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The impact of multiple infections on the risk of cervical lesions is a subject of ongoing debate. This study aims to explore whether the richness of HPV genotype infections and the biodiversity of squamous and glandular cervical dysplasias could influence the progression of precancerous lesions. We conducted a cross-sectional analysis involving 469 women who attended the Colposcopy Unit at the European Institute of Oncology in Milan, Italy, from December 2006 to December 2014. HPV type richness was measured as the number of different genotypes per patient. We calculated the associations between richness and age, as well as histologic grade, along with Simpson's biodiversity index for cervical dysplasias. We observed significant inverse relationships between the richness of high-risk (HR) genotypes and both age ( p = 0.007) and histologic grade ( p < 0.001). Furthermore, as the histologic grade increased, the mean biodiversity index of cervical dysplasias decreased, with exceptions noted in cases of normal histology and adenocarcinoma in situ. Different histologic grades formed five clusters with distinct mean ages and mean biodiversity indices. These findings suggest that HPV genotype richness and the biodiversity of cervical dysplasias may play a crucial role in predicting the risk of high-grade cervical lesions, enabling personalized management of precancers.

Fertility-sparing treatment (FTS) of endometrial cancer (EC) has a high rate of remission but also a high rate of relapse (10-88%). Many women still wish to conceive at the time of relapse, but results regarding retreatment are still lacking. This study aims to evaluate the safety, oncological and pregnancy outcomes of repeated FST in women with recurrent EC. This is a retrospective single-center study that recruited patients who had uterine recurrence after achieving a complete response (CR) with FST for FIGO stage IA, well-differentiated (G1), endometrioid EC. All eligible women underwent a second FST. Among 26 patients with recurrence, 6 decided to receive a hysterectomy and 20 received fertility-sparing retreatment. In total, 17 out of 20 women (85%) achieved a CR in a median time of 6 months. A total of 2/20 women showed a stable disease and continued the treatment for a further 6 months and finally achieved a CR. In total, 1/20 women showed disease progression and underwent demolitive surgery. After relapse and a CR, 14 patients attempted to become pregnant, among whom 7 became pregnant (pregnancy rate 50%-life birth rate 29%). Secondary FST is a safe and effective option for women who desire to preserve fertility after the recurrence of early-stage EC., Competing Interests: The authors declare no conflict of interest.

Cervico-vaginal (CV) localization of extra-mammary Paget's disease (EMPD) of the vulva is extremely rare. In order to investigate the incidence risk and the pathognomonic clinical and pathological features of this condition, a retrospective analysis was conducted including 94 women treated for vulvar EMPD at the European Institute of Oncology, Milan, Italy, from October 1997 to May 2020. Overall nine patients developed CV involvement from EMPD, with a cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI: 1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years, respectively. All cases except one were firstly detected by abnormal glandular cytology. None reported vaginal bleeding or other suspicious symptoms. The colposcopic findings were heterogeneous and could sometimes be misdiagnosed. Cervical and/or vaginal biopsies were always performed for histopathological diagnosis by identification of Paget cells in the epithelium or stroma. Most patients developed invasive EMPD (5/9) of the cervix and/or vagina and underwent hysterectomy with partial or total colpectomy. CV involvement from EMPD should not be underestimated in women with a long-standing history of vulvar Paget's disease. Liquid-based cytology with immunocytochemistry represents a valuable tool for early diagnosis and should be routinely performed during the required lifelong follow-up.

Colposcopic patterns of Vaginal Intraepithelial Neoplasia (VAIN) are not definitively related to histological grade. The aim of the present study was to investigate any correlation between clinical and colposcopic features and the development of high-grade VAIN. Two hundred and fifty-five women diagnosed with VAIN (52 VAIN1, 55 VAIN2 and 148 VAIN3) at the European Institute of Oncology, Milan, Italy, from January 2000 to June 2022, were selected for a retrospective analysis. Multivariate logistic regression was performed to estimate the association of risk factors and colposcopic patterns with VAIN grade. Smoking was associated with the development of VAIN (34.1%, p = 0.01). Most women diagnosed with VAIN3 (45.3%, p = 0.02) had a previous history of hysterectomy for CIN2+. At multivariate analysis, colposcopic grade G2 (OR = 20.4, 95%CI: 6.67−61.4, p < 0.001), papillary lesion (OR = 4.33, 95%CI: 1.79−10.5, p = 0.001) and vascularity (OR = 14.4, 95%CI: 1.86−112, p = 0.01) were significantly associated with a greater risk of VAIN3. The risk of high-grade VAIN should not be underestimated in women with a history of smoking and previous hysterectomy for CIN2+, especially when colposcopic findings reveal vaginal lesions characterized by grade 2, papillary and vascular patterns. Accurate diagnosis is crucial for an optimal personalized management, based on risk factors, colposcopic patterns and histologic grade of VAIN.

This study aims to analyze the sensitivity of vaginosonography (VGS) and magnetic resonance imaging (MRI) in the preoperative local evaluation of early-stage cervical cancers and to assess their accuracy in the detection of tumors, size of the lesions and stromal invasion by comparing them with the final histopathology report. This single-center study included 56 consecutive patients with cervical cancer who underwent VGS and MRI from November 2012 to January 2021. VGS significantly overestimated the lesion size by 2.7 mm (p = 0.002), and MRI underestimated it by 1.9 mm (p = 0.11). Both MRI and VGS had a good concordance with the pathology report (Cohen’s kappa of 0.73 and 0.81, respectively). However, MRI had a false-negative rate (38.1%) that was greater than VGS (0%) in cases of cervical tumor size <2 cm. We found a good concordance between histology and VGS in the stromal infiltration assessment, with 89% sensitivity (95% CI 0.44−0.83) and 89% specificity (95% CI 0.52−0.86). VGS is a simple, inexpensive, widely available, and fast execution method that can complement ultrasound in particular cases and show a good correlation with MRI in the assessment of tumor dimensions, with a better performance in detecting small tumors (<2 cm).

Background: The prevalence of reaches up to 5% in women younger than 40 years. Therefore, the fertility preservation should be the goal of the clinical practice in women with desire of pregnancy and low-risk features. The aim of this study is to compare oncological and reproductive outcomes of different hormonal therapies in FST of EC., Methods: A retrospective single-center study recruiting patients with presumed FIGO STAGE IA endometrioid G1 EC from 2005 to 2020 was performed. We assessed outcomes for three different therapeutic options: GnRHa + LNG-IUD vs. MA + LNG-IUD vs. MA + LNG-IUD + MET., Results: In total, 75 patients were enrolled and followed up for a median of 45 months. Complete response (CR) was achieved in 75% of patients at 12 months. Although not statistically significant, we reported an increasing rate of CR from the regimen with GnRHa to the one with MA + MET (65% vs. 83%). We showed a statistically significant lower risk of recurrence in women treated with MA + LNG-IUD + MET, when compared to GnRHa + LNG-IUD regimen. The pregnancy rate was 74% and live birth rate was 42%, with no differences among regimens., Conclusions: FST is a safe and effective option in women who desire to preserve fertility.

Objectives: To investigate the prevalence of high-risk human papillomavirus (HPV)-negative cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC) and to analyze the distribution of other genotypes in this subset., Methods: In total, 431 women who underwent excisional surgical treatment for CIN or ICC at the European Institute of Oncology, Milan, Italy, from January 2016 to December 2017 were retrospectively analyzed. The Linear Array HPV genotyping test (Roche Diagnostics) was performed on a postaliquot from high-risk-HPV-negative liquid-based cervical specimens, when available. Patient characteristics and the prevalence of high-risk-HPV-negative CIN grade 2 or worse (CIN2+) were tabulated. We used t tests to compare age between high-risk-HPV-positive and high-risk-HPV-negative patients., Results: Overall, 8.9% of CIN2+ and 7.5% of ICC cases were high-risk HPV negative. There was no age difference between high-risk-HPV-negative CIN2+ women (mean [SD], 41.3 [8.7] years) and high-risk-HPV-positive women (mean [SD], 39.5 [9.0] years) (P = .28). The Linear Array result was available in 22 cases. Most high-risk-HPV-negative patients were positive for a single other genotype infection (32.6%). HPV 73 was the most prevalent genotype, followed by HPV 53 and HPV 84. HPV 26 was detected in 1 case of ICC., Conclusions: Our results showed a not-negligible proportion of high-risk-HPV-negative CIN2+, suggesting that cotesting would not miss these cases., (© American Society for Clinical Pathology, 2021. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To study the characteristics of borderline tumors (BOT) diagnosed during pregnancy, as either first diagnosis or relapse, to evaluate safety of expectant management., Methods: 15 women affected by BOT during pregnancy were included, to evaluate clinical and histo-pathological characteristics. Age of patient, parity, gestational age, follow-up time, size of tumor, surgical approach, type and timing of surgery, FIGO stage, and histologic type were obtained through retrospective review., Results: All patients except one were diagnosed with serous BOT (BOTs). Median follow-up time was 147 ± 57 months. Eight women received first diagnosis of BOT and seven had diagnosis of BOT recurrence during pregnancy, including three with a second relapse and four with a third relapse. BOT were diagnosed at FIGO stage I in most patients (75%) of the first group and in 14.3% of the second group, respectively. Micropapillary pattern was present in 71.4% of patients with first diagnosis of BOT, but only in 14.2% in case of relapse. All relapses were BOTs. No patient with BOT and concomitant pregnancy developed an invasive recurrence later. Overall, 24 relapses occurred in 10 patients (66.7%). Altogether 24 pregnancies occurred during follow-up, with a high livebirth rate (91.6%) and only 2 spontaneous miscarriages., Conclusion: According to our experience, an "expectation management" could be a safe option in case of both relapse of BOTs during pregnancy and first suspicion of BOT in pregnant women at advanced gestational age., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hypersensitivity reactions (HSR)s to platinum agents are increasing in frequency, due to their extensive use and repeated exposures in patients with increased life expectancy. The aims of our study are to analyze the frequency of both type I and type IV HSRs in patients with gynecological cancer treated with (CBDCA) carboplatin and/or (CDDP) cisplatin, to evaluate the role of skin tests in the diagnosis and prevention of HSRs., Methods: From 2011 to 2018, we evaluated 124 consecutive female patients previously treated with CBDCA and/or CDDP for gynecological cancer. All patients, including those with and without HSR to previous platinum-based therapy, underwent in-vivo skin tests for platinum agents before starting the second or more therapeutic lines. To reduce the risk of false negative results, patients with a negative skin test at the first evaluation were re-tested after 3 weeks from the platinum re-exposure., Results: Among the 124 patients evaluated, 58 (47%) experienced HSRs to at least one platinum agent: 35% were to CBDCA, 5% to CDDP, 7% to both. Fifty-six of the 58 HSRs were classified as immediate and two delayed. Skin tests confirmed an IgE-dependent mechanism in 67% of patients with immediate-HSRs to CBDCA and identified a cross-reactivity between platinum agents in 18% of patients. Moreover, among those who had never developed an HSRs during platinum-based therapy, in-vivo skin tests identified 12% of sensitized patients., Conclusions: On the basis of our findings, skin test for platinum agents is a simple and sensitive tool for the diagnosis and prevention of HSRs to CBDCA and/or CDDP and can be useful for detecting possible cross-reactivity among platinum agents.

To evaluate the significance of HPV persistence as a predictor for the development of CIN2+ recurrence and the impact of multiple genotypes and of HPV 16/18 on recurrence risk. A prospective cohort observational study was carried out at the European Institute of Oncology, Milan, Italy, from December 2006 to December 2014. A total of 408 women surgically treated by excisional procedure for pre-neoplastic and neoplastic cervical lesions were enrolled. HPV test was performed at baseline and at first follow-up visit planned at 6 ± 3 months after treatment. Two-year cumulative incidences for relapse were estimated and compared by the Gray's test. Overall, 96 (23.5%) patients were persistent for at least one genotype at three to nine months from baseline and 21 (5.1%) patients relapsed. The two-year cumulative relapse incidence was higher in HPV persistent patients compared to not-persistent (CIF = 27.6%, 95% CI: 16.2-40.2% versus CIF = 1.7%, 95% CI: 0.3-5.8%, p < 0.001), in women with persistent multiple infections (CIF = 27.2%, 95% CI: 7.3-52.3%, p < 0.001), and with the persistence of at least one genotype between 16 and 18, irrespective of the presence of other HR genotypes (CIF = 32.7%, 95% CI: 17.9-48.3%, p < 0.001), but not significantly different from women positive for single infections or any other HR genotype, but not for 16 and 18. The risk of CIN2+ recurrence should not be underestimated when same HPV genotype infection persists after treatment.

Objectives: Diagnosis of HPV infection is usually performed from cervical liquid-based cytology specimens (LBC), but these often contain a large amount of human papillomavirus (HPV) genotypes, most of which might cause transient infections. The aim of the study was to evaluate the performance of BD Onclarity HPV test genotyping method on formalin-fixed, paraffin-embedded (FFPE) cervical specimens compared with genotyping results from LBC., Materials and Methods: Formalin-fixed, paraffin-embedded specimens from women surgically treated for cervical intraepithelial lesions (CINs) at the European Institute of Oncology, Milan, from September 2012 to June 2013 were retrieved from the archives of the Department of Pathology of the European Institute of Oncology. The FFPE and LBC specimens were genotyped using the same extended genotyping Onclarity assay., Results: We collected 99 samples (26 CIN 1, 30 CIN 2, and 43 CIN 3+), but 15 were excluded from the analysis: these 84 samples show an overall agreement of 89% for HPV status between FFPE Onclarity samples versus LBC samples. The FFPE and LBC samples showed identical genotype in 75% samples, compatible genotype (at least 1 of the genotypes detected in LBC sample was found in the tissue sample) in 14% specimens, and discrepant genotype in 11% samples., Conclusions: Our data demonstrate a very good concordance between HPV genotypes found in cytological and tissue samples, suggesting that the Onclarity method could also be used to detect HPV in tissue samples and that the HPV genotype detected in FFPE samples is one of the HPV detected in cytological samples, supporting the thesis that one lesion is caused by one HPV genotype., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2021, ASCCP.)

Placental site trophoblastic tumor [PSTT] and epithelioid trophoblastic tumor [ETT] are the rarest gestational trophoblastic neoplasias, developing from intermediate trophoblast of the implantation site and chorion leave, respectively. PSTT and ETT share some clinical-pathological features, such as slow growth rates, early stage at presentation, relatively low βhCG levels and poor response to chemotherapy. The mortality rate ranges from 6.5% to 27% for PSTT and from 10% to 24.2% for ETT. Advanced stage, long interval between antecedent pregnancy and diagnosis, and presence of clear cells are the independent prognostic variables for PSTT, and they may be similar for ETT. Hysterectomy can represent the only therapy for early disease, whereas adjuvant chemotherapy should be reserved to patients with poor risk factors, such as an interval from the antecedent pregnancy >4 years, deep myometrial invasion or serosal involvement. Few cases of fertility-sparing treatment in young women have been reported. An individualized multidisciplinary approach, including chemotherapy and debulking surgery with abdominal and/or extra-abdominal procedures, is warranted for advanced disease. EP/EMA and TP/TE are the preferred regimens in this setting. Immunohistochemistry has sometimes shown expression of EGFR, VEGF, MAPK, PDGF-R and PD-L1, and therefore investigational studies on biological agents targeting these molecules are strongly warranted for chemotherapy resistant-disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Adenocarcinoma accounts for 10-25% of all cervical cancers, and its relative and absolute rate has raised over the past decades. Most, but not all the authors, reported that adenocarcinoma has a greater propensity to lymph node, ovarian and distant metastases and a worse prognosis compared with squamous cell carcinoma. However, whether histologic type is an independent prognostic factor is still a debated issue. Moreover, adenocarcinoma is a very heterogenous disease, including different histological subtypes. Whereas radical hysterectomy and definitive radiotherapy achieve the same clinical outcome in early stage squamous cell carcinoma, surgery seems to obtain better survival compared with definitive radiotherapy in early stage adenocarcinoma. Chemoradiation is the standard treatment for locally advanced cervical cancer regardless of histologic type, although several retrospective studies showed that patients with adenocarcinoma were more likely to die than those with squamous cell carcinoma both before and after concurrent chemoradiation era. The prognostic relevance of biological variables, such as cyclin-dependent kinase inhibitors, p53, cyclooxygenase-2 [COX-2], cell surface tyrosine-kinases and programmed death-ligand [PD-L1], is still under investigation. Palliative chemotherapy is the only treatment option for persistent or recurrent cervical adenocarcinoma not amenable with surgery and radiotherapy. The use of immune checkpoint inhibitors as well as a therapeutic strategy targeting cell surface tyrosine kinases should be adequately explored in this clinical setting., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mature cystic teratomas of the ovary have an incidence of 1.2-14.2 cases per 100.000 people per year. Malignant transformation occurs in approximately 2% of the cases, and usually consists of squamous cell carcinoma. The preoperative detection is difficult and the diagnostic accuracy of ultrasound, magnetic resonance imaging, and computed tomography is debated. The diagnosis is frequently made in the operating room or on final histological examination. Standard treatment consists of bilateral salpingo-oophorectomy, total hysterectomy and comprehensive surgical staging in early disease and optimal cytoreductive surgery in advanced disease. Paclitaxel/carboplatin- based chemotherapy is the most used adjuvant treatment, whereas more aggressive regimens can be adopted in patients with high tumor burden or recurrent disease. The efficacy of radiotherapy is still unproven. The prognosis is poor when the tumor has spread beyond the ovary. There are few information to provide commonly accepted guidelines for this malignancy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Primary melanomas originating from the gynecological tract are rare and aggressive cancers. The vulva is the most frequent site (70%), followed by vagina and more rarely by cervix. The clinical outcome of patients with female genital tract melanoma is very poor, with a 5-year overall survival (OS) of 37-50% for vulvar, 13-32% for vaginal, and approximately 10% for cervical melanoma. In this systematic review, we analyzed the pathogenesis and the different factors influencing the prognosis of melanomas of the lower genital tract, with particular emphasis on biologic variables that may influence new therapeutic approaches. We evaluated the different treatment modalities described in the literature, in order to offer a possible algorithm that may help the clinicians in diagnosing and treating patients with these uncommon malignancies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Malignant transformation occurs in 1.5-2% of mature cystic teratomas (MCT)s of the ovary and usually consists of squamous cell carcinoma, whereas other malignancies are less common. Diagnosis and treatment represent a challenge for gynecologic oncologists. The preoperative detection is very difficult and the diagnostic accuracy of imaging examinations is uncertain. The tumor is usually detected post-operatively based on histopathologic findings. This paper reviewed 206 consecutive patients who underwent surgery for a histologically-proven MCT of the ovary between 2010 and 2017. Malignant transformation occurred in 3 (1.5%) of them, and consisted of squamous cell carcinoma in one, type 2 papillary renal carcinoma in one, and papillary thyroid carcinoma in another one. The paper reported the clinical, radiological and histological features of these cases and reviewed the literature data on the treatment options., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: To assess the patterns of recurrence of node-positive endometrial cancer patients., Patients and Methods: This investigation assessed 82 patients who received different postoperative treatments., Results: Recurrence developed in 36 patients after a median time of 13.5 months, and involved the vagina, pelvic nodes, para-aortic nodes and distant sites in 5, 8, 16 and 17 patients, respectively. Five-year progression-free survival (PFS) and 5-year overall survival (OS) were 51.1% and 59.8%. PFS and OS were significantly better for endometrioid than for non-endometrioid tumors. There was a trend towards a better outcome for patients who underwent chemotherapy±radiotherapy compared to those who received radiotherapy alone. Among the former, there was a better 5-year PFS (65.8% versus 33.7%, p=0.038) in patients who received platinum/paclitaxel-based regimens compared to those who received platinum-based chemotherapy., Conclusion: Disease recurred in 43.9% of patients, and platinum/paclitaxel-based chemotherapy plus radiotherapy appeared to be the best adjuvant treatment., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The presence of tumor infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICPI) have been approved for treating different types of malignancies. In this review, we assess the scanty data from literature and the perspectives of clinical research about the use of ICPI in gynecological cancers. These agents have obtained objective response rates ranging from 5.9% to 15% in early phase Ib-II trials, including patients with platinum-resistant ovarian cancer, whereas only anecdotal data are available for patients with recurrent, heavily pretreated endometrial cancer. Several ongoing trials are investigating ICPI alone or in combination with chemotherapy or with other biological agents in untreated and recurrent ovarian cancer, advanced and recurrent endometrial cancer, as well as advanced and recurrent cervical cancer. Breast cancer (BRCA)-mutated high-grade serous ovarian cancers, clear cell ovarian cancers with microsatellite instability (MSI), POLE ultramutated and MSI hypermutated endometrial cancers are likely to be sensitive to programmed cell death (PD-1)/PD-ligand 1 (PD-L1) pathway blockade, since these tumors show increased neoantigen load, increased CD8 + TIL number and PD-1 and PD-L1 overexpression. ICPI could have a role as maintenance treatment in patients with persistent, recurrent or metastatic cervical cancer in response after chemotherapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Hereditary epithelial ovarian cancer [EOC] in germline BRCA mutation (gBRCAm) carriers has a distinct clinical behavior characterized by younger age, high- grade serous histology, advanced stage, visceral distribution of disease, high response to platinum and other non-platinum agents and better clinical outcome. Sporadic EOC with homologous recombination deficiency [HDR] but no gBRCAm has the same biological and clinical behavior as EOC in gBRCAm carriers ("BRCAness"phenotype). Biomarkers are in development to enable an accurate definition of molecular features of BRCAness phenotype, and trials are warranted to determine whether such HDR signature will predict sensitivity to PARP inhibitors in sporadic EOC. Moreover, the link between PARP inhibition and angiogenesis suppression, the immunologic properties of EOC in gBRCAm carriers, the HRD induced by PI3K inhibition in EOC cells in vitro strongly support novel clinical trials testing the combination of PARP inhibitors with other biological agents., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: We assessed the clinical outcome and survival of 70 patients with primary vaginal squamous cell carcinoma undergoing radiotherapy (RT) at the Divisions of Radiotherapy, University of Pisa and ASST Cremona between January 1995 and June 2016., Methods: 58 patients received external beam RT (EBRT) to the entire vagina, para-vaginal area and pelvic nodes (total dose: 45-50.4 Gy). 29 patients (41.4%) received concomitant weekly cisplatin 40 mg/m2. 35 patients received an additional (15-36 Gy) high-dose-rate (HDR) brachytherapy (BT) boost and 13 received an additional (9-25 Gy) EBRT boost to the primary tumor site. 12 women exclusively received HDR-BT up to a total dose of (30-58 Gy)., Results: Median overall survival (OS) was 85 months. A total RT dose of > 60 Gy was significantly associated with a better OS (p = 0.015). There was a trend for a better OS for patients aged < 70 years and for those undergoing EBRT to the entire vagina and pelvis plus BT boost. The most common grade 1-2 acute toxicities were diarrhea (24.1%) and cystitis (20.7%); grade 3 cystitis only occurred in 2 patients (3.4%)., Conclusions: EBRT followed by BT boost seems to be the best treatment for vaginal carcinoma. The total dose of RT should be > 60 Gy., (© 2017 S. Karger GmbH, Freiburg.)

Homologous recombination (HR) and base excision repair (BER) are two of the major DNA-repair pathways. The proteins encoded by breast-related cancer antigen (BRCA) and poly(adenosine diphosphate-ribose) polymerases (PARP) are involved in HR and BER, respectively. Tumors with HR deficiency, including those in BRCA mutation carriers, are sensitive to BER blockade via PARP inhibitors. These represent novel therapeutic tools for HR-deficient ovarian cancer, able to improve progression-free survival of women with recurrent, platinum-sensitive disease in response to recent platinum-based chemotherapy. More research is needed to assesses whether inhibitors of PARP have any role as maintenance treatment after first-line chemotherapy and as palliative treatment of platinum-resistant disease. Germline BRCA testing should be offered to all patients with ovarian cancer, regardless of age and family history. HR deficiency has been observed not only in germline BRCA mutation carriers, but also in patients with somatic mutations or epigenetic silencing of BRCA, and with loss of function of other genes. Half of all high-grade ovarian carcinomas are HR-deficient, and additional biological and clinical investigations are strongly warranted to identify patients with this subset of tumors., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Introduction: Pharmacological treatment plays a major role in the management of advanced, persistent or recurrent uterine leiomyosarcoma (LMS), whereas its usefulness in the adjuvant setting is still debated. A thorough literature search was undertaken using the Pubmed databases. Systematic reviews and controlled trials on medical treatment of uterine LMS were collected and critically analyzed. Other study types were secondarily considered when pertinent., Areas Covered: Doxorubicin (DOX), ifosfamide and dacarbazine have been long used in the treatment of this malignancy. Novel active agents are represented by gemcitabine, docetaxel, trabectedin, pazopanib and aromatase inhibitors, whereas the role of eribulin, bevacizumab, aflibercept and mammalian target of rapamycin inhibitors is still investigational., Expert Opinion: DOX alone, gemcitabine alone, DOX + dacarbazine and gemcitabine + docetaxel may be treatment options for first-line and second-line therapies. However, the clinical benefit of the combination chemotherapy versus single-agent chemotherapy is still debated. Trabectedin is a promising agent for recurrent uterine LMS, able to obtain a prolonged disease control, with 3-month and 6-month progression-free survival rates exceeding 50 and 30%, respectively, and with sometimes unexpectedly durable responses. Pazopanib is the only approved targeted therapy. Hormone therapy with aromatase inhibitors may be a therapeutic option in heavily treated patients with slowly progressive, steroid receptor-positive tumors. Whenever possible, women with recurrent uterine LMS should be encouraged to enter well-designed clinical trials aimed to detect novel active agents.

The most important prognostic variables of cervical carcinoma are FIGO stage, lymph node status and clinical-pathological features of primary tumor. Recently, there has been increasing interest in the identification of biomarkers able to predict both response to treatment and survival. The aim of this review is to critically evaluate current published evidence on the ability of various tissue biomarkers to predict the clinical outcome of patients with cervical carcinoma. In particular, the paper takes into account DNA content, cell-cycle and apoptosis-regulatory proteins, epidermal growth factor receptor [EGFR], vascular endothelial growth factor [VEGF], cyclooxygenase [COX]-2, signal transducer and activator of transcription [Stat]3, human papilloma virus [HPV] status, tumor hypoxia, tumor infiltrating lymphocytes [TIL], microarray technology and microRNA (miRNA). The presence of HPV-18 genotype and an elevated VEGF expression appear to be poor prognostic factors in women with early disease treated with primary surgery, whereas the expression of EGFR, VEGF, COX-2 and tumor hypoxia may have a major impact on the survival of patients treated with definitive radiotherapy or chemoradiation. The data supporting the reliability of ΔNp73 and TAp73α as novel biomarkers of response to radiotherapy are interesting but still limited. DNA microarray technology could offer new laboratory tools for a rationale planning of treatment strategy, and miRNAs might represent new candidate targets to be investigated for both prognostic and therapeutic purposes. Moreover, the assessment of different types of TIL and their ligands in tumor biopsies could enable the identification of a subset of high-risk patients, paving the way to novel immune therapies aimed at blocking T-reg cell activity., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Infertility itself increases the incidence of ovarian carcinoma, while the potential additional risk associated with the use of fertility drugs is still debated. In 1992, the cumulative analysis of 12 US case-control studies revealed that women who received ovulation-inducing drugs had approximately three-fold higher incidence of invasive ovarian carcinoma. Other investigations reported a lower increase of the risk of invasive carcinoma or borderline tumor of the ovary in women treated with these agents. Conversely, several other case-control or cohort studies failed to detect a significant correlation between fertility drug use and ovarian tumor risk in either parous or nulliparous women compared with untreated infertile women. Moreover neither the number of treatment cycles nor the type of drug used was associated with an increased risk in most studies. Incessant ovulation and excessive gonadotropin secretion have been long considered to play a major role in the development of ovarian carcinoma, and therefore fertility drugs, which raise the serum levels of gonadotropins and increase the chances of multiple ovulations, have been retained as a risk factor for this malignancy, However, the large majority of literature data as well as the new hypotheses on ovarian carcinogenesis appear to exclude a relevant impact of fertility drug use on the risk of ovarian tumors, and especially of high-grade invasive epithelial ovarian cancers.

Ovarian carcinoma can be subdivided into two categories termed type I and type II. Type I tumours, usually having an indolent clinical behaviour, are often detected in early stage, and rarely harbour p53 gene mutations. Each histological type has a distinct molecular profile with mutations of genes involved in different signalling transduction pathways, such as KRAS, BRAF, CTNNB1, PTEN, PIK3CA and ARID1A. Type II tumours, accounting for 75% of the cases, have a very aggressive biological behaviour, are usually in advanced stage at presentation, harbour p53 gene mutations in 80% of the cases, and sometimes have alterations of homologous recombination (HR). Both type I and type II tumours arise from extra-ovarian precursors. Serous carcinomas derive from tubal epithelium, endometrioid and clear cell carcinomas from endometrial tissue, and mucinous and Brenner tumours from transitional epithelial cells located near the tubo-peritoneal junction. These new concepts on the pathogenesis of ovarian carcinoma could deeply modify both the preventive approach in women with germ-line BRCA₁ or BRCA₂ mutations and the treatment of patients with advanced or recurrent disease. For instance, BRAF inhibitors could be used in low-grade serous carcinomas, PIK3CA inhibitors could be employed in clear cell carcinoma, and poly (ADP-ribose) polymerase inhibitors could be used not only in hereditary ovarian carcinoma but also in non-hereditary, high-grade serous ovarian carcinoma which sometimes shows defective HR.

Several clinical-pathological parameters have been related to survival of patients with invasive squamous cell carcinoma of the vulva, whereas few studies have investigated the ability of biological variables to predict the clinical outcome of these patients. The present paper reviews the literature data on the prognostic relevance of lymph node-related parameters, primary tumor-related parameters, FIGO stage, blood variables, and tissue biological variables. Regarding these latter, the paper takes into account the analysis of DNA content, cell cycle-regulatory proteins, apoptosis-related proteins, epidermal growth factor receptor [EGFR], and proteins that are involved in tumor invasiveness, metastasis and angiogenesis. At present, the lymph node status and FIGO stage according to the new 2009 classification system are the main predictors for vulvar squamous cell carcinoma, whereas biological variables do not have yet a clinical relevance and their role is still investigational., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The term benign breast disease includes a wide and heterogenous spectrum of lesions different for histology and natural history. Approximately 70% of women who undergo a biopsy for benign breast disease have non-proliferative lesions with no increased risk of breast cancer, 26% have typical hyperplasia which is associated with a two-fold increased risk, and only 4% have atypical hyperplasia which is associated with a five-fold increased risk. The data on the effect of steroid hormones on benign breast disease come from observational studies with several potential bias. Most papers have reported that oral contraceptives protect against benign breast disease, whereas some others have suggested that effects of pill are not yet fully clear. As far as hormone replacement therapy (HRT) is concerned, some studies have shown an increased incidence of benign breast disease in long-term HRT users, whereas other investigations have found either no effect or a protective effect. The use of HRT does not appear to influence the clinical pattern of benign breast disease in postmenopausal women, although enlargement of pre-existing cysts or fibroadenomas has been sometimes reported. The limited available data failed to detect a deleterious effect of HRT use in women with benign breast disease, even in those with increased breast cancer risk due to a family history or high-risk benign breast conditions.

Aim: To assess the pattern of failures in patients with FIGO stage IIIc(1)-IIIc(2) endometrial cancer., Patients and Methods: Data were retrospectively analyzed for 34 patients with this malignancy who underwent extra-fascial total hysterectomy, bilateral salpingo-oophorectomy and pelvic/para-aortic node dissection. Postoperative treatment consisted of radiotherapy in 5 patients, 6 cycles of chemotherapy in 9, and 3-4 cycles of chemotherapy followed by radiotherapy in 20. The median follow-up of survivors was 33 months (range, 6 to 133 months)., Results: Tumour relapsed in 14 out of 34 patients (41.2%). Median time to recurrence was 17 months (range, 9.5-42 months). Vaginal recurrence developed in 2 patients (5.9%), distant recurrence in 5 (14.7%), pelvic node recurrence in 3 (8.8%) and para-aortic recurrence in 7 (20.6%). Two patients had multiple sites of recurrence. Distant failure occurred in 11.1% of the patients who received 6 cycles of chemotherapy versus 20.0% of those who had 3-4 cycles of chemotherapy followed by radiotherapy. Five-year overall survival was 60.5%, and, in particular, it was 62.5% for stage IIIc(1) and 57.0% for stage IIIc(2)., Conclusion: FIGO stage IIIc(1)-IIIc(2) endometrial cancer relapses in approximately 40% of cases, and distant sites and para-aortic nodes represent the most common sites of failure.

Aim: To assess the relationship between the timing of radiotherapy and the risk of local failure in patients with endometrioid-type endometrial cancer who had undergone surgery and adjuvant external pelvic radiotherapy (with or without brachytherapy), but not chemotherapy., Patients and Methods: One hundred and seventy seven patients were analyzed in this study. The median follow-up of the survivors was 72 months., Results: Radiotherapy was delivered after a median time of 14.6 weeks from surgery and the median overall treatment time was 6.4 weeks. The tumor relapsed in 32 (18.1%) patients after a median time of 21 months. The local recurrence (vaginal or central pelvic) occurred in 11 patients. The local recurrence rate was associated with tumor grade (p=0.02), myometrial invasion (p=0.046), FIGO stage (p=0.003), pathological node status (p=0.037) and time interval from surgery to radiotherapy using 9 weeks as the cut-off value (p=0.046), but not with the overall treatment time. All the local relapses occurred in patients who received adjuvant irradiation after an interval from surgery >9 weeks., Conclusion: The time interval from surgery to radiotherapy might affect the local recurrence rate in patients not receiving chemotherapy. Every possible effort should be made to start radiotherapy within 9 weeks, when radiotherapy only is deemed necessary as adjuvant treatment.