Genotype-defined cancer risk in juvenile polyposis syndrome.

BACKGROUND: Germline mutations in SMAD4 and BMPR1A disrupt the transforming growth factor ß signal transduction pathway, and are associated with juvenile polyposis syndrome. The effect of genotype on the pattern of disease in this syndrome is unknown. This study evaluated the differential impact of SMAD4 and BMPR1A gene mutations on cancer risk and oncological phenotype in patients with juvenile polyposis syndrome. METHODS: Patients with juvenile polyposis syndrome and germline SMAD4 or BMPR1A mutations were identified from a prospectively maintained institutional registry. Medical records were reviewed and the clinical patterns of disease were analysed. RESULTS: Thirty-five patients had germline mutations in either BMPR1A (8 patients) or SMAD4 (27). Median follow-up was 11 years. Colonic phenotype was similar between patients with SMAD4 and BMPR1A mutations, whereas SMAD4 mutations were associated with larger polyp numbers (number of patients with 50 or more gastric polyps: 14 versus 0 respectively). The numbers of patients with rectal polyps was comparable between BMPR1A and SMAD4 mutation carriers (5 versus 17). No patient was diagnosed with cancer in the BMPR1A group, whereas four men with a SMAD4 mutation developed gastrointestinal (3) or extraintestinal (1) cancer. The gastrointestinal cancer risk in patients with juvenile polyposis syndrome and a SMAD4 mutation was 11 per cent (3 of 27). CONCLUSION: The SMAD4 genotype is associated with a more aggressive upper gastrointestinal malignancy risk in juvenile polyposis syndrome.

Diagnostic yield of colonoscopy for constipation as the sole indication.

AIM: There is controversy over whether constipation as the only symptom should be an indication for routine diagnostic colonoscopy. The study was carried out to assess the prevalence of abnormal pathology on colonoscopy and to assess the risk factors for colonic neoplasia in patients with constipation but without 'high risk symptoms'. METHOD: A cross-sectional, single-centre study was conducted on individuals who underwent colonoscopy for constipation as the sole indication between 2005 and 2008. Standardized endoscopic and pathology reports were reviewed. Univariable and multivariable analyses were performed. RESULTS: A total of 786 patients (595 women, 75.7%; mean age, 57.4±13.5 years) underwent diagnostic colonoscopy for constipation. Forty-three (5.5%) had polyps, of whom 19 (2.4%) had hyperplastic polyps and 19 (2.4%) adenomas. No cancers were found. In patients with adenoma, the detection rate was 2.9% for patients below age 40 years and 1.7% for patients below age 50 years. Older age was associated with a polyp in both univariate and multivariate analysis. Gender, ethnicity and smoking were not associated with polyp or adenoma. CONCLUSION: Colonoscopy for patients with constipation as the sole indication had a lower yield of neoplastic lesions than that for patients undergoing routine screening colonoscopy. Colonoscopy in constipation may only be warranted in patients who are over 50 years of age.

Histamine receptor antagonists and incident colorectal adenomas.

BACKGROUND: Prior studies suggest that histamines may modulate the development of colorectal neoplasia. AIM: To assess whether histamine receptor antagonist use was associated with adenoma formation. METHODS: Patients (n = 2366) were drawn from three adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of adenoma(s) and were deemed free of remaining lesions; they were followed with surveillance colonoscopy. Medication use was assessed by questionnaire. Adjusted risk ratios for adenoma formation related to histamine receptor antagonist use (histamine H1 and H2 receptor, H1RA and H2RA) were determined using log linear models. RESULTS: In pooled analyses, H1RA exposure was not associated with subsequent adenoma risk (RR = 1.10; 95% CI 0.97-1.25) or multiple adenoma formation (RR = 0.85; 95% CI 0.67-1.07). H2RA use also was not associated with adenoma (RR = 0.90; 95% CI 0.77-1.06), or multiple adenoma (RR = 0.77; 95% CI 0.57-1.04) in the pooled analyses, but H2RA users in the first trial had a decreased risk of adenoma (RR = 0.70; 95% CI 0.48-1.03) and multiple adenoma (RR = 0.31; 95% CI 0.12-0.79). CONCLUSION: H2RA use was associated with reduced risk for adenoma in one trial, but not in the pooled analyses. Further study would be warranted before undertaking randomized trials of H2RAs for adenoma chemoprevention.

Fecal occult blood testing for colorectal cancer screening: use the finger.

OBJECTIVE: Fecal occult blood testing (FOBT) has been widely underused as a means of colorectal cancer screening. Less than 35% of Americans have had the recommended FOBT in the last 5 yr. Guidelines suggest FOBT of three spontaneously passed stools (SPS) on a prescribed diet. Testing stool obtained by digital rectal exam (DRE) is discouraged because its yield in colorectal cancer screening is unknown. The aim of this study is to compare the positive predictive value of FOBT for the detection of colorectal neoplasia done by SPS versus DRE in asymptomatic outpatients. METHODS: Medical records and endoscopic reports of all patients who underwent colonoscopy between 1984-1999 for a positive FOBT were reviewed. Only asymptomatic outpatients whose indication was colorectal cancer screening were included. The method of FOBT was confirmed as either SPS or DRE. Chi2 was used to compare the yield of detecting colorectal neoplasia between SPS and DRE. RESULTS: A total of 165 patients with a mean age of 61 yr (range 33-85) were included (84 patients were women). Neoplasia was detected in 29 of 80 (36%) with SPS and 28 of 85 (33%) with DRE (p = 0.18). CONCLUSIONS: The positive predictive value of FOBT on DRE for detecting neoplasia is similar to that of SPS in asymptomatic outpatients undergoing colorectal cancer screening. Positive FOBT on DRE warrants colonoscopic evaluation. Hemoccult testing by DRE may be performed in the office to increase patient compliance with colorectal cancer screening. A negative FOBT on DRE should be followed up with FOBT of SPS.

Familial adenomatous polyposis: efficacy of endoscopic and surgical treatment for advanced duodenal adenomas.

INTRODUCTION: Duodenal and periampullary cancer is the most common cause of cancer death in patients with familial adenomatous polyposis who have undergone colectomy. Endoscopic surveillance of upper gastrointestinal adenomas is recommended for patients with familial adenomatous polyposis but the timing and appropriate treatment of neoplasms is unknown. The purpose of this experiment was to report our experience with endoscopic and surgical treatment of advanced duodenal adenomas in patients with familial adenomatous polyposis. METHODS: The records of all patients with familial adenomatous polyposis who had undergone surgical or endoscopic treatment for duodenal adenomas were identified. Data including endoscopic surveillance findings, type of intervention, pathology, and follow-up of the lesions were reviewed. RESULTS: Ten neoplasms >1 cm were treated in eight patients (mean age at the time of diagnosis was 49 years). Nine lesions were histologically advanced. Five lesions involved the papilla. Endoscopic treatment was performed for six lesions. Four lesions recurred, and three were then treated surgically. Local resection was performed for five lesions. Four lesions recurred and two had further operative intervention. Pancreas-sparing duodenectomy was performed in three patients. At a mean follow-up period of 45.7 months, there has been no recurrence. CONCLUSIONS: Endoscopic eradication is an appropriate initial treatment for histologically advanced, noncancerous neoplasms or for patients who are not surgical candidates. Pancreas-sparing duodenectomy may be the treatment of choice for patients with carcinoma and those who have failed endoscopic therapy.

Colorectal cancer screening: making sense of the different guidelines.

Screening for colorectal cancer, as called for by new guidelines from three different groups, should result in a lower mortality rate from this disease. This paper reviews the guidelines' similarities and differences and gives our recommendations for situations in which the data remain incomplete and controversy persists.

The natural history of untreated duodenal and ampullary adenomas in patients with familial adenomatous polyposis followed in an endoscopic surveillance program.

BACKGROUND: Endoscopic surveillance is recommended for patients with familial adenomatous polyposis (FAP) because of the high prevalence of duodenal adenomas and the risk of periampullary cancer. The aim of this study was to assess the natural history of untreated duodenal and ampullary adenomas in FAP patients during surveillance. METHODS: One hundred fourteen FAP patients who had 2 or more surveillance examinations were followed for a mean of 51 months (range, 10 to 151 months). RESULTS: Duodenal polyps progressed in size in 26% (25 of 95), number in 32% (34 of 106), and histology in 11% (5 of 45) of patients. Morphology and histology of the main duodenal papilla progressed in 14% (15 of 110) and 11% (12 of 105) of patients, respectively. The histologic progression was mild except for one patient who developed a periampullary cancer. CONCLUSIONS: A minority of FAP patients had progression of endoscopic features and histology of duodenal polyps or the main duodenal papilla when followed over 4 years. An endoscopic surveillance interval of at least 3 years may be appropriate for the majority of untreated patients with FAP. Factors that stratify patients as being at the highest risk of periampullary cancer and thus requiring more intensive surveillance are yet to be determined.

Effect of pneumatic dilation on gastroesophageal reflux in achalasia.

The aims of this study were to assess the effect of pneumatic dilation on gastroesophageal reflux in achalasia, differentiate esophageal acid due to lactate from acid due to gastroesophageal reflux, and determine if chest pain and heartburn are reliable indicators of gastroesophageal reflux. Eight untreated achalasia patients underwent pre- and postdilation esophageal fluid/food residue lactate and pH analysis, esophageal manometry, 24-hr pH monitoring, and symptom assessment. All patients had a successful clinical outcome and a decrease in lower esophageal sphincter pressure from 29.1 +/- 12.7 to 14.7 +/- 3.8 mm Hg (mean +/- SD; P = 0.04). Abnormal acid exposure was present in two patients before and two patients after dilation. Postdilation acid exposure was mild. Lactate was detected before dilation in all patients. A lactate concentration >2 mmol/liter was associated with acidic residue and one abnormal 24-hr pH profile. There was no correlation between an abnormal 24-hr pH test and age, lower esophageal sphincter pressure, or duration of symptoms prior to treatment. Chest pain and heartburn were unrelated to drops in pH. Gastroesophageal reflux is rare in untreated achalasia and esophageal acidity may result from ingestion of acidic foods or production of lactate. Mild gastroesophageal reflux occurs after dilation but is of no clinical significance. Chest pain and heartburn are not indicators of acid reflux in achalasia.

Diagnosis and management of gastroduodenal polyps.

Upper gastrointestinal polyps are rare but common in the gastrointestinal polyposis syndromes. Although the majority of upper gastrointestinal polyps have no prognostic importance, they must be distinguished from the minority with an associated cancer risk.

Use of pancreatic Schilling test to determine efficiency of pancreatic enzyme delivery in pancreatic insufficiency.

The pancreatic Schilling test (PST), a noninvasive, sensitive pancreatic function test, was studied to determine its ability to detect pancreatic proteolytic enzyme replacement in patients with pancreatic insufficiency. Seven subjects with well-documented pancreatic insufficiency and an abnormal PST consistent with pancreatic insufficiency were studied with three enzyme regimens: (1) Viokase (four tablets), (2) Pancrease (three capsules), and (3) Pancrease (10 capsules). The effect of cimetidine on the results of the PST with high-dose Pancrease was also determined in two subjects with pancreatic insufficiency and in two normal volunteers. The results of the investigation demonstrate that the PST is a sensitive noninvasive test for the presence of orally administered proteolytic enzymes in subjects with pancreatic insufficiency and in normals. Furthermore, the studies illustrate that the administration of enzymes in a form of enteric-coated microspheres does not enhance the delivery of proteolytic enzymes to the small intestine when compared to conventional high-dose enzyme replacement. Cimetidine appears to decrease the inactivation of the proteolytic enzymes in enteric-coated microspheres, suggesting that a low pH in the small intestine and stomach are responsible for the poor delivery of the enzymes into the small intestine.

Lactoferrin secretion in alcoholic pancreatic disease.

Lactoferrin, a nonenzyme protein normally secreted in small amounts in pancreatic juice, has been reported by several investigators to be secreted in large amounts in chronic pancreatitis. Whether this increased secretion first occurs at an early or late stage of alcoholic pancreatic disease is unknown. In this study we measured lactoferrin and enzyme outputs in duodenal juice from 10 healthy subjects and three groups of alcoholic subjects: asymptomatic chronic alcoholics without evidence, clinically or biochemically, of pancreatitis (10), those recovered from acute pancreatitis (8), and those with established chronic pancreatitis (8). A multilumen, marker-perfused duodenal catheter was used to aspirate basal pancreatic secretions at the ligament of Treitz. The mean ( +/-SE) lactoferrin concentration in duodenal juice for the four groups of subjects was: healthy, 0.7 +/- 0.1 micrograms/ml; asymptomatic alcoholics, 5.5 +/- 1.5 micrograms/ml; alcoholics who had recovered from acute pancreatitis, 7.4 +/- 0.8 micrograms/ml; and alcoholics with chronic pancreatitis 7.1 +/- 1.9 micrograms/ml. The three groups of alcoholics each had a greater lactoferrin concentration than the normals (P less than 0.005). The output of lactoferrin in the four groups paralleled the concentration in that the three groups of alcoholics had a significantly greater output: healthy subjects, 3.4 +/- 0.5 micrograms/kg/hr; asymptomatic alcoholics, 25.7 +/- 7.4 micrograms/kg/hr; alcoholics recovered from acute pancreatitis, 80.1 +/- 27 micrograms/kg/hr; and alcoholics with chronic pancreatitis, 90.9 +/- 32 micrograms/kg/hr. The output of chymotrypsin and trypsin in the four groups of subjects revealed increased secretory rates in the asymptomatic alcoholics and the alcoholics recovered from acute pancreatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Cancer incidence and mortality in the Du Pont Company: an update.

In a previous publication, Pell et al described the cancer epidemiologic surveillance program that was begun in the Du Pont Company in 1956 and presented standardized cancer incidence and mortality data through 1974 for Du Pont employees compared with such data for the US general population. This report provides the analysis of an additional 10 years of cancer incidence and mortality data, and examines time trends for specific cancer sites. Conoco, Inc, acquired in 1981, is not included in the analysis.

Role of cholecystokinin in intestinal phase of human pancreatic secretion.

In this study we have utilized a sensitive and specific radioimmunoassay for cholecystokinin (CCK) to determine the effects of a jejunal infusion (5 cc/min) of amino acids (44 g/liter), saline, and amino acids with intravenous atropine (20 micrograms X lg-1 X hr) on pancreatic exocrine secretion. Amino acids were found to stimulate pancreatic output of trypsin and release CCK, while a saline infusion at the same rate and osmolality (320 mosm/liter) failed to do so. In the presence of atropine, the amino acid infusion did not stimulate the pancreatic output of trypsin, despite an augmented CCK release. The total CCK released above baseline was greatest with the infusion of amino acids with atropine, while the total trypsin output above baseline was greatest with the infusion of amino acids. These results indicate that CCK release is not under cholinergic control and that cholinergic blockade inhibits pancreatic secretion by interrupting stimulating cholinergic fibers to the pancreas.

Cancer incidence and mortality among workers exposed to acrylonitrile.

A cohort of 1,083 male employees who had potential for exposure to acrylonitrile between 1944 and 1970 at a Du Pont textile fibers plant were followed through 1981 for mortality and through 1983 for cancer incidence. In total, the 21 cancer deaths were fewer than expected based on either Du Pont or U.S. rates. No significant excesses were seen by primary site. In all, 37 cancer cases occurred as compared with 36.5 expected based on company rates. Five lung cancer cases were observed and 6.9 expected. There were 5 prostate cancer cases as compared with 1.9 expected. Of these, 4 occurred among wage employees during the 1975-1983 period, compared to 0.9 expected. This excess was statistically significant.

A statistical view of clinical trials in chronic hepatitis B.

From a review of thirty published papers it is clear that the variety of options for treatment of hepatitis B have led to a large number of small exploratory trials. However, small groups lead to imprecise estimates of seroconversion rates; for example a result of 4/10 gives an estimate of 40% with 80% confidence limits of 20% and 60%. A number of possible prognostic factors have been proposed and, whilst their importance is generally unproven, their estimated effects are considerable. Comparison between studies can therefore be misleading; for example comparing two treatments A and B of identical efficacy in two common populations could give a 1 in 4 chance of declaring B to give double the seroconversion rate of A. Larger, randomised, controlled trials on homogeneous patient groups are needed to give conclusive evidence of the efficacy or otherwise of various treatment regimes.

Role of cholecystokinin in the regulation of the interdigestive phase of pancreatic secretion.

The rate of pancreatic secretion during the interdigestive state varies with the phase of interdigestive motility. During phases II and III of interdigestive motility, pancreatic secretion is greatest, and minimal during phases I and IV. Pancreatic polypeptide and motilin have been reported to be increased during phases II and III but do not appear to be responsible for the stimulation of pancreatic secretion. We have investigated the role of cholecystokinin (CCK) in regulating pancreatic secretion during the interdigestive state. Eight volunteers underwent a study of interdigestive duodenal motility with a catheter that collected pancreatic secretions at the ligament of Treitz. The phase of motility was correlated with the output of trypsin and the plasma CCK levels. The output of trypsin during phases II and III was 0.9 +/- 0.2 and 1.0 +/- 0.2 mg/kg/h, respectively, and decreased to 0.3 +/- 0.1 mg/kg/h during phase IV-I (p less than 0.05). To determine if the output of trypsin during phases II and III was responsible for the increases in plasma CCK, the effect of intraduodenal trypsin, 3 mg/kg/h, in five volunteers was determined. The infusion significantly increased the output of trypsin to a mean of 3.1 +/- 1.9 mg/kg/h (p less than 0.05). The plasma CCK concentration increased with intraduodenal trypsin from 20.4 +/- 5 to 26.4 +/- 3.7 pg/ml (p less than 0.05). The infusion study was repeated in two volunteers with heat-inactivated trypsin. The mean CCK level rose from 19.6 +/- 4 to 23.8 pg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise for Cancer Patients: Guidelines and Precautions.

In brief: With more cancer patients recovering or surviving for long periods, techniques are needed to help them overcome the disabling effects of the disease, the therapies, and prolonged immobilization. Previous research and clinical observations indicate that exercise is a promising restorative technique for cancer patients, but it is a fairly new concept; no guidelines exist for objectively measuring the functional capacity of such patients or designing safe programs for them. Medical teams that devise such exercise programs should consider the fitness, age, and current medical and psychological status of the patient, the type and stage of cancer, the possibility of coronary artery disease, side effects of therapy, and the timing of blood tests and chemotherapy.

Epidemiologic study of workers exposed to acrylonitrile: an update.

A previous report presented the cancer morbidity and mortality experience through 1976 of a cohort of 1,345 male employees with potential for exposure to acrylonitrile at a fibers-producing plant. This study has now been updated through 1983 for cancer incidence and through 1981 for mortality. Overall, 43 cancer cases have occurred, with 37.1 expected based on company rates. A previously reported excess number of cases of lung cancer remains, but is not as marked (10 observed, 7.2 expected). Prostate cancer cases were significantly in excess, with six cases observed and 1.8 expected. Mortality analyses revealed 36 cancer deaths, with 31.6 expected. Of these, 14 were from lung cancer, with 11.6 expected based on company rates. Only one death from prostate cancer occurred, with 1.0 expected. To our knowledge, prostate cancer excesses have not been reported in any other acrylonitrile studies, and hence their significance is currently difficult to assess.

Increased interdigestive pancreatic trypsin secretion in alcoholic pancreatic disease.

Previous studies have suggested that chronic alcohol consumption in man is associated with an increased secretion of pancreatic enzymes. Precise quantitation of the output of protein and trypsin in the interdigestive state has not been possible because of large variations and small volume of pancreatic juice. We utilized a multilumen, marker-perfused duodenal catheter to simultaneously monitor intraluminal pressures and collect mixed duodenal juice at the ligament of Treitz in five groups of patients: normal volunteers (group I), alcoholics without pancreatitis (group II), alcoholics who had recovered from acute pancreatitis (group III), alcoholics with chronic pancreatitis (group IV), and nonalcoholics who had recovered from acute pancreatitis secondary to biliary tract disease (group V). The output of trypsin and protein during 30 min of phase II and 60 min of CCK-OP 40 ng/kg/hr was determined in each group. The output of trypsin during phase II was 1.3 +/- 1.2 and 3.0 +/- 2.5 mg/kg/hr in groups II and III, respectively, compared to 0 +/- 0.1 in group IV (normal = 0.6 +/- 0.5). The outputs in group V were similar to normals. The output of protein during the interdigestive state was 15.7 +/- 13.7 mg/min in group III, compared to 4.5 +/- 3.6 in normals (group I). The duodenal contraction rate was 4.6 +/- 3.0 and 3.3 +/- 2.7 contractions/min in groups III and II, respectively (significantly greater than the normal rate of 2.2 +/- 1.5).(ABSTRACT TRUNCATED AT 250 WORDS)