The organisation and value of autopsies.

BACKGROUND: There has been a considerable reduction in the frequency of autopsies over the past few decades. We wanted to investigate whether doctors consider this a proper and natural development, or whether they consider that autopsies should be given a higher priority, and in such case, how. MATERIALS AND METHODS: Resources, organisation and opinions on autopsy practice were registered using a questionnaire sent to all pathology departments at Norwegian hospitals, and to all doctors in the clinical departments of Haukeland University Hospital in Bergen, Norway. RESULTS: 392 clinicians replied (percentage of replies 50.3 %). Of these, 82 % considered autopsies to be a good means of quality assurance and quality control of the clinical work. 83 % considered that more autopsies should be performed on a national basis, and 65 % considered autopsies to be just as important today as previously, in spite of technological advances in medicine. However, 80 % of the clinicians attended autopsy demonstrations less than twice a year. The waiting time for autopsy reports was long - 66 days, on average. A majority of clinicians considered that reducing this time would lead to more autopsies being ordered. DISCUSSION: Hospital doctors still consider autopsy to be a good means to assure the quality of clinical work. A reduction in the time needed to complete an autopsy report and better communication between clinicians and pathologists should be given priority.

Small intestinal malabsorption in chronic alcoholism determined by 13C-D-xylose breath test and microscopic examination of the duodenal mucosa.

OBJECTIVE: Diarrhea, weight loss and osteoporosis are prominent symptoms and clinical signs of alcoholism. One of several possible factors causing this clinical picture is small intestinal damage leading to malabsorption. The aim of this study was to prospectively evaluate small intestinal absorption in alcoholics using the (13)C-D-xylose breath test, and to relate the breath test results to morphological findings of the duodenal mucosa. MATERIAL AND METHODS: Sixteen alcoholics without liver failure or serious illness and presenting symptoms of dyspepsia, nausea or diarrhea were included. The (13)C-D-xylose breath test was performed in 14 of the included subjects. The breath tests of the alcoholics were compared to those of untreated coeliac patients and healthy subjects. Duodenal biopsy specimens were taken for assessment of epithelial morphology in 14 of the included subjects, using light- and electron microscopic techniques. RESULTS: Alcoholics had significantly reduced absorption of (13)C-D-xylose compared to healthy subjects. The time curve of (13)C-D-xylose absorption in the group of alcoholics was similar in appearance to that of untreated coeliac patients. Alcoholic patients had few light microscopic changes, but electron microscopic examination exposed morphological pathology in the majority of the patients, with a reduced surface area of microvilli as the main finding. CONCLUSIONS: Alcoholics have a pathological (13)C-D-xylose breath test with a time curve similar to that of untreated coeliac patients. This implies a condition of malabsorption. The morphological pathology found included a reduced absorptive area due to pathology of microvilli. These findings may explain our breath test results.

Long-term prognosis in patients with severe late radiation enteropathy: a prospective cohort study.

AIM: To assess persistent symptoms and mortality in a cohort of patients with severe (grade 3-4) radiation enteropathy, 59 patients were followed up after 15-18 years. METHODS: Fifty-nine patients were prospectively enrolled by twelve surgical departments. Primary malignant disease, radiation therapy and surgical management were recorded at inclusion. The cause of death or persistence of symptoms was examined in public death records or by interview of survivors. RESULTS: Thirty-nine patients had received radiation therapy for gynaecological cancers, twelve for urological cancers, four for gastrointestinal cancers and four for other malignancies. Forty-five patients (76%) required surgical intervention. Complications occurred in 11 (25%) operated patients. Forty-seven patients had died at the time of follow-up, seven (12%) died as a direct result of radiation enteropathy, while radiation enteropathy contributed to death in an additional seven patients. Four of the twelve surviving patients suffered from chronic debilitating symptoms of radiation enteropathy, while three had moderate symptoms. CONCLUSION: Patients with severe delayed radiation enteropathy have a high risk of persistence of symptoms after surgery. At least one in ten patients dies from radiation-induced bowel injury.

Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) may be caused by mutations in mismatch repair (MMR) genes. The aim of this study was to validate immunohistochemistry and family history as prescreening tools to predict germline mutations in MLH1, MSH2, and MSH6. PATIENTS AND METHODS: Pedigrees from 250 families were extended, cancer diagnoses were verified, and families were classified according to the Amsterdam and the Bethesda criteria. Tumor specimens were examined with immunohistochemistry for the presence of MLH1, MSH2, and MSH6 proteins. Mutation analyses were performed in blood samples from the same patients. RESULTS: Blood samples from affected index persons in 181 families and tumor specimens from 127 of the affected index persons were obtained. Thirty tumors lacked one or more gene products. Sensitivity of immunohistochemistry to detect mutation carriers was 100%, specificity was 82%, and positive predictive value was 85%. Sensitivities, specificities, and positive predictive values for the Amsterdam criteria were 82%, 8%, and 45%, respectively, and for the Bethesda criteria were 100%, 0%, and 48%, respectively. Distribution of mutations was MLH1 = 4, MSH2 = 11, and MSH6 = 4. CONCLUSION: Wide clinical criteria to select HNPCC kindreds, followed by immunohistochemistry of tumor material from one affected person in each family, had high sensitivity and specificity to predict MMR mutations.

Polymorphisms of the XRCC1, XRCC3 and XPD genes and risk of colorectal adenoma and carcinoma, in a Norwegian cohort: a case control study.

BACKGROUND: Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. Less is known about other DNA repair pathways in colorectal carcinogenesis. In this study we have focused on the XRCC1, XRCC3 and XPD genes, involved in base excision repair, homologous recombinational repair and nucleotide excision repair, respectively. METHODS: We used a case-control study design (157 carcinomas, 983 adenomas and 399 controls) to test the association between five polymorphisms in these DNA repair genes (XRCC1 Arg194Trp, Arg280His, Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln), and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression model adjusting for age, gender, cigarette smoking and alcohol consumption. RESULTS: The XRCC1 280His allele was associated with an increased risk of adenomas (OR 2.30, 95% CI 1.19-4.46). The XRCC1 399Gln allele was associated with a reduction of risk of high-risk adenomas (OR 0.62, 95% CI 0.41-0.96). Carriers of the variant XPD 751Gln allele had an increased risk of low-risk adenomas (OR 1.40, 95% CI 1.03-1.89), while no association was found with risk of carcinomas. CONCLUSION: Our results suggest an increased risk for advanced colorectal neoplasia in individuals with the XRCC1 Arg280His polymorphism and a reduced risk associated with the XRCC1 Arg399Gln polymorphism. Interestingly, individuals with the XPD Lys751Gln polymorphism had an increased risk of low-risk adenomas. This may suggest a role in regression of adenomas.

GPX Pro198Leu and OGG1 Ser326Cys polymorphisms and risk of development of colorectal adenomas and colorectal cancer.

Little is known about genetic risk factors for colorectal cancer. We assessed the association between polymorphisms in two genes involved in DNA repair of oxidative stress, GPX and OGG1, and risk of colorectal carcinoma or adenomas. We studied 166 cases with adenocarcinoma, 974 with adenomas and 397 controls recruited from the Norwegian cohort NORCCAP. No associations were found between the polymorphism GPX Pro198Leu and risk of colorectal adenomas or carcinomas. Carriers of the variant allele OGG1 Ser326Cys polymorphism had a lowered risk of colorectal cancer, OR=0.56 (95% confidence interval 0.33-0.95), while no association were found with risk of adenomas. This indicates that a low repair capacity of oxidative DNA damage may not be a risk factor for development of colorectal adenomas or carcinoma.

The value of cytology in the diagnostics of lung cancer.

In order to elucidate the relative contributions made by cytology and histology in the diagnosis of lung cancer, we studied the cytology and histology reports of all patients who received a microscopic diagnosis of lung cancer in our hospital during the 7 years 1996-2002. This gave a total of 407 patients. The most frequent diagnoses were squamous cell carcinoma (34.9%), adenocarcinoma (24.8%), and small cell carcinoma (17.8%). One hundred and fifteen patients (28.3%) received their microscopic diagnosis based only on cytology, which therefore proved to be of great diagnostic value. The most useful type of cytology specimen was taken by bronchial lavage or bronchial brushing. These types of specimens provided the diagnosis in 71 patients (17.4%). Cytology was especially capable of finding squamous cell carcinomas. Small cell carcinomas were underrepresented (9.6% versus 17.8%) and unspecified carcinomas greatly overrepresented (9.6% versus 2.9%) among the diagnoses obtained by cytology alone. We conclude that cytology is of considerable diagnostic value, although not as specific as histology for the subtyping of carcinomas. Clinicians should be more aware of the usefulness of cytology, especially in cases where it is difficult to obtain bronchoscopic biopsy samples for histological examination.

The inframe MSH2 codon 596 deletion is linked with HNPCC and associated with lack of MSH2 protein in tumours.

Hereditary nonpolyposis colorectal cancer (HNPCC) may be caused by germline truncating mutations in DNA mismatch repair (MMR) genes. Whether or not missense or inframe mutations are disease-associated has become a practical clinical problem, because predictive genetic testing is employed to select high-risk persons for clinical examinations. Clinical examinations may reveal polyps to be removed and prevent cancer. One large kindred applying for health care had a N596del mutation in the MSH2 gene. The aim of this study was to determine whether or not the inframe mutation in this family was associated with disease, and to examine the tumours for presence of the MSH2 protein by immunohistochemistry. We demonstrated that the mutation was linked to disease with lod score 5.7 in the family, and all examined, but one manifest cancer, lacked the MSH2 protein.

Two distinct aetiologies of cardia cancer; evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status.

BACKGROUND: Non-cardia gastric adenocarcinoma is positively associated with Helicobacter pylori infection and atrophic gastritis. The role of H pylori infection and atrophic gastritis in cardia cancer is unclear. AIM: To compare cardia versus non-cardia cancer with respect to the premorbid state of the stomach. METHODS: Nested case-control study. To each of 129 non-cardia and 44 cardia cancers, three controls were matched. Serum collected a median of 11.9 years before the diagnosis of cancer was tested for anti-H pylori antibodies, pepsinogen I:II and gastrin. RESULTS: Non-cardia cancer was positively associated with H pylori (OR 4.75, 95% CI 2.56 to 8.81) and gastric atrophy (pepsinogen I:II <2.5; OR 4.47, 95% CI 2.71 to 7.37). The diffuse and intestinal histological subtypes of non-cardia cancer were of similar proportions and both showed a positive association with H pylori and atrophy. Cardia cancer was negatively associated with H pylori (OR 0.27, 95% CI 0.12 to 0.59), but H pylori-positive cardia cancer showed an association with gastric atrophy (OR 3.33, 95% CI 1.06 to 10.5). The predominant histological subtype of cardia cancer was intestinal and was not associated with gastric atrophy compared with the diffuse subtype ((OR 0.72, 95% CI 0.19 to 2.79) vs (OR 3.46, 95% CI 0.32 to 37.5)). Cardia cancer in patients with atrophy had an intestinal: diffuse ratio (1:1) similar to non-cardia cancer (1.9:1), whereas cardia cancers in patients without atrophy were predominantly intestinal (7:1). CONCLUSION: These findings indicate two aetiologies of cardia cancer, one associated with H pylori atrophic gastritis, resembling non-cardia cancer, and the other associated with non-atrophic gastric mucosa, resembling oesophageal adenocarcinoma. Serological markers of gastric atrophy may provide the key to determining gastric versus oesophageal origin of cardia cancer.

Gastric mucosa lesions induced by duodenogastric reflux increase penetration of N-[3H]-methyl-N-nitro-N-nitrosoguanidine into corpus mucosa of rats.

The mucosal changes by which duodenogastric reflux may predispose to gastric cancer have not been fully clarified. In this study in rats, duodenal fluid was directed into the stomach through a gastroenterostomy (jejunal reflux, N = 29) or through the pylorus (pyloric reflux, N = 30) and compared with 30 controls. Twenty-four weeks later the stomach was exposed to N-[3H]methyl-N-nitro-N-nitrosoguanidine ([3H]MNNG). The corpus mucosa was examined for proliferating cells (bromodeoxyuridine labeled) and cells at risk of methyl-N-nitro-N-nitrosoguanidine-induced carcinogenesis (cells labeled with bromodeoxyuridine and [3H]MNNG). The number of double-labeled cells increased from 0.8 +/- 0.1/mm mucosa in the control group to 5.2 +/- 0.9 in the jejunal reflux group (P < 0.05) and 2.7 +/- 0.5 in the pyloric reflux group (P < 0.05). An erosion or ulcer appeared at the gastroenterostomy in 52% of animals with jejunal reflux and 17% of those with pyloric reflux (P < 0.006). Within erosions the mean number of double-labeled cells was 9.6 +/- 2.2 in the jejunal reflux group and 7.7 +/- 4.8 in the pyloric reflux group, and significantly higher than in the nonlesion area of the mucosa (0.6 +/- 0.2 and 0.8 +/- 0.3). In erosions the distance between the gastric lumen and the proliferating cells was significantly shorter and the cell proliferation significantly higher than in the nonlesion area of the mucosa. We conclude that duodenogastric reflux increases the penetration of [3H]MNNG into the corpus mucosa of rats and also induces mucosa lesions, which further increase the penetration of [3H]MNNG into the corpus mucosa.

Ulceration as a possible link between duodenogastric reflux and neoplasms in the stomach of rats.

BACKGROUND: Duodenogastric reflux predisposes to gastric cancer. This study investigates whether ulceration induced by duodenogastric reflux is associated with the development of neoplasms in the stomach. MATERIALS AND METHODS: In a rat experiment, duodenal fluid was directed into the corpus (jejunal reflux) or through the pylorus into the antrum (pyloric reflux). Sham-operated animals served as controls. The animals were sacrificed after 24, 36, or 52 weeks. RESULTS: Ulcerations and neoplasms occurred more frequently in the corpus than in the antrum. In the corpus, ulceration was observed significantly more often in animals with jejunal reflux (62, 55, and 53% at 24, 36, and 52 weeks, respectively) than in animals with pyloric reflux (15, 21, and 30%). The incidence of neoplasm in the corpus increased significantly with time from 38% at 24 weeks to 89% at 52 weeks in animals with jejunal reflux and from 12 to 33% in animals with pyloric reflux. Ulceration and neoplasms shared location in the corpus adjacent to the gastrojejunostomy and by 24 weeks, all but one neoplasm in the jejunal reflux and one in pyloric reflux groups occurred adjacent to ulceration. In the antrum, 37% of the animals had a prepyloric ulceration after 24 weeks of pyloric reflux and only one of these animals had a neoplasm. By 52 weeks 20% of animals with pyloric reflux had a neoplasm that appeared in the prepyloric area. CONCLUSIONS: Ulceration and neoplasm occurred at the same sites in the stomach, and ulcerations preceded the development of neoplasms in the antrum and very likely in the corpus. The results suggest that ulceration plays an important role in the genesis of neoplasms in the stomach and that the vulnerability to duodenogastric reflux is more pronounced in the corpus than in the antrum mucosa.

Duodenogastric reflux increases the penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine into the antral mucosa of rats: a possible role for mucosal erosions and increased cell proliferation in gastric carcinogenesis.

Duodenogastric reflux is a risk factor for gastric carcinogenesis, but the pathogenesis is not fully understood. We studied the risk of N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis in the antrum of rats with duodenogastric reflux. Duodenal fluid was directed into the stomach through the pylorus (pyloric reflux group) or through a gastrojejunostomy (jejunal reflux group). After twenty-four weeks, 5-bromo-2-deoxyuridine (BrdU) was injected intravenously and the stomach was exposed to N-(3)H-methyl-N-nitro-N-nitrosoguanidine ((3)H-MNNG). The antral mucosa was examined with immunohistochemistry and autoradiography for identification of proliferating cells (BrdU labelled) and cells at risk of MNNG-induced carcinogenesis ((3)H-MNNG and BrdU-labelled cells). Duodenogastric reflux increased the number of double-labelled cells in the antral mucosa from 4.8 +/- 0.6 per mm in the control group to 11.3 +/- 1.9 in the jejunal reflux group (P < 0.05) and 12.7 +/- 0.9 in the pyloric reflux group (P < 0.05). Mucosal erosions were observed in 15 of 28 animals with pyloric reflux and the number of double-labelled cells in the erosion area (4.3 +/- 0.7) was higher than in the same area of animals without erosion (1.4 +/- 0.5) (P < 0.05). Duodeno-gastric reflux increased the cell proliferation and significantly changed the distance between the surface epithelial lining and the proliferating cells when compared to the controls. These results indicate that duodenogastric reflux increases the penetration of (3)H-MNNG into the antrum mucosa of rats. Increased cell proliferation and erosions increase the number of cells at risk of an initiation process from a penetrating gastric carcinogen.