Giorgio Bogani

The Relationship Between the Vaginal Microbiota and the Ovarian Cancer Microenvironment: A Journey from Ideas to Insights

Background: The tumor microenvironment offers a new perspective in gynecologic oncology. In ovarian cancer, numerous preclinical studies, especially organoid models, have highlighted cellular, immune, and biochemical mechanisms. Beyond these sophisticated findings, more practical aspects require attention, such as the role of vaginal microbiota, which represents an interplay between external agents and internal genitalia, and its potential profiling role in early detection beyond the promise of microbiota-targeted therapies. Objectives: This review aims to assess whether such a correlation is speculative or scientifically grounded. Methods: A focused literature search was conducted on vaginal microbiota and its correlation with ovarian cancer to define the current state of knowledge. Results: Mixed outcomes have been reported, yet there is a rational and scientific basis supporting further investigation. Clinical approaches increasingly consider vaginal microbiota as relevant. However, we have to say that most available evidence is still preliminary and largely preclinical to set realistic expectations for readers. Although additional studies are needed, emerging insights highlight its importance and practical implications. We present a diagnostic–therapeutic management flowchart summarizing current evidence). Discussion: Most links between the vaginal microbiota and ovarian cancer are correlational rather than causal. The idea that microbes ascend from the vagina to the ovaries is proposed but still definitely not demonstrated. Confounding factors like age, hormones, and BRCA status complicate interpretation, and ovarian cancer itself could secondarily alter the microbiota. Mechanistic studies and longitudinal data are still needed to clarify whether dysbiosis contributes to carcinogenesis or is merely a consequence. As gynecologists, we summarize key aspects and emphasize to colleagues the importance of incorporating these findings into daily clinical practice. Vaginal dysbiosis should be considered not only a local imbalance but also a potential strategy for primary cancer prevention. Conclusions: Future research on the tumor microenvironment and vaginal microbiota will expand scientific knowledge and guide innovative preventive and therapeutic strategies.

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:

Clinicopathological characteristics of multiple-classifier endometrial cancers: a cohort study and systematic review

Endometrial cancers with more than one molecular feature- To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them. Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification. Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and

Letter to the Editor: 2023 FIGO staging system for endometrial cancer

Characteristics and outcomes of surgically staged multiple classifier endometrial cancer

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. 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. 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). 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.

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.

Sentinel node–positive POLE-mutated endometrial cancer

The molecular classification of endometrial cancer has revolutionized risk stratification, with POLE-mutated tumors recognized for their excellent prognosis. However, the optimal management of patients with nodal involvement remains unclear. This multi-center retrospective study evaluates the outcomes of patients with stage IIIC endometrial cancer with positive sentinel lymph nodes harboring POLE mutations. Of 164 POLE-mutated cases undergoing sentinel node mapping, 11 (6.7%) had nodal metastases (classified as isolated tumor cells [n = 6; 54.5%], micro-metastases [n = 3; 27.3%], or macro-metastases [n = 2; 18.2%]). All patients except 1 received adjuvant therapy, tailored according to molecular and pathologic risk factors. After a median follow-up of 7.6 months, no recurrences were observed. These findings suggest excellent short-term outcomes, even in node-positive POLE-mutated endometrial cancer. Nevertheless, the study does not support omitting adjuvant therapy in this setting. Larger studies and long-term data, such as those expected from the ongoing Refining Adjuvant treatment IN endometrial cancer Based On molecular features (RAINBO)/ Blue trial are needed to guide safe de-escalation strategies.

Ninety-day surgery-related outcomes of laparoscopic hysterectomy, bilateral salpingo-oophorectomy and sentinel node mapping in apparent early-stage endometrial cancer: a secondary analysis of a prospective single-arm study

Limited prospective data are available on the outcomes and performance of sentinel node mapping (SNM) in patients with endometrial cancer (EC). This study aimed to describe the surgical outcomes related to laparoscopic staging and the performance of SNM in patients with apparent early-stage EC. This is a secondary analysis of a prospective single-arm study focusing on predictors of nodal disease in apparent early-stage EC. This analysis focused on 90-day surgical outcomes of patients undergoing laparoscopic surgery, including hysterectomy, bilateral salpingo-oophorectomy and SNM. Overall, 210 patients were evaluated: 178 (84.8 %) patients had endometrioid EC and 32 (15.2 %) patients had non-endometrioid EC. No conversions to open surgery were reported at the time of SNM. Two (1 %) patients converted to open surgery for completion of hysterectomy. Unilateral mapping was achieved in all patients (n = 210, 100 %), with a bilateral pelvic detection rate of 93.8 % (n = 197). Sentinel nodes in the para-aortic area were detected in 19 patients (9 %). The majority of sentinel nodes were located in the external iliac area (55.7 % on the right side and 58.6 % on the left side), followed by the obturator area (26.1 % on the right side and 22.9 % on the left side) and internal iliac area (11.9 % on the right side and 8.1 % on the left side). Overall, 41 patients (19.5 %) had positive nodes detected, with low-volume disease observed in 21 (10 %) patients. Eight (3.8 %) patients had moderate (grade 2) 90-day complications. Three (1.4 %) patients had severe (grade 3) 90-day complications. Laparoscopic surgical staging for apparent early-stage endometrial cancer is safe and effective. Long-term data are needed to assess oncological outcomes.

Integration of sentinel node mapping and molecular classification in endometrial cancer staging

Abstract Sentinel node mapping has gained popularity in surgical staging of endometrial cancer, providing a less invasive alternative to lymphadenectomy for staging purpose. Recent advances in molecular classification have deepened our understanding of endometrial cancer, leading to more personalized approaches in diagnosis and treatment. This review examined the interaction between sentinel node mapping and molecular classification in endometrial cancer, emphasizing the clinical implications. Surrogate molecular classification identified four distinct subtypes, each with different patterns of lymphatic spread and metastatic potential, overcoming the Bokhman's historic dualistic classification in type I (endometrioid) and type II (non‐endometrioid) endometrial cancer. Accumulating evidence supported that integrating molecular subtypes with sentinel node mapping, would improve the accuracy of lymph node staging, allowing for more tailored therapeutic strategies. The potential for artificial intelligence and machine learning to analyze molecular signatures in real‐time may further refine mapping accuracy and enable more individualized treatment plans. The development of novel molecular tracers and targeted therapies for sentinel node biopsy promises to enhance precision and minimize unnecessary lymphadenectomy. The aim of this review was to explore current methodologies, challenges, and future directions, highlighting the increasing role of molecular tools in sentinel node mapping and the personalized management of endometrial cancer.

Response to: Correspondence on ‘Predicting the risk of nodal disease with histological and molecular features in endometrial cancer: the prospective PROME trial’ by Aznar et al

Novel Insights into Molecular Mechanisms of Endometrial Diseases

Endometrial diseases are the most common gynecological pathologies in Western Countries [...]

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

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. 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. 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 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. NCT05793333.

Malignant germ cells tumor of the ovary

Malignant ovarian germ cell tumors are rare and diverse malignancies, accounting for approximately 5% of all ovarian cancers. Primarily affecting young women, these tumors present unique challenges, particularly in balancing effective treatment with fertility preservation. Early diagnosis is common due to the rapid tumor growth and symptoms such as abdominal pain and distension, leading to favorable prognoses when combined with the high chemosensitivity of platinum-based regimens. Fertility-sparing surgery is the cornerstone of treatment for stage I disease, often followed by close surveillance to minimize the long-term toxicities of chemotherapy. Pathology is pivotal for diagnosis, incorporating immunohistochemical markers to differentiate malignant ovarian germ cell tumors subtypes, including dysgerminomas, yolk sac tumors, and immature teratomas. Advanced imaging modalities like ultrasound, magnetic resonance imaging, and computed tomography are essential for staging, monitoring treatment response, and detecting recurrences. Despite high cure rates, long-term follow-up is crucial to manage late toxicities, such as gonadal dysfunction and secondary malignancies. Recurrent malignant ovarian germ cell tumors present significant therapeutic challenges. High-dose chemotherapy with stem-cell transplantation offers promise in select cases, while the role of secondary cytoreductive surgery and radiotherapy is limited to specific indications. Emerging targeted therapies and novel approaches, such as KIT inhibitors for dysgerminomas with KIT mutations, remain experimental, with limited success reported so far. The rarity and heterogeneity of malignant ovarian germ cell tumors impede large-scale research efforts, underscoring the need for greater understanding of their molecular and genetic landscape to develop more effective and personalized therapies.

Mirvetuximab soravtansine-gynx: first antibody/antigen-drug conjugate (ADC) in advanced or recurrent ovarian cancer

Mirvetuximab soravtansine-gynx (MIRV) is a conjugate of a folate receptor alpha (FRα)-directed antibody and the maytansinoid microtubule inhibitor, DM4. Accumulating pre-clinical and clinical data supported the safety and anti-tumor activity of MIRV in tumors expressing FRα. In 2017, a phase I expansion study reported the first experience of MIRV in FRα-positive platinum-resistant ovarian cancer with promising results. However, the phase III FORWARD I study failed to demonstrate a significant benefit of MIRV in FRα-positive tumors. On the basis of the data reported from this latter study, MIRV was then explored in the FRα-high population only and using a different folate receptor assay. The phase II SORAYA trial supported the adoption of MIRV in this setting. Hence, the US Food and Drug Administration granted accelerated approval of MIRV for patients with FRα-positive platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1-3 prior systemic treatment regimens. Moreover, the results of the MIRASOL trial showed a significant reduction in the risk of tumor progression or death among patients treated with MIRV versus chemotherapy. VENTANA FOLR1 (FOLR-2.1) was approved as a companion diagnostic test to identify FRα patients. MIRV appears to be a significant asset in managing advanced or recurrent ovarian cancer. Further trials are needed to confirm these promising results, even in the neoadjuvant, adjuvant, and maintenance settings.

Management of patients with ovarian cancer in the COVID‐19 era

AbstractAt the beginning of 2020, coronavirus disease 2019 (COVID‐19) spreads worldwide. Patients with ovarian cancer should be considered at high‐risk of developing severe morbidity related to COVID‐19. Most of them are diagnosed in advanced stages of disease, and they are fragile. Here, we evaluated the major impact of COVID‐19 on patients with ovarian cancer, discussing the effect of the outbreak on medical and surgical treatment.

Ten‐year follow‐up study of long‐term outcomes after conservative surgery for early‐stage ovarian cancer

AbstractObjectiveTo evaluate long‐term outcomes after surgery for apparent early‐stage ovarian cancer (OC).MethodsRetrospective analysis of women who underwent staging surgery for apparent early‐stage OC at a single center in Milan, Italy, from 1990 to 2008, and had a follow‐up longer than 10 years (living women with no recurrence). Univariate and multivariate analyses and propensity score matching were carried out.ResultsOverall, 182 women underwent radical (n=148, 81.3%) or conservative (n=34, 18.7%) procedures for early‐stage OC. Ten‐year disease‐free and overall survival were 82.9% (n=151) and 87.9% (n=160), respectively. Conservative or radical surgery had similar disease‐free (log‐rank test, P=0.783) and overall (log‐rank test, P=0.783) survival. These data were confirmed after the application of propensity score matching. High‐risk features correlated with non‐significant worse disease‐free survival (P=0.080). In the high‐risk group (≥Grade 3 or ≥ Stage IC), type of surgical approach (conservative vs radical) did not affect survival (hazard ratio, 0.81; 95% confidence interval, 0.18–3.56; P=0.781).ConclusionWomen with early‐stage OC had encouraging long‐term survival. The presence of high‐risk disease had detrimental effects on survival, regardless of surgical approach. High‐risk disease should not be considered a contraindication to conservative surgery.

Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review and meta-analysis

The role of adjuvant chemotherapy in surgically staged stage I clear cell ovarian cancer (OCCC) is unclear. Here, we performed a systematic review and meta-analysis in order to evaluate the role of chemotherapy vs. observation in stage I OCCC. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; ID: #129628). A protocol was defined prior to the search include the population criteria, description of interventions, comparisons, and the outcomes of interest, according to the PRIMA guidelines. Overall, the study population included 5073 women. Stage I OCCC experienced a 5-year disease-free survival and a 5-year overall survival of 83.7% and 86.9%, respectively. Pooled data suggested that in the overall population adjuvant chemotherapy did not impact on 5-year disease free survival (test for overall effect, Z = 0.18; p = 0.86) and 5-year overall survival (test for overall effect, Z = 0.62; p = 0.53). Focusing on 2264 stage IC OCCC we observed that adjuvant correlated with an improvement in overall survival (OR: 0.70 (95%CI: 0.52 to 0.93); Z = 2.44; p = 0.01). In conclusion our study underlines that adjuvant chemotherapy could be reserved for patients with stage IC OCCC; while in stage IA and IB it could be safely omitted. Owing to the inherent biases of the studies included in the meta-analysis further prospective evidences are needed.

Advances in small molecule maintenance therapies for high-grade serous ovarian cancer

Ovarian cancer is one of the most lethal gynecological tumors with a lack of effective treatment modalities especially in advanced/recurrent disease. Nevertheless, recently, new small molecules have emerged as an effective approach for the management of ovarian cancer patients, especially in the maintenance setting. This review summarizes the role of small molecules used in the management of high-grade serous ovarian cancer. The authors performed a critical review of current evidence and ongoing studies. Of note, tyrosine kinase inhibitors (TKIs) and poly(ADP-ribose) polymerase (PARP) inhibitors are the most intriguing medications in this setting. Protein-targeted therapies against tumor tissues have progressed significantly in the last years due to an enhanced knowledge of the biological and molecular processes of carcinogenesis. Treatment with small molecules allows the targeting of specific proteins involved in cancer biology. TKIs seem promising but further data are necessary to assess the pros and cons of adopting this treatment modality. PARP inhibitors represent the new standard of care for ovarian cancer patients harboring either a BRCA mutation or with homologous recombination deficiency (HRD). Interestingly, the accumulation of data has highlighted that PARP inhibitors provide benefits even in patients with HR proficient tumors.

Fertility-sparing surgery for women with stage I cervical cancer of 4 cm or larger: a systematic review

To investigate current evidence on oncological, fertility and obstetric outcomes of patients with stage I cervical cancer of 4 cm or larger undergoing fertility-sparing surgery (FSS). Systematic review of studies including women affected by stage I cervical cancer ≥4 cm who underwent FSS. Main outcome measures: disease-free survival (DFS), overall survival (OS), pregnancy rate, live birth rate, premature delivery rate. Fifteen studies met all eligibility criteria for this systematic review, involving 48 patients affected by cervical cancer ≥4 cm who completed FSS. Three patients (6.3%) experienced a recurrence and one of them (2.1%) died of disease. The 5-year DFS rate was 92.4%. The 5-year OS rate was 97.6%. A significantly shorter 5-year DFS was reported for high-risk patients (G3, non-squamous histotype, diameter ≥5 cm) compared with low-risk (74.7% vs. 100%; log-rank test, p=0.024). Data about fertility outcomes were available for 12 patients. Five patients out of 12 (41.7%) attempted to conceive with an estimated pregnancy rate of 80%, a live birth rate of 83.3% and a premature delivery rate of 20%. Women with high tumor grade, aggressive histology and tumor size ≥5 cm have a higher risk of recurrence. Oncologic outcomes are encouraging among low-risk patients; however, the lack of high-quality studies makes it difficult to draw any firm conclusions. Prospective multicentric clinical trials with a proper selection of inclusion/exclusion criteria should be conducted in women with low-risk factors, strong desire to preserve their fertility and high likelihood to conceive.

Systematic lymph node dissection during interval debulking surgery for advanced epithelial ovarian cancer: a systematic review and meta-analysis

To evaluate the efficacy and safety of systematic lymph node dissection (SyLND) at the time of interval debulking surgery (IDS) for advanced epithelial ovarian cancer (AEOC). Systematic literature review of studies including AEOC patients undergoing SyLND versus selective lymph node dissection (SeLND) or no lymph node dissection (NoLND) after neoadjuvant chemotherapy (NACT). Primary endpoints included progression-free survival (PFS) and overall survival (OS). Secondary endpoints included severe postoperative complications, lymphocele, lymphedema, blood loss, blood transfusions, operative time, and hospital stay. Nine retrospective studies met the eligibility criteria, involving a total of 1,660 patients: 827 (49.8%) SyLND, 490 (29.5%) SeLND, and 343 (20.7%) NoLND. The pooled estimated hazard ratios (HR) for PFS and OS were, respectively, 0.88 (95% confidence interval [CI]=0.65-1.20; p=0.43) and 0.80 (95% CI=0.50-1.30; p=0.37). The pooled estimated odds ratios (ORs) for severe postoperative complications, lymphocele, lymphedema, and blood transfusions were, respectively, 1.83 (95% CI=1.19-2.82; p=0.006), 3.38 (95% CI=1.71-6.70; p<0.001), 7.23 (95% CI=3.40-15.36; p<0.0001), and 1.22 (95% CI=0.50-2.96; p=0.67). Despite the heterogeneity in the study designs, SyLND after NACT failed to demonstrate a significant improvement in PFS and OS and resulted in a higher risk of severe postoperative complications. PROSPERO Identifier: CRD42022303577.

Age-specific predictors of cervical dysplasia recurrence after primary conization: analysis of 3,212 women

This study aimed to identify predictors of recurrence/persistence of cervical intraepithelial neoplasia grade 2+ (CIN2+) lesion (r-CIN2+) after primary conization. Retrospective analysis involving all consecutive women having conization for CIN2+ between 1998 and 2018. The risk of r-CIN2+ was assessed using Kaplan-Meier and Cox models. Data of 3,212 women were retrospectively identified. After a mean follow-up of 47 (±22.2) months, 112 (3.5%) patients developed r-CIN2+. Mean time interval between prior conization and diagnosis of r-CIN2+ was 26.2 (±13.2) months. Via multivariate analysis, presence of high-risk human papillomavirus (HPV) types at the time of CIN2+ diagnosis, hazard ratio (HR)=3.40 (95% confidence interval [CI]=1.66-6.95) for HPV16/18 and HR=2.59 (95% CI=1.21-5.55) for HPV types other than 16/18, positive margins at primary conization, HR=4.11 (95% CI=2.04-8.26) and HPV persistence after conization, HR=16.69 (95% CI=8.20-33.9), correlated with r-CIN2+, independently. Considering age-specific HPV types distribution, we observed that HPV16/18 infection correlated to an increased risk of r-CIN2+ only in young women (aged ≤25 years; p=0.031, log-rank test); while in the older population (>25 years) HPV type(s) involved had not impact on r-CIN2+ risk (p>0.200, log-rank test). HPV persistence is the main factor predicting r-CIN2+. Infection from HPV16/18 has a detrimental effect in young women, thus highlighting the need of implementing vaccination against HPV in this population. Further prospective studies are warranted for tailoring clinical decision-making for post-conization follow-up on the basis of risk factors.

Role of V-Y flap reconstruction in vulvar cancer patients: multicenter retrospective study

To assess if the use of a V-Y reconstructive flap after excisional radical surgery positively influences the surgical outcomes in patients with vulvar cancer. This was a multicenter, retrospective, controlled study. Surgical outcomes and complication rates of women with invasive vulvar cancer who underwent radical surgery and vulvar reconstruction and those who underwent radical surgery without the reconstruction step were compared. Only patients who underwent bilateral or unilateral V-Y advancement fascio-cutaneous flaps were included in the reconstruction group. Univariate and multivariate logistic regression models were used to analyze predicting variables for their association with complication rates. Overall, 361 patients were included: 190 (52%) underwent the reconstructive step after the excisional radical procedure and were compared with 171 (47.4%) who did not undergo the reconstructive step. At multivariate analysis, body mass index >30 kg/m The adoption of V-Y flaps in vulvar surgery was correlated with reduced surgical related complications, particularly in vulnerable patients involving large surgical defects following excisional radical procedures.

An update on current pharmacotherapy for vulvar cancer

Limited data on the role of pharmacotherapy for patients with locally advanced, recurrent, or metastatic vulvar cancer are available. This article aims to provide an overview of the current treatment options for patients with vulvar cancer. PubMed (MEDLINE), Embase, CENTRAL, Scopus, and Web of Science databases, as well as ClinicalTrials.gov were searched to review the current evidence as well as future perspectives on the role of pharmacotherapy in patients with vulvar carcinoma. There has been no consensus on the pharmacotherapy for patients with locally advanced, recurrent, or metastatic vulvar cancer. Concurrent platinum-based chemoradiation is the most widely used treatment modality for primary treatment or for neoadjuvant settings. Chemotherapy in metastatic disease is considered a palliative treatment. Anti-EGFR tyrosine kinase inhibitors seem to show promising anti-tumor activity in patients harboring EGFR alteration. Similarly, growing evidence supports the adoption of immune checkpoint inhibitors in both neoadjuvant and metastatic settings. Molecular and genomic profiling is advocated to identify target mutations. The

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

To evaluate oncological and obstetrical outcomes of early stage cervical cancer patients who underwent conservative management to retain childbearing potential. Data of women (aged <40 years) who underwent fertility sparing treatment for International Federation of Gynecology and Obstetrics (FIGO) stage IA1 with lymphovascular invasion (LVSI) and IB1 cervical cancer were prospectively collected. All patients underwent cervical conization/s and laparoscopic nodal evaluation (pelvic lymphadenectomy/sentinel node mapping). Oncological and obstetrical outcomes were assessed. Overall, 39 patients met inclusion criteria; 36 (92.3%) women were nulliparous. There were: 3 (7.7%) IA1-LVSI+; 11 (28.2%) IA2; and 25 (64.1%) IB1 cervical cancers, according to 2018 FIGO stage classification. Histological types were 22 (56.4%) squamous carcinoma and 17 (43.6%) adenocarcinoma. Pelvic lymphadenectomy was performed in 29 (74.4%) patients, while 10 (25.6%) patients had only sentinel node mapping. In 4 (10.3%) patients conservative treatment was discontinued due to nodal involvement and 2 (5.1%) patients requested definitive treatment (hysterectomy) after a negative lymph node evaluation. Among 33 (84.6%) patients who retained their childbearing potential, 17 (51.5%) had a second conization. 2 (6.1%) patients relapsed and underwent definitive treatment. After a median follow-up of 51 months (range 1-184) no deaths were reported. 22 (70.9%) patients attempted to conceive. There were 13 natural pregnancies among 12 (54.5%) women who got pregnant. Live birth rate was 76.9%: 9 (69.2%) term and 1 (7.7%) preterm (at 32 weeks) deliveries. 2 (15.4%) miscarriages (first and second trimester) and 1 (7.7%) termination of pregnancy for medical reasons were recorded. Conization plus laparoscopic nodal evaluation may be a safe and feasible conservative option in the setting of fertility-sparing treatment for early-stage cervical cancer patients.

Radical Hysterectomy for Early Stage Cervical Cancer

Radical hysterectomy and plus pelvic node dissection are the primary methods of treatment for patients with early stage cervical cancer. During the last decade, growing evidence has supported the adoption of a minimally invasive approach. Retrospective data suggested that minimally invasive surgery improves perioperative outcomes, without neglecting long-term oncologic outcomes. In 2018, the guidelines from the European Society of Gynaecological Oncology stated that a “minimally invasive approach is favored” in comparison with open surgery. However, the phase III, randomized Laparoscopic Approach to Cervical Cancer (LACC) trial questioned the safety of the minimally invasive approach. The LACC trial highlighted that the execution of minimally invasive radical hysterectomy correlates with an increased risk of recurrence and death. After its publication, other retrospective studies investigated this issue, with differing results. Recent evidence suggested that robotic-assisted surgery is not associated with an increased risk of worse oncologic outcomes. The phase III randomized Robotic-assisted Approach to Cervical Cancer (RACC) and the Robotic Versus Open Hysterectomy Surgery in Cervix Cancer (ROCC) trials will clarify the pros and cons of performing a robotic-assisted radical hysterectomy (with tumor containment before colpotomy) in early stage cervical cancer.

HPV persistence after cervical surgical excision of high‐grade cervical lesions

Human papillomavirus (HPV) is the primary cause of cervical dysplasia and cervical cancer. Attempts are needed to better categorize patients with HPV in order to provide useful information for prognosticating and appropriately tailoring surveillance.

Liver-directed surgical procedures during cytoreductive surgery for stage IV ovarian cancer

The incorporation of liver-directed surgical procedures into cytoreductive surgery represents a challenge in stage IV epithelial ovarian cancer. Overall, 49 patients undergoing primary or interval debulking surgery with at least one hepatobiliary procedure were retrospectively analyzed. One intraoperative complication occurred and severe postoperative morbidity (grade III or higher according to the Clavien-Dindo classification) was observed in 8 (16.4%) patients. Only one of these complications (biliary leakage requiring endoscopic stenting) was directly attributable to liver surgery. Although limited by the small sample size, these findings suggest that, in carefully selected patients and within a multidisciplinary framework, hepatobiliary surgery can be safely incorporated into cytoreductive strategies to achieve complete tumor removal.

Integrating molecular classification into endometrial cancer management

Endometrial carcinoma is biologically heterogeneous. Molecular classification derived from The Cancer Genome Atlas (TCGA) identifies clinically relevant molecular subtypes, each with distinct prognostic and therapeutic implications. FIGO 2023 recognizes tumor biology in staging, and the new 2025 ESGO guidelines incorporate molecular data into risk-stratified management. This is a position paper on the incorporation of molecular classification in endometrial cancer. We focused on molecular taxonomy, diagnostic surrogates, prognostic validation, and therapeutic implications of immune and targeted agents. The five molecular subtypes (POLEmut; MMRd/MSI-H; p53abn; NSMP ER-positive; NSMP ER-negative) provide stronger prognostic discrimination than grade or histotype alone. We recommend that molecular subtype should guide adjuvant treatment de-escalation or intensification, inform the use of immunotherapy and targeted agents, and refine risk stratification beyond conventional parameters. We also discussed implementation challenges, including test standardization, reporting, equity of access, and areas of ongoing uncertainty. This position paper aims to support consistent, equitable, and biologically informed management of endometrial carcinoma in contemporary practice.

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

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. 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. 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. 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.

Gestational choriocarcinoma

Gestational choriocarcinoma accounts for 5% of gestational trophoblastic neoplasms. Approximately 50%, 25%, and 25% of gestational choriocarcinoma occur after molar pregnancies, term pregnancies, and other gestational events, respectively. The FIGO scoring system categorizes patients into low (score 0 to 6) and high risk (score 7 or more) choriocarcinoma. Single-agent and multi-agent chemotherapy are used in low- and high-risk patients, respectively. Chemotherapy for localized disease has a goal of eradication of disease without surgery and is associated with favorable prognosis and fertility preservation. Most patients with gestational choriocarcinoma are cured with chemotherapy; however, some (<5.0%) will die as a result of multi-drug resistance, underscoring the need for novel approaches in this group of patients. Although there are limited data due to its rarity, the treatment response with immunotherapy is high, ranging between 50-70%. Novel combinations of immune checkpoint inhibitors with targeted therapies (including VEGFR-2 inhibitors) are under evaluation. PD-L1 inhibitors are considered a potential important opportunity for chemo-resistant patients, and to replace or de-escalate chemotherapy to avoid or minimize chemotherapy toxicity. In this review, the Rare Tumor Working Group and the European Organization for Research and Treatment of Cancer evaluated the current landscape and further perspective in the management of patients diagnosed with gestational choriocarcinoma.

Predictors of Node Positivity in Endometrial Cancer

To investigate the role of histological and moleculr profile of endometrial cancer patietns in predicting the risk of nodal metastases in endometrila cancer patients.

Research on Laparoscopic Fertility-Sparing Surgery in Early-Stage Cervical Cancer

Purpose: To evaluate the oncological and obstetrical outcomes of women with early-stage cervical cancer who underwent laparoscopic-assisted vaginal radical trachelectomy (LAVRT). All women with early-stage cervical cancer who planned to undergo fertility-preserved radical trachelectomy. The obstetric outcome evaluation was restricted to women with ≥12 months of follow-up and an active desire to conceive. The oncological outcome was evaluated in all patients. Statistical methods: Statistical analyses were performed using IBM SPSS Statistics, version 26. The t-test is used for analyzing the continuous variables and the chi-squared test for categorical variables.