Uterine adenosarcoma: Clinical significance of histological classification and SNP array analysis.

Mullerian adenosarcoma is a rare malignant biphasic tumor. The mesenchymal component may be low or high grade, with or without sarcomatous overgrowth (SO). Little is known about the molecular heterogeneity of these tumors. In this study, we aim to reclassify a large retrospective monocentric cohort of uterine adenosarcomas according to tumor grade and SO, to evaluate the clinical significance of pathological classification and to correlate with copy-number variations inferred from single nucleotide polymorphism array. Of the 67 uterine adenosarcomas, 18 (26.9%) were low grade without SO, 7 (10.4%) low grade with SO, 8 (11.9%) high grade without SO and 34 (50.7%) high grade with SO. SO, necrosis and RMS were more frequent in high grade than low grade adenosarcomas (p < 0.001). Low-rank test showed that recurrence-free survival was significantly shortened in high grade than low grade adenosarcomas (p = 0.035) and SO was associated with shortened overall and recurrence-free survival (p = 0.038 and p = 0.009, respectively). High-grade tumors displayed complex genomic profiles with multiple segmental losses including TP53, ATM and PTEN genes. The median genomic index was significantly higher in high grade than low grade tumors (27 [3-60] vs 5,3 [0-16], p < 0.0001) and was significantly higher in presence of SO in low grade tumors (12,8 [10-16] vs 2,6 [0-10], p = 0.0006). We propose to report sarcomatous overgrowth with the tumor grade for prognostication in adenosarcoma and representative sampling is crucial for evaluation of these histological criteria.

Correlation between peritoneal cancer index and survival in advanced epithelial ovarian cancer with complete resection.

OBJECTIVE: The aim of this study was to investigate the relation between the peritoneal cancer index, overall survival, and recurrence free survival, in patients with epithelial ovarian cancer. METHODS: Patients treated at the Gustave-Roussy Institute between December 2004 and November 2017 for advanced epithelial ovarian cancer in complete resection were included. The correlation between the peritoneal cancer index and survival was studied using statistical modeling. Multivariate analysis was performed with a logistic regression model. RESULTS: Of the 351 patients included, 94 (27%) had initial surgery and 257 (73%) had interval surgery. Median follow-up was 52.7 months (range 47.6-63.9). Median peritoneal cancer index was 10 (range 0-32). The linear model best represented the relationship between peritoneal cancer index and overall survival. Patients with neoadjuvant chemotherapy had a greater instantaneous risk of baseline death than those with initial surgery, as well as a more rapid increase in this risk as the peritoneal cancer index increased. Overall survival and recurrence free survival were better in the initial surgery group (103.4 months (79.1-not reached (NR)) vs 66.5 months (59.1-95.3) and 31.8 months (23.7-48.7) vs 25.9 months (23.2-29), respectively). Risk factors for death were body mass index, peritoneal cancer index, and need for neoadjuvant chemotherapy. CONCLUSION: The peritoneal cancer index is a prognostic indicator, but its linear relationship with survival precluded setting a unique peritoneal cancer index cut-off. Moreover, the prognostic impact of peritoneal cancer index was stronger in the setting of neoadjuvant chemotherapy.

Simple versus Radical Hysterectomy in Women with Low-Risk Cervical Cancer.

BACKGROUND: Retrospective data suggest that the incidence of parametrial infiltration is low in patients with early-stage low-risk cervical cancer, which raises questions regarding the need for radical hysterectomy in these patients. However, data from large, randomized trials comparing outcomes of radical and simple hysterectomy are lacking. METHODS: We conducted a multicenter, randomized, noninferiority trial comparing radical hysterectomy with simple hysterectomy including lymph-node assessment in patients with low-risk cervical cancer (lesions of ≤2 cm with limited stromal invasion). The primary outcome was cancer recurrence in the pelvic area (pelvic recurrence) at 3 years. The prespecified noninferiority margin for the between-group difference in pelvic recurrence at 3 years was 4 percentage points. RESULTS: Among 700 patients who underwent randomization (350 in each group), the majority had tumors that were stage IB1 according to the 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria (91.7%), that had squamous-cell histologic features (61.7%), and that were grade 1 or 2 (59.3%). With a median follow-up time of 4.5 years, the incidence of pelvic recurrence at 3 years was 2.17% in the radical hysterectomy group and 2.52% in the simple hysterectomy group (an absolute difference of 0.35 percentage points; 90% confidence interval, -1.62 to 2.32). Results were similar in a per-protocol analysis. The incidence of urinary incontinence was lower in the simple hysterectomy group than in the radical hysterectomy group within 4 weeks after surgery (2.4% vs. 5.5%; P = 0.048) and beyond 4 weeks (4.7% vs. 11.0%; P = 0.003). The incidence of urinary retention in the simple hysterectomy group was also lower than that in the radical hysterectomy group within 4 weeks after surgery (0.6% vs. 11.0%; P<0.001) and beyond 4 weeks (0.6% vs. 9.9%; P<0.001). CONCLUSIONS: In patients with low-risk cervical cancer, simple hysterectomy was not inferior to radical hysterectomy with respect to the 3-year incidence of pelvic recurrence and was associated with a lower risk of urinary incontinence or retention. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov number, NCT01658930.).

Integration of the Molecular Classification of Endometrial Carcinoma to Select Patients for Fertility Sparing Strategies.

Fertility-sparing treatment (FST) for endometrial carcinoma (EC) is an option for a subgroup of young women with low-risk disease. The low-risk group comprises patients with endometrioid EC stage IA, grade 1, with or without focal lymphovascular invasion. In the era of molecular subtyping, treatment de-escalation for some EC subtypes is recommended. Recommendations for fertility-preserving treatments were developed regardless of the molecular classification of EC. However, few studies have focused on this topic. In this review, we summarize the actual data available in the literature and discuss the impact of some molecular subtypes of FST.

[Current post-surgical treatment strategies in first-line ovarian cancer]. / Stratégies thérapeutiques post-chirurgicales actuelles dans les cancers de l'ovaire en première ligne de traitement.

Although the management of epithelial ovarian cancer has evolved significantly over the past few years, it remains a public health issue, as most patients are diagnosed at an advanced stage and relapse after first line treatment. Chemotherapy remains the standard adjuvant treatment for International Federation of Gynecology and Obstetrics (FIGO) stage I and II tumors, with some exceptions. For FIGO stage III/IV tumors, carboplatin- and paclitaxel-based chemotherapy are the standard of care, in combination with targeted therapies, especially bevacizumab and/or poly-(ADP-ribose) polymerase inhibitors, that have become a key milestone of first-line treatment. Our decision making for the maintenance therapy is based on the FIGO stage, tumor histology, timing of surgery (i.e. primary or interval debulking surgery), residual tumor, response to chemotherapy, BRCA mutation and homologous recombination (HR) status.

Homologous recombination deficiency (HRD) testing on cell-free tumor DNA from peritoneal fluid.

BACKGROUND: Knowing the homologous recombination deficiency (HRD) status in advanced epithelial ovarian cancer (EOC) is vital for patient management. HRD is determined by BRCA1/BRCA2 pathogenic variants or genomic instability. However, tumor DNA analysis is inconclusive in 15-19% of cases. Peritoneal fluid, available in > 95% of advanced EOC cases, could serve as an alternative source of cell-free tumor DNA (cftDNA) for HRD testing. Limited data show the feasibility of cancer panel gene testing on ascites cfDNA but no study, to date, has investigated HRD testing. METHODS: We collected ascites/peritoneal washings from 53 EOC patients (19 from retrospective cohort and 34 from prospective cohort) and performed a Cancer Gene Panel (CGP) using NGS for TP53/HR genes and shallow Whole Genome Sequencing (sWGS) for genomic instability on cfDNA. RESULTS: cfDNA was detectable in 49 out of 53 patients (92.5%), including those with limited peritoneal fluid. Median cfDNA was 3700 ng/ml, with a turnaround time of 21 days. TP53 pathogenic variants were detected in 86% (42/49) of patients, all with HGSOC. BRCA1 and BRCA2 pathogenic variants were found in 14% (7/49) and 10% (5/49) of cases, respectively. Peritoneal cftDNA showed high sensitivity (97%), specificity (83%), and concordance (95%) with tumor-based TP53 variant detection. NGS CGP on cftDNA identified BRCA2 pathogenic variants in one case where tumor-based testing failed. sWGS on cftDNA provided informative results even when tumor-based genomic instability testing failed. CONCLUSION: Profiling cftDNA from peritoneal fluid is feasible, providing a significant amount of tumor DNA. This fast and reliable approach enables HRD testing, including BRCA1/2 mutations and genomic instability assessment. HRD testing on cfDNA from peritoneal fluid should be offered to all primary laparoscopy patients.

Circulating Tumor DNA from Ascites as an alternative to tumor sampling for genomic profiling in ovarian cancer patients.

Genomic testing is crucial for the management of ovarian cancer. DNA from biopsies at diagnostic laparoscopies or interval debulking surgery after neoadjuvant chemotherapy, has a high failure rate. At relapse, biopsies may not be feasible. The aim of our study was to evaluate the feasibility and usefulness of measuring genomic instability score (GIS) on cell-free DNA (cfDNA) from ascites.Patients enrolled in a prospective study (NCT03010124) consented to analysis of biological samples. CfDNA was extracted from 1 to 4 ml of double-centrifuged fresh ascites. Targeted Next-generation sequencing (NGS) including TP53 mutation (TP53m) was performed on cfDNA to confirm the presence of tumor cfDNA. Single Nucleotide Polymorphism Array estimating somatic copy number alterations (SCNA) was performed to calculate GIS for Homologous-Recombination deficiency (HRD).Twenty nine ascites were collected from 20 patients with suspected or confirmed OC. 93% (27/29) samples had detectable cfDNA (median 1120 ng [24-5732]) even when obtained during chemotherapy. A deleterious mutation was identified in 100%, with high allelic frequencies (median 60% [3.3-87%]), confirming that cfDNA was tumoral. SCNA analyses on 17 patients showed 11 high GIS, and 6 low GIS. 4 patients with confirmed BRCA mutation had a high GIS on ascites. When available from the same patient, SCNA profiles on ascites and tumor were superimposable.Ascites is frequent at diagnosis and relapse and yields large amounts of tumoral cfDNA. SCNA analysis on ascitic cfDNA is feasible and can detect the same HRD scar as tumor testing. Ascites could provide an alternative to tumor sampling for HRD and BRCA testing.

Image-guided adaptive brachytherapy for advanced cervical cancer spreading to the bladder and/or rectum: Clinical outcome and prognostic factors.

INTRODUCTION: Refinements of brachytherapy techniques have led to better local control of locally advanced cervical cancer (LACC), especially with the development of image-guided adaptive brachytherapy (IGABT). Data on the efficacy of brachytherapy in cervical cancer spreading to adjacent organs are scarce. We report the experience of our institution in the treatment of these advanced tumors with IGABT. MATERIALS AND METHODS: Medical records of patients treated for a LACC spreading to the bladder and/or rectum between 2006 and 2020 at Gustave Roussy Institute were analyzed. Dosimetric parameters were collected and converted into 2 Gy per fraction equivalent doses, including the minimal dose received by 90% of the high-risk target volume (D90 CTVHR) and intermediate-risk target volume (D90 CTVIR), as well as the dose received by the most exposed 2 cm3 of the organs at risk. A Cox regression model was used to study the potential associations between clinical and dosimetric factors with survival endpoints and fistula formation. RESULTS AND STATISTICAL ANALYSIS: A total of 81 patients were identified. All patients received pelvic+/- para-aortic radiotherapy, 45 Gy in 25 fractions +/- boost to gross lymph nodes. Concomitant platinum-based chemotherapy was administered in 93.8% of cases. The median D90 CTVHR dose was 75.5 GyEQD2 (SD: 10.39 GyEQD2) and median CTVHR volume was 47.6 cm3 (SD: 27.9 cm3). Median bladder and rectal D2cm3 dose were 75.04 GyEQD2 (SD: 8.72 GyEQD2) and 64.07 GyEQD2 (SD: 6.68 GyEQD2). After a median follow-up of 27.62 ± 25.10 months, recurrence was found in 34/81 patients (42%). Metastatic failure was the most common pattern of relapse (n = 25). Use of a combined interstitial/intracavitary technique and D90 CTVHR ≥ 75.1 GyEQD2 were prognostic factors for OS in univariate analysis (HR = 0.24, 95%IC: 0.057-1, p = 0.023; HR = 0.2, 95%IC: 0.059-0.68, p = 0.0025, respectively). In multivariate analysis, a D90 CTVHR ≥ 75.1 GyEQD2 was significant for OS (HR = 0.23; 95%IC: 0.07, 0.78, p = 0.018). The occurrence of vesicovaginal fistula (VVF) was the most frequent pattern of local recurrence (HR = 4.6, 95%CI: 1.5-14, p = 0.01). CONCLUSION: Advances in brachytherapy modalities improved local control and survival while reducing toxicities. Enhancing local control through dose escalation and combined intracavitary/interstitial brachytherapy techniques is a major factor in patients cure probability, together with systemic intensification to better control distant events.

Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti-VEGF agents: a retrospective study.

PURPOSE: Kinase inhibitors (KI) and antibodies targeting the VEGF pathway are approved in a broad spectrum of cancers and associated with an increased risk of bleeding and thromboembolic events (TE). The use of direct oral anticoagulants (DOACs) apixaban and rivaroxaban is increasing in cancer patients, but limited data are available for patients receiving anti-VEGF agents. METHODS: To assess safety of DOAC with concomitant anti-VEGF agents, a retrospective chart review of all patients receiving concomitantly DOAC and anti-VEGF agents was performed from 2013 to 2020 in our center. Data on demographics, safety, and time on treatment were collected. Main outcome was safety (bleeding and thromboembolic events). RESULTS: Of 92 patients (median age 66 years (IQR: 59-72)), 40 were treated with KI and 52 with bevacizumab. The most frequent primary tumor sites were colon/rectum (24%), kidney (21%), ovary (13%), lung (11%), soft tissue sarcoma (10%), and thyroid (9%); 2% had brain metastases. Apixaban 5 mg bid (n = 41) or rivaroxaban 20 mg daily (n = 51) were given for TE (65%), atrial fibrillation (32%), or other indications (3%). The median duration of concomitant treatment was 4.8 months (95%CI: 0.7-50.0) with bevacizumab and 11.7 months (95%CI: 0.1-53.8) with KI. Grade ≥ 3 bleeding events occurred in 5 patients (5%): 4 patients receiving bevacizumab (one grade 5 upper digestive tract bleeding and three grade 3 rectal or vaginal hemorrhages) and 1 patient under cabozantinib for kidney cancer with endobronchial metastasis (grade 3 hemoptysis). Grade ≥ 3 TE occurred in 8 patients (9%): 7 patients receiving bevacizumab (including one grade 5 pulmonary embolism), and one patient receiving sunitinib (grade 3 pulmonary embolism). Median time-to-event (bleeding or thrombotic event) was not reached (NR) (95%CI: 76.9-NR) for KI and 86.9 months (95%CI: 42.9-148.0) for bevacizumab. CONCLUSIONS AND RELEVANCE: In our experience, the use of DOAC was safe in selected patients treated with KI, but unclear with bevacizumab. More data are needed to endorse guidelines in this specific group of patients.

Endometrioid Borderline Ovarian Tumor: Clinical Characteristics, Prognosis, and Managements.

BACKGROUND: Endometrioid borderline ovarian tumor (EBOT) is a rare subtype of borderline ovarian malignancies. This study was designed to determine the prognosis of a series of EBOT. METHODS: This is a retrospective review of patients with EBOT treated in or referred to our institutions and a centralized, histological review by a reference pathologist. Data on the clinical characteristics, management (surgical and medical), and oncologic outcomes of patients were required for inclusion. RESULTS: Forty-eight patients were identified. Median age was 52 years (range 14-89). Fourteen patients underwent a conservative surgery and 32 a bilateral salpingo-oophorectomy (unknown in 2 cases). Two patients had bilateral tumors. Forty-three patients had stage I disease, and five patients had stage II disease (10%). Stromal microinvasion and intraepithelial carcinoma was observed in 6 (12%) and 13 (27%) patients respectively. Endometriosis was histologically associated in 12 patients (25%). Synchronous endometrial disease was found in 7 (24%) of 29 patients with endometrial histological evaluation. The median follow-up was 72 months (range 6-146). Two patients developed a recurrence after cystectomy in form of borderline disease (5%). No death related to EBOT occurred. CONCLUSIONS: Peritoneal restaging surgery should be performed if not realized initially, because 5% of EBOTS are diagnosed at stage II-III. Fertility-sparing surgery seems a safe option in selected patients. Because synchronous endometrial diseases, including endometrial carcinoma are frequent, systematic hysterectomy (or endometrial sampling in case of fertility-sparing surgery) is mandatory. Prognosis is generally excellent. Recurrence is a rare event (6%), but it can occur in the form of invasive disease.

Clear Cell Borderline Ovarian Tumor: Clinical Characteristics, Prognosis, and Management.

BACKGROUND: Clear cell borderline ovarian tumor (CCBOT) is one of the rarest subtypes of borderline ovarian malignancies. The aim of this study was to determine the prognosis of a series of CCBOT. PATIENTS AND METHODS: A retrospective review of patients with CCBOT treated or referred to our institutions. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion. RESULTS: Nineteen patients were identified. Median age was 62 (range 36-83) years. Four patients underwent a conservative surgery and 14 a bilateral salpingo-oophorectomy +/- hysterectomy (unknown in 1 case). One patient had bilateral tumor, and all cases were stage-I disease. All CCBOTs showed an adenofibromatous pattern. Stromal microinvasion was observed in seven cases and intraepithelial carcinoma in two cases. Endometriosis was histologically associated in one case. The median follow-up was 76 (range 6-231) months. No recurrence occurred. Two patients died of intercurrent disease. CONCLUSIONS: Peritoneal staging procedures should always be associated, but restaging surgery could be omitted if there was no suspicious lesion in the peritoneum during initial surgery, since all patients reported had stage-I disease. Fertility-sparing surgery appears to be a safe alternative in young patients. Synchronous endometrial disorders with atypia are infrequent. Prognosis is generally excellent, and long-term risk of recurrence is low. The two recurrences described in literature occurred in stage-IC diseases, highlighting the importance of avoiding perioperative rupture.

Cervical Cancer and Fertility-Sparing Treatment.

Radical hysterectomy with pelvic node dissection is the standard treatment for early-stage cervical cancer. However, the latter can be diagnosed at a young age when patients have not yet achieved their pregnancy plans. Dargent first described the vaginal radical trachelectomy for patients with tumors <2 cm. It has since been described a population of low risk of recurrence: patients with tumors <2 cm, without deep stromal infiltration, without lymphovascular invasion (LVSI), and with negative lymph nodes. These patients can benefit from a less radical surgery such as conization or simple trachelectomy with the evaluation of the pelvic node status. Tumors larger than 2 cm have a higher risk of recurrence and their treatment is a challenge. There are currently two options for these patients: abdominal radical trachelectomy or neoadjuvant chemotherapy (NACT), followed by fertility-sparing surgery. All patients who wish to preserve their fertility must be referred to expert centers.

[Surgical de-escalation in gynecologic oncology]. / Désescalade chirurgicale en oncologie gynécologique.

The evolution of knowledge in gynecologic oncology is leading to surgical de-escalation in several areas, particularly in lymph node staging. Sentinel lymph node biopsy that was initially used in low and intermediate risk endometrial cancer, has now been extended to high-intermediate and high-risk endometrial cancer. Sentinel lymph node biopsy plays also an important role in the nodal staging of early-stage cervical cancer. The radicality of hysterectomies in patients with early cervical cancer is under debate. Similarly, surgical staging with para-aortic lymphadenectomy in locally advanced cervical cancer should be performed only for few cases. Systematic pelvic and para-aortic lymphadenectomy in patients with advanced ovarian cancers is not recommended anymore.

Brenner Borderline Ovarian Tumor: A Case Series and Literature Review.

BACKGROUND: Most frequent borderline ovarian tumors are serous and mucinous subtypes. Less frequent borderline diseases are endometrioid, clear-cell, and Brenner tumors (BBOT). Very little is known about the latter subtype, and most studies include very short series or case reports. The aim of this study is to determine the prognosis of a continuous series of BBOT and analyze data published in the literature on this rare entity. PATIENTS AND METHODS: A retrospective review of patients with BBOT treated or referred to our institutions was conducted. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion. RESULTS: Overall, 17 patients were identified. Median age was 62 (range 42-85) years. Six patients underwent unilateral salpingo-oophorectomy, and 11 bilateral salpingo-oophorectomy +/- hysterectomy and/or staging surgery. In total, 16 patients had unilateral tumor, and all patients had stage I disease. Stromal microinvasion was observed in three cases. Median follow-up was 60 months (range 7-118 months). One patient developed a recurrence in contralateral ovary after unilateral salpingo-oophorectomy. One patient had previous history of urothelial tumor. CONCLUSIONS: Peritoneal staging surgery is not required because all patients reported had stage I disease. One recurrence occurred. When reviewing all the 82 cases reported in the literature (including ours), 9% had previous history or synchronous urothelial tumor, suggesting the need to carefully check for urological disease in patients with BBOT.

False negative rate at 18F-FDG PET/CT in para-aortic lymphnode involvement in patients with locally advanced cervical cancer: impact of PET technology.

BACKGROUND: The identification of factors responsible for false negative (FN) rate at 18F- Fluorodeoxyglucose (FDG) Positron Emission Tomography /Computed Tomography (PET/CT) in para-aortic (PA) lymph nodes in the presurgical staging of patients with locally advanced cervical cancer (LACC) is challenging. The aim of this study was to evaluate the impact of PET/CT technology. METHODS: A total of 240 consecutive patients with LACC (International Federation of Gynecology and Obstetrics, FIGO, stage IB2-IVA) and negative Magnetic Resonance Imaging (MRI) and/or Computed Tomography (CT) and negative 18F-FDG PET/CT in the PA region, undergoing laparoscopic PA lymphadenectomy before chemoradiotherapy were included. The FN rate in patients studied with Time of flight (TOF) PET/CT (TOF PET) or non-Time of flight PET/CT (no-TOF PET) technology was retrospectively compared. RESULTS: Patients presented with FIGO stage IB (n = 78), stage IIA-B (n = 134), stage III (n = 18) and stage IVa (n = 10), squamous cell carcinoma (n = 191) and adenocarcinoma (n = 49). 141/240 patients were evaluated with no-TOF PET/CT and 99/240 with TOF PET/CT. Twenty-two patients (9%) had PA nodal involvement at histological analysis and considered PET/CT FN findings. The FN rate was 8.5% for no-TOF PET and 10% for TOF PET subgroup respectively (p = 0.98). Ninety patients (38%) presented with pelvic node uptakes at PET/CT. The FN rate in the PA region was 18% (16/90) and 4% (6/150) in patients with and without pelvic node involvement at PET/CT respectively (19 vs 3% for no-TOF PET and 17 vs 5% for TOF PET subgroup). CONCLUSIONS: In LACC, FN rate in PA lymph nodes detection is a clinical issue even for modern PET/CT, especially in patients with pelvic uptake. Surgical lymphadenectomy should be performed in case of negative PET/CT at PA level in these patients, while it could be discussed in the absence of pelvic uptake.

Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer.

BACKGROUND: At diagnosis, tumor-infiltrating lymphocytes (TILs) are prognostic in epithelial ovarian cancer (EOC). We recently demonstrated that neoadjuvant chemotherapy (NACT) significantly increased stromal TILs. Here, we investigated the impact of NACT on immune subpopulations with a particular focus on the balance of immune-reactive to tolerant subpopulations. MATERIALS AND METHODS: Tissue microarrays of EOC (145 pre-NACT, 139 post-NACT) were analyzed for CD3+, CD8+, FOXP3+, CD68+, and CD163+ by immunohistochemistry and CD4+ cells from deduction. Stromal TILs scored as percentage of stromal area, while intra-epithelial TILs scored as number of TILs in contact with tumor cells/HPF. Differences were evaluated by Wilcoxon or Chi square tests, Wilcoxon signed-rank for paired analyses, and cox model for PFS and OS. RESULTS: NACT significantly increased stromal CD3+ (p = 0.003) and CD8+ (p = 0.001) and intra-epithelial CD8+ (p = 0.022) and CD68+ (p = 0.0003) infiltration in unmatched samples and among paired samples for stromal CD3+ and CD8+. Neither CD3+, CD8+, CD4+, and CD68+ nor CD163+ expression correlated with outcome at diagnosis or post NACT. Using median value as a cut-off, high stromal CD8+/FOXP3+ ratio (HR = 0.59; p = 0.017) and high stromal CD3+/FOXP3+ ratio post NACT were associated with prolonged PFS (p = 0.0226). The more the balance shifted in favor of effector versus regulatory TILs, the better the survival. Similarly, high CD68+/CD163+ ratio post NACT improved PFS (p = 0.0445). CONCLUSION: NACT has a significant impact on the balance of immune-reactive to immune-tolerant subpopulations and a high ratio of CD8+/FOXP3+, CD3+/FOXP3+, and CD68+/CD163+ post NACT was significantly associated with improved outcomes. Whether this could select patients for immunotherapy in the post-operative setting should be investigated.

Results After Conservative Surgery of Stage II/III Serous Borderline Ovarian Tumors.

OBJECTIVE: The aim of this study was to assess the outcomes of a large series of patients treated conservatively for stage II or III serous borderline tumors of the ovary (SBOTs) with a long-term follow-up. METHODS: Patients with SBOTs and peritoneal implants, treated in or referred to our institution, were retrospectively reviewed. Outcomes of patients treated conservatively (preservation of the uterus and at least a part of one ovary) to promote subsequent fertility were specifically analyzed. RESULTS: Between 1971 and 2017, 212 patients were identified and followed-up. Among these patients, 65 underwent conservative treatment; eight patients had invasive implants. Among patients treated conservatively, 38 (58%) patients recurred. Twenty-eight recurrences were observed under the form of borderline tumor on the spared ovary and/or noninvasive implants, but eight patients had a recurrence under the form of invasive disease. Compared with radical surgery, the use of conservative treatment (p < 0.0001) was a prognostic factor on disease-free survival (DFS), but without an impact on overall survival (OS). Nevertheless, three deaths occurred. Twenty-four pregnancies (13 spontaneous) were observed in 20 patients (29 patients wanted to become pregnant). CONCLUSION: In this series collecting the largest number of patients undergoing conservative surgery for stage II/III SBOTs, spontaneous pregnancies can be achieved after conservative treatment of advanced-stage disease, but the recurrence rate is high and three deaths were observed. These patients were spared their fertility but with a high rate of recurrence. Uncertainties regarding the safety of conservative treatment should be exposed to these patients.

Distribution of novel immune-checkpoint targets in ovarian cancer tumor microenvironment: A dynamic landscape.

BACKGROUND: The disappointing activity of single agent immune-checkpoint inhibitors in epitherlial ovarian cancer (EOC) has been attributed in part to its unique tumor microenvironment (TME). IDO, PDL1, LAG3 and TIM3 have been implicated in the immunotolerance of EOC. We investigated the expression of these co-regulators, their change with neoadjuvant chemotherapy (NACT), and their association with outcome. METHOD: We identified 98 patients with EOC treated with NACT and performed IDO, PDL1, LAG3 and TIM3 immunohistochemistry on samples obtained before and after NACT. The cut-off threshold to consider a positive sample was set at 5%. RESULTS: In our cohort, TIM3 was the most prevalent co-regulator, with more than 75% of the samples being TIM3 positive. In comparison, only 22%, 28% and 17% of the samples were considered IDO, PDL1 and LAG3 positive. More than half of ovarian tumors expressed 2, 3 or even all 4 co-inhibitory molecules. However, biomarkers were not correlated with each other. NACT had a marked impact on immune co-regulator expression with over 70% of patients showing a change in biomarker status from negative to positive or vice versa. There was no significant difference in the pattern of co-regulator expression between platinum-sensitive and resistant patients. Co-expression of multiple inhibitory molecules did not appear to affect overall and progression-free survival. CONCLUSION: TIM3 is the most abundant co-inhibitory molecule in OC and may represent an attractive target. In addition, OC frequently co-expressed 2 or more markers supporting ICI combinatorial approaches. Finally, NACT significantly altered the expression of immunosuppressive molecules suggesting that the choice of ICI combinations should be adapted to the composition of the post-NACT immune TME.

A new score based on biomarker values to predict the prognosis of locally advanced cervical cancer.

OBJECTIVE: To define a prognostic score based on pretreatment values of leucocyte, platelet and hemoglobin in locally advanced cervical cancer (LACC). MATERIAL AND METHODS: We conducted a prospective study of 238 patients for LACC with negative PET imaging in the para-aortic (PA) area and who were undergoing laparoscopic PA lymphadenectomies. All patients were treated with chemo-radiation and brachytherapy. RESULTS: Patients had clinical International Federation of Gynecology and Obstetrics stages IB2 (n = 76), IIA (n = 13), IIB (n = 122), III (n = 18) or IVA (n = 9). We identified three biological parameters (at the time of diagnosis) with three cut-offs which impacted disease free survival (DFS) and overall survival (OS): <12 g/dL for hemoglobin, >10,000/µL for leucocyte and >300 × 109/L for platelet. A score is calculated, as shown in the table below, by adding the scores of all three biological parameters together (with a maximum score of three). DFS at 36 months was 87.3% [78.3-97.4], 58% [45-74.6], 79.1% [71.1-88], 58% [45-74.6] and 56.8% [37.8-85.4] for scores of 0, 1, 2 and 3 respectively. OS at 36 months was 92.6% [84.9-100], 84% [76.6-92.1], 62.5% [48.9-79.9] and 67% [46.8-96] for scores of 0, 1, 2 and 3 respectively. CONCLUSION: This score includes three biomarkers with easily remembered cut-offs that allow us to identify, at the time of diagnosis, those patients with a high risk of relapse (scores of two or three) and those requiring dose escalation.

Long term follow-up of a large series of stage-II/III atypical proliferative serous ovarian tumors.

BACKGROUND: The aim of this study was to assess prognostic factors and implications on further management in a large series of stage-II or III Atypical Proliferative Serous Tumors (APST) with a long-term follow-up. PATIENTS AND METHODS: Patients with APSTs and peritoneal implants treated in, or referred to, our institution were retrospectively reviewed. Prognostic factors on invasive recurrence, disease-free (DFS) and overall survival (OS) were analyzed. RESULTS: Between 1971 and 2017, 212 patients were identified and followed (33 having invasive implants). After a median follow-up of 115 months, 70 recurrences were observed, 28 of them under the form of invasive disease. DFS at 5 years and 10 years was 73% and 62% respectively. The use of a conservative treatment (HR = 5.5[3.33-9.08], p < .0001), the presence of ≥3 peritoneal sites with implants (HR = 1.65[1.01-2.72], p = .045) were unfavorable prognostic factors for DFS. The presence of ≥3 peritoneal sites with implants (HR = 3.02[0.96-9.53], p = .049) and the presence of stromal microinvasion (HR = 3.19[1.12-9.1], p = .022) were unfavorable prognostic factors for OS. Non-conservative surgery (HR = 7[2.35-20.87], p = .0002), invasive implants (HR = 5.37[1.29-22.26], p = .013), and ≥ 3 peritoneal sites with implants (HR = 3.56 [1.11-11.39], p = .024) were identified as predictors of recurrence in the form of an invasive disease. Invasive implants were not associated with DFS (HR = 1.39[0.77-2.51], p = .27), nor OS (HR = 1.76[0.57-5.47], p = .32). CONCLUSION: After a long-term follow-up, type of peritoneal implants is no longer a prognostic factor for OS. Implants ≥3 peritoneal sites seem to impact significantly OS and then require a specific follow-up in this subgroup of patients.