R.H.M. Verheijen

Human MUC1 mucin: a multifaceted glycoprotein.

Human MUC1 mucin, a membrane-bound glycoprotein, is a major component of the ductal cell surface of normal glandular cells. MUC1 is overexpressed and aberrantly glycosylated in carcinoma cells. The role MUC1 plays in cancer progression represents two sides of one coin: on the one hand, loss of polarity and overexpression of MUC1 in cancer cells interferes with cell adhesion and shields the tumor cell from immune recognition by the cellular arm of the immune system, thus favoring metastases; on the other hand, MUC1, in essence a self-antigen, is displaced and altered in malignancy and induces immune responses. Tumor-associated MUC1 has short carbohydrate sidechains and exposed epitopes on its peptide core; it gains access to the circulation and comes into contact with the immune system provoking humoral and cellular immune responses. Natural antibodies to MUC1 present in the circulation of cancer patients may be beneficial to the patient by restricting tumor growth and dissemination: early stage breast cancer patients with a humoral response to MUC1 have a better disease-specific survival. Several MUC1 peptide vaccines, differing in vectors, carrier proteins and adjuvants, have been tested in phase I clinical trials. They are capable of inducing predominantly humoral responses to the antigen, but evidence that these immune responses may be effective against the tumor in humans is still scarce.

Prospective multicenter evaluation of the morphometric D-score for prediction of the outcome of endometrial hyperplasias

Prospective multicenter evaluation of the WHO classification and the morphometric D-score to predict endometrial hyperplasia cancer progression. In 132 endometrial hyperplasias WHO classification was performed by two experienced gynecologic pathologists. The D-score was assessed blindly by technicians in a routine diagnostic setting. Development of endometrial carcinoma during a 1–10-year follow-up was used as the end point. Eleven of 132 patients (8%), 10 of 61 (16%) atypical hyperplasias, and 1 of 71 (1%) nonatypical hyperplasias developed cancer. Twenty-six curettings had a D-score ≤0 (“unfavorable” or endometrial intraepithelial neoplasia) of which 10 (38%) developed cancer. None of the 86 cases with a D-score >1 (“favorable”) and one of the 20 (5%) cases with 0 < D-score ≤1 (“uncertain”) developed cancer. Sensitivity of the D-score was 100%, specificity 82%, the positive and negative predictive values were 38% and 100%, respectively. These values are similar to those in three prior retrospective D-score studies but higher than the WHO values (which are 91%, 58%, 16%, and 99%, respectively). The D-score in endometrial hyperplasias is a more sensitive and specific marker for cancer prediction than the WHO classification, can be assessed in a routine clinical setting on standard hematoxylin and eosin sections (15–30 minutes per case), and is highly reproducible and cost-effective (U.S.

IFN-gamma-producing human invariant NKT cells promote tumor-associated antigen-specific cytotoxic T cell responses.

50 per case).

Classification of radical hysterectomy adopted by the Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer.

CD1d-restricted invariant NKT (iNKT) cells can enhance immunity to cancer or prevent autoimmunity, depending on the cytokine profile secreted. Antitumor effects of the iNKT cell ligand α-galactosylceramide (αGC) and iNKT cell adoptive transfer have been demonstrated in various tumor models. Together with reduced numbers of iNKT cells in cancer patients, which have been linked to poor clinical outcome, these data suggest that cancer patients may benefit from therapy aiming at iNKT cell proliferation and activation. Herein we present results of investigations on the effects of human iNKT cells on Ag-specific CTL responses. iNKT cells were expanded using αGC-pulsed allogeneic DC derived from the acute myeloid leukemia cell line MUTZ-3, transduced with CD1d to enhance iNKT cell stimulation, and with IL-12 to stimulate type 1 cytokine production. Enhanced activation and increased IFN-γ production was observed in iNKT cells, irrespective of CD4 expression, upon stimulation with IL-12-overexpressing dendritic cells. IL-12-stimulated iNKT cells strongly enhanced the MART-1 (melanoma Ag recognized by T cell 1)-specific CD8+ CTL response, which was dependent on iNKT cell-derived IFN-γ. Furthermore, autologous IL-12-overexpressing dendritic cells, loaded with Ag as well as αGC, was superior in stimulating both iNKT cells and Ag-specific CTL. This study shows that IL-12-overexpressing allogeneic dendritic cells expand IFN-γ-producing iNKT cells, which may be more effective against tumors in vivo. Furthermore, the efficacy of autologous Ag-loaded DC vaccines may well be enhanced by IL-12 overexpression and loading with αGC.

Cell cycle-related proteins p21 and bcl-2: markers of differentiation in the human fallopian tube.

The Piver classification of radical hysterectomy for the treatment of cervical cancer is outdated and misused. The Surgery Committee of the Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer (EORTC) produced, approved, and adopted a revised classification. It is hoped that at least within the EORTC participating centers, a standardization of procedures is achieved. The clinical indications of the new classification are discussed

HER-2/neu and p27Kip1 in progression of Fallopian tube carcinoma: an immunohistochemical and array comparative genomic hybridization study

lase (NSE, BBS/NC/Vi-H-14, Dako) and chromogranin A (monoclonal, Dako). The diagnosis was pericardial rhabdomyomatous spindle cell thymoma with mucinous cystic degeneration. The patient was disease-free during 28-month follow-up. Immunohistochemically, these myoid cells express muscle markers such as desmin, myoglobin, actin. Their histogenesis is still unclear. The myoid cells may play a role in triggering the autoimmune reactions. The mucinous cysts were explained as degenerate in Hassalls corpuscles. The presence of mucous substance in our case was similar to the observation of Murakami et al. They showed the presence of a mucous substance on the surface of myoid cells. We think that the myoid cell clusters with at least 20±30 cells degenerate due to an unknown, probably vascular, reason. Finally, cystic spaces with mucous substance remain. In the differential diagnosis, mediastinal rhabdomyoma and solitary ®brous tumour (SFT) should primarily be considered. Mediastinal rhabdomyoma, whose origin is probably from the myoid cells of the thymus, does not include an epithelial spindle cell component with cytokeratin expression. Histological features of the SFT may be similar to thymoma with a predominantly spindle cell pattern. However, the characteristic rosette formations, mucous cysts and myoid cells were not seen. Spindle cells in SFT show immunohistochemical reactivity to vimentin and CD34, but not to cytokeratins. The myoid cells are only immunoreactive for vimentin in thymoma. Finally, this unusual presentation site of ectopic thymoma should be considered in the differential diagnosis of problematic pericardial lesions.

Differences between hereditary and sporadic ovarian cancer

Aims:  To determine expression of p53, HER‐2/neu and p27Kip1 in serous Fallopian tube carcinoma (FTC) in relation to stage and grade, and to investigate DNA copy number changes of HER‐2 and P27KIP1 as a potential mechanism of altered expression status.

Mucin-Like Carcinoma-Associated Antigen Serum Levels in Patients with Adenocarcinomas Originating from Ovary, Breast and Colon

Approximately 5% of ovarian cancer cases can be attributed to an autosomal dominant inheritance factor. The majority of these cases are due to germline mutations in the BRCA1 or BRCA2 tumoursupressor genes. Patients with hereditary disease do not exhibit pathognomonic features that would allow distinction from non-hereditary (sporadic) cases of ovarian cancer. Our studies are aimed at identifying clinical, histopathological as well as molecular genetic differences between hereditary and sporadic ovarian cancer. Clinical studies of the ovarian cancer cases in 31 families revealed differences regarding age at onset and stage as well as in survival compared with cancer registry controls. The molecular studies of hereditary ovarian cancer are still underway and some preliminary data is discussed.

A case of loss of heterozygosity in the BRCA2 gene of a borderline ovarian tumor: case report and review of literature

The mucin-like carcinoma-associated antigen (MCA) enzyme immunoassay was tested in 962 healthy controls. MCA levels were compared with CA 125 in 70 patients with benign and 76 with malignant ovarian tumors. In addition MCA was compared with CA 15.3 in 58 patients with breast cancer and with CEA in 50 patients with colon carcinoma. In healthy controls the 95th percentile cutoff of 19.2 U/ml appeared to be higher than generally used. With the common cutoff value of 14 U/ml, a 38% sensitivity and 100% specificity was reached in malignant versus benign ovarian tumors. In colorectal cancer only 4% of patients had elevated MCA serum levels (CEA: 50%). In breast cancer patients the MCA assay performed better than CA 15.3 although only 17.2% showed elevated levels (CA 15.3: 7.4%). Thus MCA seems to be of limited value in the diagnosis and follow-up of adenocarcinomas of breast, ovary or colon.

Objective Biomarkers in Endometrioid-Type Endometrial Carcinogenesis

Germline BRCA1 and BRCA2 mutations highly increase the risk of breast and female adnexal cancer. The role of these genes in the tumorigenesis of other malignancies is still under debate. Borderline ovarian tumors (BOT) are occasionally found in families with a strong history of breast and/or female adnexal cancer with or without proven germline mutations. We investigated whether a BOT arising in a germline BRCA2 mutation carrier could be attributed to this mutation, in which case BOT should be added to the BRCA2 related tumor spectrum. Tumor DNA of a serous borderline ovarian tumor (sBOT) of a 55-year-old female carrier of a pathogenic BRCA2 mutation (6085G>T) was analyzed for loss of heterozygosity (LOH) of BRCA2. The sBOT cells, unexpectedly, revealed loss of the mutant allele of BRCA2, while ovarian stroma cells and peripheral blood lymphocytes contained both wild-type and mutant allele of BRCA2. The finding that no loss of the wild-type BRCA2 allele was found in the tumor tissue but loss of the mutant allele was seen suggests that sBOT are not part of the BRCA2 related tumor spectrum. In the literature BOTs in germline BRCA1 and BRCA2 mutation carriers are described incidentally, while in patients with a BOT a germline BRCA1 or BRCA2 mutation is rarely found. Therefore, we conclude that borderline ovarian tumors are neither part of the BRCA1- nor the BRCA2- related tumor spectrum.