Factor In Ovarian Carcinoma Research Articles

Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications.

Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.

Surgical Morbidity and its Associated Factors in Ovarian Carcinoma

Aims: To estimate 30-day surgical morbidity in patients with ovarian carcinoma and identify its associated factors.
 Methods: This was an observational study conducted at two cancer hospitals, from October 2020 to March 2021. All women with ovarian carcinoma that underwent surgery were enrolled in the study. Incidence of surgical complications was recorded. Patients were followed up to the 30 th day post- operatively. Logistic regression analyses were used to evaluate the factors affecting surgical complications and their association was determined.
 Results: A total of 31 patients were analyzed in this study. The incidence rate of surgical complications was 29%. Total 11 complications occurred in nine patients (one intra-operatively and 10 post-operatively). Post-operative complications were wound infection (n=4; 12.9%), urinary tract infection (n=2; 6.4%); one each had post-op ileus, hemorrhage and deep vein thrombosis; and one mortality. Advancing age, increased Body Mass Index, primary surgery, higher surgical complexity score, increased operative time, increased blood loss, higher American Society of Anesthesiologists (ASA) score, presence of chronic disease were associated with surgical morbidity; and their hospital stay was longer (p=0.04).
 Conclusion: The common complications were wound infection and urinary tract infection.

Upregulation of fibronectin following loss of p53 function is a poor prognostic factor in ovarian carcinoma with a unique immunophenotype

BackgroundWe previously demonstrated that ovarian high grade serous carcinomas (OHGSeCa) and ovarian clear cell carcinomas (OCCCa) with an HNF-1β+/p53+/ARID1A+ immunophenotype were associated with the worst unfavorable prognosis. To clarify the molecular mechanisms underlying this finding, we focused on alterations in the p53 signaling pathway in these tumors.MethodsChanges in cell phenotype and function following knockdown of wild-type p53 (p53-KD) were assessed using OCCCa cells expressing endogenous HNF-1β and ARID1A. The prognostic significance of molecules that were deregulated following p53-KD was also examined using 129 OCCCa/OHGSeCa cases.Resultsp53-KD cells had increased expression of Snail, phospho-Akt (pAkt), and pGSK3β, and decreased E-cadherin expression, leading to epithelial-mesenchymal transition (EMT)/cancer stem cell (CSC) features. The cells also exhibited acceleration of cell motility and inhibition of cell proliferation and apoptosis. Next generation sequencing revealed that fibronectin (FN) expression was significantly increased in the p53 KD-cells, in line with our observation that wild-type p53 (but not mutant p53) repressed FN1 promoter activity. In addition, treatment of OCCCa cells with FN significantly increased cell migration capacity and decreased cell proliferation rate, independent of induction of EMT features. In clinical samples, FN/p53 scores were significantly higher in OCCCa/OHGSeCa with the HNF-1β+/p53+/ARID1A+ immunophenotype when compared to others. Moreover, high FN/high p53 expression was associated with the worst overall survival and progression-free survival in OCCCa/OHGSeCa patients.ConclusionThese findings suggest that upregulation of FN following loss of p53 function may impact the biological behavior of OCCCa/OHGSeCa, particularly in tumors with an HNF-1β+/p53+/ARID1A+ immunophenotype, through alterations in cell mobility and cell proliferation. The accompanying induction of EMT/CSC properties and inhibition of apoptosis due to p53 abnormalities also contribute to the establishment and maintenance of tumor phenotypic characteristics.4HYHfp8oPTLQGnKo7co1TGVideo

RING finger protein 187 as a novel potential biomarker for predicting the prognosis of ovarian carcinoma in 2 cancer centers

RING finger protein 187 (RNF187) has been used to predict prognosis of several human carcinomas. However, the clinicopathologic and prognostic implication of RNF187 expression in ovarian carcinomas remains not to be evaluated. The aim of this study was to explore the clinicopathologic and the prognostic significance of RNF187 in patients with ovarian carcinomas. Expression levels of RNF187 protein were investigated by immunohistochemical staining based on tissue-microarray composed of 147 patients with ovarian carcinomas. Receiver operating characteristic curve analysis was used to select the ideal cut-off value of RNF187 expression in ovarian carcinoma, and then analyze the correlation between the status of RNF187 expression and various clinicopathologic variables by chi-square test. Univariate analysis was employed to investigate the association between clinicopathologic variables and prognosis of patients by Kaplan-Meier method. Multivariate analysis was performed to identify the independent prognostic factors by the Cox regression model. Our results demonstrated that high expression of RNF187 was significantly associated with late FIGO stage, high histologic grade and pN1 stage in ovarian carcinoma (P < 0.05). Univariate analysis uncovered patients with the high expression of RNF187 have the worse overall survival and disease-free survival (P < 0.05). More surprisingly, multivariate analysis determined that the RNF187 expression was served as an independent prognostic factor in ovarian carcinoma. The high expression of RNF187 might influence a more aggressive biological behavior in ovarian carcinoma. Therefore, RNF187 expression could be useful to act as a new independent prognostic biomarker for patients with ovarian carcinoma.

Unusual Early Cerebral Metastasis of Ovarian Carcinoma as Initial Presentation

Background: Although systemic malignancies are frequently metastasizing to the central nervous system (CNS), ovarian carcinoma, which is a common malignancy in females, is rarely affecting brain. In general, the outcome for ovarian carcinoma with brain metastases is dismal as most of these patients usually present late with metastases elsewhere.Materials and methods: A retrospective review of four cases with cerebral metastases as the initial presentation of ovarian carcinoma in patients ages 25 to 45 years. Three patients received hormonal therapy for infertility. All cases presented initially with symptoms and signs suggestive of increased intracranial pressure with unknown primary pathology. CT and MRI scans showed intracranial enhancing lesions in different locations. Full malignancy work up showed a primary lesion arising from the pelvis with no other lesions detected.Results: Three patients underwent laparotomy for ovarian carcinoma resection once their neurological condition optimized, one case died early before she had laparotomy. All cases underwent Craniotomy for excision of the solitary metastatic lesion. In all cases, the histopathology demonstrated metastatic ovarian carcinoma. Subsequently, patients received chemo-radiotherpy. Although treatment all cases died within two years.Conclusion: It is unusual for ovarian carcinoma to present initially with CNS involvement. Unlike other primary tumours, ovarian carcinoma does not have a predilection for the central nervous system. However, CNS involvement occurs at late stage of the disease. Although multimodal treatment the outcome still poor. Hormonal therapy for infertility may be a risk factor for ovarian carcinoma and its aggressive behavior with cerebral metastasis.

Tumor infiltrating lymphocytes and homologous recombination deficiency are independently associated with improved survival in ovarian carcinoma

ObjectiveThe presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contribution to overall survival. MethodsPatients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HR-mediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C. ResultsNinety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (P = 0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (P = 0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25–0.59)). ConclusionsPatients that have both CD3+ TILs and HRD OC are afforded the greatest improvement in overall survival. This finding may have therapeutic implications for OC patients treated with emerging immunotherapies.

Comprehensive analysis of PD-L1 expression, HER2 amplification, ALK/EML4 fusion, and mismatch repair deficiency as putative predictive and prognostic factors in ovarian carcinoma.

Most ovarian carcinomas (OC) are characterized by poor prognosis, particularly the most frequent type high-grade serous carcinoma. Besides PARP inhibitors, target-based therapeutic strategies are not well established. We asked the question which other therapeutic targets could be of potential value and, therefore, analyzed a large cohort of OC for several predictive factors. Two hundred eighty-eight (288) cases of OC including the major histological types were analyzed by immunohistochemistry for PD-L1HER2, ALK, and the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. HER2 amplification and ALK/EML4 fusion were assessed by fluorescence in situ hybridization. The most frequent finding was PD-L1 expression ≥ 1% in 19.5% of the cases, which correlated with a significantly better overall survival in multivariate analysis (p < 0.001). HER2 amplification was detected in 11 cases (4%), all high-grade serous carcinomas. Amplification of HER2 did not correlate with patients' survival. ALK/EML4 fusion was found in two cases (0.74%): one high-grade serous and one endometrioid carcinoma. MMR deficiency was only present in one case of stage IV high-grade serous carcinoma. Subsets of high-grade serous carcinomas show PD-L1 expression and HER2 amplification, respectively, and, therefore, could qualify for immune checkpoint inhibitor therapy or anti HER2 therapy. PD-L1 is also of prognostic impact. ALK/EML4 fusion is very rare in OC and not a putative therapeutic target.

The ABO Blood Group is an Independent Prognostic Factor in Patients with Ovarian Cancer.

Previous studies have suggested a relationship between ABO blood group and clinical outcome of various cancers. Nevertheless, little is known about the association between ABO blood group and survival in patients with ovarian carcinoma. This study aimed to investigate the prognostic significance of ABO blood group in patients with ovarian carcinoma. 941 patients who were newly diagnosed with ovarian carcinoma between February 2007 and February 2016 were enrolled in the present study. The relationship between ABO blood type and clinical features in patients with ovarian cancer was analyzed using chi-square tests. Overall survival (OS) stratified by B antigen was evaluated using log-rank test and Kaplan-Meier method. Presence of the B antigen (B/AB) had a worse OS than those in the absence of the B antigen (A/O) in all patients with ovarian cancer, especially in patients with FIGO stage I, IV, and menopause. Presence of the B antigen (B/AB) was significantly correlated with OS than those with non-B antigen (A/O) (hazard ratios 1.342; 95% confidence interval 1.069-1.685; P=0.011). Multivariate analyses revealed that presence of the B antigen (B/AB) was independently associated with OS (hazard ratios 1.532; 95% confidence interval 1.111-2.112; P=0.009). This study indicated that presence of the B antigen (B/AB) was an unfavorable prognostic factor in ovarian carcinoma, especially in patients with FIGO stage I, IV, and menopause.

Overexpression of the recently identified oncogene REDD1 correlates with tumor progression and is an independent unfavorable prognostic factor for ovarian carcinoma

BackgroundRegulated in development and DNA damage response (REDD1), a gene responding to hypoxia or multiple DNA damage events, was recently implicated in cancer development and progression. Previously, in vivo and in vitro experiments indicated that REDD1 functions as an oncogene in ovarian cancer cells. However, the role of REDD1 in cancer cell migration and invasion and in clinical significance of prognostic values is not examined in detail.MethodsWe detected the REDD1 protein expression by immunohistochemistry in 18 normal ovarian surface epithelium or fallopian tube epithelium specimens, 24 ovarian borderline tumors, and 229 ovarian cancers. Fisher’s exact test, logistic regression analysis, the Kaplan–Meier method, and the log-rank test were used to evaluate the association of REDD1 with clinical factors, overall survival and disease-free survival. The prognostic predictive value of REDD1 for ovarian cancer patients was evaluated using multivariate Cox proportional hazard regression models. REDD1 expression in HEY, HEY A8, SKOV3, SKOV3 ip1, OVCA429, OVCA433 and A2780 human ovarian epithelial cancer cell lines was detected by western blotting. The role of REDD1 in cell invasion and migration was assessed by transwell migration and invasion assays using SKOV3, A2780, HEY, HEYA8, and SKOV3-REDD1 with parental A2780-REDD1 HEY-REDD1i and HEY A8-REDD1i.ResultsHigh expression of REDD1 was observed in 35.4% of primary ovarian carcinoma samples. Overexpression of cytoplasmic REDD1 in ovarian cancer was significantly associated with serous carcinoma (P < 0.001), late-stage disease (P < 0.001), ascites (P < 0.001), and partial or non-response to chemotherapy (P < 0.001). High cytoplasmic expression of REDD1 was correlated with poorer overall survival (P < 0.001) and disease-free survival (P < 0.001). The multivariate Cox proportional hazards regression analysis indicated that patients with high cytoplasmic REDD1 expression had a high risk of death (P < 0.001) and high risk of an event (i.e., recurrence, progression, or death) (P < 0.001). REDD1 was first reported as an independent prognostic factor in ovarian cancer patients. In addition, REDD1 overexpression enhanced ovarian cancer cell migration and invasion.ConclusionREDD1 is an independent unfavorable prognostic factor in ovarian carcinoma and may promote ovarian cancer metastasis.

The Role of Hereditary Factors in Ovarian Carcinoma.

Cancer is a disease of the genome, in which mutations in particular genes and pathways give rise to tissue-specific genotype-phenotype correlations. In tumors associated with hereditary cancer syndromes, a person is generally born with the first mutation relevant to the development of their cancer. In this chapter we will discuss the genes that have been associated with germline mutations that confer a moderate to high risk for ovarian carcinoma.

Predictive factors of ovarian carcinoma for women with ovarian endometrioma aged 45\xa0years and older in China

BackgroundTo explore the risk factors of endometriosis-associated ovarian cancer (EAOC) in women with ovarian endometriosis (OEM) aged 45 years and above in China.MethodsThis study reviewed the medical records of 1038 women in total who were aged 45 years and above, surgical-pathologically diagnosed with ovarian endometriosis, and were treated at Peking Union Medical College Hospital between December 1996 and December 2016. Histology evaluation was used to determine whether the ovarian endometriosis specimen was with (n = 30) or without (n = 1008) ovarian cancer.Results2.9% (30/1038) of women with the surgical-pathological diagnosis of ovarian endometriosis were found to have EAOC. Those patients with EAOC were prone to be in the postmenopausal status at the time of the diagnosis (OR 5.50, 95%CI 2.54–11.90, P < .001) and larger size of tumor (≥8 cm, OR 7.19, 95% CI 3.34–15.50, P < .001), and higher prevalence of coexisting with endometrial disorders (OR 4.11, 95%CI 1.73–9.73, P = .003). This study showed that patients of an older age when diagnosed with OEM, were at a higher risk of developing EAOC, respectively measuring of 1.7% (13/751) at 45–49 years, 5.6% (12/215) at 50–54 years, and 10.0%(5/50) at 55–59 years (P < 0.001).ConclusionsThis study showed that for women aged 45 years and above who were diagnosed with OEM, the independent risk factors of EAOC were menopausal status, tumor size of 8 cm or greater in diameter, and coexisting endometrial disorders. Therefore, intensive follow-ups or active interventions should be considered for them.

Diagnostic Utility of Thyroid Transcription Factor-1 in Ovarian Carcinoma and Its Relationship With Clinicopathologic Prognostic Parameters.

Although thyroid transcription factor-1 (TTF-1) is considered a relatively sensitive and specific marker for lung and thyroid neoplasms, it can occasionally be expressed in other tumors. Few immunohistochemical studies have been conducted on TTF-1 expression in ovarian carcinomas with discrepant results. To date, only 1 study compared different TTF-1 clones in ovarian carcinoma. This study is designed to evaluate the expression of TTF-1 clones in ovarian carcinomas and investigate TTF-1 association with clinicopathologic prognostic parameters. A retrospective immunohistochemical study was conducted on 62 primary ovarian carcinomas and 15 normal ovarian tissues using 2 clones of TTF-1 antibody (SPT24 and 8G7G3/1). Nuclear expression of SPT24 and 8G7G3/1 clones of TTF-1 was detected in 17.7% and 3.2% of ovarian carcinomas, respectively. Positive cytoplasmic immunostaining of clone SPT24 was detected in 1.6% of cases. In contrast, normal ovarian tissue showed negative expression of both clones. A highly significant difference was observed between both clones regarding their sensitivity in ovarian carcinomas (P=0.004). A significant inverse relationship was observed between TTF-1 (SPT24 clone) expression and tumor stage (P=0.022). TTF-1 expression is not exclusive to lung and thyroid tissue. It is expressed in ovarian carcinomas where clone SPT24 is more sensitive than clone 8G7G3/1. TTF-1 might be of diagnostic utility in evaluating neoplasms of unknown primary origin as well as adenocarcinomas involving the lung in patients with a history of a gynecologic malignancy. Moreover, TTF-1 expression might be a good prognostic factor in ovarian carcinoma.

Clinical Impact of microRNAs Associated With Cancer Stem Cells as a Prognostic Factor in Ovarian Carcinoma.

Background: Ovarian carcinoma is a highly lethal gynecological malignancy due to its frequent relapses and adoption of chemoresistance. To develop new biomarkers for disease progression in ovarian carcinoma, CSCs, which are considered to contribute to disease relapse and metastasis, were isolated from human ovarian carcinoma tissues, and differentially expressed microRNAs (miRNAs) in CSCs were identified and assessed the clinical implication of expression of these miRNAs.Methods: Primary cancer cells derived from human ovarian carcinomas were cultured and spheroid-forming cells (SFCs) were isolated. Profiles of miRNA expression in CSC-like SFCs were identified by miRNA microarray and the results were validated by quantitative real-time RT-PCR (qRT-PCR). We also assessed the correlations between miRNA expression levels and clinicopathological parameters in ovarian carcinomas.Results: Five miRNAs (miR-5703, miR-630, miR-1246, miR-424-5p, and miR-320b) were significantly dysregulated in CSC-like SFCs compared with primary cancer cells. The qRT-PCR showed that miR-5703 and miR-1246 expression was significantly higher in ovarian cancer cells than in normal control cells, whereas the miR-424-5p level was significantly lower. Decreased expression of miR-424-5p was significantly associated with distant metastasis in high stage (stage IIII & IV) carcinomas (35.5% vs. 72.2%, respectively, p=0.013)Conclusion: Taken together, miR-5703, miR-630, miR-1246, miR-424-5p, and miR-320b are useful markers for enriching ovarian CSCs. Decreased expression of miR-424-5p in ovarian carcinoma might be a putative biomarker for distant metastasis in ovarian carcinoma.

Correlation of survivin and mmp9 expressions with prognosis and clinicopathological parameters in surface epithelial ovarian carcinomas

Pathological stage is the most important prognostic factor in ovarian carcinomas, and many studies have been carried out to predict prognosis. In our study, we searched the expression of survivin, which prevents apoptosis and matrix metalloproteinase-9 (MMP-9), which promotes the metastasis of the tumour by splitting up the basal membrane in primary epithelial ovarian carcinomas. We aimed to observe their effects on prognosis by comparing clinicopathological parameters. 60 cases diagnosed with epithelial ovarian carcinoma between 2003 and 2008 and treated and followed up at the oncology clinic were included in the study. 42 patients were serous, 11 endometrioid, 5 mixed type, 1 was clear cell and 1 was undifferentiated adenocarcinoma. Survivin and MMP-9 expression was evaluated in each tumour and assosication with clinicopathological parameters (age, tumour diameter, localisation, histological type of tumour, grade, stage, recurrence and metastasis) were searched and also overall survival and disease free of survival were evaluated. Survivin was statistically insignificant within the clinicopathological parameters. The correlation between the tumour grade and the staining density of MMP-9 in epithelial cells (p=0.028) and the correlation between disease free of survival and MMP-9 expression in stromal cells (p=0.0326) was significant. When the stage was compered with clinocopathologic parameters; recurrence (p=0.005) and death rates (p < 0.001) were significantly increased but overall survival (p=0.0269) was significantly decreased in advanced-stage patients. In the present study, the stage was found to be an important prognostic parameter in surface epithelial ovarian carcinomas and an association was found between MMP-9 stromal staining and survival.

Twist2 promotes ovarian cancer cell survival through activation of Akt

Hypoxia-inducible factor-1 α (HIF-1α) is an important prognostic factor in ovarian carcinoma. Hypoxia contributes to tumor progression and is involved in the epithelial-mesenchymal transition (EMT). Twist2 is an EMT regulator, however, it remains poorly understood in ovarian carcinoma. The present study evaluated the expression of HIF-1α and Twist2 and further investigated whether Twist2 is involved in hypoxia-induced apoptosis in ovarian cancer. A series of matched paraffin-embedded tissue sections from human primary ovarian cancer and normal ovarian tissues were examined through immunohistochemical analysis, a Twist2-overexpressing stable ovarian cancer cell line was established and deferoxamine (DFO) was introduced to simulate hypoxic conditions. DFO-induced apoptosis was examined by fluorescence microscopy, MTT assays and flow cytometry. In addition, a western blot analysis was performed to examine the molecular mechanism(s) of action. Twist2 increased in epithelial ovarian cancers associated with HIF-1α expression. The acquired expression of Twist2 was able to promote the survival of ovarian cancer cells through Akt phosphorylation under DFO-induced hypoxic stress. The results suggest that Twist2 activates the PI-3K-Akt pathway to protect cells from apoptosis in a hypoxic environment. Moreover, Twist2 may be involved in the HIF-1α signaling pathway in ovarian cancer.

An intracellular targeted antibody detects EGFR as an independent prognostic factor in ovarian carcinomas

BackgroundIn ovarian cancer, the reported rate of EGFR expression varies between 4-70% depending on assessment method and data on patient outcome are conflicting. Methods: In this study we investigated EGFR expression and its prognostic value in a cohort of 121 invasive ovarian carcinomas, using a novel antibody against the intracellular domain of the receptor. We further evaluated an association between EGFR, the nuclear transporter CRM1 as well as COX-2. Furthermore, we evaluated EGFR expression in ten ovarian cancer cell lines and incubated cancer cells with Leptomycin B, a CRM1 specific inhibitor.ResultsWe observed a membranous and cytoplasmic EGFR expression in 36.4% and 64% of ovarian carcinomas, respectively. Membranous EGFR was an independent prognostic factor for poor overall survival in ovarian cancer patients (HR 2.7, CI 1.1-6.4, p = 0.02) which was also found in the serous subtype (HR 4.6, CI 1.6-13.4, p = 0.004). We further observed a significant association of EGFR with COX-2 and nuclear CRM1 expression (chi-square test for trends, p = 0.006 and p = 0.013, respectively). In addition, combined membranous EGFR/COX-2 expression was significantly related to unfavorable overall survival (HR 7.2, CI 2.3-22.1, p = 0.001).In cell culture, we observed a suppression of EGFR protein levels after exposure to Leptomycin B in OVCAR-3 and SKOV-3 cells.ConclusionsOur results suggest that the EGFR/COX-2/CRM1 interaction might be involved in progression of ovarian cancer and patient prognosis. Hence, it is an interesting anti-cancer target for a combination therapy. Further studies will also be needed to investigate whether EGFR is also predictive for benefit from EGFR targeted therapies.

BMP-4 expression has prognostic significance in advanced serous ovarian carcinoma and is affected by cisplatin in OVCAR-3 cells

Several angiogenesis-promoting factors have prognostic significance in ovarian cancer. The objective of this study was to evaluate whether traditional chemotherapy affects angiogenesis-related factors in ovarian carcinoma and to assess the clinical significance of these effects. To screen for angiogenesis-related factors of possible relevance, OVCAR-3 and A2780 ovarian cancer cells were treated with IC(50) doses of cisplatin (CDDP) or docetaxel, or with bevacizumab, and mRNA expression of several angiogenesis-related factors was analyzed. Thrombospondin-1 (TSP-1), bone morphogenetic protein-4 (BMP-4), endothelin-1, and placental growth factor-2 were statistically significantly induced by CDDP. At protein level, CDDP also induced hypoxia-inducible factor-1α but not vascular endothelial growth factor. In carcinoma samples taken before and after platinum-based neoadjuvant chemotherapy from 28 patients with advanced, high-grade serous ovarian carcinoma, CD105 and factors most induced by CDDP (TSP-1 and BMP-4) were analyzed by immunohistochemistry. Strong expression of BMP-4 before chemotherapy was an independent prognostic factor of longer progression-free time (p = 0.002) and overall survival (p = 0.02), but it was not associated with neovascularization (as evaluated by CD105). However, changes in BMP-4 expression in samples analyzed before and after chemotherapy (observed in 22/28 patients) were not associated with prognosis. TSP-1 expression was not associated with clinical parameters. Our results indicate that in serous ovarian carcinoma, BMP-4 has prognostic significance, which is not angiogenesis-related. We also show that CDDP induces several angiogenesis-related growth factors in vitro and future studies are warranted to clarify the clinical significance of this phenomenon.

Age as a prognostic factor in ovarian carcinoma. The Gynecologic Oncology Group experience.

The Gynecologic Oncology Group (GOG) has completed six major randomized trials in advanced ovarian carcinoma over the 15-year period between 1976 and 1990. This large database of 2123 patients provides a well-studied patient population with which to examine the importance of age as a prognostic factor. The 2123 patients studied in the six GOG trials were analyzed as a group to determine important prognostic factors. Further analyses were then conducted to examine outcome by decade of life from younger than 40 years old to 70 years old and older and to evaluate the interaction of age with other significant prognostic variables. Three major prognostic factors were identified as exerting an influence on patient outcome in the overall patient population: age, volume of residual disease, and performance status. With regard to the effect of age, patients older than 69 years of age exhibited significantly poorer survival than those younger, even after correction for stage, residual disease, and performance status. This was not altered by variations in drugs, doses, and schedules; but there was no evidence that older patients tolerated intensive schedules less well than younger patients. Two practical conclusions result from this analysis. First, there is no evidence that modification of the drugs and schedules that make up the regimens used can overcome the adverse effect of older age. Second, age does not adversely affect the dose intensity that can be achieved; hence, age in itself is not reason to withhold or attenuate intensive chemotherapy, particularly in light of the fact that older patients have a poorer prognosis.

Decreased expression of PinX1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma

Human interacting protein X1 (PinX1) has been identified as a critical telomerase inhibitor and proposed to be a putative tumor suppressor gene. Loss of PinX1 has been found in a large variety of malignancies, but the expression status in epithelial ovarian tumors has not been investigated. In this study, immunohistochemistry for PinX1 protein was performed on a tissue microarray (TMA) of epithelial ovarian tumors (informatively containing 25 cystadenomas, 29 borderline tumors, and 157 invasive carcinomas) and 12 normal ovaries. Receiver-operator curve (ROC) analysis was used to determine cut-off scores for tumor positivity and to evaluate patients' survival status. The threshold for PinX1 positivity was determined to be above 60% (area under the curve = 0.856, P < 0.001) based on the area under the ROC. Positive expression of PinX1 was observed in 100% of normal ovarian tissues, in 84% of cystadenomas, in 75.9% borderline tumors, and 66.2% of ovarian carcinomas. Decreased expression of PinX1 was strongly related to patients with poor prognostic factors regarding presence of lymph node metastasis (P = 0.024), distant metastasis (P < 0.001), and late International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.001). In univariate survival analysis, a highly significant correlation between loss of PinX1 and shortened patient survival (mean, 48.2 months vs 99.2 months, P < 0.001) was displayed. Multivariate analysis demonstrated PinX1 expression (P = 0.027) was evaluated as an independent parameter. Our findings suggest that loss of PinX1 is an adverse independent molecular marker for epithelial ovarian carcinoma patients. PinX1 may be a novel target for telomerase-based anticancer therapy due to inhibiting telomerase activity.

Prognostic relevance of granulocyte colony-stimulating factor in ovarian carcinomas

Granulocyte colony-stimulating factor (G-CSF) producing tumours were found associated with poor prognosis. Unfortunately, this finding is based on several case reports only. Thus, we investigated the expression of G-CSF in the tumour cells and the tumour stroma in a large collective of patients with ovarian cancer with long-term follow-up. Tissue and clinical records of 175 patients with histologically confirmed ovarian carcinoma were analysed for G-CSF expression in tumour cells and the surrounding stroma. The results were compared with peripheral blood counts and other prognostic factors in ovarian cancer. No correlations were found between both G-CSF expression in tumour cells and the surrounding stroma and prognosis as well as peripheral blood counts. We only found a positive influence of granulocytes in the tumour stroma on prognosis, which however, was not significant in multifactorial analyses. In contrast to the many case reports from other entities, G-CSF expression in tumour cells and the surrounding stroma is not an adverse prognostic factor. To find out the safety of G-CSF administration for the prevention or treatment of febrile neutropenia, it is suggested for clinical trials to include long-term follow-up and immunohistochemical characterisation of the tumour.