Prognostic significance of antrum-predominant gastritis in functional dyspepsia.

BACKGROUND: The role of Helicobacter pylori infection in functional dyspepsia is still controversial, and subgroups of patients with functional dyspepsia who may benefit from H. pylori eradication should be identified. Patients with functional dyspepsia and antrum-predominant H. pylori-positive chronic gastritis, it has been argued, have fewer symptoms after eradication therapy. In the present study, we analysed the clinical significance of antrum-predominant gastritis on the long-term prognosis of functional dyspepsia. METHODS: Consecutive unselected dyspeptic patients were investigated in primary care and the patients with functional dyspepsia were enrolled in this long-term follow-up study. Altogether 182 patients were recruited: 65 with normal histology of the stomach, 36 with antrum-predominant gastritis, 21 with corpus-predominant gastritis and 60 with pangastritis. Patients' medical histories were reviewed after 6 to 7 years, with total number and outcome of repeated investigations analysed. At the end of follow-up, all patients were invited for voluntary gastroscopy. RESULTS: At the end of follow-up, the proportion of asymptomatic patients ranged from 21% (normal histology) to 26% (antrum-predominant gastritis). No statistically significant differences between groups appeared in regard to re-visits or to proportion of patients examined by sigmoideo- or colonoscopy during follow-up. Patients with antrum-predominant gastritis less often underwent upper endoscopy. Peptic ulcer was more frequent (P = 0.05) in patients with antrum gastritis than in other groups, but no other differences existed among any organic gastrointestinal findings. No significant differences between subgroups appeared among the 30% of patients using drugs for upper abdominal complaints during the previous year. CONCLUSIONS: Functional dyspepsia has an excellent long-term prognosis. Antrum-predominant gastritis in functional dyspepsia seems to carry an increased risk for peptic ulcer, and for this group in particular, H. pylori eradication should be considered. This finding requires confirmation in future studies performed in primary care.

Prevalence of gastric metaplasia in the duodenal bulb is low in Helicobacter pylori positive non-ulcer dyspepsia patients.

BACKGROUND: Gastric metaplasia in duodenum is a common phenomena in duodenal ulcer patients. However, the role of gastric metaplasia in patients with non-ulcer dyspepsia is not clear. It is not known either whether Helicobacter pylori infected non-ulcer patients who are CagA-seropositive have gastric metaplasia in duodenum more often than CagA-negative patients. AIMS: To compare prevalence of gastric metaplasia in duodenum in non-ulcer dyspepsia patients according to Helicobacter pylori status. PATIENTS AND METHODS: A series of 400 unselected dyspeptic patients in primary care were investigated. Patients with no endoscopic evidence of organic disease (n=236) were enrolled in the study. Duodenal bulb and gastric biopsies were collected, as well as blood samples for Helicobacter pylori determination. RESULTS: There were no differences between CagA-seropositive and -seronegative Helicobacter pylori infected patients as far as concerns gastric metaplasia in duodenal bulb (20% vs 25%). Helicobacter pylori negative non-ulcer patients more often had gastric metaplastic changes (46%, p<0.0001) in duodenum. CONCLUSION: Helicobacter pylori infection has no major role in development of gastric metaplasia in duodenal bulb in non-ulcer dyspeptic patients. Furthermore, it does not result in positive CagA-serology, an increased risk for gastric metaplasia compared with CagA-seronegative cases.

Reduced expression of alpha-catenin, beta-catenin, and gamma-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer.

AIMS: To investigate the expression of catenins (alpha, beta, and gamma) in non-small cell lung carcinoma (NSCLC) and its relation to clinicopathological factors and prognosis. METHODS: The expression of catenins was analysed immunohistochemically in 261 patients with resected NSCLC, diagnosed between 1978 and 1996 in eastern Finland: The cell proliferation index of the tumours was analysed by means of an image analyser. The staining results were compared with clinicopathological characteristics and survival. RESULTS: Normal catenin staining was found significantly more often in adenocarcinomas than in squamous cell carcinomas or anaplastic/large cell carcinomas. Reduced staining of alpha-catenin, beta-catenin, and gamma-catenin was related to poor differentiation of the tumour. The tumours with reduced staining of beta-catenin or gamma-catenin often had higher cell proliferation activity. Nuclear staining of beta-catenin and gamma-catenin was found in 16 (7%) and 29 (13%) cases, respectively. This nuclear staining correlated directly with increased cell proliferation and inversely with membranous staining. In survival analyses the predictors of overall and disease free survival were stage and tumour type. The expression of catenins did not affect survival. CONCLUSIONS: The expression of alpha-catenin, beta-catenin, and gamma-catenin is related to histological type and differentiation in NSCLC, although catenins have no independent prognostic value. However, this study supports the important role of the nuclear accumulation of beta-catenin and gamma-catenin in highly proliferative cells.

Prognostic value of hyaluronan expression in non-small-cell lung cancer: Increased stromal expression indicates unfavorable outcome in patients with adenocarcinoma.

The prognostic value of hyaluronan (HA) was analyzed in a large number of patients (n = 261) with non-small-cell lung cancer (NSCLC) by staining archived tumor samples with a biotinylated HA-specific probe. The level of HA in the tumor cells and surrounding stroma was scored and compared with parallel CD44 stainings, clinicopathological factors and survival data. Adenocarcinomas were characterized by a low percentage of HA-positive cells with low staining intensity compared with squamous-cell and large-cell/anaplastic carcinomas. The HA signal in the peri-tumoral stroma was often higher than that in the uninvolved stroma in all subgroups of NSCLC. CD44 and HA associated with the cancer cells showed a strong positive correlation with each other. In the whole tumor material, dominated by squamous-cell carcinomas (n = 168), recurrences were more often found in cases showing a low percentage of cancer cell-associated HA. However, within the adenocarcinoma subgroup (n = 68), a high percentage of cell-associated HA was correlated with poor tumor differentiation. Also specific for the adenocarcinoma subgroup was the increased number of recurrences in cases with a strong stromal HA signal. In survival analysis of the whole material (n = 189), a low percentage of HA-positive cancer cells was associated with a shortened disease-free survival (DFS) together with stage and tumor type. However, in the subgroup of patients with adenocarcinoma (n = 49), a strong stromal signal for HA predicted poor DFS. The level of HA in the stroma of adenocarcinomas retained its prognostic value in Cox's multivariate analysis. These results indicate that the frequency and intensity of HA has a significant prognostic value in NSCLC, particularly when the histological subtypes are analyzed as separate entities.

Reduced expression of CD44v3 variant isoform is associated with unfavorable outcome in non-small cell lung carcinoma.

The expression of CD44 standard form (CD44s) and variant isoforms v3 and v6 was analyzed in 233 resected non-small cell lung carcinoma (NSCLC) specimens by immunohistochemistry (IHC), and the mRNA status of CD44v3 and CD44v6 in a cohort of samples was determined by in situ hybridization (ISH) and further confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of CD44s, CD44v3, and CD44v6 was correlated with clinicopathologic variables and survival. The expression of CD44v3 and v6 was reduced in 97% and 90% of the adenocarcinomas and in 86% and 74% of the large cell/anaplastic carcinomas, respectively, as compared with squamous cell carcinomas, where they were reduced in 53% and 51% of the cases (P = .0001 and P = .004 for v3 and v6). The corresponding values for CD44s were 92%, 70%, and 51%, respectively (P = .011). The reduced CD44s and CD44v6 expression was associated with lymph node metastases (P = .03 and P = .005, respectively) and the reduced expression of CD44s also with advanced stage (P = .04). Recurrences during the follow-up were more often found within the tumors showing reduced expression of CD44v3 (P = .04). Combining ISH and IHC results showed that CD44v3 and v6 mRNA were not always processed into protein, suggesting a regulation disturbance posttranscriptionally since malignant transformation of cells has occurred. In survival analyses, the reduced expression of CD44s and CD44v3 was associated with a shortened disease-free survival (P = .04 and P = .01, respectively). In multivariate analysis, CD44v3 retained its independent prognostic value (P = .03). These results emphasize the value of CD44, and especially the v3 variant isoform in the behavior of NSCLC.

Reduced CD44 standard expression is associated with tumour recurrence and unfavourable outcome in differentiated thyroid carcinoma.

CD44 was detected with an antibody recognizing all forms of CD44 (CD44 standard) and others specific for its v3 and v6 variant isoforms; their prognostic value was evaluated in 213 patients with differentiated thyroid carcinoma (DTC). The staining patterns of CD44 standard (s) and CD44v6 in tumour tissue were quite similar, 176 cases (83%) being highly positive for CD44s and 153 cases (72%) for CD44v6. Only 18 (9%) tumours showed high expression of CD44v3. Papillary carcinomas were significantly more often high expressors of CD44s and CD44v6 than follicular carcinomas (p<0.001 for both). Age older than 60 years, distant metastases, and advanced pTNM stage were related to loss of expression of CD44s (p<0.001, p=0.021, and p=0.003, respectively). Tumour recurrence and cancer-related mortality were related to the reduced level of CD44s (p=0.049 and p=0.042). CD44v3 did not associate with any of the clinicopathological factors. In univariate analysis, CD44s was the only significant prognostic factor for disease-free survival (p=0.0488). In multivariate analysis, CD44s and thyroglobulin level were significant prognostic factors for disease-free survival (p=0.040 and p<0.001, respectively). The reduced level of CD44s in DTC patients seems to be an independent prognostic factor for unfavourable disease outcome.

Expression and prognostic value of alpha-, beta-, and gamma-catenins indifferentiated thyroid carcinoma.

Catenins (alpha, ss, and gamma) are a group of intracellular cell adhesion molecules that unite cytoskeleton with extracellular adhesion system. Abnormal expression of these molecules may have prognostic relevance in various carcinomas, including differentiated thyroid carcinoma (DTC). We have, therefore, evaluated the prognostic value of alpha-, ss-, and gamma-catenins along with traditional risk factors in 206 consecutive DTC patients by immunohistochemistry. Papillary carcinomas showed normal staining pattern for alpha-, ss-, and gamma-catenins in 124 (60%), 136 (67%), and 94 (46%) cases, respectively. Follicular carcinomas expressed alpha-, ss-, and gamma-catenins normally in 16 (48%), 18 (55%), and 8 (32%) cases, respectively. Follicular type of tumor showed more often reduced staining for all catenins than papillary carcinoma (P: = 0.009, P: = 0.004, and P: = 0.002, respectively). Age (>60 yr) and pTNM-stage were related to reduced alpha- and ss-catenin expression levels (P: = 0.027 and P: = 0.026, respectively) and larger size of the tumor to reduced ss- and gamma-catenin expressions (P: = 0.039 and P: = 0.007, respectively). Nodal metastases at the time of primary treatment related to reduced alpha-catenin expression and distal metastases to reduced ss- and gamma-catenin staining signals (P: = 0.022, P: = 0.014, and P: = 0.039, respectively). Reduced alpha-catenin associated with tumor recurrence (P: = 0.002) and reduced ss-catenin with cancer-related mortality (P: = 0.005). The multivariate analysis for recurrence-free survival showed that alpha-catenin and serum thyroglobulin level 1 yr after primary treatment were prognostic of recurrent disease (hazards ratio, 3.42, P: = 0.022; and hazards ratio, 10.03, P: = 0.0001). In addition, alpha-catenin retained its prognostic significance in low-stage patients (P: = 0.0151). We propose that the evaluation of alpha-catenin expression by immunohistochemistry in DTC patients has prognostic value in addition to that obtained by traditional prognostic factors.

Non-suppressed thyrotropin and elevated thyroglobulin are independent predictors of recurrence in differentiated thyroid carcinoma.

OBJECTIVE: Although in most cases differentiated thyroid carcinoma (DTC) responds to surgery and radioiodine (RaI) therapy, some patients will have recurrence and eventually cancer-related death. However, although various prognostic factors of DTC have been identified (e.g. staging, suppressed thyrotropin), none of the previous studies have assessed simultaneously their role in multivariate analysis. DESIGN AND METHODS: In this retrospective population-based study, we reviewed the clinicopathological data of 254 DTC patients treated in eastern Finland during the years 1976-1995, for clinical characteristics, primary treatment, follow-up and cancer recurrence. Tumor stage was based on pathological tumor-node-metastasis (pTNM) classification, and histopathological specimens were re-evaluated. RESULTS: DTC recurrence occurred in 33 patients (13%). In univariate analyses, the predictors of recurrence were older age (>60 years, P<0.05), follicular tumor type (P<0.01), pTNM classification system (P<0.05) and post-ablative radioiodine uptake outside the neck (P<0.05). Non-suppressed serum thyrotropin (TSH) and elevated serum thyroglobulin (>3 microg/l) measured one year after operation were both related to tumor recurrence (P<0.05 and P<0.001 respectively). In multivariate analysis the independent predictors for recurrence were both elevated thyroglobulin (P<0.001) and non-suppressed TSH (P<0.05) independent of histology, pTNM stage and RaI uptake. Adjusted risk ratio for recurrence of DTC for unsuppressed thyrotropin was 2.3, for elevated thyroglobulin 14.0 and, if both conditions were present, the risk ratio increased to 45.1. CONCLUSION: Our results suggest that both non-suppressed serum TSH and elevated serum thyroglobulin are related to an increased risk of DTC recurrence independent of tumor type and pTNM stage.

Clinical relevance of p53 index and expression of proliferating cell nuclear antigen and Ki-67 in gastric cancer.

The prognostic value of the immunohistochemical expression of p53 protein, proliferating-cell nuclear antigen (PCNA) and Ki-67 antigen was evaluated in a series of 116 stage I-II gastric cancer patients. The staining for p53 protein (staining frequency and intensity) in malignant cells was expressed as a p53 index. Similarly, the staining frequency and intensity for PCNA and Ki-67 were evaluated. The p53 index was independent of the stage and differentiation grade, but significantly related to DNA ploidy, S-phase fraction and mitotic activity. A high p53 index was a sign of inferior survival, compared to a low or intermediate index. p53-negative tumours were also associated with poor survival. In a multivariate analysis, only the depth of tumour infiltration and the presence of nodal metastases were independent prognostic factors in stage I-II gastric cancer. PCNA expression and Ki-67 antigen expression were not related to the stage, ploidy, proliferative activity or p53 expression, and they had no impact on survival. The results indicate that p53 protein expression may be of prognostic significance in gastric cancer, while PCNA and Ki-67 antigen expression have no predictive value.

Comparison of DNA ploidy and S-phase fraction with prognostic factors in gastric cancer.

OBJECTIVE: To assess the value of DNA ploidy and S-phase fraction (SPF) as prognostic factors in gastric cancer. STUDY DESIGN: DNA ploidy and SPF were analyzed in 289 gastric cancer cases using flow cytometry and compared with the clinical and histopathologic features of the tumors. RESULTS: Aneuploidy was found in 36% of the patients; it was more frequent in the intestinal type of cancer (56%) as compared to the diffuse type (15%). Aneuploidy was also related to advanced TNM stage, cardiac location and high mitotic activity. In univariate survival analysis, TNM stage and tumor size were the most important prognostic factors. High SPF was significantly related to inferior survival rates, but DNA ploidy did not have any significant correlation with survival when all patients were analyzed together. However, in diffuse-type cancer, both DNA ploidy and SPF were significant prognostic factors. In multivariate analysis, DNA ploidy proved to be an independent predictor of survival in gastric cancer. CONCLUSION: The results indicate that in addition to TNM stage, flow cytometric analysis of DNA ploidy and SPF are important prognostic factors in gastric cancer.