The relation of pepsinogen group II (PGII) expression to intestinal metaplasia and gastric cancer.

AIMS: A substantial minority of intestinal metaplasia (IM)-associated stomach cancers express a gastric product-pepsinogen group II (PGII). The aim of this study was to examine PGII expression as it relates to IM and to tumour heterogeneity. METHODS AND RESULTS: The extent of IM was divided into four levels: none, minimal, moderate, extensive. Stomach specimens (N = 165) were stained for PGII and two tumour markers, epidermal growth factor receptor (EGFr) and p53. PGII was more likely to be expressed with moderate or extensive IM than with minimal or no IM (P = 0.05). Cancers that expressed PGII were more likely to be of high stage than those that did not (P = 0.035). Of 25 cases that expressed all three markers (PGII, EGFr, p53), 20 (80%) had stage 3 or 4 disease, compared with 11 (37%) advanced cancers expressing none of the markers (P = 0.001). Cancers expressing one or two markers were between these extremes. CONCLUSIONS: PGII+ cancers in IM-associated gastric cancers may derive from residual gastric glands, or may arise from postinduction reversion to a gastric phenotype from intestinalized cells. This is supported by the more frequent association of PGII expression with the most extensive degrees of IM and its association with high-stage cancers that display heterogeneity in tumour marker expression.

TP53 and gastric carcinoma: a review.

In this article, we survey the major p53 (TP53) alterations identified in gastric carcinomas and their precursors. These include p53 expression, mutations, and loss of heterozygosity (LOH). Not only are the various abnormalities summarized, but in addition there is a survey of the literature with respect to the impact of these changes on patient prognosis and treatment response. The majority of published studies involve the immunohistochemical detection of the protein. These use different antibodies, different detection techniques, and different methods of interpretation. Therefore not surprisingly, the results of many of the studies are contradictory with one another. Overall, however, it appears that p53 alterations occur early in the development of gastric carcinoma, being present even in the nonneoplastic mucosa and they increase in frequency as one progresses along the pathway of gastric carcinoma development. p53 immunoreactivity is seen in 17%-90.7% of invasive gastric carcinomas. p53 alterations occur much more commonly in proximal lesions than in distal ones, suggesting that the molecular events leading to the development of gastric carcinoma may be very different in proximal vs. distal tumors. p53 mutations occur in 0%-77% of gastric carcinomas. The mutations are distributed widely across the gene from exons 4-11 with hot spots of mutation at codons 175, 248, 273, 282, 245, and 213. G:C>A:T transitions at CpG sites are the commonest type of mutation. At least 60% of carcinomas with mutations also exhibit p53 LOH.

Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction.

BACKGROUND: Surgical resection of adenocarcinoma of the stomach is curative in less than 40 percent of cases. We investigated the effect of surgery plus postoperative (adjuvant) chemoradiotherapy on the survival of patients with resectable adenocarcinoma of the stomach or gastroesophageal junction. METHODS: A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of 425 mg of fluorouracil per square meter of body-surface area per day, plus 20 mg of leucovorin per square meter per day, for five days, followed by 4500 cGy of radiation at 180 cGy per day, given five days per week for five weeks, with modified doses of fluorouracil and leucovorin on the first four and the last three days of radiotherapy. One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg per square meter per day) plus leucovorin (20 mg per square meter per day) were given one month apart. RESULTS: The median overall survival in the surgery-only group was 27 months, as compared with 36 months in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval, 1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to 1.86; P<0.001). Three patients (1 percent) died from toxic effects of the chemoradiotherapy; grade 3 toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group, and grade 4 toxic effects occurred in 32 percent. CONCLUSIONS: Postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection.

Variant form of diffuse corporal gastritis in NHE2 knockout mice.

Mice lacking the NHE2 Na+/H+ gene develop gastritis of the glandular mucosa as early as the tenth day of life, achieving maximal intensity of inflammation from 17 to 19 days after birth and maximal atrophy at one year. We assessed the effects of this process in such mice to 16 months of age. The stomach of NHE2 null mutants was examined at 10, 17 to 20, 24 to 35 and 49 to 70 days, and at 12 to 16 months. The NHE2 wild-type (+/+) and NHE2 heterozygous (+/-) mice were compared with the NHE2 homozygous mutant mice (-/-). The stomach of the mutant mice at all ages was characterized by a substantially reduced number of parietal cells. The 10-day-old mouse stomach had a transmural infiltrate of primarily neutrophils. With increasing age, neutrophils were replaced by lymphocytes and plasma cells in the glandular mucosa of the mutant mice. Young adult 49- to 70-day-old mice had surface cell hyperplasia and expansion of the replicating cell population. Hyperplasia of enterochromaffin-like cells and antral gastrin cells accompanied profound fundic gland and surface cell hyperplasia, and became progressively more severe with increasing age of the NHE2-/- mice. Neoplasms were not found in the mutant or control mice. This gastritis differs from that of autoimmune gastritis in that it is transmural, begins in infancy, and is associated with a predominantly neutrophilic infiltrate in its early stages. Some of the histologic changes in the adult mice can be explained on the basis of prolonged achlorhydria. This mouse may be a suitable model for prolonged effects of achlorhydria.

Serum selenium and subsequent risk of prostate cancer.

It is suspected that selenium is protective against prostate cancer. To test this hypothesis, we conducted a nested case-control study in a cohort of 9345 Japanese-American men examined between 1971 and 1977. At the time of examination, a blood specimen was obtained, and the serum was frozen. After a surveillance period of more than 20 years, 249 tissue-confirmed incident cases of prostate cancer were identified. Their stored sera and those of 249 matched controls were measured for selenium levels. Odds ratios for prostate cancer, based on quartiles of serum selenium levels, were determined using the General Estimating Equations approach. The multivariate odds ratio for the highest quartile was 0.5 (95% confidence interval, 0.3-0.9) with a two-sided P for trend of 0.02. The inverse association was more notable for cases with advanced disease and for cases diagnosed 5-15 years after phlebotomy. However, the association was mainly present in current or past cigarette smokers rather than nonsmokers, which leads to caution in the interpretation of the results.

The relation of p53 gene mutations to gastric cancer subsite and phenotype.

OBJECTIVES: We investigated p53 gene mutations in advanced gastric cancers by direct DNA sequencing, in order to determine the frequency of mutations in gastric cancers having different epidemiological backgrounds, tumors of the cardia were compared with those arising in the antrum or corpus. Intestinal type cancers were compared with diffuse or other histologic types. We have chosen to assess the frequency of mutations solely based on DNA sequencing. METHODS: Paraffin embedded tissues from 100 gastric cancers were evaluated. The mutational status of the p53 gene in exons 5 through 9 were determined by direct sequencing of PCR products. RESULTS: Mutations in exons 5, 6, 7 and 8 were found in 35 of 100(35%)stomach cancers. One tumor had mutations in both exons 5 and 8. No mutations were detected in exon 9. p53 gene mutations were significantly more frequent in cancers of the cardia (19/35; 54%) than the antrum and corpus (16/65 (25%)) (p < or = 0.005). p53 mutations were more frequent in intestinal type cancers (28/67; 42%) than diffuse cancers or other histologic types of cancer (7/33; 21%), but the difference was not statistically significant. CONCLUSIONS: Cancers of the cardia more frequently contain p53 mutations than do antral and corpus cancers, suggesting that cancers in the proximal and distal stomach evolve through different molecular pathways.

p53 immunoreactivity and single-strand conformational polymorphism analysis often fail to predict p53 mutational status.

The intent of this study was to investigate the ability of p53 expression and single-strand conformational polymorphism analysis (SSCP) to predict p53 mutational status in archival, paraffin-embedded tissues of gastric cancer. We evaluated paraffin-embedded tissues from 78 patients with advanced gastric cancer. The mutational status of the p53 gene (exons 5-9) was examined by SSCP analysis and by direct sequencing. These results were compared with p53 expression as assessed by immunohistochemical analysis (IHC). We graded p53 expression on a scale from 0 to 8 on the basis of both the intensity and the number of cells staining. Overall, we detected p53 immunoreactivity in 75.6% of the gastric cases; 19 (32.2%) of these cases scored from 1 to 4, and 40 (67.8%) cases scored from 5 to 8. p53 gene mutations were detected in 18 cases (23.1%) by SSCP and in 28 cases (36%) by direct sequencing. Thus, SSCP failed to detect 38% of the mutations found by sequencing. The majority of missed mutations involved exons 7 and 8. The concordance between IHC and SSCP was 37%, and the concordance between IHC and direct sequencing was 50%. Forty-five percent of cases positive by IHC failed to show mutations in exons 5 through 9. Five percent of cases negative by IHC (4 cases) contained mutations. One had a 1-base pair insertion; one had a mutation that resulted in a stop codon; the third had a mutation in exon 8; and the fourth had a mutation in both exons 5 and 8. Our findings indicate that p53 immunoreactivity correlates with the presence or absence of gene mutations in 50% of advanced gastric cancers when exons 5 through 9 are examined and that IHC cannot be reproducibly used as a marker of mutation in the most commonly mutated exons of the p53 gene. Furthermore, the sensitivity of SSCP for detecting mutations is only 62%. Thus, SSCP analysis cannot be used reliably to screen for p53 mutations.

Serum vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii, United States)

OBJECTIVES: Because several serum studies of vitamin D metabolites have produced equivocal results on their relation to prostate cancer risk, the purpose of this study is to evaluate this association further. METHODS: A nested case-control study in a cohort of 3,737 Japanese-American men examined from 1967 to 1970 was conducted in Hawaii (United States). At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of over 23 years, 136 tissue-confirmed incident cases of prostate cancer were identified. Their stored sera and those of 136 matched controls were measured for the following: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, phosphorus, and parathyroid hormone. RESULTS: There were no notable differences between cases and controls in their median serum levels of the five laboratory measurements. Odds ratios (OR) for prostate cancer, based on the quartiles of serum levels in controls, were also determined. The ORs for the highest quartiles relative to the lowest were 0.8 (95 percent confidence interval [CI] = 0.4-1.8) for 25-hydroxyvitamin D and 1.0 (CI = 0.5-2.1) for 1,25-dihydroxyvitamin D. CONCLUSION: It is possible that the lack of sufficient numbers of study subjects with low vitamin D levels affected the results. Nonetheless, the findings suggest that there is a lack of a strong association between vitamin D and prostate cancer.

Immunohistologic analysis of gastrointestinal and pulmonary carcinoid tumors.

Carcinoid tumors are potentially malignant neoplasms that arise in various body sites, including the lung and gastrointestinal tract. Those that appear cytologically atypical are more likely to behave aggressively than more typical carcinoid tumors. However, in the absence of cytological atypia or large tumor size, it is difficult to predict the biology of an individual tumor, because some lesions metastasize, whereas others do not. This study had four aims: (1) To study the expression pattern of p53, Ki-67, NCAM, and S-100 in carcinoid tumors and to relate these expression patterns to classical histopathologic features and to tumor location. (2) To identify nonhistological markers that might more accurately predict the early behavior of carcinoid tumors. (3) To determine whether sustentacular cells are present in carcinoid tumors arising in tissues derived from different embryological derivatives. (4) To determine the synaptophysin and chromogranin immunoreactivity in neuroendocrine tumors arising in various locations. The immunostaining reactions were quantitatively scored by three observers. Only 3 of the 39 tumors (all histologically atypical) were strongly positive for Ki-67; two of these were also strongly p53 immunoreactive. NCAM immunostaining differed according to the site of origin: 76.5% of foregut lesions, 58% of the midgut lesions, and 20% of hindgut lesions were positive. S-100 immunostaining ranged from 41% in foregut lesions to 50% in both the hindgut- and midgut-derived tumors. S-100-positive sustentacular cells were present in 20.5% of carcinoid tumors. All tumors stained with antibodies against synaptophysin. In contrast, 100% of midgut, 60% of hindgut, and 88% of foregut tumors were chromogranin positive. Carcinoid tumors tend to have low proliferative rates. p53 immunostaining tends to be strongly positive in tumors that are histologically atypical, but it is negative in typical carcinoid tumors arising in the gastrointestinal tract and lungs. Immunostaining reactions with antibodies to NCAM, S-100, and chromogranin differ depending on the site of origin. Synaptophysin stains 100% of carcinoid tumors regardless of their site of origin. In contrast, antibodies to chromogranin fail to stain 40% of hindgut tumors and 12% of foregut carcinoid tumors. S-100-positive sustentacular cells are present in foregut and midgut tumors but not in hindgut tumors.

Taking a family history in cancer patients with a simple questionnaire.

A one-page family history questionnaire was validated in two European areas covered by population-based cancer registries. Information on malignant tumor occurrence in first degree relatives was collected from 193 cancer patients in Trieste, Italy and from 64 in Basel, Switzerland. They were then compared with the corresponding data stored in the registries' files. The sensitivity of the questionnaire was 85% (Trieste) and 74% (Basel), the specificity was 97% in both studies and the overall accuracy 95% (Trieste) and 94% (Basel). The questionnaire is recommended for use in different geographical areas covered by population based registries for comparative analyses of cancer related family histories.

Serum micronutrients and prostate cancer in Japanese Americans in Hawaii.

Numerous dietary studies and several serum micronutrient studies have produced equivocal results on the relation of vitamins A and E to prostate cancer risk. To evaluate this association further, we conducted a nested case-control study in a cohort of 6860 Japanese-American men examined from 1971 to 1975. At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of more than 20 years, 142 tissue-confirmed incident cases of prostate cancer were identified. Their stored sera and those of 142 matched controls were measured by high-performance liquid chromatography for the following: total carotenoids, lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, total retinoids, retinol, total tocopherols, alpha-tocopherol, delta-tocopherol, and gamma-tocopherol. Odds ratios for prostate cancer, based on quartiles of serum micronutrient levels, were determined using conditional logistic regression analysis. The odds ratio for the highest quartiles were 1.8 (95% confidence interval, 0.9-3.9) for beta-cryptoxanthin, 1.6 (0.8-3.5) for beta-carotene, 0.8 (0.4-1.5) for retinol, and 0.7 (0.3-1.5) for gamma-tocopherol, but none of the differences was statistically significant. For the other micronutrients, the results were also unremarkable. The findings of this study indicate that none of the micronutrients is strongly associated with prostate cancer risk.

Serum micronutrients and upper aerodigestive tract cancer.

Numerous dietary studies have found that vegetables and fruits protect against upper aerodigestive tract cancer. To evaluate the role of beta-carotene and other specific carotenoids, a nested case-control study using prediagnostic serum was conducted among 6832 American men of Japanese ancestry examined from 1971 to 1975. During a surveillance period of 20 years, the study identified 28 esophageal, 23 laryngeal, and 16 oral-pharyngeal cancer cases in this cohort. The 69 cases were matched to 138 controls. A liquid chromatography technique, designed to optimize recovery and separation of the individual carotenoids, was used to measure serum levels of lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, retinol, retinyl palmitate, and alpha-, delta-, and gamma-tocopherol. With adjustment for cigarette smoking and alcohol intake, we found that alpha-carotene, beta-carotene, beta-cryptoxanthin, total carotenoids and gamma-tocopherol levels were significantly lower in the 69 upper aerodigestive tract cancer patients than in their controls. Trends in risk by tertile of serum level were significant for these five micronutrients. These significant trends persisted in cases diagnosed 10 or more years after phlebotomy for the three individual carotenoids and total carotenoid measurements. The odds ratios for the highest tertile were 0.19 (95% confidence interval, 0.05-0.75) for alpha-carotene, 0.10 (0.02-0.46) for beta-carotene, 0.25 (0.06-1.04) for beta-cryptoxanthin, and 0.22 (0.05-0.88) for total carotenoids. When the cases were separated into esophageal, laryngeal, and oral-pharyngeal cancer, both alpha-carotene and beta-carotene were consistently and strongly associated with reduced risk at each site. The findings suggest that alpha-carotene and other carotenoids, as well as beta-carotene, may be involved in the etiology of upper aerodigestive tract cancer.

Serum androgens and prostate cancer.

It is suspected that male hormones are associated with the risk of prostate cancer. To test this hypothesis, we conducted a nested case-control study in a cohort of 6860 Japanese-American men examined from 1971 to 1975. At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of more than 20 years, 141 tissue-confirmed incident cases of prostate cancer were identified, and their stored sera and those of 141 matched controls were assayed for total testosterone, free testosterone, dihydrotestosterone, 3-alpha-androstanediol glucuronide, androsterone glucuronide, and androstenedione. Odds ratios for prostate cancer, based on quartiles of serum hormone levels, were determined using conditional logistic regression methods. The odds ratios for the highest quartiles were 1.37 (95% confidence interval, 0.73-2.55) for 3-alpha-androstanediol glucuronide and 1.24 (95% confidence interval, 0.62-2.47) for androstenedione, but none of the differences was statistically significant. The results were unremarkable for the other four hormonal measurements. In addition, the patients and controls were compared by hormonal ratios (i.e., total testosterone:dihydrotestosterone), but the results were also unremarkable. The findings of this study indicate that none of these androgens is strongly associated with prostate cancer risk.

A prospective study of colon and rectal cancer among Hawaii Japanese men.

The goals of this study were to assess the association of diet, alcohol, smoking, and other life-style factors with the risk of colon and rectal cancer and to examine the differences in the risk factors associated with each cancer site. Information on diet, alcohol, smoking, and other life-style factors was obtained from 7945 Japanese-American men who were living in Hawaii and examined from 1965 through 1968. After 174,514 person-years of observation, 330 incident cases of colon cancer and 123 incident cases of rectal cancer were diagnosed by histology. The risk of both colon and rectal cancer increased with age, alcohol intake, and pack-years of cigarette smoking. For colon cancer, there was also a direct association with body mass index and heart rate, while an inverse association was observed with serum cholesterol, intake of monounsaturated fatty acid, and percentage of calories from fat. For rectal cancer, the risk decreased with an increase in the intake of carbohydrates as percentage of calories. These findings suggest that some of the risk factors for colon cancer are different from those for rectal cancer.

Hepatitis B and C virus serologies among Japanese Americans with hepatocellular carcinoma.

A cohort of 5924 Japanese American men was examined between 1967 and 1970 for hepatocellular carcinoma (HCC). By 1992, 24 incident cases of HCC were histologically confirmed in the group. Frozen serum samples from the 24 men with HCC and 72 age-matched controls were tested for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core antigen, antibodies to HBsAg, and antibodies to hepatitis C virus. HBsAg was detected in 15 (62.5%) of 24 HCC cases compared with 2 (2.8%) of 72 controls (odds ratio, 43.0; 95% confidence interval, 5.7-325.5). None of the cases and only 1 control had antibody to hepatitis C virus. This study demonstrates a strong association between hepatocellular carcinoma and hepatitis B virus infection, but not with hepatitis C virus infection, among men of Japanese ancestry in Hawaii.

Pathologic and phenotypic features of gastric cancer.

This article covers the basic pathologic features of gastric cancer. Gastric cancer is not a single entity but consists of several major tumor types. The risk factors for their development and their pathological features are discussed. The two major forms of gastric cancer, intestinal and diffuse, are described, as are the settings in which they arise. A number of prognostic factors exist for gastric cancer, including traditional pathologic variables such as histological staging grade and tumor type. Some more recent potential markers involve determinants of biologic behavior. The more frequently encountered types are covered, as well as their clinical implications. Finally, a scheme for standardized handling of gastric resection specimens is presented.

Racial factors cannot explain superior Japanese outcomes in stomach cancer.

OBJECTIVE: To compare the stage-stratified survival of Japanese patients treated in Honolulu according to Western techniques with that of Japanese patients treated in Tokyo according to Japanese techniques, thus eliminating race as a potentially confounding variable. DESIGN AND PATIENTS: Of 312 Honolulu Japanese patients surviving Western-type gastric resection for neoplasm between 1974 and 1985, 279 were identified with invasive gastric adenocarcinoma unassociated with any second malignancy. This Honolulu cohort, treated by Western methods, was retrospectively compared with a similar, previously described cohort of 3176 Tokyo Japanese patients treated according to Japanese methods. MAIN OUTCOME MEASURES: American Joint Committee on Cancer/Union Internationale Contre le Cancer criteria for stage-stratified survival. RESULTS: Despite non-TNM prognostic factors favoring higher survival for the Honolulu Japanese patients, for every TNM stage, we observed higher survival for the Tokyo Japanese patients who were treated according to Japanese techniques. For stage I disease, the survival rates were 86% vs 96%, respectively (P < .001); for state II, 69% vas 77% (P = .15); for stage III, 21% vs 49% (P < .001); and for stage IV, 4% vs 14% (P < .001). CONCLUSIONS: Because all patients in this study are Japanese, race-related factors or the "different-disease" hypothesis cannot explain these results. Lymphadenectomy-related stage-migration and/or differing therapeutic efficacy seem more likely explanations.

Gastric cancer among the Japanese in Hawaii.

The incidence rate of gastric cancer among men of Japanese ancestry living in Hawaii is about one-third as high as that of their counterparts living in Japan. Because of this difference, a prospective study was conducted to identify factors related to the development of gastric cancer in Hawaii. Eight thousand and six (8,006) men born from 1900-1919 were examined from 1965 to 1968 and followed for over 25 years. During this time, 250 incident cases of gastric cancer were identified. The study has found the following: 1) prior infection with Helicobacter pylori bacteria increased the risk for stomach cancer; 2) cigarette smoking was positively associated with gastric cancer with age at which smoking started being an important risk factor; 3) after taking cigarette smoking into account, alcohol intake was not related to stomach cancer risk; 4) a low pepsinogen I level identified subjects at increased risk for the intestinal histologic type of gastric cancer; 5) a low serum ferritin level was a marker for increased risk of stomach cancer; 6) there was a weak indication that the intake of vegetables and fruits was inversely related to gastric cancer; 7) there was no association of stomach cancer with levels of serum cholesterol, serum uric acid, serum micronutrients (retinol, beta-carotene or alpha-tocopherol) or blood hematocrit; 8) there was also no association of gastric cancer with body mass index or physical activity.