Including FIGO Stage Research Articles

Abstract 3864: Aneuploidy predicts aggressiveness and poor prognosis in endometrial cancer, and is reflected in a 9-gene signature

Abstract Introduction: Ploidy is among the most frequently studied biomarkers in endometrial cancer (EC), but lacks validation in larger studies. Mechanisms leading to tumor aneuploidy are only partly understood, and few studies have examined the molecular distinctions between diploid and aneuploid tumors in EC. Loss of the cohesin subunit STAG2 has been proposed as a driver of aneuploidy in several cancer types, but has not yet been explored for EC. Aims: In this study, we wanted to investigate ploidy status in primary EC in relation to standard clinicopathologic variables including FIGO stage, grade, histologic type and age, as well as outcome. Further, we wanted to evaluate genes differentially expressed between aneuploid and diploid primary tumor samples, and the proposed aneuploidy marker STAG2 in EC. Materials and methods: DNA ploidy was determined by flow cytometry in fresh tumor tissue for 794 patients, enrolled from 1980 - 2013. For expression analysis, RNA was extracted from fresh frozen primary tumor tissue from 144 samples, and measured with Agilent DNA microarrays (cat. no G4 112F). Significance Analysis of Microarrays (SAM) was run to identify differentially expressed genes between diploid and aneuploid cases. In order to identify the signature genes reflecting the differences between the two groups with highest accuracy, support vector machine (SVM) with 10-fold cross validation was applied. An aneuploidy score was calculated by subtracting the sum of expression of down-regulated genes from the sum of expression of up-regulated genes in the signature. Immunohistochemistry (IHC) was performed on tissue microarrays from 526 patients, with STAG2 antibody SA-2 (J12): sc-81852 (Santa Cruz Biotechnology). TCGA EC data were explored, and used for external validation. Results: Aneuploidy was significantly associated with predictors of poor outcome including FIGO stage, grade, histologic subtype and age (p<0.001), and worse 5-year disease specific survival (DSS, p<0.001). SVM identified 9 genes (3 up- and 6 down-regulated) yielding a good accuracy for identifying aneuploid tumor status. The aneuploidy score was significantly associated with all standardly applied clinicopathologic surrogate markers for outcome (p<0.01) and DSS (p = 0.001). No association was found between STAG2 expression by IHC and ploidy status, however loss of STAG2 was associated with better DSS than intact STAG2 (p = 0.05). In TCGA data, 8.1% of EC patients had STAG2 mutations, with slightly better DSS compared to patients without mutation (p = 0.05). Conclusions: DNA ploidy estimated by flow cytometry adds prognostic information in EC. Loss of STAG2 expression is not associated with aneuploidy. A 9-gene signature reflects ploidy status and predicts aggressive tumor behavior. The role of the 9 genes will be further explored to unveil potential involvement in aneuploidy development in EC. Citation Format: Karen K. Mauland, Kanthida Kusonmano, Elisabeth Wik, Mari K. Halle, Jone Trovik, Hans K. Haugland, Anne M. Oyan, Helga B. Salvesen. Aneuploidy predicts aggressiveness and poor prognosis in endometrial cancer, and is reflected in a 9-gene signature. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3864. doi:10.1158/1538-7445.AM2015-3864

Outcomes and prognostic factors of distant metastasis in patients with advanced cervical squamous cell carcinoma treated with concurrent chemoradiotherapy

To evaluate the outcomes and prognostic factors of distant metastasis in patients with advanced cervical squamous cell carcinoma treated with concurrent chemoradiotherapy (CCRT). A total of 118 patients with International Federation of Gynecology and Obstetrics (FIGO, 2009 version) stage II b-IVa cervical squamous cell carcinoma treated with CCRT between 2006 and 2010 in the Second Affiliated Hospital of Dalian Medical University were analyzed. Their median age was 48 years (range, 23-70 years). FIGO stages were as follows: IIb stage 56 cases, IIIa stage 6 cases, IIIb stage 52 cases, and IVa stage 4 cases. Of the all patients, 55 cases showed bulkly tumor (tumor size >4 cm) and 35 cases were pelvic lymph node positive. Forty patients had pretreatment hemoglobin (Hb) levels no greater than 110 g/L. Patients with elevated squamous cell carcinoma antigen (SCC- Ag) >1.5 µg/L before CCRT and at one month after CCRT were 91 cases and 34 cases, respectively. Kaplan-Meier method was used to estimate survival. For the analysis of prognostic factors affecting distant metastasis, log- rank test was used for univariate analysis, and Cox proportional hazard model was used for multivariate analysis. Thirty- seven patients were diagnosed with recurrence, 19 cases of whom developed distant metastasis, 13 cases developed loco-regional recurrence and 5 cases had both distant and loco-regional recurrence. The 5- year overall survival rates and distant disease- free survival of all patients were 64.0% and 78.8% , respectively. Two patients had grade 3 acute gastrointestinal toxicity (mainly diarrhea) and 20 cases had grade 3 to 4 hematologic toxicity. Seven patients experienced grade 3 to 4 late toxicity, 5 cases of them were gastrointestinal and 2 cases were genitourinary toxicity. Univariate analysis showed that FIGO stages, SCC-Ag level at one month after treatment, pretreatment hemoglobin level, and pelvic lymph node metastasis were significantly correlated with distant metastasis (all P < 0.05). Multivariate analysis showed that FIGO stage, SCC- Ag level at one month after treatment, and pelvic lymph node metastasis were independent prognostic factors for distant metastasis (all P < 0.05). For stage IIb-IVa cervical squamous cell carcinoma, the regimen of CCRT was efficacious and safe. The predictive factors for distant metastasis in patients with IIb-IVa stage squamous cell carcinoma of cervix treated with CCRT included FIGO stage, SCC- Ag level at one month after treatment, and pelvic lymph node metastasis. New treatment strategies should be considered to control distant metastasis for these patients.

Pharmacokinetic parameters derived from dynamic contrast enhanced MRI of cervical cancers predict chemoradiotherapy outcome

PurposeTo assess the prognostic value of pharmacokinetic parameters derived from pre-chemoradiotherapy dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of cervical cancer patients. Materials and methodsSeventy-eight patients with locally advanced cervical cancer underwent DCE-MRI with Gd-DTPA before chemoradiotherapy. The pharmacokinetic Brix and Tofts models were fitted to contrast enhancement curves in all tumor voxels, providing histograms of several pharmacokinetic parameters (Brix: ABrix, kep, kel, Tofts: Ktrans, νe). A percentile screening approach including log-rank survival tests was undertaken to identify the clinically most relevant part of the intratumoral parameter distribution. Clinical endpoints were progression-free survival (PFS) and locoregional control (LRC). Multivariate analysis including FIGO stage and tumor volume was used to assess the prognostic significance of the imaging parameters. ResultsABrix, kel, and Ktrans were significantly (P<0.05) positively associated with both clinical LRC and PFS, while νe was significantly positively correlated with PFS only. kep showed no association with any endpoint. ABrix was positively correlated with Ktrans and νe, and showed the strongest association with endpoint in the log-rank testing. kel and Ktrans were independent prognostic factors in multivariate analysis with LRC as endpoint. ConclusionsParameters estimated by pharmacokinetic analysis of DCE-MR images obtained prior to chemoradiotherapy may be used for identifying patients at risk of treatment failure.

GPR54 Is a Target for Suppression of Metastasis in Endometrial Cancer

Invasion into deep myometrium and/or lymphovascular space is a well-known risk factor for endometrial cancer metastasis, resulting in poor prognosis. It is therefore clinically important to identify novel molecules that suppress tumor invasion. Reduced expression of the metastasis suppressor, kisspeptin (KISS1), and its endogenous receptor, GPR54, has been reported in several cancers, but the significance of the KISS1/GPR54 axis in endometrial cancer metastasis has not been clarified. Metastin-10 is the minimal bioactive sequence of genetic products of KISS1. Clinicopathological analysis of 92 endometrial cancers revealed overall survival is improved in cancers with high expression of GPR54 (P < 0.05) and that GPR54 expression is associated with known prognostic factors including FIGO stage, grade, and deep myometrial invasion. Through RNAi and microarray analyses, metastin-10 was predicted to suppress metastasis of GPR54-expressing endometrial cancers in vivo. Methylation analysis revealed GPR54 is epigenetically regulated. Metastin-GPR54 axis function was restored following treatment with the DNA hypomethylating agent 5-aza-DC. These data suggest that metastin-10 may be effective at inhibiting the metastatic spread of endometrial cancers in combination with demethylating agents to induce GPR54 expression.

Gene Expression Profiles as Prognostic Markers in Women With Ovarian Cancer

The purpose was to find a gene expression profile that could distinguish short-term from long-term survivors in our collection of serous epithelial ovarian carcinomas. Furthermore, it should be able to stratify in an external validation set. Such a classifier profile will take us a step forward toward investigations for more individualized therapies and the use of gene expression profiles in the clinical practice. RNA from tumor tissue from 43 Danish patients with serous epithelial ovarian carcinoma (11 International Federation of Gynecology and Obstetrics [FIGO] stage I/II, 32 FIGO stage III/IV) was analyzed using Affymetrix U133 plus 2.0 microarrays. A multistep statistical procedure was applied to the data to find the gene set that optimally split the patients into short-term and long-term survivors in a Kaplan-Meier plot. A 14-gene prognostic profile with the ability to distinguish short-term survivors (median overall survival of 32 months) from long-term survivors (median overall survival not yet reached after a median follow-up of 76 months) with a P value of 3.4 x 10 was found. The prognostic gene set was also able to distinguish short-term from long-term survival in patients with advanced disease. Furthermore, its ability to classify in an external validation set was demonstrated. The identified 14-gene prognostic profile was able to predict survival (short- vs long-term survival) with a strength that is better than any other prognostic factor in epithelial ovarian cancer including FIGO stage. This stratification method may form the basis of determinations for new therapeutic approaches, as patients with poor prognosis could obtain the biggest advantage from new treatment modalities.

Human Papillomavirus DNA and E6/E7 mRNA Status in Relation to Survival of Patients Treated for Cervical Squamous Cell Carcinoma

The prognostic significance of human papillomavirus (HPV) DNA and E6/E7 mRNA, the presence of specific types, and the physical state of HPV DNA, were studied in 202 cervical squamous cell carcinomas. Absence or non-detectable levels of high-risk (types 16, 18, 31, 33, 35, 45, 52 and 58) E6/E7 mRNA, using the real-time nucleic acid sequence based amplification (NASBA) assay, and absence of HPV high-risk/HPV 6, 26, 66, 69, 73 (all methods collectively) were associated with poor overall survival in univariate analysis (P = 0.04 and P = 0.03, respectively) and had independent prognostic value in multivariate analysis (P = 0.01 and P = 0.03, respectively) including FIGO stage and age. Based on the individual results of type-specific PCR and in situ hybridization (ISH), the presence of HPV DNA was not found to be a prognostic factor. Likewise, concerning the presence of specific HPV types and the HPV integration status (determined by ISH), no prognostic significance was found. Mutation analyses of the TP53 gene revealed mutations in 3 of the 6 HPV negative samples (50%).

Interleukin-12 p40 gene ( IL12B) polymorphisms and the risk of cervical caner in Korean women

Objective The aim of this study was to investigate whether IL12B polymorphisms might be associated with increased risk and invasiveness of cervical cancer in Korean women. Study design Peripheral blood samples from patients with invasive cervical cancer ( n = 154) and non-cancer controls ( n = 191) were used to detect three biallelic IL12B polymorphisms at IVS2 −912, IVS4 +314, 3′UTR +1188 sites by performing SNaPshot assay. Allelic frequencies, genotype distributions, and haplotype patterns in the case group were compared with those in the control group. The relationships between these polymorphisms and cancer invasiveness were also evaluated by collating the clinicopathologic parameters including FIGO stage, lymph node status, histologic type, and parametrial invasion. The used analytic methods are chi-square test and logistic regression analysis. Results Allelic frequencies of cases (G, 0.853; A, 0.147) were not significantly different from controls (G, 0.796; A, 0.204) in IVS2 −912G/A SNP ( P = 0.054). GG genotype of IVS2 −912G/A SNP showed increased risk for cervical cancer compared with AA genotype ( P = 0.040). The IVS2 −912G:IVS4 + 314A haplotype, IVS2 −912G:IVS4 +314A:3′UTR +1188A haplotype, and IVS2 −912G:IVS4 +314A:3′UTR +1188C haplotype were also significantly associated with increased risk for cervical cancer. A subgroup analysis of the clinicopathologic parameters in cancer group also showed that there is no significant association between IL12B polymorphisms and cervical cancer invasiveness. Conclusions This study suggests that IVS2 −912GG genotype and IVS2 −912G:IVS4 +314A haplotype of IL12B gene are associated with increased risk for cervical cancer in Korean women.

RETRACTED: A study to evaluate the utility of presurgical CA125 to predict optimal tumor cytoreduction of epithelial ovarian cancer

To determine the ability of a preoperative serum CA125 to predict optimal primary tumor cytoreduction in patients with stage III and IV epithelial ovarian cancer (EOC). The records of patients with advanced stage who underwent primary surgery for EOC at Tehran University, Vali-Asr Hospital between 2000 and 2002 were reviewed. Inclusion criteria included FIGO stage III/IV disease, surgery by gynecologic oncology faculty, preoperative CA125, and an operative note clearly defining volume of residual disease. Without optimal cytoreduction was determined using the receiver operator curve (ROC). One hundred and twenty cases of advanced stage EOC were identified, of which 90 cases of stage III/IV met our inclusion criteria. Serum CA125 < or = 400 was identified with OD > or = 75% of the time. Conversely, optimal cytoreduction was performed in < or = 40% of patients with CA125 > or =4000. The area under the ROC curve for CA125 was 0.680. The optimal cytoreduction rate for those with and without ascites was 38% and 77%, respectively (P<0.001). In a multivariate analysis using CA125, age, and ascites, the area under the curve was 0.696. We conclude that CA125 level did not reliably predict optimal cytoreduction in patients with stage III-IV EOC.

Contribution of surgery in patients with bulky residual disease after chemoradiation for advanced cervical carcinoma

Aim To report the outcome of 30 patients who underwent surgery after concomitant chemoradiation for locally advanced cervical cancer with residual disease ≥2 cm. Methods From 1988 to 2004, 143 patients with FIGO stage IB2–IVA cervical cancer underwent surgery after concurrent chemoradiotherapy. Among them, 30 had a residual cervical tumour ≥2 cm prior to surgery. Surgery consisted in a simple or radical hysterectomy ( n = 15) or in a pelvic exenteration ( n = 15). Endpoints were recurrence and distant metastasis rates, overall survival (OS) and disease-free survival (DFS) at 3 and 5 years. Analysis included FIGO stage, response to chemoradiation, para-aortic lymphatic status or type of surgery: palliative (remaining disease after surgery) or curative (no evidence of remaining disease after surgery). Results Surgery has been only palliative in 11 cases. Pelvic recurrences occurred in 8 patients after a median interval of 8.8 months. Distant metastases occurred in 8 patients after a median interval of 13 months. So far, 16 patients have died (53.3%). The 3-year and 5-year OS rates are 64.9% and 55.6%, respectively, for the 19 patients who had a curative surgery. The DFS rate is 50.8% at 3 and 5 years in this latter group. Overall 12 patients (40%) are alive and free of disease after a median follow-up of 32.5 months. Conclusions Adjuvant surgery may improve the outcome of patients with bulky residual tumour after chemoradiation for locally advanced cervical cancer, allowing a 5-year OS of 55.6% after curative intervention.

A Phase II study of acute toxicity for Celebrex™ (celecoxib) and chemoradiation in patients with locally advanced cervical cancer: Primary endpoint analysis of RTOG 0128

To determine treatment-related acute toxicity rates in patients with locally advanced cervical cancer treated by oral celecoxib, i.v. cisplatin and 5-FU, and concurrent pelvic radiation therapy. Eligible patients on this RTOG Phase I-II study for advanced cervix cancer included FIGO Stage IIB-IVA or patients with FIGO Stage IB through IIA with biopsy proven pelvic node metastases or tumor size > or =5 cm. Patients were treated with pelvic radiotherapy and brachytherapy. Celecoxib was prescribed at 400 mg twice daily beginning on day 1 for 1 year. Cisplatin (75 mg/m2) and 5-FU (1g/m2 for 4 days) were administered every 3 weeks times 3. The primary end point of the study was treatment related toxicity. Between August 2001 and March 2004, 84 patients were accrued to the study and 77 patients were evaluable for toxicity. Regarding the primary end point, toxicities were observed in the following areas: blood/bone marrow (16), gastrointestinal (14), pain (7), renal/genitourinary (6), cardiovascular (3), hemorrhage (1), and neurologic (1). For the first 75 evaluable patients, a toxicity failure was identified in 36 patients for a rate of 48%. Celecoxib at 400 mg twice daily together with concurrent cisplatin and 5-FU and pelvic radiotherapy has a high incidence of acute toxicities. The most frequent toxicities were hematologic. Albeit, the toxicity was deemed excessive in this trial, the rate of toxicities was not too different compared to other recent experiences with concurrent chemoradiation for advanced cervix cancer.

Ezrin Promotes Ovarian Carcinoma Cell Invasion and Its Retained Expression Predicts Poor Prognosis in Ovarian Carcinoma

The majority of patients diagnosed with ovarian carcinoma are classified as being in advanced stage of disease. In a situation of cancer spread throughout the abdominal cavity, a successful curative treatment is difficult to achieve. Therefore, preventing binding of tumor cells to the mesothelium is crucial for patients' outcome. One important mechanism is the interaction between hyaluronic acid and the CD44 receptor with its submembrane linking complex. This consists of ezrin, radixin, and moesin and connects the CD44 receptor with the cytoskeleton. To assess the role of ezrin and moesinfor ovarian carcinoma progression, we analyzed ovarian carcinoma samples from 105 patients for expression of ezrin and moesin by immunohistochemistry and correlated these data with several clinicopathological parameters. To elucidate the functional importance of ezrin and moesin, their expression was inhibited in SKOV-3 cells by RNA interference. Ezrin and moesin were strongly expressed in 49 and 48% of ovarian carcinoma samples, respectively, and their presence correlated with reduced overall survival in univariate analysis (ezrin, p=0.0189; moesin, p=0.0351). In multivariate analysis (including FIGO stage, residual tumor, histological type, and Silverberg grading), ezrin still remained significant as an independent risk factor (relative risk, 2.39; p=0.012). In SKOV-3 cells, siRNA against ezrin but not moesin inhibited in vitro invasion. These data imply that ezrin is necessary for tumor cell invasion, and the better prognosis of ovarian carcinomas lacking ezrin is probably related to their impaired invasion.

The utility of presurgical CA125 to predict optimal tumor cytoreduction of epithelial ovarian cancer

The objective of this study was to evaluate the ability of a preoperative serum CA125 to predict whether optimal debulking (OD) could be achieved for patients with stage III and IV epithelial ovarian cancer (EOC). The records of consecutive patients who underwent primary surgery for EOC at Indiana University Hospital between January 1997 and January 2003 were reviewed. Eligibility criteria included FIGO stage III/IV disease, surgery by gynecologic oncology faculty, preoperative CA125, and an operative note clearly defining volume of residual disease. The Medcalc software statistical package was used to generate a receiver-operating characteristic (ROC) curve. Two hundred and eighty-nine cases of stage III/IV EOC were identified, of which 164 met the eligibility criteria. Serum CA125 </=400 was associated with OD >/=75% of the time. Conversely, OD was achieved in </=40% of patients with CA125 >/=4500. The area under the ROC curve for CA125 was .670. The OD rate for those with and without ascites was 49% and 79%, respectively (P < 0.001). In a multivariate analysis using CA125, age, and ascites, the area under the curve was 0.686. We conclude that preoperative serum CA125 did not reliably predict OD in patients with stage III-IV EOC.

Expression of estrogen receptor-related receptor isoforms and clinical significance in endometrial adenocarcinoma

Estrogen receptor-related receptors (ERRs) are members of orphan nuclear receptors closely related to the estrogen receptors (ERs). Researches showed that the ERRs bound to estrogen response elements and interfered in the ER signal pathway. Therefore, it might be associated with estrogen-dependent diseases. The purpose of this study was to explore whether ERRs were involved in the tumorigenesis of endometrial adenocarcinoma. We examined the expression of ERRs in endometrial adenocarcinoma and normal endometrium using semiquantitative reverse transcription-polymerase chain reaction and immunohistochemistry. Clinicopathologic features including FIGO stage, histologic grade, myometrial invasion, and nodal metastasis were reviewed. Results showed that messenger RNA (mRNA) levels of ERRalpha, ERRbeta, and ERRgamma were positively associated with the immunoreactivities (P= 0.009, P= 0.014, and P= 0.001, respectively). The expression rate and relative level of ERRalpha mRNA in ERalpha-positive endometrial adenocarcinomas were lower than in normal endometriums (P= 0.049 and P= 0.023), whereas the relative level of ERRgamma mRNA in ERalpha-positive endometrial adenocarcinomas was higher than in normal endometriums (P= 0.014). Expression of ERRalpha mRNA was positively correlated with FIGO stage (P= 0.019) and myometrial invasion (P= 0.043). A negative correlation was observed between expression of ERRgamma mRNA and nodal metastasis (P= 0.021). Results suggested that ERRalpha and ERRgamma might participate in the tumorigenesis of endometrial adenocarcinoma. ERRalpha and ERRgamma are promising to be new prognostic factors in endometrial adenocarcinoma.

The prognostic impact of EphB2/B4 expression on patients with advanced ovarian carcinoma

Objectives. To analyze expressions of the EphB2 and EphB4 receptors in ovarian carcinomas and explore their clinicopathological correlations and prognostic value. Methods. 115 patients with advanced ovarian carcinoma FIGO IIB to IV were involved. RT-PCR and immunohistochemistry were used to examine the expressions of EphB2/B4 receptor mRNA and protein. Correlations between protein expression and clinicopathological factors were also analyzed. Results. Ovarian carcinoma patients with age elder than 60 years had higher EphB2 expression than younger patients. Expression of EphB2 and EphB4 protein did not significantly correlate with any other clinical variables, including FIGO stage, residual tumor, histological type and differentiation grade. No significant correlation between mRNA and protein expression level for both of these receptors was seen. It was found that patients with strong immunostaining for EphB2 ( P = 0.03) or EphB4 ( P = 0.003) receptors had poorer survival, and patients with strong immunostaining for EphB4 receptor showed poorer response to chemotherapy ( P = 0.036). Conclusions. These studies suggest that EphB2 and B4 receptors are of prognostic value and EphB4 receptor may be an independent predictor of chemotherapy response in ovarian cancer patients.

Long-term survival after concomitant chemoradiotherapy prior to surgery in advanced cervical carcinoma

Objective. To report the long-term survival of 35 patients who underwent surgery after concomitant chemoradiation for locally advanced cervical cancers. Methods. From 1988 to 1992, 20 bulky IB–IIB patients and 15 stage III–IVA patients underwent surgery after concurrent chemotherapy (CDDP and 5-FU) and radiotherapy. 26 had a hysterectomy, 8 had an exenteration, 1 had no tumor resection. 21 had a para-aortic lymphadenectomy. Endpoints were recurrence and distant metastasis rates, overall survival (OS) and disease-free survival (DFS) at 5 and 10 years. Analysis included FIGO stage, type of surgery (palliative or curative), response to chemoradiation or para-aortic lymphatic status. Results. Surgery had been only palliative in 6 cases (17.1%). A pelvic control has been achieved in 31 patients (88.6%). Pelvic recurrences occurred after a median interval of 7 months. Distant metastases occurred in 10 patients (28.6%), after a median interval of 20 months. So far, 16 patients have died (45.7%). The 10-year DFS is 56.7% in the whole series. Only the type of surgery significantly affected the OS. Only the para-aortic lymphatic status significantly affected the DFS. Conclusion. Associating chemoradiation with curative surgery, we obtained a 10-year DFS of 66.4% (OS 57.7%). Adjuvant surgery may increase the survival as it reduces the risk of local relapse.

Analysis of prognostic factors of malignant ovarian tumor after fertility-preserving treatment

To explore the prognostic factors of malignant ovarian tumor after fertility-preserving treatment. 189 patients with malignant ovarian tumor who had undergone fertility-preserving management in the past 20 years were retrospectively analyzed. The correlative factors for survival, recurrence and reproductive status were evaluated. Among the patients, 136 cases suffered from ovarian germ cell tumor (OGCT), 31 cases suffered from ovarian sex cord-stromal tumor (OSCST), and 22 cases suffered from epithelial ovarian cancer (EOC). The median follow-up time of different groups was 50 months for OGCT, 46 months for OSCST, 45 months for EOC respectively. The 5-year survival rates for OGCT, OSCST and EOC groups were 94.0% (131/134), 77.1% (26/30) and 64.7% (16/21) respectively. The recurrent rates were 29.9% (40/134), 20.0% (6/30) and 47.6% (10/21) respectively. 46 babies were delivered during the follow-up period. Standard chemotherapy was the most important prognostic factor for OGCT. FIGO stage and standard chemotherapy were favourable factors for prognosis in OSCST group. The important prognostic factors included FIGO stage and standard comprehensive surgical staging for EOC. Fertility-preserving treatment should be considered for OGCT without limitation of FIGO stage, whereas it should be performed individually for OSCST and EOC. The treatment outcome for OGCT is the best, for EOC the worst.

Pretreatment normalization of mild anemia with epoetin alfa predicts long-term outcome for women with epithelial ovarian cancer

5132 Background: In a previous study (Marinaccio et al. Proc.ASCO 2003;Abstr1952) we assumed that pretreatment normalization of mild anemia with epoetin alfa could improve the outcome in patients with epithelial ovarian cancer. The aim of this larger trial was to understand better the influence of recombinant human erythropoietin (rHuEPO) on the outcome of ovarian cancer patients showing anemia before undergoing surgery and chemotherapy. Methods: Between 1999 and 2003, 42 patients with mild anemia (Hgb 10.6–11.9 g/dL) secondary to advanced epithelial ovarian cancer were randomized to receive epoetin alfa (21 pts.) or not (21 pts.) before primary surgery. All patients were without past or present second malignancy and aged less than 76 years. FIGO stage at diagnosis was as follows: IC 13/42; II 5/42; III 19/42; IV 5/42. After surgery all patients underwent adjuvant chemotherapy with paclitaxel (175mg/mq) plus carboplatin (AUC5). Patients in the treatment group were administered rHuEPO, 10.000 IU, three times a week subcutaneously for 4–6 weeks. The patients receiving rHuEPO had a significantly greater increase in hematocrit and Hgb compared with the control group (p<0.01). Survival curves were described by Kaplan-Meier method. The relationship of Hgb to survival was determined by Cox Regression analysis after adjusting for the effect of known prognostic variables including FIGO stage, tumor grade and residual tumor. Results: The mean age of patients was 54.1 years. The median duration of follow-up was 30 months. The median relapse-free survival time was found to be 26 months in patients treated with rHuEPO and 18 months in the control arm; the evaluation of median survival time is in progress, however Kaplan-Meier 12-month estimates of survival were 65% for the rHuEPO arm and 50 % for the control arm, revealing a trend in overall survival favoring normalization of pre-treatment anemia with rHuEPO (Kaplan-Meier analysis p=0.12, Cox regression analysis p=0.044). Conclusions: Pretreatment of mild anemia with epoetin alfa in patients with epithelial ovarian cancer offers an excellent possibility of improving the outcome. No significant financial relationships to disclose.

Independence of the prognostic value of tumor suppressor protein expression in ovarian adenocarcinomas: A multivariate analysis of expression of p53, retinoblastoma, and related proteins

Accurate estimation of prognosis of ovarian cancer is difficult. For this report, in a group of 73 patients with ovarian adenocarcinomas, clinical factors and protein expression status of p53, retinoblastoma (Rb), and related proteins were evaluated for potential prognostic values. Clinical factors included FIGO stage, age, histopathologic type, and protein expression of p53, Rb, MDM2, p14ARF, p21WAF(1)/CIP(1) was determined by an immunohistochemical technique. Univariate Cox proportional hazard regression analysis was used to determine the significant prognostic value of FIGO stage (P &lt; 0.0001), p53 status (0.0021), and patient age (P = 0.0255), and we report here, for the first time, the significant (P = 0.0072) prognostic value of Rb status. Histopathologic type and MDM2, p14ARF, p21WAF(1)/CIP(1) status did not show any prognostic value. To examine further the independence of prognostic values, we next applied multivariate analysis: We found that FIGO stage (P &lt; 0.0001) and p53 status (P = 0.0108) were independent prognostic factors, while age and Rb status were not. Independence of prognostic value of p53 has heretofore been controversial, but we found a definite independent prognostic value for p53 status in ovarian adenocarcinomas. We also found that selection of appropriate antibodies for immunohistochemistry was essential to obtain significant results. We used five kinds of antibodies for p53 immunolocalization, and correlation with prognosis was obtained by three of these with different grades of statistical significance.

Expression of p53, bcl-2 and heat shock protein (hsp72) in malignant and benign ovarian tumours.

The occurrence of p53, bcl-2 and heat shock protein (HSP) expression in ovarian tumours was examined and the correlation was investigated between the expression of these proteins and other disease parameters, including FIGO stage, histological subtype, tumour differentiation and steroid hormone receptor status. We analysed p53, bcl-2 and HSP expression in 100 smears of patients with epithelial ovarian carcinomas, 16 smears of patients with borderline malignancy and 20 smears of patients with benign ovarian neoplasms by using immunocytochemical techniques. There were 29 patients with stage I disease, 24 with stage II disease, 40 with stage III disease and seven with stage IV disease according to the FIGO classification. The sensitivities and specificities of bcl-2, p53 and HSP for malignancy were 53% and 40%, 43% and 80%, and 37% and 90%, respectively. HSP was statistically significantly associated with malignant rather than benign tumours. Significant association was also observed between bcl-2 and p53, and p53 and HSP. The association of HSP with malignant tumours is confined to the premenopausal group of patients and in this group by itself there is also a significant association between p53 and malignancy. HSP and p53 were associated with undifferentiated carcinomas, bcl-2 and p53 expression is reduced as disease stage progresses in serous carcinomas and bcl-2 expression is increased as disease progresses in endometrioid carcinomas. There was no significant association between bcl-2 and ER/PR status. In conclusion, HSP has a high specificity for malignant ovarian tumours, bcl-2 and p53 have only moderate to low sensitivity and specificity. Changes in the frequency of bcl-2 and p53 overexpression between FIGO I and FIGO III stage disease of different ovarian carcinomas indicate a different role of these substances in cellular survival mechanisms in different carcinomas. bcl-2 probably is associated with cell proliferation but not with differentiation.

Conservative and Individualized Surgery for Early Squamous Carcinoma of the Vulva: The Treatment of Choice for Stage I and II (T1-2 N0-1 M0) Disease

We studied the outcome of patients undergoing radical local excision (modified radical vulvectomy) with inguinal-femoral lymphadenectomy through separate groin incisions for stage I and II invasive squamous carcinoma of the vulva. The purpose was to determine whether less radical and more individualized surgery is consistent with local control and cure. We have reported previously our experience using radical local excision and modified radical vulvectomy in stage I disease (Obstet. Gynecol. 63, 155 (1984)) and with separate groin incisions (Obstet. Gynecol. 58, 574 (1981)). This current report expands our experience with stage I and adds stage II patients treated over the past decade. Seventy-four patients were studied retrospectively over the 5-year period ending in January 1990. Reviews of both patient charts and histopathology reports were correlated with recurrence and survival. Factors analyzed included FIGO stage and grade, histology, lesion size and depth of invasion, surgical procedure, radiotherapy, lymph node status, interval to and site of recurrence, and survival. Thirty-nine patients had stage I disease and 35 had stage II. The primary operation was a radical local excision (modified radical vulvectomy) in 56 patients and radical vulvectomy in 18 patients; 13 underwent ipsilateral inguinal-femoral lymphadenectomy and 58 bilateral lymphadenectomy, each through separate groin incisions. The survival of those treated conservatively (97 and 90% for stages I and II, respectively) is the same as those undergoing a radical vulvectomy (100 and 75% for stages I and II, respectively) with only the presence of inguinal-femoral lymph node metastases impacting negatively on survival. In the entire group, the survival for negative and positive nodes was 98 and 45%, respectively. In conclusion, conservative, modified, and individualized vulvectomy in both stage I and II disease is associated with the same outcome and survival as radical vulvectomy, and lymph node status is the most important prognostic factor.