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Objective:To evaluate the difference in operative and clinical outcome for patients with primary advanced ovarian cancer (AOC) after optimal primary debulking surgery (PDS) versus interval debulking surgery (IDS).Methods:Tumor dissemination pattern and surgical outcome, as defined by morbidity, progression-free (PFS) survival and overall survival (OS) were systematically analyzed in AOC patients who underwent surgery in our institution between September 2000 and August 2009. Overall survival and PFS were calculated by Kaplan-Meier curves. Univariate and Cox regression analysis were performed to identify the impact of IDS on surgical outcome and survival.Results:Overall, 372 consecutive patients with histologically proven AOC (FIGO [International Federation of Gynecology and Obstetrics] stage III/IV) were evaluated. Forty patients (10.8%) underwent IDS after a median of 5 cycles (range, 2-6 cycles) platinum- and taxane-based chemotherapy, and 332 patients (89.2%) underwent PDS. Patients who underwent IDS had a significantly lower rate of tumor involvement of the lower (78.9% vs 98.8%; P < 0.001) and middle abdomen (68.4% vs 83.1%; P = 0.044) compared with PDS patients. During IDS, a significantly higher probability for complete tumor resection occurred when compared with PDS (85% vs 58.7%; P = 0.02) by equivalent rates of operative complications (36.4% vs 36.5%; P = 1.00). However, mean PFS was significantly reduced in IDS patients (14.6 vs 33.2 months; P < 0.001). Mean OS was also higher in PDS patients, but this reached a statistical significance only when complete tumor resection was obtained (65.4 vs 37.9 months; P = 0.005). Multivariate analysis identified that IDS was associated with an unfavorable OS and PFS.Conclusions:It seems that PDS has a more favorable outcome than IDS on both OS and PFS in AOC patients, even though IDS leads to significantly higher rates of complete tumor resection.

OBJECTIVECytoreductive surgery for epithelial ovarian cancer (EOC) is the cornerstone of multimodal therapy and considered as a high-risk surgery because of extensive multivisceral procedures. In most patients, ascites is present, but its impact on the surgical and clinical outcomes is unclear. METHODSOne hundred nineteen patients undergoing surgical cytoreduction because of EOC between 2005 and 2008 were included. All surgical data and the individual tumor pattern were collected systematically based on a validated documentation tool (intraoperative mapping of ovarian cancer) during primary surgery. The amount of ascites was determined at the time of surgery, and 3 groups were classified (no ascites [NOA, n = 56], low amount of ascites [< 500 mL, n = 42], and high amount of ascites [HAS > 500 mL, n = 21]). RESULTSGroup NOA compared with HAS showed less transfusions of packed red blood cells (median [quartiles], 0 [0–2] vs 0 [0–2] vs 3 [1–4] U; P < 0.001) and fresh frozen plasma (median [quartiles], 0 [0–2] vs 0 [0–4] vs 2 [2–6] U; P < 0.001). In addition, in patients with ascites, noradrenaline was administered more frequently and in higher doses. The postoperative length of stay in the intensive care unit was significantly shorter in the NOA versus the group with low amount of ascites and HAS (median [quartiles], 1 [0–1] vs 1 [0–2] vs 2 [1–5] days; P < 0.001). The hospital length of stay is extended in HAS compared with that in NOA (median [quartiles], 16 [13–20] vs 17 [14–22] vs 21 [17–41] days; P = 0.004). Postoperative complications were increased in patients with ascites at the time of surgery (P = 0.007). CONCLUSIONSThe presence of a high amount of ascites at cytoreductive surgery because of EOC is associated with higher amounts of blood transfusions, whereas the length of hospital stay and the postoperative intensive care unit treatment are significantly prolonged compared with those of patients without ascites.

Background Historically, blue dyes, 99 Tc or a combination of the two tracers have been used for sentinel lymph node (SLN) mapping in cervical and endometrial cancer patients. Indocyanine green (ICG), as a tracer, has been recently introduced in this setting. Our goal was to assess the differences in overall and bilateral detection rates as well as in false-negative rates among the different tracers. Methods The electronic databases PubMed, MEDLINE, and Scopus were searched in January 2016 by searching the terms “sentinel lymph node” and “dye” and “indocyanine green,” and “cervical cancer” or “endometrial cancer.” Series comparing different tracers injected intracervically and reporting the detection rate and/or SLN false-negative rate were selected. Results Forty-five studies were retrieved. Six studies including 538 patients met selection criteria. Compared with blue dyes, ICG SLN mapping had higher overall (odds ratio [OR] 0.27; 95 % confidence interval [CI] 0.15–0.50; p  < 0.0001) and bilateral detection rates (OR 0.27; 95 % CI 0.19–0.40; p  < 0.00001). No differences were found between ICG and 99 TC, although these results are based on data of a single series. No differences in overall and bilateral detection rates were found between ICG and the combination of blue dyes and 99 TC. The pooled analysis of false-negative rates data showed no difference in false-negative rates between tracers. Conclusions In cervical and endometrial cancer, ICG SLN mapping seems to be equivalent to the combination of blue dyes and 99 TC in terms of overall and bilateral detection rates. Its safety profile and ease of use may favor its employment respect to conventional tracers.

The European Society of Gynaecological Oncology and the European Society for Paediatric Oncology jointly developed clinically relevant and evidence-based guidelines for the management of adolescents and young adults aged 15 to 25 years with non-epithelial ovarian cancers, including malignant ovarian germ cell tumours, sex cord-stromal tumours, and small cell carcinoma of the ovary of hypercalcaemic type. The developmental process of these guidelines is based on a systematic literature review and critical appraisal process involving an international multidisciplinary developmental group consisting of experts from relevant disciplines (paediatric oncology, paediatric surgery, medical oncology, pathology, psycho-oncology, gynaecological oncology, and reproductive endocrinology). Given the specific and often complex issues involved in treating this group of patients, fertility sparing surgery and decrease of acute and long-term toxicities from treatment were important criteria for guidelines definition. Prior to publication, the guidelines were reviewed by 54 independent international practitioners in cancer care delivery.

Background Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. Methods The interaction between ERRα and HIF-1α was verified using co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERRα on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database. Results Triggered by a hypoxic microenvironment, highly expressed ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERRα activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in EC progression. Conclusions ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.

Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1–5) plus either oral sorafenib 400 mg or placebo twice daily on days 6–15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01047891. Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43–0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8–7·6) with sorafenib versus 4·4 months (3·7–5·0) with placebo. The most common grade 3–4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]). Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies. Bayer, Amgen, and GlaxoSmithKline.

Epithelial ovarian cancer (EOC) was previously shown to be associated with glycosylation changes of total serum and total IgG proteins. However, as a majority of previous studies analyzed released glycan profiles, still little is known about IgG subclass-specific alterations in ovarian cancer. Hence, in this study, we investigated EOC-related glycosylation changes of the three most abundant IgG subclasses, namely, IgG , IgG and IgG isolated from sera of 87 EOC patients and 74 age-matched healthy controls. In order to separate IgG and IgG , we performed a two-step affinity purification employing Protein A and Protein G Sepharose. After tryptic digestion, IgG glycopeptides were enriched and measured by MALDI-TOF-MS. Finally, EOC-related glycosylation changes were monitored at the level of total agalactosylation, monogalactosylation, digalactosylation, sialylation, bisection and fucosylation, which were calculated separately for each IgG subclass. Interestingly, aside from an EOC-related increase in agalactosylation/decrease in monogalactosylation and digalactosylation observed in all IgG subclasses, some subclass-specific trends were detected. Glycosylation of IgG was found to be most strongly affected in EOC, as it exhibited the highest number of significant differences between healthy controls and EOC patients. Specifically, IgG was the only subclass that showed a significant decrease in sialylation and a significant increase in fucosylation in EOC patients. Interestingly, IgG and IgG that were often investigated collectively in previous studies, were found to have distinct glycosylation patterns. IgG displayed stronger EOC-related increase in agalactosylation/decrease in digalactosylation and was characterized by notably higher sialylation, which consequently decreased in EOC patients. In conclusion, our study indicates that IgG subclasses exhibit subtly distinct glycosylation patterns of EOC-related alterations and that IgG and IgG agalactosylation show the strongest association with CA125, the routine diagnostic marker. Additionally, our results show that simultaneous analyses of IgG and IgG might lead to wrong conclusions as these two subclasses exhibit noticeably different glycosylation phenotypes.

Background To evaluate the diagnostic value of adding human epididymis protein 4 (HE4), cancer antigen 125 (CA125) and risk of malignancy algorithm (ROMA) to ultrasound for detecting ovarian cancer in patients with a pelvic mass. Methods This was a prospective, observational, multicenter study. Patients aged > 18 years who were scheduled to undergo surgery for a suspicious pelvic mass had CA125 and HE4 levels measured prior to surgery, in addition to a routine transvaginal ultrasound scan. The diagnostic performance of CA125, HE4 and ROMA for distinguishing between benign and malignant adnexal masses was assessed using receiver operating characteristic (ROC) analysis and the corresponding area under the curve (AUC). Results Of 965 evaluable patients, 804 were diagnosed with benign tumors and 161 were diagnosed with ovarian cancer. In late-stage ovarian cancer, CA125, HE4 and ROMA all had an excellent diagnostic performance (AUC > 0.92), whereas in stage I and II, diagnostic performance of all three biomarkers was less adequate (AUC < 0.77). In the differential diagnosis of ovarian cancer and endometriosis, ROMA and HE4 performed better than CA125 with 99 and 98.1% versus 75.0% sensitivity, respectively, at 75.4% specificity. Conclusions ROMA and HE4 could be valuable biomarkers to help with the diagnosis of ovarian cancer in premenopausal patients in order to differentiate from endometriosis, whereas CA125 may be more adequate for postmenopausal patients. Highlights • Serum biomarkers can help to distinguish benign from malignant pelvic masses • We evaluated the diagnostic value of adding HE4, CA125 and ROMA to ultrasound for detecting ovarian cancer • In stage III and IV ovarian cancer all three biomarkers showed excellent performance • ROMA and HE4 performed better than CA125 in the differential diagnosis of ovarian cancer and endometriosis

The present prospective study aimed at determining the impact of cell-free tumor DNA (ct-DNA), CA125 and HE4 from blood and ascites for quantification of tumor burden in patients with advanced high-grade serous epithelial ovarian cancer (EOC). Genomic DNA was extracted from tumor FFPE and ct-DNA from plasma before surgery and on subsequent post-surgical days. Extracted DNA was subjected to hybrid-capture based next generation sequencing. Blood and ascites were sampled before surgery and on subsequent post-surgical days. 20 patients (10 undergoing complete resection (TR0), 10 undergoing incomplete resection (TR>0)) were included. The minor allele frequency (MAF) of TP53 mutations in ct-DNA of all patients with TR0 decreased significantly, compared to only one patient with TR>0. It was not possible to distinguish between patients with TR0 and patients with TR>0, using CA125 and HE4 from blood and ascites. Based upon the present findings, ct-DNA assessment in patients with high-grade serous EOC might help to better determine disease burden compared to standard tumor markers. Further studies should prospectively evaluate whether this enhancement of accuracy can help to optimize management of patients with EOC.

Introduction/BackgroundEvery year, around 127,634 women in Europe are diagnosed with ovarian cancer (OC). The majority of the patients detected are diagnosed in advanced stages due to lack or unspecific symptoms and/or no effective screening methods. Hence prognosis is poor. Although most of the patients will be in complete remission following primary cytoreduction and platinum-based chemotherapy, half of the advanced ovarian cancer patients will experience relapse within two years after the diagnosis. In the recurrent therapy option, PARP became a new target in ovarian cancer. Maintenance with PARP inhibitors significantly improved progression free survival in both primary and relapsed high grade ovarian cancer.We have previously investigated patients’ preferences and expectations from cancer maintenance treatment regimens (Expression IV project). The results from this project indicated that patients choose maintenance therapy primarily to improve the therapeutic outcome and secondarily to improve their quality of life. Based on these results, we considered to perform a fully prospective study characterizing the real-world adherence and progression-free-survival time (PFS), as there is currently limited information available about the adherence to novel therapies such as rucaparib.MethodologyThis study will recruit 150 patients with histologically diagnosed platinum-sensitive relapsed high grade ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, that are eligible for rucaparib maintenance therapy according to Summary of Product Characteristics (SmPC). Throughout the study, individual patient data will be collected at baseline and every three months until disease progression or patient’s death whichever occurs first. To capture adherence to rucaparib therapy an adaption (according to the rucaparib therapy) of the ‘Essener Compliance Score’ (ECS) is used. As of June 2022, 13 patients have been included in this study.Results/Conclusion/