Splenectomy in epithelial ovarian cancer surgery.

OBJECTIVE: Splenectomy is performed in 4-32% of cytoreductive surgeries for ovarian cancer. The objective of our study was to assess splenectomy and evaluate its impact on overall and disease-free survival. METHODS: We conducted a retrospective single-center study between January 2000 and December 2016. Patients who underwent a cytoreduction for epithelial ovarian cancer, regardless of stage and surgical approach, were eligible for the study. Patients deemed not operable were excluded from the study. Patients were stratified into two groups, splenectomy or no splenectomy. A univariate analysis followed by a multivariate analysis was conducted to evaluate the postoperative complications after splenectomy and the overall and disease-free survival. RESULTS: This cohort included 464 patients. Disease stages, peritoneal carcinomatosis scores, and the rate of radical surgery (Pomel classification) were significantly higher in the splenectomy group, p=0.04, p<0.0001, and p<0.001, respectively. However, no significant difference was found in the rate of complete cytoreduction between the two groups (p=0.26) after multivariate analysis. In univariate analysis, splenectomy was significantly associated with extensive surgical procedures. In multivariate analysis, the two more prevalent complications in the splenectomy group were the risk of abdominopelvic lymphocele (overall response (OR) =4.2; p=0.01) and blood transfusion (OR=2.4; p=0.008). The average length of hospital stay was significantly longer in the splenectomy group, 17.4 vs 14.6 days (p<0.0001). The delay in adjuvant chemotherapy was longer in the splenectomy group (p=0.001). There was no significant difference in overall and disease-free survival (p=0.09) and (p=0.79), respectively. CONCLUSION: Splenectomy may be considered an acceptable and safe procedure; however, with no impact on overall or disease-free survival. In addition, it is associated with longer hospital stay and longer time to chemotherapy.

Update on Prognostic and Predictive Markers in Mucinous Ovarian Cancer.

This review includes state-of-the-art prognostic and predictive factors of mucinous ovarian cancer (MOC), a rare tumor. Clinical, pathological, and molecular features and treatment options according to prognosis are comprehensively discussed. Different clinical implications of MOC are described according to the The International Federation of Gynecology and Obstetrics (FIGO) stage: early MOC (stage I-II) and advanced MOC (stage III-IV). Early MOC is characterized by a good prognosis. Surgery is the mainstay of treatment. Fertility-sparing surgery could be performed in patients who wish to become pregnant and that present low recurrence risk of disease. Adjuvant chemotherapy is not recommended, except in patients with high-risk clinical and pathological features. Regarding the histological features, an infiltrative growth pattern is the major prognostic factor of MOC. Furthermore, novel molecular biomarkers are emerging for tailored management of early-stage MOC. In contrast, advanced MOC is characterized by poor survival. Radical surgery is the cornerstone of treatment and adjuvant chemotherapy is recommended, although the efficacy is limited by the intrinsic chemoresistance of these tumors. Several molecular hallmarks of advanced MOC have been described in recent years (e.g., HER2 amplification, distinct methylation profiles, peculiar immunological microenvironment), but target therapy for these rare tumors is not available yet.

Clinical and Histopathological Predictors of Recurrence in Uterine Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP): A Multicenter Retrospective Cohort Study of Tertiary Centers.

BACKGROUND: The term uterine smooth muscle tumor of uncertain malignant potential (STUMP) indicates a rare, equivocal entity between benign leiomyomas and leiomyosarcomas. In the present study, we evaluated a comprehensive range of clinical, surgical, and pathological features in a large multicenter series of patients with STUMP to identify risk factors for recurrence. METHODS: This is a retrospective study performed by collecting consecutive cases diagnosed between January 2000 and December 2020 in five tertiary centers. Associations between STUMP recurrence and clinicopathological characteristics as well as surgical treatment modality were investigated. RESULTS: Eighty-seven patients affected by STUMP were considered. Of them, 18 cases (20.7%) recurred: 11 as leiomyosarcoma (LMS) and 7 as STUMP. The mean time to recurrence was 79 months. We found that fragmentation/morcellation, epithelioid features, high mitotic count, Ki-67 value > 20%, progesterone receptor (PR) < 83%, and p16 diffuse expression were associated with higher risk of recurrence and shorter recurrence-free survival (RFS). Furthermore, morcellation/fragmentation and mitotic count remained independent risk factors for recurrence and shorter RFS after multivariate analysis, while the presence of epithelioid features was an independent risk factor for recurrence only. CONCLUSIONS: Our results suggest that morcellation is associated with risk of recurrence and shorter RFS, thus it should be avoided if a STUMP is suspected preoperatively. Epithelioid features, high proliferation activity, low PR expression, and diffuse p16 expression are also unfavorable prognostic factors, so patients presenting these features should be closely followed up.

Low-Grade Uterine Endometrial Stromal Sarcoma: Prognostic Analysis of Clinico-Pathological Characteristics, Surgical Management, and Adjuvant Treatments. Experience From Two Referral Centers.

Objective: Low-grade uterine endometrial stromal sarcoma (LG-ESS) is a rare tumor characterized by an overall good survival but showing a indolent behavior and a variable risk of recurrence. There is no clear consensus on the optimal management of these tumors and no prognostic or predictive factors have been established. With this study, we evaluated the prognostic relevance of several clinical, surgical, and pathological features in patients affected by LG-ESS to identify risk factors associated with recurrence. Methods: We retrospectively analyzed 52 LG-ESS cases, treated from January 1st, 1994, to May 31st, 2020, in two referral centers. The relationship between recurrence and clinicopathological characteristics as well as surgical treatment was investigated. Risk of recurrence and disease-free survival (DFS) were estimated by Cox regression and the Kaplan-Meier analysis, respectively. Results: Of 52 patients with LG-ESS, 8 experienced recurrence (15%). The median follow-up was 100 months (SD ± 96, range: 15-336). By univariate analysis, fragmentation/morcellation, tumor size, FIGO stage, higher mitotic count, presence of necrosis, and lymphovascular space invasion (LSVI) resulted associated with a poorer outcome. Conversely, the surgical modality (laparotomic vs laparoscopic and hysterectomy with bilateral salpingo-oophorectomy vs local excision) and pelvic lymphadenectomy were not. Even the different modalities of adjuvant therapy (hormonal therapy, radiotherapy, and chemotherapy) showed no prognostic significance. Tumor fragmentation/morcellation and higher mitotic count resulted independent prognostic variables at multivariate analysis. Conclusions: This data supports the avoidance of any type of morcellation if LG-ESS is suspected preoperatively. Higher mitotic count and, possibly, tumor size, advanced FIGO stage, necrosis, and LVSI could be exploited to tailor the adjuvant therapy, but these results need to be confirmed in larger prospective studies.

From Uterus to Brain: An Update on Epidemiology, Clinical Features, and Treatment of Brain Metastases From Gestational Trophoblastic Neoplasia.

In this review, we provide the state of the art about brain metastases (BMs) from gestational trophoblastic neoplasia (GTN), a rare condition. Data concerning the epidemiology, clinical presentation, innovations in therapeutic modalities, and outcomes of GTN BMs are comprehensively presented with particular attention to the role of radiotherapy, neurosurgery, and the most recent chemotherapy regimens. Good response rates have been achieved thanks to multi-agent chemotherapy, but brain involvement by GTNs entails significant risks for patients' health since sudden and extensive intracranial hemorrhages are possible. Moreover, despite the evolution of treatment protocols, a small proportion of these patients ultimately develops a resistant disease. To tackle this unmet clinical need, immunotherapy has been recently proposed. The role of this novel option for this subset of patients as well as the achieved results so far are also discussed.

SLFN11 captures cancer-immunity interactions associated with platinum sensitivity in high-grade serous ovarian cancer.

Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDAs), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens before platinum-based chemotherapy treatment, we show, for the first time to our knowledge, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 was associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in an SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation. In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer cell-intrinsic functional dispositions associated with sensitivity to DDA treatment.

Molecular Characterization of Ovarian Yolk Sac Tumor (OYST).

Most patients with malignant ovarian germ cell tumors (MOGTCs) have a very good prognosis and chemotherapy provides curative treatment; however, patients with yolk sac tumors (OYSTs) have a significantly worse prognosis. OYSTs are rare tumors and promising results are expected with the use of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens. We initiated a project in collaboration with EORTC SPECTA, to explore the molecular characteristics of OYSTs. The pilot project used retrospective samples from ten OYST relapsed and disease-free patients. Each patient had a molecular analysis performed with FoundationOne CDx describing the following variables according to the Foundation Medicine Incorporation (FMI): alteration type (SNV, deletion), actionable gene alteration, therapies approved in EU (for patient's tumor type and other tumor types), tumor mutational burden (TMB), and microsatellite instability (MSI) status. A total of 10 patients with OYST diagnosed between 2007 and 2017 had a molecular analysis. A molecular alteration was identified in four patients (40%). A subset of three patients (33.3% of all patients) harbored targetable oncogenic mutations in KRAS, KIT, ARID1A. Two patients at relapse harbored a targetable mutation. This retrospective study identifies clinically relevant molecular alterations for all relapsed patients with molecular analysis. Dedicated studies are needed to demonstrate the efficacy of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens and to explore the potential relationship of a molecular alteration and patient outcome.

A simplified fascial model of pelvic anatomical surgery: going beyond parametrium-centered surgical anatomy.

The classical surgical anatomy of the female pelvis is limited by its gynecological oncological focus on the parametrium and burdened by its modeling based on personal techniques of different surgeons. However, surgical treatment of pelvic diseases, spreading beyond the anatomical area of origin, requires extra-regional procedures and a thorough pelvic anatomical knowledge. This study evaluated the feasibility of a comprehensive and simplified model of pelvic retroperitoneal compartmentalization, based on anatomical rather than surgical anatomical structures. Such a model aims at providing an easier, holistic approach useful for clinical, surgical and educational purposes. Six fresh-frozen female pelves were macroscopically and systematically dissected. Three superficial structures, i.e., the obliterated umbilical artery, the ureter and the sacrouterine ligament, were identified as the landmarks of 3 deeper fascial-ligamentous structures, i.e., the umbilicovesical fascia, the urogenital-hypogastric fascia and the sacropubic ligament. The retroperitoneal areolar tissue was then gently teased away, exposing the compartments delimited by these deep fascial structures. Four compartments were identified as a result of the intrapelvic development of the umbilicovesical fascia along the obliterated umbilical artery, the urogenital-hypogastric fascia along the mesoureter and the sacropubic ligaments. The retroperitoneal compartments were named: parietal, laterally to the umbilicovesical fascia; vascular, between the two fasciae; neural, medially to the urogenital-hypogastric fascia and visceral between the sacropubic ligaments. The study provides the scientific rational for a model of pelvic retroperitoneal anatomy based on identifiable anatomical structures and suitable for surgical planning and training.

A Fascial Reinterpretation of the Classical Female Pelvic Surgical Anatomy: Seeing Things from a Different Angle.

STUDY OBJECTIVE: The classical surgical anatomy of the female pelvis was born with radical hysterectomy [1] and focused on the pivotal role of the lateral parametrium, a conceptually complex structure, an artifact of surgical anatomy [2] without which the whole classical model would collapse. Here, using natural planes, we tried to simplify the puzzle of the virtual spaces surrounding this structure [3,4]. With the aim of better conceptualizing the classical model of the female pelvic surgical anatomy, we broadened its perspective, which had been narrowly focused on the historic gynecologic setting, by developing a comprehensive model of pelvic retroperitoneal compartmentalization. This dissection was based on the invariable anatomic (fasciae) rather than the surgical-anatomic (parametrium) structures and aimed at providing a holistic, more user-friendly approach intended for surgical and educational purposes [5]. Because each compartment has its own surgical function (hence the name), the excavation of a single compartment may be used as a rational guide to tailor surgery to the site of the pathologic condition to be treated or the type of procedure required, whereas the compartments' sequential development may be useful in planning surgical strategies. Redefining the classical model according to the anatomic fascial planes of dissection potentially allows for an intrinsic surgical reproducibility, minimizing dissective bias. A reinterpretation of the known anatomy is required to enhance education. The breaking down of such a complex system (the pelvis) into smaller parts (compartments) will hopefully provide a useful guide for conceptualization and navigation; surgical navigation requires a holistic mental map and a few invariable anatomic reference points or landmarks. DESIGN: A step-by-step laparoscopic demonstration of the fascial model, developed on a fresh frozen female pelvis, and its correlation with the classical female retroperitoneal surgical anatomy. SETTING: Cadaver Laboratory, Department of Legal Medicine, University of Turin. INTERVENTIONS: The first part of the video shows the progressive development of the 3 hemicompartments in the right hemipelvis and of the fourth median compartment after the identification of 3 invariable anatomic reference points: the obliterated umbilical artery, the ureter, and the sacrouterine ligament as superficial landmarks of 3 deeper fascial-ligamentous structures: the umbilicovesical fascia, the urogenital-hypogastric fascia, and the sacropubic ligament, respectively (Figure 1). The areas delimited by the aforementioned deep fascial ligamentous structures have been designated as compartments: • the right parietal hemicompartment, so called because it is bordered by the sidewall of the pelvis, lateral to the umbilicovesical fascia • the right vascular hemicompartment, so called because of the presence of the internal iliac vessel's visceral branches between the umbilicovesical fascia and the urogenital-hypogastric fascia • the visceral compartment, so called because it contains the pelvic organs between the sacropubic ligaments • the right neural hemicompartment, so called because of the presence of the organ-specific vegetative bundles, medial to the urogenital-hypogastric fascia. The second part of the video describes the retrorectal, presacral, and retropubic connection areas between the neural, vascular, and parietal hemicompartments of each hemipelvis, justifying their overall crescent shape. Finally, the spaces of classical surgical anatomy included in each hemicompartment are listed not only according to their anatomic criterion, but also according to their functional criterion. In fact, the parietal compartment should be developed for the evaluation of the pelvic lymph node status or during exenterative and urogynecologic procedures. The vascular compartment must be prepared when sectioning of the vascular visceral pedicles at their origin is required. Development of the neural compartment is required whenever visceral neural components are to be spared. The visceral compartment has to be developed for complete organ mobilization and exposure. CONCLUSION: Taken as a whole, our 4-compartment model of pelvic anatomic surgery is intended for use in planning and optimizing surgical strategies. Moreover, it is potentially able to simplify surgical teaching and training, allowing the fitting together of puzzle-like pieces of disjointed organ-specific retroperitoneal spaces according to their function (Figure 2). The correlation of this approach to clinical outcomes is still being determined.

Affected Ovary Relative Volume: A Novel Sonographic Predictor of Ovarian Reserve in Patients with Unilateral Endometrioma-A Pilot Study.

BACKGROUND: The assessment of ovarian reserve in the case of endometrioma is of pivotal importance for planning a tailored management. However, both the antral follicle count (AFC) and the antimüllerian hormone (AMH) dosage are subject to a fair degree of variability in ovarian endometriosis. This study aimed to identify a sonographic parameter of ovarian reserve that could implement current available markers in patients with unilateral endometrioma. METHODS: Patients with unilateral endometrioma admitted to our Endometriosis Center between March 2018 and April 2019 were enrolled. Transvaginal ultrasonography for the evaluation of eight sonographic indicators and AMH level determination were performed. The relationship between AMH level and each indicator was assessed. RESULTS: Thirty-four women were included. There was a positive significant correlation between AMH level and the healthy ovary AFC (HO-AFC) (r = 0.36 p = 0.034). A stronger, negative correlation between AMH level and the ratio between the volume of the affected and the healthy ovary (affected ovary relative volume, AORV) (r = -0.47; p = 0.005) was evidenced. AORV had a satisfactory accuracy (AUC 0.73; CI 0.61-0.90; p = 0.0008), and the cut-off value of 5.96 had the best balance of sensitivity/specificity in distinguishing between patients with a good ovarian reserve (AMH ≥ 2 ng/mL) and those at risk of ovarian reserve depletion after excisional surgery. CONCLUSION: AORV may be a useful tool to assess ovarian reserve in patients with unilateral endometrioma without previous surgery and to guide physicians in clinical management.

Impact of multidisciplinary tumour board in the management of ovarian carcinoma in the first-line setting. Exhaustive analysis from the Rhone-Alpes region.

OBJECTIVE: Epithelial ovarian cancer (EOC) is a poor prognosis disease partly linked to diagnosis at an advanced stage. The quality of care management is a factor that needs to be explored, more specifically optimal organisation of first-line treatment. METHODS: A retrospective study, dealing with all patients diagnosed within the Rhone-Alpes region with initial diagnosis EOC in 2012, was performed. The aim was to describe the impact of multidisciplinary tumour boards (MTB) in the organisation of care and the consequence on the patient's outcomes. RESULTS: 271 EOC were analysed. 206 patients had an advanced EOC. Median progression-free survival (PFS) is 17.8 months (CI95%, 14.6-21.2) for AOC. 157 patients (57.9%) had a front-line surgery versus 114 patients (42.1%) interval debulking surgery. PFS for AOC patients with no residual disease is 24.3 months compared with 15.3 months for patients with residual disease (p = .01). No macroscopic residual disease is more frequent in the patients discussed before surgery in MTB compared with patients not submitted before surgery (73% vs. 56.2%, p < .001). CONCLUSION: These results highlight the heterogeneity of medical practices in terms of front-line surgery versus interval surgery, in the administration of neoadjuvant chemotherapy and in the setting of MTB discussion.

EVAN-G score in patients undergoing minimally invasive gynecology oncologic surgery in an Enhanced Recovery After Surgery (ERAS) program.

INTRODUCTION: Enhanced Recovery After Surgery (ERAS) has been proven to decrease the length of hospital stay without increasing re-admission rates or complications. There are limited data on the satisfaction of patients undergoing minimally invasive surgery for gynecologic malignancy within ERAS programs. The aim of this study was to evaluate patient satisfaction after minimally invasive surgery for gynecologic malignancy within the ERAS program using the 'Evaluation du Vécu de l'Anésthésie Génerale (EVAN-G)' questionnaire. METHODS: This observational retrospective study was conducted at the Paoli-Calmettes Institute between June 2016 and December 2018. All the included patients underwent minimally invasive surgery for a gynecologic malignancy. EVAN-G, a validated questionnaire, was used to measure peri-operative patient satisfaction. This questionnaire consists of 26 items assessing six elements: attention, privacy, information, pain, discomfort, and waiting time. Each element is assessed via a 5-step numerical scale and then transformed to a 0-100 scale according to the degree of satisfaction. The EVAN-G questionnaire was given to patients before surgery and collected during the post-operative consultation (2-3 weeks after surgery). RESULTS: A total of 175 patients underwent minimally invasive surgery for gynecologic malignancy within the ERAS program. Of these, 92 patients were included in the study and 83 patients were excluded. The overall patient compliance rate with our ERAS program was 90%. The analysis of the EVAN-G score of all participants showed an overall high level of satisfaction with a mean score of 81.9 (range 41.6-100). Patients with peri-operative complications or having prolonged hospitalization also showed high levels of satisfaction with a mean score of 80.5 (41.6-100) and 83.2(55-100), respectively. CONCLUSION: In this study we showed a high patient satisfaction with the ERAS program. When comparing length of stay and complications, neither extended length of stay nor development of complications after minimally invasive surgery impacted patient satisfaction.

Correction to: Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer.

In the original publication of the article, the funding information was incorrectly published. The corrected funding statement is given in this correction article.

Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer.

PURPOSE: Breast cancer (BC) is a heterogeneous disorder, with variable response to systemic chemotherapy. Likewise, BC shows highly complex immune activation patterns, only in part reflecting classical histopathological subtyping. Schlafen-11 (SLFN11) is a nuclear protein we independently described as causal factor of sensitivity to DNA damaging agents (DDA) in cancer cell line models. SLFN11 has been reported as a predictive biomarker for DDA and PARP inhibitors in human neoplasms. SLFN11 has been implicated in several immune processes such as thymocyte maturation and antiviral response through the activation of interferon signaling pathway, suggesting its potential relevance as a link between immunity and cancer. In the present work, we investigated the transcriptional landscape of SLFN11, its potential prognostic value, and the clinico-pathological associations with its variability in BC. METHODS: We assessed SLFN11 determinants in a gene expression meta-set of 5061 breast cancer patients annotated with clinical data and multigene signatures. RESULTS: We found that 537 transcripts are highly correlated with SLFN11, identifying "immune response", "lymphocyte activation", and "T cell activation" as top Gene Ontology processes. We established a strong association of SLFN11 with stromal signatures of basal-like phenotype and response to chemotherapy in estrogen receptor negative (ER-) BC. We identified a distinct subgroup of patients, characterized by high SLFN11 levels, ER- status, basal-like phenotype, immune activation, and younger age. Finally, we observed an independent positive predictive role for SLFN11 in BC. CONCLUSIONS: Our findings are suggestive of a relevant role for SLFN11 in BC and its immune and molecular variability.

Current state of the art and emerging pharmacotherapy for uterine leiomyosarcomas.

INTRODUCTION: Uterine leiomyosarcomas (ULMS) account for 1% of all uterine malignancies and for 30% of all uterine sarcomas. The preoperative diagnosis of ULMS is challenging for the physicians, as the symptoms of these tumors are often vague and nonspecific. Moreover, as ULMS have an aggressive biologic behavior, affected women frequently have very poor prognosis. AREAS COVERED: The aim of this review is to describe the current pharmacotherapy for ULMS, including the ongoing clinical trials. EXPERT OPINION: Surgery is the standard treatment for patients with early-stage ULMS. In this setting, the role of adjuvant therapies is still unclear. In the case of advanced, persistent, or recurrent ULMS, chemotherapy is the standard care with the most frequently used drug being doxorubicin. As the outcomes for patients with the currently available conventional single or combined regimens are far from being satisfactory, new alternative and innovative medical compounds have or are being evaluated. Recently, pazopanib, and olaratumab, two innovative targeted drugs, have been approved by the Food and Drug Administration (FDA) for treating advanced soft-tissue sarcoma, including ULMS. However, further clinical investigations into new and innovation therapeutic options are warranted.

Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer.

INTRODUCTION: Endometrial cancer (EC) is the most common neoplasm of the female genital tract in developed countries. Despite the progress in early detection and treatment, a significant number of cases of advanced ECs are still diagnosed. These patients have few treatment options and a poor prognosis. Our understanding of EC pathogenesis and progression has been enhanced by recent genomic studies. Among the relevant biological pathways, phosphatidylinositol 3-kinase/AKT (PIK3/AKT)-mammalian target of rapamycin (mTOR) signaling is frequently upregulated in this cancer. AREAS COVERED: This review covers investigational EC therapeutics acting on the PI3K/AKT/mTOR pathway. The authors review the results of clinical studies and highlight ongoing trials. EXPERT OPINION: Several new agents are under evaluation for treating patients with metastatic, recurrent, and persistent EC. Clinical trials investigating PI3K/AKT/mTOR inhibitors have yielded controversial results. In the near future, new studies with dual inhibitors or multi-pathways inhibitors as mono or combination therapies with conventional chemotherapy (CT) or other targeted drugs may provide more promising data. Moreover, the evaluation of new serum and histological biomarkers is an attractive strategy for patient selection.