Recomendaciones sobre el tratamiento farmacológico del cáncer de ovario epitelial en México / Recommendations on the pharmacological treatment of epithelial ovarian cancer in Mexico

Resumen El cáncer de ovario es la tercera neoplasia maligna ginecológica más frecuente globalmente y también en México, con una elevada tasa de mortalidad debido a que en muchos casos su diagnóstico se realiza en etapas avanzadas. Para establecer su pronóstico es importante la determinación del subtipo y del grado de evolución. En los últimos años, el manejo del cáncer de ovario ha sufrido una importante evolución con la incorporación de nuevas opciones terapéuticas, que a su vez representan un incremento en la supervivencia de estas pacientes. Se presentan las recomendaciones para el manejo del cáncer de ovario elaboradas por un panel de expertos mexicanos basadas en la evidencia disponible hasta el momento y en las características de la atención sanitaria del país.

Abstract Ovarian cancer is the third most frequent gynaecological malignancy worldwide and in Mexico, with a high mortality rate, due to that in many cases its diagnosis is made in advanced stages. Prognosis is important for determining the subtype and the degree of evolution. During lasts years, the management of ovarian cancer has undergone an important evolution with the incorporation of new therapeutic options, which in turn represent an increase in the survival of these patients. We present recommendations for the management of ovarian cancer developed by an expert panel Mexican based on available evidence so far and the characteristics of health care in the country.

The power of the Risk of Ovarian Malignancy Algorithm considering menopausal status: a comparison with CA 125 and HE4 / 부인종양

OBJECTIVE: To identify the power of tumor markers for predicting ovarian cancer according to menopausal status. METHODS: The medical records of 876 women with ovarian cysts were retrospectively reviewed. Cancer antigen 125 (CA 125), human epididymis protein 4 (HE4), and Risk of Ovarian Malignancy Algorithm (ROMA) were analyzed. Sensitivity, specificity, and the receiver operating characteristic (ROC) curve analyses of these tumor markers were evaluated. RESULTS: The sensitivity of ROMA was 66.7% and the specificity was 86.8% to detect ovarian malignancy. The patients were divided into 2 groups according to menopausal status: premenopause (n=532, 60.7%) and postmenopause (n=344, 39.3%). For diagnostic accuracy, ROMA was lower than HE4 in premenopausal women (82.7% vs. 91.4%) and lower than CA 125 in postmenopausal women (86.9% vs. 88.7%). The ROC curve analysis revealed that the power of ROMA was not significantly better than that of HE4 in premenopausal women (area under the curve [AUC], 0.731 vs. 0.732, p=0.832), and it was also not significantly better than that of CA 125 in postmenopausal women (AUC, 0.871 vs. 0.888, p=0.440). CONCLUSION: The discrimination power of tumor markers for ovarian cancer was different according to menopausal status. In predicting ovarian malignancy, ROMA was neither superior to HE4 in premenopausal women nor superior to CA 125 in postmenopausal women.

Development of Web-Based Nomograms to Predict Treatment Response and Prognosis of Epithelial Ovarian Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Discovery of models predicting the exact prognosis of epithelial ovarian cancer (EOC) is necessary as the first step of implementation of individualized treatment. This study aimed to develop nomograms predicting treatment response and prognosis in EOC. MATERIALS AND METHODS: We comprehensively reviewed medical records of 866 patients diagnosed with and treated for EOC at two tertiary institutional hospitals between 2007 and 2016. Patients’ clinico-pathologic characteristics, details of primary treatment, intra-operative surgical findings, and survival outcomes were collected. To construct predictive nomograms for platinum sensitivity, 3-year progression-free survival (PFS), and 5-year overall survival (OS), we performed stepwise variable selection by measuring the area under the receiver operating characteristic curve (AUC) with leave-one-out cross-validation. For model validation, 10-fold cross-validation was applied. RESULTS: The median length of observation was 42.4 months (interquartile range, 25.7 to 69.9 months), during which 441 patients (50.9%) experienced disease recurrence. The median value of PFS was 32.6 months and 3-year PFS rate was 47.8% while 5-year OS rate was 68.4%. The AUCs of the newly developed nomograms predicting platinum sensitivity, 3-year PFS, and 5-year OS were 0.758, 0.841, and 0.805, respectively. We also developed predictive nomograms confined to the patients who underwent primary debulking surgery. The AUCs for platinum sensitivity, 3-year PFS, and 5-year OS were 0.713, 0.839, and 0.803, respectively. CONCLUSION: We successfully developed nomograms predicting treatment response and prognosis of patients with EOC. These nomograms are expected to be useful in clinical practice and designing clinical trials.

Detection of Germline Mutations in Patients with Epithelial Ovarian Cancer Using Multi-gene Panels: Beyond BRCA1/2 / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Next-generation sequencing (NGS) allows simultaneous sequencing of multiple cancer susceptibility genes and may represent a more efficient and less expensive approach than sequential testing. We assessed the frequency of germline mutations in individuals with epithelial ovarian cancer (EOC), using multi-gene panels and NGS. MATERIALS AND METHODS: Patients with EOC (n=117) with/without a family history of breast or ovarian cancer were recruited consecutively, from March 2016 toDecember 2016.GermlineDNAwas sequenced using 35-gene NGS panel, in order to identify mutations. Upon the detection of a genetic alteration using the panel, results were cross-validated using direct sequencing. RESULTS: Thirty-eight patients (32.5%) had 39 pathogenic or likely pathogenic mutations in eight genes, including BRCA1 (n=21), BRCA2 (n=10), BRIP1 (n=1), CHEK2 (n=2), MSH2 (n=1), POLE (n=1), RAD51C (n=2), and RAD51D (n=2). Among 64 patients with a family history of cancer, 27 (42.2%) had 27 pathogenic or likely pathogenic mutations, and six (9.3%) had mutations in genes other than BRCA1/2, such as CHECK2, MSH2, POLE, and RAD51C. Fifty-five patients (47.0%) were identified to carry only variants of uncertain significance. CONCLUSION: Using the multi-gene panel test, we found that, of all patients included in our study, 32.5% had germline cancer-predisposing mutations. NGS was confirmed to substantially improve the detection rates of a wide spectrum of mutations in EOC patients compared with those obtained with the BRCA1/2 testing alone.

Analysis of LncRNAs and mRNAs expression profiles in ovarian epithelial cancer cell lines by gene microarray / 临床检验杂志

Objective To Analyze the expression profiles of LncRNAs and mRNAs in ovarian epithelial cancer cell lines by gene mi-croarray, and then provide experimental evidences for investigating the function of LncRNAs associated with ovarian cancer. Methods The differentially expressed LncRNAs and mRNAs in ovarian epithelial cancer cell lines, such as A2780, HO8910 and SKOV3, and ovarian epithelial cell line HOSEpiC were analyzed by gene microarray. The differentially expressed mRNAs were further performed the KEGG pathway enrichment analysis. The expression levels of six candidate LncRNAs, which had significant difference between the o-varian epithelial cancer cell line and the ovarian epithelial cell line, were further verified by qRT-PCR. Results There were 227 up-regulated LncRNAs and 483 down-regulated LncRNAs in A2780, HO8910 and SKOV3 cell lines. The differentially expressed mRNAs in A2780, HO8910 and SKOV3 cell lines were mainly enriched in the tumor-related pathways such as PI3K-AKT, mTOR and TNF-α( P<0.05) . The expression levels of PTPRG-AS1, CCNT2-AS1, XLOC 009869 and LINC01138 in ovarian epithelial cancer A2780, SKOV3 and OVCR3 cell lines were up-regulated (P<0.05), while those of RP11-252P19.2 and RP11-744I24.2 in ovarian epithelial cancer A2780, SKOV3, OVCR3 and 3AO cell lines were down-regulated ( P<0.05) . Conclusion The differentially expressed LncR-NAs and mRNAs in ovarian epithelial cancer cell lines may be obtained by gene microarray, and the differentially expressed mRNAs are associated with the tumor-related pathways such as PI3K-AKT, mTOR and TNF-α, which may provide new targets for the diagnosis and treatment of ovarian cancer.

Predictive value of Annexin A3 protein expression in peripheral blood and tumor tissue for platinum resistance in ovarian epithelial cancer / 重庆医学

Objective To compare the values of peripheral blood and tumor tissue Annexin A3 protein expressions for predictinge platinum resistance in ovarian epithelial cancer. Methods A total of 72 cases of newly treated ovarian epithelial cancer and undergoing platinum based chemotherapy after surgery,and completely followed up in this hospital from February 2010 to February 2012 were selected and divided into the platinum-sensitive group(54 cases) and platinum-resistant group(18 cases) according to the platinum resistance evaluation criteria. Peripheral blood Annexin A3 level was detected by chemiluminescence immunoassay. Tumor tissue Annexin A3 level was detected by adopting the immunohistochemical staining. The predictive value of peripheral blood and tumor tissue Annexin A3 for predicting platinum resistance was analyzed by drawing the ROC curve. Results The peripheral blood Annexin A3 level in the platinum-sensitive group was significantly lower than that in the platinum-resistant group,the difference was statistically significant(P<0.05), the positive rate of tumor tissue Annexin A3 expression in the platinum sensitivity group was significantly lower than that of platinum-resistant group(P<0.05). The median survival time in peripheral blood Annexin A3 low concentration group was significantly higher than that of high concentration group(31.2 months vs. 20.4 months, P<0.05). The median survival time in tissue Annexin A3 low expression group was significantly higher than that in the high expression group (35.2 months vs. 23.1 months P<0.05). The multivariate analysis showed that the level of Annexin A3 expression in serum and tumor tissue were the independent risk factor for affecting platinum resistance (all P<0.05). The area of curve (AUC) of peripheral blood Annexin A3 in predicting platinum resistance was 0. 821, which of tissue Annexin A3 in predicting platinum was 0. 763, peripheral blood Annexin A3 for predicting platinum resistance was significantly higher than tissue Annexin A3 (P< 0.05). Conclusion The expression levels of Annexin A3 protein in peripheral blood and tumor tissue are significantly increased in the patients with platinum resistant ovarian cancer,the predictive value of Annexin A3 protein in peripheral blood for platinum resistance is better than that of tissue Annexin A3 protein.

Establishment and Application of Immunomagnetic Bead Negative Enrichment and Immunofluorescence Antibody Technique for Detection of CTCs in Peripheral Blood of Patients with Ovarian Cancer / 现代检验医学杂志

Objective To establish a cell level-based negative enrichmen technique to detect circulating tumor cells (CTCs) in the peripheral blood of patients with epithelial ovarian cancer.Methods The colon cancer SKOV-3 cells were mixed with 2 ml whole blood from healthy donors at different ratio.Quantification of CTCs was performed using immunomagnetic bead based negative enrichment combined with immunofluorescence antibody method.The method was evaluated the recovery rate of target cells,Samples of 32 patients with ovarian cancer and 10 controls were assayed for CTCs detection by above method.Results ①The recovery rate was ranging from 64％ ～80％ by spiking varying numbers of SKOV-3 into 2 ml blood samples of healthy volunteers.Regression analysis of number of recovered SKOV-3 cells yielded a regression equation of Y=0.782X-1.408 and a coefficient of determination of R2 =0.998.②Did not detect CK8/18-+ circulating tumor cells in 10 controls,and CK8/18+ circulating tumor cells in 18 cases of 32 Patients with ovarian cancer.The positive rate of CK 8/18 + circulating tumor cells was significantly differences between the two groups (x2 =7.681,P＜0.01).③The presence ofCTCs was significantly correlated with distant metastasis (x2 =5.776,P＜0.05).Conclusion The method of immunomagnetic bead based negative enrichment combined with immunofluorescence antibody technique for CTCs detection in peripheral blood of patients with ovarian cancer has a clinical value of application and extension.

Patient-Derived Xenograft Models of Epithelial Ovarian Cancer for Preclinical Studies / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Patient-derived tumor xenografts (PDXs) can provide more reliable information about tumor biology than cell line models. We developed PDXs for epithelial ovarian cancer (EOC) that have histopathologic and genetic similarities to the primary patient tissues and evaluated their potential for use as a platform for translational EOC research. MATERIALS AND METHODS: We successfully established PDXs by subrenal capsule implantation of primary EOC tissues into female BALB/C-nude mice. The rate of successful PDX engraftment was 48.8% (22/45 cases). Hematoxylin and eosin staining and short tandem repeat analysis showed histopathological and genetic similarity between the PDX and primary patient tissues. RESULTS: Patients whose tumors were successfully engrafted in mice had significantly inferior overall survival when compared with those whose tumors failed to engraft (p=0.040). In preclinical tests of this model, we found that paclitaxel-carboplatin combination chemotherapy significantly deceased tumor weight in PDXs compared with the control treatment (p=0.013). Moreover, erlotinib treatment significantly decreased tumor weight in epidermal growth factor receptor–overexpressing PDX with clear cell histology (p=0.023). CONCLUSION: PDXs for EOC with histopathological and genetic stability can be efficiently developed by subrenal capsule implantation and have the potential to provide a promising platform for future translational research and precision medicine for EOC.

Prognostic value of preoperative lymphocyte-monocyte ratio in elderly patients with advanced epithelial ovarian cancer

OBJECTIVE: To investigate the prognostic significance of preoperative lymphocyte-monocyte ratio (LMR) in elderly patients with advanced epithelial ovarian cancer (EOC) receiving primary cytoreductive surgery and adjuvant platinum-based chemotherapy. METHODS: A total of 42 elderly patients (≥65 years) diagnosed with EOC who are receiving primary cytoreductive surgery and adjuvant platinum-based chemotherapy from 2009 to 2012 was included. LMR was calculated from complete blood cell count sampled before operation. Receiver operating characteristic (ROC) curves were used to calculate optimal cut-off values for LMR. Prognostic significance with respect to overall survival (OS) and progression-free survival (PFS) were determined using log-rank test and Cox regression analysis. RESULTS: The optimized LMR cut-off value determined by ROC curve analysis was 3.63 for PFS and OS. The high LMR group (LMR ≥3.63) was found to be significantly more associated with optimal debulking (P=0.045) and platinum response (P=0.018) than the low LMR group. In addition, Kaplan-Meier analysis revealed the LMR-high group was significantly more associated with high PFS and OS rates (P=0.023 and P=0.033, respectively), and univariate analysis revealed that a high LMR, histology type, and optimal debulking and platinum responses were significantly associated with prolonged PFS and OS. However, subsequent Cox multivariate analysis showed only optimal debulking and platinum response were independent prognostic factors of PFS or OS. CONCLUSION: This study suggests that LMR might be associated with treatment and survival outcomes in elderly patients with EOC receiving standard oncology treatment.

Comparison of Clinical Outcomes of BRCA1/2 Pathologic Mutation, Variants of Unknown Significance, or Wild Type Epithelial Ovarian Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to investigate the clinical features of epithelial ovarian cancer (EOC) patients according to BRCA1/2 mutation status (mutation, variant of uncertain significance [VUS], or wild type). MATERIALS AND METHODS: We analyzed 116 patients whose BRCA1/2 genetic test results were available for mutation type and clinical features, including progression-free survival (PFS), overall survival (OS), and response rate. These characteristics were compared according to BRCA1/2 mutation status. RESULTS: Thirty-seven (37/116, 31.9%) BRCA1/2mutations were identified (BRCA1, 30; BRCA2, 7). Mutation of c.3627_3628insA (p.Leu1209_Glu1210?fs) in BRCA1 was observed in five patients (5/37, 13.5%). Twenty-five patients had BRCA1/2 VUSs (25/116, 21.6%). Personal histories of breast cancer were observed in 48.6% of patients with BRCA1/2 mutation (18/37), 16.0% of patients with BRCA1/2 VUS (4/25), and 7.4% of patients with BRCA wild type (4/54) (p < 0.001). Patients with BRCA1/2 mutation showed longer OS than those with BRCA1/2 wild type (p=0.005). No significant differences were detected in PFS, OS, or response rates between patients with BRCA1/2 VUS and BRCA1/2 mutation (p=0.772, p=0.459, and p=0.898, respectively). CONCLUSION: Patientswith BRCA1/2 mutation had longer OS than thosewith BRCA1/2wild type. Patients with BRCA1/2 mutation and BRCA1/2 VUS displayed similar prognoses.

The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients / 부인종양

OBJECTIVE: We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients. METHODS: In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and < or = median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients' survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. RESULTS: Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells. CONCLUSION: Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.

Distal pancreatectomy with splenectomy for the management of splenic hilum metastasis in cytoreductive surgery of epithelial ovarian cancer / 부인종양

OBJECTIVE: Distal pancreatectomy with splenectomy may be required for optimal cytoreductive surgery in patients with epithelial ovarian cancer (EOC) metastasized to splenic hilum. This study evaluates the morbidity and treatment outcomes of the uncommon procedure in the management of advanced or recurrent EOC. METHODS: This study recruited 18 patients who underwent distal pancreatectomy with splenectomy during cytoreductive surgery of EOC. Their clinicopathological characteristics and follow-up data were retrospectively analyzed. RESULTS: All tumors were confirmed as high-grade serous carcinomas. The median diameter of metastatic tumors located in splenic hilum was 3.5 cm (range, 1 to 10 cm). Optimal cytoreduction was achieved in all patients. Eight patients (44.4%) suffered from postoperative complications. The morbidity associated with distal pancreatectomy and splenectomy included pancreatic leakage (22.2%), encapsulated effusion in the left upper quadrant (11.1%), intra-abdominal infection (11.1%), pleural effusion with or without pulmonary atelectasis (11.1%), intestinal obstruction (5.6%), pneumonia (5.6%), postoperative hemorrhage (5.6%), and pancreatic pseudocyst (5.6%). There was no perioperative mortality. The majority of complications were treated successfully with conservative management. During the median follow-up duration of 25 months, nine patients experienced recurrence, and three patients died of the disease. The 2-year progression-free survival and overall survival were 40.2% and 84.8%, respectively. CONCLUSION: The inclusion of distal pancreatectomy with splenectomy as part of cytoreduction for the management of ovarian cancer was associated with high morbidity; however, the majority of complications could be managed with conservative therapy.

Major clinical research advances in gynecologic cancer in 2015 / 부인종양

In 2015, fourteen topics were selected as major research advances in gynecologic oncology. For ovarian cancer, high-level evidence for annual screening with multimodal strategy which could reduce ovarian cancer deaths was reported. The best preventive strategies with current status of evidence level were also summarized. Final report of chemotherapy or upfront surgery (CHORUS) trial of neoadjuvant chemotherapy in advanced stage ovarian cancer and individualized therapy based on gene characteristics followed. There was no sign of abating in great interest in immunotherapy as well as targeted therapies in various gynecologic cancers. The fifth Ovarian Cancer Consensus Conference which was held in November 7–9 in Tokyo was briefly introduced. For cervical cancer, update of human papillomavirus vaccines regarding two-dose regimen, 9-valent vaccine, and therapeutic vaccine was reviewed. For corpus cancer, the safety concern of power morcellation in presumed fibroids was explored again with regard to age and prevalence of corpus malignancy. Hormone therapy and endometrial cancer risk, trabectedin as an option for leiomyosarcoma, endometrial cancer and Lynch syndrome, and the radiation therapy guidelines were also discussed. In addition, adjuvant therapy in vulvar cancer and the updated of targeted therapy in gynecologic cancer were addressed. For breast cancer, palbociclib in hormone-receptor-positive advanced disease, oncotype DX Recurrence Score in low-risk patients, regional nodal irradiation to internal mammary, supraclavicular, and axillary lymph nodes, and cavity shave margins were summarized as the last topics covered in this review.

Outcomes of laparoscopic fertility-sparing surgery in clinically early-stage epithelial ovarian cancer / 부인종양

OBJECTIVE: Fertility-sparing surgery (FSS) is becoming an important technique in the surgical management of young women with early-stage epithelial ovarian cancer (EOC). We retrospectively evaluated the outcome of laparoscopic FSS in presumed clinically early-stage EOC. METHODS: We retrospectively searched databases of patients who received laparoscopic FSS for EOC between January 1999 and December 2012 at Samsung Medical Center. Women aged < or =40 years were included. The perioperative, oncological, and obstetric outcomes of these patients were evaluated. RESULTS: A total of 18 patients was evaluated. The median age of the patients was 33.5 years (range, 14 to 40 years). The number of patients with clinically stage IA and IC was 6 (33.3%) and 12 (66.7%), respectively. There were 7 (38.9%), 5 (27.8%), 3 (16.7%), and 3 patients (16.7%) with mucinous, endometrioid, clear cell, and serous tumor types, respectively. Complete surgical staging to preserve the uterus and one ovary with adnexa was performed in 4 patients (22.2%). Two out of them were upstaged to The International Federation of Gynecology and Obstetrics stage IIIA1. During the median follow-up of 47.3 months (range, 11.5 to 195.3 months), there were no perioperative or long term surgical complications. Four women (22.2%) conceived after their respective ovarian cancer treatments. Three (16.7%) of them completed full-term delivery and one is expecting a baby. One patient had disease recurrence. No patient died of the disease. CONCLUSION: FSS in young patients with presumed clinically early-stage EOC is a challenging and cautious procedure. Further studies are urgent to determine the safety and feasibility of laparoscopic FSS in young patients with presumed clinically early-stage EOC.

Safety of Fertility-Sparing Surgery in Primary Mucinous Carcinoma of the Ovary / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The aim of this study is to evaluate the safety of fertility-sparing surgery as the treatment for patients with primary mucinous epithelial ovarian cancer. MATERIALS AND METHODS: A retrospective study of patients with mucinous ovarian cancer between 1991 and 2010 was performed. The demographics and survival outcomes were compared between patients who underwent fertility-sparing surgery and those who underwent radical surgery. RESULTS: A total of 110 patients underwent primary surgery. At the time of surgery, tumors appeared to be grossly confined to the ovaries in 90 patients, and evidence of metastasis was definite in 20 patients. Of the 90 patients with tumors that appeared to be grossly confined to the ovaries at surgical exploration, 35 (38.9%) underwent fertility-sparing surgery. The Kaplan- Meier curve and the log rank test showed no difference in either recurrence-free survival (p=0.792) or disease-specific survival (p=0.706) between the two groups. Furthermore, there was no significant difference in recurrence-free survival (p=0.126) or disease-specific survival (p=0.377) between the two groups, even when the analysis was limited to women below the age of 40. In a multivariate Cox model, fertility-sparing surgery had no effect on either recurrence-free survival (recurrence hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.25 to 5.71) or disease-specific survival (death HR, 0.88; 95% CI, 0.17 to 4.60). CONCLUSION: Fertility-sparing surgery in primary mucinous cancer grossly confined to the ovaries may be a safe option and one not associated with an increase in recurrence or mortality.

The Role of TWIST in Ovarian Epithelial Cancers

BACKGROUND: Epithelial-mesenchymal transition (EMT) is associated with tumor hypoxia. EMT is regulated, in part, by the action of TWIST, which inhibits of E-cadherin expression and may interfere with the p53 tumor-suppressor pathway. METHODS: We examined the expression of TWIST, E-cadherin, hypoxia-inducible factor 1alpha (HIF1alpha), and p53 by immunohistochemistry in 123 cases of ovarian epithelial cancers (OEC) to evaluate the role of TWIST in OEC. We assessed the association between protein expression and clinicopathologic parameters. RESULTS: The expression of TWIST, E-cadherin, HIF1alpha, and p53 proteins was found in 28.5%, 51.2%, 35.0%, and 29.3% of cases, respectively. TWIST expression was associated with higher histologic grade and unfavorable survival. TWIST expression was correlated with HIF1alpha expression and reduced E-cadherin expression. The altered HIF1alpha/TWIST/E-cadherin pathway was associated with lower overall survival (OS), while the co-expression of TWIST and p53 was correlated with lower progression-free survival. In the multivariate analyses, TWIST expression was an independent prognostic factor for OS. CONCLUSIONS: Our data imply that TWIST expression could be a useful predictor of unfavorable prognosis for OEC. TWIST may affect the p53 tumor-suppressor pathway. Moreover, hypoxia-mediated EMT, which involves the HIF1alpha/TWIST/E-cadherin pathway may play an important role in the progression of OEC.

Expression and significance of phosphatase and tensin homolog deleted on chromosome 10 in ovarian epithelial cancers / 中国综合临床

Objective To analyse the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in ovarian epithelial cancer and to investigate the relationship between PTEN and clinical pathology and prognosis of ovarian epithelial cancer.Methods Expression of PTEN in 10 normal ovarian tissues,20 benign tumors and 60 cases of ovarian epithelial cancers were detected by immunohistochemical method.Results The positive expression of PTEN in normal ovarian and benign tumor tissues were significantly higher than that in ovarian epithelial cancers (100％ (10/10) vs 80.0％ (16/20) vs 53.3％ (32/60),x2 =7.778 and 4.444 respectively,P ＜ 0.05).The expression of PTEN was correlated to clinical stage,histilogical grade,presence and metastasis of lymph node (x2 =4.339;6.465 ;3.896;10.452;P ＜0.01),but there was no correlation to age,histological type and ascites (x2 =0.004 ;0.388 ; 1.057 ; P ＞ 0.05).Conclusion The expression of PTEN is related to ovarian carcinogenesis and development and may has great value in clinical diagnosis and prognosis of ovarian carcinogenesis.

Prognostic Relevance of the Expression of CA IX, GLUT-1, and VEGF in Ovarian Epithelial Cancers

BACKGROUND: Tumor hypoxia is associated with malignant progression and treatment resistance. Hypoxia-related factors, such as carbonic anhydrase IX (CA IX), glucose transporter-1 (GLUT-1), and vascular endothelial growth factor (VEGF) permit tumor cell adaptation to hypoxia. We attempted to elucidate the correlation of these markers with variable clinicopathological factors and overall prognosis. METHODS: Immunohistochemistry for CA IX, GLUT-1, and VEGF was performed on formalin-fixed, paraffin-embedded tissues from 125 cases of ovarian epithelial cancer (OEC). RESULTS: CA IX expression was significantly associated with an endometrioid and mucinous histology, nuclear grade, tumor necrosis, and mitosis. GLUT-1 expression was associated with tumor necrosis and mitosis. VEGF expression was correlated only with disease recurrence. Expression of each marker was not significant in terms of overall survival in OECs; however, there was a significant correlation between poor overall survival rate and high coexpression of these markers. CONCLUSIONS: The present study suggests that it is questionable whether CA IX, GLUT-1, or VEGF can be used alone as independent prognostic factors in OECs. Using at least two markers helps to predict patient outcomes in total OECs. Moreover, the inhibition of two target gene combinations might prove to be a novel anticancer therapy.

Fatal Ifosfamide-Induced Metabolic Encephalopathy in Patients with Recurrent Epithelial Ovarian Cancer: Report of Two Cases / Journal of the Korean Cancer Association, 대한암학회지

Central nervous system (CNS) toxicity has been reported in approximately 10-30% of patients receiving intravenous infusions of ifosfamide. Encephalopathy is a rare but serious CNS adverse reaction in these patients, and although usually transient and reversible, may cause persistent neurological dysfunction or death. Clinical features range from fatigue and confusion to coma and death. Although methylene blue can be used to treat ifosfamide-induced neurotoxicity, including encephalopathy, its mechanism of action remains poorly defined. We describe here two patients with recurrent epithelial ovarian cancer who experienced fatal encephalopathy following ifosfamide/mesna treatment.

Expressions of RhoC and MMP-2 proteins in epithelial ovarian cancer tissues and their clinical significances / 吉林大学学报(医学版)

Objective To study the expressions of RhoC and MMP-2 proteins in epithelial ovarian cancer and their clinical significances in order to provid the basis for assessing the biological behaviour of epithelial ovarian cancer.Methods Immunohistochemistry was used to detect the expressions of RhoC and MMP-2 proteins in 10 cases of normal ovarian tissues,12 cases of epithelial benign ovarian tumor and 91 cases of epithelial ovarian cancer,and the relationship with the clinical features was analyzed.Results The RhoC and MMP-2 proteins positive expression rates in ovarian benign tumor and ovarian normal tissues were 0 respectively; the positive expression rates of RhoC and MMP-2 proteins in epithelial ovarian cancer were 37.3% and 68.1%.The expressions of RhoC and MMP-2 proteins in ovarian cancer were significantly higher than those in ovarian benign tumor and ovarian normal tissues.The positive expression rates of RhoC and MMP-2 in moderately and poorly differentiated cancer were significantly higher than those in well differentiated cancer(P