Spatial profiling of ovarian carcinoma and tumor microenvironment evolution under neoadjuvant chemotherapy.

PURPOSE: Immune tumor microenvironment (iTME) determines ovarian cancer development. This study investigates changes in HLA-I expression, CD8+/Foxp3 ratio, CD8+ cells and coregulators density at diagnosis and upon neoadjuvant chemotherapy (NACT), correlating changes with clinical outcomes. EXPERIMENTAL DESIGN: Multiplexed immune profiling and cell clustering analysis was performed on paired matched OC samples to characterize the iTME at diagnosis and under NACT from patients enrolled in the CHIVA trial (NCT01583322). RESULTS: Several immune cells (IC) subsets and immune coregulators were quantified pre-/post-NACT. At diagnosis, patients with higher CD8+ T cells and HLA-1+ enriched tumors were associated with -better outcome. The CD8+/Foxp3+ ratio increased significantly post-NACT in favor of increased immune surveillance and the influx of CD8+ T cells predicted better outcomes. Clustering analysis stratified pre-NACT tumors into 4 subsets: high Binf, enriched in B clusters; high Tinf, low Tinf, according to their CD8+ density; and desert clusters. At baseline, these clusters were not correlated with patient outcomes. Under NACT, tumors segregated into 3 clusters: high BinfTinf, low Tinf and desert. The high BinfTinf, more diverse in IC composition encompassing T, B and NK cell, correlated with improved survival. PD-L1 was rarely expressed, while TIM-3, LAG- and IDO-1 were more prevalent. CONCLUSIONS: Several iTMEs exist during tumor evolution and NACT impact on iTME is heterogeneous. Clustering analysis of patients, unravels several IC subsets within OC and can guide future personalized approaches. Targeting different checkpoints such as TIM-3, LAG-3 and IDO-1, more prevalent than PD-L1, could more effectively harness anti-tumor immunity in this anti-PD-L1 resistant malignancy.

The Influence of Surgical Complexity and Center Experience on Postoperative Morbidity After Minimally Invasive Surgery in Gynecologic Oncology: Lessons Learned from the ROBOGYN-1004 Trial.

BACKGROUND: This study was a secondary analysis of the ROBOGYN-1004 trial conducted between 2010 and 2015. The study aimed to identify factors that affect postoperative morbidity after either robot-assisted laparoscopy (RL) or conventional laparoscopy (CL) in gynecologic oncology. METHODS: The study used two-level logistic regression analyses to evaluate the prognostic and predictive value of patient, surgery, and center characteristics in predicting severe postoperative morbidity 6 months after surgery. RESULTS: This analysis included 368 patients. Severe morbidity occurred in 49 (28 %) of 176 patients who underwent RL versus 41 (21 %) of 192 patients who underwent CL (p = 0.15). In the multivariate analysis, after adjustment for the treatment group (RL vs CL), the risk of severe morbidity increased significantly for patients who had poorer performance status, with an odds ratio (OR) of 1.62 for the 1-point difference in the WHO performance score (95 % CI 1.06-2.47; p = 0.027) and according to the type of surgery (p < 0.001). A focus on complex surgical acts showed significant more morbidity in the RL group than in the CL group at the less experienced centers (OR, 3.31; 95 % CI 1.0-11; p = 0.05) compared with no impact at the experienced centers (OR, 0.87; 95 % CI 0.38-1.99; p = 0.75). CONCLUSION: The findings suggest that the center's experience may have an impact on the risk of morbidity for patients undergoing complex robot-assisted surgical procedures.

Intraepithelial tumor-infiltrating lymphocytes shape loco-regional PET/CT spread of locally advanced cervical cancer.

BACKGROUND: Data suggest an association between positron emission tomography/CT (PET/CT) metabolic metrics and tumor microenvironment in several malignancies, and a potential role of PET/CT to monitor response to immunotherapy. OBJECTIVE: To evaluate the correlation between tumor loco-regional extension and tumor-infiltrating lymphocyte infiltration in locally advanced cervical cancer prior to concurrent chemo-radiotherapy.The secondary objective was to assess the association between tumor-infiltrating lymphocytes and PET/CT metabolic metrics. METHODS: Patients with locally advanced cervical cancer and negative para-aortic extensions on PET/CT were included. Two senior nuclear medicine physicians specializing in gynecologic oncology reviewed all PET/CT exams, and extracted tumor maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis, as well as pelvic lymph node involvement. One senior gynecologic oncology pathologist assessed intraepithelial tumor-infiltrating lymphocytes and stromal tumor-infiltrating lymphocytes. Intraepithelial tumor-infiltrating lymphocytes were categorized following previous studies as <1% and >1%. The cut-off for stromal tumor-infiltrating lymphocytes was chosen empirically: intermediate <60% and high >60%. RESULTS: 86 patients were included. Intraepithelial tumor-infiltrating lymphocytes were not significantly associated with tumor metabolic metrics. Intraepithelial tumor-infiltrating lymphocytes were not significantly associated with maximum standard uptake value (p=0.16), or metabolic tumor volume (p=0.19). Tumors with <1% intraepithelial tumor-infiltrating lymphocytes score were associated with a higher MRI tumor size (≥ median) (63.3% vs 39.3%, p=0.04). Patients with pelvic lymph node uptake were significantly more frequent in patients with high stromal tumor-infiltrating lymphocytes score (≥60%) (61.5% vs 31.7%, p=0.009). CONCLUSIONS: Poor or absent intraepithelial tumor-infiltrating lymphocytes were associated with more advanced disease at diagnosis and larger tumor size. Tumor-infiltrating lymphocytes were not associated with tumor metabolic activity. Intraepithelial and stroma tumor-infiltrating lymphocytes are not redundant and should be assessed separately. Further work is needed to evaluate the association between tumor metabolic profile and immune populations, including different T-cell subtypes for patient selection for immunotherapy strategies.

Gynecological sarcomas, surgical management: primary, metastatic, and recurrent disease.

Adult-type gynecological soft tissue and visceral sarcomas are rare tumors, with an estimated incidence of 13% of all sarcomas and 4% of all gynecological malignancies. They most often develop in the uterus (83%), followed by the ovaries (8%), vulva and vagina (5%), and other gynecological organs (2%). The objective of this review is to provide an overview of the current management of gynecological sarcomas, according to international guidelines. The management of gynecological sarcomas should follow the recommendations for the management of soft tissue and visceral sarcomas. Centralizing cases in expert centers improves patient survival, both for the diagnostic phase and for multidisciplinary therapeutic management. In the case of pelvic soft tissue sarcomas, a radiological biopsy is essential before any surgical decision is taken. In the case of a myometrial tumour which may correspond to a sarcoma, if conservative surgery such as myomectomy or morcellation is planned, an ultrasound-guided biopsy with pathological analysis including comparative genomic hybridization analysis must be carried out. In all cases, en bloc surgery, without rupture, is mandatory. Many rare histological subtypes require specific surgical management.

Consensus on surgical technique for sentinel lymph node dissection in cervical cancer.

OBJECTIVE: The purpose of this study was to establish a consensus on the surgical technique for sentinel lymph node (SLN) dissection in cervical cancer. METHODS: A 26 question survey was emailed to international expert gynecological oncology surgeons. A two-step modified Delphi method was used to establish consensus. After a first round of online survey, the questions were amended and a second round, along with semistructured interviews was performed. Consensus was defined using a 70% cut-off for agreement. RESULTS: Twenty-five of 38 (65.8%) experts responded to the first and second rounds of the online survey. Agreement ≥70% was reached for 13 (50.0%) questions in the first round and for 15 (57.7%) in the final round. Consensus agreement identified 15 recommended, three optional, and five not recommended steps. Experts agreed on the following recommended procedures: use of indocyanine green as a tracer; superficial (with or without deep) injection at 3 and 9 o'clock; injection at the margins of uninvolved mucosa avoiding vaginal fornices; grasping the cervix with forceps only in part of the cervix is free of tumor; use of a minimally invasive approach for SLN biopsy in the case of simple trachelectomy/conization; identification of the ureter, obliterated umbilical artery, and external iliac vessels before SLN excision; commencing the dissection at the level of the uterine artery and continuing laterally; and completing dissection in one hemi-pelvis before proceeding to the contralateral side. Consensus was also reached in recommending against injection at 6 and 12 o'clock, and injection directly into the tumor in cases of the tumor completely replacing the cervix; against removal of nodes through port without protective maneuvers; absence of an ultrastaging protocol; and against modifying tracer concentration at the time of re-injection after mapping failure. CONCLUSION: Recommended, optional, and not recommended steps of SLN dissection in cervical cancer have been identified based on consensus among international experts. These represent a surgical guide that may be used by surgeons in clinical trials and for quality assurance in routine practice.

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.).

PPARγ activation modulates the balance of peritoneal macrophage populations to suppress ovarian tumor growth and tumor-induced immunosuppression.

BACKGROUND: Ovarian adenocarcinoma (OVAD) frequently metastasizes to the peritoneal cavity and manifests by the formation of ascites, which constitutes a tumor-promoting microenvironment. In the peritoneal cavity, two developmentally, phenotypically and functionally distinct macrophage subsets, immunocompetent large peritoneal macrophages (LPM) and immunosuppressive small peritoneal macrophages (SPM), coexist. Because peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor participating in macrophage differentiation and cooperates with CCAAT/enhancer binding protein ß (C/EBPß), a transcription factor essential for SPM-to-LPM differentiation, PPARγ could be also involved in the regulation of SPM/LPM balance and could be a promising therapeutic target. METHODS: To evaluate the 15(S)-hydroxyeicosatetraenoic acid (HETE), a PPARγ endogenous ligand, impact on ovarian tumor growth, we intraperitoneally injected 15(S)-HETE into a murine ovarian cancer model. This experimental model consists in the intraperitoneally injection of ID8 cells expressing luciferase into syngeneic C57BL/6 female mice. This ID8 orthotopic mouse model is a well-established experimental model of end-stage epithelial OVAD. Tumor progression was monitored using an in vivo imaging system. Peritoneal immune cells in ascites were analyzed by flow cytometry and cell sorting. To determine whether the impact of 15(S)-HETE in tumor development is mediated through the macrophages, these cells were depleted by injection of liposomal clodronate. To further dissect how 15(S)-HETE mediated its antitumor effect, we assessed the tumor burden in tumor-bearing mice in which the PPARγ gene was selectively disrupted in myeloid-derived cells and in mice deficient of the recombination-activating gene Rag2. Finally, to validate our data in humans, we isolated and treated macrophages from ascites of individuals with OVAD. RESULTS: Here we show, in the murine experimental model of OVAD, that 15(S)-HETE treatment significantly suppresses the tumor growth, which is associated with the differentiation of SPM into LPM and the LPM residency in the peritoneal cavity. We demonstrate that C/EBPß and GATA6 play a central role in SPM-to-LPM differentiation and in LPM peritoneal residence through PPARγ activation during OVAD. Moreover, this SPM-to-LPM switch is associated with the increase of the effector/regulatory T-cell ratio. Finally, we report that 15(S)-HETE attenuates immunosuppressive properties of human ovarian tumor-associated macrophages from ascites. CONCLUSION: Altogether, these results promote PPARγ as a potential therapeutic target to restrain OVAD development and strengthen the use of PPARγ agonists in anticancer therapy.

Recommandations pour la pratique clinique Nice/Saint-Paul-de-Vence 2022­2023 : Prise en charge du cancer de l'endomètre métastatique et/ou en rechute.

Recommendations for clinical practice Nice/Saint-Paul-de-Vence 2022-2023 : Management of advanced/relapsing endometrial cancer Since the first recommendations in 2020 concerning metastatic and/or relapsed endometrial cancer, new treatment options have shown a benefit on patients' life expectancy, justifying their update. In first line, the choice will be made between chemotherapy with carboplatin/paclitaxel or hormone therapy with progestin, depending on tumor characteristics (histological type, grade, expression of hormone receptors, rate of progression). In case of a dMMR tumors, the use of immunotherapy within the framework of a therapeutic trial is an option. Beyond first-line chemotherapy, current standard treatment consists of the combination of pembrolizumab and lenvatinib, regardless of MMR status. Close clinical and biological monitoring is however necessary given the potential toxicity. Chemotherapy retains its place either as monotherapy (paclitaxel or doxorubicin) in the event of failure or contraindication to pembrolizumab-lenvatinib, or in combination with carboplatin in the event of a long free interval and pMMR tumor. The numerous ongoing clinical trials evaluating new therapeutic targets or strategies adapted to molecular or histological types should allow further improvements the prognosis of patients with metastatic endometrial cancer.

Outcomes of DIEP flap reconstruction after pelvic cancer surgery: A retrospective multicenter case series.

BACKGROUND: Flap reconstruction is often required after pelvic tumor resection to reduce wound complications. The use of perforator flaps has been shown to reduce donor site morbidity. The purpose of this study was to evaluate the outcomes of pedicled deep inferior epigastric perforator (pDIEP) flap reconstruction. METHODS: This was a retrospective multicenter study of patients who underwent immediate pDIEP flap reconstruction for a pelvic or perineal defect after tumor resection between November 2012 and June 2022. The primary outcome was abdominal donor site morbidity, and the secondary outcome was perineal morbidity. RESULTS: Thirty-four patients (median age, 57.5 years) who underwent pelvic exenteration (n = 31), extralevator abdominoperineal excision (n = 2), or extended vaginal hysterectomy (n = 1) were included. The most common indications were recurrent cervical (n = 19) and anal (n = 4) squamous cell carcinoma. Twenty-nine patients (85%) had a history of radiotherapy. Only one patient (3%) had major (Clavien-Dindo ≥ III) donor site complications (surgical site infection due to tumor recurrence). Eleven patients (32%) had at least one major recipient site complication (surgical site infection [n = 1], total [n = 2] or partial [n = 1] flap loss, perineal dehiscence [n = 2], hematoma [n = 1], fistula [n = 5]). No incisional or perineal hernias were observed during follow-up. Ninety-day survival was 100%. CONCLUSION: Pedicled DIEP flap reconstructions performed by experienced surgical teams had good outcomes for perineal or vaginal reconstruction, with low abdominal morbidity, in patients with advanced pelvic malignancies who had undergone median laparotomy. The risks and benefits of this procedure should be carefully evaluated preoperatively using clinical and imaging data.

Survival analysis and prognostic factors of retroperitoneal liposarcoma curative surgery in a single centre. Analysis of adjacent organ invasion between imaging and definitive histopathology.

INTRODUCTION: Retroperitoneal liposarcoma (RPL) is a rare primary mesenchymal tumour that develops in retroperitoneal adipose tissue. Unlike the majority of published series, this homogeneous cohort focuses on RPL. The main purpose of this study is to evaluate the overall and recurrence-free survival of RPLs who underwent excision surgery and the prognostic factors involved. PATIENTS AND METHODS: A total of 82 patients from a single centre, who underwent curative surgery for histologically confirmed retroperitoneal liposarcoma between 2008 and 2020, were analysed in the study. Compartmental surgical excision was advised as per the guidelines. The primary endpoints were 5 years of overall survival and recurrence-free survival. Predictable tumour invasion of adjacent organs, based on a pre-operative CT scan, was also investigated to test the correlation between pre-operative imaging and pathological data. RESULTS: Median follow-up was 61.6 months. Five year overall survival was 71.9% [95% CI: 59.8; 80.9] and 5 year recurrence-free survival was 49% [95% CI: 36.4; 60.5]. Following multivariable analysis, the factors influencing overall survival were tumour rupture and onset of severe complications (Dindo-Clavien grade ≥3). Factors influencing recurrence-free survival were neoadjuvant radiotherapy and tumour rupture. A significant correlation (p < 0.05) was found between predicted invasion based on a CT scan of the colon, spleen, adrenal gland, posterior abdominal wall and diaphragm, and pathological invasion. CONCLUSIONS: Curative compartmental surgery remains the gold standard treatment for RPL. This study, highlights the fact that the quality of the surgical excision is a crucial factor in patient prognosis.

High dose (54 Gy) pre-operative helical tomotherapy for retroperitoneal liposarcoma: Results of a phase II multicenter study.

PURPOSE: To evaluate efficacy and feasibility of high-dose intensity-modulated radiotherapy (RT) with pre-operative helical tomotherapy, delivering 54 Gy/30 fractions in patients with retroperitoneal liposarcomas (RPLS). MATERIALS AND METHODS: Patients with operable, biopsy-proven, RPLS were included in this phase II multicenter study (ClinicalTrials.gov: NCT01841047). The primary objectives were to analyze loco-regional relapse free survival (LRFS), overall survival (OS) and toxicities, graded according to CTCAE V3.0. RESULTS: From April 2009 to September 2013, 48 patients were included. Histological types were: 20 well differentiated and 28 dedifferentiated liposarcomas. Median clinical target volume (CTV) was 2570 cc (range, 230-8734 cc). The radio-surgical schedule was completed as planned in all patients apart from one. A monobloc wide excision was achieved for all patients. Surgical margins were R0 (16; 34%), R1 (28; 60%), R2 (2; 4%) or missing (1, 2%).With a median follow-up of 5.5 years, 3-year LRFS rate was 74.2% (95%CI: [59.1%; 84.5%]). At 5 years, cumulative incidence of loco-regional relapse for well differentiated and dedifferentiated RPLS was 10% and 18%, respectively. The 5-year OS was 73.9% [95%CI: 58.7-84.3%]. During RT, the most common grade 3-4 adverse events were hematological (N = 20; 41.6%). After surgery and during follow-up, 17 patients (35.4%) presented a grade 3-4 toxicity. Two patients (4.1%) died due to a duodenal toxicity. Nine second cancers were observed. CONCLUSION: From this phase II trial of preoperative RT in RPLS patients, the dose level proposed cannot be considered safe, leading to non-negligible toxicity and second cancers rates. Our results, combined with STRASS-1 study, suggest that the ideal indication of RT for patients with RPLS still remains to be determined.

Dissecting the Origin of Heterogeneity in Uterine and Ovarian Carcinosarcomas.

Gynecologic carcinosarcomas (CS) are biphasic neoplasms composed of carcinomatous (C) and sarcomatous (S) malignant components. Because of their rarity and histologic complexity, genetic and functional studies on CS are scarce and the mechanisms of initiation and development remain largely unknown. Whole-genome analysis of the C and S components reveals shared genomic alterations, thus emphasizing the clonal evolution of CS. Reconstructions of the evolutionary history of each tumor further reveal that C and S samples are composed of both ancestral cell populations and component-specific subclones, supporting a common origin followed by distinct evolutionary trajectories. However, while we do not find any recurrent genomic features associated with phenotypic divergence, transcriptomic and methylome analyses identify a common mechanism across the cohort, the epithelial-to-mesenchymal transition (EMT), suggesting a role for nongenetic factors in inflicting changes to cellular fate. Altogether, these data accredit the hypothesis that CS tumors are driven by both clonal evolution and transcriptomic reprogramming, essential for susceptibility to transdifferentiation upon encountering environmental cues, thus linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences. Significance: We have provided a detailed characterization of the genomic landscape of CS and identified EMT as a common mechanism associated with phenotypic divergence, linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences.

A RAD51 functional assay as a candidate test for homologous recombination deficiency in ovarian cancer.

RATIONALE: Homologous recombination deficiency (HRD), defined as BRCA1/2 mutation (BRCAmut) or high genomic instability, is used to identify ovarian cancer (OC) patients most likely to benefit from PARP inhibitors. While these tests are useful, they are imperfect. Another approach is to measure the capacity of tumor cells to form RAD51 foci in the presence of DNA damage using an immunofluorescence assay (IF). We aimed to describe for the first time this assay in OC and correlate it to platinum response and BRCAmut. METHODS: Tumor samples were prospectively collected from the randomized CHIVA trial of neoadjuvant platinum +/- nintedanib. IF for RAD51, GMN and gH2AX was performed on FFPE blocks. Tumors were considered RAD51-low if ≤10% of GMN-positive tumor cells had ≥5 RAD51 foci. BRCAmut were identified by NGS. RESULTS: 155 samples were available. RAD51 assay was contributive for 92% of samples and NGS available for 77%. gH2AX foci confirmed the presence of significant basal DNA damage. 54% of samples were considered HRD by RAD51 and presented higher overall response rates to neoadjuvant platinum (P = 0.04) and longer progression-free survival (P = 0.02). In addition, 67% of BRCAmut were HRD by RAD51. Among BRCAmut, RAD51-high tumors seem to harbor poorer response to chemotherapy (P = 0.02). CONCLUSIONS: We evaluated a functional assay of HR competency. OC demonstrate high levels of DNA damage, yet 54% fail to form RAD51 foci. These RAD51-low OC tend to be more sensitive to neoadjuvant platinum. The RAD51 assay also identified a subset of RAD51-high BRCAmut tumors with unexpected poor platinum response.

[State of results of HIPEC for epithelial ovarian cancer in the primary treatment or for relapse]. / État des lieux des résultats en termes de survie de la CHIP en primo-traitement et en récidive dans le cancer épithélial de l'Ovaire.

Peritoneal carcinomatosis is an unavoidable development of ovarian cancer, from the first treatment to relapses, and is the main cause of patients death. Hyperthermic intraperitoneal chemotherapy (HIPEC), is a hope for cure for patients with ovarian cancer. HIPEC is based on direct application of chemotherapy on the perioneum with high concentration of chemotherapy enhanced with specific effects of hyperthermia. Theoretically, HIPEC could be proposed at different steps of ovarian cancer development. But the hypothesis of efficiency of a new treatment must be assessed before being routinely applied. Numerous clinical series are already published about HIPEC used in primary treatment of ovarian cancer or for relapses. These series are mostly retrospectives and based on heterogeneous parameters as inclusion criteria of patients, intra peritoneal chemotherapy, concentration, temperature, duration of HIPEC. Taking into account this heterogeneity it is not possible to draw strong scientific conclusions about HIPEC efficiency to treat ovarian cancer patients. We proposed a review allowing a better understanding of current recommendations of the use of HIPEC in ovarian cancer patients.

Prophylactic Radical Fimbriectomy with Delayed Oophorectomy in Women with a High Risk of Developing an Ovarian Carcinoma: Results of a Prospective National Pilot Study.

Risk-reducing salpingo-oophorectomy is the gold standard for the prophylaxis of ovarian cancer in high-risk women. Due to significant adverse effects, 20-30% of women delay or refuse early oophorectomy. This prospective pilot study (NCT01608074) aimed to assess the efficacy of radical fimbriectomy followed by a delayed oophorectomy in preventing ovarian and pelvic invasive cancer (the primary endpoint) and to evaluate the safety of both procedures. The key eligibility criteria were pre-menopausal women ≥35 years with a high risk of ovarian cancer who refused a risk-reducing salpingo-oophorectomy. All the surgical specimens were subjected to the SEE-FIM protocol. From January 2012 to October 2014, 121 patients underwent RF, with 51 in an ambulatory setting. Occult neoplasia was found in two cases, with one tubal high-grade serous ovarian carcinoma. Two patients experienced grade 1 intraoperative complications. No early or delayed grade ≥3 post-operative complications occurred. After 7.3 years of median follow-up, no cases of pelvic invasive cancer have been noted. Three of the fifty-two patients developed de novo breast cancer. One BRCA1-mutated woman delivered twins safely. Twenty-five patients underwent menopause, including fifteen who had received chemotherapy for breast cancer, and twenty-three underwent menopause before the delayed oophorectomy, while two did not undergo a delayed oophorectomy at all. Overall, 46 women underwent a delayed oophorectomy. No abnormalities were found in any delayed oophorectomy specimens. Radical fimbriectomy followed by delayed oophorectomy appears to be a safe and well-tolerated risk-reducing approach, which avoids early menopause for patients with a high risk of breast and ovarian cancer.

Distinct Cellular Origins and Differentiation Process Account for Distinct Oncogenic and Clinical Behaviors of Leiomyosarcomas.

In leiomyosarcoma (LMS), a very aggressive disease, a relatively transcriptionally uniform subgroup of well-differentiated tumors has been described and is associated with poor survival. The question raised how differentiation and tumor progression, two apparently antagonist processes, coexist and allow tumor malignancy. We first identified the most transcriptionally homogeneous LMS subgroup in three independent cohorts, which we named 'hLMS'. The integration of multi-omics data and functional analysis suggests that hLMS originate from vascular smooth muscle cells and show that hLMS transcriptional program reflects both modulations of smooth muscle contraction activity controlled by MYOCD/SRF regulatory network and activation of the cell cycle activity controlled by E2F/RB1 pathway. We propose that the phenotypic plasticity of vascular smooth muscle cells coupled with MYOCD/SRF pathway amplification, essential for hLMS survival, concomitant with PTEN absence and RB1 alteration, could explain how hLMS balance this uncommon interplay between differentiation and aggressiveness.

Open abdominal vacuum pack technique for the management of severe abdominal complications after cytoreductive surgery in ovarian cancer.

INTRODUCTION: The aim of this study was to evaluate the indications and management of grade III-IV postoperative complications in patients requiring vacuum-assisted open abdomen after debulking surgery for ovarian carcinomatosis. METHODS: Retrospective study of prospectively collected data from patients who underwent a cytoreductive surgery by laparotomy for an epithelial ovarian cancer that required postoperative management of an open abdomen. An abdominal vacuum-assisted wound closure (VAWC) was applied in cases of abdominal compartmental syndrome (ACS) or intra-abdominal hypertension, to prevent ACS. The fascia was closed with a suture or a biologic mesh. The primary aim was to achieve primary fascial closure. Secondary outcomes considered included complications of cytoreductive surgery (CRS) and open abdominal wounds (hernia, fistula). RESULTS: Two percent of patients who underwent CRS required VAWC during the study's patient inclusion period. VAWC indications included: (i) seven cases of gastro-intestinal perforation, (ii) three necrotic enterocolitis, (iii) two intestinal ischemia, (iv) three anastomotic leakages and (v) four intra-abdominal hemorrhages. VAWC was used to treat indications (i) to (iv) (which represented 73.7% of cases), to prevent compartmental syndrome. Primary fascia closure was achieved in 100% of cases, in four cases (21.0%) a biologic mesh was used. Median hospital stay was 65 days (range: 18-153). Four patients died during hospitalization, three of these within 30 days of VAWC completion. CONCLUSION: VAWC for managing open abdominal wounds is a reliable technique to treat surgical post-CRS complications in advanced ovarian cancer and reduces the early post-operative mortality in cases presenting with severe complications.