Publications by authors named "Francesco Raspagliesi"

271 Publications

SUCCOR cone study: conization before radical hysterectomy.

Int J Gynecol Cancer 2022 Jan 17. Epub 2022 Jan 17.

Gynaecology, LUMC, Leiden, Netherlands.

Objective: To evaluate disease-free survival of cervical conization prior to radical hysterectomy in patients with stage IB1 cervical cancer (International Federation of Gynecology and Obstetrics (FIGO) 2009).

Methods: A multicenter retrospective observational cohort study was conducted including patients from the Surgery in Cervical Cancer Comparing Different Surgical Aproaches in Stage IB1 Cervical Cancer (SUCCOR) database with FIGO 2009 IB1 cervical carcinoma treated with radical hysterectomy between January 1, 2013, and December 31, 2014. We used propensity score matching to minimize the potential allocation biases arising from the retrospective design. Patients who underwent conization but were similar for other measured characteristics were matched 1:1 to patients from the non-cone group using a caliper width ≤0.2 standard deviations of the logit odds of the estimated propensity score.

Results: We obtained a weighted cohort of 374 patients (187 patients with prior conization and 187 non-conization patients). We found a 65% reduction in the risk of relapse for patients who had cervical conization prior to radical hysterectomy (hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.16 to 0.75, p=0.007) and a 75% reduction in the risk of death for the same sample (HR 0.25, 95% CI 0.07 to 0.90, p=0.033). In addition, patients who underwent minimally invasive surgery without prior conization had a 5.63 times higher chance of relapse compared with those who had an open approach and previous conization (HR 5.63, 95% CI 1.64 to 19.3, p=0.006). Patients who underwent minimally invasive surgery with prior conization and those who underwent open surgery without prior conization showed no differences in relapse rates compared with those who underwent open surgery with prior cone biopsy (reference) (HR 1.94, 95% CI 0.49 to 7.76, p=0.349 and HR 2.94, 95% CI 0.80 to 10.86, p=0.106 respectively).

Conclusions: In this retrospective study, patients undergoing cervical conization before radical hysterectomy had a significantly lower risk of relapse and death.
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http://dx.doi.org/10.1136/ijgc-2021-002544DOI Listing
January 2022

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.

Eur J Cancer 2022 01 15;161:55-63. Epub 2021 Dec 15.

Department of Research, Unit of Molecular Therapies, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.ejca.2021.11.003DOI Listing
January 2022

Characteristics and patterns of care of endometrial cancer before and during COVID-19 pandemic.

J Gynecol Oncol 2022 01 12;33(1):e10. Epub 2021 Nov 12.

Clinica Ostetrica e Ginecologica - Dipartimento Scienze Mediche - Università di Ferrara, Ferarra, Italy.

Objective: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients.

Methods: This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak.

Results: Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001).

Conclusion: Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic.
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http://dx.doi.org/10.3802/jgo.2022.33.e10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728669PMC
January 2022

Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer.

N Engl J Med 2021 12;385(23):2123-2131

From the Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen (P. Harter, A.B.), the Department of Gynecology with Center for Oncological Surgery, Charité Berlin, Berlin (J.S.), the Coordinating Center for Clinical Trials (A. Reuss) and Department of Gynecology (P. Harter), Philipps University, Marburg, the Department of Obstetrics and Gynecology, Heinrich-Heine-University, Duesseldorf (W.M.), the Department of Gynecology and Obstetrics, Hannover Medical School, Hannover (P. Hillemanns), the University Medical Center Mainz, Department of Gynecology and Obstetrics, Mainz (A.H.), and Mammazentrum Hamburg at Jerusalem Hospital, Hamburg (F.H.) - all in Germany; the Department of Gynecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium (I.V.); the Department of Surgical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer, Toulouse (G.F.), the Department of Medical Oncology, Groupe Hospitalier Diaconesses Croix Saint-Simon (F.S.), and Institut Curie, Oncologie Gynécologique and Université de Paris (F.L.), Paris, the Department of Surgical Oncology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux (F.G.), the Department of Surgical Oncology, Jean Perrin Cancer Center, Clermont-Ferrand (C.P.), and Institut de Cancerologie de l'Ouest, Université de Médecine, Nantes (J.-M.C.) - all in France; the Gynecologic Oncology Unit, Istituto Nazionale Tumori di Napoli, Fondazione IRCCS Pascale, Naples (S.G.), and Fondazione IRCCS Istituto Nazionale Tumori, Milan (F.R.) - both in Italy; the Gyne-Oncology Department of Gynecology (B.J.M.), Copenhagen University Hospital Rigshospitalet (M.R.M.), Copenhagen, the Department of Gynecology, Aarhus University Hospital and Aarhus University, Institute of Clinical Medicine, Faculty of Health, Aarhus (P.J.), and Aalborg University Hospital, Aalborg (B.L.) - all in Denmark; the Ovarian Cancer Program, Department of Gynecologic Oncology, Fudan University Zhongshan Hospital, Shanghai, China (R.Z.); the Department of Oncology-Pathology, Karolinska Institutet, Stockholm (E.A.-L.); the Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea (J.-W.K.); University Hospital of Bellvitge, Barcelona (J.P.), and the Gynecologic Oncology Unit, La Fe University Hospital, Valencia (A.S.) - both in Spain; the Department of Gynecologic Oncology and Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo (G.K.); the Department of Surgery and Cancer, Imperial College London (S.G.-M.), and the Department of Gynaecological Oncology, University College London Hospital (A.O.) - both in London; and the Department of Gynecology and Gynecological Oncology, Medical University of Vienna, Vienna (A. Reinthaller).

Background: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear.

Methods: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival.

Results: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery.

Conclusions: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).
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http://dx.doi.org/10.1056/NEJMoa2103294DOI Listing
December 2021

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

Gynecol Oncol 2022 Jan 8;164(1):76-84. Epub 2021 Nov 8.

Gynecologic Oncology Centre, Department of Obstetrics and Gynaecology, First Faculty of Medicine, Charles University and General University Hospital, Central and Eastern European Gynecologic Oncology Group, CEEGOG, Prague, Czech Republic. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ygyno.2021.10.089DOI Listing
January 2022

Uterine serous carcinoma: role of surgery, risk factors and oncologic outcomes. Experience of a tertiary center.

Eur J Surg Oncol 2021 Oct 26. Epub 2021 Oct 26.

Department of Gynecologic Oncology, IRCCS National Cancer Institute, Milan, Italy.

Objective: To evaluate factors impacting survival outcomes in patients with uterine serous carcinoma (USC).

Methods: Data of consecutive patients diagnosed with USC undergoing surgery between 2000 and 2020 at Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy) were reviewed. Progression-free (PFS) and overall survival (OS) outcomes were evaluated using Kaplan-Meier and Cox proportional hazard models.

Results: Records of 147 consecutive patients meeting the inclusion criteria were analyzed. Stage distribution was: 67 (45.6%) patients with early-stage with uterine confined disease and 80 (54.4%) with advanced stages disease. Minimally invasive surgery was performed in 43 patients (29.5%). The median follow-up period was 78.6 months (IQ range = 35.7-117.3 months). The overall recurrence rate was 41% (60 patients): 19/67 patients (28.4%) with early-stage disease and 41/80 patients (51.3%) with advanced stage. The 5-year PFS rate was 35.0% (95% confidence interval [CI]: 27.5-44.7%). In multivariate analysis, age, BMI, depth of myometrial invasion, cytology, and optimal cytoreduction with postoperative residual tumor absent significantly impacted on PFS. The 5-year OS rates were 46.5% (95% CI: 38.1-56.8). The result of multivariate analysis showed that there was significant difference in OS based only on optimal cytoreduction and accuracy of retroperitoneal surgery.

Conclusions: In apparent early-stage USC, peritoneal and retroperitoneal staging allows to identify patients with disease harboring outside the uterus. Optimal cytoreduction is the most significant prognostic factor. Further collaborative studies are warranted in order to improve outcomes of USC patients.
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http://dx.doi.org/10.1016/j.ejso.2021.10.011DOI Listing
October 2021

Factors predicting morbidity in surgically-staged high-risk endometrial cancer patients.

Eur J Obstet Gynecol Reprod Biol 2021 Nov 28;266:169-174. Epub 2021 Sep 28.

Gynecological Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.

Objective: To investigate factors predicting the risk of developing 90-day postoperative complications and lymphatic-specific morbidity in patients undergoing surgical staging for high-risk endometrial cancer.

Methods: This is a multi-institutional retrospective cohort study. Patients affected by apparent early-stage high-risk endometrial cancer (endometrioid FIGO grade 3 with deep myometrial invasion and non-endometrioid endometrial cancer) undergoing surgical staging between 2007 and 2019. Complications were graded according to the Clavien-Dindo classification system. Martin criteria were applied to improve quality of complications reporting.

Results: Charts of 279 patients were evaluated. Lymphadenectomy, sentinel node mapping (SNM), and SNM followed by back-up lymphadenectomy were performed in 83 (29.7%), 50 (17.9%), and 146 (52.4%) patients, respectively. The former group of patients included 13 patients who had lymphadenectomy after the failure of the SNM technique. Thirteen (4.6%) patients developed severe postoperative events (grade 3 or worse). At multivariate analysis, body mass index (OR: 1.08 (95%CI: 1.01, 1.17)) and open abdominal surgery (OR: 2.27 (95%CI: 1.02, 5.32)) were the two independent factors predictive of surgery-related morbidity. Seven severe lymphatic complications occurred. The adoption of laparoscopic approach (p < 0.001, log-rank test) and SNM (p = 0.038, log-rank test) correlated with a lower risk of developing surgery-related events. Independently, open abdominal surgery was associated with an increased risk of developing lymphatic morbidity (OR: 37.4 (95%CI: 4.38, 319.5); p = 0.001).

Conclusion: The adoption of the laparoscopic approach and SNM technique were associated with lower 90-day complication rates than open surgery in high-risk endometrial cancer undergoing staging surgery.
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http://dx.doi.org/10.1016/j.ejogrb.2021.09.029DOI Listing
November 2021

Fertility-Sparing Treatment of Patients with Endometrial Cancer: A Review of the Literature.

J Clin Med 2021 Oct 19;10(20). Epub 2021 Oct 19.

Gynecologic Oncology, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.

Endometrial cancer (EC) is currently the most common malignancy of the female genital tract in developed countries. Although it is more common in postmenopausal women, it may affect up to 25% in the premenopausal age and 3-5% under the age of 40 years. Furthermore, in the last decades a significant shift to pregnancy at older maternal ages, particularly in resource-rich countries, has been observed. Therefore, in this scenario fertility-sparing alternatives should be discussed with patients affected by EC. This study summarizes available literature on fertility-sparing management of patients affected by EC, focusing on the oncologic and reproductive outcomes. A systematic computerized search of the literature was performed in two electronic databases (PubMed and MEDLINE) in order to identify relevant articles to be included for the purpose of this systematic review. On the basis of available evidence, fertility-sparing alternatives are oral progestins alone or in combination with other drugs, levonorgestrel intrauterine system and hysteroscopic resection in association with progestin therapies. These strategies seem feasible and safe for young patients with G1 endometrioid EC limited to the endometrium. However, there is a lack of high-quality evidence on the efficacy and safety of fertility-sparing treatments and future well-designed studies are required.
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http://dx.doi.org/10.3390/jcm10204784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539778PMC
October 2021

Population-adjusted indirect treatment comparison of the SOLO1 and PAOLA-1/ENGOT-ov25 trials evaluating maintenance olaparib or bevacizumab or the combination of both in newly diagnosed, advanced BRCA-mutated ovarian cancer.

Eur J Cancer 2021 11 28;157:415-423. Epub 2021 Sep 28.

Women & Infants Hospital, Providence, RI, USA.

Background: In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm).

Methods: An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled. Each arm of PAOLA-1 was weighted so that key baseline patient characteristics were similar to the SOLO1 cohort. Analyses were performed in patients with complete baseline data. Weighted Cox regression analysis was used to estimate the comparative efficacy of different maintenance therapy strategies, supplemented by weighted Kaplan-Meier analyses.

Results: Data from SOLO1 patients (olaparib, n = 254; placebo, n = 126) were compared with data from BRCA-mutated PAOLA-1 patients (olaparib plus bevacizumab, n = 151; placebo plus bevacizumab, n = 71). Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95).

Conclusions: Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm.
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http://dx.doi.org/10.1016/j.ejca.2021.08.023DOI Listing
November 2021

Trend of HPV 16/18 Genotypes in Cervical Intraepithelial Neoplasia Grade 3: Data for 2007-2018.

Infect Drug Resist 2021 16;14:3763-3771. Epub 2021 Sep 16.

Woman's Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy.

Aim: In the post-vaccination era, the starting age and time intervals of cervical screening could change (older age and longer screening intervals). This scenario may be achieved by significantly reducing human papillomavirus (HPV) 16/18 prevalence (genotypes included in the current vaccines). In this regard, assessing the trend over time of these HPV infections in high-grade cervical lesions can provide information on the objective. The present study aimed to evaluate the trend of HPV 16/18 over the years 2007-2018 in women with cervical intraepithelial neoplasia (CIN) grade 3.

Methods: This is a retrospective multi-institutional study including HPV genotyped and unvaccinated women under 30 with CIN3. The sample was divided into the following periods: 2007-2010, 2011-2014, 2015-2018. HPV genotypes were grouped in genotypes 16/18, genotypes 31/33/35/52/58/67 (genetically related to HPV16), genotypes 39/45/59/68/70 (genetically related to HPV18), genotypes 31/33/45/52/58 (high-risk types included in the nonavalent vaccine), possibly carcinogenic HPV (genotypes 26/30/53/67/70/73/82/85), low-risk HPV (genotypes 6/11/40/42/43/44/54/55/61). The trend between periods and HPV genotypes was measured using the Cochran-Armitage test for trend.

Results: The final analysis included 474 participants. HPV 16/18 prevalence decreased significantly over the years (77.8% vs 68.9% vs 66.0%, respectively, Ptrend=0.027). Possibly carcinogenic HPV (genotypes 26/30/53/67/70/73/82/85) showed a significant negative prevalence trend over time (4.9% vs 1.1% vs 1.3%, respectively, Ptrend=0.046). Finally, there was a significant positive trend over the years for high-risk HPV genotypes 31/33/45/52/58 in women under 25 (9.9% vs 17.0% vs 24.0%, respectively, Ptrend=0.048).

Conclusion: The prevalence of CIN3 lesions related to HPV 16/18 genotypes decreased over time from 2007 to 2018. These data highlight a herd effect of the HPV vaccine. However, fifteen years after HPV vaccine introduction, we are still a long way from herd immunity. The increase in high-risk types 31/33/45/52/58 will need to be reassessed when the nonavalent vaccine impact will be more reliable.
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http://dx.doi.org/10.2147/IDR.S326851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453441PMC
September 2021

Thromboembolic events and antithrombotic prophylaxis in advanced ovarian cancer patients treated with bevacizumab: secondary analysis of the phase IV MITO-16A/MaNGO-OV2A trial.

Int J Gynecol Cancer 2021 10 30;31(10):1348-1355. Epub 2021 Aug 30.

Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy.

Introduction: The use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian cancer patients. We report on the incidence of thromboembolic events and the prevalence of antithrombotic therapy in patients enrolled in the single arm, phase IV, MITO-16A/MaNGO-OV2A trial.

Methods: In this trial, potential prognostic factors for patients with previously untreated ovarian cancer receiving a combination of platinum-based chemotherapy and bevacizumab were explored and the final analysis has already been reported. In this secondary analysis, the occurrence of thromboembolic events and the use of antithrombotic therapy were described according to the clinical characteristics of the patients. The prognostic role of thromboembolic events for progression-free and overall survival were also evaluated.

Results: From October 2012 to November 2014, 398 eligible patients were enrolled. 76 patients (19.1%) were receiving some type of anticoagulant or anti-aggregant treatment at baseline. Overall, 24 thromboembolic events were reported (cumulative incidence of 6.0%). The occurrence of thromboembolic events was not associated with baseline patient characteristics and was not modified by the use of antithrombotic prophylaxis (HR 0.60, 95% CI 0.18 to 2.0). Occurrence of thromboembolic events was not associated with progression-free survival (HR 1.34, 95% CI 0.83 to 2.15) or overall survival (HR 0.78, 95% CI 0.37 to 1.61).

Conclusions: In our study, a 6.0% rate of thromboembolic events was reported during treatment with bevacizumab plus chemotherapy. Thromboembolic events were not associated with the clinical characteristics of the patients or with the use of antithrombotic prophylaxis, nor did they significantly affect the long-term prognosis.

Trial Registration Number: NCT01706120.
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http://dx.doi.org/10.1136/ijgc-2021-002786DOI Listing
October 2021

Radical hysterectomy in early cervical cancer in Europe: characteristics, outcomes and evaluation of ESGO quality indicators.

Int J Gynecol Cancer 2021 09 28;31(9):1212-1219. Epub 2021 Jul 28.

Division of Gynecologic Oncology, 1st Department of Obstetrics and Gynecology, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Introduction: Comprehensive updated information on cervical cancer surgical treatment in Europe is scarce.

Objective: To evaluate baseline characteristics of women with early cervical cancer and to analyze the outcomes of the ESGO quality indicators after radical hysterectomy in the SUCCOR database.

Methods: The SUCCOR database consisted of 1272 patients who underwent radical hysterectomy for stage IB1 cervical cancer (FIGO 2009) between January 2013 and December 2014. After exclusion criteria, the final sample included 1156 patients. This study first described the clinical, surgical, pathological, and follow-up variables of this population and then analyzed the outcomes (disease-free survival and overall survival) after radical hysterectomy. Surgical-related ESGO quality indicators were assessed and the accomplishment of the stated recommendations was verified.

Results: The mean age of the patients was 47.1 years (SD 10.8), with a mean body mass index of 25.4 kg/m (SD 4.9). A total of 423 (36.6%) patients had a previous cone biopsy. Tumor size (clinical examination) <2 cm was observed in 667 (57.7%) patients. The most frequent histology type was squamous carcinoma (794 (68.7%) patients), and positive lymph nodes were found in 143 (12.4%) patients. A total of 633 (54.8%) patients were operated by open abdominal surgery. Intra-operative complications occurred in 108 (9.3%) patients, and post-operative complications during the first month occurred in 249 (21.5%) patients, with bladder dysfunction as the most frequent event (119 (10.3%) patients). Clavien-Dindo grade III or higher complication occurred in 56 (4.8%) patients. A total of 510 (44.1%) patients received adjuvant therapy. After a median follow-up of 58 months (range 0-84), the 5-year disease-free survival was 88.3%, and the overall survival was 94.9%. In our population, 10 of the 11 surgical-related quality indicators currently recommended by ESGO were fully fulfilled 5 years before its implementation.

Conclusions: In this European cohort, the rate of adjuvant therapy after radical hysterectomy is higher than for most similar patients reported in the literature. The majority of centers were already following the European recommendations even 5 years prior to the ESGO quality indicator implementations.
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http://dx.doi.org/10.1136/ijgc-2021-002587DOI Listing
September 2021

A decision support system based on radiomics and machine learning to predict the risk of malignancy of ovarian masses from transvaginal ultrasonography and serum CA-125.

Eur Radiol Exp 2021 Jul 26;5(1):28. Epub 2021 Jul 26.

Department of Gynecologic Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133, Milan, Italy.

Background: To evaluate the performance of a decision support system (DSS) based on radiomics and machine learning in predicting the risk of malignancy of ovarian masses (OMs) from transvaginal ultrasonography (TUS) and serum CA-125.

Methods: A total of 274 consecutive patients who underwent TUS (by different examiners and with different ultrasound machines) and surgery, with suspicious OMs and known CA-125 serum level were used to train and test a DSS. The DSS was used to predict the risk of malignancy of these masses (very low versus medium-high risk), based on the US appearance (solid, liquid, or mixed) and radiomic features (morphometry and regional texture features) within the masses, on the shadow presence (yes/no), and on the level of serum CA-125. Reproducibility of results among the examiners, and performance accuracy, sensitivity, specificity, and area under the curve were tested in a real-world clinical setting.

Results: The DSS showed a mean 88% accuracy, 99% sensitivity, and 77% specificity for the 239 patients used for training, cross-validation, and testing, and a mean 91% accuracy, 100% sensitivity, and 80% specificity for the 35 patients used for independent testing.

Conclusions: This DSS is a promising tool in women diagnosed with OMs at TUS, allowing to predict the individual risk of malignancy, supporting clinical decision making.
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http://dx.doi.org/10.1186/s41747-021-00226-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310829PMC
July 2021

Oncologic outcomes of endometrial cancer in patients with low-volume metastasis in the sentinel lymph nodes: An international multi-institutional study.

Gynecol Oncol 2021 09 15;162(3):590-598. Epub 2021 Jul 15.

Turkish Society of Gynecologic Oncology, Istanbul, Turkey; Department of Gynecologic Oncology, Koc University School of Medicine, Istanbul, Turkey.

Objective: To assess oncologic outcomes in endometrial cancer patients with low-volume metastasis (LVM) in the sentinel lymph nodes (SLNs).

Methods: Patients with endometrial cancer and SLN-LVM (≤2 mm) from December 3, 2009, to December 31, 2018, were retrospectively identified from 22 centers worldwide. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV, adnexal involvement, or unknown adjuvant therapy (ATx) were excluded.

Results: Of 247 patients included, 132 had isolated tumor cell (ITC) and 115 had micrometastasis (MM). Overall 4-year recurrence-free survival (RFS) was 77.6% (95% CI, 70.2%-85.9%); median follow-up for patients without recurrence was 29.6 (interquartile range, 19.2-41.5) months. At multivariate analysis, Non-endometrioid (NE) (HR, 5.00; 95% CI, 2.50-9.99; P < .001), lymphovascular space invasion (LVSI) (HR, 3.26; 95% CI, 1.45-7.31; P = .004), and uterine serosal invasion (USI) (HR, 3.70; 95% CI, 1.44-9.54; P = .007) were independent predictors of recurrence. Among 47 endometrioid ITC patients without ATx, 4-year RFS was 82.6% (95% CI, 70.1%-97.2). Considering 18 ITC patients with endometrioid grade 1 disease, without LVSI, USI, or ATx, only 1 had recurrence (median follow-up, 24.8 months).

Conclusions: In patients with SLN-LVM, NE, LVSI, and USI were independent risk factors for recurrence. Patients with any risk factor had poor prognosis, even when receiving ATx. Patients with ITC and grade 1 endometrioid disease (no LVSI/USI) had favorable prognosis, even without ATx. Further analysis (with more patients and longer follow-up) is needed to assess whether ATx can be withheld in this low-risk subgroup.
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http://dx.doi.org/10.1016/j.ygyno.2021.06.031DOI Listing
September 2021

Fertility preservation in childhood and adolescent female tumor survivors.

Fertil Steril 2021 10 5;116(4):1087-1095. Epub 2021 Jul 5.

Pediatric Oncology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy.

Objective: To assess the proportion of female childhood and adolescent tumor survivors who could benefit from oocyte cryopreservation.

Design: Case series of female childhood and adolescent tumor survivors referred for fertility counseling.

Setting: A referral cancer center and an infertility unit of an academic hospital.

Patient(s): Young female childhood and adolescent tumor survivors who received gonadotoxic treatments.

Intervention(s): Patients were prescribed tests of ovarian reserve and a personalized counseling was given. Oocyte cryopreservation was considered in subjects aged ≥18 years who were diagnosed with diminished ovarian reserve (DOR) (antimüllerian hormone level <2 ng/mL or total antral follicle count ≤10).

Main Outcome Measure(s): Rate of women with DOR who stored their oocytes.

Result(s): Ninety out of 126 evaluated women completed the assessments. We documented preserved ovarian reserve, DOR, and premature ovarian insufficiency in 36 (40%), 35 (39%), and 19 (21%) cases, respectively. Overall, 13 subjects with DOR were eligible for oocyte cryostorage, of whom 9 (69%) underwent the procedure. Considering the whole cohort of evaluated young women (n = 90), the rate of those who had egg freezing was 10%. Finally, nine women started seeking pregnancy after the counseling (six with DOR), and seven of them became pregnant. When the data were analyzed separately according to most gonadotoxic treatments, considerable differences emerged but the evidence did not support the idea that counseling should be restricted to particular subgroups of women.

Conclusion(s): Ovarian reserve impairment is common in female childhood and adolescent tumor survivors. Postcancer oocyte cryopreservation may be part of the armamentarium of fertility preservation options.
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http://dx.doi.org/10.1016/j.fertnstert.2021.06.012DOI Listing
October 2021

Surveillance alone in stage I malignant ovarian germ cell tumors: a MITO (Multicenter Italian Trials in Ovarian cancer) prospective observational study.

Int J Gynecol Cancer 2021 09 25;31(9):1242-1247. Epub 2021 May 25.

Department of Obstetrics and Gynecology, IRCCS Ospedale San Raffaele, Milano, Italy

Objective: The aim of this study was to analyze the oncological outcome of stage I malignant ovarian germ cell tumors patients included in the MITO-9 study to identify those who might be recommended routine surveillance alone after complete surgical staging.

Methods: MITO-9 was a prospective observational study analyzing data collected between January 2013 and December 2019. Three groups were identified: group A included 13 patients stage IA dysgerminoma and IAG1 immature teratoma; group B included 29 patients with stage IB-C dysgerminomas, IA-C G2-G3 immature teratomas and stage IA mixed malignant ovarian germ cell tumors and yolk sac tumors; and group C included five patients (two patients with stage IC1 and one patient with stage IC2 yolk sac tumors and two patients with mixed-stage IC2 malignant ovarian germ cell tumors).

Results: A total of 47 patients with stage I conservatively treated malignant ovarian germ cell tumors were analyzed. Two patients in group B were excluded from the routine surveillance alone group due to positive surgical restaging. Therefore, a total of 45 patients were included in the study. Median follow-up was 46.2 months (range; 6-83). In total, 14 of 45 patients (31.1%) received chemotherapy, while 31 (68.9%%) underwent surveillance alone. One patient in group A, with stage IA dysgerminoma had a relapse, successfully managed with conservative surgery and chemotherapy. None of the patients in group B and C relapsed. All patients were alive at completion of the study. Overall, among 31 patients (68.9%) who underwent surveillance alone, only one patient relapsed but was treated successfully.

Conclusions: Our data showed that close surveillance alone could be an alternative option to avoid adjuvant chemotherapy in properly staged IB-C dysgerminomas, IA-IC G2-G3 immature teratomas, and IA mixed malignant ovarian germ cell tumors with yolk sac tumor component.
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http://dx.doi.org/10.1136/ijgc-2021-002575DOI Listing
September 2021

Cytoreductive surgery followed by chemotherapy and olaparib maintenance in BRCA 1/2 mutated recurrent ovarian cancer: a retrospective MITO group study.

Int J Gynecol Cancer 2021 07 14;31(7):1031-1036. Epub 2021 May 14.

Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy

Introduction: The role of cytoreductive surgery in the poly-ADP ribose polymerase inhibitors era is not fully investigated. We evaluated the impact of surgery performed prior to platinum-based chemotherapy followed by olaparib maintenance in platinum-sensitive BRCA-mutated recurrent ovarian cancer.

Methods: This retrospective study included platinum-sensitive recurrent ovarian cancer BRCA-mutated patients from 13 Multicenter Italian Trials in Ovarian cancer and gynecological malignancies centers treated between September 2015 and May 2019. The primary outcomes were progression-free survival and overall survival. Data on post-progression treatment was also assessed.

Results: Among 209 patients, 72 patients (34.5%) underwent cytoreductive surgery followed by platinum-based chemotherapy and olaparib maintenance, while 137 patients (65.5%) underwent chemotherapy treatment alone. After a median follow-up of 37.3 months (95% CI: 33.4 to 40.8), median progression-free survival in the surgery group was not reached, compared with 11 months in patients receiving chemotherapy alone (P<0.001). Median overall survival was nearly double in patients undergoing surgery before chemotherapy (55 vs 28 months, P<0.001). Post-progression therapy was assessed in 127 patients: response rate to chemotherapy was 29.2%, 8.8%, and 9.0% in patients with platinum-free interval >12 months, between 6 and 12 months, and <6 months, respectively.

Conclusion: Cytoreductive surgery performed before platinum therapy and olaparib maintenance was associated with longer progression-free survival and overall survival in BRCA-mutated platinum-sensitive relapsed ovarian cancer patients. In accordance with our preliminary results, the response rate to chemotherapy given after progression during olaparib was associated with platinum-free interval.
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http://dx.doi.org/10.1136/ijgc-2020-002343DOI Listing
July 2021

Uterine serous carcinoma.

Gynecol Oncol 2021 07 30;162(1):226-234. Epub 2021 Apr 30.

Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy.

Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease.
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http://dx.doi.org/10.1016/j.ygyno.2021.04.029DOI Listing
July 2021

Bevacizumab, carboplatin, and paclitaxel in the first line treatment of advanced ovarian cancer patients: the phase IV MITO-16A/MaNGO-OV2A study.

Int J Gynecol Cancer 2021 06 30;31(6):875-882. Epub 2021 Apr 30.

Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.

Objective: To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab.

Methods: A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints.

Results: From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1-40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported.

Conclusions: Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors.

Trial Registration Number: EudraCT 2012-003043-29; NCT01706120.
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http://dx.doi.org/10.1136/ijgc-2021-002434DOI Listing
June 2021

Immune-Checkpoint Inhibitors in Platinum-Resistant Ovarian Cancer.

Cancers (Basel) 2021 Apr 1;13(7). Epub 2021 Apr 1.

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Giacomo Venezian 1, 20133 Milano, Italy.

Platinum-resistant ovarian cancer (OC) has limited treatment options and is associated with a poor prognosis. There appears to be an overlap between molecular mechanisms responsible for platinum resistance and immunogenicity in OC. Immunotherapy with single agent checkpoint inhibitors has been evaluated in a few clinical trials with disappointing results. This has prompted exploration of immunotherapy combination strategies with chemotherapy, anti-angiogenics, poly (ADP-ribose) polymerase (PARP) inhibitors and other targeted agents. The role of immunotherapy in the treatment of platinum-resistant OC remains undefined. The aim of this review is to describe the immunobiology of OC and likely benefit from immunotherapy, discuss clinical trial data and biomarkers that warrant further exploration, as well as provide an overview of future drug development strategies.
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http://dx.doi.org/10.3390/cancers13071663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037571PMC
April 2021

Is a tailored strategy using proton beam radiotherapy for reirradiation advantageous for elderly women? A case report.

Tumori 2021 Dec 25;107(6):NP67-NP72. Epub 2021 Apr 25.

Radiation Oncology, Clinical Department, National Center for Oncological Hadrontherapy (CNAO), Pavia, Italy.

Background: The management of primary or recurrent vaginal tumours in an aging population is challenging for gynecologic and radiation oncologists. In patients unsuited for surgery and already irradiated on the pelvis, proton beam radiotherapy may be worthwhile due to its ballistic advantages.

Case Report: We report the case of an 80-year-old woman with a squamous cell carcinoma of the vagina after a history of pelvic radiation and vaginal brachytherapy delivered for a previous endometrial adenocarcinoma. She received proton beam radiotherapy with a complete response after 12 months and mild toxicity.

Conclusions: The complexity of reirradiation management in the frail and elderly population requires attention. Efforts should be focused on maintaining autonomy and quality of life in order to improve adherence and clinical compliance to the treatment. In the era of the tailored approach, hadrontherapy can play an important role to minimize toxicity, obtain good local control, and reduce the overall treatment time.
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http://dx.doi.org/10.1177/03008916211007930DOI Listing
December 2021

Age-related distribution of uncommon HPV genotypes in cervical intraepithelial neoplasia grade 3.

Gynecol Oncol 2021 06 29;161(3):741-747. Epub 2021 Mar 29.

Woman's Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy. Electronic address:

Aim: Cervical cancer prevention guidelines include Human Papillomavirus (HPV) test, cytology, and HPV-16/18 typing for triage to determine the risk of cervical intraepithelial neoplasia (CIN) grade 3 as the best proxy of cervical cancer risk. In doing that, they do not consider how age can modify the type-specific risk of CIN3. The present study aimed to evaluate the age-related distribution of HPV genotypes affecting the risk-assessment in cervical cancer screening programs: non-screening-type-HPV and non-HPV-16/18 in unvaccinated women with CIN3.

Methods: Retrospective multi-institutional study, including HPV genotyped women with CIN3 on cone histology treated between 2014 and 2019. The sample was divided into three categories of age: <30, 30-44, ≥45. HPV genotypes were grouped in non-screening-type-HPV (not-including genotypes 16/18/31/33/35/39/45/51/52/56/58/59/66/68) and non-HPV-16/18. Associations and trends between different age-groups and HPV genotypes were measured.

Results: 1332 women were analyzed. Non-screening-type-HPV CIN3 were 73 (5.5%). Non-HPV-16/18 were found in 417 participants (31.3%). Women over 45 associated with non-screening-type HPV [odds ratio (OR) = 1.87, 95% confidence interval (CI) 1.07-3.25; p = 0.027]. Non-screening-type-HPV prevalence increased significantly with age (3.9% vs 5.1% vs 9.0%, p = 0.016). Women under 30 showed a lower rate of non-HPV-16/18 (OR = 0.65, 95% CI 0.47-0.89; p = 0.007). There was a positive trend with age of non-HPV-16/18 CIN3 (23.6% vs 32.1% vs 38.0%, p = 0.0004).

Conclusion: The proportion of CIN3 lesions unrelated to genotypes detected by primary screening tests increased with age. This implies that age probably modifies the risk of CIN3 and possibly of cancer associated with HPV types. The risk-based recommendation should take into consideration age to define the management of HPV positive women.
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http://dx.doi.org/10.1016/j.ygyno.2021.03.025DOI Listing
June 2021

Fertility-sparing treatment in advanced-stage serous borderline ovarian tumors. An analysis from the MITO14 study database.

Gynecol Oncol 2021 06 27;161(3):825-831. Epub 2021 Mar 27.

Department of Gynecologic Oncology, Istituto Nazionale Tumori, IRCSS, "Fondazione G. Pascale", Naples, Italy. Electronic address:

Objectives: To evaluate oncological and reproductive outcomes of women undergoing fertility-sparing surgery (FSS) for stage II-III serous borderline ovarian tumors (BOTs).

Methods: A multi-institutional retrospective study was conducted within the MITO Group.

Results: A total of 91 patients were recruited. The median follow-up time from primary cytoreduction was 127 months (IQR range 91-179). Forty-nine patients (53.8%) experienced at least one recurrence (median time to first relapse 22 months, IQR range 9.5-57). At univariable analysis, significant predictors of relapse were: size of largest extra-ovarian lesion, peritoneal cancer index, completeness of cytoreduction, type of implants. After multivariable analysis, the size of extra-ovarian lesions and the presence of invasive implants resulted as the only independent predictors of recurrence. Median disease-free survival (DFS) was 96 months (95% CI, 24.6-167.3), while median disease-specific survival (DSS) was not reached. Twenty-nine patients (31.8%) attempted to conceive: 20 (68.9%) achieved at least one pregnancy and 18 (62%) gave birth to a healthy child. At the end of the observation period, 88 patients (96.7%) showed no evidence of disease, 2 (2.2%) were alive with disease, and 1 patient (1.1%) died from BOT.

Conclusions: Despite the recurrence high rate, FSS provides good chances of reproductive success with no impact on DSS. The presence of invasive peritoneal implants affects the DFS but not DSS nor reproductive outcome. The risk of recurrence would not seem to be related to the ovarian preservation per se, but to the natural history of the initial peritoneal spread.
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http://dx.doi.org/10.1016/j.ygyno.2021.03.023DOI Listing
June 2021

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27-45 years of age compared to women 16-26 years of age: An open-label phase 3 study.

Vaccine 2021 05 3;39(20):2800-2809. Epub 2021 Mar 3.

Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address:

Background: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16-26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27-45 versus 16-26 years of age.

Methods: This international, open-label study (NCT03158220) was conducted in women 16-45 years of age. Participants (16-26 years, n = 570 and 27-45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study.

Results: At month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27-45 years were compared to those in women 16-26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27-45 years to 16-26 years) was 0.60-0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27-45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16-26 years, and 85.2% and 24.1% of women 27-45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study.

Conclusions: The 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27-45 years compared with women 16-26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16-26 years to women 27-45 years of age. Clinical trial registration NCT03158220.
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http://dx.doi.org/10.1016/j.vaccine.2021.01.074DOI Listing
May 2021

Conization and lymph node evaluation as a fertility-sparing treatment for early stage cervical cancer.

Int J Gynecol Cancer 2021 03;31(3):457-461

Gynecologic Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Introduction: To evaluate oncological and obstetrical outcomes of early stage cervical cancer patients who underwent conservative management to retain childbearing potential.

Methods: Data of women (aged <40 years) who underwent fertility sparing treatment for International Federation of Gynecology and Obstetrics (FIGO) stage IA1 with lymphovascular invasion (LVSI) and IB1 cervical cancer were prospectively collected. All patients underwent cervical conization/s and laparoscopic nodal evaluation (pelvic lymphadenectomy/sentinel node mapping). Oncological and obstetrical outcomes were assessed.

Results: Overall, 39 patients met inclusion criteria; 36 (92.3%) women were nulliparous. There were: 3 (7.7%) IA1-LVSI+; 11 (28.2%) IA2; and 25 (64.1%) IB1 cervical cancers, according to 2018 FIGO stage classification. Histological types were 22 (56.4%) squamous carcinoma and 17 (43.6%) adenocarcinoma. Pelvic lymphadenectomy was performed in 29 (74.4%) patients, while 10 (25.6%) patients had only sentinel node mapping. In 4 (10.3%) patients conservative treatment was discontinued due to nodal involvement and 2 (5.1%) patients requested definitive treatment (hysterectomy) after a negative lymph node evaluation. Among 33 (84.6%) patients who retained their childbearing potential, 17 (51.5%) had a second conization. 2 (6.1%) patients relapsed and underwent definitive treatment. After a median follow-up of 51 months (range 1-184) no deaths were reported. 22 (70.9%) patients attempted to conceive. There were 13 natural pregnancies among 12 (54.5%) women who got pregnant. Live birth rate was 76.9%: 9 (69.2%) term and 1 (7.7%) preterm (at 32 weeks) deliveries. 2 (15.4%) miscarriages (first and second trimester) and 1 (7.7%) termination of pregnancy for medical reasons were recorded.

Conclusion: Conization plus laparoscopic nodal evaluation may be a safe and feasible conservative option in the setting of fertility-sparing treatment for early-stage cervical cancer patients.
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http://dx.doi.org/10.1136/ijgc-2020-001740DOI Listing
March 2021

Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial.

Lancet Oncol 2021 02;22(2):267-276

Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Ginecologia Oncologica-Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore di Roma, Rome, Italy.

Background: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug.

Methods: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17.

Findings: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related.

Interpretation: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice.

Funding: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.
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http://dx.doi.org/10.1016/S1470-2045(20)30637-9DOI Listing
February 2021

High-risk HPV-positive and -negative high-grade cervical dysplasia: Analysis of 5-year outcomes.

Gynecol Oncol 2021 04 26;161(1):173-178. Epub 2021 Jan 26.

Department of Woman's and Child's Health, Obstetrics and Gynecological Unit, San Camillo-Forlanini Hospital, Rome, Italy.

Objective: To evaluate the outcomes of high-risk (HR) HPV-positive and -negative women affected by high-grade cervical dysplasia.

Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with high-grade cervical dysplasia undergoing conization between 2010 and 2014 were retrieved. All patients included had at least 5 years of follow-up. A propensity-score matching was adopted in order to reduce the presence of confounding factors between groups. Kaplan-Meir and Cox hazard models were used to estimate 5-year outcomes.

Results: Overall, data of 2966 women, affected by high-grade cervical dysplasia were reviewed. The study population included 1478 (85%) and 260 (15%) women affected by HR-HPV-positive and HR-HPV-negative high-grade cervical dysplasia. The prevalence of CIN2 and CIN3 among the HR-HPV-positive and -negative cohort was similar (p = 0.315). Patients with HR-HPV-positive high-grade cervical dysplasia were at higher risk of 5-year recurrence (after primary conization) that HR-HPV-negative patients (p < 0.001, log-rank test). Via multivariate analysis, HR-HPV-negative women were at low risk of recurrence (HR: 1.69 (95%CI: 1.05, 4.80); p = 0.018, Cox Hazard model). A propensity-score matched comparison was carried out in order to reduce biases that are related to the retrospective study design. In comparison to HR-HPV-negative patients, thosewith HR-HPV-positive CIN3 was associate with a 8-fold increase in the risk of recurrence (p < 0.001, log-rank test).

Conclusions: HR-HPV-negative high-grade cervical dysplasia is not uncommon, accounting for 15% of our study population. Those patients experience more favorable outcomes than patients with documented HR-HPV infection(s). Further prospective studies are needed to corroborate our data.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.020DOI Listing
April 2021

Oncological outcomes of laparoscopic radical hysterectomy versus radical abdominal hysterectomy in patients with early-stage cervical cancer: a multicenter analysis.

Int J Gynecol Cancer 2021 04 27;31(4):504-511. Epub 2021 Jan 27.

Department of Gynecologic Oncology, Instituto Nacional de Cancerologia, Bogota, Colombia

Introduction: Recent evidence has shown adverse oncological outcomes when minimally invasive surgery is used in early-stage cervical cancer. The objective of this study was to compare disease-free survival in patients that had undergone radical hysterectomy and pelvic lymphadenectomy, either by laparoscopy or laparotomy.

Methods: We performed a multicenter, retrospective cohort study of patients with cervical cancer stage IA1 with lymph-vascular invasion, IA2, and IB1 (FIGO 2009 classification), between January 1, 2006 to December 31, 2017, at seven cancer centers from six countries. We included squamous, adenocarcinoma, and adenosquamous histologies. We used an inverse probability of treatment weighting based on propensity score to construct a weighted cohort of women, including predictor variables selected a priori with the possibility of confounding the relationship between the surgical approach and survival. We estimated the HR for all-cause mortality after radical hysterectomy with weighted Cox proportional hazard models.

Results: A total of 1379 patients were included in the final analysis, with 681 (49.4%) operated by laparoscopy and 698 (50.6%) by laparotomy. There were no differences regarding the surgical approach in the rates of positive vaginal margins, deep stromal invasion, and lymphovascular space invasion. Median follow-up was 52.1 months (range, 0.8-201.2) in the laparoscopic group and 52.6 months (range, 0.4-166.6) in the laparotomy group. Women who underwent laparoscopic radical hysterectomy had a lower rate of disease-free survival compared with the laparotomy group (4-year rate, 88.7% vs 93.0%; HR for recurrence or death from cervical cancer 1.64; 95% CI 1.09-2.46; P=0.02). In sensitivity analyzes, after adjustment for adjuvant treatment, radical hysterectomy by laparoscopy compared with laparotomy was associated with increased hazards of recurrence or death from cervical cancer (HR 1.7; 95% CI 1.13 to 2.57; P=0.01) and death for any cause (HR 2.14; 95% CI 1.05-4.37; P=0.03).

Conclusion: In this retrospective multicenter study, laparoscopy was associated with worse disease-free survival, compared to laparotomy.
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http://dx.doi.org/10.1136/ijgc-2020-002086DOI Listing
April 2021

Sentinel node mapping vs. sentinel node mapping plus back-up lymphadenectomy in high-risk endometrial cancer patients: Results from a multi-institutional study.

Gynecol Oncol 2021 04 20;161(1):122-129. Epub 2021 Jan 20.

Gynecological Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy.

Objective: Sentinel node mapping (SLN) has replaced lymphadenectomy for staging surgery in apparent early-stage low and intermediate risk endometrial cancer (EC). Only limited data about the adoption of SNM in high risk EC is still available. Here, we evaluate the outcomes of high-risk EC undergoing SNM (with or without back-up lymphadenectomy).

Methods: This is a multi-institutional international retrospective study, evaluating data of high-risk (FIGO grade 3 endometrioid EC with myometrial invasion >50% and non-endometrioid histology) EC patients undergoing SNM followed by back-up lymphadenectomy and SNM alone.

Results: Chart of consecutive 196 patients were evaluated. The study population included 83 and 113 patients with endometrioid and non-endometrioid EC, respectively. SNM alone and SNM followed by back-up lymphadenectomy were performed in 50 and 146 patients, respectively. Among patients having SNM alone, 14 (28%) were diagnosed with nodal disease. In the group of patients undergoing SNM plus back-up lymphadenectomy 34 (23.2%) were diagnosed with nodal disease via SNM. Back-up lymphadenectomy identified 2 (1%) additional patients with nodal disease (in the para-aortic area). Back-up lymphadenectomy allowed to remove adjunctive positive nodes in 16 (11%) patients. After the adoption of propensity-matched algorithm, we observed that patients undergoing SNM plus back-up lymphadenectomy experienced similar disease-free survival (p = 0.416, log-rank test) and overall survival (p = 0.940, log-rank test) than patients undergoing SLN alone.

Conclusions: Although the small sample size, and the retrospective study design this study highlighted that type of nodal assessment did not impact survival outcomes in high-risk EC. Theoretically, back-up lymphadenectomy would be useful in improving the removal of positive nodes, but its therapeutic value remains controversial. Further prospective evidence is needed.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.008DOI Listing
April 2021
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