Targeting BRAF pathway in low-grade serous ovarian cancer.

Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities including ovarian carcinomas. In the recent years, several inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Low grade serous ovarian carcinoma, is a rare gynecological tumor which shows favorable overall survival, compared to the general ovarian cancer population, but worrying resistance to conventional chemotherapies. The clinical behavior of low grade serous ovarian carcinoma reflects the different gene profile compared to high-grade serous carcinoma: KRAS/BRAF mutations. BRAF inhibitors as single agents were approved for the treatment of BRAF mutated tumors. Nevertheless, many patients face progressive disease. The understanding of the mechanisms of resistance to BRAF inhibitors therapy and preclinical studies showing that BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors combined therapy delays the onset of resistance compared to BRAF inhibitor single agent, led to the clinical investigation of combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors on ovarian carcinomas, in particularly focusing on low grade serous ovarian carcinoma.

Old Issues and New Perspectives on Endometrial Cancer Therapy: How Molecular Characteristics Are Changing the Therapeutic Pathway.

The Cancer Genome Atlas (TCGA) has radically changed the history of endometrial cancer by outlining a new classification, based on its molecular characteristics. In the field of oncology, we are approaching the new era of molecular biology, particularly regarding endometrial cancer, with the increasing importance of targeted therapy. This paper is a review of phase III randomized controlled trials published in English between January 2019 and December 2023, comparing drugs of interest with standard adjuvant treatment and molecular subtypes in endometrial cancer. The use of immunotherapy alone or in combination with chemotherapy as therapy in patients with recurrent or advanced primary or metastatic endometrial cancer significantly improves the prognosis of these patients. The results show greater efficacy of all proposed treatments for mismatch repair deficiency (dMMR/MSI-H) patients compared to mismatch repair proficiency (pMMR) patients. Progression-free survival (PFS) and overall survival (OS) are better in dMMR patients in all studies analysed. Immunotherapy has the potential to revolutionize the gynaecological cancer treatment landscape, offering a new pathway and new hope for endometrial cancer patients, improving their outcomes in the future. Given the exciting results obtained in dMMR/MSI-H patients, MMR status should be investigated in every patient with advanced endometrial cancer at the time of diagnosis.

Predicting the Risk of nOdal disease with histological and Molecular features in Endometrial cancer: the prospective PROME trial.

OBJECTIVE: To assess the role of histopathological and molecular features in predicting the risk of nodal metastases in apparent early-stage endometrial cancer patients undergoing sentinel node mapping. METHODS: This is a prospective trial. Consecutive patients with apparent early-stage endometrial cancer, undergoing laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and sentinel node mapping, were enrolled. Histological and molecular features were used to predict the node positivity. RESULTS: Charts of 223 apparent early-stage endometrial cancer patients were included in this study. Four (1.8%) patients were excluded from this study due to the lack of data about molecular features. Additionally, nine (4%) patients did not meet the inclusion criteria (due to the presence of peritoneal carcinomatosis or bulky nodes (the presence of p53 abnormality correlated with the presence of advanced stage disease (p<0.001)). The study population included 178 (84.8%) and 32 (15.2%) patients with endometrioid and non-endometrioid endometrial cancer, respectively. According to pathological uterine risk factors, 93 (44.3%), 45 (21.4%), 40 (19.1%), and 32 (15.2%) were classified as low, intermediate, intermediate-high, and high-risk, respectively. Using the surrogate molecular classification, 10 (4.8%), 42 (20%), 57 (27.1%), and 101 (48.1%) were included in the POLE mutated, p53 abnormal, MMRd/MSI-H, and NSMP, respectively. Overall, 41 (19.5%) patients were detected with positive nodes. Molecular features were not associated with the risk of having nodal metastases (OR 1.03, 95% CI 0.21 to 5.05, p=0.969 for POLE mutated; OR 0.788, 95% CI 0.32 to 1.98, p=0.602 for p53 abnormal; OR 1.14, 95% CI 0.53 to 2.42, p=0.733 for MMRd/MSI-H). At multivariable analysis, only deep myometrial invasion (OR 3.318, 95% CI 1.357 to 8.150, p=0.009) and lymphovascular space invasion (OR 6.584, 95% CI 2.663 to 16.279, p<0.001) correlated with the increased risk of positive nodes. CONCLUSION: Our data suggest that molecular classification does not seem useful to tailor the need of nodal dissection in apparent early-stage endometrial cancer. p53 abnormality predicts the risk of having advanced disease at presentation. Further external validation is needed. CLINICAL TRIAL REGISTRATION: NCT05793333.

The great debate: Surgical outcomes of laparoscopic versus laparotomic myomectomy. A meta-analysis to critically evaluate current evidence and look over the horizon.

Myomectomy is one of the most common surgical procedure in the field of gynecology. However, the role of laparoscopic myomectomy is still debated for many factors, including surgical considerations, safety and fertility concerns, long-term outcomes, and cost-related issues. The aim of this study is to evaluate the surgical peri- and post-operative outcomes of laparoscopic and abdominal myomectomy. A systematic search for studies was performed up to June 2023 through MEDLINE, Pubmed, Embase. Studies reporting the comparison of surgical and obstetrical outcomes in laparoscopic versus laparotomic myomectomy were included for the following outcomes: time of surgery, estimated blood loss, decrease of postoperative hemoglobin, hospital stay, intra-operative complication rates, postoperative complications rates, postoperative analgesic use, postoperative pain at 24 h and pregnancy rate. The meta-analysis was performed using the Cochrane Review software. Fifty-six relevant articles were retrieved through the process of evidence acquisition. Eleven articles met inclusion criteria, for a total of 2,133 patients undergoing laparoscopic or laparotomic myomectomy. The estimated blood loss [standard mean differences (SMD) 0.72, IC 95 % 0.22 to 1.22], the hospital stays [SMD 3.12, IC 95 % 0.57 to 4.28], were significantly lower in laparoscopic than in open group. No statistically significant difference in intra-operative and post-operative complication rates, in pregnancy rate and others obstetrical outcomes between two surgical approaches were found. The findings of present metanalysis suggest that laparoscopic myomectomy offers multiple benefits, including reduced blood loss, shorter hospital stays, and less postoperative analgesic need, without a significant increase in complication rates and similar results in obstetrical outcomes when compared to abdominal myomectomy. However, the presence of few randomized studies on selected population may limit the generalizability of the findings to the entire population. Therefore, more well-designed studies or large population programdata to draw definitive conclusions are therefore warranted.

"Pelvic Neuro-Visualization: An Anatomical Illustration of the Autonomic Pelvic Nervous Network in Gynecologic Surgery".

OBJECTIVE: During radical pelvic surgeries fibers of the autonomic pelvic nervous network can be accidentally damaged leading to significant visceral sequelae, which dramatically affect women's quality of life because of urinary, anorectal, and sexual postoperative dysfunctions.1,2 Direct visualization is one way to preserve hypogastric nerves (HNs), pelvic splanchnic nerves (PSNs), and the bladder branches from the inferior hypogastric plexus (IHP). However, the literature lacks critical photos and/or illustrations that are necessary to understand the precise anatomy needed to preserve the pelvic autonomic fibers. DESIGN: Narrated laparoscopic video footage for identifying, dissecting, and preserving the autonomic nerve bundles during pelvic surgery. SETTING: Tertiary level hospital-"IRCCS Istituto Nazionale dei Tumori", Milano, Italy. INTERVENTIONS: Visceral pelvic innervation is established by the superior hypogastric plexus(SHP) located anteriorly to the aortic bifurcation and the median sacral vessels and carries mostly sympathetic fibers. SHP divides in front of the sacrum into the right and left HN. At the level of the paracervix, the HNs join the parasympathetic PSNs coming out from sacral root S2, S3, S4 to form the IHP.2-5 Here, we performed laparoscopic surgery, before "Laparoscopic Approach to Cervical Cancer" trial (LACC) era, identifying key anatomic landmarks useful to highlight the path of the most commonly encountered autonomic pelvic nerves in gynecologic radical surgery: during the narration we describe and illustrate the procedure to identify all autonomic pelvic nerves, the sympathetic fibers, the PSNs, and the bladder branch emerging from the IHP in order to preserve their anatomic and functional integrity. This technique is anatomically and surgically indicated for adequate removal of the parametrical issues and vagina while preserving the total pelvic nervous system. CONCLUSION: Nerve-sparing surgery reduces bowel-, bladder- and sexual- dysfunction without decreasing surgical efficacy.1,2 To accomplish safe and effective surgery, comprehension of the 3 dimensional structure of the vascular and nerve anatomy in the pelvis is essential. This video provides a great resource to educate surgeons, especially the youngest ones, about the retroperitoneal nervous networking: we identified the autonomic nerve pathway from adjacent tissues along the pathway consisting of cardinal, sacro-uterine, rectouterine/vaginal, and vesico-uterine ligaments.

Long-Term Follow-Up Outcomes in Women with In Situ/Microinvasive Adenocarcinoma of the Uterine Cervix Undergoing Conservative Treatment-Cervical Adenocarcinoma Study Group Italian Society of Colposcopy and Cervico-Vaginal Pathology.

OBJECTIVE: The present study aimed to assess long-term follow-up outcomes in women with in situ/microinvasive adenocarcinoma (AC) of the uterine cervix treated conservatively. METHODS: Retrospective multi-institutional study including women with early glandular lesions and 5-year follow-up undergoing fertility-sparing treatment. Independent variables associated with recurrence were evaluated. Logistic regression analysis and Kaplan-Meier survival analysis with Logrank test were performed. RESULTS: Of 269 women diagnosed with in situ/microinvasive AC, 127 participants underwent conservative treatment. During follow-up, recurrences were found in nine women (7.1%). The only factor associated with recurrence during follow-up was positive high-risk Human Papillomavirus (hr-HPV) testing (odds ratio 6.21, confidence interval 1.47-26.08, p = 0.012). HPV positivity in follow-up showed a recurrence rate of 21.7% against 3.8% in patients who were HPV-negative (p = 0.002, Logrank test). Among women with negative high-risk HPV tests in follow-up, recurrences occurred in 20.0% of non-usual-type histology vs. 2.1% of usual-type cases (p = 0.005). CONCLUSION: HPV testing in follow-up is of pivotal importance in women with early glandular lesions undergoing conservative treatment, given its recurrence predictive value. However, women who are high-risk HPV-negative in follow-up with non-usual-type histopathology may represent a sub-population at increased risk of recurrences. Further studies should confirm these findings.

Sentinel node mapping in high-intermediate and high-risk endometrial cancer: Analysis of 5-year oncologic outcomes.

OBJECTIVE: To assess 5-year oncologic outcomes of apparent early-stage high-intermediate and high-risk endometrial cancer undergoing sentinel node mapping versus systematic lymphadenectomy. METHODS: This is a multi-institutional retrospective, propensity-matched study evaluating data of high-intermediate and high-risk endometrial cancer (according to ESGO/ESTRO/ESP guidelines) undergoing sentinel node mapping versus systematic pelvic lymphadenectomy (with and without para-aortic lymphadenectomy). Survival outcomes were assessed using Kaplan-Meier and Cox proportional hazard methods. RESULTS: Overall, the charts of 242 patients with high-intermediate and high-risk endometrial cancer were retrieved. Data on 73 (30.1%) patients undergoing hysterectomy plus sentinel node mapping were analyzed. Forty-two (57.5%) and 31 (42.5%) patients were classified in the high-intermediate and high-risk groups, respectively. Unilateral sentinel node mapping was achieved in all patients. Bilateral mapping was achieved in 67 (91.7%) patients. Three (4.1%) patients had site-specific lymphadenectomy (two pelvic areas only and one pelvic plus para-aortic area), while adjunctive nodal dissection was omitted in the hemipelvis of the other three (4.1%) patients. Sentinel nodes were detected in the para-aortic area in eight (10.9%) patients. Twenty-four (32.8%) patients were diagnosed with nodal disease. A propensity-score matching was used to compare the aforementioned group of patients undergoing sentinel node mapping with a group of patients undergoing lymphadenectomy. Seventy patient pairs were selected (70 having sentinel node mapping vs. 70 having lymphadenectomy). Patients undergoing sentinel node mapping experienced similar 5-year disease-free survival (HR: 1.233; 95%CI: 0.6217 to 2.444; p = 0.547, log-rank test) and 5-year overall survival (HR: 1.505; 95%CI: 0.6752 to 3.355; p = 0.256, log-rank test) than patients undergoing lymphadenectomy. CONCLUSIONS: Sentinel node mapping does not negatively impact 5-year outcomes of high-intermediate and high-risk endometrial cancer. Further prospective studies are warranted.

Are biomarkers expression and clinical-pathological factors predictive markers of the efficacy of neoadjuvant chemotherapy for locally advanced cervical cancer?

INTRODUCTION: To predict the overall pathologic response to neoadjuvant chemotherapy (NACT) of patients with locally advanced cervical cancer (LACC) creating a prediction model based on clinical-pathological factors and biomarkers (p53, Bcl1 and Bcl2) and to evaluate the prognostic outcomes of NACT. MATERIALS AND METHODS: This is a retrospective study of 88 consecutive patients with LACC who underwent NACT followed by nerve sparing surgery with retroperitoneal lymphadenectomy at National Cancer Institute of Milan, between January 2000 and June 2013. Clinical pathologic data were retrieved from the institutional database. Biomarkers (p53, Bcl1 and Bcl2) were evaluated before and after NACT in the specimen. To investigate their role as predictors of response, we tried several statistical machine learning algorithms. RESULTS: Responders to NACT showed a 5-years survival between 100%(CR) and 85.7%(PR). Clinical factors were the most important predictor of response. Age, BMI and grade represented the most important predictors of response at random forest analysis. Tree-based boosting revealed that after adjusting for other prognostic factors, age, grade, BMI and tumor size were independent predictors of response to NACT, while p53 was moderately related to response to NACT. Area under the curve (crude estimate): 0.871. Whereas Bcl1 and Bcl2, were not predictors for response to NACT. The final logistic regression reported that grade was the only significant predictor of response to NACT. CONCLUSION: Combined model that included clinical pathologic variables plus p53 cannot predict response to NACT. Despite this, NACT remain a safe treatment in chemosensitive patients avoiding collateral sequelae related to chemo-radiotherapy.

Hormone replacement therapy in gynecological cancer survivors and BRCA mutation carriers: a MITO group survey.

OBJECTIVE: Early iatrogenic menopause in gynecological cancer survivors and BRCA mutation (BRCAm) carriers undergoing risk-reducing salpingo-oophorectomy (RRSO) is a major health concern. Hormone replacement therapy (HRT) is the most effective remedy, but remains underused in clinical practice. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) group promoted a national survey to investigate the knowledge and attitudes of healthcare professionals regarding the prescription of HRT. METHODS: The survey consisted of a self-administered, multiple-choice 45-item questionnaire, available online to all MITO members for 2 months starting from January 2022. RESULTS: A total of 61 participants completed the questionnaire (47 out of 180 MITO centers; compliance: 26.1%). Most respondents were female (73.8%), younger than 50 years (65.6%), and gynecologic oncologists (55.7%), working in public general hospitals (49.2%). An 84.4% of specialists actively discuss HRT with patients and 51.0% of patients ask the specialist for an opinion on HRT. The rate of specialists globally in favor of prescribing HRT was 22.9% for ovarian cancer, 49.1% for cervical cancer, and 8.2% for endometrial cancer patients. Most respondents (70.5%) believe HRT is safe for BRCA-mutated patients after RRSO. Nearly 70% of physicians prescribe systemic HRT, while 23.8% prefer local HRT. Most specialists recommend HRT for as long as there is a benefit and generally for up to 5 years. CONCLUSION: Real-world data suggest that many healthcare professionals still do not easily prescribe HRT for gynecological cancer survivors and BRCA mutation carriers after RRSO. Further efforts are required to implement the use of HRT in clinical practice and to support both clinicians in recommending HRT and patients in accepting it.

Pattern of recurrence in endometrial cancer. The murderer always returns to the scene of the crime.

BACKGROUND: Endometrial cancer recurrence occurs in about 18 % of patients. This study aims to analyze the pattern recurrence of endometrial cancer and the relationship between the initial site of primary disease and the relapse site in patients undergoing surgical treatment. METHODS: We retrospectively reviewed all surgically treated patients with endometrial cancer selecting those with recurrence. We defined primary site disease as uterus, lymph nodes, or peritoneum according to pathology analysis of the surgical specimen. The site of recurrence was defined as vaginal cuff, lymph nodes, peritoneum, and parenchymatous organs. Our primary endpoint was to correlate the site of initial disease with the site of recurrence. RESULTS: The study enrolled 1416 patients. The overall recurrence rate was 17,5 % with 248 relapses included in the study. An increase of 9.9, 5.7, and 5.7 times in the odds of relapse on the lymph node, peritoneum, and abdominal parenchymatous sites respectively was observed in case of nodal initial disease (p < 0.001). A not significant difference in odds was observed in terms of vaginal cuff relapse (OR 0.9) between lymph node ad uterine primary disease (p = 0.78). An increasing OR of 8.7 times for nodal recurrences, 46.6 times for peritoneum, and 23.3 times for parenchymatous abdominal recurrences were found in the case of primary peritoneal disease (p < 0.001). CONCLUSION: Endometrial cancer tends to recur at the initial site of the disease. Intraoperative inspection of the adjacent sites of primary disease and targeted instrumental examination of the initial sites of disease during follow-up are strongly recommended.

Polycystic Ovary Syndrome and Alteration of Vocal Function: A Systematic Review and Meta-Analysis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common hormonal disorder among young women, correlated with hyperandrogenism. Among the symptoms of PCOS, vocal alterations are quite unknown. Dysphonia may be related to hyperandrogenism, and there is no consensus about its prevalence and the severity of vocal disorders, which can cause noticeable discomfort. METHODS: A systematic review of the literature was conducted. Four studies on PCOS that evaluated the phonatory system were included for a total of 174 patients (96 PCOS, 78 controls), and a meta-analysis on comparable data was performed. RESULTS: Four studies evaluated parameters related to vocal symptomatology, altered audiometric examination, and findings at the laryngoscopy in patients affected by PCOS versus controls. Although the individual studies showed increased incidence of alterations and a tendency to develop speech fatigue in women with PCOS, when the results of studies were pulled in meta-analysis, the overall difference was not statistically significant. The studies themselves were very different from each other; therefore, it is hard to draw any firm conclusions. DISCUSSION: The aim of this study was to assess the prevalence of vocal alterations, the correlation with hyperandrogenism, the quality of life, and the voice changes after starting a therapy for PCOS. The present meta-analysis failed to find any difference in terms of PCOS and control cohort. However, the lack of high-quality studies makes it difficult to draw firm conclusions. New and larger studies or big population program data are therefore warranted.

Sentinel lymph node biopsy in endometrial cancer: When, how and in which patients.

The role of nodal dissection in patients with endometrial cancer has been intensively studied in several studies. Historically, systematic pelvic and para-aortic lymphadenectomy represented the gold standard surgical treatment to assess potential nodal involvement and consequently define the appropriate stage of the tumor. Over the last years, sentinel node biopsy (SLNB) has been introduced as a more targeted alternative to lymph node dissection for lymph node staging and it has become popular among gynecologic oncologists. However, no level A evidence is still available, and several features of the SLNB technique have been matter of discussion among clinicians and a universally accepted methodology is still not currently available. This narrative review aims to summarize the body of knowledge on SLNB to offer the reader a complete picture about the evolution of this technique over the last decades.

Sentinel node mapping in endometrial cancer.

Nodal status is one of the most important prognostic factors for patients with apparent early stage endometrial cancer. The role of retroperitoneal staging in endometrial cancer is controversial. Nodal status provides useful prognostic data, and allows to tailor the need of postoperative treatments. However, two independent randomized trials showed that the execution of (pelvic) lymphadenectomy increases the risk of having surgery-related complication without improving patients' outcomes. Sentinel node mapping aims to achieve data regarding nodal status without increasing morbidity. Sentinel node mapping is the removal of first (clinically negative) lymph nodes draining the uterus. Several studies suggested that sentinel node mapping is not inferior to lymphadenectomy in identifying patients with nodal disease. More importantly, thorough ultrastaging sentinel node mapping allows the detection of low volume disease (micrometastases and isolated tumor cells), that are not always detectable via conventional pathological examination. Therefore, the adoption of sentinel node mapping guarantees a higher identification of patients with nodal disease than lymphadenectomy. Further evidence is needed to assess the value of various adjuvant strategies in patients with low volume disease and to tailor those treatments also on the basis of the molecular and genomic characterization of endometrial tumors.

Oncological outcomes of unexpected uterine leiomyosarcoma: A single-center retrospective analysis of 5528 consecutive hysterectomies.

BACKGROUND AND METHODS: Uterine leiomyosarcomas (uLMS) are rare malignant tumors, often incidentally discovered, with an estimated annual incidence of five cases per one million women in the United States. This study aimed to compare the oncological outcomes of two groups of patients: those with uLMS incidentally found during surgery and those who underwent surgery due to suspected or confirmed uLMS before the procedure. The study assessed patients who had undergone hysterectomy and were diagnosed with stage I uLMS at a tertiary gynecologic oncology referral center in Italy between January 2000 and December 2019. Data on patients' baseline characteristics, surgical procedures, and oncological outcomes were collected. The patients were classified into two groups based on whether uLMS was unexpectedly discovered or suspected before the surgery. Survival rates and factors influencing recurrence were analyzed. RESULTS: The study included 36 patients meeting the inclusion criteria, with 12 having preoperatively suspected or proven uLMS and 24 having incidentally discovered uLMS. No significant differences were observed between the two groups regarding disease-free survival (23.7 vs. 27.3 months, log rank = 0.28), disease-specific survival (median not reached, log rank = 0.78), or sites of relapse. Notably, among patients who underwent laparoscopic hysterectomy (compared to open surgery), a significantly higher rate of locoregional recurrence was found (78% vs. 33.3%, p = 0.04). Nevertheless, no significant differences in survival were observed based on the surgical approach. CONCLUSIONS: Preoperative suspicion for uLMS did not seem to impact survival outcomes or the pattern of recurrence. Furthermore, although patients who underwent laparoscopic hysterectomy showed a higher rate of locoregional relapse, this did not affect their overall survival.

Characteristics and outcomes of surgically staged multiple classifier endometrial cancer.

OBJECTIVE: The growing adoption of molecular and genomic characterization is changing the current landscape of treatment of endometrial cancer patients. Using the surrogate molecular classification, endometrial cancer patients can be classified in four subgroups: POLE mutated (POLEmut), MMRd/MSI-H, p53 abnormal (p53abn), and no specific mutational profile (NSMP). However, some patients can harbor two or more molecular features (defined as multiple classifier). Since the rarity of this occurrence, evidence regarding multiple classifiers is still limited. Here, we described characteristics and outcomes of multiple classifiers. METHODS: This is a multi-institutional retrospective study. Data of consecutive patients having 2 or more molecular features were collected. Survival was assessed using the Kaplan-Meier and Cox proportional hazard methods. RESULTS: Charts of 72 multiple classifiers were reviewed. Median (range) follow-up was 9.8 (1.2, 37.5) months. Overall, 31 (43%) patients had POLEmut. Patients with POLEmut-MMRd/MSI-H, POLEmut-p53abn, and POLEmut-MMRd/MSI-H-p53abn were 6 (8.3%), 20 (27.8%), and 5 (6.9%), respectively. Among those 31 patients, no recurrence occurred within a median follow-up of 10.5 months (only seven (22.6%) patients had at least 2-year follow-up). The remaining 41 (56.9%) patients were diagnosed with tumors harboring both p53 and MMRd/MSI-H. Among them, four (9.8%) recurrences occurred at a median follow-up time of 8.9 months. Adjuvant therapy (other than vaginal brachytherapy) was administered in 5/31 (16%) and 25/41 (61%) patients with and without POLEmut, respectively (p < 0.001). CONCLUSIONS: Multiple classifiers endometrial cancer with POLEmut are characterized by good prognosis even in case of presence of MMRd/MSI-H and/or p53abn. Additional studies with long-term follow-up are needed.

The role of L1CAM as predictor of poor prognosis in stage I endometrial cancer: a systematic review and meta-analysis.

INTRODUCTION: Molecular and genomic profiling in endometrial cancer is increasing popularity. L1 cell adhesion molecule (L1CAM) is frequently mutated in endometrial cancer. In this paper, we aim to evaluate the prognostic role of L1CAM in patients with stage I endometrial cancer. METHODS: We performed a systematic review and meta-analysis searching in PubMed (MEDLINE), EMBASE, and Web of Science database to identify studies reporting the expression of L1CAM in endometrial cancer. The primary endpoint measure was to assess and evaluate the impact of L1CAM on survival outcomes. This study was performed according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. RESULTS: Five studies were included. The pooled results suggested that L1CAM expression influences survival outcomes in stage I endometrial cancer. High L1CAM expression correlated with worse disease-free survival (HR 4.11, 95% CI 1.02-16.59, p = 0.047) and overall survival (HR 3.62, 95% CI 1.32-9.31, p = 0.012). High L1CAM level was also associated with a more aggressive FIGO grade and with older age. CONCLUSION: This systematic review supported that L1CAM have a prognostic role in stage I endometrial cancer, thus providing a potential useful tool for tailoring the need of adjuvant therapy.

HPV-related lesions after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer: A focus on the potential role of vaccination.

OBJECTIVE: To date, no data supports the execution of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia (CIN2+) and early-stage cervical cancer. We aim to evaluate the potential effect of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer. METHODS: This is a multi-center retrospective study evaluating data of women who develop lower genital tract dysplasia (including anal, vulvar and vaginal intra-epithelial neoplasia) after having hysterectomy for CIN2+ and FIGO stage IA1- IB1 cervical cancer. RESULTS: Overall, charts for 77 patients who developed lower genital tract dysplasia were collected. The study population included 62 (80.5%) and 15 (19.5%) patients with CIN2+ and early-stage cervical cancer, respectively. The median (range) time between hysterectomy and diagnosis of develop lower genital tract dysplasia was 38 (range, 14-62) months. HPV types covered by the nonavalent HPV vaccination would potentially cover 94.8% of the development of lower genital tract dysplasia. Restricting the analysis to the 18 patients with available HPV data at the time of hysterectomy, the beneficial effect of nonvalent vaccination was 89%. However, considering that patients with persistent HPV types (with the same HPV types at the time of hysterectomy and who developed lower genital tract dysplasia) would not benefit from vaccination, we estimated the potential protective effect of vaccination to be 67% (12 out of 18 patients; four patients had a persistent infection for the same HPV type(s)). CONCLUSIONS: Our retrospective analysis supported the adoption of HPV vaccination in patients having treatment for HPV-related disease. Even in the absence of the uterine cervix, HPV vaccination would protect against develop lower genital tract dysplasia. Further prospective studies have to confirm our preliminary research.