International Journal of Gynecological Cancer

The objective of the study was to determine the impact of brachytherapy implant quality on outcome among cervical cancer patients treated on Radiation Therapy Oncology Group prospective trials 0116 and 0128. All enrolled patients received concurrent chemoradiation followed by brachytherapy. Individual brachytherapy parameters, including the symmetry of ovoids in relation to the tandem, displacement of ovoids in relation to the cervical os, tandem bisecting the ovoids, tandem in the midpelvis, and appropriateness of packing, were scored for each implant. Multivariate Cox proportional hazards models were constructed for each parameter for local recurrence (LR), regional recurrence, distant recurrence, disease-free survival (DFS), and overall survival. Records for 103 patients were analyzed. The median follow-up time was 24.5 months. Patients with unacceptable symmetry of ovoids to the tandem had a significantly higher risk of LR than patients in the acceptable group (hazard ratio [HR], 2.67; 95% confidence interval [CI], 1.11-6.45; P = 0.03). Patients with displacement of ovoids in relation to the cervical os had a significantly increased risk of LR (HR, 2.50; 95% CI, 1.05-5.93; P = 0.04) and a lower DFS rate (HR, 2.28; 95% CI, 1.18-4.41; P = 0.01). Inappropriate placement of packing resulted in a lower DFS rate (HR, 2.06; 95% CI, 1.08-3.92; P = 0.03). Assessment of the quality of a brachytherapy implant is imperative, as proper placement has an impact on patient DFS. If feasible, inappropriate placements should be corrected before treatment initiation. Brachytherapy applicators for cervical cancer should preferably be placed and assessed by experienced practitioners.

Radiation Therapy Oncology Group (RTOG) 0116 was designed to test the ability of amifostine (Ethyol; MedImmune LLC, Gaithersburg, MD), a cytoprotective agent, to reduce the acute toxicity of combined therapy with extended-field irradiation, brachytherapy, and cisplatin chemotherapy in patients with cervical cancer with para-aortic or high common iliac disease. This report presents the results of part 2. Radiation Therapy Oncology Group 0116 was a 2-part trial. Part 1 delivered extended-field irradiation, brachytherapy, and cisplatin; part 2 added amifostine and required 16 evaluable patients to assess an improved toxicity profile. Eligibility included evidence for high common iliac or para-aortic metastasis. Patients were treated for a total dose of 45 Gy in 25 fractions with intracavitary irradiation. Intensity-modulated radiation therapy was not allowed. The final point A dose was 85 Gy low-dose rate equivalent. High-dose rate techniques were allowed. The positive para-aortic and iliac nodes were to be boosted to 54 to 59.4 Gy. Amifostine at 500 mg was to be delivered with every fraction of radiotherapy. The study opened on August 1, 2001, and closed March 3, 2007, after accruing 45 patients, 18 for the second part with amifostine. This analysis reports the primary end point for the patients entered on part 2 of the study. Three patients were excluded, one was ineligible, and 2 withdrew. The median follow-up was 22.9 months (range, 6.5-45.4 months). The median dose of amifostine delivered was 5000 mg (range, 500-13,500 mg). Thirteen patients (87%) experienced an acute grade 3/4 toxicity (excluding grade 3 leukopenia). This compared to an 81% rate in part 1 of the trial. The estimated median survival was 34.8 months with a 20% late grade 3/4 toxicity rate. Amifostine, as delivered in this study, did not reduce acute toxicity in this patient population.

The Gynecological Cancer Intergroup (GCIG) has previously reached consensus regarding the criteria that should be used in clinical trial protocols to define progression-free survival after first-line therapy as well as the criteria to define response to treatment in recurrent disease using the serum marker CA 125 and has specified the situations where these criteria should be used. However, the publications did not include detailed definitions, nor were they written to accommodate the new version of Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) now available. Thus, we recommend that the definitions described later in detail are incorporated into clinical trial protocols to maintain consistency. The criteria for defining progression are now acceptable in clinical trials of recurrent disease as they have since been validated (Pujade-Lauraine, personal communication, 2010). The GCIG requests that data from all clinical trials using these definitions are made available to GCIG trial centers so that continual validation and improvement can be accomplished. These definitions were developed from analyzing patients receiving cytotoxic chemotherapy and have not yet been validated in patients receiving molecular targeting agents.

We studied the immunoexpression of p14ARF, MDM2, and p53, in addition to relationships between those protein expressions and estrogen receptor (ER)alpha in ovarian serous tumors including benign (n= 23), borderline (n= 41), and malignant (n= 94). The aberrant expressions of p14ARF, MDM2, and p53 were observed in 19.6% (31/158), 47.5% (75/158), and 39.9% (63/158) of cases, respectively. The expression of MDM2 was significantly higher in borderline tumors compared to benign (P= 0.04) and malignant (P < 0.01) tumors. p53 expression in borderline tumors was uncommon, and p14ARF expression loss was mainly observed in carcinomas. Altered expression of p14ARF, MDM2, and p53 shows significant relationship with stage. Overexpression of MDM2 (P= 0.01) and loss of p14ARF expression (P= 0.04) were significantly associated with ER expression. Our results suggest that alteration of p14ARF-MDM2-p53 pathway proteins may contribute significantly to the tumorigenesis of ovarian serous neoplasms, and ER is involved in cellular regulation of p14ARF-MDM2-p53 pathway in ovarian serous neoplasms.

The purpose of this study is to review FIGO stage IB2 cervical cancers in Korea for the past 10 years, and evaluate the most frequently employed and appropriate management strategy, and also assess the survival benefits of neoadjuvant chemotherapy (NAC). This is a retrospective chart review of 727 FIGO stage IB2 patients from 1995 to 2005. Six hundred ninety-two patients were enrolled, and all dates on which the patients died were double checked through the "National Registry of Death Statistics" of the Korea National Statistical Office. Management strategies were divided into five groups according to the primary treatment modality. The most frequently employed primary treatment modality for stage IB2 cervical cancer in Korea during the past 10 years was radical hysterectomy (RH). The next was NAC, followed by radiotherapy (RT) and/or extrafascial hysterectomy, concurrent chemoradiotherapy (CCRT) and/or extrafascial hysterectomy, in descending order. The surgery group showed the best results, with an 89% 5-year disease-free survival rate. However, there was no statistical difference between the surgery, NAC, and CCRT groups. For FIGO stage IB2 cervical cancer during the past 10 years in Korea, RH and adjuvant RT or CCRT was the most frequently employed treatment strategy. As a primary modality, RH, NAC, and CCRT showed similar survival rates. However, RH demonstrated the best survival rate among the above treatment strategies.

Preclinical data show that belinostat (Bel) is synergistic with carboplatin and paclitaxel in ovarian cancer. To further evaluate the clinical activity of belinostat, carboplatin, and paclitaxel (BelCaP), a phase 1b/2 study was performed, with an exploratory phase 2 expansion planned specifically for women with recurrent epithelial ovarian cancer (EOC). Thirty-five women were treated on the phase 2 expansion cohort. BelCap was given as follows: belinostat, 1000 mg/m² daily for 5 days with carboplatin, AUC 5; and paclitaxel, 175 mg/m² given on day 3 of a 21-day cycle. The primary end point was overall response rate (ORR), using a Simon 2 stage design. The median age was 60 years (range, 39-80 years), and patients had received a median of 3 prior regimens (range, 1-4). Fifty-four percent had received more than two prior platinum-based combinations, sixteen patients (46%) had primary platinum-resistant disease, whereas 19 patients (54%) recurred within 6 months of their most recent platinum treatment. The median number of cycles of BelCaP administered was 6 (range, 1-23). Three patients had a complete response, and 12 had a partial response, for an ORR of 43% (95% confidence interval, 26%-61%). When stratified by primary platinum status, the ORR was 44% among resistant patients and 63% among sensitive patients. The most common drug-related adverse events related to BelCaP were nausea (83%), fatigue (74%), vomiting (63%), alopecia (57%), and diarrhea (37%). With a median follow-up of 4 months (range, 0-23.3 months), 6-month progression-free survival is 48% (95% confidence interval, 31%-66%). Median overall survival was not reached during study follow-up. Belinostat, carboplatin, and paclitaxel combined was reasonably well tolerated and demonstrated clinical benefit in heavily-pretreated patients with EOC. The addition of belinostat to this platinum-based regimen represents a novel approach to EOC therapy and warrants further exploration.

To evaluate the efficacy and safety of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of patients with recurrent ovarian cancer after previous treatment with platinum and taxane agents. A total of 42 patients with recurrent ovarian cancer who had an evaluable lesion and provided informed consent for participation in the present study were analyzed. Irinotecan was administered intravenously at a dose of 60 mg/m on days 1 and 15. Etoposide was administered orally at a daily dose of 50 mg/body weight from days 1 to 21. A 28-day period comprised one cycle. The tumor response, adverse events, progression-free survival, and overall survival were examined. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors and the serum CA125 levels (Gynecologic Cancer Intergroup criteria). Adverse events were assessed according to the NCI-CTCAE (version 3.0). Partial response was observed in 21 patients, stable disease in 14 patients, and progressive disease in 7 patients. The response rate was 50.0%, and the clinical benefit (partial response + stable disease) rate was 83.3%. Hematological toxicities of at least grade 3 severity included leukopenia in 21 patients (50.0%), neutropenia in 22 patients (52.4%), thrombocytopenia in 1 patient (2.4%), anemia in 9 patients (21.4%), and febrile neutropenia in 3 patients (7.1%). Nonhematological toxicities of at least grade 3 severity included queasy feeling in 5 patients (11.9%), vomiting in 3 patients (7.1%), and diarrhea in 2 patients (4.8%). Acute myeloid leukemia occurred in one patient (2.4%). It is suggested that combination chemotherapy with irinotecan plus oral etoposide offers significant clinical benefit to patients with recurrent ovarian cancer previously treated with platinum and taxane agents.

Abdominal radical trachelectomy (ART) is a type C resection (uterine vessels ligated at origin from the hypogastric vessels). Questions arise as to whether fertility is maintained after ART, particularly when uterine vessels are sacrificed. We report an international series on ART to describe fertility and oncologic outcomes. Databases at 3 institutions were queried to identify patients planned for ART from 1999 to 2011. Clinical and demographic data were gathered. One hundred one patients underwent ART. Mean age was 31 years (range, 19-43 years). Histologic classifications were adenocarcinoma (n = 54), squamous cell carcinoma (n = 40), adenosquamous carcinoma (n = 6), and clear cell carcinoma (n = 1). Twenty patients (20%) required conversion to hysterectomy (10 margins and 10 nodes). Eight patients underwent completion hysterectomy owing to the following: positive margins on final pathology (n = 3), patient's choice (n = 4), or recurrence (n = 1). Postoperatively, 20 patients (20%) received adjuvant chemotherapy and/or radiation (4 final pathology margins and 16 nodes). Four patients (4%) had recurrence and lived 22 to 35 months after diagnosis. Of the 70 women who had neither hysterectomy nor adjuvant therapy, 38 (54%) attempted pregnancy and 28 (74%) achieved pregnancy. Thirty-one pregnancies resulted in 16 (52%) third trimester deliveries. Six patients are currently pregnant with outcomes pending. These data demonstrate that ART preserves fertility and maintains excellent oncologic outcomes. Most women (74%) attempting pregnancy after ART are able to achieve pregnancy and deliver in the third trimester (52%). Preservation of the uterine vasculature is not necessary for fertility; obstetrical outcomes are similar to those of the historical vaginal radical trachelectomy cohorts.

A number of diverse biologic parameters have been assessed prior to treatment in a series of patients with cervical carcinoma. Factors analyzed were HPV DNA presence, MHC class I expression, expression of the oncofetal antigen 5T4, the proportions of macrophages, lymphocytes and granulocytes in cell suspensions prepared from tumors, in vitro colony-forming efficiency (CFE) and a measure of intrinsic radiosensitivity, surviving fraction at 2 Gy. Several associations were found. First, HPV DNA-negative tumors contained a small, but significant, decreased number of tumor infiltrating macrophages compared with HPV DNA-positive tumors. Secondly, patients with HPV-positive tumors were significantly younger than those where no HPV was detected. Thirdly, loss of one or more specific alleles in MHC class I positive tumors resulted in higher numbers of tumor lymphocytes and CFEs. Finally, strong expression of the 5T4 antigen was related to a reduction in the proportion of macrophages in tumor cell suspensions. In addition, for stage I and II patients expression of the MHC class I molecule was associated with improved survival compared with patients with tumors where loss of expression was seen.

Concurrent presence of endometrial hyperplasia or cancer in patients with granulosa cell tumors (GCTs) is common, with reported incidences of 25.6% to 65.5%. Consequently, bilateral salpingo-oophorectomy and hysterectomy is usually recommended in patients with a GCT, but this remains debatable. Our aim was to evaluate the need for hysterectomy in patients with GCTs by studying the incidence of pathologically confirmed endometrial abnormalities at the time of diagnosis of GCT and during follow-up. All cases of GCT between 1991 and 2012 were evaluated for endometrial pathology using the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). A total of 1031 cases of GCT were identified at a mean ± SD age of 55 ± 17 years. The incidence of GCTs in the period 1991-2012 was 0.61 per 100,000 women per year. Concurrent endometrial cancer at the time of diagnosis of GCT was found in 58 patients (5.9%) and endometrial hyperplasia in 251 patients (25.5%), including complex hyperplasia in 89 patients (9.1%) and simple hyperplasia in 162 patients (16.5%). Long-term follow-up of 490 patients (47.5%) without a hysterectomy showed that endometrial abnormalities were found in 10 patients (2.0%) of which 2 had endometrial cancer. Interestingly, 8 (80%) of the 10 patients with endometrial abnormalities had recurrent GCT at the time of diagnosis of endometrial hyperplasia or cancer. Our data suggest that after surgical removal of GCT, development of an endometrial abnormality, especially cancer, is very rare. Therefore, hysterectomy is not recommended in patients with a GCT without endometrial abnormalities at the time of diagnosis.

Endometrial brush samples were taken from 1042 symptomatic hospital patients using Uterobrush(R), and the results were compared either to the histology of the endometrium obtained with dilatation and curettage (n = 313) or the patients' follow-up (n = 729). Only one cancer (100%) among patients </= 51 years of age (n = 677) was found by this method. Of the 12 cancers among patients> 51 years of age (n = 365), 11 (91.7%) were detected by Papanicolaou classes III-V. One cancer was missed, whereas no false positive results were found. The diagnostic accuracy in this group of patients varied from 92.3% to 97.8%, depending on the group (true positive vs true negative) to which the Papanicolaou class III was placed. We conclude that endometrial cytology obtained by brushing is useful for symptomatic patients of all age groups and gives an indication for further examination. If cytology is normal and bleeding continues in postmenopausal patients, curettage is indicated.

Carcinoma of the uterine cervix is the most common malignancy affecting women in developing countries like India. This retrospective study was made to analyze our results of radiotherapy alone in the treatment of carcinoma cervix. Between January 1996 and December 2001, 1069 patients of carcinoma cervix were treated at our center with external beam radiotherapy (EBRT) and intracavitary radiotherapy (871) or EBRT alone (198). The median dose to point A was 81 Gy. Overall survival (OS), disease-free survival (DFS), and pelvic control at 5 years were 51.8%, 49.4%, and 63.9%, respectively. For the patients who could receive intracavitary radiotherapy (871), the OS, DFS, and pelvic control rates were 60.7%, 58.6%, and 73.5%, respectively. On multivariate analysis, bulk, overall treatment time (OTT) and response to EBRT were found to affect OS and DFS independently. Similarly, OTT, response to EBRT, stage, and age were the factors that influenced pelvic control. Incidence of severe late toxicities (grade 3/4) in the rectum, bladder, small intestine, and skin were 1.1%, 1.2%, 0.2%, and 1.2%, respectively. In developing countries like India, where chemoradiation can be afforded by a minority only, judicious use of radiotherapy still produces satisfactory results with acceptable toxicity. The addition of chemotherapy may be beneficial in patients with adverse prognostic factors.

Advanced or recurrent endometrial cancer (EC) no longer amenable to surgery or radiotherapy is a life-threatening disease with limited therapeutic options left. Eighty percent of ECs express receptors for luteinizing hormone-releasing hormone (LHRH), which can be targeted by AEZS-108 (zoptarelin doxorubicin acetate). This phase 2 trial was performed to assess the efficacy and safety of AEZS-108 in this group of patients. Patients had FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) III or IV or recurrent EC, LHRH receptor-positive tumor status, and at least had 1 measurable lesion (Response Evaluation Criteria in Solid Tumors). Prior anthracycline therapy was not allowed. Patients received AEZS-108 as a 2-hour infusion on day 1 of a 21-day cycle. The treatment was continued for a maximum of 6 to 8 cycles. The primary end point was the response rate determined by the Response Evaluation Criteria in Solid Tumors. From April 2008 to November 2009, 44 patients were included in the study at 8 centers in Germany (AGO) and 3 centers in Bulgaria. Forty-three of these patients were eligible. Two (5%) patients had a complete remission, and 8 (18%) achieved a partial remission. Stable disease for at least 6 weeks was observed in 44%. The median time to progression was 7 months, and the median overall survival was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%). AEZS-108, an LHRH-agonist coupled to doxorubicin, has significant activity and low toxicity in women with advanced or recurrent LHRH receptor-positive EC, supporting the principle of receptor-mediated targeted chemotherapy.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Exfoliated cervical cells from 321 Japanese women were examined for human papillomavirus (HPV) DNA types 6, 11, 16, 18, 31, 33 and 35 using polymerase chain reaction (PCR) and dot-blot hybridization methods. HPV DNA was present in 9.3% of patients with normal cervixes, 72.7% of patients with cervical intraepithelial neoplasia (CIN) and 77.8% of patients with invasive carcinoma. Younger patients (</=29 years) with normal cervixes had a 18.5% incidence of HPV DNA, whilst similar older patients (>/=50 years) had a 1.9% incidence, a significant difference (chi2= 6.478, P < 0.01). In the CIN I and II groups, an incidence of 11.1% of types 16 and 18 was found, while in the CIN III or invasive carcinoma group the incidence was 58.1%, again a significant difference (chi2 = 12.075, P < 0.01). Furthermore, persistence or progression of CIN showed a significant correlation with infections by types 16 and 33 (chi2= 4.904, P < 0.01). However, no significantly different incidence of HPV infection was found between the CIN and the invasive carcinoma groups. It is suggested that (a) younger patients with normal cervixes have a higher incidence of HPV infection than do older patients; (b) HPV types 16, 18 and 33 are important etiologic agents of CIN III and invasive carcinoma, as well as in the persistence and progression of CIN; (c) progression of CIN to invasive carcinoma may depend on factors other than HPV infection in the cervix.

The anti-proliferative effects of interferon gamma (IFN-gamma) and CPT-11, a new derivative of camptothecin, both singly and in combination, on two human endometrial carcinoma cell lines, HHUA and ISHIKAWA, were examined in vitro. The HHUA cells were responsive dose-dependently to IFN-gamma, while the ISHIKAWA cells were unresponsive to IFN-gamma. Both cell lines were responsive dose-dependently to CPT-11. In both cell lines, IFN-gamma at clinically achievable concentrations (10 and 100 U ml-1 enhanced the anti-proliferative activity of CPT-11 in the range of concentrations where CPT-11 showed more than 10% cell growth inhibition. Sequential treatment with CPT-11 followed by incubation with IFN-gamma resulted in significant cell growth inhibition, but not vice versa. Flow cytometric studies indicated that the combined anti-proliferative effect did not correlate with cytokinetic alterations. Treatment with IFN-gamma did not change the extractable topoisomerase I activity of the HHUA and ISHIKAWA cells. The combination therapy of IFN-gamma and CPT-11 could provide a new approach against endometrial cancer.

Borderline ovarian tumors (BOTs) make up around 10-20% of all epithelial ovarian tumors. The aim of the present study was to investigate the outcome of a complete large population-based cohort of patients treated for BOT. All patients (n= 399) treated for BOT in the western part of Sweden (population around 1.6 million) between 1993 and 2004 were followed. The treatment consisted of primary staging surgery with addition of platinum-based adjuvant chemotherapy for the majority of aneuploid tumors. Data relating to the surgical procedure, FIGO stage, histopathology, ploidy status, adjuvant chemotherapy, and disease state (recurrence or death) at follow-up visits were continuously entered into a cancer quality registry. Data concerning cases and deaths were also controlled against the Swedish National Cancer Registry. The median age of the BOT patients was 55 years (range 16-90). The relative 5- and 10-year survivals were 99.9% (95% CI 96.3-102.4) and 103.5% (95% CI 97.2-108.2), respectively. Aneuploidy was found in 63 (17%) patients, with significantly more aneuploid tumors found among patients of older (>60 years) age. Out of the 399 patients, 8 had recurrence of the disease. Three of the eight patients died from the disease. Five patients with recurrence are alive, three of these patients with no signs of disease after additional treatment. This complete long-term follow-up of a large population-based cohort of BOT patients shows that there is a good overall survival in this patient group.

Data on epidemiology of HPV infection are needed for the development of human papillomavirus (HPV) vaccine recommendations, especially in countries where HPV vaccination is not yet included in public vaccination programs. The aim of this study was to determine the prevalence of serum antibodies to HPV types 6, 11, 16, and 18 and associated factors among young women after birth of the first child. This cross-sectional study was carried out in a large public maternity hospital in Sao Paulo, Brazil. Three hundred one women aged 15 to 24 years who gave birth to their first child were recruited between 43 and 60 days after delivery. Seroprevalence was performed using a type-specific enzyme-linked immunosorbent assay based on HPV Late protein 1 viruslike particles. The association of seroreactivity with these 4 HPV types with selected demographic and behavioral factors was assessed by Generalized Linear Model analysis. Fifty-eight (19.3%) women (95% confidence interval, 15.0%-24.2%) had antibodies to any of the 4 viruslike particles tested. The overall seroprevalence rates of the HPV types were: HPV16, 9.0%; HPV18, 7.0%; and HPV 6+11, 7.7%, which are targeted by the HPV prophylactic vaccines. In the multivariate analysis, only age (inversely, P = 0.044 for trend) and previous sexually transmitted disease (P = 0.008) were 2 factors independently associated with HPV seropositivity. These data offer additional information on the epidemiology of HPV in a group of young Brazilian women after first delivery and contribute to establish a baseline of HPV seroprevalence against which post-HPV vaccine era seroprevalence can be compared.

Eleven patients with uterine adenosarcoma diagnosed between 1970 and 1995 were evaluated according to DNA ploidy, S-phase fraction, p53 and mdm-2 expression, and traditional clinical and pathological prognostic factors, such as tumor stage, grade and mitotic index. DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors. The patients ranged in age from 41 to 90 years (median, 76 years). Only one patient was premenopausal at the time of diagnosis and five (45%) were nulliparous. One patient had received previous pelvic irradiation for anal squamous carcinoma. Six of the tumors (55%) were pure adenosarcoma and five (45%) were adenosarcoma with sarcomatous overgrowth. Nine patients had a stage I tumor and two had a stage II tumor. Among the six adenosarcomas we found three DNA diploid tumors, two DNA aneuploid tumors, and one DNA multiploid tumor. All adenosarcomas had an S-phase fraction less than 10%, except one that was not assessable. None was p53 positive and only one overexpressed mdm-2. All five adenosarcomas with sarcomatous overgrowth were DNA aneuploid, three (60%) had an S-phase fraction > 10%, two (40%) were p53 positive, and one (20%) overexpressed mdm-2. Five of the eleven patients suffered recurrences, and three (60%) of these developed lung metastases. During the observation period four (36%) patients (2 adenosarcomas and 2 adenosarcoma with sarcomatous overgrowth) died of disease, three patients died of intercurrent disease without recurrence, and the remaining four are alive with no evidence of disease. The overall five-year survival rate for all stages was 69%; for patients with AS it was 80%, while for those with adenosarcoma with sarcomatous overgrowth it was 50%. There were no variables which correlated with survival. In conclusion, we found hat the typical adenosarcoma had a tendency to be of low stage, have a lower mitotic rate and an S-phase fraction <10%. On the other hand, adenosarcomas with sarcomatous overgrowth were of high grade, had a high mitotic rate, and were DNA aneuploid with an S-phase fraction >10%. None of the variables studied correlated with survival. Tumors that were p53-positive or overexpressed mdm-2 did not behave worse than their negative counterpart. All patients who recurred with distant metastases died of disease.

The Helene Harris Memorial Trust organizes biennial international meetings of leading clinicians and scientists to discuss progress in the understanding and treatment of ovarian cancer. The conclusions of this meeting, together with recommendations for future research are published as a guide to others working in this field. The 107 conclusions and recommendations presented cover the full range of current topics in ovarian cancer research including the biology of early and borderline tumors, the relationship of benign to malignant tumors, in vitro models, the role of cytokines, genetic epidemiology, oncogenes and tumor suppressor genes, allele loss, localization of the BRCA1 gene, DNA ploidy in prognosis, the therapeutic use of interferon, platinum and taxoid drugs, screening with panels of tumor antigensm immunotherapy and potenial for gene therapy.

We report the clinical profiles and immunohistochemical features of small-cell carcinoma of the uterine cervix. Eleven cases that we have encountered at the Department of Gynecology, Kitasato University Hospital, between 1971 and 2003 are presented. Of 1370 invasive carcinomas of the uterine cervix, the incidence of small-cell carcinoma was 0.8%. Patient ages ranged between 32 and 65 years, with a mean age of 46.3 years. The clinical stages at diagnosis were Ib in four patients, IIb in three, IIIb in three, and IVb in one. All patients presented with abnormal vaginal bleeding. Two patients who are alive with no evidence of disease for 12 years and 3 years 6 months, while eight patients died of primary carcinoma between 4 and 25 months after treatment. Histopathologic findings showed solid nests with marked peripheral palisading pattern and rosette formation. Small tumor cells with scant cytoplasm demonstrated a very high nuclear/cytoplasm ratio and indistinct cell borders. The nuclei were round to oval and demonstrated increased but fine granular chromatin. Nucleoli were indistinct in all cases. Immunohistochemical findings were positive in 81.8% each for neuron-specific enolase and protein gene product 9.5, 72.7% for synaptophysin, 63.6% for chromogranin A, and 54.5% for neural cell adhesion molecule. All specimens were positive for at least one of the above. In conclusion, small-cell carcinoma of the uterine cervix revealed poor prognosis. Making an accurate diagnosis of small-cell carcinoma before performing treatment is of great significance but often difficult. Immunohistochemical analysis using several kinds of neuroendocrine markers is helpful in establishing the correct diagnosis in addition to focusing on characteristic histo- and cytopathologic features.

The outcome of screening and prophylactic surgery in 269 women at high risk of hereditary ovarian cancer is reported. Screening was performed using transvaginal ultrasound and serum CA125 testing. Mean follow-up was 26 months (583 person-years). A total of 113 (42%) of 269 women had a pathogenic BRCA1 or BRCA2 mutation, and 127 (47%) of 269 women underwent salpingo-oophorectomy. No occult cancers were found. In eight women having both elevated CA125 levels and abnormal ultrasound findings, a malignancy was found. Four of these cancers (one borderline, one stage Ia, one stage IIIb, and one stage IIIc ovarian or peritoneal cancer) were detected at the first screening visit. One stage IIIb and one stage IIIc cancer were detected at the second screening visit after 12 months, and two interval stage IIIc and IV cancers were detected 8 and 10 months after the first screening visit. No peritoneal carcinoma was found among those 114 women who underwent bilateral salpingo-oophorectomy with normal or benign pathology results, after a mean follow-up of 16 months (152 person-years). We conclude that the efficacy of screening women at high risk of ovarian cancer seems poor because the majority of cancers were detected at an advanced stage.

The clinical significance of cadherins in gestational trophoblastic diseases (GTD) is not fully understood. In this study, the expression of E-cadherin and cadherin-11 in 12 normal placentas, 32 cases of hydatidiform mole (HM) including 15 complete HMs and 17 partial HMs, and five choriocarcinomas was investigated by immunohistochemistry and correlated with follow-up of HMs. Cases with available frozen blocks were further analyzed by western blot and semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). Methylation of E-cadherin was investigated by methylation-specific PCR in six normal first trimester placentas, 19 HMs and their associated deciduas. E-cadherin expression was localized to cytotrophoblast and intermediate trophoblast whereas cadherin-11 was expressed in syncytiotrophoblast, intermediate trophoblast, and decidua. Immunoreactivity of E-cadherin was reduced in choriocarcinoma and complete HM when compared with that in normal first trimester placenta (P < 0.01, P = 0.04). Hypermethylation of E-cadherin was demonstrated in three complete HMs with the lowest level of E-cadherin. Compared with normal first trimester placenta, immunoreactivity of cadherin-11 was higher in complete HM (P = 0.02), but lower in choriocarcinoma (P = 0.02). Such differential expression was confirmed by western blot and semiquantitative RT-PCR. No obvious association was observed between the development of persistent trophoblastic disease with the expression of E-cadherin and cadherin-11.

Human papillomavirus (HPV) is a major causative agent of anogenital warts and a necessary cause of cervical cancer. This report will serve to assess the safety and immunogenicity of quadrivalent (types 6, 11, 16, and 18) HPV L1 virus-like particle (VLP) vaccine in the Korean population. We performed a randomized, double-blind, placebo-controlled study in 176 volunteers aged 9-23 years. Using a 2:1 ratio for randomization, 117 women were assigned to quadrivalent HPV (20 mug type 6, 40 mug type 11, 40 mug type 16, and 20 mug type 18) vaccine and 59 women to placebo. Individuals received vaccine at day 1, month 2, and month 6 and provided blood samples for analysis at enrollment at month 7. Analyses were done as specified in the study protocol. Quadrivalent HPV vaccine was generally well tolerated, with no vaccine-related serious adverse experiences. Quadrivalent HPV vaccine induced seroconversion for each vaccine-related HPV type. At month 7, vaccine-induced type-specific antibody titer was high. In conclusion, administration of quadrivalent HPV VLP vaccine to Korean women aged 9-23 years was generally well tolerated and highly immunogenic.

The purpose of this study was to evaluate the prognostic impact of image cytometry DNA ploidy, MIB-1, and p53 in relation to clinicopathologic variables in 376 consecutive patients with endometrial carcinoma stages I-IV. Following primary treatment 358 patients were considered tumor-free. Relapses and tumor-specific deaths of these patients were noted. Image cytometry DNA ploidy (n = 340) and expression of MIB-1 (n = 318) and p53 (n = 323) were studied. In univariate analysis, stage (P < 0.001), histopathologic subtype (P < 0.001), degree of differentiation (P < 0.001), HRT (P = 0.034), DNA ploidy (P < 0.001), and p53 (P < 0.001) were significant predictors of relapse. Patient age showed that the estimated mean risk of relapse increases with nearly 64% per decade in life (P 0.003), and the MIB-1 expression with 21% per 10-unit increment (P 0.004). In multivariate analysis, degree of differentiation, MIB-1, and p53 lost their prognostic capability. However, after stage and histopathologic subtype, image cytometry DNA ploidy was the strongest predictor of outcome and was of value in predicting the risk for relapse. The combination of DNA ploidy, MIB-1, and p53 expression was an even stronger predictor of relapse-free survival than the individual prognostic factors.

Already published data were further analyzed regarding the association between the CHEK2*1100delC germ line mutation and estrogen receptor (ER) status in patients with breast cancer. The CHEK2*1100delC mutation was more prevalent among the patients with a positive ER status (4.2% versus 1.0%). An ER-negative status was beside CHEK2*1100delC mutation and independently associated with an earlier of age onset of breast cancer. There was a trend that an ER-negative status, beside the presence of a CHEK2*1100delC mutation, was associated with a worse disease-free survival. There might be an association between ER status and a CHEK2*1100delC mutation. More studies with larger number of patients are needed to further investigate the relation between CHEK2*1100delC and ER status.