesis. In the liver, cytokines are secreted by activated Kupffer cells and T-lymphocytes. The aim of this study was to investigate the effects of TNF-alpha on normal and iron-loaded rat hepatocytes exposed to oxidative stress. METHODS: Primary cultures of hepatocytes from rats fed a normal rat chow or a carbonyl iron-enriched diet were incubated with TNF-alpha before incubation with tert-butyl hydroperoxide. Malondialdehyde concentrations, activities of lactate dehydrogenase, ferritin H and manganese superoxide dismutase mRNA and ferritin H protein were analysed. The total amounts of glutathione and chelatable iron were measured. RESULTS: TNF-alpha diminished the concentrations of malondialdehyde and activities of lactate dehydrogenase in hepatocytes exposed to tert-butyl hydroperoxide. This was seen in hepatocytes from normal but not iron-loaded animals. The transcription of manganese-superoxide dismutase mRNA was increased in both cell types, whereas total glutathione contents of cells were unaffected. The transcription and translation of ferritin H was induced in cells from normal but not from iron-loaded animals. The amount of chelatable iron was significantly lowered only in hepatocytes from normal rats. CONCLUSIONS: TNF-alpha protects rat hepatocytes from normal but not iron-loaded rats from oxidative stress. The protection may be due to an induction of the ferritin synthesis.

HLA class II markers and clinical heterogeneity in Swedish patients with primary biliary cirrhosis.

Genetic susceptibility to PBC can, at least in part, be ascribed to the major histocompatibility complex. The relevance of immunogenetic markers for the clinical presentation and course, however, is unclear. Thus, the aim of this study was to investigate the contribution of HLA class II genes to susceptibility, clinical presentation and course of disease in PBC patients. HLA genotyping for HLA-DRB1, -DQB1 and -DPB1 was carried out in a total of 99 Swedish PBC patients and 158 controls. Clinical parameters including epidemiologic variables, signs and symptoms of PBC-related liver disease and histologic data were collected and analyzed in 92 patients at study entry and at follow-up five years later. Significant clinical heterogeneity was seen among PBC patients upon study entry. Although a significant disease association was seen for HLA DRB1*08 and DQB1*0402, immunogenetic markers identified neither a particular subset of patients nor an association with the clinical course of the disease. HLA-DRB1*08 and DQB1*0402 provide the strongest immunogenetic influence in PBC. However, this association is not restricted to any particular, clinically defined subgroup of patients and it is not predictive for the course of the disease.

Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: cumulative risks and APC gene mutations.

BACKGROUND & AIMS: Patients with familial adenomatous polyposis (FAP) have a high prevalence of duodenal adenomas, and the region of the ampulla of Vater is the predilection site for duodenal adenocarcinomas. This study assessed the risk of stage IV periampullary adenomas according to the Spigelman classification and periampullary adenocarcinomas in Swedish FAP patients screened by esophagogastroduodenoscopy (EGD). The genotype of patients with stage IV periampullary adenomas and periampullary adenocarcinomas was also investigated. METHODS: A retrospective study of 180 patients screened by EGD in 1982-1999 was undertaken. Kaplan-Meier analysis was performed to evaluate cumulative risk. Mutation analysis was carried out in patients with periampullary adenocarcinomas diagnosed outside the screening program, in addition to patients in the screening group with stage IV periampullary adenomas and adenocarcinomas. RESULTS: Periampullary adenoma stage IV was diagnosed in 14 patients (7.8%), with a cumulative risk of 20% at age 60 years. Periampullary adenocarcinoma was diagnosed in 5 patients (2.8%), with a cumulative risk of 10% at age 60. Three of the adenocarcinomas occurred in patients with stage IV periampullary adenomas compared with 2 in patients with less severe periampullary adenomatosis at screening (odds ratio, 31; 95% confidence interval, 4.6-215). Fifteen (88%) of the APC gene mutations were detected; 12 of these were located downstream from codon 1051 in exon 15. CONCLUSIONS: The life time risk of severe periampullary lesions in FAP patients is high, and an association between stage IV periampullary adenomas and a malignant course of the periampullary adenomatosis is strongly suggestive. Mutations downstream from codon 1051 seem to be associated with severe periampullary lesions.

Outcome of primary and secondary ileal pouch-anal anastomosis and ileorectal anastomosis in patients with familial adenomatous polyposis.

PURPOSE: The aim of this study was to present Swedish experiences of the ileal pouch-anal anastomosis in patients with familial adenomatous polyposis from the introduction in 1984. The study also compared the surgical and functional outcome of different anal continence preserving procedures: ileal pouch-anal anastomosis as primary surgery, ileal pouch-anal anastomosis as secondary surgery after colectomy and ileorectal anastomosis, and ileorectal anastomosis alone. METHODS: The material comprises all 120 patients with familial adenomatous polyposis reported to the Swedish Polyposis Registry who had undergone prophylactic colorectal surgery, including those operated on because of colorectal cancer from 1984 until the end of 1996. Anal continence preserving surgery was performed on 102 patients: 20 had ileal pouch-anal anastomosis as primary surgery at a median age of 24.5 years, 39 had ileal pouch-anal anastomosis as secondary surgery at a median age of 34 years, and 43 had ileorectal anastomosis alone, at a median age of 26 years, because 6 of the initially ileorectal anastomosis-operated patients were converted to ileal pouch-anal anastomosis as secondary surgery. Surgical outcome was assessed on the basis of hospital records. A questionnaire was used to evaluate the functional outcome. Fisher's exact probability test was used for statistical analysis. RESULTS: Complications occurred in 51 percent of the patients after ileal pouch-anal anastomosis: 40 percent after ileal pouch-anal anastomosis as primary surgery and 56 percent after ileal pouch-anal anastomosis as secondary surgery. When the previous ileorectal anastomosis was taken into account 67 percent of the patients suffered complications which was significantly more compared with ileal pouch-anal anastomosis as primary surgery. After ileorectal anastomosis, 26 percent had complications which was significantly less compared with all other procedures but ileal pouch-anal anastomosis as primary surgery. No cancer occurred after ileal pouch-anal anastomosis, either in the ileal pouch or in retained rectal mucosa, but two of the patients who had an ileorectal anastomosis developed rectal cancer. One pouch excision was performed compared with ten rectal excisions. Functional outcome did not differ between ileal pouch-anal anastomosis as primary surgery and ileal pouch-anal anastomosis as secondary surgery. However, ileorectal anastomosis-operated patients had significantly better bowel function with regard to nighttime stool frequency, continence and perianal soreness. CONCLUSION: These findings indicate that major advantages of ileal pouch-anal anastomosis are the low excision rate and, so far, no cancer in the ileal pouch. Moreover, the surgical outcome of ileal pouch-anal anastomosis as primary surgery is not significantly different from that of ileorectal anastomosis. However, the good surgical and functional outcome of ileorectal anastomosis, despite the long-range prognosis including rectal cancer and excision risks, has to be taken into consideration when selecting patients with familial adenomatous polyposis for primary surgery.

Dynamic 99Tcm-HIDA SPET: non-invasive measuring of intrahepatic bile flow. Description of the method and a study in primary sclerosing cholangitis.

In this study dynamic 99Tcm-HIDA single photon emission tomography (SPET) was performed in patients with primary sclerosing cholangitis and normal test subjects. The method offers the possibility of functional analysis of individual liver segments. After injection of 120 MBq of 99Tcm-HIDA, 12 consecutive SPET examinations were performed at 6-min intervals. The segmental borders of liver segments as seen on computed tomography or magnetic resonance examinations were superimposed on the scintigraphic images allowing placement of regions of interest (ROIs) in specific liver segments. Sampling from the same ROIs in consecutive SPET images enabled creation of time-activity curves for individual liver segments. A range of normal values was created by quantitative analysis of normal volunteer studies. Results of the studies in patients correlated well with cholangiographic extent of disease, liver function tests and histological stage. The technique may have particular value in diseases that affect the liver in a nonhomogenous or segmental fashion. Giving an indication of bile clearance from individual liver segments, it can quantify the functional importance of radiologically detected strictures. Percutaneous liver biopsy can be directed to the worst affected parts of the liver, making biopsy more representative. Sequential studies may allow monitoring of disease progression, aiding in selection and timing of therapeutic procedures.