Antonio Gil-Moreno

Pelvic peritonectomy versus rectosigmoid resection in advanced epithelial ovarian cancer with Douglas pouch involvement: a systematic review and meta-analysis

To compare the oncologic outcomes in patients with advanced epithelial ovarian cancer and Douglas pouch involvement who underwent pelvic peritonectomy vs rectosigmoid resection as part of cytoreductive surgery. A systematic literature review and meta-analysis were conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses checklist. MEDLINE (through Ovid), Embase, and Cochrane Central Register of Controlled Trials were searched from inception until March 2024. We included studies with 2 arms of intervention comparing pelvic peritonectomy and rectosigmoid resection in patients diagnosed with advanced epithelial ovarian cancer (International Federation of Gynecology and Obstetrics 2014 stage IIB-IVB). Randomized controlled trials and prospective and retrospective observational studies were considered. The protocol was registered in PROSPERO (CRD42024535681). The search identified 821 articles; 598 studies were considered potentially eligible after removing duplicates, and 4 met the selection criteria, including a total of 623 patients. All 4 studies were retrospective. There was no statistically significant difference between patients undergoing pelvic peritonectomy compared to rectosigmoid resection in terms of overall recurrences (OR 0.99, 95% CI 0.53 to 1.83, I The comparison between pelvic peritonectomy and rectosigmoid resection for the treatment of Douglas pouch carcinomatosis in advanced ovarian cancer revealed no significant differences in overall and pelvic recurrence rates. Disease-free and overall survival were comparable between the 2 surgical techniques. However, pelvic peritonectomy was associated with shorter surgeries, reduced stoma formation, shorter hospital stay, and lower blood loss and transfusion requirements.

Improving pre-operative binary grading: relevance of p53 and PR expression in grade 2 endometrioid endometrial carcinoma

This study aimed to evaluate the association between pre-operative progesterone receptor (PR) and p53 expression and prognosis in pre-operative grade 2 endometrioid endometrial carcinoma compared with grade 1 and grade 3 carcinomas. Three European endometrial carcinoma cohort studies were included. Patients with pre-operative grade 2 endometrioid carcinoma and known pre-operative PR and p53 status were included (n = 400), as were patients with pre-operative grade 1 (n = 602) or grade 3 (n = 148) endometrioid carcinomas. Kaplan-Meier and Cox regression analyses were performed to analyze disease-specific and disease-free survival. Patients with pre-operative grade 2 endometrial carcinoma and wild-type p53 plus PR-positive expression showed a similar 7-year disease-specific survival to grade 1 endometrial carcinoma patients (95.8% vs 97.5%, p = .13), while the 7-year disease-specific survival of patients with grade 2 endometrial carcinoma with p53 aberrant and/or negative PR expression (83.5%) was significantly lower (p < .001). The combination of these markers was an independent prognostic factor in multivariate Cox regression analyses. The prognostic impact of pre-operative p53 and PR expression in patients with grade 2 endometrioid endometrial carcinoma supports a modified binary grading system in which grade 2 patients should be pre-operatively classified as low- or high-grade depending on p53 and PR expression.

Molecular profile in endometrial carcinoma: can we predict the lymph node status? A systematic review and meta-analysis

Molecular classification of endometrial cancer (EC) has become a promising information to tailor preoperatively the surgical treatment. We aimed to evaluate the rate of lymph node metastases (LNM) in patients with EC according to molecular profile. A systematic review and meta-analysis were performed according to PRISMA guidelines by searching in two major electronic databases (PubMed and Scopus), including original articles reporting lymph node metastases according to the molecular classification of EC as categorized in the ESGO-ESMO-ESP guidelines. Fifteen studies enrolling 3056 patients were included. Pooled prevalence LNM when considering only patients undergoing lymph node assessment was 4% for POLE-mutated (95%CI: 0-12%), 22% for no specific molecular profile (95% CI: 9-39%), 23% for Mismatch repair-deficiency (95%CI: 10-40%) and 31% for p53-abnormal (95%CI: 24-39%). The presence of LNM seems to be influenced by molecular classification. P53-abnormal group presents the highest rate of nodal involvement, and POLE-mutated the lowest.

Simple radiologic assessment of visceral obesity and prediction of surgical morbidity in endometrial cancer patients undergoing laparoscopic aortic lymphadenectomy: A reliability and accuracy study

AbstractAimTo evaluate the reliability of sagittal abdominal diameter (SAD)—a surrogate of visceral obesity—in magnetic resonance imaging, and its accuracy to predict the surgical morbidity of aortic lymphadenectomy.MethodsWe conducted a multicenter reliability (phase 1) and accuracy (phase 2) cohort study in three Spanish referral hospitals. We retrospectively analyzed data from the STELLA‐2 randomized controlled trial that included high‐risk endometrial cancer patients undergoing minimally invasive surgical staging. Patients were classified into subgroups: conventional versus robotic‐assisted laparoscopy, and transperitoneal versus extraperitoneal technique. In the first phase, we measured the agreement of three SAD measurements (at the umbilicus, renal vein, and inferior mesenteric artery) and selected the most reliable one. In phase 2, we evaluated the diagnostic accuracy of SAD to predict surgical morbidity. Surgical morbidity was the main outcome measure, it was defined by a core outcome set including variables related to blood loss, operative time, surgical complications, and para‐aortic lymphadenectomy difficulty.ResultsIn phase 1, all measurements showed good inter‐rater and intra‐rater agreement. Umbilical SAD (u‐SAD) was the most reliable one. In phase 2, we included 136 patients. u‐SAD had a good diagnostic accuracy to predict surgical morbidity in patients undergoing transperitoneal laparoscopic lymphadenectomy (0.73 in ROC curve). It performed better than body mass index and other anthropometric measurements. We calculated a cut‐off point of 246 mm (sensitivity: 0.56, specificity: 0.80).Conclusionsu‐SAD is a simple, reliable, and potentially useful measurement to predict surgical morbidity in endometrial cancer patients undergoing minimally invasive surgical staging, especially when facing transperitoneal aortic lymphadenectomy.

The cutoff for estrogen and progesterone receptor expression in endometrial cancer revisited: a European Network for Individualized Treatment of Endometrial Cancer collaboration study

There is no consensus on the cutoff for positivity of estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer (EC). Therefore, we determined the cutoff value for ER and PR expression with the strongest prognostic impact on the outcome. Immunohistochemical expression of ER and PR was scored as a percentage of positive EC cell nuclei. Cutoff values were related to disease-specific survival (DSS) and disease-free survival (DFS) using sensitivity, specificity, and multivariable regression analysis. The results were validated in an independent cohort. The study cohort (n = 527) included 82% of grade 1-2 and 18% of grade 3 EC. Specificity for DSS and DFS was highest for the cutoff values of 1-30%. Sensitivity was highest for the cutoff values of 80-90%. ER and PR expression were independent markers for DSS at cutoff values of 10% and 80%. Consequently, three subgroups with distinct clinical outcomes were identified: 0-10% of ER/PR expression with, unfavorable outcome (5-year DSS = 75.9-83.3%); 20-80% of ER/PR expression with, intermediate outcome (5-year DSS = 93.0-93.9%); and 90-100% of ER/PR expression with, favorable outcome (5-year DSS = 97.8-100%). The association between ER/PR subgroups and outcomes was confirmed in the validation cohort (n = 265). We propose classification of ER and PR expression based on a high-risk (0-10%), intermediate-risk (20-80%), and low-risk (90-100%) group.

Survival outcomes and prognostic factors of endometrial stromal sarcoma and undifferentiated uterine sarcoma

To review the diagnostic and therapeutic procedures of patients diagnosed with Endometrial Stromal Sarcoma (ESS) and Undifferentiated Uterine Sarcoma (USS) at our institution and investigate their clinical outcomes and factors affecting prognosis. We retrospectively collected demographic data, preoperative diagnostic methods and therapeutic management of patients treated for ESS and UUS between January 1995 and December 2019 at Vall d'Hebron Barcelona Hospital Campus, Spain. Overall survival and disease-free survival were calculated. Cox proportional-hazards regression models were calculated. Sixty-three patients were included in the study, of which 51(81%) had a diagnosis of ESS and 12(19%) of UUS. Twenty patients (31.7%) were diagnosed after a previous non-oncologic surgery, and 12 of them (60%) suffered from tumor disruption. Cytoreductive procedures were needed in 29 patients (46%), and optimal cytoreduction was achieved in 80.9% of the patients. The median follow-up was 7.6 years (IQR = 0.99-14.31). Five-year overall survival was 57.6% (44.2-68.8) and was significantly better for low-grade ESS (LG-ESS) patients (p < 0.01). Five-year disease-free survival was 57.1% (42.8-69.1) and was also significantly higher in LG-ESS cohort (p = 0.03). After multivariate analysis histological type, age, FIGO stage, optimal surgery and mitotic index were found significantly correlated with survival. For high-grade EES (HG-ESS) and USS patients adjuvant radiotherapy also correlated with improved survival. Overall survival and disease-free survival are significantly better in patients with LG-ESS cohort. HG-ESS and UUS show similar survival outcomes. Age, FIGO stage, optimal surgery and histological type were significantly correlated with survival in the global cohort, whilst adjuvant radiotherapy correlated with improved survival in HG-ESS and UUS patients.

Effect of tumor burden and radical surgery on survival difference between upfront, early interval or delayed cytoreductive surgery in ovarian cancer

We sought to evaluate the impact on survival of tumor burden and surgical complexity in relation to the number of cycles of neoadjuvant chemotherapy (NACT) in patients with advanced ovarian cancer (OC) with minimal (CC-1) or no residual disease (CC-0). This retrospective study included patients with International Federation of Gynaecology and Obstetrics IIIC-IV stage OC who underwent debulking surgery at 4 high-volume institutions between January 2008 and December 2015. We assessed the overall survival (OS) of primary debulking surgery (PDS group), early interval debulking surgery after 3-4 cycles of NACT (early IDS group) and delayed debulking surgery after 6 cycles (DDS group) with CC-0 or CC-1 according to peritoneal cancer index (PCI) and Aletti score. Five hundred forty-nine women were included: 175 (31.9%) had PDS, 224 (40.8%) early IDS and 150 (27.3%) DDS. Regardless of Aletti score, median OS after PDS was significantly higher than after early IDS or DDS, but the survival difference was higher in women with an Aletti score 10, there were no differences between PDS and early IDS, but DDS was associated with decreased OS. The benefit of complete PDS compared with NACT was maximal in patients with a low complexity score. In patients with low tumor burden, there was a survival benefit of PDS over early IDS or DDS. In women with high tumor load, DDS impaired the oncological outcome.

The extent of aortic lymphadenectomy in locally advanced cervical cancer impacts on survival

The prognostic impact of surgical paraaortic staging remains unclear in patients with locally advanced cervical cancer (LACC). The objective of our study was to evaluate the results of the surgical technique of preoperative aortic lymphadenectomy in LACC related to tumor burden and disease spread to assess its influence on survival. Data of 1,072 patients with cervical cancer were taken from 11 Spanish hospitals (Spain-Gynecologic Oncology Group [GOG] working group). Complete aortic lymphadenectomy surgery (CALS) was considered when the lymph nodes (LNs) were excised up to the left renal vein. The extent of the disease was performed evaluating the LNs by calculating the geometric means and quantifying the log odds between positive LNs and negative LNs. The Kaplan-Meier method was used to estimate the survival distribution. A Cox proportional hazards model was used to account for the influence of multiple variables. A total of 394 patients were included. Pathological analysis revealed positive aortic LNs in 119 patients (30%). LODDS cut-off value of -2 was established as a prognostic indicator. CALS and LODDS <-2 were associated with better disease free survival and overall survival than suboptimal aortic lymphadenectomy surgery and LODDS ≥-2. In a multivariate model analysis, CALS is revealed as an independent prognostic factor in LACC. When performing preoperative surgical staging in LACC, it is not advisable to take simple samples from the regional nodes. Radical dissection of the aortic and pelvic regions offers a more reliable staging of the LNs and has a favorable influence on survival.

SUROVA study: global real-world treatment strategies and mortality risk prediction in advanced ovarian cancer

This study aimed to compare 5-year overall survival between primary debulking surgery and neoadjuvant chemotherapy followed by interval surgery in patients with stage IIIB to IVB epithelial ovarian cancer, using global real-world data. Secondary objectives included evaluation of progression-free survival and the influence of race, post-operative complications, and residual disease. SUROVA is a retrospective, international cohort study involving patients treated between 2018 and 2019 across 174 centers in 55 countries. Patients underwent primary surgery or received neoadjuvant chemotherapy followed by interval surgery, per institutional protocols. Propensity score matching was based on 7 baseline variables: age, race, Eastern Cooperative Oncology Group performance status at diagnosis, CA125 level at diagnosis, FIGO (International Federation of Gynecology and Obstetrics) stage IV disease, presence of ascites, and final tumor grade. Cox regression models with time-dependent effects and interaction terms were applied. A clinical risk calculator was developed and internally validated. A total of 3286 patients had a mean age of 60.0 years (SD 12); 2978 (90.6%) had high-grade serous carcinoma, and 795 (24.7%) presented with FIGO stage IV disease. A total of 1666 patients (50.7%) underwent primary cytoreductive surgery, and 1620 (49.3%) received neoadjuvant chemotherapy. The median follow-up duration was 43.8 months (interquartile range; 22.6-59.3). After propensity score matching (n=1524), overall survival was similar between groups (67.2 vs 65.0 months; HR 1.002, 95% CI 0.85 to 1.18, p=.98). Outcomes differed by ethnicity, residual disease, and post-operative complications. Post-operative complications (28%) significantly worsened survival (66 vs 46 months; HR 1.5, 95% CI 1.2 to 1.9, p<.001), especially among patients undergoing primary surgery (73 vs 46 months; HR 1.85, 95% CI 1.43 to 2.37, p<.001). The most favorable outcomes were observed among patients with primary surgery, complete resection, and no complications, with median overall survival not reached (HR 1.25, 95% CI 1.12 to 1.40, p<.001). Although overall survival was similar between groups, treatment effects differed by ethnicity, residual disease, and complications. Post-operative complications were associated with significantly worse survival, particularly among patients undergoing primary surgery, while the best outcomes were achieved in those who had primary surgery with complete resection and no complications.

ENDORISK-2: A personalized Bayesian network for preoperative risk stratification in endometrial cancer, integrating molecular classification and preoperative myometrial invasion assessment

ENDORISK is a Bayesian network that can assist in preoperative risk estimation of lymph node metastasis (LNM) risk in endometrial cancer (EC) with consistent performance in external validations. To reflect state of the art care, ENDORISK was optimized by integrating molecular classification and preoperative assessment of myometrial invasion (MI). Variables for POLE, MSI, and preoperative assessment of MI, either by expert transvaginal ultrasound or pelvic magnetic resonance imaging (MRI), were added to develop ENDORISK-2. The p53 biomarker, part of the molecular classification, was already included in ENDORISK. External validation of ENDORISK-2 for LNM prediction was performed in two independent cohorts from: Brno (CZ), (n = 581) and Tübingen (DE), (n = 247). ENDORISK-2 yielded AUCs of 0·85 (95 % CI 0·80-0·90) (CZ) and 0·86 (95 % CI 0·77-0·96) (DE) for predicting LNM. In patients with low-grade histology, 83 % (CZ) and 89 % (DE) were estimated having less than 10 % risk of LNM, with false negative rates (FNR) of 4·3 % (CZ) and 2·2 % (DE). The previously defined set of minimally required variables, i.e.: preoperative tumor grade, three of the four immunohistochemical (IHC) markers, and one clinical marker, could be interchanged with the new variables, with comparable validation metrics, including AUC values of 0·79-0·87 for LNM prediction. Incorporation of molecular data and preoperative MI improved the flexibility of ENDORISK with comparable diagnostic accuracy for estimating LNM as when based on low-cost immunohistochemical biomarkers. In addition, the high diagnostic accuracy in patients with low-grade EC demonstrates how ENDORISK-2 could aid clinicians in identifying patients in whom surgical lymph node assessment may safely be omitted. These results underline its power for clinical use in both high and low resource countries.

Current challenges and emerging tools in endometrial cancer diagnosis

The diagnostic process of endometrial cancer includes imaging methods such as trans-vaginal ultrasound, along with procedures to obtain endometrial tissue for histologic evaluation. Common techniques for tissue sampling include Pipelle endometrial biopsy, hysteroscopy, and dilation and curettage, which are used to confirm the diagnosis, determine tumor histology, grade, and molecular profile. However, diagnostic algorithms for endometrial cancer differ significantly across countries, influenced by local resources, protocols, and the availability of diagnostic methods. These variations include differences in the endometrial thickness threshold for recommending a biopsy and the choice of the initial diagnostic test. Moreover, patients often have multiple tests and appointments before a definitive diagnosis, although only 5%-10% of women with post-menopausal bleeding are diagnosed with endometrial cancer. Current diagnostic techniques have limitations. Pipelle endometrial biopsy has a significant false-negative rate (10%-20%) and may fail to provide adequate diagnostic material in up to 30% of cases. Hysteroscopy, while useful, is associated with pain in up to 65% of patients and can delay diagnosis because of limited availability. Dilation and curettage is an invasive procedure requiring general anesthesia and has a higher complication rate. In response to these challenges, there is growing interest in developing new diagnostic tools that are less invasive and provide 1-step diagnoses, including liquid biopsies from urine, blood, cervico-vaginal and endometrial fluid samples by means of genomics and proteomics. This review will examine the current diagnostic algorithms in European and American guidelines, evaluate the sensitivity, specificity, and accuracy of current techniques, and explore new diagnostic tools under development.

Cervical Cancer Evades the Host Immune System through the Inhibition of Type I Interferon and CXCL9 by LIF

Abstract Purpose: Cervical cancer is a viral-associated tumor caused by the infection with the human papilloma virus. Cervical cancer is an immunogenic cancer that expresses viral antigens. Despite being immunogenic, cervical cancer does not fully respond to immune checkpoint inhibitors (ICI). LIF is a crucial cytokine in embryo implantation, involved in maternal tolerance that acts as an immunomodulatory factor in cancer. LIF is expressed in cervical cancer and high levels of LIF is associated with poor prognosis in cervical cancer. Experimental Design: We evaluated the impact of LIF on the immune response to ICI using primary plasmocytoid dendritic cells (pDC) and macrophage cultures, syngeneic animals and patient-derived models that recapitulate the human tumor microenvironment. Results: We found that the viral proteins E6 and E7 induce the expression of LIF via the NFκB pathway. The secreted LIF can then repress type I interferon expressed in pDCs and CXCL9 expressed in tumor-associated macrophages. Blockade of LIF promotes the induction of type I interferon and CXCL9 inducing the tumor infiltration of CD8 T cells. This results in the sensitization of the tumor to ICI. Importantly, we observed that patients with cervical cancer expressing high levels of LIF tend to be resistant to ICI. Conclusions: Our data show that the HPV virus induces the expression of LIF to provide a selective advantage to the tumor cell by generating local immunosuppression via the repression of type I interferon and CXCL9. Combinatory treatment with blocking antibodies against LIF and ICI could be effective against cervical cancer expressing high levels of LIF.

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

AbstractIntroductionSerum 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 methodsThis 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.ResultsAnastomotic 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).ConclusionsProcalcitonin 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.

Oncological outcomes of intraperitoneal chemotherapy in advanced ovarian cancer: BRCA mutation role

The knowledge of BRCA status offers a chance to evaluate the role of the intraperitoneal route in patients selected by biomolecular profiles after primary cytoreduction surgery in advanced ovarian cancer. We performed a retrospective, multicenter study to assess oncological outcomes depending on adjuvant treatment (intraperitoneal [IP] vs intravenous [IV]) and BRCA status (BRCA1/2 mutated vs. BRCA wild type [WT]). The primary endpoint was to determine progression-free survival. The secondary objectives were overall survival and toxicity. A total of 288 women from eight centers were included: 177 in the IP arm and 111 in the IV arm, grouped into four arms according to BRCA1/2 status. Significantly better PFS was observed in BRCA1/2-mutated patients with IP chemotherapy (HR: 0.35; 95% CI, 0.16-0.75, p = 0.007), which was not present in BRCA1/2-mutated patients with IV chemotherapy (HR: 0.65; 95% CI, 0.37-1.12, p = 0.14). Significantly better OS was also observed in IP chemotherapy (HR: 0.17; 95% CI, 0.06-043, p < 0.0001), but was not present in IV chemotherapy in relation with BRCA mutation (HR: 0.52; 95% CI, 0.22-1.27, p = 0.15). For BRCA WT patients, worse survival was observed regardless of the adjuvant route used. The IP route was more toxic compared to the IV route, but toxicity was equivalent at the long-term follow-up. This retrospective study suggests that BRCA status can help to offer an individualized, systematic treatment after optimal primary surgery for advanced ovarian cancer, but is limited by the small sample size. Prospective trials are essential to confirm these results.