"7, 10 and 14-days rabeprazole-based standard triple therapies for H. pylori eradication: are they still effective? A randomized trial".

BACKGROUND & STUDY AIMS: Increasing data suggests that the efficiency of standard triple therapies of 7-10-14 days duration has fallen below the threshold for acceptability (80% cure rates in intention to treat analysis). Use of rabeprazole, a PPI less influenced by CYP2C19 gene polymorphisms is reported to lead to improved eradication rates. This study aims to re-examine the effectiveness of 7-10-14 days triple therapies based on rabeprazole in Greek patients. PATIENTS AND METHODS: 307 patients, from 2 endoscopic centers in Greece, were randomized to receive Rabeprazole 20 mg bid, Clarithromycin 500 mg bid, and Amoxycillin 1gr bid for 7-days, for 10-days or for 14-days. Cure rates were assessed by CLO-test and histology. Clarithromycin sensitivity tests were carried out in the cultured pre-treatment H.pylori strains. The success rates were calculated by both intention-to-treat (ITT) and per protocol (PP) analyses. RESULTS: The eradication rates according to ITT analyses were 74.5% (95% CI: 66.5-82.9%) for 7-days, 80.6% (95% CI: 73.2-88.2%) for 10-days and 90.2% (95% CI: 84.5-95.9%) for 14-days treatment. PP cure rates were 76% (95% CI: 68.4-85.0%) for 7-days, 83% (95% CI: 76.6-91.0%) for 10-days and 93.9% (95% CI: 86.7-973%) for 14-days treatment. Side effects were generally minor and comparable in all treatment groups. CONCLUSIONS: Both 10- and 14-days rabeprazole-based triple regimens reached eradication rates above the threshold of 80% on an intention to treat basis. In our setting, the current regimen using rabeprazole, amoxicillin and clarithromycin was well tolerated, is still effective and should continue to be recommended as first-line therapy for H. pylori eradication.

Old ectopic pregnancy remnants with morphological features of placental site nodule occurring in fallopian tube and broad ligament.

Placental site nodule (PSN) is an asymptomatic benign proliferation of intermediate trophoblast from a previous gestation that failed to involute. It is most commonly found in the endometrium or endocervix; however, placental site nodule has recently been reported to occur at sites of ectopic gestation. This is the first case of PSN in the broad ligament in direct contact with the fallopian tube. The patient underwent surgery for an adenocarcinoma of the opposite tube. Microscopically and immunohistochemically, the lesion showed the characteristics of a proliferation of intermediate trophoblast.

Expression of p53, p21, mdm2, Rb, bax and Ki67 proteins in lymphomas of the mucosa-associated lymphoid (MALT) tissue.

We have investigated by immunohistochemistry 38 cases of B-cell MALT-NHL comprising 23 high grade (HG) and 15 low grade-(LG) tumours for the expression of p53, mdm2, p21, Rb, Ki67, bcl2 and Bax proteins. P53, mdm2 and p21 proteins were found in at least 5% of the tumour cells in 13/23, 2/23 and 11/23 HG tumours, respectively. These proteins were detected in very rare tumour cells in LG tumours. The following patterns were recorded in HG tumours: p53+/p21+/mdm2+ (2 cases), p53+/p21+/mdm2- (7 cases), p53+/p21-/mdm2- (4 cases), p53-/p21-/mdm2- (18 cases) and p53-/p21+/mdm2-(2 cases). Proliferative Ki67 index and Rb protein expression were higher in HG than in LG MALT-NHL. Bcl2 protein was expressed in all LG MALT-NHL, whereas only 2/23 HG MALT-NHL were bcl2 positive in most tumour cells. Bax protein was expressed in all MALT-NHL with HG tumours being positive in higher proportion of tumour cells than LG tumours. These findings show that significant expression of p53, mdm2, p21,Ki67 and Rb proteins occurs more frequently in aggressive histotypes of MALT-NHL. The parallel Rb/Ki67 expression suggests that Rb protein expression in MALT-NHL is normally regulated in relation to the proliferative growth fraction of the tumours. The pattern p53+/p21+/mdm2 +/- may represent MALT-NHL with wild type (wt) p53 gene since mdm2 and p21 proteins are inducible by wt p53 gene. The pattern p53+/mdm2-/p21-may represent MALT-NHL with p53 gene mutations unable to activate expression of mdm2 and p21 proteins. MALT-NHL with the p53-/mdm2-/p21 + pattern may be consistent with p53-independent p21 expression. Bax protein expression in all MALT-NHL suggests a role for this protein in the pathogenesis of these tumours.

P21/waf1 protein expression in nasopharyngeal carcinoma. Comparative study with PCNA, p53 and MDM-2 protein expression.

We investigated the immunohistochemical expression of p21/waf1 protein in 59 cases of nasopharyngeal carcinomas (NPC) and compared p21 expression with PCNA, p53 and mdm2 protein expression. We found p21, PCNA, p53 and mdm2 in 59/59, 59/59, 18/59 and 12/59 nasopharyngeal carcinomas, respectively. We observed a tendency to a relationship between high expression of PCNA (> 25% positivity in tumour cells) and low expression of p21 protein. Parallel p53/p21 protein expression was found in 18 cases. Twelve were also mdm2 positive. This pattern may represent NPC with wild type (wt) p53 since mdm2 and p21 proteins are inducible by wt p53 gene. In these cases p53 protein expression may be due to stabilisation to mdm2 protein. This could be important in the pathogenesis of these cases since mdm2 may deregulate the p53-dependent growth suppressive pathway. Discordant p53-/p21+ protein expression was found in 41 cases. All were also mdm2 negative. This pattern suggests immunohistochemically undetectable wt p53 gene which is able to induce p21 protein expression.

Expression of p53, mdm2, p21/waf1 and bcl-2 proteins in thymomas.

We have investigated the immunohistochemical expression of p53, mdm2, p21/waf1 and bcl-2 proteins in 31 thymic epithelial tumours comprising five medullary thymomas (MDT), four mixed thymomas (MT), 12 cortical thymomas (CT), eight predominately cortical thymomas (PCT) and two well-differentiated thymic carcinomas (WDTC). We have found p53, mdm2, p21 and bcl-2 protein expression in 25/31, 8/31, 5/31 and 10/31 thymic epithelial tumours, respectively. Coexpression of p53 and mdm2 proteins was found in eight cases (three CT, four PCT and one WDTC). Five of them were also p21 positive and three p21 negative. Discordant p53+/mdm2-/p21- protein expression was found in 19 cases (three MDT, three MT, nine CT, three PCT and one WDTC). Mdm2 and p21 proteins were not expressed in the absence of p53 protein. Coexpression of bcl-2 and p53 proteins was found in seven cases (three MDT, three MT and one WDTC). Eighteen cases were p53+/bcl-2- (10 CT, seven PCT and one WDTC) and three cases (two MDT and one MT) were bcl-2+/p53-. Our findings indicate that in thymomas, p53 expression is more frequently associated with cortical histotypes while bcl-2 expression is strongly associated with medullary and mixed histotypes. In addition, there is an inverse correlation between p53 and bcl-2 protein expression in thymomas. Coexpression of p53/mdm2/p21 proteins may reflect thymomas with wild-type (wt), p53 gene since mdm2 and p21 proteins are inducible by wt p53 gene. However, in view of previous findings that p53 mutation is an early event in thymomas, the possibility of p53 gene mutation with p53-independent mdm2 and p21 expression should be considered in these cases. Discordant p53+/mdm2-/p21- protein expression may represent thymomas with p53 gene mutations unable to activate expression of mdm2 and p21 proteins.

p53 protein expression in breast carcinomas. Comparative study with the wild type p53 induced proteins mdm2 and p21/waf1.

The aim was to investigate the pattern of expression of p53 protein and two wild-type (wt) p53-induced proteins (mdm2 and p21/waf1), as an indirect way of assessing p53 gene status in breast carcinomas. Formalin-fixed paraffin embedded tissue from 102 cases of breast carcinomas comprising mostly ductal carcinomas (88 cases) was stained by immunohistochemistry for p53, mdm2 and p21/waf1 proteins. We found p53, mdm2 and waf1/p21 protein expression in 33/102, 20/102 and 38/102 breast carcinomas, respectively. Parallel p53/mdm2 protein expression was found in 9 cases. Five were also p21/waf1 positive. Discordant p53+/ mdm2-protein expression was found in 24 cases. Nine were p21/waf1 positive and the remaining fifteen were p21/waf1 negative. The patterns mdm2+/p53-/p21- and p21+/p53-(+)/mdm2- were found in 6 and 20 cases, respectively. Parallel p53/mdm2/p21 protein expression may represent breast carcinomas with wt p53 gene since mdm2 and p21 proteins are inducible by wt p53 gene. In these cases p53 protein expression may be due to stabilisation to mdm2 protein. This could be important in the pathogenesis of these cases since mdm2 may deregulate the p53-dependent growth suppressive pathway. Discordant p53+/mdm2-/p21- protein expression may represent breast carcinomas with p53 gene mutations unable to activate expression of mdm2 and p21 proteins. Breast carcinomas with p53+/mdm2/p21+ protein expression may have either wt p53 with deregulated mdm2 gene expression or mutated p53 gene with p53-independent p21 expression. Cases with only mdm2 expression may represent tumours with mdm2 gene amplification or overexpression and cases with only p21 expression may reflect p53-independent regulation of p21 protein.

p53 protein expression in non-Hodgkin's lymphoma. Comparative study with the wild type p53 induced proteins mdm2 and p21/waf1.

Aims-To investigate the pattern of expression of p53 protein and two wild type p53 induced proteins (mdm2 and p21/waf1) as an indirect way of assessing p53 gene status in non-Hodgkin's lymphoma.Methods-Formalin fixed, paraffin wax embedded tissue from 87 cases of nodal non-Hodgkin's lymphoma, comprising 52 high grade and 35 low grade tumours, was stained by immunohistochemistry for p53, mdm2 and p21/waf1 proteins.Results-p53, mdm2 and waf1/p21 proteins were expressed in 36/52, 21/52 and 31/52 high grade and 3/35, 21/35 and 3/35 low grade non-Hodgkin's lymphomas, respectively. Parallel p53/mdm2 protein expression was found in 23 cases (21 high grade and two low grade). These 23 cases were also positive for p21/waf1 protein expression. Discordant p53 positive/mdm2 negative protein expression was found in 16 cases (15 high grade and one low grade). Eleven (10 high grade and one low grade) of these 16 cases were p21/waf1 positive and the remaining five high grade non-Hodgkin's lymphomas were p21/waf1 negative. Mdm2 and p21/waf1 proteins were not expressed in the absence of p53 protein expression.Conclusions-p53, mdm2 and waf1/p21 protein expression is more frequently associated with aggressive histotypes of non-Hodgkin's lymphoma. Parallel expression of p53, mdm2 and p21 proteins may represent non-Hodgkin's lymphomas with a wild type p53 gene as mdm2 and p21 proteins can be induced by the wild type gene. In these cases p53 protein expression may result from stabilisation via complex formation with the mdm2 protein. This could be important in the pathogenesis of these cases as mdm2 may deregulate the p53 dependent growth suppressive pathway. Discordant p53 positive/mdm2 negative/p21 negative protein expression may represent non-Hodgkin's lymphoma with p53 gene mutations unable to activate expression of mdm2 and p21 proteins. Non-Hodgkin's lymphoma with p53 positive/mdm2 negative/p21 positive protein expression may have either wild type p53 with deregulated mdm2 gene expression or mutated p53 gene with p53 independent p21 expression.

Expression of p53 and mdm-2 proteins in Hodgkin's Disease. Absence of correlation with the presence of Epstein-Barr virus.

The expression of p53 and mdm-2 proteins was analysed in parrafin sections from 39 cases of Hodgkin's disease (HD) and compared to the presence of Epstein-Barr Virus (EBV). P53 protein was found in Hodgkin and Reed-Sternberg (HRS) cells in 12/39 cases. Mdm-2 protein was found in HRS cells in 10/39 cases. EBV-encoded EBER1-2 mRNAs and LMP-1 protein expression were found in HRS cells in 16/39 cases. In view of the LMP-1 oncogenic potential in vitro, these findings suggest that EBV may be involved in the pathogenesis of a proportion of HD cases. The coexpression of mdm-2 and p53 proteins was found in HRS cells in 10 cases, whereas in 27 cases neither was identified and in 2 cases there was no coexpression of mdm-2/p53. The simultaneous p53/mdm-2 protein expression, in view of previous findings which showed that most cases of HD display no p53 gene mutations, suggests that mdm-2 protein expression may be one of the factors responsible for the stabilisation of p53 protein in these cases. This could be important, in the pathogenesis of these cases of HD, since mdm-2 may deregulate the p53 dependent growth suppressive pathway. Mdm-2-/ p53+ protein expression may reflect the stabilisation of p53 protein by proteins other than mdm-2, mutations in the p53 gene making it unable to activate mdm-2, or the deregulation of the mdm-2 gene. No relationship was found between the presence of EBV and the expression of p53 and/or mdm-2 proteins.

Major histocompatibility complex (MHC)-I and MHC-II expression in Hodgkin's disease in relation to the presence of Epstein-Barr Virus (EBV).

We have investigated the immunohistochemical expression of beta2-microglobulin and HLA-DR proteins in Hodgkin's disease (HD) in relation to the expression of the EBV-encoded EBER1-2 mRNAs and the LMP-1 protein. beta2-microglobulin is expressed in association with MHC-I molecules on most nucleated cells and HLA-DR belongs to the MHC-II molecules which are expressed mostly on antigen-presenting cells. Formalin-fixed paraffin embedded tissue from 39 cases of lymphonodal HD were stained by immunohistochemistry for beta2-microglobulin, HLA-DR and LMP-1 proteins and by RNA in situ hybridization for EBER1-2 mRNAs. beta2-microglobulin positive staining was found in Reed-Sternberg and Hodgkin cells (HRS cells) in 18/39 cases of HD. HLA-DR positive staining was found in HRS cells in all cases of HD. EBER1-2 transcripts and LMP-1 protein were detected in HRS cells in 16/39 cases of HD. No correlation as found between the presence of EBER 1-2 transcripts or the LMP-1 protein and the detection of beta2-microglobulin and HLA-DR proteins in HD. Thus, EBV does not seem to use downregulation of MHC-I to avoid the T-cell cytotoxic immune response in HD. In addition, EBV does not seem to be the only factor responsible for the HLA-DR expression in HRS cells of HD, although it could participate in the induction of the expression of HLA-DR molecule in the EBV positive cases of HD.

MDM-2 protein expression in nasopharyngeal carcinomas. Comparative study with p53 protein expression.

Aims-To investigate the immunohistochemical expression of MDM-2 protein in comparison with that of p53 protein in nasopharyngeal carcinomas.Methods-Formalin fixed, paraffin wax embedded tissue from 59 cases of nasopharyngeal carcinoma was stained by immunohistochemistry for MDM-2 and p53 proteins.Results-The tumours were divided histologically into seven cases of keratinising nasopharyngeal carcinoma (KNPC), 14 cases of non-keratinising nasopharyngeal carcinoma (NKNPC), and 38 cases of undifferentiated nasopharyngeal carcinoma (UNPC). MDM-2 nuclear expression was observed in 0/7 KNPC, 1/14 NKNPC, and 11/38 UNPC. p53 nuclear expression was observed in 1/7 KNPC, 2/14 NKNPC, and 15/38 UNPC. Parallel MDM-2 and p53 expression was found in 12 cases (11 UNPC and one NKNPC). Discordant MDM-2-/p53 + expression was found in six cases (four UNPC, one NKNPC, and one KNPC), and absence of expression of both proteins in the remaining 41 cases.Conclusions-Expression of MDM-2 and p53 proteins may be associated with the level of tumour cell differentiation in nasopharyngeal carcinoma. Simultaneous expression of MDM-2/p53 in a proportion of UNPC suggests that MDM-2 protein may be responsible for stabilisation of p53 protein in these cases, in view of the previous demonstration of the p53 gene in germ line configuration. This could be important in the pathogenesis of these cases, since MDM-2 may deregulate the p53 dependent growth suppressive pathway. Discordant MDM-2-/p53 + expression in a few cases of nasopharyngeal carcinoma may reflect stabilisation of p53 protein by other proteins, or p53 mutations unable to activate MDM-2.

Expression of bcl-2 and p53 proteins in nasopharyngeal carcinoma. Absence of correlation with the presence of EBV encoded EBER1-2 transcripts and latent membrane protein-1.

Aims-To investigate the immunohistochemical expression of bcl-2 and p53 proteins in nasopharyngeal carcinomas in relation to the expression of the Epstein-Barr virus (EBV) encoded EBER messenger RNAs (mRNAs) and latent membrane protein-1 (LMP-1).Methods-Formalin fixed, paraffin wax embedded tissue from 44 nasopharyngeal carcinomas (NPCs) was stained by immunohistochemistry for p53, bcl-2 and LMP-1 proteins and by RNA in situ hybridisation for EBER mRNAs.Results-The tumours were divided histologically into 13 cases of keratinising squamous cell NPC (KNPC), 15 cases of non-keratinising squamous cell NPC (NKNPC) and 16 cases of undifferentiated NPC (UNPC). Bcl-2 expression was observed in five of 15 NKNPC cases and in six of 16 UNPC cases; p53 expression was observed in one of 13 KNPC, two of 15 NKNPC and four of 16 UNPC cases. EBER 1-2 transcripts were detected in five of 15 NKNPC and nine of 16 UNPC cases, while LMP-1 expression was observed in one of 16 UNPC cases. All 13 KNPCs were EBV and bcl-2 negative. No correlation was found between the presence of EBER 1-2 transcripts and the detection of bcl-2 or p53 proteins, or both, in NPC cells.Conclusions-The expression of bcl-2 and p53 proteins may be associated with the level of the tumour cell differentiation in NPC. In addition, in view of the important role of the bcl-2 protein in the inhibition of apoptosis, the expression of bcl-2 protein may contribute to tumour cell survival in a proportion of NPCs. Furthermore, in the light of previous findings that the p53 gene in most UNPCs is in the wild-type configuration, mechanisms other than mutation may be responsible for stabilisation of the p53 protein in UNPCs.

Beta 2-microglobulin and HLA-DR expression in relation to the presence of Epstein-Barr virus in nasopharyngeal carcinomas.

We have investigated the immunohistochemical expression of beta 2-microglobulin and HLA-DR proteins in nasopharyngeal carcinoma (NPC) in relation to the expression of the Epstein-Barr virus (EBV)-encoded EBER 1-2 mRNAs and LMP-1 protein. beta 2-Microglobulin is expressed in association with MHC-I molecules on most nucleated cells and HLA-DR belongs to the MHC-II molecules which are expressed mostly on antigen-presenting cells. Formalin-fixed paraffin-embedded tissue from 37 NPC cases was stained with immunohistochemistry for beta 2-microglobulin, HLA-DR and LMP-1 proteins and by RNA in situ hybridization for EBER 1-2 mRNAs. beta 2-Microglobulin-positive staining was found in neoplastic cells in all cases. In 19/37 NPC cases the positive staining was found in most neoplastic cells. In the remaining 18 NPC cases more than 25% of the neoplastic cells showed significantly reduced or negative staining in comparison to the normal epithelium and infiltrating small lymphocytes. HLA-DR-positive staining was found in 27/37 NPC cases. EBER 1-2 transcripts were deteced in neoplastic cells in 13/37 NPC cases. LMP-1 expression in tumour cells was found in 4/13 EBER1-2-positive cases. No correlation was found between the presence of EBER1-2 transcripts or LMP-1 protein and the beta 2-microglobulin-reduced expression in NPC. Thus, EBV does not seem to use downregulation of MHC-I to avoid the T cell cytotoxic immune response in NPC. HLA-DR expression was observed in all 13 EBV-positive cases of NPC, suggesting that EBV may participate in the induction of HLA-DR expression in a proportion of NPC.

Effect of forceps size and mode of orientation on endoscopic small bowel biopsy evaluation.

Endoscopy is increasingly being used to obtain duodenal biopsy specimens in suspected small intestinal malabsorption. We have prospectively evaluated the effect of standard and jumbo biopsy forceps, as well as the mode of orientation of the specimens (naked eye or stereomicroscopy), on duodenal biopsy weight, length, depth, and orientation in 18 consecutive patients. A pair of biopsy specimens was obtained from each patient by each type of forceps in random order. After they had been weighed, one biopsy specimen from each pair was oriented stereomicroscopically and all four were blindly evaluated by two pathologists. The biopsy specimens obtained with the jumbo forceps were significantly larger (15.9 +/- 6.9 mg, mean +/- SD) and longer (0.6 +/- 0.2 cm) than those obtained with the standard forceps (8.0 +/- 1.3 mg, 0.4 +/- 0.2 cm, respectively; p < 0.001). Seventy-two percent of the jumbo biopsy specimens that were oriented with stereomicroscopy included a minimum of four villi in a row, as compared to 44% of the eye-oriented jumbo specimens and less than 39% of the standard specimens, irrespective of the mode of orientation (p = 0.02). These results indicate that the jumbo forceps is superior to the standard, because it produces a larger duodenal mucosal specimen, usually suitable for optimal histologic evaluation when oriented with stereomicroscopy.