Validation of MiROvaR, a microRNA-based predictor of early relapse in early stage epithelial ovarian cancer as a new strategy to optimise patients' prognostic assessment.

AIM: Early-stage epithelial ovarian cancer (eEOC) patients have a generally favorable prognosis but unpredictable recurrence. Accurate prediction of risk of relapse is still a major concern, essentially to avoid overtreatment. Our robust tissue-based miRNA signature named MiROvaR, predicting early EOC recurrence in mostly advanced-stage EOC patients, is here challenged in an independent cohort to extend its classifying ability in the early-stage EOC setting. METHODS: We retrospectively selected patients who underwent comprehensive surgical staging at our institution including stages from IA to IIB. miRNA expression profile was analysed in 89 cases and MiROvaR algorithm was applied using the previously validated cut-off for patients' classification. The primary endpoint was progression-free survival (PFS) at 5 years. Complete follow-up time (median = 112 months) was also considered as secondary analysis. RESULTS: MiROvaR was assessable on 87 cases (19 events of disease progression) and classified 68 (78%) low-risk and 19 (22%) high-risk patients. Recurrence rate at primary end-point was 39% for high-risk patients as compared to 9.5% for low-risk ones. Accordingly, their Kaplan-Meier PFS curves were significantly different at both primary and secondary analysis (p = 0.0006 and p = 0.03, respectively). While none of the prominent clinical variables had prognostic relevance, MiROvaR significantly predicted disease recurrence at the 5-year assessment (primary endpoint analysis; HR:5.43, 95%CI:1.82-16.1, p = 0.0024; AUC = 0.78, 95%CI:0.53-0.82) and at complete follow-up time (HR:2.67, 95%CI:1.04-6.8, p = 0.041; AUC:0.68, 95%CI:0.52-0.82). CONCLUSIONS: We validated MiROvaR performance in identifying at diagnosis eEOC patients' at higher risk of early relapse thus enabling selection of the most effective therapeutic approach.

Challenges in lower limb lymphoedema assessment based on limb volume change: Lessons learnt from the SENTIX prospective multicentre study.

BACKGROUND: Lower limb lymphoedema (LLL) is the most disabling adverse effect of surgical staging of pelvic lymph nodes. However, the lack of standardisation of volumetric LLL assessment hinders direct comparison between the studies and makes LLL reporting unreliable. The aim of our study is to report outcomes from a prospective trial that have implications for LLL assessment standardisation. METHODS: In the prospective international multicentre trial SENTIX, a group of 150 patients with stage IA1-IB2 cervical cancer treated by uterine surgery with bilateral sentinel lymph node biopsy was prospectively evaluated by objective LLL assessment, based on limb volume change (LVC) using circumferrential limb measurements and subjective patient-reported swelling. The assessments were conducted in six-month periods over 24 months post-surgery. RESULTS: Patient LVC substantially fluctuated in both positive and negative directions, which were comparable in frequency up to ±14% change. Thirty-eight patients experienced persistent LVC increase >10% classified as LLL, with nine months median time to onset. Some 34.2% of cases experienced onset later than one year after the surgery. Thirty-three patients (22%) experienced transient oedema characterised as LVC >10%, which resolved without intervention between two consequent follow-up visits. No significant correlation between LVC >10% and a patient-reported swelling was observed. CONCLUSIONS: Given that we observed comparable fluctuations of the the lower-limb volumes after surgical treatment of cervical cancer in both positive and negative direction up to ±14%, the diagnostic threshold for LLL diagnosis based on LVC should be increased to >15% LVC. The distinction of transient oedema from persistent LLL requires repeated measurements. Also, as one-third of LLL cases are diagnosed >1-year post-surgery, a sufficient follow-up duration needs to be ensured. Patient-reported swelling correlated poorly with LVC and should only be used as an adjunct to objective LLL assessment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02494063.

Spotlight on the role of human papillomavirus vaccines.

In high income setting, the massive implementation of screening programs has reduced the incidence of cervical cancer, dramatically. However, cervical cancer still remains a major health concern, being one of the most common cause of death for cancer among women. The adoption of primary prevention through vaccination against HPV aims to reduce the prevalence of HPV-related lesions and cervical cancer. Accumulating data highlighted the cost-effectiveness of introducing HPV vaccination for adolescent and young adults. In the present review, we critically evaluated the role of vaccination against HPV, focusing much more on the role of vaccination in specific cluster of subjects (eg, post-treatment and older adults). Additionally, we evaluated the available evidence on the role of vaccination in HIV-positive subjects and in women receiving solid organs transplantation. We observed that although vaccination might be considered effective in those cluster of subjects; further evidence is needed to assess the cost-effectiveness of vaccination in these settings.

Sentinel lymph node mapping and intraoperative assessment in a prospective, international, multicentre, observational trial of patients with cervical cancer: The SENTIX trial.

BACKGROUND: SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multicentre, prospective observational trial evaluating sentinel lymph node (SLN) biopsy without pelvic lymph node dissection in patients with early-stage cervical cancer. We report the final preplanned analysis of the secondary end-points: SLN mapping and outcomes of intraoperative SLN pathology. METHODS: Forty-seven sites (18 countries) with experience of SLN biopsy participated in SENTIX. We preregistered patients with stage IA1/lymphovascular space invasion-positive to IB2 (4 cm or smaller or 2 cm or smaller for fertility-sparing treatment) cervical cancer without suspicious lymph nodes on imaging before surgery. SLN frozen section assessment and pathological ultrastaging were mandatory. Patients were registered postoperatively if SLN were bilaterally detected in the pelvis, and frozen sections were negative. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02494063). RESULTS: We analysed data for 395 preregistered patients. Bilateral detection was achieved in 91% (355/395), and it was unaffected by tumour size, tumour stage or body mass index, but it was lower in older patients, in patients who underwent open surgery, and in sites with fewer cases. No SLN were found outside the seven anatomical pelvic regions. Most SLN and positive SLN were localised below the common iliac artery bifurcation. Single positive SLN above the iliac bifurcation were found in 2% of cases. Frozen sections failed to detect 54% of positive lymph nodes (pN1), including 28% of cases with macrometastases and 90% with micrometastases. INTERPRETATION: SLN biopsy can achieve high bilateral SLN detection in patients with tumours of 4 cm or smaller. At experienced centres, all SLN were found in the pelvis, and most were located below the iliac vessel bifurcation. SLN frozen section assessment is an unreliable tool for intraoperative triage because it only detects about half of N1 cases.

High-throughput assessment of the antibody profile in ovarian cancer ascitic fluids.

The identification of effective biomarkers for early diagnosis, prognosis, and response to treatments remains a challenge in ovarian cancer (OC) research. Here, we present an unbiased high-throughput approach to profile ascitic fluid autoantibodies in order to obtain a tumor-specific antigen signature in OC. We first reported the reactivity of immunoglobulins (Igs) purified from OC patient ascites towards two different OC cell lines. Using a discovery set of Igs, we selected tumor-specific antigens from a phage display cDNA library. After biopanning, 700 proteins were expressed as fusion protein and used in protein array to enable large-scale immunoscreening with independent sets of cancer and noncancerous control. Finally, the selected antigens were validated by ELISA. The initial screening identified eight antigenic clones: CREB3, MRPL46, EXOSC10, BCOR, HMGN2, HIP1R, OLFM4, and KIAA1755. These antigens were all validated by ELISA in a study involving ascitic Igs from 153 patients (69 with OC, 34 with other cancers and 50 without cancer), with CREB3 showing the highest sensitivity (86.95%) and specificity (98%). Notably, we were able to identify an association between the tumor-associated (TA) antibody response and the response to a first-line tumor treatment (platinum-based chemotherapy). A stronger association was found by combining three antigens (BCOR, CREB3, and MRLP46) as a single antibody signature. Measurement of an ascitic fluid antibody response to multiple TA antigens may aid in the identification of new prognostic signatures in OC patients and shift attention to new potentially relevant targets.

New prophylactics human papilloma virus (HPV) vaccines against cervical cancer.

Human papillomavirus (HPV) is causatively associated with cervical cancer (CC), the fourth most common malignant disease of women worldwide. The introduction of first generation prophylactic HPV vaccines in several national vaccination programmes has substantially decreased the global incidence of HPV cervical infections. Despite the success obtained, the two-licenced bivalent and quadrivalent L1 (the major HPV capsid protein) virus-like particle (VLP)-based vaccines (2vHPV and 4vHPV) present some limitations, such as a virus-type restricted protection, the high cost of the manufacture, and an absence of therapeutic activity on the established lesions. The second-generation prophylactic HPV vaccines, constituted by alternative viral components (such as capsomere or minor capsid HPV L2 protein) or made by more cost-effective strategies of production, are undergoing an intense clinical evaluation. This review aims to offer the reader a complete and updated overview on the HPV vaccination. The authors describe the effectiveness and the limitations of the approved HPV vaccines, and highlight the main characteristics of the new generation vaccines. IMPACT STATEMENT What is already known on this subject? CC is the fourth most common cancer of women in the world. HPV is the etiologic cause of almost all CCs. After being approved by the FDA, the first prophylactic 2vHPV and 4vHPV have been implemented into a routine vaccination schedule around the world, substantially decreasing the incidence of HPV and related-diseases in countries with high coverage rates. Currently, research is focusing on finding innovative and alternative systems to produce and deliver new HPV vaccines, overcoming all of the limitations that have partly restricted the potential benefit of previous vaccines on public health. What do the results of this study add? This narrative review was performed to find all the published studies reporting the efficacy and limitations of 2vHPV and 4vHPV, and evaluating the new HPV vaccines under pre- and clinical investigation. What are the implications of these findings for clinical practice and/or further research? Next generation of HPV vaccines will address many, if not all, of the limitations associated with current vaccines and will represent a step forward in the fight against CC.

Factors Predictive of 90-Day Morbidity, Readmission, and Costs in Patients Undergoing Pelvic Exenteration.

OBJECTIVE: Pelvic exenteration for recurrent gynecological malignancies is characterized by a high rate of severe complications. Factors predictive of morbidity, readmission, and cost were analyzed. METHODS: Data of consecutive patients undergoing pelvic exenteration between January 2007 and December 2016 were prospectively evaluated. RESULTS: Fifty-eight patients were included in the analysis. Anterior, posterior, and total exenterations were executed in 39 (67%), 9 (16%), and 10 (17%) patients, respectively. Ten (15.5%) severe complications occurred: 8 (20.5%), 0 (0%), and 1 (10%) after anterior, posterior, and total exenterations, respectively. Radiotherapy dosage, time between radiotherapy and surgery, and previous administration of chemotherapy did not influence 90-day complications and readmission. At multivariable analysis, albumin levels less than 3.5 g/dL (odds ratio, 16.2 [95% confidence interval, 2.85-92.8]; P = 0.002) and history of deep vein thrombosis (odds ratio, 9.6 [95% confidence interval, 0.93-98.2]; P = 0.057) were associated with 90-day morbidity. Low albumin levels independently correlated with readmission (P = 0.011). The occurrence of 90-day postoperative complications and readmission increased costs of a median of +12,500 and +6000 euros, respectively (P < 0.05). CONCLUSIONS: Preoperative patient selection is a key point for the reduction of postoperative complications after pelvic exenteration. Further prospective studies are warranted to improve patient selection.

Female fertility preserving practices at a pediatric unit: a challenge of multiprofessional and multidisciplinary cooperation.

INTRODUCTION: Being able to have children could have an important positive effect on the future lives of pediatric cancer survivors. Working at a cancer institute makes us responsible for filling the gaps in our knowledge in this area of patient care. METHODS: We describe our activities in a series of young females diagnosed with cancer and evaluated for fertility preservation options. We discuss the developed skills and organization as well as the practical difficulties encountered in managing fertility preservation. RESULTS: Since September 2012, laparoscopy and cryopreservation of cortical ovarian tissue has been performed in 16 girls (with ovary transposition in 3, and after several cycles of chemotherapy in 5) and egg banking in 4 young women (before chemotherapy in 2 and several years after treatment in 2). CONCLUSIONS: Recommendations on fertility preservation indicate that discussing the problems early on is crucial to future success. It is unthinkable to simply provide information and offer the opportunity to choose a fertility preserving technique without helping and accompanying patients and their families in their decisions and choices on the matter.

A critical assessment on the role of sentinel node mapping in endometrial cancer.

Endometrial cancer is the most common gynecologic malignancy in the developed countries. Although the high incidence of this occurrence no consensus, about the role of retroperitoneal staging, still exists. Growing evidence support the safety and efficacy of sentinel lymph node mapping. This technique is emerging as a new standard for endometrial cancer staging procedures. In the present paper, we discuss the role of sentinel lymph node mapping in endometrial cancer, highlighting the most controversies features.