Investigator
University Of Turin
Is total mesorectal excision mandatory in advanced ovarian cancer patients undergoing posterior pelvic exenteration? Prognostic role of mesorectal space involvement in a prospective ovarian cancer cohort
In advanced epithelial ovarian cancer (AEOC), debulking surgery with posterior pelvic exenteration (PPE) is performed in 35-70 % of the patients to achieve no macroscopic residual disease. This study aims to evaluate the incidence of mesorectal involvement and its prognostic role in AEOC patients undergoing PPE. This prospective study analyzes data from a cohort of AEOC patients who underwent primary debulking surgery (PDS) or interval debulking surgery (IDS) with PPE at the Léon Bérard Cancer Center in Lyon between 2018 and 2022. 73 patients underwent debulking surgery with PPE during the study period. 27 (34 %) underwent PPE during PDS and 46 (66 %) during IDS. 23 patients (31.5 %) had only serosal involvement, 19 (26 %) had bowel involvement up to the muscularis propria, and 7 (9.6 %) had up to the mucosa. Mesorectal involvement was observed in 40 cases (54.7 %) and was significantly associated with positive MLNs and higher liver recurrence rates. Hepatic metastases had an early onset (months, 9.8 vs 28.8; p = 0.0001) and were correlated with poorer OS (months, 20.9 vs 51.5) compared to recurrences in other sites. The persistence of positive mesorectum after neoadjuvant chemotherapy in the IDS group seemed to be linked to poor OS (NR vs 42.7 months). Debulking surgery with PPE in AEOC patients is often needed. Total mesorectal excision should be performed in AEOC to achieve no residual disease because positive mesorectum after neoadjuvant chemotherapy seemed to be linked with poor OS, with early onset and increased incidence of liver metastasis.
Oncolytic Viruses in Ovarian Cancer: Where Do We Stand? A Narrative Review
Ovarian cancer (OC) remains the most lethal gynecologic malignancy with limited effective treatment options. Oncolytic viruses (OVs) have emerged as a promising therapeutic approach for cancer treatment, capable of selectively infecting and lysing cancer cells while stimulating anti-tumor immune responses. Preclinical studies have demonstrated significant tumor regression and prolonged survival in OC models using various OVs, such as herpes simplex. Early-phase clinical trials have shown a favorable safety profile, though the impact on patient survival has been modest. Current research focuses on combining OVs with other treatments like immune checkpoint inhibitors to enhance their efficacy. We provide a comprehensive overview of the current understanding and future directions for utilizing OVs in the management of OC.
Ovarian clear cell carcinoma: open questions on the management and treatment algorithm
Abstract Ovarian clear cell carcinoma (OCCC) accounts for ~10% of all epithelial ovarian cancers and is considered a different entity from the more common high-grade serous ovarian carcinoma (HGSC), with distinct clinical presentations, different risk, and prognostic factors, and specific molecular features. Most OCCCs are diagnosed at an early stage and show favorable outcomes, in contrast to those diagnosed at advanced stages, which exhibit intrinsic resistance to platinum-based chemotherapy regimens and a very poor prognosis. The standard treatment of advanced OCCC is currently based on primary debulking surgery followed by platinum-based chemotherapy according to recent international guidelines. However, these recommendations are extrapolated from several trials mainly featuring a large cohort of HGSC, with only a small minority of OCCC. Because of its rarity, many questions remain unanswered regarding the surgical and medical treatment. Lymph node staging, fertility-sparing treatment, the use of targeted therapies and radiotherapy as well as the adjuvant treatment for early-stage disease and second or further lines of chemotherapy are still under debate. This review aims to address these unresolved issues, by providing a comprehensive overview of the current data on this disease, and to suggest possible directions for future research.
Targeting TOP2A in Ovarian Cancer: Biological and Clinical Implications
The enzyme topoisomerase II alpha (TOP2A) plays a critical role in DNA replication and cell proliferation, making it a promising target for cancer therapy. In epithelial ovarian cancer (EOC), TOP2A overexpression is associated with poor prognosis and resistance to conventional treatments. This review explores the biological functions of TOP2A in EOC and discusses its potential as a therapeutic target. We highlight studies on the mechanisms through which TOP2A contributes to tumor progression and recurrence. Additionally, we evaluate the clinical implications of targeting TOP2A, including the use of TOP2A inhibitors and their combination with novel drugs. We provide a comprehensive overview of the current understanding and future directions for targeting TOP2A in the management of EOC.
Response: Comment on searching for prognostic markers for stage I epithelial ovarian cancer: A role for systemic inflammatory markers
Link between isolated para-aortic lymph node metastasis and intrauterine cancer site in early stage endometrial cancer
Missing occult para-aortic lymph node metastasis is one of the primary concerns of sentinel lymph node biopsy in endometrial cancer. Our study aimed to evaluate the relationship between intrauterine cancer site and isolated para-aortic lymph node metastasis to tailor treatment and reduce the false negative rate of the sentinel lymph node procedure. A retrospective, multicenter, case control study was performed in four international centers. All patients with positive lymph nodes who had complete surgical staging with pelvic and para-aortic lymphadenectomy, between January 2013 and December 2023, were included. Detailed descriptions of the cancer location within the uterine cavity on the cranio-caudal plane and the myometrial wall involvement on the cranio-caudal and ventro-dorsal planes were collected, as were clinical data and cancer histological features. Patients with isolated para-aortic lymph node metastasis were allocated to group 1; patients with pelvic lymph node metastasis and those with both pelvic and para-aortic lymph node metastasis were allocated to group 2. The groups were compared according to the variables collected. 200 preoperative early stage endometrial cancer patients with postoperative International Federation of Gynecology and Obstetrics 2009/2023 stage IIIC1/IIIC2 were included in our study: 42 patients (21%) with isolated para-aortic lymph node metastasis were allocated to group 1 and the remaining patients to group 2. The two groups had comparable clinical and pathological characteristics (p>0.05): mean age was 66.5±10.3 (group 1) and 63.5±11.9 (group 2); endometrioid histotype was the predominant one for both groups (50%); most patients had myometrial infiltration >50% (80.9% and 79.7%), grade 3 (61.9% and 63.9%), and lymph vascular space invasion (78.5% and 82.2%). Cancers involving the fundal uterine cavity, the fundal myometrial wall, or the anterior myometrial wall were 3.11 (1.04-9.27), 3.03 (1.12-8.21), and 2.12 (0.77-5.80) times more likely to metastasize only to para-aortic lymph nodes compared with cancers located in other uterine sites. In this study, the intrauterine location of the cancer determined the site of lymph node metastasis. When the tumor involved the fundus (cavity or wall) and infiltrated exclusively the anterior wall, the baseline risk of spreading only into the para-aortic area increased significantly in selected patients at risk of nodal disease.
Comedo-like growth pattern in invasive early-stage cervical cancer: A new feature related to parametrial involvement
The standard surgical treatment for early-stage cervical cancer includes hysterectomy and bilateral oophorectomy along the removal of parametrial tissue to achieve surgical radicality. However, in recent years, the role of simple hysterectomy for cervical cancer with favorable prognostic characteristics has been re-evaluated. One of the challenges in early-stage cervical cancer is identifying predictive factors for neoplastic parametrial infiltration and lymph node metastases that cannot be detected during the preoperative assessment. We hypothesized that histological tumor growth patterns may be associated with these features and could thus be useful for the management of apparent early-stage cervical cancer. We identified 3 different histological patterns: the comedo-like, the infiltrative, and the expansive. We analyzed a series of clinic-pathological characteristics to determine the association of eachpatternwith aggressive features. Furthermore, we estimated odd ratios (ORs) in univariate and multivariate analyses for parametrial infiltration and lymph node metastasis. We found that comedo-like pattern is associated to advanced FIGO stages, larger tumor size, lymphovascular space invasion, deeper invasion depth, parametrium involvement, and lymph node metastases. By univariate analysis, comedo-like pattern was statistically associated with both parametrial involvement (OR: 19.3, CI 5.47-68.6, p-value = < 0.001) and lymph node metastases (OR: 4.98, CI 1.71-14.5, p-value = 0.003). By multivariate analysis, the association between comedo-like pattern and parametrial involvement was confirmed (OR: 8.76, CI 2.34-32.75, p-value = 0.01). The specific growth pattern of cervical cancer, assessed in a conization specimen before hysterectomy, can be useful to tailor surgical radicality.
Searching for prognostic markers for Stage I epithelial ovarian cancer: A role for systemic inflammatory markers
AbstractObjectiveTo determine the prognostic role of systemic inflammatory markers for Stage I epithelial ovarian cancer (EOC).Materials and MethodsWe performed a retrospective, single‐center, observational study. We included patients with Stage I EOC cancer undergoing primary surgery between 1993 and 2016. Inflammatory markers were assessed by analyzing blood samples collected at initial diagnosis before EOC surgery. We evaluated these markers' association with disease‐free survival (DFS) and cancer‐specific survival (CSS).ResultsWe included 176 women in our study. The neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were related to both DFS and CSS in the univariate analysis. In the multivariate Cox analysis, adjuvant chemotherapy (hazard ratio [HR] 0.17, 95% confidence interval [CI] 0.04–0.71, P = 0.02) and SII ≥730 (HR 6.84, 95% CI 1.30–35.9, P = 0.023) were independent predictors of DFS, while FIGO Stage IB–IC (HR 7.91, 95% CI 1.04–59.8, P = 0.04), NLR ≥3 (HR 56.8, 95% CI 7.46–433, P < 0.001) and PLR ≥169 (HR 49.1 95% CI 11.1–217.8, P = 0.005) were independent predictors of CSS.ConclusionsSystemic inflammatory markers are easily obtainable from patients' routine blood analyses and may represent inexpensive and reproducible prognostic markers in early‐stage EOC.
Human papillomavirus genotyping in high‐grade vaginal intraepithelial neoplasia: A multicentric Italian study
Abstract This study aimed to analyze the human papillomavirus (HPV) genotype distribution in a large cohort of high‐grade vaginal intraepithelial neoplasia (VaIN) (vaginal HSIL, VaIN2/3) patients from two Italian referral centers. We included all patients with histologically confirmed VaIN2/3 from the Department of Surgical Sciences, Sant'Anna Hospital, University of Torino, Torino, Italy, and Ospedale Maggiore della Carità, Novara, Italy, between 2003 and 2022. After the histological evaluation of formalin‐fixed paraffin‐embedded samples, we performed HPV genotyping with VisionArray HPV Chip 1.0. We detected HPV DNA in 94.4% of VaIN2/3 (168/178), with HPV 16 as the most prevalent genotype, accounting for 51.8% of all infections, 41.2% of VaIN2 and 77.6% of VaIN3 cases. Other frequent genotypes were HPV 58 (8.3%, 10.9% of VaIN2 and 2.0% of VaIN3), HPV 73 (5.4%, 5.0% of VaIN2 and 6.1% of VaIN3), and HPV 31 (5.4%, 6.7% of VaIN2 and 2.0% of VaIN3). 73.2% of VaIN2/3 had a single HPV genotype infection and 26.8% a multiple infection (20.8% a double infection, 4.8% a triple infection, and 1.2% a quadruple infection). Single infection was more frequently present in VaIN3 than VaIN2 (81.6% vs. 69.8%). 69.1% of single infections and 73.3% of multiple infections had one or more genotypes covered by nine‐valent HPV vaccine. HPV vaccination is expected to have a large impact on reducing the incidence of vaginal intraepithelial neoplasia.
Biomarkers of Central Nervous System Involvement from Epithelial Ovarian Cancer
Epithelial ovarian cancer (EOC) is the leading cause of death among women affected by gynaecological malignancies. Most patients show advanced disease at diagnosis (FIGO stage III-IV) and, despite the introduction of new therapeutic options, most women experience relapses. In most cases, recurrence is abdominal-pelvic; however, EOC can occasionally metastasize to distant organs, including the central nervous system. The incidence of brain metastases (BMs) from EOC is low, but it has grown over time; currently, there are no follow-up strategies available. In the last decade, a few biomarkers able to predict the risk of developing BMs from OC or as potential therapeutic targets have been investigated by several authors; to date, none have entered clinical practice. The purpose of this review is to offer a summary on the role of the most relevant predictors of central nervous system (CNS) involvement (hormone receptors; BRCA; MRD1; PD-1/PD-L1) and to highlight possible therapeutic strategies for the management of metastatic brain disease in EOC
Copy number alterations in stage I epithelial ovarian cancer highlight three genomic patterns associated with prognosis
Stage I epithelial ovarian cancer (EOC) encompasses five histologically different subtypes of tumors confined to the ovaries with a generally favorable prognosis. Despite the intrinsic heterogeneity, all stage I EOCs are treated with complete resection and adjuvant therapy in most of the cases. Owing to the lack of robust prognostic markers, this often leads to overtreatment. Therefore, a better molecular characterization of stage I EOCs could improve the assessment of the risk of relapse and the refinement of optimal treatment options. 205 stage I EOCs tumor biopsies with a median follow-up of eight years were gathered from two independent Italian tumor tissue collections, and the genome distribution of somatic copy number alterations (SCNAs) was investigated by shallow whole genome sequencing (sWGS) approach. Despite the variability in SCNAs distribution both across and within the histotypes, we were able to define three common genomic instability patterns, namely stable, unstable, and highly unstable. These patterns were based on the percentage of the genome affected by SCNAs and on their length. The genomic instability pattern was strongly predictive of patients' prognosis also with multivariate models including currently used clinico-pathological variables. The results obtained in this study support the idea that novel molecular markers, in this case genomic instability patterns, can anticipate the behavior of stage I EOC regardless of tumor subtype and provide valuable prognostic information. Thus, it might be propitious to extend the study of these genomic instability patterns to improve rational management of this disease.
Ovarian Cancer Cells in Ascites Form Aggregates That Display a Hybrid Epithelial-Mesenchymal Phenotype and Allows Survival and Proliferation of Metastasizing Cells
Peritoneal metastases are the leading cause of morbidity and mortality in ovarian cancer. Cancer cells float in peritoneal fluid, named ascites, together with a definitely higher number of non neo-neoplastic cells, as single cells or multicellular aggregates. The aim of this work is to uncover the features that make these aggregates the metastasizing units. Immunofluorescence revealed that aggregates are made almost exclusively of ovarian cancer cells expressing the specific nuclear PAX8 protein. The same cells expressed epithelial and mesenchymal markers, such as EPCAM and αSMA, respectively. Expression of fibronectin further supported a hybrid epithelia-mesenchymal phenotype, that is maintained when aggregates are cultivated and proliferate. Hematopoietic cells as well as macrophages are negligible in the aggregates, while abundant in the ascitic fluid confirming their prominent role in establishing an eco-system necessary for the survival of ovarian cancer cells. Using ovarian cancer cell lines, we show that cells forming 3D structures neo-expressed thoroughly fibronectin and αSMA. Functional assays showed that αSMA and fibronectin are necessary for the compaction and survival of 3D structures. Altogether these data show that metastasizing units display a hybrid phenotype that allows maintenance of the 3D structures and the plasticity necessary for implant and seeding into peritoneal lining.
Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review
Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.
Immunotherapy for Cervical Cancer: Are We Ready for Prime Time?
The prognosis of invasive cervical cancer (CC) remains poor, with a treatment approach that has remained the same for several decades. Lately, a better understanding of the interactions between the disease and the host immune system has allowed researchers to focus on the employment of immune therapy in various clinical settings. The most advanced strategy is immune checkpoint inhibitors (ICIs) with numerous phase II and III trials recently concluded with very encouraging results, assessing single agent therapy, combinations with chemotherapy and radiotherapy. Apart from ICIs, several other compounds have gained the spotlight. Tumor Infiltrating Lymphocytes (TILs) due to their highly selective tumoricidal effect and manageable adverse effect profile have received the FDA’s Breakthrough Therapy designation in 2019. The antibody drug conjugate (ADC) Tisotumab-Vedotin has shown activity in metastatic CC relapsed after at least one line of chemotherapy, with a phase III trial currently actively enrolling patients. Moreover, the deeper understanding of the ever-changing immune landscape of CC carcinogenesis has resulted in the development of active therapeutic vaccines. This review highlights the different immunotherapeutic strategies being explored reflects on what role immunotherapy might have in therapeutic algorithms of CC and addresses the role of predictive biomarkers.
Uterine smooth muscle tumors: a multicenter, retrospective, comparative study of clinical and ultrasound features
To evaluate a wide range of clinical and ultrasound characteristics of different uterine smooth muscle tumors to identify features capable of discriminating between these types. This was a retrospective, multicenter study that included 285 patients diagnosed with uterine smooth muscle tumors (50 leiomyosarcomas, 35 smooth muscle tumors of uncertain malignant potential, and 200 leiomyomas). The patients were divided into three groups based on the histological type of their tumors, and the groups were compared according to the variables collected. Leiomyosarcomas were more common in older and post-menopausal women. Compared with leiomyomas, smooth muscle tumors of uncertain malignant potential and leiomyosarcomas had similar ultrasound features such as absence of normal myometrium, multilocular appearance, hyper-echogenicity in case of uniform echogenicity, absence of posterior shadows, echogenic areas, and hyperechoic rim. Leiomyosarcomas were larger, had more cystic areas, and were associated with a higher prevalence of pelvic free fluid. Smooth muscle tumors of uncertain malignant potential were characterized by a higher frequency of International Federation of Gynecology and Obstetrics (FIGO) type 6-7, the absence of internal shadows, and, in the case of cystic area, the presence of a regular internal wall. Tumor outline varied among the three histological types. A color score of 1 was typical of leiomyoma, a color score 2 was mainly observed in leiomyomas and smooth muscle tumors of uncertain malignant potential, a color score 3 did not differ among the tumors, while a color of score 4 was related to leiomyosarcomas. When combining color scores 3 and 4, leiomyosarcomas and smooth muscle tumors of uncertain malignant potential showed a high percentage of both circumferential and intra-lesional vascularization. A cooked appearance was not statistically different among the tumors. Based on our findings, specific ultrasonographic features as well as age and menopausal status are associated with different uterine smooth muscle tumor types. Integration of these data can help the pre-operative assessment of these lesions for proper management.
Radiomics‐based ultrasOund Model for differentiating Uterine Sarcomas from leiomyomas ( ROMUS ): a retrospective pilot Multicenter Italian Trials in Ovarian Cancer ( MITO ) study
ABSTRACT Objective To develop machine‐learning models that incorporate clinical information and radiomics features extracted from ultrasound images to distinguish uterine sarcomas from leiomyomas. Methods This retrospective, multicenter, pilot case–control study included 200 patients (100 with a uterine sarcoma and 100 with a usual‐type leiomyoma, i.e. including no benign leiomyoma variants) who underwent preoperative ultrasound examination between January 2010 and June 2022. The patient cohort was split (70:30) into training and validation sets, with the same proportion of leiomyomas and sarcomas in each subset. We extracted radiomics features belonging to different families: intensity‐based statistical features and textural features. The variables used in model building were patient age and the radiomics features that differed statistically significantly between sarcomas and leiomyomas and that were not redundant based on Spearman's correlation coefficient. Logistic regression, random forest, extreme gradient boosting (XGBoost) and support vector machine models were tested in the model development process. We evaluated the performance of the models in differentiating between sarcomas and leiomyomas using the area under the receiver‐operating‐characteristics curve (AUC), accuracy, sensitivity and specificity. We compared these results to those of subjective assessment by the original ultrasound examiner and to those of two independent expert ultrasound examiners who, blinded to clinical history, reviewed the same grayscale ultrasound images as those used for the radiomics analysis. Results Sixty‐three radiomics features were extracted. Of these, eight differed statistically significantly between sarcomas and leiomyomas and were not correlated, so were selected for inclusion in model building. In the validation set, the model that performed best in differentiating between sarcomas and leiomyomas was an XGBoost model integrating patient age and radiomics features. In the validation set, this model had an AUC of 0.93, sensitivity of 0.93 and specificity of 0.83, at a risk‐of‐malignancy cut‐off of 47% (the cut‐off that yielded the highest number of correct classifications based on Youden's index in the training set). The corresponding results for the model integrating only the radiomics features were: AUC of 0.87, sensitivity of 0.87 and specificity of 0.83. Subjective assessment by the original ultrasound examiner had a sensitivity of 0.87 and specificity of 1 in the validation set, while retrospective review of grayscale ultrasound images by ultrasound experts had a sensitivity of 0.87 and specificity of 0.80 (same results for both reviewers). Conclusion A model including eight radiomics features and patient age demonstrated reasonably good discriminative and classification performance for distinguishing uterine sarcomas from leiomyomas. Its classification ability was similar to that of subjective assessment by the original ultrasound examiner, being more sensitive but less specific. To confirm the role of radiomics for discriminating between uterine sarcomas and leiomyomas, large prospective studies including benign leiomyoma variants are needed. If good performance of radiomics models can be confirmed, integrating automated radiomics analysis into ultrasound machine software may help ultrasound examiners to discriminate between sarcomas and benign leiomyomas. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
