Patient-derived organoids and high grade serous ovarian cancer: from disease modeling to personalized medicine.

BACKGROUND: High grade serous ovarian cancer (HGSOC) is among the deadliest human cancers and its prognosis remains extremely poor. Tumor heterogeneity and rapid acquisition of resistance to conventional chemotherapeutic approaches strongly contribute to poor outcome of patients. The clinical landscape of HGSOC has been radically transformed since the advent of targeted therapies in the last decade. Nevertheless, the lack of predictive biomarkers informing on the differential clinical benefit in select subgroups, and allowing patient-centric approaches, currently limits the efficacy of these novel therapies. Thus, rational selection of the best possible treatment for each patient represents a clinical priority in order to improve outcome, while limiting undesirable effects. MAIN BODY: In this review, we describe the state of the art and the unmet needs in HGSOC management, illustrate the treatment options that are available and the biomarkers that are currently employed to orient clinical decisions. We also describe the ongoing clinical trials that are testing new therapeutic approaches for HGSOC. Next, we introduce the organoid technology as a promising, expanding strategy to study cancer and to develop personalized therapeutic approaches. In particular, we discuss recent studies that have characterized the translational potential of Patient's Derived Organoids (PDOs) to inform on drug sensitivity of HGSOC patients. CONCLUSIONS: PDOs can predict the response of patients to treatments and may therefore guide therapeutic decisions. Although preliminary results appear encouraging, organoids still need to be generated and expanded efficiently to enable drug screening in a clinically meaningful time window. A new generation of clinical trials based on the organoid technology should guarantee tailored approaches to ovarian cancer management, as it is now clear that the one-size-fits-all approach cannot lead to efficient and meaningful therapeutic advancements.

Exploring the clinical significance of serous tubal intraepithelial carcinoma associated with advanced high-grade serous ovarian cancer: A Memorial Sloan Kettering Team Ovary Study.

OBJECTIVE: To evaluate the clinical significance and genomic associations of concurrent serous tubal intraepithelial carcinoma (STIC) with high-grade serous carcinoma (HGSC) of the ovary in women undergoing primary debulking surgery (PDS). METHODS: All patients who underwent PDS for HGSC between 01/2015 and 12/2018 were captured in a prospectively maintained institutional database. Patients were categorized based on the presence or absence of concurrent STIC noted on final pathology. Demographic, perioperative, and outcomes data were collected, and groups were compared using standard statistical tests. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method. For comparison of differences in somatic alterations between the two cohorts, specimens were sequenced using MSK-IMPACT. RESULTS: Of 306 eligible patients, 87 (28%) had a concurrent STIC lesion (+STIC) and 219 (72%) did not (no-STIC). Demographics and clinicopathological factors were similar between the two cohorts, except for a significantly higher median preoperative CA-125 level in the no-STIC group (423 U/mL vs. 321 U/mL; p=0.029). There were no significant differences in median PFS (22.7 months [95%CI: 18.9-28.4] vs. 27.7 months [95%CI: 25.5-30.5]; p=0.126) and 3- year OS rate (81% [95%CI: 70-88%] vs. 85% [95%CI: 78-90%]; p=0.392) between +STIC and no-STIC patients, respectively. Targeted DNA-sequencing via MSK-IMPACT showed a similar distribution of driver mutations or structural genetic alterations, and affected genetic signaling pathways were similar between the cohorts. CONCLUSIONS: There were no identifiable clinical and genetic differences in patients with HGSC and concurrent STIC. These data suggest a comparable, if not identical, disease process.

Effect of shikonin on the proliferation and apoptosis of human ovarian cancer cell SKOV3: A protocol of systematic review and meta-analysis.

BACKGROUND: This study will investigate the effect of shikonin on the proliferation and apoptosis of human ovarian cancer cell SKOV3 (HOCC-SKOV3). METHODS: We will retrieve potential studies from inception to the March 1, 2020 in Cochrane Library, MEDLINE, EMBASE, Scopus, Cumulative Index to Nursing and Allied Health Literature, WANGFANG, and China National Knowledge In-frastructure. There are not restrictions related to the language and publication status. This study will include case-controlled studies (CCSs) or randomized controlled studies (RCSs) that examine the effect of shikonin on the proliferation and apoptosis of HOCC-SKOV3. Two researchers will independently identify literatures, extract data, and appraise study quality. Any disagreements will be resolved by discussion with another researcher. RevMan 5.3 software will be placed to perform statistical analysis. RESULTS: This study will summarize the present evidence to test the effect of shikonin on the proliferation and apoptosis of HOCC-SKOV3. CONCLUSION: It will provide evidence to investigate the effect of shikonin on the proliferation and apoptosis of HOCC-SKOV3, and will supply reference for further study.Systematic review registration: INPLASY202040146.

Mixed large and small cell neuroendocrine carcinoma of the endometrium with serous carcinoma: A case report and literature review.

RATIONALE: Endometrial neuroendocrine carcinoma is a rare histological subtype of endometrial cancer, divided into low-grade neuroendocrine carcinoma (carcinoid) and high-grade neuroendocrine carcinoma (small cell and large cell neuroendocrine carcinoma). It is characterized by high invasiveness and poor prognosis. L/SCNEC is an extremely rare pathological type of endometrial carcinoma, and the number of reports on this condition is few globally. PATIENT CONCERNS: A 54-year-old Chinese female presented with vaginal bleeding. DIAGNOSES: Outpatient hysteroscopy and endometrial biopsy were performed, and the pathological examination revealed that cervix was invaded by endometrial malignancy. The patient underwent a laparoscopic radical hysterectomy was diagnosed with the mixed large and small cell neuroendocrine carcinoma (L/SCNEC) of the endometrium combined with serous carcinoma III C2 (FIGO2009). INTERVENTIONS: Chemotherapy-radiotherapy-chemotherapy "sandwich" treatment was performed as postoperative therapy. OUTCOMES: After three chemotherapy circles, the patient showed no evidence of further disease progression. LESSONS: L/SCNEC is a rare and invasive disease. Once diagnosed, comprehensive treatments including surgery, radiotherapy, and chemotherapy can prolong the survival of patients and improve the prognosis.

Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines.

High grade serous ovarian cancer (HGSOC) is the most common and aggressive ovarian cancer subtype with the worst clinical outcome due to intrinsic or acquired drug resistance. Standard treatment involves platinum compounds. Cancer development and chemoresistance is often associated with an increase in histone deacetylase (HDAC) activity. The purpose of this study was to examine the potential of HDAC inhibitors (HDACi) to increase platinum potency in HGSOC. Four HGSOC cell lines with different cisplatin sensitivity were treated with combinations of cisplatin and entinostat (class I HDACi), panobinostat (pan-HDACi), or nexturastat A (class IIb HDACi), respectively. Inhibition of class I HDACs by entinostat turned out superior in increasing cisplatin potency than pan-HDAC inhibition in cell viability assays (MTT), apoptosis induction (subG1), and caspase 3/7 activation. Entinostat was synergistic with cisplatin in all cell lines in MTT and caspase activation assays. MTT assays gave combination indices (CI values) < 0.9 indicating synergism. The effect of HDAC inhibitors could be attributed to the upregulation of pro-apoptotic genes (CDNK1A, APAF1, PUMA, BAK1) and downregulation of survivin. In conclusion, the combination of entinostat and cisplatin is synergistic in HGSOC and could be an effective strategy for the treatment of aggressive ovarian cancer.

PD-L1 expression on stromal tumor-infiltrating lymphocytes is a favorable prognostic factor in ovarian serous carcinoma.

BACKGROUND: PD-L1 expression levels determined by immunostaining are known to be related to the survival rate and prognosis of patients with various types of cancers, as well as to the therapeutic response to immune checkpoint inhibitors. Recently, the U.S. Food and Drug Administration approved an immune checkpoint inhibitor for the treatment of non-small cell lung cancer along with the clones used for PD-L1 immunostaining to predict the resulting response. In this study, we performed PD-L1 immunostaining of tissue microarrays from ovarian epithelial cancer using SP263, an approved clone, and examined the effect of PD-L1 expression on survival rate and prognosis. METHODS: Tissue microarrays were constructed from ovarian epithelial cancer tissues of 248 patients and PD-L1 immunostaining was performed using the SP263 clone. PD-L1 expression levels in tumor cells, intraepithelial tumor-infiltrating lymphocytes, and stromal tumor-infiltrating lymphocytes were evaluated, and the effect of PD-L1 expression on survival and prognosis was analyzed. RESULTS: PD-L1 was detected in tumor cells as well as intraepithelial tumor-infiltrating lymphocytes and stromal tumor-infiltrating lymphocytes. It was most frequently expressed in stromal tumor-infiltrating lymphocytes. The Kaplan-Meier curve analysis and log rank test showed that only high stromal PD-L1 expression was associated with increased overall survival in ovarian serous carcinoma. Multivariate and univariate Cox regression analyses revealed that stromal PD-L1 expression was an independent prognostic factor, especially in ovarian serous carcinoma. CONCLUSIONS: PD-L1 immunostaining using SP263 was observed in tumor cells as well as intraepithelial and stromal tumor-infiltrating lymphocytes. PD-L1-expressing stromal tumor-infiltrating lymphocytes were associated with an increased overall survival rate and may serve as a favorable prognostic factor in ovarian cancer, particularly serous carcinoma.

miRNA-301b-3p accelerates migration and invasion of high-grade ovarian serous tumor via targeting CPEB3/EGFR axis.

High-grade ovarian serous carcinoma (HGS-OvCa), a type of ovarian cancer with poor prognosis due to distant metastasis, is urgently in need of new therapeutic targets. microRNAs (miRNAs), a class of small noncoding RNAs, perform significant roles in tumor progression. Mounting evidence has revealed the aberrant expression of miRNA in various cancers, one of which is HGS-OvCa. Present study planned to investigate that miRNA-301b-3p accelerates migration and invasion of high-grade ovarian serous tumor via targeting CPEB3/EGFR axis. Upregulation of miR-301b-3p was uncovered in HGS-OvCa tissues and cell lines, and was identified to be associated with metastasis. The Kaplan-Meier analysis confirmed the association of miR-301b-3p with poor prognosis of HGS-OvCa patients. Transwell assay validated the oncogenic effect of miR-301b-3p on migration and invasion of HGS-OvCa cells. Cytoplasmic polyadenylation element binding protein 3 (CPEB3) was then identified as a target of miR-301b-3p. It was also discovered that CPEB3 was downregulated in HGS-OvCa tissues and cell lines. The Spearman correlation curve presented the negative correlation of CPEB3 expression with miR-301b-3p. Furthermore, rescue assays proved that miRNA-301b-3p regulated the invasion and migration through CPEB3. Western blot and qRT-PCR analysis showed that miRNA-301b-3p induced epidermal growth factor receptor and downstream metastasis-related proteins, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2), through CPEB3. To be concluded, these results indicated that miRNA-301b-3p accelerated migration and invasion of high-grade ovarian serous tumor via targeting CPEB3/EGFR axis.

Ubiquitin-Proteasome Axis, Especially Ubiquitin-Specific Protease-17 (USP17) Gene Family, is a Potential Target for Epithelial-Mesenchymal Transition in High-Grade Serous Ovarian Cancer.

OBJECTIVES: To investigate gene expression differences and related functions between primary tumor, malignant cells in ascites, and metastatic peritoneal implant in high-grade serous ovarian cancer. METHODS: Biopsies from primary tumor, peritoneal implant, and ascites were collected from 10 patients operated primarily for high-grade, advanced-staged serous ovarian cancer. Total RNA isolation was performed from collected tissue biopsy and fluid samples, and RNA expression profile was measured. Messenger RNA expression profiles of 3 different groups were compared. Functional analyses of candidate genes were carried out by gene ontology and pathway analysis. RESULTS: There were significant differences in the expression of 5 genes between primary tumor and peritoneal implant, 979 genes between primary tumor and malignant cells in ascites, and 649 genes between peritoneal implant and malignant cells in ascites. Three commonly enriched gene ontology functions between "primary tumor and malignant cells in the ascites" and "peritoneal implant and malignant cells in the ascites" were protein deubiquitination, ubiquitin-dependent protein catabolism, and apoptotic processes. All genes related to these functions belonged to USP17 gene family. CONCLUSION: Gene expression difference between primary tumor and the peritoneal implant is not as much as the difference between primary tumor and free cells in the ascites. These results show that malignant cells in the ascites return into its genetic origin after they invade on the peritoneum. Significantly increased expression of DUB-enzyme genes, SNAR gene family, and ribosomal pathway genes in epithelial-mesenchymal transition suggests that this regulation is ubiquitin-proteasome dependent. Especially, this is the first study that offers USP17 as a potential target for epithelial-mesenchymal transition.

STICS, SCOUTs and p53 signatures; a new language for pelvic serous carcinogenesis.

The events leading to the most common and most lethal ovarian carcinoma - high grade serous carcinoma - have been poorly understood. However, the detailed pathologic study of asymptomatic women with germ-line BRCA 1 or BRCA2 (BCRA+) mutations has unearthed an early malignancy, serous tubal intraepithelial carcinomas (STIC), which has linked many peritoneal and ovarian serous carcinomas to the fimbria. The distinction between high-grade serous and endometrioid carcinomas continues to narrow, with shared alterations in expression of pTEN, PAX2 and p53. Moreover, the discovery of clonal alterations in p53 in benign tubal epithelium, - p53 signatures - has established a foundation for a serous cancer precursor in the fimbria. We have expanded this concept to include a generic secretory cell outgrowth (SCOUT) in the fallopian tube that is associated with altered PAX2 expression. As the repertoire of gene alterations is expanded and its link to serous carcinogenesis clarified, a cogent pathway to high-grade Mullerian carcinomas will emerge. This will challenge conventional thinking about ovarian carcinogenesis but will provide a new template for studies of ovarian cancer prevention.

Overexpression of tyrosine kinase receptor B promotes metastasis of ovarian serous adenocarcinoma by lymphangiogenesis.

AIMS AND BACKGROUND: The aim of this study was to detect the expression features of tyrosine kinase receptor B (TrkB) and analyze the possible correlation between TrkB expression and lymph vessel density (LVD) in metastasis of ovarian serous adenocarcinoma. METHODS: An immunohistochemical method was used to evaluate TrkB expression in 139 ovarian tumor sections (103 primary ovarian serous adenocarcinomas and 36 serous adenomas) and investigate the correlation between TrkB expression and LVD, which was estimated by means of VEGFR-3 assessment. RESULTS: TrkB was significantly upregulated in serous adenocarcinomas and absent in serous adenomas. There was no association between TrkB expression and the histological grade of cancer cells. The expression of TrkB was correlated with surgicopathological stage and metastasis in serous adenocarcinomas. The level of TrkB was higher in advanced-stage than in early-stage disease. TrkB was overexpressed in metastatic lesions compared with the corresponding primary lesions. Furthermore, a positive correlation between TrkB expression and LVD in serous adenocarcinomas was observed. CONCLUSIONS: TrkB was overexpressed in ovarian serous adenocarcinomas and might be involved in cancer metastasis by associated lymphangiogenesis.

Serous cystadenocarcinoma of the ovary in an 11-year-old girl with extensive dissemination and chylothorax: a case report and a brief review of literature.

Ovarian neoplasms account for only 1% of all tumors in girls below the age of 17 years, and among these, malignant epithelial ovarian tumors are even more uncommon. We would like to report a case of ovarian epithelial malignancy presenting at 11 years of age with extensive peritoneal dissemination. The child ultimately succumbed to the illness and an autopsy was performed.

[Effects of trichostatin A and paclitaxel on apoptosis and mitochondrial membrane potential of human endometrial carcinoma Ark2 cells].

BACKGROUND & OBJECTIVE: Patients suffered from advanced endometrial cancer have poor prognosis. The five-year survival is only 25%. Histone deacetylase inhibitors have shown promise in the treatment for a variety of malignancies. In combination with traditional cytotoxic chemotherapy, histone deacetylase inhibitors can enhance the survival rate of cancer patients. This study was to investigate the effect and mechanism of trichostatin A (TSA), a histone deacetylase inhibitor, combined with paclitaxel (PTX) on the apoptosis of human endometrial carcinoma cell line Ark2. METHODS: Ark2 cells were cultured in RPMI-1640 and treated with PTX alone, TSA alone or the two drugs in combination. Cell apoptosis was detected using Annexin V and Hoechst staining; perturbation of mitochondrial membrane potential was detected using MitoTracker red Poly (ADP-ribose) polymerase; caspase-9 degradation products and tubulin acetylation were detected by Western blot. RESULTS: Results of Annexin V showed that PTX (1.5 nmol/L) plus TSA (25 nmol/L) induced a significantly higher apoptotic rate (45.2%) than PTX alone (14.1%) or TSA alone (11.2%) did in Ark2 cells after drug treatment for three days. The results of Hoechst staining and Annexin V were consistent. A loss of mitochondrial membrane potential could activate the apoptotic cascade. Cleavages of PARP and caspase-9 were significantly apparent in PTX plus TSA group than in PTX group or TSA group (P<0.05). PTX and TSA could induce tubulin acetylation. PTX in combination with TSA increased acetylated tublins and microtubule stability compared with either drug alone. The loss of mitochondrial membrane potential was more dramatic in the drug combination group than the single drug group. The effects of TSA and PTX were synergistic (q=2.54). CONCLUSION: TSA and PTX could induce apoptosis of Ark2 cells, which may be through the loss of mitochondrial membrane potential and acetylation of non-histone proteins induced by histone deacetylase inhibitors.

Tight junction formation in epithelial ovarian adenocarcinoma.

BACKGROUND: Epithelial cells are characterised by their ability to form polarised cell sheets with barriers between two tissue compartments. Epithelial tightness and apical/basolateral orientation are maintained through adherens and tight junctions (TJs). Alterations in junction formation and function could promote tumorigenesis via increased access to growth factors and cytokines. The etiology and development of epithelial ovarian cancer (EOC) are far from understood. The ovarian surface epithelium (OSE), regarded as progenitor cells of EOC, form weak functional TJs in culture without expressing typical junction proteins. However, these integral membrane epithelial proteins, E-cadherin, claudin-3 and claudin-4, are often found in EOC. METHODS: To clarify whether EOC can form functional TJs, 4 different ovarian cancer cell lines of various histology were analysed for their expression of TJ (claudin-1, claudin-3, claudin-4 and zonola occludens-1 (ZO-1)) and adherens junction (AJ) (E-cadherin and N-cadherin) proteins, and the ability to build up trans-epithelial resistance (TER) in culture was measured. RESULTS: We found expression for all cell-junction proteins with a typical honeycomb-staining pattern in the serous adenocarcinomas indicating proper junction formation. Clear-cell and endometrioid adenocarcinomas showed a different expression pattern. By measuring TER, including Ca(2+) switch experiments, functional TJs were shown to build up only in serous adenocarcinomas. CONCLUSION: Serous adenocarcinomas formed functional TJs in vitro. The presence of claudin-4 might be essential for the function of TJs in ovarian cancer.

The power Doppler velocity index, pulsatility index, and resistive index can assist in making a differential diagnosis of primary ovarian carcinoma and Krukenberg tumors: a preliminary study.

OBJECTIVE: The aim of this study was to compare the effectiveness of transvaginal power Doppler sonography with spectral Doppler analysis as an aid in preoperatively distinguishing primary ovarian carcinoma and metastatic carcinoma to the ovary (Krukenberg tumors). METHODS: Fifty women with ovarian disease were preoperatively examined with transvaginal power Doppler sonography. Six basic parameters were measured, including intratumoral peak systolic velocity, end-diastolic velocity, time-averaged maximum velocity, pulsatility index (PI), resistive index (RI), and velocity index (VeI). Blood flow analyses were detectable in all patients. Twelve patients with metastatic carcinoma to the ovary were classified as group 1; 38 patients with primary ovarian carcinoma were classified as group 2. Comparison of intratumoral blood flow analyses between the two groups was performed. RESULTS: The PI, RI, and VeI were significantly lower in patients with metastatic carcinoma to the ovary than those with primary ovarian carcinoma (P < .05). There were no significant differences in the peak systolic velocity (P = .871), end-diastolic velocity (P = .508), and time-averaged maximum velocity (P = .850) between the two groups. CONCLUSIONS: Transvaginal power Doppler sonography with spectral Doppler analysis is an effective method in evaluating intratumoral blood flow of Krukenberg tumors. Low impedance (PI, RI, and VeI) might assist us in making differential diagnoses between primary ovarian carcinoma and Krukenberg tumors according to our preliminary results.

Primary papillary serous carcinoma of the peritoneum: report of a case with diagnosis by fine needle aspiration and immunocytochemistry.

BACKGROUND: Primary papillary serous carcinoma (PPSC) of the peritoneum is a rare neoplasm, histologically indistinguishable from papillary serous carcinoma of the ovary, which diffusely involves the peritoneum but spares or minimally invades the ovaries. To the best of our knowledge, the preoperative and the fine needle aspiration diagnosis of this disorder have not been reported before. CASE: A woman developed an extensive peritoneal neoplasm 4 years after hysterectomy and bilateral salpingo-oophorectomy for benign disease. Fine needle aspiration of the tumor was performed, and the cytologic and immunocytochemical findings were consistent with papillary serous carcinoma. A diagnosis of PPSC of the peritoneum was rendered because review of all slides from previous surgical specimens showed no evidence of carcinoma and no other primary tumors were found elsewhere. CONCLUSION: Fine needle aspiration cytology coupled with immunocytochemical and clinical data allows an unequivocal preoperative diagnosis of papillary serous carcinoma (primary peritoneal or with an ovarian origin). The sole limitation to establish a primary peritoneal origin before surgery is the requirement to histologically study the ovaries. Based on this fact, the preoperative fine needle aspiration cytology diagnosis of PSCP should be restricted to oophorectomized patients.

Impact of different pressures and exposure times of a simulated carbon dioxide pneumoperitoneum environment on proliferation and apoptosis of human ovarian cancer cell lines.

BACKGROUND: This study aimed too evaluate the proliferation and apoptosis of human ovarian cancer cell lines HO8910 and SKOV3 after exposure to a simulated laparoscopic carbon dioxide (CO2) pneumoperitoneum environment at different pressures and lengths of exposure time. METHODS: The effects of the simulated laparoscopic CO2 pneumoperitoneum environment at different CO2 pressures (0-16 mmHg) and exposure times (1-4 h) on tumor cell growth and apoptosis were assessed by 3-[4,5-Dimethylthiazol]-2; 5-diphenyltetrazolium bromide (MTT) chromometry and proliferative index (PI) staining or Annexin V and PI double-staining flow cytometry. Cells cultured in a standard environment were used as the control group. RESULTS: In this study, HO8910 cell growth tended to slow down with the increase in CO2 pressure and exposure time. A significantly lower PI was observed at 72 h of culture after exposure to both 8 and 16 mmHg of pressure, as compared with the control and 0 mmHg pressure group (p < 0.05). The PI of SKOV3 cells tended to decline after exposure. Significantly lower PI was observed in the group with exposure to 16 mmHg for 4 h over a 72-h period, as compared with the control groups exposed to 0 mmHg (p < 0.05). The inhibition of cell growth was associated with an increase in the proportion of cells at stage G1. The apoptotic index and the percentage of apoptotic cells tended to increase with an increase in pressure and a prolonged time of exposure. CONCLUSIONS: The results suggest inhibited cell proliferation and increased cell apoptosis of human ovarian cancer cells were positively related to CO2 pressure and exposure time.

Transvaginal gray scale and color Doppler sonography in primary ovarian cancer and metastatic tumors to the ovary.

OBJECTIVE: To compare gray scale and color Doppler features of primary and metastatic ovarian carcinomas. METHODS: Clinical, sonographic (gray scale and color Doppler), and histopathologic data of 143 patients with primary (n = 127 adnexal masses) and metastatic (n = 34 adnexal masses) ovarian cancer were reviewed. Morphologic gray scale parameters assessed were bilaterality, tumor volume, echogenicity, and presence of septa, papillary projections, or solid areas. Color Doppler parameters were presence of blood flow, tumor blood flow location (central versus peripheral), subjective impression of blood flow amount (scanty, moderate, or abundant), lowest resistive index, lowest pulsatility index, and maximal peak systolic velocity (centimeters per second). RESULTS: No statistical differences were found in bilaterality, tumor volume, presence of septa, papillary projections or solid areas, presence of blood flow, tumor blood flow location, subjective impression of blood flow amount, lowest resistive index, lowest pulsatility index, and maximal peak systolic velocity. Metastatic carcinomas were more frequently purely solid tumors (47% versus 26%; P = .001; likelihood ratio, 2.4; 95% confidence interval, 1.2-4.7). CONCLUSIONS: The presence of a purely solid tumor indicates a higher probability of metastatic carcinoma than primary ovarian cancer. However, with the use of gray scale and color Doppler sonography, it is difficult to differentiate primary ovarian carcinomas from metastatic tumors to the ovary.

LHRH might act as a negative autocrine regulator of proliferation of human ovarian cancer.

OBJECTIVE: More than 80% of human ovarian cancers express LHRH and its receptor. The proliferation of human ovarian cancer cell lines is reduced by both LHRH agonists and antagonists. This study was designed to further clarify the possible biological function of this LHRH system. DESIGN: As LHRH agonists and antagonists uniformly reduce proliferation of human ovarian cancer in a dose-dependent way, the effect of low concentrations of authentic LHRH was studied. In addition, longer periods of treatment (up to 9 days) were analyzed. To assess the physiological role of LHRH produced by ovarian cancer cells it was neutralized by adequate concentrations of a specific LHRH antiserum. METHODS: Human ovarian cancer cells EFO-21 and EFO-27, which express LHRH and its receptor, were incubated for 1-9 days with increasing concentrations (1pmol/l to 10 micromol/l) of authentic LHRH or with concentrations of LHRH antiserum capable of neutralizing at least 1nmol/l LHRH. Proliferation was assessed by counting cells. RESULTS AND CONCLUSIONS: Authentic LHRH reduced time- and dose-dependently proliferation (by maximally mean+/-s.e.m. 32.7 +/- 4.4%, Newman-Keuls, P < 0.001) of both ovarian cancer cell lines. At very low concentrations (1pmol/l) a marginal reduction of proliferation or no effect was observed. A mitogenic effect of authentic LHRH was never detected. Treatment of ovarian cancer cell cultures with antiserum to LHRH significantly increased (up to mean+/-s.e.m. 121.0 +/- 2.8% of controls, Newman-Keuls P <0.001) proliferation of EFO-21 and EFO-27 cells. These findings suggest that LHRH produced by human ovarian cancer cells might act as a negative autocrine regulator of proliferation.

Expression of vascular endothelial growth factor related to 72-kilodalton metalloproteinase immunostaining in patients with serous ovarian tumors.

BACKGROUND: The aim of the current study was to investigate the expression of vascular endothelial growth factor (VEGF) by neoplastic cells in patients with serous ovarian tumors. The correlation between neoangiogenesis and 72-kilodalton metalloproteinase (MMP2) immunostaining also was evaluated. METHODS: Fifty-eight patients with serous ovarian tumors who were treated at the Institute of Gynecology and Obstetrics of Ancona University (Ancona, Italy) were used as the study population; 10 women had serous cystoadenoma, 16 women had a serous borderline tumor, and 32 women had invasive cystoadenocarcinoma. Expression of VEGF and MMP2 was evaluated immunohistochemically by polyclonal antibody anti-VEGF (dilution, 1:100) and affinity purified, rabbit anti-MMP2, formalin fixed, paraffin embedded tissue. Positive staining was expressed as a percentage of positive cells per 10(3) counted neoplastic cells. RESULTS: Compared with cystoadenomas and borderline tumors, the tessutal VEGF immunostaining was significantly higher in cystoadenocarcinomas, with the highest values detected in architectural International Federation of Gynecology and Obstetrics Grade 3 neoplasms (P2 < 0.001). A direct relation was observed between VEGF and MMP2 immunostaining (correlation coefficient, 0.44; P2 = 0.013). A relation was found between VEGF expression and disease free survival as evaluated by Cox hazards analysis (P2 = 0.03). CONCLUSIONS: Neoangiogenesis detected by VEGF immunostaining appears to be a promising indicator of aggressiveness in serous ovarian tumors. In cystoadenocarcinomas, VEGF expression appears to be related to MMP2 index.