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C J Meijer

Publications and source records attributed to C J Meijer.

At least 37 records · Page 2Linked to original sources
PubMed2001

Nuclear cytometric changes in breast carcinogenesis.

Breast cancer is thought to originate through progressively aberrant precursor lesions, paralleled by increasing morphological changes. The aim of this study was to quantify nuclear features by image cytometry in invasive breast cancer and its early (hyperplasia) and late (ductal carcinoma in situ) precursor lesions, in order to objectively describe nuclear changes in the spectrum of proliferative intraductal and invasive breast lesions. Image cytometry was performed on tissue sections of 20 samples of normal breast tissue, 71 of usual ductal hyperplasia (UDH), nine of atypical ductal hyperplasia (ADH), and 11 of well-differentiated and 13 of poorly differentiated ductal carcinoma in situ (DCIS) lesions. The invasive breast carcinomas consisted of 19 well-differentiated and 24 poorly differentiated lesions. Through the spectrum from normal breast tissue to invasive carcinoma, progressive changes in many nuclear features were measured. Significant differences were found between nuclei of florid ductal hyperplasia compared with mild and moderate ductal hyperplastic lesions, suggesting that florid ductal hyperplasia may be a more advanced lesion than assumed and may contain cancer precursor cells. No differences were found between ADH and well-differentiated DCIS, suggesting that these lesions are closely related. Feature values of well-differentiated DCIS were comparable to values found in well-differentiated invasive carcinoma and the same applied to poorly differentiated DCIS and invasive lesions. These results support the hypothesis that breast cancer develops through different routes of progression, one leading to well-differentiated invasive cancer through well-differentiated DCIS, and one leading to poorly differentiated invasive cancer through poorly differentiated DCIS. In conclusion, image cytometry reveals progressive changes in nuclear morphological and subvisual chromatin distribution features in the spectrum from intraductal proliferations to invasive breast cancer. This provides evidence for a progression from usual to atypical ductal hyperplasia and then to invasive cancer, through different routes for well-differentiated and poorly differentiated lesions.

Breast↗
PubMed2001

Differential expression of human Polycomb group proteins in various tissues and cell types.

Polycomb group proteins are involved in the maintenance of cellular identity. As multimeric complexes they repress cell type-specific sets of target genes. One model predicts that the composition of Polycomb group complexes determines the specificity for their target genes. To study this hypothesis, we analyzed the expression of Polycomb group genes in various human tissues using Northern blotting and immunohistochemistry. We found that Polycomb group expression varies greatly among tissues and even among specific cell types within a particular tissue. Variations in mRNA expression ranged from expression of all analyzed Polycomb group genes in the heart and testis to no detectable Polycomb group expression at all in bone marrow. Furthermore, each Polycomb group gene was expressed in a different number of tissues. RING1 was expressed in practically all tissues, while HPH1 was expressed in only a few tissues. Also within one tissue the level of Polycomb group expression varied greatly. Cell type-specific Polycomb group expression patterns were observed in thyroid, pancreas, and kidney. Finally, in various developmental stages of fetal kidney, different Polycomb group expression patterns were observed. We conclude that Polycomb group expression can vary depending on the tissue, cell type, and development stage. Polycomb group complexes can only be composed of the Polycomb group proteins that are expressed. This implies that with cell type-specific Polycomb group expression patterns, cell type-specific Polycomb group complexes exist. The fact that there are cell type-specific Polycomb group targets and cell type-specific Polycomb group complexes fits well with the hypothesis that the composition of Polycomb group complexes may determine their target specificity. J. Cell. Biochem. Suppl. 36: 129-143, 2001.

Blotting, Northern↗
PubMed2001

Similarity in expression of cell cycle proteins between in situ and invasive ductal breast lesions of same differentiation grade.

There is increasing evidence that there are different progression routes leading to invasive breast cancer, depending on histology and differentiation grade. The aim of this study was to determine alterations in the expression of proteins involved in proliferation and apoptosis in non-invasive and invasive ductal breast lesions. Immunohistochemistry was performed on 106 usual ductal hyperplasias (UDH), 61 DCIS lesions and 53 invasive ductal breast carcinomas. Increased proliferation (Ki67), overexpression of cyclin D1, HER-2/neu, p21 and p53, and decreased expression of bcl-2 and p27 could already be found in UDH. Significant differences between UDH and DCIS lesions were found for only one protein when UDH was compared with well-differentiated DCIS (p27), for three proteins when compared with intermediately differentiated DCIS (p21, cyclin D1, Ki-67), and for all proteins when compared with poorly-differentiated DCIS. Comparing DCIS with invasive lesions of same differentiation grade, proliferation was elevated in the invasive lesions. Altered expression of the other proteins was in general only slightly increased in the invasive lesion compared with DCIS. The number of proteins with altered expression per lesion was highest in poorly-differentiated lesions and was comparable between DCIS and invasive cancer of the same differentiation grade. In conclusion, the biggest changes in expression of these proliferation and apoptosis related proteins appear to occur during the transition from hyperplasia to DCIS; they probably play a minor role in the transition from DCIS to invasive breast lesion of same differentiation grade. Well-differentiated in situ and invasive breast lesions share many of the aberrations in expression of these proteins, as do poorly-differentiated in situ and invasive lesions. However, there are many differences between the well and poorly-differentiated lesions. This further supports the existence of different progression routes leading to breast cancer.

Apoptosis↗
PubMed2001

Absence of tpr-met and expression of c-met in human gastric mucosa and carcinoma.

The c-met proto-oncogene, encoding the hepatocyte growth factor receptor, can be activated by various mechanisms. These include, among others, gene amplification with concomitant overexpression and the tpr-met oncogenic rearrangement. In the case of gastric cancer, contradictory results on the presence of the tpr-met oncogenic rearrangement have been published. The current study aimed therefore to assess the prevalence of tpr-met expression in Caucasian gastric adenocarcinomas, to evaluate the importance of this oncogene in their carcinogenesis. In addition, the level of c-met expression was determined, to evaluate the role of this alternative mode of activation of the proto-oncogene. A series of Caucasian gastric adenocarcinomas (n=43) and normal gastric mucosal samples (n=14) was analysed for tpr-met and c-met expression. Expression of tpr-met mRNA in the samples was performed by two reverse transcriptase polymerase chain reaction (RT-PCR) assays, with excellent correlation. The specificity of both methods was confirmed by direct sequencing of the PCR products of the MNNG-HOS cell line, which is known to contain the rearrangement. The level of c-met expression was assessed using semi-quantitative RT-PCR assays and immunohistochemistry (IHC). None of the normal gastric mucosal or gastric adenocarcinoma samples expressed tpr-met mRNA, as determined by both RT-PCR assays. Seventy per cent of the adenocarcinomas showed overexpression of c-met, according to elevated c-met mRNA levels, compared with the expression level of normal gastric mucosa. A significant correlation was found between the level of c-met mRNA and protein expression. In conclusion, these results strongly suggest that tpr-met activation does not play a role in Caucasian gastric carcinogenesis, while overexpression of the c-met gene occurs in the majority of Caucasian gastric adenocarcinomas.

Adenocarcinoma↗
PubMed2001

High-risk HPV testing in women with borderline and mild dyskaryosis: long-term follow-up data and clinical relevance.

In The Netherlands and most other European countries, women with two serial cervical smears with borderline or mild dyskaryosis (BMD) within 6 months are referred for colposcopy-directed biopsies. Only about 10% of these women have high-grade cervical intraepithelial neoplasia (CIN). This study therefore investigated whether human papillomavirus (HPV) testing could identify which women with smears read as BMD are most likely to have high-grade CIN, either at referral or during follow-up and the relationship was determined between clearance of high-risk HPV and regression of abnormal cytology. Women with smears read as BMD (n=278) were referred to the gynaecologist for colposcopy. They were subdivided into two groups; group A comprised women with a single smear (n=172) and group B women with two sequential smears (n=106) read as BMD before referral. High-risk HPV detection with Hybrid Capture II (HC II) was performed on a cervical scrape taken at the first visit before colposcopy (i.e. baseline smear) and during follow-up. Biopsies were taken when lesions suspected for CIN were seen at colposcopy. High-risk HPV DNA was present in the baseline smears of 126 (45.0%) women; 26 (20.6%) of them had histologically confirmed CIN 2/3 at the first visit and another 14 (11.1%) during follow-up. Only one of the 152 women (0.7%) with a negative high-risk HPV test had a CIN 2 lesion at the first visit and no CIN lesions were detected during follow-up of these women. After exclusion of women who were treated for prevalent high-grade CIN, the median follow-up times were 1.3 years (range 0.0-4.3 years) and 1.6 years (range 0.0-4.5 years) for women with HPV-negative and HPV-positive baseline smears, respectively. The sensitivity of a positive high-risk HPV test for CIN 2/3 at the first visit was 96.3%, the specificity 60.2%, the positive predictive value 20.6%, and the negative predictive value 99.3%. These values did not change markedly when stratified for group A or group B. Thus, a high-risk HPV positive test was strongly associated with the presence at the first visit and the development of CIN 2/3 lesions during follow-up. Moreover, regression of abnormal cytology in women with a positive high-risk HPV test at baseline was strongly associated with viral clearance and occurred 0.3 years (range -1.2 to 1.7 years) later than HPV clearance. This study establishes the value of a high-risk HPV positive test for women at risk of high-grade CIN, with virtually no risk for missing CIN 2/3. Addition of a test on high-risk HPV in women with BMD could prevent 55% of the referrals and/or repeat smears.

Adult↗
PubMed2001

T cell infiltration and MHC I and II expression in the presence of tumor antigens: An immunohistochemical study in patients with serous epithelial ovarian cancer.

OBJECTIVES: Ovarian cancer is a frequent cause of death among women with gynaecologic malignancies despite the introduction of combination chemotherapy. There is therefore a need for new therapeutic strategies for patients with ovarian cancer, such as cellular immunotherapy. In this immunohistochemical study we analysed the expression of three tumor antigens, p53, HER-2/neu and MUC-1 in relation to the expression of major histocompatibility complex (MHC) class I and II on tumor cells, and we searched for the presence of (activated) immune effector cells at the tumor site. STUDY DESIGN: The study was carried out retrospectively in tumor tissue from 29 patients with serous ovarian cancer. Material used had been formalin fixed and paraffin embedded. Material had been obtained from 15 patients at staging laparotomy and from 14 patients during second look or intervention laparotomy. RESULTS: A positive staining for p53 was found in 19/29 (66%) of the tumors, with a high positivity in 13/29 (45%). HER-2/neu and MUC-1 staining was positive in 8/29 (28%) and 21/28 (75%), respectively. Downregulation of MHC class I on tumor cells was found in a minority of the patients, beta-2-microglobin (beta2m) was expressed on tumor cells in all patients. High staining for CD45RO correlated with a high positive staining for granzyme-B (R=0.40, P=0.04) and TIA-1 (R=0.39, P=0.04). A statistically significant better survival in the group with lower stage of disease was found. CONCLUSIONS: As only three out of 29 patients were negative for the tumor antigens p53, HER-2/neu and MUC-1, immunotherapy aiming at all three could serve almost all patients with ovarian cancer. We found that granzyme-B, TIA-1 and CD45RO+ T cells are present in the tumor biopsies, increasing this number by immunotherapy may be beneficial. The immune escape mechanism by MHC class I and beta2m downregulation seems to be of minor importance. Our data support the view that immunotherapy may offer new possibilities with high specificity in ovarian cancer.

Adult↗
PubMed2001

Polycomb-group genes as regulators of mammalian lymphopoiesis.

Polycomb proteins form DNA-binding protein complexes with gene-suppressing activity. They maintain cell identity but, also, contribute to the regulation of cell proliferation. Mice with mutated Polycomb-group genes exhibit various hematological disorders, ranging from the loss of mature B and T cells to development of lymphomas. Lymphopoiesis in humans is associated with characteristic expression patterns of Polycomb-group genes in defined lymphocyte populations. Collectively, these results indicate that Polycomb-group genes encode novel gene regulators involved in the differentiation of lymphocytes. The underlying mechanism is related, most probably, to gene silencing by chromatin modification, and might affect proliferative behavior and account for the irreversibility of lineage choice.

Animals↗
PubMed2001

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors.

Application of recombinant adenoviral vectors for cancer gene therapy is currently limited due to lack of specificity for tumor cells. For gastric and esophageal adenocarcinoma, we present here that the relative abundant expression of the primary adenovirus receptor, coxsackie/adenovirus receptor (CAR), on normal epithelium compared to carcinoma favors the transduction of the epithelium. As such, to achieve specific transduction of cancer cells, targeting approaches are required that ablate the binding of the virus to CAR and redirect the virus to tumor-specific receptors. By immunohistochemistry and reverse transcriptase polymerase chain reaction assays, we demonstrate a marked difference in expression of the human epithelial cell adhesion molecule (EpCAM) between normal and (pre)malignant lesions of the stomach and esophagus. Based on this, we explored the feasibility of using EpCAM to achieve gastric and esophageal adenocarcinoma selective gene transfer. Adenoviral vectors redirected to EpCAM using bispecific antibodies against the adenovirus fiber-knob protein and EpCAM specifically infected gastric and esophageal cancer cell lines. Using primary human cells, an improved ratio of tumor transduction over normal epithelium transduction was accomplished by the EpCAM-targeted vectors. This study thus indicates that EpCAM-targeted adenoviral vectors may be useful for gastric and esophageal cancer-specific gene therapy in patients.

Adenocarcinoma↗
PubMed2001

Percentage of activated cytotoxic T-lymphocytes in anaplastic large cell lymphoma and Hodgkin's disease: an independent biological prognostic marker.

Recently, we demonstrated that the presence of high percentages of activated cytotoxic T-lymphocytes (CTLs) in biopsy specimens of both Hodgkin's disease (HD) and ALK negative anaplastic large cell lymphoma (ALCL) is associated with a poor prognosis. To test whether this biological prognostic factor is more important in predicting clinical outcome than histological diagnosis or clinical factors, we compared the prognostic value of these parameters in an expanded group of classical HD and ALK negative ALCL. Tumor biopsies of classical HD (n = 83) and ALK negative systemic nodal ALCL (n = 43) were investigated for the presence of activated CTLs by immunohistochemistry, using a monoclonal antibody directed against granzyme B. Percentages of activated CTLs were quantified using Q-PRODIT, and their prognostic value was compared to that of histological diagnosis and clinical parameters, including age and stage. Both in classical HD and ALK negative ALCL, a high percentage of activated CTLs (ie > or = 15%) identified a group of patients with poor overall and progression-free survival time, even when adjusted for stage. In multivariate analysis, percentage of activated CTLs remained a strong independent prognostic marker, and was more sensitive than histological diagnosis or clinical factors in predicting overall survival time. We conclude that a high percentage of activated CTLs in the reactive infiltrate of ALK negative ALCL and classical HD is a strong indicator for an unfavorable clinical outcome, regardless of histological diagnosis or clinical parameters. As such, this biological parameter may be an especially helpful tool to determine therapeutic strategies in cases in which the differentiation between ALK negative ALCL and HD remains difficult.

Adolescent↗
PubMed2001

Lymphomatoid papulosis with a natural killer-cell phenotype.

Lymphomatoid papulosis (LyP) is defined as a recurrent self-healing papulonodular eruption with the histological features of a (CD30+) cutaneous T-cell lymphoma. The atypical cells usually have a CD3+/-, CD4+/-, CD8-, CD30+, CD56- T-cell phenotype. We report an unusual case of LyP, in which the atypical cells expressed a CD3-, CD4-, CD8-, CD30+, CD56+ phenotype. Detailed phenotypic and genotypic analysis confirmed that these cells had a natural killer (NK)-cell phenotype. Lymphomas with an NK-cell phenotype usually have a poor prognosis. However, the waxing and waning of papular lesions for more than 20 years and the excellent response to low-dose oral methotrexate in this patient suggest similar clinical behaviour to LyP cases with a T-cell phenotype.

CD56 Antigen↗
PubMed2001

The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma.

Polycomb group (PcG) proteins are involved in the stable transmittance of the repressive state of their gene targets throughout the cell cycle. Mis-expression of PcG proteins can lead to proliferative defects and tumorigenesis. There are two separate multimeric PcG protein complexes: an EED-EZH2-containing complex and a BMI1-RING1-containing complex. In the normal human follicle mantle, both PcG complexes have mutually exclusive expression patterns. BMI1-RING1 is expressed, but EZH2-EED is not. Here, we studied the expression of both complexes in six cases of mantle cell lymphoma (MCL), which is derived from the follicle mantle. MCL cells can be cultured in vitro and stimulated to proliferation. We found that resting MCL cells expressed BMI1-RING1, but not EZH2-EED, like normal mantle cells. Proliferating MCL cells, however, showed strongly enhanced expression of EZH2. Also, BMI1 and RING1 continued to be expressed in proliferating MCL. This is the first demonstration that EZH2 expression can be upregulated in fresh lymphoma cells. To test whether the enhanced EZH2 expression was causal for the increased proliferation in MCL, we overexpressed EZH2 in two different cell lines. In the B cell-derived Ramos cell line, EZH2 overexpression caused an increase in the proliferation rate. This suggests a possible causal effect between EZH2 upregulation and increased proliferation in haematopoietic cells.

Blotting, Western↗
PubMed2001

Peripheral T/NK-cell lymphoma: a report of the IXth Workshop of the European Association for Haematopathology.

AIMS: In April 1998, The European Association for Haematopathology organized the IXth workshop on peripheral T-cell and NK-cell lymphomas and leukaemias. The workshop focused on unusual subtypes of these rare malignancies, allowing evaluation of the recently published WHO classification of neoplastic diseases of the lymphoid tissues. METHODS AND RESULTS: One-hundred and three cases were centrally immunophenotyped and hybridized for EBER1/2 of Epstein--Barr virus. All cases were reviewed by a panel of experienced haematopathologists and classified according to the new WHO classification for lymphoid neoplasms. Three cases were considered as precursor T-cell and 95 cases as peripheral T/NK-cell lymphoma/leukaemia. Although the cases represented a selected series of unusual cases, the following conclusions could be made: (i) Most lymphomas except the hepatosplenic gamma/delta T-cell lymphomas showed a rather broad morphological spectrum, with differences both between and within individual tumours. (ii) This heterogeneity was also reflected by the immunophenotype, for instance a variable expression of CD30 was found in many enteropathy type T-cell lymphomas. (iii) Exceptions in phenotype were regularly found in almost all categories, indicating that phenotype should not be the final determining factor in classification. (iv) The great majority of T-cell lymphomas expressed the alpha/beta T-cell receptor, with the exception of all but one hepatosplenic T-cell lymphomas and a few other extranodal peripheral T cell lymphomas. (v) Malignancies of precursor cells, blastic NK-cell lymphoma/leukaemia, adult T-cell lymphoma/leukaemia and most AIL-type T-cell lymphomas did not express cytotoxic molecules such as TIA1 and granzyme-B. In contrast, all five aggressive NK/T-cell lymphomas/leukaemias, a single case of large granular lymphocyte leukaemia and 40 of 47 primary extranodal lymphoma/leukaemias expressed these molecules. In hepatosplenic gamma/delta T-cell lymphoma, five of six cases showed expression of TIA1 but not of granzyme-B. (vi) Seven tumours developed after organ-transplant, four cases being EBV-positive. No distinct phenotype could be attributed to these cases. CONCLUSIONS: Most peripheral T/NK cell lymphomas could be categorized as distinct entities as described in the recently proposed WHO classification for lymphoid neoplasms.

Adult↗
PubMed2001

Distinct chromosomal aberrations in Epstein-Barr virus-carrying gastric carcinomas tested by comparative genomic hybridization.

BACKGROUND & AIMS: Approximately 10% of gastric adenocarcinomas carry the human pathogenic Epstein-Barr virus (EBV). The role of EBV in the pathogenesis of these carcinomas remains to be established. METHODS: To obtain a comprehensive overview of chromosomal aberrations in EBV-carrying and EBV-negative gastric carcinomas we performed comparative genomic hybridization (CGH) on 44 gastric carcinomas, 10 EBV-positive, and 34 EBV-negative. Additionally, DNA flow cytometry was done. RESULTS: Loss of chromosome 4p (P < 0.001) and of 11p (P < 0.02) was exclusively restricted to EBV-carrying gastric carcinomas. In addition, loss of 18q (P < 0.02) was significantly more frequent in EBV-carrying gastric carcinomas. The latter involves loci, which have already been linked to gastric carcinogenesis such as the DCC and SMAD4 gene. In contrast, the losses on chromosome 4 and 11 do not yet harbor a gene related to gastric carcinogenesis. No significant correlation was found between DNA-ploidy and the EBV-status. A number of chromosomal aberrations were found at comparable frequencies in both groups, i.e., losses of chromosome 17, 12q, and loss of 1p. Interestingly, gains of 13q (10/34) and 3q (5/34) and loss of 1q (5/34) were solely observed in EBV-negative gastric carcinomas. CONCLUSIONS: These data indicate that EBV-carrying and EBV-negative gastric carcinomas have different pathogenetic pathways in which EBV might play a crucial role.

Adenocarcinoma↗
PubMed2001

High prevalence of human papillomavirus infection in Mexican males: comparative study of penile-urethral swabs and urine samples.

BACKGROUND: Although extensive information has been gathered about the prevalence and determinants of human papillomavirus infection among women, little is known about the prevalence and natural history of this infection among males. GOAL: To investigate the potential usefulness of urine specimens to assess the presence of genital human papillomavirus DNA infection. STUDY DESIGN: The authors conducted a study of 120 healthy men from Cuernavaca, Mexico. A urine specimen and urethral and coronal sulcus swab samples were collected and tested for human papillomavirus using the GP5+/6+ polymerase chain reaction enzyme immunoassay method. RESULTS: In 95% of the urethral-coronal sulcus samples, the beta-globin gene was detectable, indicating adequacy of the specimen for DNA amplification; however, only 14% of the urine specimens had detectable beta-globin. Removal of inhibitors by DNA purification in a sample of subjects produced beta-globin amplification, but no increase in human papillomavirus DNA positivity was detected. Human papillomavirus DNA was not detectable in penile-urethral swab samples in any of the subjects who reported not having engaged in sexual activity but was present in 43% of men who reported sexual activity, a strong indication of the sexual transmission of human papillomavirus. CONCLUSIONS: Human papillomavirus is a common sexually transmitted infection among Mexican males, and urine sample specimens cannot adequately detect the presence of this infection in males.

Adolescent↗
PubMed2001

Prevalence of anti-human papillomavirus type 16, 18, 31, and 58 virus-like particles in women in the general population and in prostitutes.

Genital human papillomavirus (HPV) infection is sexually transmitted. The aim of the study was to characterize serological responses to HPV types 16, 18, 31, and 58 by exploring type-specific virus-like particles (VLPs) in two groups of women with very distinct sexual behaviors. Anti-VLP antibodies for types 16, 18, 31, and 58 and HPV DNA in cervical cells were investigated with 177 prostitutes and 283 age-matched controls from the female general population in Spain. Anti-VLP positivity increased with number of lifetime sexual partners in women from the general population, and no seroresponse was found in virgins. However, in prostitutes HPV infection was characterized by higher multireactivity to three or four VLPs (25%) than the general population (3%) and by a more frequent antibody response to HPV-58 than in the general population. About 75% of the women seropositive for type 58 had been born in a Latin American country. Seroprevalence of HPV and cervical HPV DNA in prostitutes were 14 and 10 times higher than observed in women in the general population (prevalence odds ratio [POR] of HPV seropositivity, 14.04 [95%; CI = 8.4 to 23.6] and POR for HPV DNA, 10.4 [95% CI = 3.9 to 27.6). Our results indicate that prostitutes are at an increased risk of oncogenic HPV infections, and they confirm the validity of anti-VLPs as markers of present or past HPV infection, that the number of sexual partners is the major determinant in acquisition of oncogenic HPV, and that anti-VLPs could be used as a marker of repeated infection in prostitutes.

Adolescent↗