Frequency and prediction of deep uterine involvement in advanced high-grade epithelial ovarian cancer: is uterine preservation an option?

INTRODUCTION: Hysterectomy is traditionally part of the surgical treatment for advanced high-grade epithelial ovarian carcinomas, although the incidence of uterine involvement has not been fully investigated. Some young patients with advanced high-grade epithelial ovarian carcinomas want uterine preservation. We aimed to determine the frequency of non-serosal (deep) uterine involvement in patients with high-grade epithelial ovarian carcinomas and to establish predictive factors for such involvement. METHODS: A retrospective cohort study was performed of 366 consecutive patients with advanced high-grade epithelial ovarian carcinomas who had surgery between January 2012 and December 2019. Data collected included demographic and clinical details, and surgical and pathological reports to determine macroscopic and microscopic deep uterine involvement. The characteristics of the patients with and without deep uterine involvement were compared and univariate and multivariate Cox proportional hazard models were used to assess correlations and determine risk factors. RESULTS: A total of 311 patients were included in the final analysis. The mean age was 62±11.6 years, with 32 (10.3%) being younger than 45. Most (92.3%) had serous carcinoma. Uterine involvement, excluding superficial (serosa-only), was present microscopically in 194 patients (62.4%) but was detected macroscopically at surgery in only 166 patients. Deep involvement was missed at surgery in 28 patients (14.4%), including parametrial involvement (n=18), parametria plus cervix (n=2), cervical involvement (n=3), endometrium (n=3), and myometrium (n=2). Multivariate analysis identified factors associated with deep uterine involvement including residual disease at surgery (HR 2.43, 95% CI 1.13 to 4.48; p=0.004) and CA125 >1000 U (HR 1.8, 95% CI 1.09 to 2.94; p=0.02). CONCLUSIONS: The incidence of deep uterine involvement in high-grade epithelial ovarian carcinomas is high. It can be diagnosed in most but not all cases on gross examination at surgery and is associated with residual disease and CA125 >1000 U. Patients who desire uterine preservation should be advised on an individual basis, given these factors and the operative findings.

Fertility preservation in women with borderline ovarian tumors - how does it impact disease outcome? A cohort study.

INTRODUCTION: Borderline ovarian tumors are typically indolent neoplasms. Since many are diagnosed in younger women, fertility conservation is an important consideration and has been advocated based on retrospective data. The objective of this study was to identify features impacting on recurrence and survival in a series of borderline ovarian tumors, and to assess the safety of a fertility-sparing approach. MATERIAL AND METHODS: A historical cohort study of consecutive borderline ovarian tumors cases treated at a single institution over 30 years (1981-2011). Data on surgical approach (fertility-sparing or otherwise), disease stage, CA125 levels, histological features, adjuvant treatment and follow-up data were collected. Recurrence and survival were assessed using the Kaplan-Meier method and associations with the variables of interest were evaluated using a multivariate Cox proportional hazards model. RESULTS: 213 patients were included. Of 132 women age 40 years and below at diagnosis, 112 (85%) had a fertility-sparing procedure and 60 (46%) had conservation of an involved ovary. Fifty patients (24%) developed recurrences; fertility preservation (hazard ratio = 2.57; 95% confidence interval 1.1-6; p = 0.029) and advanced stage (hazard ratio = 4.15; 95% confidence interval 2.3-7.6; p < 0.001) were independently associated with recurrence on multivariate analysis. Eleven (5%) patients died of their disease. Fertility preservation was not associated with compromised survival. CONCLUSIONS: Borderline ovarian tumors carry a good prognosis overall. Fertility preservation is associated with a higher risk of disease relapse; however, as most relapses are localized and may be salvaged with surgical treatment, overall survival is not compromised.

Malignant Pericardial Effusion in Ovarian Malignancy: A Treatable Oncologic Emergency.

BACKGROUND: Pericardial tamponade is a life-threatening condition that can occur, albeit rarely, in patients with ovarian cancer. Whether or not prolonged survival is possible after such an event is debatable. Our aim was to describe our experience with seven ovarian cancer patients who experienced malignant cardiac tamponade at tumor diagnosis or at recurrence. CASE REPORT: Six patients were treated with pericardiocentesis and one with pericardial fenestration. Survival after tamponade ranged from 3 to 72 weeks. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We suggest that when pericardial effusion occurs in patients with recurrent ovarian cancer, timely diagnosis and proper management might allow palliation and prolongation of life.

Effect of treatment delay on survival in patients with cervical cancer: a historical cohort study.

OBJECTIVE: The objective of this study was to evaluate the effect of treatment delay on prognosis in patients with cervical cancer. METHODS: The study group of this historic cohort study comprised 321 patients newly diagnosed with cervical cancer between 1999 and 2010. Time from diagnosis to treatment was analyzed both as a continuous variable and as a categorical variable in 3 groups that differed in waiting time between diagnosis and treatment initiation: 30 days or less (group 1, n = 134), 30 to 45 days (group 2, n = 86), and more than 45 days (group 3, n = 101). Associations between waiting time group, patients' characteristics, and disease outcome were investigated using t tests, analyses of variance and Cox regression analyses, Kaplan-Meier survival analysis, and log-rank (Mantel-Cox) tests. RESULTS: Time from diagnosis to treatment initiation, when analyzed as a continuous variable, was not a significant factor in survival. There were no between-group differences in age, smoking rate, marital status, gravidity, parity, tumor histology, or lymph node involvement. Early-stage disease and small tumor diameter were diagnosed most frequently in group 3. However, there was no significant between-group difference in 3-year survival rates (74.6%, 82.2%, and 80.8% in groups 1, 2, and 3, respectively; P = 0.38). On multivariate analysis, only stage, histology, and lymph node involvement were significant prognostic factors for survival. Before starting treatment, 28 patients underwent ovarian preservation procedures. CONCLUSIONS: Longer waiting time from diagnosis to treatment was not associated with worse survival. Our findings imply that if patients desire fertility or ovarian preservation procedures before starting treatment, it is acceptable to allow time for them.

Use of titanium spiral tacks for long-term oophoropexy before pelvic irradiation.

BACKGROUND: Ovarian transposition before planned pelvic irradiation can preserve ovarian function in young patients with pelvic malignancies. The transposed ovaries are fixed to the posterolateral abdominal wall. We described the use of a titanium spiral tack as a fixation device and compared it with other methods of oophoropexy. METHODS: Medical and surgical records of all consecutive patients who underwent oophoropexy in our institution between 2007 and 2013 were reviewed. Demographic and clinical data were summarized; follicle-stimulating hormone values, recorded; and imaging scans, reviewed. RESULTS: Oophoropexy was performed in 30 patients: 28 with cervical carcinomas and 2 with pelvic sarcomas. The procedure was done through laparoscopy in 13 patients and through laparotomy in 17. Titanium spiral tack was used for ovarian fixation in 14 patients, Vicryl suturing in 14, and in 2 cases the ovaries were pulled up through a retroperitoneal tunnel and fixed to the peritoneum with sutures. Titanium spiral tack fixation took a few seconds to perform. There were no immediate intraoperative or postoperative complications. Ovarian function was preserved in 15 patients (7/14 with spiral tack, 6/14 with sutures, and in both patients with retroperitoneal tunneling). Postoperative imaging results showed that all ovaries retained their extrapelvic location for a median period of 11.6 months (range, 2.3-63 months). CONCLUSIONS: Spiral tack is a simple, reliable method for oophoropexy before pelvic irradiation. Its efficacy is comparable with that of suture fixation, with the added advantage of ultrashort operative time. It is therefore worth considering as an alternative to suturing.

Abdominopelvic cytoreduction rates and recurrence sites in stage IV ovarian cancer: is there a case for thoracic cytoreduction?

OBJECTIVE: We report the rates of optimal abdominopelvic cytoreduction and the sites of recurrence in stage IV ovarian cancer patients, with particular attention to the potential impact of thoracic cytoreduction on treatment results in patients with intra-thoracic spread. METHODS: A historic cohort study of all stage IV ovarian cancer patients diagnosed between 1994 and 2010 and underwent abdominopelvic cytoreductive surgery. Controls were stage IIIc patients. Statistical analyses included χ(2) test, Cox proportional hazards regression models and Kaplan-Meier curves with log-rank tests. RESULTS: Group 1 included 76 stage IV patients, 55% with thoracic spread. Group 2 included 142 stage IIIc patients. Age, histology, primary peritoneal tumor and ascites rates were similar for the two groups. Respective rates of optimal abdominopelvic cytoreduction were 68% vs. 83.5% (p<0.05), median time to progression 5.3 vs. 12.3 months (p<0.01) and overall survival 27.2 vs. 46.1 months (p<0.01). Optimal cytoreduction and survival rates were similar for all group 1 patients regardless of spread location. Sites of recurrence in stage IV were abdomen (59.3%), thorax (6.8%), both (28.8%) or other (5.1%). The four patients with thoracic recurrence alone were all initially diagnosed with malignant pleural effusion. Three of them developed abdominal recurrence within 15‒6 months. CONCLUSIONS: Optimal abdominopelvic cytoreduction was achievable in stage IV patients, although in significantly fewer patients than in stage IIIc. Sites of recurrence were rarely thorax alone, implying that thoracic debulking is likely to change the course of disease in only few patients and thus should be carefully individualized.

Appendectomy and cancer risk in Jewish BRCA1 and BRCA2 mutation carriers.

Previous studies suggested that appendectomy may affect cancer risk in the general population. No data on the effect of appendectomy on cancer risk in BRCA1 and BRCA2 carriers is available. Data on appendectomy, cancer type, and age at diagnosis were collected from BRCA1 (n = 677) and BRCA2 (n = 270) female Jewish Israeli mutation carriers counseled in a single medical center. Data were also collected on 225 consecutive ovarian cancer cases treated at the same medical center. Overall, 367/947 (38.7%) of mutation carriers had breast cancer (age at diagnosis 44.1 ± 10.4 years), 142 (15.0%) ovarian cancer (53.6 ± 10.1 years), and 438 (46.25%) were asymptomatic carriers (age at counseling 41.4 ± 11.2 years). Mean age at diagnosis of consecutive ovarian cancer cases was 53.6 ± 10.1 years. Of mutation carriers, 28/367 breast cancer cases (7.6%), 15/142 ovarian cancer cases (10.6%), and 11/438 asymptomatic carriers (2.5%) underwent prior appendectomy (P = 0.001 for breast/ovarian cancer when compared with asymptomatic carriers). In all but two cases, appendectomy was performed more than 10 years before cancer diagnosis or age at counseling. Of ovarian cancer patients, 12/225 (5.3%) underwent appendectomy, and in 10 appendectomy was performed 10 years or more before ovarian cancer diagnosis (P = 0.068 when compared with inherited ovarian cancer cases). This study suggests that prior appendectomy is more frequently noted in BRCA1 and BRCA2 carriers with breast and ovarian cancer than in unaffected mutation carriers. The mechanism for this association is elusive, and future analyses of ethnically diverse mutation carriers are needed to validate these results.

Palliative urinary diversion in patients with malignant ureteric obstruction due to gynaecological cancer.

OBJECTIVES: To identify factors aiding the selection of patients with gynaecological cancer with malignant urinary obstruction who are least likely to benefit from palliative urinary diversion (UD), and to create a risk-stratification model for decision-making. METHODS: This historic cohort study comprised 74 consecutive patients with urinary obstruction resulting from gynaecological malignancies. All underwent palliative UD by percutaneous nephrostomy (PCN). Using the Cox proportional hazards regression model and Kaplan-Meier curves with the log-rank test, we developed a prognostic score identifying candidates least likely to benefit from the intervention. RESULTS: The median follow-up was 4.72 (range 0-5.71) years. Hydronephrosis was diagnosed in most patients on recurrent or persistent disease (81%). It was bilateral in 37.8%. Intervention-related complications included urinary sepsis (8%), catheter dislodgment requiring replacement (17%) and gross haematuria necessitating blood transfusions (13%). After PCN, conversion to an internal ureteral stent was feasible in 46%. The median survival was 11.13 (range 0-67) months. Two patients died within a month of UD. Multivariate analysis identified diabetes mellitus (DM), poor Eastern Cooperative Oncology Group (ECOG) performance status >1 and ascites as significant negative survival factors. A prognostic index based on those factors identified the short-term and long-term survivors. Risk factor-based mortality HRs were 11.37 (95% CI 4.12 to 31.37) with one factor, 26.57 (95% CI 9.14 to 77.26) with two factors and 67.25 (95% CI 15.6 to 289.63) with three factors (all with p<0.0001). CONCLUSIONS: Our proposed prognostic index, based on ascites, ECOG performance status and DM, might help select patients with gynaecological cancer least likely to benefit from palliative UD.

FOXL2 C402G mutation detection using MALDI-TOF-MS in DNA extracted from Israeli granulosa cell tumors.

OBJECTIVE: To develop a rapid, sensitive and reliable method to detect FOXL2 C402G mutation in granulosa cell tumor (GCT) and to investigate the prevalence of FOXL2 mutation in granulose cell tumors among Israeli patients. METHODS: We designed and optimized a matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) genotyping assay to detect FOXL2 C402G mutation in DNA isolated from formalin-fixed paraffin-embedded tissue samples. We examined 20 tumor samples obtained from Israeli patients diagnosed with granulose cell tumor. RESULTS: Eighteen out of 20 samples were found to harbor FOXL2 C402G mutation. Pathological review of the two tumors harboring wild type FOXL2 (C402) concluded that they were adenocarcinomas and has been misclassified at initial diagnosis. We found that the prevalence of FOXL2 mutations among Israeli patients with GCT (100%) is similar to previous reports. CONCLUSIONS: Our results indicate that the FOXL2 mutations can be reliably detected by MALDI-TOF-MS genotyping. MALDI-TOF-MS genotyping is a simple, robust and highly sensitive method to detect FOXL2 C402G mutation. Our results confirm previous studies reporting over 95% prevalence of FOXL2 mutation in GCT. Furthermore, we suggest that testing for the presence of the FOXL2 C402G mutation may improve diagnostic accuracy.

Prolonged conservative treatment of endometrial cancer patients: more than 1 pregnancy can be achieved.

BACKGROUND: Preserving reproductive function in young patients with early endometrial cancer is an accepted concept today. The safety and feasibility of long-term conservative treatment, allowing more than 1 pregnancy, remain to be ascertained. METHODS: This study was a retrospective chart review of a 27 women with endometrioid adenocarcinoma of the endometrium, who were treated conservatively at 2 tertiary-care institutions. Treatment comprised oral high-dose progestins with or without a levonorgestrel-releasing intrauterine device. Endometrial biopsy was repeated every 2 to 3 months. RESULTS: Over 7.8 to 412 months (median, 57.4 months), tumors regressed completely in 24 (89%) of 27 patients and partially in 2 patients, with 79% responding within 1 to 17 months. Of the complete responders, 15 (62%) of 24 had a recurrence; 4 underwent hysterectomy, and 11 underwent subsequent progestational treatment. All 11 responded, and 3 subsequently conceived. After 2 to 4 years, 5 patients again had a recurrence, of whom 3 underwent hysterectomy. Overall, 2 patients developed ovarian adenocarcinoma. All patients are currently disease-free. Conception occurred in 14 (51.8%) of 27 patients, in 5 more than once. There were 17 live births, and 2 patients are pregnant. CONCLUSIONS: According to our data, prolonged progestational therapy for early-stage endometrial adenocarcinoma, allowing women to conceive, is feasible and apparently does not alter clinical outcome. Patients should be advised of the high recurrence rate and possible concomitant ovarian malignancy.

Uterine leiomyosarcoma: does the primary surgical procedure matter?

BACKGROUND: Uterine leiomyosarcoma (LMS) has a poor prognosis even after early-stage diagnosis. Because there are no accurate diagnostic tools for preoperatively distinguishing LMS from uterine leiomyoma, surgeons might opt for partial surgical procedures such as myomectomy or subtotal hysterectomy. We sought to determine whether a surgical procedure that cuts through the tumor influences prognosis. MATERIALS AND METHODS: Demographic and clinical data of consecutive patients with stage I LMS treated between 1969 and 2005 were reviewed. The study population was divided into group A: patients whose first surgical intervention was total hysterectomy (n = 21); and group B: patients who underwent procedures involving tumor injury, for example, myomectomy, laparoscopic hysterectomy with a morcellator knife, or hysteroscopic myomectomy (n = 16). Survival rates were analyzed and compared. A Cox proportional hazards model was used to assess the association between variables of interest and prognosis. RESULTS: The median age at diagnosis was 50 years (range, 30-74 years). Median follow-up duration was 44 months. The 2 groups did not differ significantly in age at diagnosis, menopausal status, gravidity, parity, postoperative radiotherapy, or time to last follow-up. Kaplan-Meier curves showed significantly better survival rates (P = 0.04) and a significant advantage in recurrence rate (P = 0.03) for group A compared with group B. Survival in group A was 2.8-fold better than that in group B (95% confidence interval, 1.02-7.67). These estimates remained stable after adjustment for age, menopausal status, and radiotherapy. CONCLUSIONS: In patients with stage I LMS, primary surgery involving tumor injury seems to be associated with a worse prognosis than total hysterectomy as a primary intervention.

Promising effect of aromatase inhibitors on recurrent granulosa cell tumors.

Recurring adult-type granulosa cell tumors of the ovary are usually treated by surgical resection followed by chemotherapy or radiation. However, the results of such treatment are disappointing. We describe 4 patients in whom recurrent ovarian granulosa cell tumors were treated with an aromatase inhibitor, with promising results.

Villoglandular papillary adenocarcinoma of the uterine cervix: a diagnostic challenge.

Villoglandular papillary adenocarcinoma (VGA) is a rare subtype of cervical adenocarcinoma. It tends to appear in younger women and its indolent behavior permits fertility-preserving treatments. Pathologically, VGA presents a diagnostic challenge. The aim of our study was to evaluate the reliability of histological assessment for pre-treatment diagnosis of VGA. The data from the outpatient files of 12 patients in whom VGA had been diagnosed were reviewed. Median age at diagnosis was 38.8 years (range 27-65). Final pathology results confirmed VGA in nine patients. Of these, only two had been correctly diagnosed preoperatively, while in three, the initial biopsies were benign or pre-malignant. In four patients, the biopsy results had been interpreted as an invasive malignant tumor necessitating hysterectomy. The final histological report on the remaining three patients was invasive cervical adenocarcinoma. We conclude that pre-treatment diagnosis should not be based solely on a simple punch biopsy because of its low rate of diagnostic accuracy.

Anti-mesothelin antibodies and circulating mesothelin relate to the clinical state in ovarian cancer patients.

Most human ovarian carcinomas express mesothelin, which is shed as a diagnostically useful biomarker. We applied an ELISA to measure antibodies to native mesothelin in serum from a series of patients with divergent clinical outcomes. The level of anti-mesothelin antibodies determined as OD(450 nm) and referred to as absorption units (AU) for 1:20 diluted serum was higher in patients who remained disease-free after therapy [no evidence of disease (NED); n = 14] than in patients whose disease recurred [clinical evidence of disease (CED); n = 21; P < 0.01]. Applying AU > or = 0.5 at a serum dilution of 1:20 as cutoff, 10 of 14 (71%) ovarian carcinoma patients with NED and 9 of 21 (43%) patients with CED had antibodies to mesothelin compared with 6 of 23 (26%) healthy women (P < 0.008) and 5 of 24 (21%) women with other benign gynecologic diseases (P < 0.003), whereas 7 of 9 (78%) of women with pelvic inflammatory disease were positive. Three of the 14 (21%) NED patients had circulating mesothelin detected as an AU > or = 0.2 at a serum dilution of 1:40 (P < 0.005) compared with 15 of 21 (71%) CED patients, and 9 of 14 (64%) NED patients (P < 0.0002) were positive for antibodies and negative for antigen compared with 1 of 21 (5%) CED patients. Although our data indicate that an antibody response to mesothelin is an important correlate of ovarian carcinoma, prospective studies are needed to show whether the measurement of such antibodies (alone or together with antigen) aids the diagnosis and monitoring of patients.

Young Israeli women with epithelial ovarian cancer: prevalence of BRCA mutations and clinical correlates.

OBJECTIVE: The current study investigates disease patterns and outcomes in young Israeli epithelial ovarian cancer (EOC) patients and their association with BRCA mutation status. METHODS: Consecutive EOC patients diagnosed at or below 50 years in a single institution between 1995-2011 were identified. All patients are referred for genetic counseling and testing for the predominant Jewish BRCA mutations: BRCA1-185delAG, BRCA1-5382insC, and BRCA2-6174delT. A comparison between BRCA mutation carriers and non-carriers was undertaken across demographic, pathologic, and clinical features; recurrence and survival were compared using the Kaplan-Meier method and associations with the variables of interest were analyzed using the Cox proportional hazards method. RESULTS: One hundred eighty-six patients diagnosed with EOC at 50 years or younger were included, with a total follow-up of 1,088 person years. Mean age at diagnosis was 44±5 years. Of 113 patients with documented BRCA testing, 49.6% carried a germline BRCA mutation, compared with 29% in the general Israeli EOC population (p=0.001). BRCA mutation carriers had a higher rate of serous tumors (75% vs. 64%, p=0.040) and higher CA125 levels at diagnosis (median, 401 vs. 157, p=0.001) than non-carriers. No significant association between BRCA mutations and recurrence (hazard ratio [HR]=1.03; p=0.940) or survival (HR=1.40; p=0.390) was found. CONCLUSION: BRCA mutations are encountered in almost 50% of young Israeli ovarian cancer patients; they are associated with serous tumors and high CA125 levels at diagnosis, but are not independently associated with recurrence or survival in this patient population.

The 471delAAAG mutation and C353T polymorphism in the RNASEL gene in sporadic and inherited cancer in Israel.

The rate of RNASEL 471delAAAG mutation was previously reported to be less than 7% in Ashkenazi prostate cancer patients. It seems plausible that the same mutation may also be involved in breast/ovarian cancer predisposition in Jewish individuals. To evaluate the role of this mutation in cancer predisposition, a total of 1011 individuals including 294 Jewish men with prostate cancer, 61 Ashkenazi women with ovarian cancer and 50 unaffected women, matched for age and ethnicity, were genotyped for sequence anomalies in a single RNASEL gene amplicon using DGGE and sequencing. Additionally, 209 Ashkenazi BRCA1/2 mutation carriers, 205 high-risk non-carriers matched for cancer type and age at diagnosis, and 192 healthy Ashkenazi women were screened, using DHPLC and restriction methods. The 471delAAAG mutation was detected in a single male with prostate cancer (1/294, 0.3%), in two ovarian cancer patients (2/141, 1.4%) and in one of 242 healthy controls (0.41%). An abnormal DHPLC profile identical to the one produced by the 471delAAAG mutation was noted in 23 additional women. The rate of this polymorphism was significantly elevated in high-risk non-carrier women (16/205; 7.8%) than in BRCA1/2 carriers (2/209; 1.0%) and controls (5/192; 2.6%) (chi = 11.670; P < 0.001). Sequence analysis disclosed a silent polymorphism in Valine at codon 118: c.353 C- > T.The 471delAAAG mutation occurs rarely in Israeli prostate and breast/ovarian cancer patients. A silent polymorphism in the RNASEL gene occurs more prevalently in high-risk Ashkenazi breast/ovarian cancer patients without a BRCA1/2 mutation.

In silico chromosomal clustering of genes displaying altered expression patterns in ovarian cancer.

Ovarian cancer, the leading cause of death due to gynecological malignancy, is diagnosed in most cases at an advanced stage. Combined with the paucity of symptoms of early-stage disease, the need to develop novel effective markers for the detection of potentially curable, early-stage disease is self-evident. Comprehensive analyses of somatic gene expression patterns in ovarian cancer were reported previously (n=17) and yielded substantial information on somatically altered genes, information that can potentially be useful in developing early detection markers. To further substantiate the role that these genes play in ovarian cancer tumorogenesis, we surveyed these reports and arranged the significantly altered genes from all reported studies by their chromosomal location (in silico chromosomal clustering). Subsequent comparison of this clustering to known genomic somatic alterations at the DNA level from data obtained using comparative genomic hybridization (CGH) was carried out. The major chromosomal regions that displayed overexpressed genes were correlated with the major CGH-detectable DNA amplification areas at 20q (harboring HE4, SLPI, MYBL2, UBE2C, and SDC4) and 1q (harboring MUC1). These genes may provide insights into ovarian cancer pathogenesis and may also prove to be useful as early detection tools.

PEA3 is the second Ets family transcription factor involved in tumor progression in ovarian carcinoma.

PURPOSE: The purpose of this study was to analyze the possible correlation between PEA3 mRNA expression and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome. EXPERIMENTAL DESIGN: Sections from 61 primary ovarian carcinomas and metastatic lesions from 36 patients diagnosed with advanced-stage ovarian carcinoma [International Federation of Gynecologists and Obstetricians (FIGO) stages III-IV] were evaluated for expression of PEA3 using mRNA in situ hybridization. Patients were divided into long-term (n = 16) and short-term (n = 20) survivors. RESULTS: The mean values for disease-free survival and overall survival were 119 and 137 months for long-term survivors, as compared with 4 and 22 months for short-term survivors, respectively. Expression of PEA3 mRNA was detected in carcinoma cells and stromal cells in 56 of 61 lesions (92%) and 54 of 61 lesions (89%), respectively. Intense stromal expression was detected only in the vicinity of grade 2-3 tumors (P = 0.04). PEA3 expression in stromal cells showed a significant association with matrix metalloproteinase 2 mRNA expression in carcinoma cells (P = 0.022). PEA3 expression in carcinoma cells showed an association with mRNA expression of the beta(1) integrin subunit in the same compartment (P = 0.039). It was also associated with mRNA expression of beta(1) integrin subunit (P = 0.012), basic fibroblast growth factor (P = 0.036), and the matrix metalloproteinase inducer EMMPRIN (P = 0.038) in stromal cells. PEA3 mRNA was detected more often in both carcinoma and stromal cells in tumors of short-term survivors (P = 0.021 for stromal cells). In univariate survival analysis, PEA3 expression in stromal cells correlated with both shorter disease-free survival (P = 0.019) and overall survival (P = 0.029), whereas tumor cell expression predicted poor overall survival (P = 0.049). PEA3 mRNA expression in stromal cells emerged as an independent predictor of poor outcome in multivariate survival analysis, in which all molecules previously studied in this patient cohort were included (P = 0.015). CONCLUSIONS: To the best of our knowledge, this is the first evidence associating PEA3 mRNA expression and poor survival in human epithelial malignancy. PEA3 is thus a novel prognostic marker in advanced-stage ovarian carcinoma. The association between PEA3 mRNA expression and the expression of the beta(1) integrin subunit, basic fibroblast growth factor, and EMMPRIN, first documented in our patient cohort, points to the central role of this transcription factor in tumor progression in ovarian carcinoma.

Treating gynecologic malignancies in elderly patients.

AIM: To determine the relative benefits of full and partial treatment for gynecologic malignancies in elderly patients. METHODS: A retrospective cohort study of all consecutive patients (n=169) aged 79 and older (median age 82 y; range, 79 to 94 y), diagnosed between 1971 and 2007 with various types of gynecologic malignancies (endometrial, 52%; ovarian, 26%; vulvar, 11%; cervical, 5%; other, 6%) was conducted. Stages were I to II (47%), III to IV (35.5%), and unknown (17.5%). Major comorbidities were hypertension (51%), diabetes (17%), cardiac diseases (34%), and other malignancy (12%). Regardless of age or chronic illnesses, patients were grouped on the basis of having been treated optimally (100 patients; 59.2%), defined as the accepted standard for each diagnosis and stage including surgery and adjuvant radiation or chemotherapy as indicated; or suboptimally (69 patients; 40.8%), that is, no or only partial treatment. Kaplan-Meier survival analysis and Cox proportional hazard models, univariate and multivariable were conducted. RESULTS: For all patients with suboptimal treatment, the age-and-stage-adjusted hazard ratio for death was 1.76 (95% CI, 1.203-2.570; P=0.004) compared with optimal treatment. Age-adjusted hazard ratio was 2.15 (95% CI, 1.127-4.114; P=0.02) and 2.3 (95% CI, 1.415-3.779; P=0.001) for ovarian and endometrial cancer patients, respectively. Age-adjusted and stage-adjusted hazard ratio was 2.8 (95% CI, 1.099-5.157; P=0.028) and 1.53 (95% CI, 0.867-2.702; P=0.1420) for ovarian and endometrial cancer patients, respectively. CONCLUSIONS: Optimal treatment in patients with gynecologic malignancies evidently improves survival in elderly patients at any age, and in patients with ovarian cancer at any stage. Regardless of chronological age, the aim should be to deliver optimal treatment.

Safety of ovarian conservation and fertility preservation in advanced borderline ovarian tumors.

OBJECTIVE: To assess the impact of a fertility-sparing approach on disease recurrence in women with advanced borderline ovarian tumors. DESIGN: Historic cohort study. SETTING: A tertiary referral center for gynecological oncology patients and a university teaching hospital. PATIENT(S): Consecutive patients with advanced borderline ovarian tumors defined as stage IC and above, treated at a single institution during a span of 30 years. INTERVENTION(S): Data on surgical approach (e.g., fertility sparing, ovarian conserving) as well as histopathology, disease stage, CA-125 level, and use of chemotherapy were collected from the medical records, and their impact on disease recurrence was assessed. MAIN OUTCOME MEASURE(S): Recurrence-free interval. Its association with the type of surgery and with other clinical and pathological features was assessed using the Kaplan Meier and Cox proportional hazards methods. RESULT(S): Fifty-nine patients with advanced disease were identified. Median follow-up was 55.3 months. Mean age at diagnosis was 35 years. Most of the tumors (51, 84.4%) had serous histology. Twenty-seven patients (45.8%) developed recurrences and 6 (10%) died of their disease. Mean time to recurrence was 30.6 months. Of 44 women ≤40 years, 33 (75%) had a fertility-sparing procedure. Fertility preservation was not associated with disease recurrence. A total of 34 pregnancies and 26 live births were documented among 21 patients attempting conception. CONCLUSION(S): Borderline ovarian tumors carry a favorable prognosis, even at an advanced stage. Fertility preservation was not found to be associated with an increased risk of relapse in young patients with advanced disease, and may be reasonably considered.