Elevated serum CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic ADAM protease activity.

Background: In certain cancers, expression of CXCL16 and its receptor CXCR6 associate with lymphocyte infiltration, possibly aiding anti-tumour immune response. In other cancers, CXCL16 and CXCR6 associate with pro-metastatic activity. In the current study, we aimed to characterise the role of CXCL16, sCXCL16, and CXCR6 in ovarian cancer (OC).

Nutlin-3 preferentially sensitises wild-type p53-expressing cancer cells to DR5-selective TRAIL over rhTRAIL.

Background: Tumour cell-selective activation of apoptosis by recombinant human TNF-related apoptosis-inducing ligand (rhTRAIL) is enhanced through co-activation of p53 by chemotherapeutic drugs. The novel anticancer agent nutlin-3 provides a promising alternative for p53 activation by disrupting the interaction between p53 and its negative feedback regulator MDM2.

Methods: We examined whether nutlin-3 enhances apoptosis induction by rhTRAIL and the DR5-selective TRAIL variant D269H/E195R in wild-type p53-expressing ovarian, colon and lung cancer cell lines and in an ex vivo model of human ovarian cancer.

Multiple VEGF family members are simultaneously expressed in ovarian cancer: a proposed model for bevacizumab resistance.

Objective: Insight into the expression of multiple vascular endothelial growth factor (VEGF) family members can support the implementation of anti-angiogenic therapy. This study aimed to assess VEGF family member expression in ovarian cancers and related omental metastases.

Methods: Tissue microarrays encompassing 270 primary cancers and 112 paired metastases were immunostained for VEGF-A, VEGF-B, VEGF-C and VEGF-D.

The role of ATM and 53BP1 as predictive markers in cervical cancer.

Treatment of advanced-stage cervical cancers with (chemo)radiation causes cytotoxicity through induction of high levels of DNA damage. Tumour cells respond to DNA damage by activation of the 'DNA damage response' (DDR), which induces DNA repair and may counteract chemoradiation efficacy. Here, we investigated DDR components as potential therapeutic targets and verified the predictive and prognostic value of DDR activation in patients with cervical cancer treated with (chemo)radiation.

Clinicopathologic characteristics and survival in BRCA1- and BRCA2-related adnexal cancer: are they different?

Objective: Our aim was to examine the clinicopathologic characteristics and survival of ovarian, tubal, and peritoneal (further denoted "adnexal") cancer in BRCA1 compared with BRCA2 carriers.

Methods: A consecutive series of adnexal cancers in BRCA1/2 mutation carriers diagnosed in 1980 to 2010 at the University Medical Center Groningen was analyzed.

Results: We evaluated 55 BRCA1- and 16 BRCA2-related adnexal cancers, consisting of 51 ovarian, 13 tubal, and 7 peritoneal cancers.

Status of cellular immunity lacks prognostic significance in vulvar squamous carcinoma.

Objective: It is generally recognized that the immune system has an important role in regulating cancer development. Evidence indicating a prognostic role of the immune system in vulvar carcinoma is scarce. This study investigated the presence and prognostic significance of several aspects of the immune system in vulvar squamous carcinoma.

Serum tryptophan and kynurenine concentrations as parameters for indoleamine 2,3-dioxygenase activity in patients with endometrial, ovarian, and vulvar cancer.

Objective: Indoleamine 2,3-dioxygenase (IDO) suppresses the function of T-lymphocytes and is involved in immune escape of cancers. Indoleamine 2,3-dioxygenase catalyzes the initial rate-limiting step in the degradation of the essential amino acid tryptophan. In this study, we investigated cancer-induced IDO activity in sera of endometrial, ovarian, and vulvar cancer patients.

Tumor-infiltrating cytotoxic T lymphocytes as independent prognostic factor in epithelial ovarian cancer with wilms tumor protein 1 overexpression.

Immune response characterization at the primary tumor site enables the design of therapeutic vaccination strategies with higher efficacy in epithelial ovarian cancer (EOC). In this study, we related Wilms tumor protein 1 (WT1) overexpression, a well-established immunotherapeutic target, to clinicopathological characteristics, immunological parameters, and survival in primary EOC. WT1 overexpression was evaluated in primary EOC tissue of 270 patients by immunohistochemistry on tissue microarrays (TMAs).

Involvement of the TGF-beta and beta-catenin pathways in pelvic lymph node metastasis in early-stage cervical cancer.

Purpose: Presence of pelvic lymph node metastases is the main prognostic factor in early-stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early-stage cervical cancer.

Experimental Design: Gene expression profiles (Affymetrix U133 plus 2.

The epidermal growth factor receptor pathway in relation to pelvic lymph node metastasis and survival in early-stage cervical cancer.

The objective of this study is to correlate the expression of epidermal growth factor receptor (EGFR) components with clinical behavior of early-stage cervical cancer. Tissue samples of 336 consecutive Federation of International Gynecologists and Obstetricians stage IB-IIA cervical cancer patients all treated primarily by radical surgery were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up.

Potential target antigens for a universal vaccine in epithelial ovarian cancer.

The prognosis of epithelial ovarian cancer (EOC), the primary cause of death from gynaecological malignancies, has only modestly improved over the last decades. Immunotherapeutic treatment using a cocktail of antigens has been proposed as a "universal" vaccine strategy. We determined the expression of tumor antigens in the context of MHC class I expression in 270 primary tumor samples using tissue microarray.

Identification of genes and pathways associated with cytotoxic T lymphocyte infiltration of serous ovarian cancer.

Background: Tumour-infiltrating lymphocytes (TILs) are predictors of disease-specific survival (DSS) in ovarian cancer. It is largely unknown what factors contribute to lymphocyte recruitment. Our aim was to evaluate genes and pathways contributing to infiltration of cytotoxic T lymphocytes (CTLs) in advanced-stage serous ovarian cancer.

Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer.

Purpose: Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been reported to induce resistance to (chemo)radiation in cancers, such as head and neck cancer, whereas EGFR-targeted agents in combination with (chemo)radiation seem to improve treatment efficacy. The aim of this study was to determine the relation between proteins involved in the EGFR pathway and response to (chemo)radiation and survival in a large, well-documented series of cervical cancer patients.

Experimental Design: Pretreatment tissue samples of 375 consecutive International Federation of Gynecologists and Obstetricians stage Ib to IVa cervical cancer patients treated with (chemo)radiation between January 1980 and December 2006 were collected.

The prognostic value of TRAIL and its death receptors in cervical cancer.

Purpose: Preclinical data indicate a synergistic effect on apoptosis between irradiation and recombinant human (rh) tumor necrosis factor-related apoptosis inducing ligand (TRAIL), making the TRAIL death receptors (DR) interesting drug targets. The aim of our study was to analyze the expression of DR4, DR5, and TRAIL in cervical cancer and to determine their predictive and prognostic value.

Methods And Materials: Tissue microarrays were constructed from tumors of 645 cervical cancer patients treated with surgery and/or (chemo-)radiation between 1980 and 2004.

Aromatase, cyclooxygenase 2, HER-2/neu, and p53 as prognostic factors in endometrioid endometrial cancer.

The prognostic value of aromatase, cyclooxygenase 2 (COX-2), HER-2/neu, and p53 expression was determined in endometrioid endometrial cancer. Tissue microarrays were constructed comprising samples from 315 endometrioid endometrial cancer patients. Expression of aromatase, COX-2, HER-2/neu, and p53 was determined by immunostaining and related to classical clinicohistopathologic parameters, in addition to recurrence of disease and survival.

Effect of tamoxifen on the endometrium and the menstrual cycle of premenopausal breast cancer patients.

Objective: Tamoxifen, a nonsteroidal antiestrogen, is the agent of choice in the treatment of premenopausal receptor-positive breast cancer. This study aimed to investigate the influence of tamoxifen on the menstrual cycle and serum hormone levels and the subsequent endometrial response in premenopausal breast cancer patients.

Methods: In tamoxifen-using breast cancer patients aged 55 years or younger, the last menstrual period was registered, serum hormone levels measured, and the endometrial response visualized by transvaginal ultrasonography every 6 months.

Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer.

Objective: Presence of tumor-infiltrating lymphocytes (TIL) is of prognostic importance in a variety of malignancies. This study aims to determine the prognostic value of CD8(+) cytotoxic T-lymphocytes (CTL), FoxP3(+) regulatory T-lymphocytes (Treg) and CD45R0(+) memory T-lymphocytes in endometrial cancer.

Methods: The number of tumor-infiltrating CD8(+), FoxP3(+), and CD45R0(+) T-lymphocytes was determined by immunohistochemistry on tissue microarrays containing tumor material from 368 FIGO stage I-IV endometrial cancer patients.

Down-regulation of proteasomal subunit MB1 is an independent predictor of improved survival in ovarian cancer.

Objective: To investigate the expression and to determine the prognostic impact of components of the antigen processing and presentation pathway (APPP) in ovarian cancer.

Methods: Expression of MB1, LMP7, TAP1, TAP2, ERp57, ERAP1, beta(2)-microglobulin and the alpha-chains, HLA-B/C and HLA-A, of the MHC class I molecules was evaluated on tissue microarrays containing primary tumor samples from 232 FIGO stages I-IV ovarian cancer patients. Expression levels were correlated to clinicopathological data and disease specific (DSS) survival.

Role of endocervical curettage in the preoperative staging of endometrial carcinoma.

Objective: The presence of cervical involvement is important to establish a rational treatment for endometrial cancer patients. We investigated the value of preoperative endocervical curettage (ECC) in predicting cervical involvement.

Methods: Preoperative ECC of 290 patients with clinical stage I epithelial endometrial cancer was compared with histopathology of the uterus.

Expression of estrogen receptor-alpha and -beta and progesterone receptor-A and -B in a large cohort of patients with endometrioid endometrial cancer.

Objective: The estrogen receptor (ER)-alpha and -beta and progesterone receptor (PR)-A and -B were determined in endometrioid endometrial cancer, and their prognostic values were assessed.

Methods: Tissue microarrays were constructed from 315 endometrioid endometrial cancer patients. Receptor expression was assessed by immunostaining, and their semi-quantitatively determined expression levels were correlated to classical clinico-histopathological parameters in addition to disease free and disease specific survival.

Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer.

Purpose: Ovarian cancer patients with intra-tumoral CD3(+) T-lymphocytes in primary tumor tissue have a better prognosis. This study aims to analyze the presence and relative influence of three important T-lymphocyte subsets, tumor-infiltrating CD8(+) cytotoxic T-lymphocytes (CTL), CD45R0(+) memory T-lymphocytes, and FoxP3(+) regulatory T-lymphocytes (Treg), in primary tumor tissue and omental metastases of patients with ovarian cancer.

Experimental Design: The number of CD8(+), CD45R0(+), and FoxP3(+) T-lymphocytes was determined by immunohistochemistry on a tissue micro array containing ovarian tumor tissue and/or omental metastases obtained at primary debulking surgery from 306 FIGO stage I-IV ovarian cancer patients.

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer.

Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear.

A robust ex vivo model for evaluation of induction of apoptosis by rhTRAIL in combination with proteasome inhibitor MG132 in human premalignant cervical explants.

Development of medical therapies for high-grade cervical intraepithelial neoplasia (CIN II/III) is hampered by the lack of CIN II/III cell lines. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis upon binding to its receptors DR4 or DR5. Proteasome inhibition by MG132 sensitized cervical cancer cell lines to recombinant human (rh)TRAIL.

MEIS and PBX homeobox proteins in ovarian cancer.

Three amino-acid loop extension (TALE) homeobox proteins MEIS and PBX are cofactors for HOX-class homeobox proteins, which control growth and differentiation during embryogenesis and homeostasis. We showed that MEIS and PBX expression are related to cisplatin resistance in ovarian cancer cell lines. Therefore, MEIS1, MEIS2 and PBX expression were investigated immunohistochemically in a tissue microarray (N=232) of ovarian cancers and ovarian surface epithelium (N=15).