Search

Purpose: Gene expression profile was analyzed in 68 stage I and 15 borderline ovarian cancers to determine if different clinical features of stage I ovarian cancer such as histotype, grade, and survival are related to differential gene expression.Experimental Design: Tumors were obtained directly at surgery and immediately frozen in liquid nitrogen until analysis. Glass arrays containing 16,000 genes were used in a dual-color assay labeling protocol.Results: Unsupervised analysis identified eight major patient partitions, one of which was statistically associated to overall survival, grading, and histotype and another with grading and histotype. Supervised analysis allowed detection of gene profiles clearly associated to histotype or to degree of differentiation. No difference was found between borderline and grade 1 tumors. As to recurrence, a subset of genes able to differentiate relapsers from nonrelapsers was identified. Among these, cyclin E and minichromosome maintenance protein 5 were found particularly relevant, as their expression was inversely correlated to progression-free survival (P = 0.00033 and 0.017, respectively).Conclusions: Specific molecular signatures define different histotypes and prognosis of stage I ovarian cancer. Mucinous and clear cells histotypes can be distinguished from the others regardless of tumor grade. Cyclin E and minichromosome maintenance protein 5, whose expression was found previously to be related to a bad prognosis of advanced ovarian cancer, appear to be potential prognostic markers in stage I ovarian cancer too, independent of other pathologic and clinical variables.

Supplementary Data from Analysis of Gene Expression in Early-Stage Ovarian Cancer

Background: The objective of this study is to evaluate the safety of fertility-sparing surgery (FSS) for early-stage epithelial ovarian cancer (EOC). Methods: A retrospective analysis was performed to identify patients treated for early-stage EOC and to compare the clinical outcomes of patients treated with FSS and radical surgery (RS). Results: A total of 1031 patients were treated at two Institutions, 242 with FSS (group A) and 789 with RS (group B). Median duration of follow-up was 11.9 years. At univariate analyses, FSS was associated with decreased risk of relapse (P=0.002) and of tumour-related death (P=0.001). Multivariate analysis did not confirm the independent positive role of FSS neither on relapse-free interval (RFI) nor on cancer-specific survival (CSS). Tumour grade was associated with shorter RFI (P

Sentinel lymph node (SLN) mapping is emerging as an effective method for surgical staging of different gynecologic malignancies. Near-infrared (NIR) technology using a fluorescent dye such as indocyanine green (ICG) represents an interesting and feasible method for SLN mapping even in traditional open surgeries by applying video telescope operating microscope (VITOM) system technology. We report our preliminary experience in 12 women who underwent surgical nodal staging for early-stage vulvar and uterine or cervical cancer. Surgical and pathological outcomes are described, and the VITOM II ICG system's intraoperative image quality, handling and docking, and teaching value are assessed. The general impression of the surgical staff was that the VITOM II system is easy to use, and that the image quality of the anatomic structures is impressive. Traditional open SLN mapping with ICG appears to be easy to perform and reproducible, providing a new tool in the management of patients with gynecologic malignancies. Moreover, we believe that this technology has great potential as an operative teaching and learning modality for trainers for open surgical cases. Additional studies involving the VITOM system with a large sample size of patients are needed to confirm these promising results.

Objective Neoadjuvant chemotherapy (NACT) is a valid treatment option for women with locally advanced cervical cancer (LACC). This study aims to evaluate the impact of sociodemographic factors, clinical factors, and NACT regimens on survival endpoints. The role of pathological response to NACT as a surrogate endpoint of survival was also assessed. Materials and Methods Retrospective analysis of consecutive sample data from women with LACC (stages Ib2-IVa) who underwent NACT followed by radical surgery was performed. Response was classified as optimal response (including complete response and optimal partial response), suboptimal partial response, stable disease, and progressive disease. Results Four hundred forty-six women who had undergone surgery from 1992 to 2011 were analyzed. The overall optimal response was 35.4%. At a median follow-up of 12.7 years, 165 women (37.0%) experienced recurrence or died. Increase in patient age at surgery, International Federation of Gynecology and Obstetrics stage III/IV versus stage Ib2, and lymph-node positivity versus negativity seemed to impact negatively on survival, whereas neoadjuvant platinum-Taxol–containing regimens (compared with platinum-based regimens) improved survival. Response to NACT could be considered a surrogate endpoint of survival. Conclusions Age, International Federation of Gynecology and Obstetrics stage III/IV, lymph-node involvement, and type of NACT administered have a significant impact on survival. Response to NACT is a good surrogate endpoint of survival in patients with LACC.

Objective This retrospective study aimed to compare the sentinel lymph node (SLN) mapping results of methylene blue (MB) and indocyanine green (ICG) in women with early-stage endometrial or cervical cancer. Methods From August 2011 to March 2015, all consecutive patients with stage I endometrial or cervical cancer who underwent SLN mapping with intracervical injection of MB or ICG using a 22-gauge spinal needle were included in the study. Radical or simple hysterectomy with bilateral pelvic and/or aortic lymphadenectomy was performed after SLN mapping. Results Overall, 81 women (64 women with endometrial cancer and 17 women with cervical cancer) underwent surgery, including SLN mapping. Sixty-five patients (80%) underwent minimally invasive surgery. The overall detection rate was 84% (34 of 38) and 100% (43 of 43) for MB and ICG, respectively (P = 0.041). Bilateral SLN detection was higher in the ICG group than in the MB group (88% vs 50; P = 0.002). Eleven patients (13.5%) were found to have positive nodes with at least 1 positive SLN. The sensitivity and negative predictive value of SLN were 100%. Conclusions Real-time florescence mapping with ICG shows better overall detection rate and bilateral mapping than MB alone. In our pilot study, the differences are statistically significant. The higher number of bilateral mapping of ICG may increase the quality of life and recovery of women by reducing the need for complete lymphadenectomy.

Aim To perform a subset analysis of patients with very platinum-sensitive recurrent ovarian cancer (ROC) enrolled in the phase III CALYPSO trial. Patients and methods The international non-inferiority trial enrolled women with ROC that relapsed >6 months following first- or second-line platinum- and paclitaxel-based therapies. Patients were randomised to CD [carboplatin–pegylated liposomal doxorubicin (PLD)] or CP (carboplatin–paclitaxel) and stratified by treatment-free interval (TFI). In this analysis, patients with a TFI > 24 months were analysed separately for progression free survival (PFS), the primary endpoint of CALYPSO, overall survival (OS) and safety. Results A total of 259 very platinum-sensitive patients were included ( n = 131, CD; n = 128, CP). Median PFS was 12.0 months for the CD arm and 12.3 months for CP [HR = 1.05 (95% CI, 0.79–1.40); P = 0.73 for superiority] and median OS was 40.2 months for CD and 43.9 for CP [HR = 1.18 (95% CI 0.85–1.63); P = 0.33 for superiority]. Overall response rates were 42% and 38%, respectively ( P = 0.46). Toxicities were more common with CP versus CD, including grade 3/4 neutropenia (40.8% versus 27.5%; P = 0.025), nausea (4.8% versus 3.1%; P = 0.47), allergic reaction (8% versus 3.1%; P = 0.082) sensory neuropathy (4.8% versus 2.3%; P = 0.27) and grade 2 alopecia (88% versus 9.2%; P P = 0.007) and mucositis (2.3% versus 0%; P = 0.089) were more common with CD. Grade 3/4 hand-foot syndrome occurred rarely with CD (3 patients versus 0 in CP arm; P = 0.089). Conclusion CP and CD were equally effective treatment regimens for patients with very platinum-sensitive ROC. The favourable risk–benefit profile suggests carboplatin–PLD as treatment of choice for these patients.

Circulating HPV DNA has been previously described in women with advanced stages of cervical cancer and has been suggested to be a prognostic marker of disease recurrences and metastases. Only a few studies have reported the presence of HPV DNA in bloodstream of patients with low grade or precancerous cervical lesions. This study aimed to define if HPV DNA could be detected in plasma samples of 120 women referred for a recent history of cervical dysplasia who presented with lesions ranging from High Squamous Intraepithelial Lesion (H-SIL) to regressed normal cytology. HPV DNA detection was carried out in both plasma and cervical samples using type-specific real-time quantitative PCR assays identifying oncogenic HPV 16, 18, 31, 33, 45, 51 and 52. Overall, 34.2% (41/120) of plasma samples were shown to be positive for HPV DNA detection; HPV 45 (46.3%), HPV-51 (29.6%), and HPV 16 (18.5%) were the most frequently identified genotypes. The rate of HPV detection in paired cervical and plasma samples increased with advancing disease stage, ranging from 15.4% in women with regressed lesions to 38.9% in women with HSIL; HPV 16 resulted the most common genotype identified in women found to be HPV DNA positive in both cervical and plasma samples. Moreover, HPV 16 showed the highest median viral load value in both cervical and plasma samples, with 48,313 copies/104 cells and 1,099 copies/ml, respectively. Results obtained in this study confirm that HPV DNA can be detected and quantified in plasma samples of women with asymptomatic cervical infection. Further knowledge on HPV dissemination through the blood stream of women with cervical lesions would be very important in better understanding the natural history of HPV infection as well as its potential role in other distant tumors.

Even if ovarian cancer patients are very responsive to a cisplatinum-based therapy, most will relapse with a resistant disease. New experimental animal models are needed to explore the mechanisms of resistance, to better tailor treatment and improve patient prognosis. To address these aims, seven patient-derived high-grade serous/endometrioid ovarian cancer xenografts were characterized for the antitumor response after one and two cycles of cisplatinum and classified as Very Responsive, Responsive, and Low Responsive to drug treatment. Xenografts re-growing after the first drug cycle were much less responsive to the second one. The expression of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) genes was investigated in cisplatinum-treated and not-treated tumors. We found that different EMT (TCF3, CAMK2N1, EGFR, and IGFBP4) and CSCs (SMO, DLL1, STAT3, and ITGA6) genes were expressed at higher levels in Low Responsive than in Responsive and Very Responsive xenografts. The expression of STAT3 was found to be associated with lower survival (HR = 13.7; p = 0.013) in the TCGA patient data set. MMP9, CD44, DLL4, FOXP1, MERTK, and PTPRC genes were found more expressed in tumors re-growing after cisplatinum treatment than in untreated tumors. We here describe a new in vivo ovarian carcinoma experimental setting that will be instrumental for specific trials of combination therapy to counteract cisplatinum resistance in order to improve the prognosis of ovarian patients.

The introduction of 18-FDG-PET/CT during preoperative evaluation of patients with epithelial ovarian cancer (EOC) has led to an increase of the detection of extra-abdominal metastases. However, the clinical impact of this upstage remains unclear.Patients with suspected advanced EOC underwent 18-FDG-PET/CT within two weeks prior to debulking surgery.Between 2006 and 2011 95 patients met the inclusion criteria. Based on the concordance or the discrepancy of clinical and PET/CT stage, patients were divided into 3 groups (A: clinical and PET III; B: clinical III and PET IV; C: clinical and PET IV). Twenty-five patients were upstaged from FIGO stage III to stage IV by PET/CT. The proportion of patients who achieved a residual tumor1cm in group B and C was similar, whereas it was significantly lower compared to group A. Similarly, complete response to adjuvant chemotherapy was achieved more frequently in patients in group A. PFS was similar in the three groups (17, 17 and 12 months in group A, B and C), as well as OS (51, 41 and 35 months).PET/CT is able to detect distant metastases in EOC patients. The presence of extra-abdominal disease probably indicates a more aggressive disease which also shows a lower response to standard chemotherapy. However, upstaged patients have a similar prognosis compared to stage III patients, probably because intra-abdominal disease is more likely to lead patients to death. This might also explain why residual tumor is the most important prognostic factor for advanced EOC patients.

Objectives: The purpose of this study was to assess the quality of care in patients who underwent sentinel lymph node (SLN) mapping for endometrial and cervical cancer staging, and evaluate the impact of different techniques on patient satisfaction, i.e. radiotracer Tc99m versus indocyanine green (ICG) or methylene blue injection. Method: Women with preoperative stage I endometrial cancer or stage I (1A2–1B1) cervical cancer who underwent surgical staging, including SLN mapping, were considered for this study. Patient satisfaction was assessed using the European Organisation for Research and Treatment of Cancer IN-PATSAT32 questionnaire. Women were classified into two groups according to the different nodal mapping techniques: intracervical preoperative injection of Tc99m nanocolloid + intraoperative blue dye (Group 1) versus intraoperative cervical injection of ICG or blue dye (Group 2). Differences in patient satisfaction scores between the groups were analyzed. Results: Of the 178 eligible women, 143 were included in the study (endometrial cancer n = 106, cervical cancer n = 37): 57 underwent SLN mapping with Tc99m and blue dye (Group 1), and 86 women were mapped intraoperatively with blue dye alone or ICG (Group 2). Analysis of IN-PATSAT32 questionnaire scores showed a higher patient satisfaction score for patients in Group 2 (p = 0.001), which was independent of the physician and surgical outcomes evaluated. The scores were statistically better for Group 2, and also in rating doctors (p = 0.0001), nurses (p = 0.006), and care and services organizations (p = 0.001). Conclusions: Cervical and endometrial cancer patients who underwent SLN mapping by ICG or blue dye perceived a better quality of care when compared with those patients who underwent the combined radiocolloid and blue dye technique.

Objective: Nodal status is one of the most important findings in patients with early-stage cervical cancer that requires post-surgical adjuvant therapies and influences prognosis of patients. The purpose of this study was to determine the diagnostic accuracy of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG-PET/CT) in the detection of nodal metastases. Methods: From 2004 to 2010 women with Ib1-IIa < 4 cm cervical cancer underwent 18F-FDG-PET/CT followed by radical hysterectomy and pelvic lymphadenectomy in our institution. 18F-FDG-PET/CT images were analyzed and histopathological findings served as the reference standard. Diagnostic performance of 18F-FDG-PET/CT in nodal disease detection was reported in terms of accuracy value. A sub analysis of women with tumor diameter < 2 cm (group 1) or 2-4 cm (group 2) was performed in order to verify the efficacy of 18F-FDG-PET/CT in each group. Results: One hundred fifty-nine women were enrolled. 65% had squamous histotype and 51% had grade 3 disease. Median number of nodes dissected was 29 (range 11-61). 28/159 women (18%) showed nodal metastases. Overall patient-based sensitivity, specificity, positive and negative predictive value of 18F-FDG-PET/CT for detection of nodal disease were 32.1%, 96.9%, 69.2%and 87.0% respectively. Among the 97 (61%) women included in group 1, 8 had nodal metastases (8.2%) and 2 was discovered through 18F-FDG-PET/CT (25%), while 20/62 women of the group 2 (32.3%) had nodal involvement, of which 7 (35%) was detected by 18F-FDG-PET/CT. Conclusions: This study showed that 18F-FDG-PET/CT had low sensitivity and had a minimal clinical impact in the pretreatment planning of stage Ib1-IIa < 4 cm cervical cancer. © 2011 Elsevier Inc. All rights reserved.

Background. High risk clinical stage I endometrial cancer (grade 2 and deep myometrial invasion, grade 3 and serous and clear-cell carcinoma) had 10-35% of nodal involvement. Surgical staging is considered reasonable in this setting of women, although unnecessary in 70-90%. The Purpose of this study was to determine prospectively the diagnostic accuracy of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography 18F-FDG PET/CT in the detection of nodal metastases in patients with high Fisk endometrial cancer. Methods. Eleven women with grade 2 and deep myometrial invasion and 26 with grade 3 endometrial cancer underwent 18F-FDG PET/CT, followed by total hysterectomy, bilateral salpingo-oophorectomy and systematic pelvic lymphadenectomy. Histopathological findings served as the reference standard. Diagnostic performance of 18F-FDG PET/CT in nodal disease detection was reported in terms of accuracy value both in a patient-based and a lesion site-based analysis. Results. Pelvic nodes metastases were found at histopathological analysis in 9 of the 37 patients (24.3%). Patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG PET/CT for detection of nodal disease were 77.8%, 100.0%, 100.0%, 93.1% and 94.4%, respectively. Nodal lesion site-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG PET/CT were 66.7%, 99.4%, 90.9%, 97.2% and 96.8%, respectively. Conclusion. This study shows that 18F-FDG PET/CT is an accurate method for the presurgical evaluation of pelvic nodes metastases. The high negative predictive value may be useful in selecting patients who only may benefit from lymphadenectomy, minimizing operative and surgical complications. (C) 2009 Elsevier Inc. All rights reserved.

A phase II clinical trial conducted to evaluate the efficacy and tolerability of topotecan and carboplatin as first-line therapy for women with advanced epithelial ovarian cancer was the objective of this study. Patients had histologically confirmed ovarian epithelial cancer with at least one measurable lesion. Patients received topotecan 1.5 mg/m2on days 1–3 and carboplatin at an area under the curve (AUC) of 5 on day 3 every 21 days for six cycles. All 42 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was six. Overall response rate was 71%, with 19 clinical complete responses (45%) and 11 clinical partial responses (26%). Median survival time was 47 months and 5-year survival was 42%. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 100% of patients. However, this toxicity was transient and easily manageable; no patients experienced febrile neutropenia. The combination of topotecan and carboplatin is active in advanced epithelial ovarian cancer. Delay of therapy by 1 week or topotecan dose reduction to 1.25 mg/m2is the first-choice option to reduce topotecan toxicity without affecting the efficacy. Moreover, a chemotherapy regimen using weekly topotecan, which is currently being tested, should be considered.

Background Clinical and pathological parameters of patients with epithelial ovarian cancer (EOC) do not thoroughly predict patients' outcome. Despite the good outcome of stage I EOC compared with that of stages III and IV, the risk assessment and treatments are almost the same. However, only 20% of stage I EOC cases relapse and die, meaning that only a proportion of patients need intensive treatment and closer follow-up. Thus, the identification of cell mechanisms that could improve outcome prediction and rationalize therapeutic options is an urgent need in the clinical practice. Patients and methods We have gathered together 203 patients with stage I EOC diagnosis, from whom snap-frozen tumor biopsies were available at the time of primary surgery before any treatment. Patients, with a median follow-up of 7 years, were stratified into a training set and a validation set. Results and conclusions Integrated analysis of miRNA and gene expression profiles allowed to identify a prognostic cell pathway, composed of 16 miRNAs and 10 genes, wiring the cell cycle, ‘Activins/Inhibins’ and ‘Hedgehog’ signaling pathways. Once validated by an independent technique, all the elements of the circuit resulted associated with overall survival (OS) and progression-free survival (PFS), in both univariate and multivariate models. For each patient, the circuit expressions have been translated into an activation state index (integrated signature classifier, ISC), used to stratify patients into classes of risk. This prediction reaches the 89.7% of sensitivity and 96.6% of specificity for the detection of PFS events. The prognostic value was then confirmed in the external independent validation set in which the PFS events are predicted with 75% sensitivity and 94.7% specificity. Moreover, the ISC shows higher classification performance than conventional clinical classifiers. Thus, the identified circuit enhances the understanding of the molecular mechanisms lagging behind stage I EOC and the ISC improves our capabilities to assess, at the time of diagnosis, the patient risk of relapse.

Persistent infection with oncogenic human papillomavirus (HPV) is a prerequisite for cervical disease development, yet data regarding the host immune response to infection at the genotype level are quite limited. We created pseudoviruses bearing the major (L1) and minor (L2) capsid proteins and L1 virus-like particles representing the reference sequence and a consensus of 34 European sequences of HPV51. Despite the formation of similarly sized particles, motifs in the reference L1 and L2 genes had a profound impact on the immunogenicity, antigenicity and infectivity of these antigens. The antibody status of women exhibiting low-grade disease was similar between HPV16 and the consensus HPV51, but both demonstrated discrepancies between binding and neutralizing antibody responses. These data support the use of pseudoviruses as the preferred target antigen in studies of natural HPV infection and the need to consider variation in both the L1 and L2 proteins for the appropriate presentation of antibody epitopes.

PURPOSE: To assess the activity, efficacy, and tolerability of single-agent paclitaxel and a platinum-containing regimen in previously treated patients with recurrent ovarian cancer. PATIENTS AND METHODS: Patients who achieved complete remission with platinum-based regimens and whose disease recurred after a progression-free interval of more than 12 months were included in the study. Every 21 days, patients received paclitaxel 175 mg/m2 intravenously (IV) over 3 hours or cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, and cisplatin 50 mg/m2 (CAP) IV. RESULTS: Between June 1992 and May 1995, 97 consecutive patients with assessable or measurable disease were randomized to paclitaxel (n = 50) or CAP (n = 47). The median number of cycles on each arm was six. Toxicities included grade 3/4 leukopenia (4% for paclitaxel v 34% for CAP), grade 3/4 neutropenia (13% v 36%), grade 1/2 myalgia (19% v 4%), allergic reactions (15% v 2%), and grade 2/3 nausea and vomiting (17% v 51%). Complete responses were achieved in 17% and 30% of patients receiving paclitaxel and CAP, respectively, and partial responses were achieved in 28% and 25%, respectively (P = .062). At a median follow-up time of 49 months, median progression-free intervals were 9 months for paclitaxel and 15.7 months for CAP (Cox analysis: hazards ratio [HR], 0.60; 95% confidence interval [CI], 0.37 to 0.97; P = .038); median overall survival times were 25.8 months for paclitaxel and 34.7 months for CAP (Cox analysis: HR, 0.58; 95% CI, 0.34 to 0.98; P = .043). CONCLUSION: Rechallenge with either single-agent paclitaxel or platinum-based chemotherapy is effective in this patient population. Preliminary results suggest that single-agent paclitaxel may not be as active as platinum-based chemotherapy in recurrent ovarian cancer. Larger randomized trials are needed.

Background Systematic aortic and pelvic lymphadenectomy (SAPL) is a milestone procedure in the treatment of early stage ovarian cancer. It defines staging and prognosis and helps in tailoring adjuvant chemotherapy. Only limited data are available about SAPL at second look surgery in patients with apparent early stage ovarian cancer who underwent inadequate surgical staging and adjuvant platinum based chemotherapy. Methods From January 1991 through January 2013, 66 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA–IIA epithelial ovarian carcinoma suboptimally surgically staged and treated with adjuvant chemotherapy, were referred to our center and underwent second look surgery including SAPL. Results Twenty-two women underwent bilateral and 44 unilateral SAPL. A total of 2168 nodes were removed and analyzed. The median number of lymph nodes dissected was 29 (range 14–73); in particular it was 29 (range 14–60) in case of unilateral and 37 (range 17–73) in case of bilateral SAPL. Only one woman had nodal metastasis (1.5%). After a median follow-up of 78months, 10 women (15.2%) relapsed and 5 (7.6%) died of progressive disease. The 5-year disease-free survival and overall survival are 91.7% and 96%. Conclusion The risk of nodal metastases in stage I–IIA unstaged ovarian cancer after adjuvant chemotherapy is negligible. Our study suggests that SAPL at second look is not indicated in this subset of women.

Objective To evaluate the efficacy of tunneled lotus petal flap in terms of anatomical and cosmetic results in patients who underwent vulvoperineal reconstruction for vulvar malignancy. Methods Between March 2010 and July 2011, 22 women underwent vulvoperineal reconstruction using tunneled lotus petal flap for primary or recurrent disease at San Gerardo Hospital, Monza. In 16 cases, lotus flaps were bilateral, whereas in 6 cases, they were monolateral. Results The median age was 72 years (range, 53–87 years). The mean operating time was 85 minutes. The mean length of follow-up was 10 months (range, 2–16 months). Postoperative complications occurred in 2 patients, including one case of partial flap necrosis and one case of donor site breakdown. Conclusions Tunneled lotus petal flap is safe, easy and fast to perform, has a low rate of complications, and good functional and cosmetic results. This technique represents an optimal solution for plastic reconstruction in case of primary or recurrent vulvar disease, or in case of introital stenosis after primary inadequate closure.

Objective Treatment of locally invasive cervical cancer diagnosed during pregnancy in women who desire to retain their pregnancy is a major challenge to physicians. Neoadjuvant chemotherapy followed by radical hysterectomy has been reported to be an attractive option to delay delivery until fetal viability has been reached. Methods Between 1994 and 2009 9 patients were treated at San Gerardo Hospital (Monza, Italy) for cervical cancer during pregnancy. Results FIGO stage was IB1 in four patients and IB2 in five. Tumor diameter ranged between 20 and 70mm. After neoadjuvant platinum-based chemotherapy partial response was achieved in 5 patients, while 4 had a stable disease. One patient received a second-line chemotherapy during pregnancy due to progressive disease, achieving a partial response. Median duration of therapy delay until cesarean section was 16weeks. Between 30 and 36weeks of gestation all patients underwent cesarean section. Piver II radical hysterectomy with pelvic lymphadenectomy was performed. Two children had mild perinatal morbidities and were discharged in good conditions after 14 and 40days. Three patients received adjuvant therapy for pathological risk factors. Four patients relapsed (44%) and two of them (23%) died because of tumor progression. Conclusion During pregnancy, the oncological outcome of cervical cancer patients is similar to non-pregnant ones. Chemotherapy does not seem to affect fetal health and development, even if longer follow-up is required. Therefore, neoadjuvant chemotherapy for the treatment of locally invasive cervical cancer during pregnancy seems to be a reasonable option for delay definitive treatment until fetal viability is obtained.

Objectives: Simple conization represents a plausible treatment scheme for managing stage IA1-2 tumors conservatively. However its curative potential has not been widely exploited as regards stage IB1 lesions. Recent studies suggest that, in selected circumstances, patients with stage IB1 disease undergoing radical hysterectomy could have been safely cured by simple hysterectomy and even by cervical conization. Methods: Patients with stage IB1 cervical cancer desiring conservative management underwent simple conization and pelvic lymphadenectomy in three Italian institutes. Results: Thirty-six women received the conservative treatment since 1995 to 2010. Median age was 31 (range 24-40) years and median tumor size was 11.7 mm (range 8-25 mm). Adenocarcinoma was present in 12 cases (33%) and grade 3 neoplasia in 5 (14%). Lymph-vascular space involvement was detected in five patients (14%). Eleven had already a child while two had experienced an early abortion and a fetal loss at second trimester. After a median follow-up of 66 months (range 6-168) only one pelvic lymphnodal relapse was observed. Twenty-one pregnancies occurred in 17 patients and 14 live babies have been born (two preterm at 27 and 32 weeks) while one is ongoing. Three first-trimester miscarriages, one second-trimester fetal loss, an ectopic pregnancy and a termination of pregnancy have been recorded. Five patients decided to undergo hysterectomy after 3-12 years after conservative therapy: in one residual microinvasive adenocarcinoma was found. Conclusions: Cervical conization represents a feasible conservative management of stage IB1 cervical cancer and shows a low risk of relapse, provided that patients are selected carefully. Conization would be suitable to treat stage IB lesions smaller than 15-20 mm. with pathologic negative lymphnodes. © 2011 Elsevier Inc. All rights reserved.

To describe and analyze observed hypersensitivity reactions (HSR) from the randomized, multicenter phase III CALYPSO trial that evaluated the efficacy and safety of the combination of carboplatin and pegylated liposomal doxorubicin (CD) compared with standard carboplatin-paclitaxel (CP) in patients with platinum-sensitive relapsed ovarian cancer (ROC).HSR documented within case report forms and SAE reports were specifically analyzed. Analyses were based on the population with allergy of any grade and for grade2 allergy.Overall 976 patients were recruited to this phase III trial, with toxicity data available for 466 and 502 on the CD and CP arms, respectively. There was a 15.5% HSR rate associated with CD (2.4% grade2) versus 33.1% with CP (8.8% grade2), p0.001. HSRs occurred more often during first cycle in the CD (46%) arm than in the CP arm (16%). Multivariate predictors of allergy were chemotherapy regimen and age; patients randomized to CD and patients ≥ 70 years old on CP had less allergy. Few patients (6%) stopped treatment due to allergy. Allergy rates were higher in patients who did not receive prior supportive treatment; however there was no relationship between allergy and the type of carboplatin product received, or response rate.Use of PLD with carboplatin instead of paclitaxel and older age were the only 2 factors predicting a low rate of HSRs in patients with ROC. CD has previously demonstrated superior progression-free survival and therapeutic index than CP. Taken together these data support the use of CD as a safe and effective therapeutic option for platinum-sensitive ROC.

Background The efficacy and tolerability of the regimen containing paclitaxel and cisplatin (TP) in the neo-adjuvant treatment of locally advanced squamous cell cervical cancer are unknown. The TIP regimen (TP plus ifosfamide) showed high efficacy but high toxicity and it is used as an internal control. Patients and methods In all, 154 patients were randomized to TP (paclitaxel 175 mg/m2 + cisplatin 75 mg/m2; n = 80) or TIP (TP + ifosfamide 5 g/m2; n = 74), three cycles, followed by radical surgery. Pathological response to chemotherapy was classified as optimal [no residual tumor (complete response) or residual disease with ≤3 mm stromal invasion (PR1)] or suboptimal response. Results Patient characteristics (TP/TIP): stage IB2 (56%/64%), IIA (18%/14%), IIB (20%/19%), III–IVA (5%/4%) and median age (42 years/45 years). The optimal response rate in the TP group was 25%, 95% confidence interval (CI) = 16% to 37% and 43%, 95% CI = 31% to 55% in the TIP group. Grades 3–4 leukopenia (6%/53%) and neutropenia (26%/76%) were significantly more frequent on TIP. Conclusion TP performance was below expectation since the lower 95% confidence limit of the optimal response rate failed to reach the prespecified minimum requirement of efficacy, i.e. 22%. The TIP regimen confirmed its activity but was associated with higher haematological toxicity than TP.

A cross-sectional study was carried out in a population of North Italy to determine the prevalence of eight oncogenic human papillomavirus (HPV) types most commonly found in cervical carcinoma and to study the relationship between HPV DNA loads and severity of disease. A total of 597 cervical samples obtained from patients with pathological findings (n = 472) and from women with normal cytology (n = 125) were analyzed by means of normalized Real-time PCR assays to quantify HPV-16, -18, -31, -45, and -33 group (including -33, -52, -58, -67); the normalization of oncogenic HPV viral load was carried out by quantitation of a single copy gene. The two most common oncogenic HPV types found were 16 and 31 (24.3% and 22.9% of pathological samples, respectively); multiple infections were demonstrated in 22% of pathological samples. Overall, the HPV total viral load was found to increase with increasing severity of associated lesions, although a stronger association was observed only for HPV-31 and HPV-16 (gamma = 0.49 and 0.41, respectively) as compared to HPV-18 and -33 group (gamma = 0.19 and 0.02, respectively). However, we found that high levels of HPV-31 or 33 group DNA could be prognostic of minor oncogenic risk for high-grade squamous intraepithelial lesions (H-SIL) (age adjusted odds ratio [AORs] = 1.57 and 1.26, respectively) than HPV-16 and HPV-18 (AORs = 30 and 8, respectively). The AORs also increased with HPV total viral load and reached a maximum of AORs = 15.7. Thus, HPV load is a type-dependent risk marker for the development of H-SIL.

AIM: To evaluate safety, feasibility and oncological outcome of total laparoscopic radical hysterectomy (TLRH) in patients with early invasive cervical cancer. METHODS: Data of patients with Ib1 cervical cancer who underwent TLRH were prospectively collected. Inclusion criteria were: good general condition, tumor size

Purpose: Gene expression profile was analyzed in 68 stage I and 15 borderline ovarian cancers to determine if different clinical features of stage I ovarian cancer such as histotype, grade, and survival are related to differential gene expression. Experimental Design: Tumors were obtained directly at surgery and immediately frozen in liquid nitrogen until analysis. Glass arrays containing 16,000 genes were used in a dual-color assay labeling protocol. Results: Unsupervised analysis identified eight major patient partitions, one of which was statistically associated to overall survival, grading, and histotype and another with grading and histotype. Supervised analysis allowed detection of gene profiles clearly associated to histotype or to degree of differentiation. No difference was found between borderline and grade 1 tumors. As to recurrence, a subset of genes able to differentiate relapsers from nonrelapsers was identified. Among these, cyclin E and minichromosome maintenance protein 5 were found particularly relevant, as their expression was inversely correlated to progression-free survival (P = 0.00033 and 0.017, respectively). Conclusions: Specific molecular signatures define different histotypes and prognosis of stage I ovarian cancer. Mucinous and clear cells histotypes can be distinguished from the others regardless of tumor grade. Cyclin E and minichromosome maintenance protein 5, whose expression was found previously to be related to a bad prognosis of advanced ovarian cancer, appear to be potential prognostic markers in stage I ovarian cancer too, independent of other pathologic and clinical variables.

Background: The role of systematic aortic and pelvic lymphadenectomy in patients with optimally debulked advanced ovarian cancer is unclear and has not been addressed by randomized studies. We conducted a randomized clinical trial to determine whether systematic aortic and pelvic lymphadenectomy improves progression-free and overall survival compared with resection of bulky nodes only. Methods: From January 1991 through May 2003, 427 eligible patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB-C and IV epithelial ovarian carcinoma were randomly assigned to undergo systematic pelvic and para-aortic lymphadenectomy (n = 216) or resection of bulky nodes only (n = 211). Progression-free survival and overall survival were analyzed using a log-rank statistic and a Cox multivariable regression analysis. All statistical tests were two-sided. Results: After a median follow-up of 68.4 months, 292 events (i.e., recurrences or deaths) were observed, and 202 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for first event was statistically significantly lower in the systematic lymphadenectomy arm (hazard ratio [HR] = .75, 95% confidence interval [CI] = 0.59 to 0.94; P = .01) than in the no-lymphadenectomy arm, corresponding to 5-year progression-free survival rates of 31.2 and 21.6% in the systematic lymphadenectomy and control arms, respectively (difference = 9.6%, 95% CI = 1.5% to 21.6%), and to median progression-free survival of 29.4 and 22.4 months, respectively (difference = 7 months, 95% CI = 1.0 to 14.4 months). The risk of death was similar in both arms (HR = 0.97, 95% CI = 0.74 to 1.29; P = .85), corresponding to 5-year overall survival rates of 48.5 and 47%, respectively (difference = 1.5%, 95% CI = -8.4% to 10.6%), and to median overall survival of 58.7 and 56.3 months, respectively (difference = 2.4 months, 95% CI = -11.8 to 21.0 months). Median operating time was longer, and the percentage of patients requiring blood transfusions was higher in the systematic lymphadenectomy arm than in the no-lymphadenectomy arm (300 versus 210 minutes, P

To analyze 15 consecutive cases of placental site trophoblastic tumor seen in a single reference institution for gestational trophoblastic disease, San Gerardo Hospital, Monza, Italy.Consecutive patients affected by placental site trophoblastic tumors were selected from our computerized database.There were 15 patients with placental site trophoblastic tumor, with a median age of 35 years. The antecedent pregnancy was a term one in 6 cases (40%), a miscarriage in 4 cases (27%), a termination in 2 cases (13%) and a molar abortion in 2 cases (13%). In 1 case the previous pregnancy was unrecognized. The median interval from the last pregnancy was 12 months, and the presenting symptom in 11 cases was vaginal bleeding, in 2 cases amenorrhea, in 1case a nephrotic syndrome and in 1 case, presenting with metastatic disease, hemoptysis. Six patients were treated using neoadjuvant chemotherapy with etoposide/methotrexate/actinomycin-etoposide/ vincristine (EMA-CO) followed in 5 of 6 (83%) cases by hysterectomy. One patient had only medical treatment with EMA-CO because of a strong desire for or childbearing and had a complete response; after 15 months she was free from disease. The last 9 patients underwent surgery as the first therapy. Among these patients 1 had presented with metastatic pulmonary disease and underwent chemotherapy, with complete disappearance of the pulmonary lesions. Two of these 9 patients had a relapse; the mirst patient had a pelvic and bladder relapse, and 14 months after multiple chemotherapy and surgery, she died. The second had a suburethral relapse 2 months after initial surgery; after chemotherapy and surgery she was well and free of disease.Our experience suggests that the role of chemotherapy may be reconsidered not only for metastatic disease but als of or uterine disease when choosing conservative management in young, fertile patients who desire childbearing. Chemotherapy may play an important role in avoiding relapse or early metastases even in patients who underwent hysterectomy as primary treatment.

Ifosfamide, a cyclophosphamide analogue, has demonstrated a wide spectrum of activity against numerous neoplasms in different oncologic areas, including paediatric, haematological, breast, lung and testicular cancers, soft tissue sarcomas and gynaecological cancer. In gynaecologic cancers in particular, evidence suggests activity in the treatment of epithelial ovarian cancer, cervical carcinoma, germ cell carcinoma of the ovary. Cervical cancer has long been considered a poorly chemosensitive tumour and for several years the role of chemotherapy in the treatment of this tumour was confined to persistent or recurrent disease after failure of surgery and/or radiotherapy. In the management of cervical cancer, chemotherapy has received increasing attention in the last two decades and is currently used in neoadjuvant regimens, as salvage treatment in patients with disseminated or recurrent disease, or as a radiosensitizer. Over the past 30 years, several agents have been tested but cisplatin and ifosfamide are the agents that have attracted the greater attention. Cisplatin represents the cornerstone of chemotherapy for cervical cancer. Ifosfamide has been studied as a single agent or in combination with other drugs in different studies. In this paper we reviewed the approach with systemic therapy and, in particular, the role of ifosfamide in advanced or recurrent, and less advanced cervical cancer.

5068 Background: The role of systematic pelvic and para-aortic lymphadenectomy at SLS in ovarian cancer patients has not been addressed by randomized clinical trials (RCTs). We conducted a RCT to determine whether LY improves progression-free (PFS) and overall survival (OS) compared with SA. Methods: From January 1991 through December 1999, 303 eligible patients (i.e. patients with FIGO stage I-IV epithelial ovarian carcinoma at up front surgery and in complete remission after primary debulking surgery and first line chemotherapy) were randomly assigned to undergo LY (N = 156) or SA (N = 147) at the end of SLS. Survival was analyzed using a Cox multivariable regression analysis. All statistical tests were two-sided. Results: Median operating time was longer and the percentage of patients requiring blood transfusions was higher in the LY arm than the SA (240 vs 135 min., P < .001, and 30% vs 10%, P < .001, respectively). In the LY arm and SA arm the median number of removed nodes and the percentages of patients with nodal involvement was statistically different (44 vs 8, P < .0001, and 24% vs 13%, P = 0.018, respectively). At a median follow-up of 59 months, 156 events (i.e., recurrences or deaths) were observed, and 98 patients had died. The 5-year progression-free and overall survival was 41% and 65% for LY, 49% and 61% for SA, respectively. The risk for first event (hazard ratio [HR] = 1.11, 95% CI = 0.81 to 1.53; P = .50) and death (HR = 0.79, 95% CI = 0.53 to 1.18; P = .24) after adjustment for residual tumor at first surgery was not significantly different between the two arms. Conclusions: Although LY at SLS seemed to improve overall survival, this survival gain (21% decrease in the hazard of death) was not statistically significant and therefore the routine use of LY at SLS for ovarian cancer is not supported by this RCT. No significant financial relationships to disclose.