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1.  Metronomic oral cyclophosphamide (MOC) in the salvage therapy of heavily treated recurrent ovarian cancer patients: a retrospective, multicenter study 
BMC Cancer  2014;14(1):947.
The aim of this multicenter, retrospective study was to evaluate the efficacy and safety of metronomic oral cyclophosphamide (MOC) in heavily treated, relapsed ovarian cancer (ROC) patients.
oral cyclophosphamide (Endoxan®, Baxter, Italy) was administered at the dose of 50 mg daily, continuously. Treatment-related toxicity and response to treatment were assessed by the NCI-CTC criteria, and RECIST criteria, respectively. Progression-free (PFS), and overall survival (OS) were also assessed.
54 patients were analyzed: 20 patients (37.0%) were considered primarily platinum refractory/resistant, while 34 patients (63.0%) were defined as platinum sensitive; 79.6% of patients had received ≥2 previous lines before starting MOC. The objective response rate (ORR) was 20.4%. Eleven patients (20.4%) experienced stable disease and 8 of them had a response duration ≥6 months. A total of 32 patients (59.2.%) progressed during treatment. Median PFS was 4 months, and the 12-month PFS rate was 19.6%; median OS was 13 months, and the 12-month OS rate was 51.5% . Patients responding to MOC showed a more favorable PFS (median = 17 months) compared to patients with stabilization (median = 6 months) or progression of disease (median = 3 months) (p value = 0.0001). Median OS of responding patients was 30 months compared to 11 months in cases achieving stabilization, or progression of disease (median = 8 months) (p value = 0.0001). Only 1 patient experienced grade 3 anemia. Non-hematological grade 3 toxicity was registered in 2 patients.
MOC could provide a valid alternative in terms of risk/benefit ratio in the palliative treatment of heavily treated ROC patients.
PMCID: PMC4301460  PMID: 25495785
Cyclophosphamide; Metronomic administration; Ovarian cancer; Salvage treatment
2.  Herpes Virus MicroRNA Expression and Significance in Serous Ovarian Cancer 
PLoS ONE  2014;9(12):e114750.
Serous ovarian cancer (SEOC) is the deadliest gynecologic malignancy. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate gene expression and protein translation. MiRNAs are also encoded by viruses with the intent of regulating their own genes and those of the infected cells. This is the first study assessing viral miRNAs in SEOC. MiRNAs sequencing data from 487 SEOC patients were downloaded from the TCGA website and analyzed through in-house sequencing pipeline. To cross-validate TCGA analysis, we measured the expression of miR-H25 by quantitative immunofluorescence in an additional cohort of 161 SEOC patients. Gene, miRNA expression, and cytotoxicity assay were performed on multiple ovarian cancer cell lines transfected with miR-H25 and miR-BART7. Outcome analysis was performed using multivariate Cox and Kaplan-Meier method. Viral miRNAs are more expressed in SEOC than in normal tissues. Moreover, Herpetic viral miRNAs (miR-BART7 from EBV and miR-H25 from HSV-2) are significant and predictive biomarkers of outcome in multivariate Cox analysis. MiR-BART7 correlates with resistance to first line chemotherapy and early death, whereas miR-H25 appears to impart a protective effect and long term survival. Integrated analysis of gene and viral miRNAs expression suggests that miR-BART7 induces directly cisplatin-resistance, while miR-H25 alters RNA processing and affects the expression of noxious human miRNAs such as miR-143. This is the first investigation linking viral miRNA expression to ovarian cancer outcome. Viral miRNAs can be useful to develop biomarkers for early diagnosis and as a potential therapeutic tool to reduce SEOC lethality.
PMCID: PMC4259392  PMID: 25485872
3.  Long-term efficacy and safety of human papillomavirus vaccination 
In this paper, we review the published evidence about the long-term efficacy of the available human papillomavirus (HPV) vaccines and their safety profile. Two prophylactic HPV vaccines – bivalent (bHPV) and quadrivalent (qHPV) – are now available, and vaccination programs are being widely implemented, primarily targeting adolescent girls. Efficacy has been widely demonstrated for both vaccines. Since the risk of HPV exposure potentially persists throughout a woman’s sexual life, vaccine duration of protection is critical to overall effectiveness. Interpreting the results of long-term efficacy studies for the two HPV vaccines can be puzzling, due to the heterogeneity of studies, different methods used in the assessment of immunogenicity, histopathological and virological end points, and statistical power issues. Moreover, an immunologic correlate of protection has not yet been established, and it is unknown whether higher antibody levels will really result in a longer duration of protection. Disease prevention remains the most important measure of long-term duration of vaccine efficacy. To date, the longest follow-up of an HPV vaccine has been 9.4 years for the bHPV vaccine. Long-term follow-up for qHPV vaccine goes up to 8 years. The vaccine continues to be immunogenic and well tolerated up to 9 years following vaccination. All randomized controlled clinical trials of the bHPV and the qHPV vaccines provide evidence of an excellent safety profile. The most common complaint reported is pain in the injection site, which is self-limiting and spontaneously resolved. The incidence of systemic adverse events (AEs), serious AEs, and discontinuations due to a serious AE reported in clinical studies are similar between the two vaccines and their control groups. In particular, no increased risk of autoimmune disease has been shown among HPV-vaccinated subjects in long-term observation studies. As these are crucial topics in HPV vaccination, it is important to establish systems for continued monitoring of vaccine immunogenicity, efficacy, and safety over time.
PMCID: PMC4262378  PMID: 25587221
HPV vaccines; effectiveness; adverse events
4.  Clinical utility of trabectedin for the treatment of ovarian cancer: current evidence 
OncoTargets and therapy  2014;7:1273-1284.
Among the pharmaceutical options available for treatment of ovarian cancer, attention has been increasingly focused on trabectedin (ET-743), a drug which displays a unique mechanism of action and has been shown to be active in several human malignancies. Currently, single agent trabectedin is approved for treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, and in association with pegylated liposomal doxorubicin for treatment of patients with relapsed partially platinum-sensitive ovarian cancer. This review aims at summarizing the available evidence about the clinical role of trabectedin in the management of patients with epithelial ovarian cancer. Novel perspectives coming from a better understanding of trabectedin mechanisms of action and definition of patients subgroups likely susceptible to benefit of trabectedin treatment are also presented.
PMCID: PMC4103925  PMID: 25050069
ET-743; ovarian cancer; clinical trials
5.  Gender Effect in Experimental Models of Human Medulloblastoma: Does the Estrogen Receptor β Signaling Play a Role? 
PLoS ONE  2014;9(7):e101623.
The male-to-female sex ratio for medulloblastoma (MB) is approximately 1.5∶1, female gender being also a favorable prognostic factor. This study aimed at evaluating the impact of gender on MB tumorigenesis.
In vitro activity of 17β-estradiol (E2), DPN [2,3-bis(4-hydroxyphenyl)-propionitrile, a selective estrogen receptor β (ERβ)-agonist], PPT [4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, a selective ERα-agonist] or DHT (5 alpha-dihydrotestosterone) was evaluated in three human MB cell lines. D283 Med cells were transplanted into athymic mice.
A significant expression of ERβ, with little or no ERα, and low AR (androgen receptor) was found in MB cell lines. The compounds tested did not affect cell proliferation. In vivo, we observed a significantly lower growth of D283 Med in nude female mice compared to males. At microscopic examination, tumors from females showed a shift towards differentiation, as evaluated by lower nestin, and higher NSE (neuron-specific enolase) and GFAP (glial fibrillary acidic protein) expression compared to males. Tumors from females also showed lower Ki67 and p53 expression. The wild-type ERβ protein (ERβ1) was lost in male tumors, while it was a permanent feature in females, and a strong negative correlation was found between Ki67 and ERβ1 expression. Conversely, tumor levels of ERβ2 and ERβ5 did not significantly differ between genders. Increased levels of cyclin-dependent kinase inhibitor p21 were observed in females, suggesting that estrogen may decrease tumor growth through blocking cell cycle progression. An inhibition of the insulin-like growth factor I (IGF-I) signaling was also evident in females.
We provides mechanistic evidence supporting the idea that ERβ1 signaling may have pro-differentiation and tumor suppressive function in medulloblastomas.
PMCID: PMC4084991  PMID: 25000562
6.  HGF/c-Met axis drives cancer aggressiveness in the neo-adjuvant setting of ovarian cancer 
Oncotarget  2014;5(13):4855-4867.
Ovarian cancer is the most lethal gynecologic malignancy. Recently, NACT (Neo Adjuvant Chemotherapy) has been tested as alternative approach for the management of ovarian cancer patients. A biological predictor helpful in selecting patients for NACT would be desirable. This study was aimed at identifying actionable mechanisms of resistance to NACT.
Expression of a panel of microRNAs was screened in a discovery set of 85 patients. Analysis of the potential targets was conducted in the same RNAs by calculating significant correlations between microRNAs and genes. Quantitative fluorescent immunohistochemistry was employed in a validation set of 109 patients.
MiR-193a-5p was significantly overexpressed in the NACT setting. Analysis of its potential targets demonstrated that this microRNA is also significantly correlated with HGF and MET genes. Analysis of protein expression in samples taken before and after NACT demonstrated that both HGF and c-Met are increased after NACT. Patients who relapse shortly after NACT exhibited the highest relative basal expression of both HGF and c-Met, while the opposite phenomenon was observed in the best responders.
Mir-193a-5p, HGF and c-Met expression may help select eligible patients for this modality of treatment. Moreover, inhibitors of this pathway may improve the efficacy of NACT.
PMCID: PMC4148105  PMID: 24952592
HGF; c-MET; Ovarian Cancer; Neo-Adjuvant Chemotherapy
7.  The first leg video endoscopic groin lymphadenectomy in vulvar cancer: A case report 
The current management of vulvar cancer depends on the extension of disease, and includes primary tumor resection with safety margin as well as inguinofemoral lymph node staging. We report the case of the first leg videoendoscopic inguinal lymphadenectomy performed in a woman with a squamous cell vulvar carcinoma.
A 74 years old female referred to our institution complaining of vulvar mass associated with bleeding and swelling from external genitals, vaginal burning sensation and dysuria for 5 months. A vulvar–vaginal examination under narcosis reported a right major labium lesion of 5 cm with an irregular and ulcerated surface, easily bleeding on palpation, involving anteriorly the clitoral region and with a histological finding of a poorly differentiated squamous cell invasive carcinoma of the vulva ulcerating the surface epithelium. We performed, after adequate informed consent, a radical vulvectomy with a standard right inguinofemoral lymphadenectomy and a contralateral simultaneous video endoscopic inguinal lymphadenectomy-Leg procedure.
Our minimally invasive VEIL-Leg approach, performed for the first time in literature in a woman with vulvar cancer, could reduce the presence of high risk factors represented by surgical incision and by procedure-related complications, including wound infection and breakdown, hematoma, cellulitis and hernia formation.
A multicenter prospective randomized study will be helpful to clarify how this procedure could replace the standard laparotomic approach to inguinal lymphadenectomy in the vulvar cancer treatment and staging.
PMCID: PMC4147650  PMID: 24973526
VEIL; Vulvar cancer; Video endoscopic inguinal lymphadenectomy; Vulvectomy
8.  Sexual and Reproductive Outcomes in Early Stage Cervical Cancer Patients after Excisional Cone as a Fertility-sparing Surgery: An Italian Experience 
The purpose of this study was to analyze the quality of life in terms of sexual and reproductive outcome in patients suffering from early stage cervical cancer, submitted to an excisional cone as fertility-sparing treatment.
A multicenter retrospective analysis about specific dimensions of physical, psychological, reproductive and sexual functions after a cold-knife conization plus pelvic laparoscopic lymphadenectomy was conducted at Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome-Italy and at Division of Gynecology, European Institute of Oncology, Milan-Italy. The aim of this study was twofold. It aimed to analyze the quality of life in patients submitted to minimally invasive surgery and to compare these data with radical trachelectomy.
Twenty-three patients with an average age of 30 years decided to participate in this study. After the treatment, all women (100%) had regular menstruation, 7 (30.4%) had increased not invalidating dysmenorrhea; 1 (4.4%) experienced a cervical stenosis; 6 among 10 patients that tried to conceive (60%) obtained one spontaneous pregnancy; 4 more (40%) underwent in vitro fertilization and embryo transfer and only 1 of them (25%) was successful. About sexual assessment, 1 patient (4.4%) had trouble in lubricating, 3 (13%) had anxiety about performance, 6 (26.1%) complained of dyspareunia which was resolved within 3 subsequent months. All patients (100%) obtained a complete psychological and physical recovery.
This study demonstrated preliminary encouraging data about sexual and reproductive outcome after excisional conization. A comparison with trachelectomy surely needs longer follow-ups, more cases and prospective analyses.
PMCID: PMC3955421  PMID: 24696793
Cervical cancer; Conservative approach; Excisional cone; Fertility-sparing surgery; Quality of life
9.  Insights into the Role of Helicobacter pylori Infection in Preeclampsia: From the Bench to the Bedside 
Preeclampsia (PE) is defined as a hypertensive and coagulative disorder affecting about 2–8% of all pregnancies and is one of the main causes of maternal and fetal morbidity and mortality. Despite the great amount of studies run in this field, little is known about the precise pathogenic mechanisms behind PE. While endothelial and trophoblast dysfunctions, exaggerated inflammatory response, and hypercoagulative state have been shown to play a key role in the occurrence of PE, the primary trigger is still unknown. One of the hypotheses is that some infectious agents may represent a trigger for PE onset. Consistently, higher seroprevalence of Helicobacter pylori (HP) infection, a Gram-negative bacterium with a specific tropism for human gastric mucosa, has been shown in women with PE. Even tighter association has been found between PE and infection with cytotoxin-associated gene-A (CagA)-positive strains of HP. Recent in vitro studies have shown that anti-CagA antibodies cross-react with human trophoblast cells and determine a functional impairment in terms of cell invasiveness, thus, providing the first pathogenic model of HP infection-mediated placental damage. Since in the early process of implantation and placental development, trophoblast invasion of maternal decidua is a crucial step, the proposed autoimmune mechanism induced by HP infection, negatively interfering with the fetal side of the early developing placenta, may represent a mechanism explaining the higher seropositivity for HP infection among PE women. However, the contribution of HP infection to the pathogenesis of PE or to the worsening of its clinical presentation need to be further investigated as well as the possible impact of pre-pregnancy screening and eradication of HP infection on the incidence of the syndrome.
PMCID: PMC4191300  PMID: 25346732
preeclampsia; Helicobacter pylori; infection; placenta; anti-CagA antibody
10.  Fetal Cholelithiasis: A Diagnostic Update and a Literature Review 
Fetal gallstones and cholelithiasis, detected by routine third trimester ultrasound, have been described in the literature with controversial clinical significance. We report a case of fetal cholelithiasis detected at 35 weeks gestation during a routine scan. The diagnosis was performed using an integrated 2-dimensional (2-D) and 3-dimensional (3-D) ultrasound approach in order to obtain a better definition of the fetal gallbladder and its content. A neonatal follow-up was achieved. The present study has a twofold purpose: firstly, to update the diagnostic approach using the innovative 3-D modalities and secondly, to review the management of this condition during fetal and postnatal life.
PMCID: PMC3825565  PMID: 24250237
fetal cholelithiasis; prenatal diagnosis; third trimester; ultrasound; management
11.  Antibodies Anti-Caga Cross-React with Trophoblast Cells: A Risk Factor for Pre-Eclampsia? 
Helicobacter  2012;17(6):426-434.
Previous studies reported an epidemiological association between CagA-positive H. pylori strains and pre-eclampsia. As antibodies anti-CagA cross-react with endothelial cells and trophoblast cells show an endothelial phenotypic profile, we hypothesized that anti-CagA antibodies may recognize antigens of cytotrophoblast cells, thus impairing their function.
Materials and Methods
Placenta samples were obtained from healthy women. Cytotrophoblast cells were cultured in a medium containing increasing concentration of polyclonal anti-CagA antibodies. Binding of anti-CagA antibodies to cytotrophoblast cells was evaluated by cell ELISA and immunofluorescence assay. Invasive potential of those cells was assessed by an invasion culture system and by measuring of MMP-2. Protein sequencing was performed on antigens precipitated by anti-CagA antibodies. Measurement of phosphorylated ERK expression and NF-kB DNA-binding activity in trophoblast cells incubated with anti-CagA or irrelevant antibodies was also performed.
Anti-CagA antibodies recognized β-actin of cytotrophoblast cells, showing a dose-dependent binding. Incubation of cytotrophoblast cells with increasing doses of anti-CagA antibodies significantly reduced their invasiveness and determined a significant decrease in phosphorylated ERK expression and a reduced NF-kB translocation activity.
This study shows that anti-CagA antibodies recognize β-actin of cytotrophoblast cells, reducing their invasiveness ability, possibly giving a biological explanation for the epidemiological association.
PMCID: PMC3739447  PMID: 23066738
CagA+; Helicobacter pylori; pregnancy
12.  Free Testosterone Drives Cancer Aggressiveness: Evidence from US Population Studies 
PLoS ONE  2013;8(4):e61955.
Cancer incidence and mortality are higher in males than in females, suggesting that some gender-related factors are behind such a difference. To analyze this phenomenon the most recent Surveillance, Epidemiology and End Results (SEER) database served to access cancer survival data for the US population. Patients with gender-specific cancer and with limited information were excluded and this fact limited the sample size to 1,194,490 patients. NHANES III provided the distribution of physiologic variables in US population (n = 29,314). Cox model and Kaplan-Meier method were used to test the impact of gender on survival across age, and to calculate the gender-specific hazard ratio of dying from cancer five years following diagnosis. The distribution of the hazard ratio across age was then compared with the distribution of 65 physiological variables assessed in NHANES III. Spearman and Kolmogorov-Smirnov test assessed the homology. Cancer survival was lower in males than in females in the age range 17 to 61 years. The risk of death from cancer in males was about 30% higher than that of females of the same age. This effect was present only in sarcomas and epithelial solid tumors with distant disease and the effect was more prominent in African-Americans than Caucasians. When compared to the variables assessed in the NHANES III study, the hazard ratio almost exactly matched the distribution of free testosterone in males; none of the other analyzed variables exhibited a similar homology. Our findings suggest that male sex hormones give rise to cancer aggressiveness in patients younger than 61 years.
PMCID: PMC3634830  PMID: 23637935
13.  Laparoendoscopic Single-Site Isobaric Hysterectomy in Endometrial Cancer 
This case highlights the feasibility of laparoendoscopic single-site surgery and isobaric hysterectomy for early clinical stage, low-risk endometrial cancer.
PMCID: PMC3771810  PMID: 23925037
14.  Extracranial radiosurgery with volumetric modulated arc therapy: Feasibility evaluation of a phase I trial 
Oncology Letters  2013;5(6):1889-1896.
The aim of this study was to report early clinical experience in stereotactic body radiosurgery (SBRS) delivered using volumetric intensity modulated arc therapy (VMAT) in patients with primary or metastatic tumors in various extra-cranial body sites. Each enrolled subject was included in a different phase I study arm, depending on the tumor site and the disease stage (lung, liver, bone, metastatic), and sequentially assigned to a particular dose level. Technical feasibility and dosimetric results were investigated. The acute toxicity, tumor response and early local control were also studied. In total, 25 lesions in 20 consecutive patients (male/female, 11/9; median age, 67 years; age range, 47–86 years) were treated. Of these 25 lesions, 4 were primary or metastatic lung tumors, 6 were liver metastases, 8 were bone metastases and 7 were nodal metastases. The dose-volume constraints for organs at risk (OARs) were observed in 19 patients using a single-arc technique. Only in one patient were two arcs required. The treatment was performed without interruption or any other technical issues. The prescribed dose ranged from 12–26 Gy to the planning target volume (PTV). Delivery time ranged from 4 min to 9 min and 13 sec (median, 6 min and 6 sec). No incidence of grade 2–4 acute toxicity was recorded. The overall response rate was 48% (95% confidence interval (CI), 24.2–70.2) based on computed tomography (CT)/magnetic resonance imaging (MRI) and 89% (95% CI, 58.6–98.7) based on the positron emission tomography (PET) scan. SBRS delivered by means of VMAT allowed the required target coverage to be achieved while remaining within the normal tissue dose-volume constraints in the 20 consecutive patients. VMAT-SBRS resulted in adequate technical feasibility; the maximum tolerable dose has not yet been reached in any study arm.
PMCID: PMC3700848  PMID: 23833662
extracranial radiosurgery; stereotactic body radiosurgery; volumetric modulated arc therapy; volumetric intensity modulated arc therapy; feasibility; phase I
15.  Expression of the Glioma-Associated Oncogene Homolog 1 (Gli1) in Advanced Serous Ovarian Cancer Is Associated with Unfavorable Overall Survival 
PLoS ONE  2013;8(3):e60145.
Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, glioblastoma, melanoma as well as pancreas, colorectal, and prostate carcinomas. Here we investigated the role of the transcription factor Gli1 in ovarian cancer. To this end, the expression profile of Gli1 was examined in normal ovaries, ovarian tumors, and ovarian cancer cell lines, and the in vitro effects of a specific Hh-pathway blocker, KAAD-cyclopamine, or a specific Gli1 inhibitor (GANT58) on cell proliferation and on Hh target gene expression were also assessed. Results obtained showed that epithelial cells in ovarian cancer tissue express significantly higher levels of nuclear Gli1 than in normal ovarian tissue, where the protein was almost undetectable. In addition, multivariate analysis showed that nuclear Gli1 was independently associated to poor survival in advanced serous ovarian cancer patients (HR = 2.2, 95%CI 1.0–5.1, p = 0.04). In vitro experiments demonstrated Gli1 expression in the three ovarian carcinoma cell lines tested, A2780, SKOV-3 and OVCAR-3. Remarkably, although KAAD-cyclopamine led to decreased cell proliferation, this treatment did not inhibit hedgehog target gene expression in any of the three ovarian cancer cell lines, suggesting that the inhibition of cell proliferation was a nonspecific or toxic effect. In line with these data, no differences on cell proliferation were observed when cell lines were treated with GANT58. Overall, our clinical data support the role of Gli1 as a prognostic marker in advanced serous ovarian cancer and as a possible therapeutic target in this disease. However, our in vitro findings draw attention to the need for selection of appropriate experimental models that accurately represent human tumor for testing future therapies involving Hh pathway inhibitors.
PMCID: PMC3610749  PMID: 23555905
16.  Long-term prospective longitudinal evaluation of emotional distress and quality of life in cervical cancer patients who remained disease-free 2-years from diagnosis 
BMC Cancer  2013;13:127.
A long-term prospective assessment of QoL in cervical cancer patients is still lacking. Here, we provide the first 2-years prospective, longitudinal study evaluating emotional distress and QoL in early stage (ECC) and locally advanced (LACC) cervical cancer patients who remained disease-free 2-years from diagnosis.
The questionnaires: Hospital Anxiety and Depression Scale (HADS), Global Health Status items of EORTC QLQ-C30 (GHS), and EORTC QLQ-CX24 (CX24) have been administered by a dedicated team of psycho-oncologists, administered at baseline, and after 3, 6, 12 and 24 months from surgery The Generalized Linear Model for repeated measure was used to analyze modifications of QoL measures over time.
In both groups, an early reduction of the percentage of patients with anxiety levels ≥11 was observed at the 3-month evaluation (ECC: 25.7% at baseline Vs 14.7% after 3 months, p value=0.001; LACC: 22.2% at baseline Vs 15.4% after 3 months, p value=0.001). Despite this favorable trend, after 2 years from diagnosis, 11.9% of ECC and 15.6% of LACC patients still showed an anxiety score ≥11. No significant changes over time were observed in term of Depression levels. Focusing on QoL issues, mean GHS and Sexual Activity scores showed an improvement over time in both groups compared to baseline (GHS: 5.7% difference for ECC, p value=0.001, and 11.0% in LACC, p value=0.001; SXA: 13.9% difference for ECC, p value=0.001; and 6.1% in LACC, p value=0.008). On the other hand, Body Image mean scores were significantly impaired by chemoradiation administration in LACC patients, without long-term recovery (7.5% difference, p value=0.001). Finally, in both groups, lymphedema (LY) and menopausal symptoms (MS) showed an early worsening which persisted 2-year after surgery (LY: 19.5% difference for ECC, p value=0.014, and 27.3% in LACC, p value=0.001; MS: 14.4% difference for ECC, p value=0.004, and 16.0% in LACC, p value=0.002).
Despite a significant improvement over time, elevated anxiety levels are still detectable at 24 months after surgery in approximately 10% of cervical cancer patients. Much more attention should be focused on surgical/medical approaches able to minimize the negative impact of lymphedema and menopausal symptoms on QoL.
PMCID: PMC3608958  PMID: 23506235
Quality of life; Emotional distress; Cervical cancer; Prospective study; Long-term evaluation
17.  MiR-200c and HuR in ovarian cancer 
BMC Cancer  2013;13:72.
MicroRNAs in solid malignancies can behave as predictors of either good or poor outcome. This is the case with members of the miR-200 family, which are the primary regulators of the epithelial to mesenchymal transition and have been reported to act as both oncogenes and tumor suppressors. This study assessed the role of miR-200c as regulator of class III β-tubulin (TUBB3), a factor associated with drug-resistance and poor prognosis in ovarian cancer.
Expression of miR-200c was assessed in a panel of ovarian cancer cell lines with inherent or acquired drug-resistance. Stable overexpression of miR-200c was obtained in A2780 and Hey cell lines. Crosslinking-coupled affinity purification method and ribonucleic-immunoprecipitation assay were used to characterise the complexes between miR-200c, HuR and 3′UTR region of TUBB3 mRNA. Nanofluidic technology and immunohistochemistry were used to analyze the expression of HuR, TUBB3 and miR-200c in 220 ovarian cancer patients.
In a panel of ovarian adenocarcinoma cell lines, we observed a direct correlation between miR-200c expression and chemoresistance. In A2780 cells miR-200c targeted TUBB3 3′UTR, while a positive correlation was observed between miR-200c and TUBB3 expression in most of the other cell lines. Through the analysis of 3′UTR-associated complexes, we found that the miR-200c can increase the association of the RNA binding protein HuR with TUBB3 mRNA, whereas HuR binding enhanced TUBB3 mRNA translation. Most importantly, in our analysis on 220 ovarian cancer patients we observed that overexpression of miR-200c correlated with poor or good outcome depending on the cellular localization of HuR.
This study suggests a model for the combined regulatory activity of miR-200c and HuR on TUBB3 expression in ovarian cancer. When HuR is nuclear, high expression of miR-200c inhibits TUBB3 expression and results in a good prognosis, whereas when HuR occurs in cytoplasm, the same miRNA enhances TUBB3 expression and produces a poor outcome. These findings reveal the usefulness of multidimensional analysis in the investigation of the prognostic role of miRNA expression.
PMCID: PMC3576328  PMID: 23394580
Ovarian cancer; miR-200c; Class III beta-tubulin; HuR; Predictive biomarkers
18.  Child Nutritional Status: A Representative Survey in a Metropolitan School 
Journal of Obesity  2013;2013:395671.
Objective. To assess the prevalence of obesity, overweight, and thinness among children in an Italian school. Methods. Five hundred ninety-five children (289 males and 306 females) were enrolled, aged between 6 and 19 years old, in Italian school in Rome. Body mass index (BMI) was calculated according to International Obesity Task Force (IOFT) cut-off points. By age criterion all participants have been classified in age classes. Results. A normal BMI was recorded in 73.6% of all cases. Obesity, overweight, and thinness prevalence was 5.9%, 9.6%, and 10.9%, respectively, without statistical differences in both genders, except the prevalence of overweight that resulted statistically significant (13.1% males versus 6.2% females, P < 0.05). Differences in the age groups have been found. About 23.4% of children between 7 to 11 years were defined obese and about 42.3% between 6 to 8 years thin grade 2, respectively. Conclusion. The study reports the low prevalence of overweight and obesity, in contrast to the unexpected thinness prevalence. The identification of specific age groups with abnormal nutritional status could be the first step to address future epidemiological investigations in order to plan strategic approach in selected age periods.
PMCID: PMC3568893  PMID: 23431424
19.  Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer - results from two randomised studies 
Endometrial cancer patients with high grade tumours, deep myometrial invasion, or advanced stage disease have a poor prognosis. Randomized studies have demonstrated prevention of loco-regional relapses with radiotherapy with no effect on overall survival. The possible additive effect of chemotherapy remains unclear. Two randomized clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival in high-risk endometrial cancer. The two studies were pooled.
Patients (n=540; 534 evaluable) with operated endometrial cancer FIGO stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.
In the NSGO/EORTC study, combined modality treatment was associated with a 36 % reduction in the risk for relapse or death (HR 0.64, 95 % CI 0.41-0.99; P=0.04); two-sided tests were used. The result from the MaNGO-study pointed in the same direction (HR 0.61), but was not significant. In combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in overall survival. In combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P = 0.07) and cancer-specific survival was significant (HR 0.55, CI 0.35-0.88; p=0.01).
Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and high risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.
PMCID: PMC3552301  PMID: 20619634
adjuvant therapy; chemotherapy; radiotherapy; chemoradiotherapy; endometrial cancer; randomised clinical trial
20.  Total Microlaparoscopic Radical Hysterectomy in Early Cervical Cancer 
This report suggests that microlaparoscopy has a role in the management of early cervical cancer with results comparable with standard laparoscopy.
Background and Objective:
In less than 2 decades, laparoscopy has contributed to modification in the management of early cervical cancer patients, and all comparisons between open and laparoscopic-based radical operations showed an identical oncological outcome. The aim of this study is to describe surgical instrumentations and technique to perform total microlaparoscopy radical hysterectomy in early cervical cancer patients and report our preliminary results in terms of operative time and perioperative outcomes.
Between January 1, 2012, and March 25, 2012, 4 consecutive early cervical cancer patients were enrolled in this study.
We performed 3 type B2 and 1 type C1-B2 total microlaparoscopy radical hysterectomy, and in all cases concomitant bilateral salpingo-oophorectomy and pelvic lymphadenectomy were carried out. Median operative time was 165 minutes (range: 155 to 215) (mean: 186), and median estimated blood loss was 30 mL (range: 20 to 50). Median number of pelvic lymph nodes removed was 12 (range: 11 to 15). All procedures were completed without 5-mm port insertion and without conversion. No intraoperative or early postoperative complications were reported.
This report suggests a role of microlaparoscopy in the surgical management of early cervical cancer with adequate oncological results, superimposable operative time, and perioperative outcomes with respect to standard laparoscopy.
PMCID: PMC3662727  PMID: 23743381
Microlaparoscopy; Radical hysterectomy; Cervical cancer
21.  Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma 
Multiple myeloma (MM) is a plasma cell malignancy with a multifaceted immune dysfunction. Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan into kynurenine (KYN), which inhibits effector T cells and promote regulatory T-cell (Treg) differentiation. It is presently unknown whether MM cells express IDO1 and whether IDO1 activity correlates with immune system impairment.
We investigated IDO1 expression in 25 consecutive patients with symptomatic MM and in 7 patients with either monoclonal gammopathy of unknown significance (MGUS; n=3) or smoldering MM (SMM; n=4). IDO1-driven tryptophan breakdown was correlated with the release of hepatocyte growth factor (HGF) and with the frequency of Treg cells and NY-ESO-1-specific CD8+ T cells.
KYN was increased in 75% of patients with symptomatic MM and correlated with the expansion of CD4+CD25+FoxP3+ Treg cells and the contraction of NY-ESO-1-specific CD8+ T cells. In vitro, primary MM cells promoted the differentiation of allogeneic CD4+ T cells into bona fide CD4+CD25hiFoxP3hi Treg cells and suppressed IFN-γ/IL-2 secretion, while preserving IL-4 and IL-10 production. Both Treg expansion and inhibition of Th1 differentiation by MM cells were reverted, at least in part, by d,l-1-methyl-tryptophan, a chemical inhibitor of IDO. Notably, HGF levels were higher within the BM microenvironment of patients with IDO+ myeloma disease compared with patients having IDO- MM. Mechanistically, the antagonism of MET receptor for HGF with SU11274, a MET inhibitor, prevented HGF-induced AKT phosphorylation in MM cells and translated into reduced IDO protein levels and functional activity.
These data suggest that IDO1 expression may contribute to immune suppression in patients with MM and possibly other HGF-producing cancers.
PMCID: PMC3543251  PMID: 23232072
22.  Adrenomedullin in Ovarian Cancer: Foe In Vitro and Friend In Vivo? 
PLoS ONE  2012;7(7):e40678.
Stromal elements within a tumor interact with cancer cells to create a microenvironment that supports tumor growth and survival. Adrenomedullin (ADM) is an autocrine/paracrine factor produced by both stromal cells and cancer cells to create such a microenvironment. During differentiation of macrophages, ADM is produced in response to pro-inflammatory stimuli and hypoxia. In this study we investigated the role of ADM as a growth factor for ovarian cancer cells and as a modulator of macrophages. We also analyzed ADM expression levels in a retrospective clinical study using nanofluidic technology and assessment of ADM at the gene level in 220 ovarian cancer patients. To study the effects of ADM, ovarian cancer cell lines A2780, OVCAR-3, and HEY and their drug-resistant counterparts were used for proliferation assays, while monocytes from healthy donors were differentiated in vitro. ADM was a weak growth factor, as revealed by proliferation assays and cell cycle analysis. After culturing cancer cells under stressing conditions, such as serum starvation and/or hypoxia, ADM was found to be a survival factor in HEY but not in other cell lines. In macrophages, ADM showed activity on proliferation/differentiation, primarily in type 2 macrophages (M2). Unexpectedly, the clinical study revealed that high expression of ADM was linked to positive outcome and to cancer with low Ca125. In conclusion, although in vitro ADM was a potential factor in biological aggressiveness, this possibility was not confirmed in patients. Therefore, use of an ADM antagonist would be inappropriate in managing ovarian cancer patients.
PMCID: PMC3408475  PMID: 22859951
23.  Syphilis Infection during Pregnancy: Fetal Risks and Clinical Management 
Congenital syphilis is still a cause of perinatal morbidity and mortality. Untreated maternal infection leads to adverse pregnancy outcomes, including early fetal loss, stillbirth, prematurity, low birth weight, neonatal and infant death, and congenital disease among newborns. Clinical manifestations of congenital syphilis are influenced by gestational age, stage of maternal syphilis, maternal treatment, and immunological response of the fetus. It has been traditionally classified in early congenital syphilis and late congenital syphilis. Diagnosis of maternal infection is based on clinical findings, serological tests, and direct identification of treponemes in clinical specimens. Adequate treatment of maternal infection is effective for preventing maternal transmission to the fetus and for treating fetal infection. Prenatal diagnosis of congenital syphilis includes noninvasive and invasive diagnosis. Serological screening during pregnancy and during preconception period should be performed to reduce the incidence of congenital syphilis.
PMCID: PMC3398589  PMID: 22829747
24.  Herpes Simplex Virus Infection in Pregnancy 
Infection with herpes simplex is one of the most common sexually transmitted infections. Because the infection is common in women of reproductive age it can be contracted and transmitted to the fetus during pregnancy and the newborn. Herpes simplex virus is an important cause of neonatal infection, which can lead to death or long-term disabilities. Rarely in the uterus, it occurs frequently during the transmission delivery. The greatest risk of transmission to the fetus and the newborn occurs in case of an initial maternal infection contracted in the second half of pregnancy. The risk of transmission of maternal-fetal-neonatal herpes simplex can be decreased by performing a treatment with antiviral drugs or resorting to a caesarean section in some specific cases. The purpose of this paper is to provide recommendations on management of herpes simplex infections in pregnancy and strategies to prevent transmission from mother to fetus.
PMCID: PMC3332182  PMID: 22566740
25.  Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid Antibodies (aPL) – Mediated Inhibition of Endometrial Angiogenesis 
PLoS ONE  2012;7(1):e29660.
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies (aPL). Different pathogenic mechanisms for aPL-mediated pregnancy failure have been proposed. In particular a direct effect of aPL on both maternal and fetal side of the placental tissue has been reported, since their reactivity with β2-glycoprotein I (β2GPI) makes them adhere to trophoblast and human endometrial endothelial cell (HEEC) membranes. β2GPI can be recognized by aPL that, once bound, interfere with both trophoblast functions and with the HEEC differentiation.
APS patients can be successfully treated with Low Molecular Weight Heparin (LMWH). Recent reports suggest that LMWH acts through mechanisms alternative to its well known anticoagulant effect, because of its ability to bind β2GPI. In our previous studies, we showed that LMWH is able to reduce the aPL binding to trophoblasts and restore cell invasiveness and differentiation. So far, however, no study has described its effects on endometrial angiogenesis.
The aim of our research was to evaluate whether two LMWHs, tinzaparin and enoxaparin, have an effect on the aPL-inhibited endometrial angiogenesis. This prompted us to investigate: (i) in vitro HEEC angiogenesis through a Matrigel assay; (ii) VEGF secretion by ELISA; (iii) matrix metalloproteinase-2 (MMP-2) activity by gelatin zymography; (iv) Nuclear Factor-κB (NF-κB) DNA binding activity by colorimetric assay; (v) STAT-3 activation by a sandwich-ELISA kit. Furthermore, using an in vivo murine model we investigated the LMWHs effects on angiogenesis.
We demonstrated that the addition of LMWHs prevents aPL-inhibited HEEC angiogenesis, both in vitro and in vivo, and is able to restore the aPL inhibited NF-κB and/or STAT-3 activity, the VEGF secretion and the MMPs activity.
The demonstration of a beneficial role for LMWHs on the aPL-inhibited HEEC angiogenesis might provide additional mechanisms whereby this treatment protects early pregnancy in APS.
PMCID: PMC3250466  PMID: 22235321

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