Procalcitonin and C-reactive protein as early markers of anastomotic leakage in intestinal resections for advanced ovarian cancer (EDMOCS).

INTRODUCTION: Serum levels of procalcitonin and C-reactive protein (CRP) have been used to predict anastomotic leakage after colorectal surgery, but information is scarce in advanced ovarian cancer (AOC) surgery with bowel resection. This study aimed to assess the predictive value of procalcitonin and CRP in detecting anastomotic leakage after AOC surgery with bowel resection. The study also aimed to determine the optimal postoperative reference values and the best day for evaluating these markers. MATERIAL AND METHODS: This prospective, observational and multicentric trial included 92 patients with AOC undergoing debulking surgery with bowel resection between 2017 and 2020 in 10 reference hospitals in Spain. Procalcitonin and CRP levels were measured at baseline and on postoperative days 1-6. Receiver operating characteristic analysis was performed to evaluate the predictive value of procalcitonin and CRP at each postoperative day. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: Anastomotic leakage was detected in six patients (6.5%). Procalcitonin and CRP values were consistently higher in patients with anastomotic leakage at all postoperative days. The maximum area under the curve (AUC) for procalcitonin was observed at postoperative day 1 (AUC = 0.823) with a cutoff value of 3.8 ng/mL (83.3% sensitivity, 81.3% specificity). For CRP, the maximum AUC was found at postoperative day 3 (AUC = 0.833) with a cutoff level of 30.5 mg/dL (100% sensitivity, 80.4% specificity). CONCLUSIONS: Procalcitonin and C-reactive protein are potential biomarkers for early detection of anastomotic leakage after ovarian cancer surgery with bowel resection. Further prospective studies with a larger sample size are needed to confirm these findings.

European Enhanced Recovery After Surgery (ERAS) gynecologic oncology survey: Status of ERAS protocol implementation across Europe.

OBJECTIVE: To acquire a comprehensive assessment of the current status of implementation of Enhanced Recovery After Surgery (ERAS) protocols across Europe. METHODS: The survey was launched by The European Network of Young Gynecologic Oncologists (ENYGO). A 45-item survey was disseminated online through the European Society of Gynecological Oncology (ESGO) Network database. RESULTS: A total of 116 ESGO centers participated in the survey between December 2020 and June 2021. Overall, 80 (70%) centers reported that ERAS was implemented at their institution: 63% reported a length of stay (LOS) for advanced ovarian cancer surgery between 5 and 7 days; 57 (81%) centers reported a LOS between 2 and 4 days in patients who underwent an early-stage gynecologic cancer surgery. The ERAS items with high reported compliance (>75% "normally-always") included deep vein thrombosis prophylaxis (89%), antibiotic prophylaxis (79%), prevention of hypothermia (55%), and early mobilization (55%). The ERAS items that were poorly adhered to (less than 50%) included early removal of urinary catheter (33%), and avoidance of drains (25%). CONCLUSION: This survey shows broad implementation of ERAS protocols across Europe; however, a wide variation in adherence to the various ERAS protocol items was reported.

Discontinuation of mechanical bowel preparation in advanced ovarian cancer surgery: an enhanced recovery after surgery (ERAS) initiative.

OBJECTIVE: To investigate the impact of discontinuation of mechanical bowel preparation in advanced ovarian cancer surgery within the context of the ERAS program. METHODS: We retrospectively reviewed the medical records of patients with advanced ovarian cancer who underwent cytoreductive surgery with simultaneous colon and/or rectal resection from January 2012 to November 2020. Patients were divided into two groups based on whether preoperative mechanical bowel preparation (MBP) was given (pre-ERAS) or not (post-ERAS). Patient characteristics, including duration of antibiotic treatment, surgical complexity, and incidence of surgical and nonsurgical complications, were compared. RESULTS: During the study period, 114 patients who underwent colon and/or rectal resection were examined, of whom 39 received MBP and 75 did not receive MBP (NMBP). On comparison between the two groups, no significant differences were noted in the assessed patient characteristics, including mean age, FIGO stage, ASA class, BMI, or residual tumor. One patient (2.6%) in the MBP group, and 4 patients (5.3%) in the NMBP group experienced an anastomotic leakage (p = 0.11). No significant differences were found with respect to surgical site infection. (p = 0.5). CONCLUSION: MBP was not associated with any specific benefit for advanced ovarian cancer surgery. Gynecologic oncologists who use MBP should consider discontinuing this practice.

A combination of molecular and clinical parameters provides a new strategy for high-grade serous ovarian cancer patient management.

BACKGROUND: High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer. Although most patients will initially respond to first-line treatment with a combination of surgery and platinum-based chemotherapy, up to a quarter will be resistant to treatment. We aimed to identify a new strategy to improve HGSC patient management at the time of cancer diagnosis (HGSC-1LTR). METHODS: A total of 109 ready-available formalin-fixed paraffin-embedded HGSC tissues obtained at the time of HGSC diagnosis were selected for proteomic analysis. Clinical data, treatment approach and outcomes were collected for all patients. An initial discovery cohort (n = 21) were divided into chemoresistant and chemosensitive groups and evaluated using discovery mass-spectrometry (MS)-based proteomics. Proteins showing differential abundance between groups were verified in a verification cohort (n = 88) using targeted MS-based proteomics. A logistic regression model was used to select those proteins able to correctly classify patients into chemoresistant and chemosensitive. The classification performance of the protein and clinical data combinations were assessed through the generation of receiver operating characteristic (ROC) curves. RESULTS: Using the HGSC-1LTR strategy we have identified a molecular signature (TKT, LAMC1 and FUCO) that combined with ready available clinical data (patients' age, menopausal status, serum CA125 levels, and treatment approach) is able to predict patient response to first-line treatment with an AUC: 0.82 (95% CI 0.72-0.92). CONCLUSIONS: We have established a new strategy that combines molecular and clinical parameters to predict the response to first-line treatment in HGSC patients (HGSC-1LTR). This strategy can allow the identification of chemoresistance at the time of diagnosis providing the optimization of therapeutic decision making and the evaluation of alternative treatment strategies. Thus, advancing towards the improvement of patient outcome and the individualization of HGSC patients' care.

BRCA1 mutations in high-grade serous ovarian cancer are associated with proteomic changes in DNA repair, splicing, transcription regulation and signaling.

Despite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood. Here we provide a comprehensive molecular understanding of the signaling processes that drive HGSC pathogenesis with the addition of valuable ubiquitination profiling, and their dependency on BRCA1 mutation-state directly in patient-derived tissues. Using a multilayered proteomic approach, we show the tight coordination between the ubiquitination and phosphorylation regulatory layers and their role in key cellular processes related to BRCA1-dependent HGSC pathogenesis. In addition, we identify key bridging proteins, kinase activity, and post-translational modifications responsible for molding distinct cancer phenotypes, thus providing new opportunities for therapeutic intervention, and ultimately advance towards a more personalized patient care.

Importance of Enhanced Recovery After Surgery (ERAS) Protocol Compliance for Length of Stay in Ovarian Cancer Surgery.

OBJECTIVES: Enhanced Recovery After Surgery (ERAS) programs include multiple perioperative care elements, which when implemented together are designed to improve recovery after surgery with subsequent reduction in hospital length of stay (LOS). The aim of this study is to examine the impact of ERAS protocol compliance on LOS in patients undergoing advanced ovarian cancer surgery within the context of a randomized clinical trial. METHODS: Patients were enrolled in a prospective, consecutive, interventional randomized clinical trial between June 2014 and March 2018. Women with either suspected or confirmed advanced ovarian cancer with International Federation of Gynecology and Obstetrics (FIGO) stages IIB-IVA and recurrent ovarian cancer, who underwent cytoreduction surgery, were randomly assigned to either a conventional management (CM) protocol or an ERAS protocol. Demographic items, preoperative clinical data, and surgical characteristics of patients were recorded, as were LOS and ERAS protocol compliance. Negative binomial regression was used to model the relation between length of stay and ERAS protocol compliance. RESULTS: We included 49 patients in the CM group and 50 patients in the ERAS group. The overall rate of ERAS compliance was 92%. We observed that increasing ERAS protocol compliance was associated with shorter median LOS, and in patients who underwent higher complex surgeries, the length of stay reduction was greater. CONCLUSION: This study identifies a correlation between increasing ERAS protocol compliance and decreasing LOS in ovarian cancer surgery. This finding underlines the necessity to implement as many ERAS protocol elements as possible to achieve optimal clinical outcome improvements.

M-TRAP: Safety and performance of metastatic tumor cell trap device in advanced ovarian cancer patients.

OBJECTIVE: Despite radical surgery and chemotherapy, most patients with ovarian cancer die due to disease progression. M-Trap is an implantable medical device designed to capture peritoneal disseminated tumor cells with the aim to focalize the disease. This trial analyzed the safety and performance of the device. METHODS: This first-in-human prospective, multi-center, non-blinded, single-arm study enrolled 23 women with high-grade serous advanced ovarian cancer. After primary or interval debulking surgery, 3 M-Trap devices were placed in the peritoneum of the abdominal cavity. 18-months post-implantation or at disease progression, devices were initially removed by laparoscopy. The primary safety endpoint was freedom from device and procedure-related major adverse events (MAEs) through 6-months post-implantation compared to an historical control. The primary performance endpoint was histopathologic evidence of tumor cells capture. RESULTS: Only one major adverse event was attributable to the device. 18 women were free of device and procedure related MAEs (78.3%). However, the primary safety endpoint was not achieved (p = 0.131), primarily attributable to the greater surgical complexity of the M-Trap patient population. 62% of recurrent patients demonstrated tumor cell capture in at least one device with a minimal tumor cell infiltration. No other long-term device-related adverse events were reported. The secondary performance endpoint demonstrated a lack of disease focalization. CONCLUSIONS: The M-Trap technology failed to meet its primary safety objective, although when adjusted for surgical complexity, the study approved it. Likewise, the devices did not demonstrate the anticipated benefits in terms of tumor cell capture and disease focalization in recurrent ovarian cancer.

PROFAST: A randomised trial implementing enhanced recovery after surgery for highcomplexity advanced ovarian cancer surgery.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs include multiple perioperative elements designed to achieve early recovery after surgery and a shorter length of stay (LOS) in hospital. The PROFAST trial aimed to expand the evidence base for implementing ERAS in advanced gynaecologic oncology surgery. METHODS: This prospective, interventional randomised clinical trial enrolled women undergoing surgery for either suspected or diagnosed advanced ovarian cancer, at a reference hospital in gynaecologic oncology in Barcelona (Spain) and who were treated after either an ERAS protocol or conventional management (CM) protocol. All enrolled women who underwent cytoreductive surgery were included in the primary analysis. The primary outcome was reduction in LOS, and secondary outcomes were incidence and type of intraoperative and postoperative complications, rate of readmission and mortality within a 30-d follow-up period. This trial is registered at ClinicalTrials.gov, number NCT02172638. FINDINGS: From June 2014 to March 2018, 110 women were recruited, of which eleven were excluded. The ERAS group comprised 50 patients, and the CM group, 49 patients. Both groups were comparable with respect to baseline characteristics and complexity of the cytoreductive surgery, with an overall medium/high Aletti surgical complexity score of 7.4. Overall compliance to the ERAS protocol was 92%. As compared with the patients in the CM group, patients in the ERAS group had a decreased median of LOS of two days (7 versus 9 days; p = 0.0099) and a decreased rate of readmission (6% versus 20%, p = 0.0334). No further significant differences were detected with respect to incidence of intraoperative or postoperative complications, severe (Clavien-Dindo grade IIIB-IV) complications, Comprehensive Complication Index, reoperation during primary stay, or mortality. INTERPRETATION: Patients with advanced ovarian cancer in the ERAS program had a decreased LOS and decreased rate of readmission as compared with those in CM, with no increased morbidity or mortality. This study provides important evidence for the benefits of ERAS management even for gynaecologic surgeries of medium/high complexity and suggests that ERAS should be a standard practice for cytoreductive surgeries for peritoneal carcinomatosis.

Intraoperative Human Papillomavirus Test Predicts 24-Month High-Grade Squamous Intraepithelial Lesion Recurrence Saving Costs: A Prospective Cohort Study.

OBJECTIVES: The human papilloma virus (HPV) test is recommended in the posttreatment follow-up of cervical intraepithelial neoplasia. The aim of the study was to assess whether the intraoperative HPV (IOP-HPV) test had a similar diagnostic accuracy that HPV test performed at 6 months to predict high-grade squamous intraepithelial lesion (HSIL) recurrence. MATERIALS AND METHODS: In a prospective cohort study, 304 women diagnosed with HSIL by biopsy and/or endocervical curettage before treatment and/or confirmation in the histological specimen were included. Immediately after surgery, HPV testing was performed. This test was compared with the test at 6 months and other predictors of recurrence. Patients were followed for 24 months. An economic analysis was performed to compare the costs of IOP-HPV and HPV test at 6 months. RESULTS: Recurrence rate of HSIL was 6.2% (19 patients). The diagnostic accuracy of the IOP-HPV test to predict HSIL recurrence at 24 months was similar to the HPV test at 6 months, with comparative sensitivities of 100% versus 86.7%, specificities of 82.0% versus 77.9%, positive predictive values of 27.1% versus 18.1%, and negative predictive values of 100% versus 99.0%. Direct economic saving per high-grade intraepithelial lesion patient was 172.8 &OV0556;. CONCLUSIONS: The HPV test performed after loop electrosurgical resection procedure predicted recurrence of HSIL at 24 months with a similar diagnostic accuracy than the HPV test at 6 months. The use of the IOP-HPV test in the management of HSIL will allow early detection of the risk of recurrent disease and to save costs because of potential suppression of the need of HPV and follow-up controls at 6 months.

A giant superinfected uterine angioleiomyoma with distant septic metastases: an extremely rare presentation of a benign process and a systematic review of the literature.

PURPOSE: Uterine angioleiomyoma is a rare type of leiomyoma variant and there are few cases reported in the literature. The definitive diagnosis is usually obtained only after the histopathologic examination because there are no specific imaging criteria for this disease. The objective of this article is to review published cases about this clinical condition. METHODS: We report a case of giant angioleiomyoma superinfected by S. agalactiae with the development of latero-cervical distant metastasis in a premenopausal woman. Firstly, the case herein reported was orientated as an endometrial stroma sarcoma in the peri-operative histologic examination by frozen sections. It was treated with laparotomic total hysterectomy, bilateral salpingo-oophorectomy, inframesocolic omentectomy and pelvic and paraaortic lymph node dissection. Postoperative definitive anatomopathological analyses using a proper immunohistochemical panel revealed a case of uterine angioleiomyoma. We also review other case reports published about this clinical condition. RESULTS: We present the first case reported in the literature, in our knowledge, of a giant angioleiomyoma superinfected by S. agalactiae with the development of distant septic metastases. Immunohistochemistry permitted the definitive diagnosis of angioleiomyoma. Treatments previously reported are hysterectomy or tumor resection and any patient recurred. CONCLUSIONS: The definitive diagnosis is usually obtained after the definitive histopathologic examination since the use of immunohistochemical study has an important role in this regard. Complete surgical removal of the lesion is the treatment of choice, with no recurrent cases reported to date.

Nerve-sparing versus non-nerve-sparing radical hysterectomy: surgical and long-term oncological outcomes.

OBJECTIVES: There are controversies regarding the long-term oncological safety of preservation of pelvic innervation during radical hysterectomy (RH). This study aimed to analyze the feasibility and safety of nerve-sparing radical hysterectomy (NSRH) for cervical cancer compared with non-NSRH following 17 years of experience in a tertiary cancer referral center. MATERIALS AND METHODS: Between May 1999 and June 2016, all patients who underwent RH for cervical cancer were followed-up prospectively. Comparison analyses regarding surgical outcomes, complications, overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were performed between patients treated with NSRH and non-NSRH. RESULTS: A total of 188 patients were included (113 non-NSRH and 75 NSRH). The median follow-up was 112 months. Estimated blood loss and hospital stay were all significantly lower in the NSRH group. Overall intraoperative complication rate (p = 0.02) and need for transfusion (p = 0.016) were lower in the NSRH group. There were no differences in the median operation time, OS, DFS, CSS, or recurrence rates between the NSRH and non-NSRH group. CONCLUSIONS: Our study provides a wide perspective on the developments of nerve-sparing procedures for the management of women with early-stage cervical cancer. Our results suggest that NSRH is a feasible and safe procedure, with reduced morbidity outcomes.

Vaginal Intraepithelial Neoplasia: Clinical Presentation, Management, and Outcomes in Relation to HIV Infection Status.

OBJECTIVES: The data available on vaginal intraepithelial neoplasia (VAIN) and infection by HIV are scarce. We therefore aimed to review the clinical presentation, management, and survival outcomes of VAIN in this group of women. MATERIALS AND METHODS: This is an observational cohort study of women diagnosed with VAIN for a 23-year period. Clinical characteristics and outcomes were analyzed according to women's HIV infection status. Disease-free and progression-free survival were compared between groups. RESULTS: Twenty-two of 87 women were HIV positive (25.3%) compared with the HIV-negative group, HIV-positive women were younger (median age = 39 vs 57 years, p < .001) and more frequently smokers (p < .001). They also presented with multifocal and multicentric disease more often (p = .004 and p = .033, respectively) in relation to infection by human papillomavirus. All HIV-positive women were receiving antiretroviral treatment. The median time from the diagnosis of HIV to the development of VAIN was 14 years (range = 1-22 years). There were no significant differences in survival outcomes between groups. CONCLUSIONS: HIV-positive women are at an increased risk of developing VAIN and frequently present at a younger age with multifocal and multicentric disease. Vaginal intraepithelial neoplasia lesions can develop many years after the initial diagnosis of HIV infection reason why prolonged surveillance is essential to enable prompt diagnosis and treatment.

Impact of Laparoscopy to Assess Resectability in Stage IIIC Epithelial Ovarian, Tubal and Peritoneal Cancer Patients.

AIMS: To evaluate overall survival (OS) and progression-free survival (PFS) in patients with stage IIIC epithelial ovarian, tubal and peritoneal cancer (EOC) who underwent a laparoscopy to assess surgical resectability prior to Primary Debulking Surgery (PDS) or Interval Debulking Surgery (IDS). METHODS: Retrospective cohort study that included all women with stage IIIC EOC treated at our center between 2000 and 2010. Patients were classified in groups: PDS, neoadjuvant chemotherapy (NACT) with IDS, NACT without IDS; and then sub-classified based on residual tumor (RT). A laparoscopy to assess resectability was performed before PDS and IDS. RESULTS: Among 111 patients included, 66 underwent PDS, and 45 were treated with NACT, 80% of them receiving subsequent IDS. OS was 75.6 months in the PDS group, and 52.8 months for IDS group (p = 0.100); the PFS was 30 months and 19.2 months respectively (p = 0.049). Median OS was 104.4 and 52.8 months for patients with optimal cytoreduction (RT = 0) in the PDS and IDS group respectively (p < 0.05). Laparoscopy did not modify the preoperative consideration for PDS; however, 9 laparotomies were avoided based on laparoscopic findings after NACT. CONCLUSION: Laparoscopy for the assessment of surgical resectability in stage IIIC EOC has no impact on survival; but it still could be useful for the reduction of unnecessary laparotomies after NACT.

Prospective Randomized Trial Comparing Transperitoneal Versus Extraperitoneal Laparoscopic Aortic Lymphadenectomy for Surgical Staging of Endometrial and Ovarian Cancer: The STELLA Trial.

BACKGROUND: There is an ongoing debate on which approach, transperitoneal or extraperitoneal, is superior for the performance of laparoscopic aortic lymphadenectomy (LPA-LND) for the surgical staging of gynecologic cancer. A prospective randomized trial (STELLA trial) was designed to compare the perioperative outcomes and node retrieval of extraperitoneal versus transperitoneal aortic lymphadenectomy by laparoscopy or robot-assisted laparoscopy. METHODS: Patients with endometrial or ovarian carcinoma requiring aortic lymphadenectomy for surgical staging were randomized to an extraperitoneal or transperitoneal approach by laparoscopy or robot-assisted laparoscopy between June 2012 and July 2014. RESULTS: A total of 60 patients were entered into the study, 48 with endometrial cancer (80 %) and 12 with ovarian cancer (20 %). Thirty-one patients (51.6 %) were randomly assigned to the extraperitoneal group and 29 to the transperitoneal group (48.3 %). The means LPA-LND operating time was 90 min in both group (p = 0.343). The mean (range) blood loss was 105 (10-400) mL for extraperitoneal versus 100 (5-1000) mL for transperitoneal group (p = 0.541). There were no differences in the number of collected lymph nodes between the two groups [median (range) for extraperitoneal 12 (4-41) vs. 13 (4-29) for transperitoneal (p = 0.719)]. CONCLUSIONS: The extraperitoneal and transperitoneal approaches for laparoscopic and robotic aortic lymphadenectomy provide similar perioperative outcomes and nodal yields. TRIAL REGISTRATION: The STELLA trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT01810874.

Vulvar intraepithelial neoplasia: clinical presentation, management and outcomes in women infected with HIV.

OBJECTIVE: Immunocompromised patients are at increased risk of developing preinvasive lesions of the lower genital tract. There are a limited number of studies on vulvar intraepithelial neoplasia (VIN) in HIV-positive women. We aimed to review the clinical presentation of VIN, management and survival outcomes in this group of patients. DESIGN: Observational cohort study. METHODS: Data was collected from women diagnosed with VIN at the Hospital Vall d'Hebron between September 1994 and October 2011. The main outcome measures were recurrence-free survival (RFS) and progression-free survival (PFS). Risk factors for recurrence and progression were assessed using univariate and multivariate analyses. RESULTS: Thirty-seven out of 107 women were HIV positive (34.6%). The median follow-up time was 32 (range 12-179) months. Compared with the HIV-negative group, HIV-positive women were younger (median age 37 vs. 44 years, P = 0.003) and presented with multifocal and multicentric disease more frequently (63.6 vs. 22.2% and 84.8 vs. 43.3%, respectively, P < 0.0001). RFS and PFS were lower in the HIV-positive group (42.4 vs. 71.4% P = 0.043 and 69.7 vs. 95.2% P = 0.006, respectively). RFS was significantly associated to multicentric and multifocal disease on multivariate analysis. PFS was associated to HIV infection on univariate analysis. CONCLUSION: HIV-positive women are at increased risk of developing VIN and frequently present at a younger age with multifocal and multicentric disease. They have shorter RFS and PFS compared with HIV-negative women. Close surveillance of the lower genital tract is mandatory to enable early recognition and treatment of any suspicious lesions. Close follow-up after treatment of VIN is essential to exclude early recurrence or progression.

MicroRNAs as prognostic markers in ovarian cancer.

Ovarian cancer (OC) is the most lethal gynecological malignancy among women. Over 70% of women with OC are diagnosed in advanced stages and most of these cases are incurable. Although most patients respond well to primary chemotherapy, tumors become resistant to treatment. Mechanisms of chemoresistance in cancer cells may be associated with mutational events and/or alterations of gene expression through epigenetic events. Although focusing on known genes has already yielded new information, previously unknown non-coding RNAs, such as microRNAs (miRNAs), also lead insight into the biology of chemoresistance. In this review we summarize the current evidence examining the role of miRNAs as biomarkers of response and survival to therapy in OC. Beside their clinical implications, we also discuss important differences between studies that may have limited their use as clinical biomarkers and suggest new approaches.