Publications by authors named "Stefano Greggi"

70 Publications

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

Gynecol Oncol 2021 Mar 26. Epub 2021 Mar 26.

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
March 2021

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

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

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

Assessing the Long-Term Role of Vaccination against HPV after Loop Electrosurgical Excision Procedure (LEEP): A Propensity-Score Matched Comparison.

Vaccines (Basel) 2020 Dec 1;8(4). Epub 2020 Dec 1.

Department of Gynecological, Obstetrical and Urological Sciences, "Sapienza" University of Rome, 00185 Rome, Italy.

: Primary prevention through vaccination is a prophylactic approach aiming to reduce the risk of developing human papillomavirus (HPV)-related lesions. No mature and long-term data supported the adoption of vaccination in women undergoing conization. This is a retrospective multi-institutional study. Charts of consecutive patients undergoing conization between 2010 and 2014 were collected. All patients included had at least 5 years of follow-up. We compared outcomes of patients undergoing conization plus vaccination and conization alone. A propensity-score matching algorithm was applied in order to reduce allocation biases. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. : Overall, charts of 1914 women were analyzed. The study group included 116 (6.1%) and 1798 (93.9%) women undergoing conization plus vaccination and conization alone, respectively. Five-year recurrence rate was 1.7% ( = 2) and 5.7% ( = 102) after conization plus vaccination and conization alone, respectively ( = 0.068). After the application of a propensity-score matching, we selected 100 patients undergoing conization plus vaccination and 200 patients undergoing conization alone. The crude number of recurrences was 2 (2%) and 11 (5.5%) for patients undergoing conization plus vaccination and conization alone, respectively ( = 0.231). Vaccination had no impact on persistent lesions (no negative examination between conization and new cervical dysplasia; = 0.603), but reduced the risk of recurrent disease (patients who had at least one negative examination between conization and the diagnosis of recurrent cervical dysplasia; = 0.031). Patients having vaccination experience a slightly lower risk of recurrence than women who had not, although not statistically significantly different. Further evidence is needed to assess the cost effectiveness of adopting vaccination in this setting.
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http://dx.doi.org/10.3390/vaccines8040717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711506PMC
December 2020

Impact of COVID-19 in gynecologic oncology: a Nationwide Italian Survey of the SIGO and MITO groups.

J Gynecol Oncol 2020 11;31(6):e92

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Objective: Coronavirus disease 2019 (COVID-19) has caused rapid and drastic changes in cancer management. The Italian Society of Gynecology and Obstetrics (SIGO), and the Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) promoted a national survey aiming to evaluate the impact of COVID-19 on clinical activity of gynecologist oncologists and to assess the implementation of containment measures against COVID-19 diffusion.

Methods: The survey consisted of a self-administered, anonymous, online questionnaire. The survey was sent via email to all the members of the SIGO, and MITO groups on April 7, 2020, and was closed on April 20, 2020.

Results: Overall, 604 participants completed the questionnaire with a response-rate of 70%. The results of this survey suggest that gynecologic oncology units had set a proactive approach to COVID-19 outbreak. Triage methods were adopted in order to minimize in-hospital diffusion of COVID-19. Only 38% of gynecologic surgeons were concerned about COVID-19 outbreak. Although 73% of the participants stated that COVID-19 has not significantly modified their everyday practice, 21% declared a decrease of the use of laparoscopy in favor of open surgery (19%). However, less than 50% of surgeons adopted specific protection against COVID-19. Additionally, responders suggested to delay cancer treatment (10%-15%), and to perform less radical surgical procedures (20%-25%) during COVID-19 pandemic.

Conclusions: National guidelines should be implemented to further promote the safety of patients and health care providers. International cooperation is of paramount importance, as heavily affected nations can serve as an example to find out ways to safely preserve clinical activity during the COVID-19 outbreak.
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http://dx.doi.org/10.3802/jgo.2020.31.e92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593217PMC
November 2020

Recurrence rate after loop electrosurgical excision procedure (LEEP) and laser Conization: A 5-year follow-up study.

Gynecol Oncol 2020 12 3;159(3):636-641. Epub 2020 Sep 3.

Gynecological Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via G Venezian 1, Milano, 20133, MI, Italy.

Objective: Conization aims to remove pre-neoplastic lesions of the uterine cervix. Several techniques for conization have been compared, but evidence regarding the most effective therapeutic option is scant. Here, we aimed to compare the recurrence rate following laser conization and loop electrosurgical excision procedure (LEEP) in patients with high-grade cervical dysplasia (HSIL/CIN2+).

Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with HSIL/CIN2+ undergoing conization between 2010 and 2014 were retrieved. A propensity-score matching (PSM) was applied in order to reduce allocation bias. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models.

Results: Overall, 2966 patients had conization over the study period, including 567 (20%) and 2399 (80%) patients having laser conization and LEEP, respectively. Looking at predictors of recurrence, diagnosis of CIN3 (HR:3.80 (95%CI:2.01,7.21); p < 0.001) and HPV persistence (HR:1.81 (95%CI:1.11,2.96); p < 0.001) correlated with an increased risk of recurrence. After applying a PSM we selected 500 patients undergoing laser conization and 1000 undergoing LEEP. Patients undergoing LEEP were at higher risk of having positive surgical margins in comparison to patients undergoing laser conization (11.2% vs. 4.2%). The risk of having persistence of HPV was similar between the two groups (15.0% vs. 11.6%;p = 0.256). Five-year recurrence rate was 8.1% and 4% after LEEP and laser conization, respectively (p = 0.023). HPV persistence was the only factor associated with [5-]year recurrence after both laser conization (p = 0.003) and LEEP (p = 0.001).

Conclusions: HPV persistence is the only factor associated with an increased risk of recurrence after either laser conization or LEEP. Owing to the lack of data regarding obstetrical outcomes, we are not able to assess the best therapeutic option for women with cervical dysplasia.
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http://dx.doi.org/10.1016/j.ygyno.2020.08.025DOI Listing
December 2020

Immunotherapy in cervix cancer.

Cancer Treat Rev 2020 Nov 7;90:102088. Epub 2020 Aug 7.

Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. Electronic address:

The treatment approach to cervix cancer has remained unchanged for several decades and new therapeutic strategies are now required to improve outcomes, as the prognosis is still poor. In the last years, a better understanding of HPV tumor-host immune system interactions and the development of new therapeutics targeting immune checkpoints generated interest in the use of immunotherapy in cervix cancer. Preliminary phase I-II trials demonstrated the efficacy, the duration of responses and the manageable safety of this approach. Currently, many phase II and III studies are ongoing in both locally advanced and metastatic cervical cancer, assessing immunotherapy as a single agent or in combination with chemotherapy and radiotherapy. We reviewed the published data and the therapeutic implications of the most promising novel immunotherapeutic agents under investigation in cervix cancer.
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http://dx.doi.org/10.1016/j.ctrv.2020.102088DOI Listing
November 2020

Fertility-sparing treatment for intramucous, moderately differentiated, endometrioid endometrial cancer: a Gynecologic Cancer Inter-Group (GCIG) study.

J Gynecol Oncol 2020 Sep;31(5):e74

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

Objective: 'The Endometrial Cancer Conservative Treatment (E.C.Co.). A multicentre archive' is a worldwide project endorsed by the Gynecologic Cancer Inter-Group, aimed at registering conservatively treated endometrial cancer (EC) patients. This paper reports the oncological and reproductive outcomes of intramucous, G2, endometrioid EC patients from this archive.

Methods: Twenty-three patients (Stage IA, G2, endometrioid EC) were enrolled between January 2004 and March 2019. Primary and secondary endpoints were, respectively, complete regression (CR) and recurrence rates, and pregnancy and live birth rates.

Results: A median follow-up of 35 months (9-148) was achieved. Hysteroscopic resection (HR) plus progestin was adopted in 74% (17/23) of cases. Seventeen patients showed CR (median time to CR, 6 months; 3-13). Among the 6 non-responders, one showed persistence and 5 progressed, all submitted to definitive surgery, with an unfavorauble outcome in one. The recurrence rate was 41.1%. Ten (58.8%) complete responders attempted to conceive, of whom 3 achieved at least one pregnancy with a live-birth. Two out of the 11 candidate patients underwent definitive surgery, while the remaining 9 have so far refused. To date, 22 patients show no evidence of disease, and one is still alive with disease.

Conclusions: Fertility-sparing treatment seems to be feasible even in G2 EC, although caution should be kept considering the potential pathological undergrading or non-endometrioid histology misdiagnosis. The low rate of attempt to conceive and of compliance to definitive surgery underline the need for a 'global' counselling extended to the follow-up period.
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http://dx.doi.org/10.3802/jgo.2020.31.e74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440989PMC
September 2020

Survival implication of lymphadenectomy in patients surgically treated for apparent early-stage uterine serous carcinoma.

J Gynecol Oncol 2020 Sep;31(5):e64

Department of Obstetrics and Gynecology, University of Insubria, Varese, Italy.

Objective: Uterine serous carcinoma (USC) is a rare highly aggressive disease. In the present study, we aimed to investigate the survival implication of the systematic lymphadenectomy in patients who underwent surgery for apparent early-stage USC.

Methods: Consecutive patients with apparent early-stage USC surgically treated at six Italian referral cancer centers were analyzed. A comparison was made between patients who underwent retroperitoneal staging including at least pelvic lymphadenectomy "LND" vs. those who underwent hysterectomy alone "NO-LND". Baseline, surgical and oncological outcomes were analyzed. Kaplan- Meier curves were calculated for disease-free survival (DFS) and disease-specific survival (DSS). Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR).

Results: One hundred forty patients were analyzed, 106 LND and 34 NO-LND. NO-LND group (compared to LND group) included older patients (median age, 73 vs.67 years) and with higher comorbidities (median Charlson Comorbidity Index, 6 vs. 5) (p<0.001). No differences in terms of recurrence rate (LND vs. NO-LND, 33.1% vs. 41.4%; p=0.240) were observed. At Cox regression analysis lymphadenectomy did not significantly influence DFS (HR=0.59; 95% confidence interval [CI]=0.32-1.08; p=0.09), and DSS (HR=0.14; 95% CI=0.02-1.21; multivariable analysis p=0.07). Positive node was independently associated with worse DFS (HR=6.22; 95% CI=3.08-12.60; p<0.001) and DSS (HR=5.51; 95% CI=2.31-13.10; p<0.001), while adjuvant chemotherapy was associated with improved DFS (HR=0.38; 95% CI=0.17-0.86; p=0.02) and age was independently associated with worse DSS (HR=1.07; 95% CI=1.02-1.13; p<0.001).

Conclusions: Although lymphadenectomy did not show survival benefits in patients who underwent surgery for apparent early-stage USC, the presence of lymph node metastasis was the main adverse prognostic factors, supporting the prognostic role of the retroperitoneal staging also in this histological subtype.
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http://dx.doi.org/10.3802/jgo.2020.31.e64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440990PMC
September 2020

Cytoreductive Surgery for Heavily Pre-Treated, Platinum-Resistant Epithelial Ovarian Carcinoma: A Two-Center Retrospective Experience.

Cancers (Basel) 2020 Aug 10;12(8). Epub 2020 Aug 10.

Candiolo Cancer Institute, FPO-IRCCS-Candiolo, 10060 Torino, Italy.

Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival and surgical morbidity and mortality after maximal cytoreduction in this setting. We evaluated all consecutive patients undergoing cytoreduction for platinum-resistance over an 8-year period (2010-2018) in two different centers. Fifty patients (median age 52.5 years, range 34-75) were included; the median number of previous chemotherapy lines was three (range 1-7) and the median number of previous surgeries was one (range 1-4). Completeness of cytoreduction (CC = 0) was achieved in 22 patients (44%). Rates of major operative morbidity and 30-day mortality were 38% and 8%, respectively. Median follow-up was 35 months. The absence of tumor residual (CC = 0) was associated with a significantly better overall survival (OS) compared to the CC > 0 subgroup (median OS 32.9 months (95% CI 21.6-44.2) vs. 4.8 months (95% CI n.a.-9.8), hazard ratio (HR) 4.21 (95% CI 2.07-8.60), < 0.001). Optimal cytoreduction is feasible and associated with promising OS in selected, heavily pre-treated PROCs. Further prospective studies are required to better define the role of surgery in platinum-resistant disease.
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http://dx.doi.org/10.3390/cancers12082239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464658PMC
August 2020

Evaluation of surgical resection in advanced ovarian, fallopian tube, and primary peritoneal cancer: laparoscopic assessment. A European Network of Gynaecological Oncology Trial (ENGOT) group survey.

Int J Gynecol Cancer 2020 06 30;30(6):819-824. Epub 2020 Apr 30.

Grupo Español de Investigación en Cáncer de Ovario (GEICO) and Department of Medical Oncology, Clínica Universidad de Navarra, Madrid, Spain.

Objective: Laparoscopy is one of the diagnostic tools available for the complex clinical decision-making process in advanced ovarian, fallopian tube, and peritoneal carcinoma. This article presents the results of a survey conducted within the European Network of Gynaecological Oncology Trial (ENGOT) group aimed at reviewing the current patterns of practice at gynecologic oncology centers with regard to the evaluation of resection in advanced ovarian, fallopian tube, and peritoneal carcinoma.

Methods: A 24-item questionnaire was sent to the chair of the 20 cooperative groups that are currently part of the ENGOT group, and forwarded to the members within each group.

Results: A total of 142 questionnaires were returned. Only 39 respondents (27.5%) reported using some form of clinical (not operative) score for the evaluation of resection. The frequency of use of diagnostic laparoscopy to assess disease status and feasibility of resection was as follows: never, 21 centers (15%); only in select cases, 83 centers (58.5%); and routinely, 36 centers (25.4%). When laparoscopy was performed, 64% of users declared they made the decision to proceed with maximal effort cytoreductive surgery based on their personal/staff opinion, and 36% based on a laparoscopic score. To the question of whether laparoscopy should be considered the gold standard in the evaluation of resection, 71 respondents (50%) answered no, 66 respondents (46.5%) answered yes, whereas 5 respondents (3.5%) did not provide an answer.

Conclusions: This study found that laparoscopy was routinely performed to assess feasibility of cytoreduction in only 25.4% of centers in Europe. However, it was commonly used to select patients and in a minority of centers it was never used . When laparoscopy was adopted, the treatment strategy was based on laparoscopic scores only in a minority of centers.
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http://dx.doi.org/10.1136/ijgc-2019-001172DOI Listing
June 2020

Surgical Management of Early Cervical Cancer: When Is Laparoscopic Appropriate?

Curr Oncol Rep 2020 Jan 27;22(1). Epub 2020 Jan 27.

Gynecologic Oncology, Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale, Naples, Italy.

Purpose Of Review: This paper reviews the recent literature data on minimally invasive surgical approach to early cervical cancer compared to abdominal approach, with the aim of evaluate the oncological outcomes and the appropriateness of current indications.

Recent Findings: A recent multicenter randomized controlled trial and a concurrent large epidemiological study, contrary to the previous retrospective data, showed that minimally invasive surgery is associated with significantly poorer survival than the open approach. Open surgery is to be considered the standard of care for early cervical cancer as implemented in the current guidelines, and the patients must be carefully counseled if minimally invasive surgery is offered. Minimally invasive surgery can be considered safe only for sentinel lymph node mapping in a fertility-sparing setting and could be considered after preoperative conization and for small tumors, adopting preventive surgical maneuvers and in reference centers. However, prospective evidences about the suggested indications are not yet available.
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http://dx.doi.org/10.1007/s11912-020-0876-1DOI Listing
January 2020

Targeting the Formyl Peptide Receptor type 1 to prevent the adhesion of ovarian cancer cells onto mesothelium and subsequent invasion.

J Exp Clin Cancer Res 2019 Nov 8;38(1):459. Epub 2019 Nov 8.

Neoplastic Progression Unit, Istituto Nazionale Tumori IRCCS 'Fondazione G. Pascale', Via M.Semmola, 80131, Naples, Italy.

Background: The biological behavior of epithelial ovarian cancer (EOC) is unique since EOC cells metastasize early to the peritoneum. Thereby, new anti-target agents designed to block trans-coelomic dissemination of EOC cells may be useful as anti-metastatic drugs. The Urokinase Plasminogen Activator Receptor (uPAR) is overexpressed in EOC tissues, and its truncated forms released in sera and/or ascitic fluid are associated with poor prognosis and unfavorable clinical outcome. We documented that uPAR triggers intra-abdominal dissemination of EOC cells through the interaction of its 84-95 sequence with the Formyl Peptide Receptor type 1 (FPR1), even as short linear peptide Ser-Arg-Ser-Arg-Tyr (SRSRY). While the pro-metastatic role of uPAR is well documented, little information regarding the expression and role of FPR1 in EOC is currently available.

Methods: Expression levels of uPAR and FPR1 in EOC cells and tissues were assessed by immunofluorescence, Western blot, or immunohystochemistry. Cell adhesion to extra-cellular matrix proteins and mesothelium as well as mesothelium invasion kinetics by EOC cells were monitored using the xCELLigence technology or assessed by measuring cell-associated fluorescence. Cell internalization of FPR1 was identified on multiple z-series by confocal microscopy. Data from in vitro assays were analysed by one-way ANOVA and post-hoc Dunnett t-test for multiple comparisons. Tissue microarray data were analyzed with the Pearson's Chi-square (χ) test.

Results: Co-expression of uPAR and FPR1 by SKOV-3 and primary EOC cells confers a marked adhesion to vitronectin. The extent of cell adhesion decreases to basal level by pre-exposure to anti-uPAR84-95 Abs, or to the RI-3 peptide, blocking the uPAR84-95/FPR1 interaction. Furthermore, EOC cells exposed to RI-3 or desensitized with an excess of SRSRY, fail to adhere also to mesothelial cell monolayers, losing the ability to cross them. Finally, primary and metastatic EOC tissues express a high level of FPR1.

Conclusions: Our findings identify for the first time FPR1 as a potential biomarker of aggressive EOC and suggests that inhibitors of the uPAR84-95/FPR1 crosstalk may be useful for the treatment of metastatic EOC.
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http://dx.doi.org/10.1186/s13046-019-1465-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839174PMC
November 2019

TRUST: Trial of Radical Upfront Surgical Therapy in advanced ovarian cancer (ENGOT ov33/AGO-OVAR OP7).

Int J Gynecol Cancer 2019 10 15;29(8):1327-1331. Epub 2019 Aug 15.

AGO Study Group and Department of Obstetrics and Gynecology, University Hospital, Ludwig Maximilians University Munich, Munich, Bayern, Germany.

Background: Primary cytoreductive surgery followed by chemotherapy has been considered standard management for patients with advanced ovarian cancer over decades. An alternative approach of interval debulking surgery following neoadjuvant chemotherapy was subsequently reported by two randomized phase III trials (EORTC-GCG, CHORUS), which were criticized owing to important limitations, especially regarding the rate of complete resection.

Primary Objective: To clarify the optimal timing of surgical therapy in advanced ovarian cancer.

Study Hypothesis: Primary cytoreductive surgery is superior to interval cytoreductive surgery following neoadjuvant chemotherapy for overall survival in patients with advanced ovarian cancer.

Trial Design: TRUST is an international open, randomized, controlled multi-center trial investigating overall survival after primary cytoreductive surgery versus neoadjuvant chemotherapy and subsequent interval cytoreductive surgery in patients with FIGO stage IIIB-IVB ovarian, tubal, and peritoneal carcinoma. To guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (eg, ≥50% complete resection rate in upfront surgery for FIGO IIIB-IVB patients, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST quality committee delegates. Patients in the primary cytoreductive surgery arm undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas patients in the interval cytoreductive surgery arm undergo 3 cycles of neoadjuvant chemotherapy after histologic confirmation of the disease, followed by interval cytoreductive surgery and subsequently, 3 cycles of platinum-based chemotherapy. The intention of surgery for both groups is complete tumor resection according to guideline recommendations.

Major Inclusion/exclusion Criteria: Major inclusion criteria are suspected or histologically confirmed, newly diagnosed invasive epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma FIGO stage IIIB-IVB (IV only if resectable metastasis). Major exclusion criteria are non-epithelial ovarian malignancies and borderline tumors; prior chemotherapy for ovarian cancer; or abdominal/pelvic radiotherapy.

Primary Endpoint: Overall survival.

Sample Size: 772 patients.

Estimated Dates For Completing Accrual And Presenting Results: Accrual completion approximately mid-2019, results are expected after 5 years' follow-up in 2024.

Trial Registration: NCT02828618.
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http://dx.doi.org/10.1136/ijgc-2019-000682DOI Listing
October 2019

Application of the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to patients conservatively treated: Outcomes from an institutional series.

Eur J Obstet Gynecol Reprod Biol 2019 Sep 13;240:220-225. Epub 2019 Jul 13.

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

Objective: To test the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) and determine the frequency of specific/prognostic molecular alterations within a cohort of endometrial cancer (EC) women conservatively treated by combined hysteroscopic resection and progestin therapy.

Study Design: We used blocks of formalin-fixed paraffin-embedded tissue from the primary tumors of patients enrolled into the ECCo trial (EudraCT 2010-018581-23) between 2007 and 2016. In order to assign EC resectoscopic specimens to one of four ProMisE subgroups, testing involved sequential assessment of i) immunohistochemistry (IHC) for mismatch repair (MMR) proteins MLH1, MSH2, MSH6 and PMS2; ii) sequencing for POLE/POLD1 exonuclease domain mutations (EDMs); iii) p53 IHC.

Results: Molecular analysis methods were used in 25 patients (stage IA, G1-2 endometrioid EC), of whom 15 (60%) represented fully evaluable cases. Seven cases (46.7%) had abnormal MMR IHC, POLE/POLD1 EDMs were found in 3 cases (20%), and abnormal p53 IHC in 1 case (6.6%). Three patients (20%) had more than one molecular feature. Among 10 (40%) 'unclassifiable' patients, six failures in achieving complete molecular categorization were due to the low tumor volume. Molecular classification of the 15 fully evaluable cases yielded the following ProMisE subtypes: 7 (46.7%) MMR IHC abnormal, 1 (6.6%) POLE EDM, 0 (0%) p53 IHC abnormal, 7 (46.7%) p53 IHC wild-type.

Conclusions: Although larger series are needed to further assess the feasibility of a molecular categorization in a fertility-sparing setting, data presented are promising. In women with early stage low-volume disease, operative hysteroscopy could be advantageous to provide samples allowing complete genetic risk assessment.
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http://dx.doi.org/10.1016/j.ejogrb.2019.07.013DOI Listing
September 2019

The MITO CERV-2 trial: A randomized phase II study of cetuximab plus carboplatin and paclitaxel, in advanced or recurrent cervical cancer.

Gynecol Oncol 2019 06 9;153(3):535-540. Epub 2019 Apr 9.

Clinical Trial Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G.Pascale" IRCCS, Napoli, Italy. Electronic address:

Background: Cervical cancer cells often express Epidermal Growth Factor Receptor (EGFR). Cetuximab (CET), an anti-EGFR antibody, can be safely combined with carboplatin (C) and paclitaxel (P), a standard treatment for advanced/recurrent cervical cancer (ARCC) patients.

Patients And Methods: ARCC patients, ECOG PS ≤ 1, were randomized to CP for 6 cycles with or without CET (400 mg/m one week before starting CP, then 250 mg/m weekly) until disease progression or unacceptable toxicity. Event-free survival (EFS) was the primary endpoint. With a 4.5 months expected median EFS and a 6.4 months predicted EFS (HR 0.70), 0.20 one-tailed α and 80% power, 89 events were required for the final intent-to-treat analysis.

Results: 108 patients were assigned to CP (n = 53) or CP-CET (n = 55). Median age was 50, 69% were PS0, 76% had recurrent disease, 91% had distant metastasis and 57% had received previous chemotherapy. After a median follow-up of 23 months, 102 patients had an event, 97 progressed and 61 died. Median EFS was 4.7 and 6.0 months (one-tail P = 0.43), median PFS was 5.2 and 7.6 months (one-tail P = 0.20) and median OS was 17.7 and 17 months (one-tail P = 0.27), with CP and CP-CET, respectively. There was no difference in the occurrence of severe adverse events, except for skin toxicity. Biomarker analysis, in a small subgroup of patients, suggests that PIK3CA mutation might be predictive of CET resistance.

Conclusion: CP-CET was not more active than CP alone in unselected ARCC patients.
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http://dx.doi.org/10.1016/j.ygyno.2019.03.260DOI Listing
June 2019

A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms.

N Engl J Med 2019 02;380(9):822-832

From the Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen (P. Harter, A. du Bois), Department of Gynecology, Charité-Universitätsmedizin Berlin, Berlin (J.S.), the Coordinating Center for Clinical Trials, Philipps University Marburg (A.R., C.S.-B.), and the Department of Gynecology and Obstetrics, University Hospital Giessen and Marburg (U.W.), Marburg, the Department of Gynecology and Obstetrics, Kaiserswerther Diakonie (B.L.), and the Department of Obstetrics and Gynecology, Heinrich-Heine-University Düsseldorf (W.M.), Düsseldorf, the Department of Gynecology and Obstetrics, University Medicine Greifswald, Greifswald (A.M.), the Department of Gynecology, University Medical Center Hamburg-Eppendorf (S.M.), and the Department of Gynecology and Obstetrics, Albertinen Krankenhaus (I.L.), Hamburg, University Women's Hospital, Department of Gynecology and Reproductive Medicine and Center for Gynecologic Oncology, Jena University Hospital, Jena (I.B.R.), the Department of Obstetrics and Gynecology, University Munich rechts der Isar (B.S.), and the Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-Universität München (A. Burges), Munich, West German Cancer Center, Department of Gynecology and Obstetrics, University of Duisburg-Essen, Duisburg (R.K.), the Department of Gynecology and Obstetrics, University Hospital Kiel, Kiel (F.H.), University Medical Center Freiburg, Freiburg (A.H.), University Medical Center Mainz, Department of Gynecology and Obstetrics, Mainz (A.H.), and the Department of Gynecology and Obstetrics, Hannover Medical School, Hannover (P. Hillemanns) - all in Germany; the Gynecologic Oncology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori (D.L., F.R.), and the Department of Gynecologic Oncology, European Institute of Oncology, University of Milan (G.A.), Milan, the Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome (G.S.), Gynecologic Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori di Napoli, IRCCS Fondazione G. Pascale, Naples (S.G.), and the Cancer Reference Center, Centro di Riferimento Oncologico, Aviano (G.G.) - all in Italy; the Department of Gynecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium (I.V.); the Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria (C.M.); the Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea (J.-W.K.); and the Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic (D.C.).

Background: Systematic pelvic and paraaortic lymphadenectomy has been widely used in the surgical treatment of patients with advanced ovarian cancer, although supporting evidence from randomized clinical trials has been limited.

Methods: We intraoperatively randomly assigned patients with newly diagnosed advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIB through IV) who had undergone macroscopically complete resection and had normal lymph nodes both before and during surgery to either undergo or not undergo lymphadenectomy. All centers had to qualify with regard to surgical skills before participation in the trial. The primary end point was overall survival.

Results: A total of 647 patients underwent randomization from December 2008 through January 2012, were assigned to undergo lymphadenectomy (323 patients) or not undergo lymphadenectomy (324), and were included in the analysis. Among patients who underwent lymphadenectomy, the median number of removed nodes was 57 (35 pelvic and 22 paraaortic nodes). The median overall survival was 69.2 months in the no-lymphadenectomy group and 65.5 months in the lymphadenectomy group (hazard ratio for death in the lymphadenectomy group, 1.06; 95% confidence interval [CI], 0.83 to 1.34; P = 0.65), and median progression-free survival was 25.5 months in both groups (hazard ratio for progression or death in the lymphadenectomy group, 1.11; 95% CI, 0.92 to 1.34; P = 0.29). Serious postoperative complications occurred more frequently in the lymphadenectomy group (e.g., incidence of repeat laparotomy, 12.4% vs. 6.5% [P = 0.01]; mortality within 60 days after surgery, 3.1% vs. 0.9% [P = 0.049]).

Conclusions: Systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdominal macroscopically complete resection and had normal lymph nodes both before and during surgery was not associated with longer overall or progression-free survival than no lymphadenectomy and was associated with a higher incidence of postoperative complications. (Funded by Deutsche Forschungsgemeinschaft and the Austrian Science Fund; LION ClinicalTrials.gov number, NCT00712218.).
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http://dx.doi.org/10.1056/NEJMoa1808424DOI Listing
February 2019

Survival in clinical stage I endometrial cancer with single vs. multiple positive pelvic nodes: results of a multi-institutional Italian study.

J Gynecol Oncol 2018 Nov;29(6):e100

Department of Obstetrics and Gynecology, University of Insubria, Varese, Italy.

Objective: To investigate survival outcomes in endometrioid endometrial cancer (EEC) patients with single vs. multiple positive pelvic lymph nodes.

Methods: We performed a retrospective evaluation of all consecutive patients with histologically proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 EEC who underwent primary surgical treatment between 2004 and 2014 at seven Italian gynecologic oncology referral centers. Patients with pre- or intra-operative evidence of extra-uterine disease (including the presence of bulky nodes) and patients with stage IIIC2 disease were excluded, in order to obtain a homogeneous population.

Results: Overall 140 patients met the inclusion criteria. The presence of >1 metastatic pelvic node was significantly associated with an increased risk of recurrence and mortality, compared to only 1 metastatic node, at both univariate (recurrence: hazard ratio [HR]=2.19; 95% confidence interval [CI]=1.2-3.99; p=0.01; mortality: HR=2.8; 95% CI=1.24-6.29; p=0.01) and multivariable analysis (recurrence: HR=1.91; 95% CI=1.02-3.56; p=0.04; mortality: HR=2.62; 95% CI=1.13-6.05; p=0.02) and it was the only independent predictor of prognosis in this subset of patients. Disease-free survival (DFS) and disease-specific survival (DSS) were significantly longer in patients with only 1 metastatic node compared to those with more than 1 metastatic node (p=0.008 and 0.009, respectively).

Conclusion: The presence of multiple metastatic nodes in stage IIIC1 EEC represents an independent predictor of worse survival, compared to only one positive node. Our data suggest that EEC patients may be categorized according to the number of positive nodes.
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http://dx.doi.org/10.3802/jgo.2018.29.e100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189435PMC
November 2018

Prevalence of "unclassified" HPV genotypes among women with abnormal cytology.

Infect Agent Cancer 2018 24;13:26. Epub 2018 Jul 24.

Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", via M Semmola, 80131 Naples, Italy.

Background: High risk human papillomaviruses (HPVs) have been unequivocally recognised as the necessary cause of squamous intraepithelial lesions (SIL) and invasive carcinoma of the cervix. The distribution and the role of unclassified risk HPV genotypes in cervical neoplasia has not been fully elucidated.

Methods: Liquid-based cytological samples were collected from 337 women referred for colposcopy following an abnormal cytological diagnosis. HPV DNA was detected by broad-spectrum PCR and genotypes identified by nucleotide sequencing analysis and reverse line blot (RLB).

Results: The overall frequency of HPV infection was 36.5% (35 out of 96) in samples negative for intraepithelial lesions or malignancy (NILM), 80% (181 out of 226) in low grade SIL and 93.3% (14 out of 15) in high grade SIL ( < 0.001). Thirty-five different genotypes were identified among the 230 HPV-positive cases. The Group 1 oncogenic viruses (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59) were found in 21.9, 46.5, and 86.7% of NILM, low grade SIL and high grade SIL, respectively. The Group 2A, including the probably oncogenic virus HPV68, was found in 1 and 0.8% of NILM and low grade SIL, respectively. The Group 2b possibly oncogenic HPVs (HPV34, 53, 66, 67, 70, 73, 82 and 85) were found in 4.2, 21.7 and 26.7% of NILM, low grade SIL and high grade SIL, respectively. The unclassified viruses (HPV12, 42, 54, 55, 61, 62, 81, 83, 84, 89, 90, 91) were detected in 8.3 and 14.6% of NILM and low grade SIL, respectively, and never in high grade SIL.

Conclusions: Group 1 HPVs were mainly prevalent in high grade SIL and low grade SIL while Group 2B were equally distributed among the two groups. The dominant frequency of unclassified HPVs in low grade SIL and NILM and their rarity in high grade SIL suggests their marginal role in cervical neoplasia of the studied population.
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http://dx.doi.org/10.1186/s13027-018-0199-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056927PMC
July 2018

Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma.

Int J Cancer 2018 09 17;143(5):1153-1161. Epub 2018 Apr 17.

Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy.

Two recurrent mutations (-124 G > A and -146 G > A) in the core promoter region of the human telomerase reverse transcriptase (TERT) gene create consensus binding sites for ETS transcription factors and cause increased TERT expression in several tumour types. We analyzed TERT promoter mutations and TERT mRNA levels in head and neck cancer, cervical carcinoma and cervical intraepithelial neoplasia (CIN) as well as in C-4I, CaSki, HeLa and SiHa cervical cell lines. Nucleotide sequence analysis of TERT promoter region showed that 33.3% of oral squamous cell carcinoma (SCC) and 16.8% of cervical SCC harboured mutually exclusive G to A transitions at nucleotide position -124 or -146. TERT promoter was mutated at nucleotide -146 (G > A) in SiHa cell line. Other nucleotide changes creating in some cases putative ETS binding sites were more frequent in oral SCC (26.7%) than in cervical carcinoma (4.8%). The frequency of mutations was independent of human papillomavirus (HPV) tumour status in both cervical and oral cancer. Expression of TERT gene was significantly higher in TERT promoter mutated (-124G > A or -146G > A) cervical SCC compared to not mutated SCC irrespective of HPV16 E6 and E7 levels. Such hot spot changes were not detected in oropharyngeal SCC, cervical adenocarcinoma and CIN lesions. Our results suggest that TERT promoter mutations play a relevant role in oral SCC as well as in cervical SCC, besides the already known effect of HPV16 E6 protein on TERT expression.
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http://dx.doi.org/10.1002/ijc.31412DOI Listing
September 2018

Anesthetic dreaming, anesthesia awareness and patient satisfaction after deep sedation with propofol target controlled infusion: A prospective cohort study of patients undergoing day case breast surgery.

Oncotarget 2017 Oct 19;8(45):79248-79256. Epub 2017 Apr 19.

Department of Anesthesia, Endoscopy and Cardiology, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italia.

Background: Anesthetic dreaming and anesthesia awareness are well distinct phenomena. Although the incidence of intraoperative awareness is more common among patients who reported a dream after surgery, the exact correlation between the two phenomena remains an unsolved rebus. The main purpose of this study was to investigate anesthetic dreaming, anesthesia awareness and psychological consequences eventually occurred under deep sedation. Intraoperative dreaming experiences were correlated with dream features in natural sleep.

Methods: Fifty-one patients, undergoing surgical excision of fibroadenomas under a Bispectral index-guided deep sedation anesthesia with propofol target controlled infusion, were enrolled into this prospective study. Psychological assessment was performed through the State Trait Anxiety Inventory. A questionnaire was adopted to register dreaming and anesthesia awareness. Data were collected after emergence (t0), 24 hours (t1), 1 month (t2), 6 months (t3).

Results: Six patients (12%) reported anesthetic dreaming at t0 confirming the response at each subsequent evaluation. One patient (2%) confirmed dreaming during anesthesia in all, but denied it at t0. There was a high correlation between the intraoperative dream contents and the features of dreams in natural sleep. No cases of anesthesia awareness were detected. A similar level of satisfaction was observed in dreaming and no-dreaming patients.

Conclusions: Anesthetic dreaming does not seem to influence satisfaction of patients undergoing deep sedation with propofol target controlled infusion. A psychological assessment would seem to improve the evaluation of possible psychological consequences in dreamer patient.
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http://dx.doi.org/10.18632/oncotarget.17238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668036PMC
October 2017

New cell block containing agarose for cytopathological diagnosis of tumor samples.

Diagn Cytopathol 2017 Nov 30;45(11):1057-1060. Epub 2017 Jun 30.

Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy.

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http://dx.doi.org/10.1002/dc.23778DOI Listing
November 2017

1st Evidence-based Italian consensus conference on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinosis from ovarian cancer.

Tumori 2017 Nov 20;103(6):525-536. Epub 2017 Apr 20.

Department of Digestive Surgery, Regina Elena National Cancer Institute, IRCCS-IFO, Rome - Italy.

Ovarian cancer (OC) remains relatively rare, although it is among the top 4 causes of cancer death for women younger than 50. The aggressive nature of the disease and its often late diagnosis with peritoneal involvement have an impact on prognosis. The current scientific literature presents ambiguous or uncertain indications for management of peritoneal carcinosis (PC) from OC, both owing to the lack of sufficient scientific data and their heterogeneity or lack of consistency. Therefore, the Italian Society of Surgical Oncology (SICO), the Italian Society of Obstetrics and Gynaecology, the Italian Association of Hospital Obstetricians and Gynaecologists, and the Italian Association of Medical Oncology conducted a multidisciplinary consensus conference (CC) on management of advanced OC presenting with PC during the SICO annual meeting in Naples, Italy, on September 10-11, 2015. An expert committee developed questions on diagnosis and staging work-up, indications, and procedural aspects for peritonectomy, systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy for PC from OC. These questions were provided to 6 invited speakers who answered with an evidence-based report. Each report was submitted to a jury panel, representative of Italian experts in the fields of surgical oncology, gynecology, and medical oncology. The jury panel revised the reports before and after the open discussion during the CC. This article is the final document containing the clinical evidence reports and statements, revised and approved by all the authors before submission.
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http://dx.doi.org/10.5301/tj.5000623DOI Listing
November 2017

Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma.

Oncotarget 2017 May;8(21):34070-34081

Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, Italy.

Human papillomavirus type 16 (HPV16) is the major cause of cervical cancer and of a fraction of oropharyngeal carcinoma. Few studies compared the viral expression profiles in the two types of tumor. We analyzed HPV genotypes and viral load as well as early (E2/E4, E5, E6, E6*I, E6*II, E7) and late (L1 and L2) gene expression of HPV16 in cervical and oropharyngeal cancer biopsies. The study included 28 cervical squamous cell carcinoma (SCC) and ten oropharyngeal SCC, along with pair-matched non-tumor tissues, as well as four oropharynx dysplastic tissues and 112 cervical intraepithelial neoplasia biopsies. Viral load was found higher in cervical SCC (<1 to 694 copies/cell) and CIN (<1 to 43 copies/cell) compared to oropharyngeal SCC (<1 to 4 copies/cell). HPV16 E2/E4 and E5 as well as L1 and L2 mRNA levels were low in cervical SCC and CIN and undetectable in oropharynx cases. The HPV16 E6 and E7 mRNAs were consistently high in cervical SCC and low in oropharyngeal SCC. The analysis of HPV16 E6 mRNA expression pattern showed statistically significant higher levels of E6*I versus E6*II isoform in cervical SCC (p = 0.002) and a slightly higher expression of E6*I versus E6*II in oropharyngeal cases. In conclusion, the HPV16 E5, E6, E6*I, E6*II and E7 mRNA levels were more abundant in cervical SCC compared to oropharyngeal SCC suggesting different carcinogenic mechanisms in the two types of HPV-related cancers.
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http://dx.doi.org/10.18632/oncotarget.15977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470952PMC
May 2017

Feasibility and outcome of interval debulking surgery (IDS) after carboplatin-paclitaxel-bevacizumab (CPB): A subgroup analysis of the MITO-16A-MaNGO OV2A phase 4 trial.

Gynecol Oncol 2017 Feb 16;144(2):256-259. Epub 2016 Dec 16.

Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy. Electronic address:

Background: Few data are available on the outcome of surgery after a bevacizumab-containing regimen. The MITO 16A- MaNGO OV2A phase 4 trial evaluates the outcomes of first-line CPB in a clinical-practice-like setting. Here we present the results of the subgroup of patients undergoing IDS after neoadjuvant treatment or suboptimal primary surgery.

Methods: 400 chemonaïve epithelial ovarian cancer patients, age≥18, ECOG PS 0-2 were eligible to receive C (AUC 5 d1, q21) plus P (175mg/m d1, q21) and B (15mg/kg d1 q21) for 6cycles followed by B maintenance until cycle 22nd.

Results: 79 patients (20%) underwent IDS. Overall, 74 patients received at least one administration of B before IDS. Median age was 61.2, 70% of the patients had FIGO IIIC disease. The median number of cycles before IDS was 3 both for chemotherapy and bevacizumab respectively. A residual disease ≤1cm was achieved in 64 patients (86.5%). Four percent of the patients experienced fever and 4% required blood transfusion after surgery. Surgical wound infection and/or dehiscence, pelvic abscess, intestinal sub-occlusion and fistula were experienced by one patient each.

Conclusions: In the MITO16A-MaNGO OV2A phase 4 trial, combined chemotherapy and bevacizumab did not hamper IDS and the rate of perioperative complications was similar to what expected without bevacizumab. These data support the hypothesis that adding bevacizumab to first line chemotherapy for ovarian cancer might not be denied to patients for whom IDS is planned.
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http://dx.doi.org/10.1016/j.ygyno.2016.12.011DOI Listing
February 2017

Long-Term Oncologic and Reproductive Outcomes in Young Women With Early Endometrial Cancer Conservatively Treated: A Prospective Study and Literature Update.

Int J Gynecol Cancer 2016 11;26(9):1650-1657

*Gynecologic Oncology Surgery, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS; †Department of Woman, Child, and General and Specialized Surgery, Seconda Università degli Studi di Napoli; and ‡Surgical Pathology Unit, §Radiology Unit, and ‖Department of Anesthesia, Endoscopy and Cardiology, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.

Objective: This study aimed to analyze the long-term oncologic and reproductive outcomes in endometrial cancer (EC) in young patients conservatively treated by combined hysteroscopic resection (HR) and levonorgestrel intrauterine device (LNG-IUD).

Methods: Twenty-one patients (age ≤ 40 years; Stage IA, G1-2 endometrioid EC), wishing to preserve their fertility, were enrolled into this prospective study. The HR was used to resect (1) the tumor lesion, (2) the endometrium adjacent to the tumor, and (3) the myometrium underlying the tumor. Hormonal therapy consisted of LNG-IUD (52 mg) for at least 6 months.

Results: The median follow-up time is 85 months (range, 30-114). After 3 months from the progestin start date, 18 patients (85.7%) showed a complete regression (CR), 2 (9.5%) showed persistent disease, whereas 1 patient (4.8%) presented with progressive disease and underwent definitive surgery (Stage IA, G3 endometrioid). At 6 months, 1 of the 2 persistences underwent definitive surgery (Stage IA, G1 endometrioid), whereas the other was successfully re-treated. Two recurrences (10.5%) were observed, both involving the endometrium and synchronous ovarian cancer (OC) (atypical hyperplasia and Stage IIB G1 endometrioid OC; Stage IA endometrioid G1 EC, and Stage IA G1 endometrioid OC). The median duration of complete response was 85 months (range, 8-117). Sixty-three percent of complete responders attempted to conceive with 92% and 83% pregnancy and live birth rates, respectively. To date, all patients are alive and have no evidence of disease.

Conclusions: After a long follow-up, combined HR and LNG-IUD would seem to improve the efficacy of progestin alone. High pregnancy and live birth rates were observed in women attempting to conceive. This approach is still experimental and should be offered only in the framework of scientific protocols conducted in cancer centers.
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http://dx.doi.org/10.1097/IGC.0000000000000825DOI Listing
November 2016

Fertility preserving treatment with hysteroscopic resection followed by progestin therapy in young women with early endometrial cancer.

J Gynecol Oncol 2017 Jan 8;28(1):e2. Epub 2016 Aug 8.

Gynecologic Oncology Surgery, National Cancer Institute of Naples-IRCCS "Fondazione G. Pascale", Naples, Italy.

Objective: To report our 15-year institutional experience of fertility-sparing treatment in young patients with early endometrial cancer (EC) treated by combined hysteroscopic resection and progestin therapy.

Methods: Twenty-eight patients (stage IA, G1 and 2 endometrioid EC) wishing to preserve their fertility were enrolled into this prospective study. Hysteroscopic resection was used to resect the tumor, endometrium adjacent to the tumor and myometrium underlying the tumor. Adjuvant hormonal therapy consisted of oral megestrol acetate or levonorgestrel intrauterine device for 6 months or more.

Results: After 3 months from the progestin start date, 25 patients (89.3%) showed a complete regression (median time to complete regression, 3 months [range, 3-9 months]), two (7.1%) showed persistent disease, while one patient (3.6%) presented with progressive disease and underwent definitive surgery (stage IA, G3 endometrioid). At 6 months, one of the two patients with persistent disease underwent definitive surgery (stage IA, G1 endometrioid), while the other one was successfully re-treated. Two recurrences were observed (7.7%) both involving the endometrium and synchronous ovarian cancer. The median duration of complete response was 94.5 months (range, 8-175 months). More than half of the responders (57.7%) attempted to conceive with 93.3% and 86.6% pregnancy and live birth rates, respectively.

Conclusion: The addition of a standardized three-step resectoscopy to progestin would seem to improve the efficacy of progestin alone. High pregnancy and live birth rates were observed in women attempting to conceive.
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http://dx.doi.org/10.3802/jgo.2017.28.e2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165067PMC
January 2017

Detection of human papillomavirus DNA in peri-tumor tissues and pelvic lymph nodes as potential molecular marker of micrometastasis in cervical cancer.

Infect Agent Cancer 2016 11;11:22. Epub 2016 May 11.

Molecular Biology and Viral Oncology Division, Istituto Nazionale Tumori "Fond. Pascale" - IRCCS, 80131 Napoli, Italy.

Background: The association between high risk human papillomaviruses (HPV) and cervical cancer has been firmly established. HPV genome is present in nearly all cases of cervical cancer and detection of viral DNA could therefore be used as a surrogate marker of micrometastasis in peri-tumor tissues and lymph nodes.

Methods: We analyzed primary cervical carcinomas, peri-tumor biopsies and pelvic lymph nodes in 20 women with invasive cancer (FIGO stage I-II) who underwent radical pelvic surgery and lymphadenectomy. HPV DNA was searched by broad spectrum PCR in 142 DNA samples extracted from paraffin embedded tissues. Viral genotypes were identified by direct sequencing analysis.

Results: HPV DNA sequences were identified in all available primary cervical tumors (n = 15). The most common genotype was HPV16 (60 %), followed by HPV18 (20 %), HPV35 (7 %), HPV45 (7 %) and HPV66 (7 %). Seven out of 20 (35 %) women had metastatic spread in peri-tumor tissues and/or lymph nodes, as determined by histology. HPV DNA was detected in all histological positive samples as well as in 16 and 25 % of histological negative peri-tumor tissues and lymph nodes, respectively. Three out of 20 (15 %) women without histological evidence of metastatic spread had HPV-positive lymph nodes. HPV genotype was found always concordant between primary tumor and metastatic lesions. The remaining 10 women (50 %) were histology and HPV-negative in all peri-tumor biopsies and lymph nodes analyzed.

Conclusions: Evaluation of HPV DNA in peri-tumor tissues as well as pelvic lymph nodes could be a sensitive marker to identify micrometastasis or isolated tumor cells and to monitor the risk of disease recurrence in women with cervical cancer.
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http://dx.doi.org/10.1186/s13027-016-0068-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863320PMC
May 2016

Primary surgical cytoreduction in advanced ovarian cancer: An outcome analysis within the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group.

Gynecol Oncol 2016 Mar 26;140(3):425-9. Epub 2016 Jan 26.

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

Objective: To draw a reliable picture of the surgical management of advanced ovarian cancer (AOC) within the MITO Group, trying to correlate the disease extent at presentation, the category of center, and surgical outcome.

Methods: Three tertiary referral centers for gynecologic oncology and four non-oncologic referral gynecologic surgical centers, participated in the project. A questionnaire was adopted to register perioperative data on AOCs (FIGO Stage IIICIV) consecutively operated on for a period of 12months.

Results: A total of 205 patients were registered into the study: 140 and 65 were recruited in oncological referral centers and non-referral centers, respectively. Following a multivariate analysis, the Eisenkop score and the category of center resulted the most potent predictors of complete surgical cytoreduction followed by PCI, preoperative CA125, and ASA score. Complete surgical cytoreduction was associated with oncological referral centers (60% vs 24.6%, p<0.001). The proportion of patients undergoing additional surgical procedures was significantly different comparing the two categories of centers (at least one additional procedure was performed in 81.4% vs 50.8% in oncological referral centers compared to the others, p<0.001). Despite the more aggressive surgery performed in oncological referral centers, the perioperative outcome measures were not significantly different in the two groups.

Conclusions: The chance of obtaining a complete cytoreduction mainly depends on patient characteristics, tumor spread, and quality of treatment. The latter is amenable for direct influence, and therefore, seems to be of utmost importance when considering efforts aiming at improvement in the outcome of this disease.
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http://dx.doi.org/10.1016/j.ygyno.2016.01.025DOI Listing
March 2016

Fertility-sparing management of low-grade endometrial stromal sarcoma: analysis of an institutional series and review of the literature.

Eur J Obstet Gynecol Reprod Biol 2015 Dec 8;195:61-6. Epub 2015 Oct 8.

Gynecologic Oncology Surgery, Istituto Nazionale Tumori "Fondazione G. Pascale" IRCCS, Naples, Italy. Electronic address:

Objective: Low-grade endometrial stromal sarcoma (LG-ESS) is a rare malignancy, often occurring before menopause. There is no consensus regarding its optimal management. Total hysterectomy and bilateral salpingo-oophorectomy precludes future fertility and may thus be undesirable by women wishing to maintain their reproductive potential. However, experience of fertility-sparing management in LG-ESS is very limited. In this paper, the disease outcome is presented in six young women with LG-ESS conservatively treated by combined hysteroscopic resection and hormonal therapy.

Study Design: From October 2009 to February 2013, at the Gynecologic Oncology Department of the National Cancer Institute of Naples, six women, with early-stage LG-ESS aged 18-40 years who desired childbearing and/or retaining their fertility, were enrolled into a pilot study of fertility-sparing management. Diagnosis of LG-ESS was made on specimens from hysteroscopic resection performed on a presumed benign lesion. All patients were planned to be treated with adjuvant megestrol acetate for two years. Hormonal therapy was started within 6 weeks from the hysteroscopic resection, with orally megestrol acetate at 40mg daily, increasing gradually according to patient's tolerance to the recommended total dose of 160mg daily.

Results: All patients were submitted to hysteroscopic resection in a one-step procedure. Five patients started megestrol acetate within 6 weeks from the hysteroscopic resection (one patient did not start hormonal therapy because of early pregnancy after the hysteroscopic resection). Hormonal therapy was well tolerated; one patient stopped megestrol acetate after 12 months because of self-supporting strong desire to conceive; the other four patients regularly completed the hormonal therapy. To date, all patients show no evidence of disease.

Conclusions: Although fertility-sparing management is not the current standard of care for young women with early-stage LG-ESS, our preliminary data are promising. Larger series with a longer follow-up are needed to further assess safety and efficacy of combined hysteroscopic resection and hormonal therapy.
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http://dx.doi.org/10.1016/j.ejogrb.2015.09.041DOI Listing
December 2015

Long-Term Toxicity and Quality of Life in Patients Treated for Locally Advanced Cervical Cancer.

Oncology 2016 17;90(1):29-35. Epub 2015 Oct 17.

Department of Urology and Gynecology, Istituto Nazionale Tumori x2018;Fondazione G. Pascale', IRCCS, Naples, Italy.

Objective: The aim of this study was to analyze the long-term toxicity and quality of life (QOL) in patients with locally advanced cervical cancer (LACC) treated with chemoradiation [chemotherapy/radiotherapy (CT/RT)] or neoadjuvant CT (NACT) followed by radical surgery (RS).

Methods: Fifty-nine patients with LACC in remission after treatment with NACT + RS (n = 34) or CT/RT (n = 25) were interviewed with an Incontinence Impact Questionnaire (IIQ-7), a Quality of Life Questionnaire (EORTC QLQ-C30), and a Quality of Life Questionnaire for Cervical Cancer (EORTC QLQ-CX24) to compare long-term toxicity and QOL.

Results: The mean age was 53 ± 9.8 and 59 ± 11.5 years in the NACT + RS and CT/RT groups, respectively. Overall, diarrhea and constipation were reported in 15 and 68%, respectively, while bladder complaints and a low level of sexual enjoyment were reported in 36 and 47%, respectively. The NACT + RS patients showed a worse sexual activity (74.71 ± 33.57 vs. 92.06 ± 17.96; p = 0.019) and sexual enjoyment (71.21 ± 23.67 vs. 88.88 ± 21.71; p = 0.040) and more frequently complained of constipation (49.01 ± 34.06 vs. 26.66 ± 31.66; p = 0.013), while CT/RT patients more frequently suffered from diarrhea (1.96 ± 7.96 vs. 14.66 ± 28.40; p = 0.017).

Conclusions: Many patients treated for LACC have long-term complaints regarding sexual activity and bladder and bowel function. The majority of QOL aspects were similar in the two groups at long-term follow-up. However, diarrhea was more frequent and severe in CT/RT patients, while constipation was more frequent and severe in NACT + RS patients, and they showed a worse sexual life perception. Larger randomized trials addressing these issues are needed.
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http://dx.doi.org/10.1159/000441226DOI Listing
July 2016