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There were 12 intrauterine fetal death (IUFD) and 1 neonatal death (15.7%) in AFP against 3 (4.4%) in hCG Group, despite tertiary perinatal care. Mean gestational age at delivery was 34.5 weeks (range 21–41) for AFP and 37.7 weeks (range 22–42) for hCG Group. 6 (7.2%) in AFP and 3 (4.4%) in hCG Group developed severe preeclampsia. Multimodal screening predicted preterm delivery < 32 weeks with a likelihood ratio (LR+) of 6.932 in AFP against 0 in hCG group and IUFD with LR+ of 4.438 in AFP against 0 in hCG group. Conclusion: Predictive value of placental morphology and uterine artery Doppler was higher in the AFP group. Pregnancies with an elevated maternal serum AFP are more commonly associated with adverse perinatal outcomes than those with elevated hCG warranting increased maternal and fetal surveillance.

5060 Background: Cyclooxygenase-2 (COX-2) expression is associated with a poor chance of response to chemotherapy and poor prognosis in ovarian cancer (OC). Celecoxib, an orally active COX-2 inhibi...

790 Background: Aim of the study was to assess the efficacy and safety of the combination gemcitabine (GEM) and liposomal doxorubicin (PLD) in patients (pts) with measurable recurrence/metastasis f...

and this therapy was continued for eight weeks. The reduction of the volume as well as the weight of the xenografts was significantly shown by this combined therapy, in comparison to a group of the drug used alone, ultrasound irradioation alone, or in the controls. No major side effect was observed in any mice of the groups. The effect of anti-angiogenesis for this tumor was remarkably demonstrated on real-time by contrasted color ultrasound, non-invasively. The microvessel density of the tumors was significantly decreased in this combination therapy compared to other groups. These results suggest that there is an accelerated (boosting) effect of ultrasound for anti-angiogenesis drug therapy for human uterine sarcoma and this combination therapy might be a potential candidate for a new cancer treatment.

5078 Background: We conducted a phase II study in order to evaluate the efficacy and safety of the combination of OXA and DTX in recurrent platinum-sensitive ovarian cancer patients. Methods: Patie...

The gene dosage of cyclin D1 gene (CCND1) was examined in 51 primary laryngeal squamous cell carcinomas and amplification of the gene was found in 9 cases (17.6%). CCND1 amplification did not correlate with the clinico-pathological parameters. In a median follow-up period of 29 months the overall survival rate was 71.4% for patients affected with tumors displaying normal CCND1 dosage, and only 25% for patients with tumors carrying amplified CCND1. In multivariate analysis, only CCND1 and tumor size retained a statistically significant prognostic value ( P = 0.037, P = 0.041). This is the first report in which CCND1 amplification is identified as a significant independent prognostic factor in laryngeal squamous cell carcinoma.

Epidermal growth factor (EGF) seems to modulate the in vitro and in vivo growth of normal and neoplastic breast cells. We determined, by a radio-receptor assay, EGF levels in cyst fluid and in plasma of patients with gross cystic disease of the breast. The mean levels of EGF were lower in plasma than in breast cyst fluid (BCF) (p less than 0.001). In BCF of apocrine cysts we found higher EGF levels than in flattened cysts (p less than 0.001). The EGF content of apocrine BCF seems to be under sex steroid hormone control, being higher in reproductive age than in post menopause (p less than 0.05). Since it has been reported that patients with apocrine cysts are at a greater risk of developing breast cancer, we hypothesize that the high EGF concentration in apocrine BCF may play a role in the autocrine breast cyst epithelium growth control and neoplastic transformation.

In the last decades, the active research in the field of tumor angiogenesis has led to the development of a class of agents providing an effective inhibition of neo-vessel formation through the blockade of VEGF related pathways. More recently, the identification of other factors involved in tumor angiogenesis, such as platelet-derived growth factor, fibroblast growth factor and Angiopoietins has emphasized the need to develop agents targeting multiple pro-angiogenic pathways. Although contrasting data are currently available regarding the clinical efficacy of multikinase inhibitors, Sunitinib, Sorafenib and Pazopanib have displayed encouraging results, and have fuelled further evaluations. Moreover, definitive data are also eagerly awaited regarding the clinical role of angiopoietins inhibitors. On the other hand, the existence of morphological, functional and architectural differences between normal and tumor vasculature has provided solid basis for the development of a novel class of compounds, known as Vascular Disrupting Agents (VDAs) able to selectively disrupt existing tumor vessels. After initial concerns related to the potential development of severe cardiovascular toxicities, further clinical investigations have shown a safe toxicity profile for these agents. Moreover, despite the discouraging data on dolostatin-10 and ASA404, several VDAs, including CAP4, Ombrabulin and Pinabulin have already shown promising activity in phase I-II clinical trials warranting more advanced evaluations. In this review we aimed at summarizing the most relevant VEGF-independent strategies targeting tumor vasculature, focusing on the clinical development of novel antiangiogenic agents including multikinase and angiopoietins inhibitors as well as VDAs.

We investigated the effect of the flavonoid quercetin (Q) on the proliferation of the ovarian cancer cell line OVCA 433. Growth experiments demonstrated that Q exerted a reversible dose-dependent inhibition of cell proliferation in the range of concentrations between 10 nM and 10 microM. Two other flavonoids tested, rutin and hesperidin, were ineffective in inhibiting cell growth. Cell cycle analysis showed that the growth inhibitory effect of Q was due to a blocking effect in the GO/G1 phase. Using a whole cell assay with (6.7-3H) oestradiol (3H-E2) as tracer we demonstrated that OVCA 433 cells contain type II oestrogen binding sites (type II EBS). Competition analysis showed that Q competed for 3H-E2 binding to type II EBS while both rutin and hesperidin did not. Appreciable amounts of type II EBS were also detected in seven primary ovarian tumours. Our results suggest that Q may regulate ovarian cancer cell growth through a mechanism involving a binding interaction with type II EBS. This mechanism could also be active in vivo since primary ovarian tumours contain type II EBS.

Endometrial carcinosarcoma is a rare, aggressive disease, accounting for approximately 3% of all uterine neoplasms. The emergence of sarcomatous elements is considered the evolution of subclones arising from high grade endometrial carcinomas. Here, we report two cases of primary endometrial carcinomas recurring as carcinosarcoma. Case 1. a 58-year-old postmenopausal woman diagnosed to have a poorly differentiated endometrial endometrioid adenocarcinoma (FIGO stage IB) developed an intra-abdominal recurrence of disease after 17 months from diagnosis. Histopathological analysis documented a biphasic neoplasia consisting of an epithelial (grade 3 endometrial endometrioid adenocarcinoma) and a sarcomatous component. Salvage chemotherapy with cisplatin, ifosfamide, epirubicin, and then with taxotere was attempted. The patient died after 2 months. Case 2. A 56-year-old woman with a diagnosis of grade 3 endometrial adenosquamous carcinoma of the endometrium (FIGO stage IIIA) experienced pelvic recurrence after five months from completion of chemotherapy. Definitive histology was malignant mixed mesodermal tumor with focal areas of chondrosarcomatous elements. The patient was triaged to exclusive concomitant chemoradiotherapy and salvage chemotherapy. The patient died after 3 months. We describe two cases of high grade endometrial carcinomas recurring as carcinosarcoma, thus providing evidence that the metaplastic sarcomatous evolution is a very rare event which can occur in patients with anaplastic endometrial cancer.

Thirty-four ovarian and breast cancer patients received autologous peripheral blood progenitor cell transplantation after high-dose myeloablative chemotherapy and either granulocyte-colony-stimulating factor (G-CSF) or granulocyte/macrophage-colony-stimulating fictor (GM-CSF) in the immediate post-transplant period. The recovery of T cell functionality was monitored by a three-color flow-cytometric approach using carboxyfluorescein diacetate succinimidyl ester, a probe the fluorescence intensity of which halves at each round of cell replication, in conjunction with CD3 and CD25 monoclonal antibodies. There was no significant difference between the two treatments on days 12, 20, and 40, T cell proliferation always being considerably lower than that of control cultures from healthy donors. At day 80, a significantly higher proportion of mitogen-stimulated T cells from GM-CSF-treated patients expressed interleukin-2 receptor, and a higher proportion of these T cells were actively proliferating. This phenomenon did not reflect any difference in the relative proportion of various lymphocyte subsets (T cells, CD4 and CD8+ T cells, CD45RA+ and CD45RO- T cells, and natural killer cells). At the end of follow-up (1-1.5 years) T cell proliferation had returned to values typically observed in healthy individuals in both groups of patients. Soon after transplantation (day 12), neutrophils from G-CSF-treated patients had a more elevated Fcgamma receptor I density and monocytes from GM-CSF-treated patients had a more elevated Fcgamma receptor II and MHC class II molecules density. The up-modulation of Fcgamma receptor II was maintained until day 40. Thus, administering G-CSF and GM-CSF in the post-transplant period affects T lymphocyte proliferation and phagocyte membrane molecules differently.

Objective The purpose of this study was to evaluate the efficacy of a new contrast-dedicated ultrasound technology, contrast-tuned imaging (CnTI), implemented on an endovaginal probe and using the second-generation contrast agent SonoVue (Bracco International BV, Amsterdam, the Netherlands), compared with the standard ultrasound examination in different gynecologic diseases. Methods Eighty-nine patients were enrolled in the study in 4 different clinical centers. The study included 40 patients with uncertain pelvic adnexal masses, 10 patients with pelvic masses indicative of recurrences of gynecologic tumors, 26 patients with uterine pathologic features, and 13 patients with cervical lesions. Results Application of CnTI technology after the SonoVue injection gave a picture of the intralesional microvascularization dramatically different from that obtained during color Doppler examination. Of the 40 pelvic masses, 15 (37.5%) were considered benign and 25 (62.5%) were considered malignant at B-mode and color Doppler examinations. Contrast-enhanced sonography showed no intralesional contrast perfusion in 11 (73%) of 15 cases, and all these were benign at final diagnosis. Of the 4 (27%) cases that had perfusion, 2 were malignant. Conversely, of the 25 cases with positive findings at color Doppler examination and therefore expected to show the appearance of contrast tissue-filling morphologic characteristics, 13 (52%) were malignant at final diagnosis. For evaluation of uterine pathologic features, the CnTI-SonoVue technology did not appear to be superior to the B-mode and color Doppler examinations; however, for the evaluation of cervical cancer, CnTI-SonoVue technology revealed a better definition of the margins of the neoplastic lesions in 4 (40%) of 10 cases. Conclusions In the evaluation of uncertain pelvic masses, the CnTI technology led to an improvement in the ability of the practitioner to differentiate benign from malignant adnexal lesions.

Aims and background This prospective, phase II study aimed to test the efficacy of concurrent 5-fluorouracil, mitomycin C and radiation, with or without brachytherapy, on the clinical outcome of a series of recurrent endometrial cancer patients and to determine the prognostic impact of a subset of factors. Methods Thirty patients with locally recurrent, nonmetastatic endometrial cancer received external beam radiation (4-week split course: 23.4 + 23.4 Gy) plus two courses of concomitant chemotherapy (5-fluorouracil, 96-h continous infusion, days 1-4; 1 g/m2/day; mitomycin C, 10 mg/m2, bolus iv, day 1). Nineteen patients (63.3%) underwent endocavitary, low-dose brachytherapy boost (20-25 Gy); eight patients (26.7%) received external beam radiation boost (14-20 Gy). Results Eleven complete responses (36.7%), 11 partial responses (36.7%), 6 disease stabilizations (20.0%) and 2 progressions (6.6%) were observed. After a median follow-up of 27 months (range, 1-108), overall actuarial 3-year survival, progression-free survival and local progression-free survival were 46.8%, 35.2% and 41.2%, respectively. Two patients (6.7%) experienced hematological grade 3 toxicity. Two patients (6.7%) had grade 3 intestinal toxicity. Severe late toxicity was infrequent, only 3 patients showing severe vaginal stenosis (10.0%). A clinical score of 0 to 1 was assigned to each patient on the basis of the absence (score = 0) or presence (score = 1) of any of the following prognostic factors: time between surgery and recurrence shorter than 12 months, pelvic wall site of recurrence, positive lymph nodes, hemoglobin Conclusions Our data suggest that this combined modality therapy was relatively well tolerated and resulted in reasonable local control and survival. The scoring system proved to be helpful in identifying patients with the best chance of benefiting from the treatment.

Overexpression of cyclooxygenase-2 (COX-2), characterizes tumors with high potential for local invasion and lymph node involvement. We investigated the expression of COX-2 in primary tumors and metastatic regional lymph nodes (TDL) from untreated and chemotherapy treated cervical cancer, as well as vulvar cancer. Immunostaining of COX-2, expressed as values of COX-2 intensity density (COX-2 IDV) was performed on 57 metastatic TDL and 24 corresponding primary rumors from 14 cervical and 9 vulvar cancer patients admitted to the Department of Obstetrics and Gynecology, Catholic University of Rome. In 6 locally advanced cervical cancer tissue samples, from both primary tumor and TDL, were obtained after chemotherapy treatment. In untreated cervical cancer, COX-2 IDV in tumor cells from positive TDL were significantly lower (median 0.69, range 0.22-0.92) than those from primary tumors (median = 3.84, range 0.19-7.67) (p=0.011). In cervical cancer exposed to chemotherapy, COX-2 IDV in tumor cells from positive TDL were significantly lower (median = 2.06, range 1.48-6.52) than those from primary tumors (median = 6.4, range 4.5-13.7) (p=0.037). In vulvar cancer COX-2 IDV in tumor cells from positive TDL were lower (median = 0.39, range 0.02-6.09) than those from primary tumors (median = 2.49, range 0.71-8.10) (p=0.04). In conclusion, we showed that COX-2 expression is down-regulated in cervical and vulvar tumor cells invading the regional lymph nodes with respect to primary tumors, thus emphasizing the need for deeper insight into the tissue specific relation between tumor cells and node microenvironment.

We investigated the role of the EGF-EGFR system as a regulator of ovarian cancer cell growth. In five (OVCA 433, OV 166, OV 1225, OV RS 1000, JA1) of six ovarian cancer cell lines examined we showed the presence of a single high-affinity 125I-EGF binding site with Kd varying from 0.24 to 0.86 nM and a number of binding sites/cell from 9700 to 75 000. In OVCA 433, OV 166, and OV RS 1000 cells we demonstrated a low-affinity 125I-EGF binding site with Kd ranging from 1.10 to 2.12 nM. TR-170 cells lacked the EGF binding and were unresponsive to EGF in terms of cell proliferation while all EGFR+ cells except JA 1 exhibited a proliferative response to EGF. Moreover, the growth response of the four EGF-sensitive cell lines showed different patterns since at high EGF concentrations (100 ng ml−1) there was no longer a stimulatory effect in OV 1225, OV 166, and OV RS 1000 cells while the mitogenic activity was still present in OVCA 433 cells. Our results demonstrate that EGF plays a role in regulating ovarian cancer cell growth. However, the presence of EGFR is not a perfect indicator of the EGFR system functionality. The cell lines we have examined could be useful models to clarify the mechanism of EGF action and the role played by the EGF system in the onset and spread of ovarian tumors.

Aims To investigate the technical feasibility of utilizing the Active Breathing Coordinator for planning of postoperative three-dimensional conformal radiation therapy in patients with early stage breast cancer undergoing breast conservation therapy. Methods Patients with early stage breast cancer for whom adjuvant radiotherapy after breast-conserving surgery was planned were consecutively enrolled. Five sessions of simulation with the Active Breathing Coordinator were planned for each patient. Computed tomography for simulation was not acquired until a good level of compliance with the procedure was achieved by the patient. Patients who did not show a satisfactory level of compliance after the planned fifth session were defined as noncom-pliant. Two simulation computed tomography scans were acquired: the first without the Active Breathing Coordinator during free breathing, the second with the Active Breathing Coordinator. Forward intensity-modulated treatment plans were calculated. Mean lung dose (MLDipsilateral) and V30 (V30lung) for the ipsilateral lung and V30 for the heart (V30heart), were evaluated. Results Twenty consecutive patients were enrolled (6 with left-sided breast cancer and 14 with right-sided breast cancer). Eighteen of the patients completed the simulation computed tomography with the Active Breathing Coordinator after 1–5 sessions (median, 3). In 16 of the 18 patients, a reduction of V30lung was observed with the Active Breathing Coordinator. In 15 of the 18 patients, a reduction of MLDipsilateral was also observed. In 5 of the 6 patients with left-sided breast cancer, a reduction of V30heart was noted. Conclusions Routine application of the Active Breathing Coordinator in clinical practice is feasible, even though it requires an increased workload. Dosimetric results are encouraging in terms of a better sparing of the ipsilateral lung and the heart.

Aims and purpose This is a prospective, phase II study aimed to evaluate the effect of concurrent 5-fluorouracil, mitomycin C, and radiation with or without brachytherapy on the clinical outcome of a series of recurrent cervical cancer patients and to determine the prognostic impact of a subset of factors. Methods Thirty-three patients with locally recurrent, non-metastatic cervical cancer received external beam radiation (4-week split course: 23.4 + 23.4 Gy) plus two courses of concomitant chemotherapy (5-fluorouracil, 96-h continuous infusion, days 1–4, 1 g/m2/day; mitomycin C, 10 mg/m2, bolus iv, day 1). Twelve patients with vaginal recurrence (36.4%) underwent endocavitary low-dose rate brachytherapy boost (20–25 Gy); 11 patients with lateral pelvic recurrence (33.3%) received external beam radiation boost (14–20 Gy). Results Fourteen complete responses (42.4%), 7 partial responses (21.2%), 5 disease stabilizations (15.1%) and 7 progressions (21.2%) were obtained. After a median follow-up of 34 months (range, 6–127), overall actuarial 3-year survival, progression-free survival and local progression-free survival were 59.7%, 48.1% and 51.7%, respectively. Patients with vaginal recurrence of less than 4 cm and negative lymph nodes proved to respond best to the treatment. Two patients (6.1%) experienced hematologic grade 3 toxicity. One patient had grade 3 intestinal toxicity (3.0%). No patient had major skin or urological acute toxicity. Severe late toxicity was infrequent Three patients had prolonged leukopenia (9.0%). Four patients showed severe vaginal stenosis (12.1%). A clinical score of 0 to 1 was assigned to each patient on the basis of the absence (score = 0) or presence (score = 1) of any of the following prognostic factors: time between surgery and recurrence shorter than 12 months, pelvic wall site of recurrence, positive lymph nodes, hemoglobin 2, P = 0.06), local control of the disease (65% vs 20% after 3 years, P = 0.001,) and overall survival (75% vs 30% after 3 years, P = 0.032). Conclusions Our data suggest that this combined modality therapy was relatively well tolerated and resulted in reasonable local control and survival. The scoring system proved to be helpful to identify patients with the greatest chance of benefiting from the treatment Further studies are probably needed to salvage the other patients, whose prognosis remains severe.

Background The occurrence of skeletal muscle metastases is a very rare event. Only two cases of late skeletal muscle recurrence from cervical cancer have been documented until now. Case presentation A 38-year old patient, submitted to radical hysterectomy and pelvic lymphadenectomy for a squamous FIGO stage IB1 cervical carcinoma, presented after 76 months with a palpable, and painless swelling on the left hemithorax. MRI showed a nodule located in the context of the intercostal muscles. Pathology revealed the presence of metastasis of squamous cell carcinoma of similar morphology as the primary. On the basis of FDG-PET findings, which excluded other sites of disease, surgical excision of the lesion was performed. The patient was triaged to chemotherapy plus external radiotherapy. Conclusion A case of skeletal muscle recurrence from cervical cancer after a very long interval from primary diagnosis is reported. Muscular pain or weakness, or just a palpable mass in a patient with a history of cancer has always to raise the suspicion of muscle metastasis.

LBA5501 Background: Three-weekly (3w) CP is standard first-line chemotherapy for AOC pts. Weekly (w) P combined with 3w C prolonged PFS and OS in a JGOG phase III trial. MITO-7 is an academic randomized phase III study, comparing 3w vs. w CP. Methods: AOC chemonaive pts, stage IC-IV, age≤75, ECOG PS≤2, were randomized to 3wCP (C AUC6 + P 175mg/m², d1q21) for 6 cycles or to wCP (C AUC2 + P 60mg/m²) for 18 administrations. Coprimary endpoints were PFS and quality of life (QoL), measured by FACT-O and FACT/GOG-Ntx. With 80% power in detecting HR of 0.75, 2-sided α=0.05, 383 events were needed for PFS analysis. The arms were compared with a log-rank test and in a Cox model adjusted by stage, PS, residual disease, age and size of institution, following intention-to-treat. QoL was measured at baseline and weekly for 9 wks. Interaction between arm and QoL time was tested in a linear mixed model. Toxicity was coded by NCI-CTCAE v3.0. Results: 822 pts were enrolled by MITO, MANGO, and GINECO. Median age was 60; st...

LBA5508 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. No significant financial relationships to disclose.