Federico Ferrari

Oxford Classic–Defined EMT Risk Stratification of High-Grade Serous Ovarian Cancer for Guiding Treatment Decisions

Abstract Purpose: The association between epithelial-to-mesenchymal transition (EMT) in high-grade serous ovarian cancer (HGSOC) and poor prognosis is known. However, molecularly defining a subset of tumors that reproducibly associates with poor prognosis has been an elusive goal in this disease. A molecular signature that can robustly identify patients with poor prognosis and guide treatment decisions, including surgical strategy and targeted therapies, can improve survival rates. Experimental Design: We carried out RNA sequencing of 139 tumor samples (Brescia cohort); an external validation on 362 and 126 patients from the Scottish and Garsed cohorts, respectively; and a meta-analysis of 1,023 tumors to develop clinically useful risk groups. Identification of therapeutic targets was carried out by transcriptomic analyses of fluorescence-activated cell sorted (FACS) tumor epithelial cells and multiplex immunofluorescence assessment of tissue sections. Results: In this study, we have validated the prognostic strength of the Oxford Classic–defined EMT in three independent patient cohorts: Brescia [HR = 3.6; 95% confidence interval (CI) of 1.59–7.97; P = 1.99e−03], Scottish (HR = 1.71; 95% CI of 1.08–2.70; P = 2.23e−02), and Garsed (Kruskal–Wallis P = 0.00071). OxC-based risk stratification of HGSOC could robustly identify poor-risk patients with a 5-year median survival for OxC high-risk and OxC low-risk groups of 13% and 50%, respectively (95% CI of 7.1%–23.5% vs. 36.1%–69.3%) in the Brescia cohort. Further analysis of the risk groups suggests that an alternative surgical strategy and a combination therapy involving EMT targeting drugs and immunomodulators could elicit improved clinical response in poor-risk patients. Conclusions: This study provides a clinically useful risk stratification strategy for HGSOC, as well as targeted treatment options for high-risk patients. See related commentary by Venegas et al., p. 10

The Role of Tumor Biomarkers in Tailoring the Approach to Advanced Ovarian Cancer

Growing evidence has demonstrated the role of mutations of tumor biomarkers in diagnosing and treating epithelial ovarian cancer. This review aims to analyze recent literature on the correlation between tumor biomarkers and chemotherapy in nonmucinous ovarian cancer, providing suggestions for personalized treatment approaches. An extensive literature search was conducted to identify relevant studies and trials. BRCA1/2 mutations are central in homologous recombination repair deficiency (HRD) in ovarian cancer, but several other genetic mutations also contribute to varying cancer risks. While the role of MMR testing in ovarian cancer is debated, it is more commonly linked to non-serous ovarian cancer, often associated with Lynch syndrome. A significant proportion of ovarian cancer patients have HRD, affecting treatment decisions in both first-line (especially in advanced stages) and second-line therapy due to HRD’s connection with platinum-based therapy and PARP inhibitors’ response. However, validated genetic tests to identify HRD have not yet been universally implemented. There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool.

Prognostic role of immunohistochemical and molecular markers in no specific molecular profile endometrial cancer: a systematic review and meta-analysis

No specific molecular profile endometrial cancer represents nearly half of the diagnoses, characterized by substantial molecular heterogeneity and intermediate recurrence and survival outcomes. Currently, no immunohistochemical or molecular markers are established in guidelines to improve prognosis estimation and personalize treatment in no specific molecular profile endometrial cancer. This systematic review and meta-analysis aimed to evaluate the prognostic significance of potential immunohistochemical and molecular surrogate markers in no specific molecular profile endometrial cancers. This systematic review and meta-analysis adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered with the International Prospective Register of Systematic Reviews (CRD42024601035). A comprehensive literature search was conducted using Scopus, PubMed/MEDLINE, ScienceDirect, and the Cochrane Library (January 1994-December 2024). Studies assessing the prognostic roles of L1 cell adhesion molecule, catenin beta 1, AT-rich interactive domain-containing protein 1A, estrogen receptor, progesterone receptor, and STMN1 expression or mutation status in no specific molecular profile endometrial cancers were included. Methodological quality was assessed using the Newcastle-Ottawa Scale and the Quality in Prognosis Studies tool for risk of bias in prognostic studies. Certainty of evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation approach. Hazard ratios for recurrence and survival were calculated using random-effects or fixed-effects models depending on heterogeneity. Fourteen retrospective studies including 4654 no specific molecular profile endometrial cancers were analyzed. L1 cell adhesion molecule overexpression significantly predicted higher recurrence (hazard ratio=3.42; 95% confidence interval, 1.86-6.29; P<.001) and worse survival (hazard ratio=4.31; 95% confidence interval, 2.62-7.09; P<.001). Estrogen receptor positivity correlated significantly with reduced recurrence risk (hazard ratio=0.37; 95% confidence interval, 0.26-0.53) and improved survival (hazard ratio=0.22; 95% confidence interval, 0.17-0.29). Loss of progesterone receptor expression was associated with increased recurrence and poorer survival outcomes. Conversely, AT-rich interactive domain-containing protein 1A and catenin beta 1 mutations and STATHMIN1 overexpression did not significantly impact recurrence or survival outcomes. L1 cell adhesion molecule overexpression, estrogen receptor positivity, and progesterone receptor status demonstrate considerable prognostic relevance in no specific molecular profile endometrial cancer, warranting consideration as potential markers for improving patient management, including fertility-sparing approach.

Validation of an enhanced recovery after surgery protocol in gynecologic surgery: an Italian randomized study

The enhanced recovery after surgery concept, which was introduced 20 years ago, is based on a multimodal approach to improve the functional rehabilitation of patients after surgery. This study aimed to validate an enhanced recovery after surgery protocol in gynecologic surgery for both benign and malignant diseases (endometrial cancer and advanced ovarian cancer) and to measure the adherence to the enhanced recovery after surgery protocol items in a randomized trial setting. In this trial (NCT03347409), we randomly assigned patients to undergo standard perioperative care or enhanced recovery after surgery protocol. The primary outcome is a shorter length of stay in favor of the enhanced recovery after surgery protocol. Secondary outcomes include measurement of adherence to the enhanced recovery after surgery protocol items: comparison of postoperative pain, vomiting, and nausea; anesthesiologic and surgical complications up to 30 days after surgery; rate of readmissions; the time to event in hours for bowel movements, flatus, drinking, hunger, eating, and walking; and the quality of recovery using a validated questionnaire (QoR-15). Finally, we explored the length of stay in the prespecified subgroups at randomization, based on the type of surgical access and gynecologic disease. A total of 168 women were available for analysis: 85 women (50.6%) were assigned to the standard perioperative care group, and 83 women (49.4%) were assigned to the enhanced recovery after surgery protocol group. The 2 groups were similar for age, body mass index, comorbidities, anesthesiological risk, smoking habits, surgical access, and complexity of surgical procedures. Seventy-two patients (42.9%) underwent surgery for benign disease, 48 (28.6%) for endometrial cancer, and 48 (28.6%) for ovarian cancer. Women in the enhanced recovery after surgery protocol group had a shorter length of stay (median: 2 [interquartile range, 2-3] vs 4 [interquartile range, 4-7] days; P<.001). A decreased rate of postoperative complications was noted for the enhanced recovery after surgery protocol group, as well as an earlier time to occur for all the events. Mean adherence to protocol items was 84.8% (95% confidence interval, 79.7-89.8), and we registered a better satisfaction in the enhanced recovery after surgery protocol group. The shortening of the length of stay was confirmed also in the prespecified subgroup analysis. Application of the enhanced recovery after surgery protocol in gynecologic surgery translated to a shorter length of stay regardless of surgical access and type of gynecologic disease. Adherence to the enhanced recovery after surgery protocol items in the setting of a randomized trial was high.

Minimally invasive surgery in the management of early stage cervical cancer after the publication of SHAPE trial

Extra-abdominal ovarian cancer presenting with breast metastases at diagnosis: Case report and literature review

Malignant ovarian tumours are diagnosed at an advanced stage in the majority of cases. However, only a small percentage present as extra-abdominal, non-lymph-node solid metastases, as in the breast, and they are usually cases of relapse. The discovery of mono- or bilateral breast lesions with peritoneal carcinosis and/or abdomino-pelvic lesions can be cumbersome in the differential diagnosis of primary tumours. This article aims to summarize current evidence on the detection of breast metastases at diagnosis of ovarian cancer. A systematic review of the literature in Scopus, PubMed/MEDLINE, ScienceDirect and the Cochrane Library, including case reports and case series, was undertaken. Data regarding study features; population characteristics; clinical, radiological and histological assessment of the disease; treatment and follow-up were collected. In addition, a case report of a patient managed at the authors' centre is provided. According to the search strategy, 16 articles (18 patients) were included in this review. Serous ovarian, fallopian tube or primary peritoneal cancer was detected in 61% of cases, while another type or a non-specified type of epithelial ovarian cancer was detected in 27.7% of cases; there was one case with granulosa cell tumour of the ovary and one case with mucinous ovarian tumour of low malignant potential. Breast metastases were mainly monolateral (66.6%), with other extra-abdominal sites of disease in the majority of the cases. A minority of patients (16.6%) received treatment for primary breast cancer with a subsequent diagnosis of ovarian cancer. Concomitant breast and abdominal surgery can be an option. PAX8, WT1 and CA125 immunohistochemical staining can aid in differential diagnosis. Breast metastases of malignant ovarian tumours must be promptly recognized to ensure proper treatment. Specific immunohistochemical analysis can be a decisive assessment in uncertain cases.

Feasibility of laparoscopic diaphragmatic peritonectomy during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer

To describe the surgical technique and evaluate the safety, feasibility and efficacy of laparoscopic diaphragmatic peritonectomy during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer (OC). This report is part of a Service Evaluation Protocol (Trust number 3267) on laparoscopy in patients with OC following neo-adjuvant chemotherapy. Between April 2015 and November 2017, all patients underwent to exploratory laparoscopy and a selected court was offered laparoscopic VPD. Laparoscopic diaphragmatic surgery was considered if there was no full thickness involvement. Primary endpoints of this part of the study were the safety, feasibility and efficacy of laparoscopic diaphragmatic peritonectomy. We report the surgical technique and outcomes. Ninety-six patients underwent diaphragmatic surgery during the study period. Fifty patients (52.1%) had intra-operative exclusion criteria and/or full thickness diaphragmatic resection, 46 (47.9%) had peritonectomy and were included in the study. Laparoscopic diaphragmatic peritonectomy was performed in 21 patients (45.4%, group 1), while in 25 patients (54.6%, group 2) laparotomy was necessary. Extent of disease and complexity of surgery were similar. Reasons for conversions were disease coalescing the liver to the diaphragm preventing safe mobilization (22 patients) and accidental pleural opening (3 patients). Overall, intra- and post-operative morbidity was lower in group 1 and pulmonary specific morbidity was very low. Diaphragmatic peritonectomy can be safely accomplished by laparoscopy in almost half of the patients with OC whose disease is limited to the diaphragmatic peritoneum.

Tozzi classification of diaphragmatic surgery in patients with stage IIIC–IV ovarian cancer based on surgical findings and complexity

To introduce a systematic classification of diaphragmatic surgery in patients with ovarian cancer based on disease spread and surgical complexity. For all consecutive patients who underwent diaphragmatic surgery during Visceral-Peritoneal debulking (VPD) in the period 2009-2017, we extracted: initial surgical finding, extent of liver mobilization and type of procedure. Combining these features, we aimed to classify the surgical procedures necessary to tackle different presentation of diaphragmatic disease. We also report histology, intra- and post-operative specific complication rate based on the classification. A total of 170 patients were included in this study, 110 (64.7%) had a peritonectomy, while 60 (35.3%) had a full thickness resection with pleurectomy. We identified 3 types of surgical procedures. Type I treated 28 out of 170 patients (16.5%) who only had anterior diaphragm disease, needed no liver mobilization, included peritonectomy and had no morbidity recorded. Type II pertained to 105 out of 170 patients (61.7%) who had anterior and posterior disease, needed partial and sometimes full liver mobilization, had a mix of peritonectomy and full thickness resection, and experienced 10% specific morbidity. Type III included 37 out of 170 patients (21.7%) who needed full mobilization of the liver, always had full thickness resection, and suffered 30% specific morbidity. Diaphragmatic surgery can be classified in 3 types. The adoption of this classification can facilitate standardization of the surgery, comparison of data and define the expertise required. Finally, this classification can be a benchmark to establish the training required to treat diaphragmatic disease.