Multimodale prädiktive und prognostische Faktoren zum klinischen Verlauf von Patientinnen mit Ovarialkarzinom

Although a plethora of biomarkers have been analyzes in the last decades and ultrasound criteria have been developed, ovarian cancer is mostly diagnosed in advanced stages. Despite more extensive surgical procedures and improvement in surgical outcome, ovarian cancer remains a deadly disease with most of the patients developing relapse and platinum resistance. Although progresses in understanding the molecular biology of EOC have been done in the last years, targeted therapies failed to improve overall survival rates in ovarian cancer patients. The here presented data focuses on three major bottle necks of multimodal management of ovarian cancer: predictive biomarkers for early diagnosis of EOC, role and limitations of BRCA1 epigenetic changes and predictive biomarkers and clinical parameters for clinical outcome. Borderline tumors of the ovary (BOT) are a special entity of epithelial tumors, usually having a benign behavior. Nevertheless, optimal surgical staging is mandatory, as BOT could be a precursor of low grade serous ovarian cancers. Using ultrasound, BOT together with some benign tumors, are the most difficult pelvic tumors to be assessed. They have both malignant as also benign characteristics. In our study, presented here, we analyzed the role of HE4 and CA125 alone and in combination within ROMA algorithm to predict the presence of BOT in pelvic mass patients. Our results showed that HE4 and ROMA (an algorithm combining CA125, Both biomarkers together with ROMA had poor sensitivity and specificity. Therefore there is still an urgent need of new diagnostic strategies with regards to BOT. Furthermore we analyzed the role of GLYCOV for the diagnosis of early ovarian cancer. GLYCOV is a newly discovered biomarker panel, formed by 11 N-glycan biomarkers, more specific four high- mannose and seven complex-type fucosylated N-glycans. Regarding to available data CA125 is increased in up to 80% of ovarian cancer patients, but only in 50% of early stages. Therefore CA125 remains a poor biomarker for early detection. In our study, GLYCOV had a better sensitivity and specificity than CA125 alone, with an AUC of 0.992 in detecting early stages EOC (FIGO stage I and II). This study included 20 FIGO I and II ovarian cancer patients, therefore further validation studies are needed. Homologous recombination deficiency (HRD) has been reported in up to 50% of high grade serous ovarian cancer patients. Mutations in BRCA1 and 2 genes are usually responsible for HRD. Epigenetic changes of BRCA1/2 promoter as also functional loss of proteins involved in HDR showed similar behavior as BRCA1/2 mutant tumors. Current trials showed that PARP inhibition increased progression free survival in BRCA mutant tumors. Therefore understanding inactivation mechanisms of the BRCA1 gene is of high clinical importance. In our study, we showed that methylation of BRCA1 promoter gene in HGSOC was not associated with platinum response, or with better overall or progression free survival rates. Hyper- methylation was associated with younger age at first diagnosis. No significant correlation between methylation status and surgical outcome have been detected. Residual mass after primary tumor debulking is an important prognostic factor. Optimal surgery can be achieved in ca. 60-70% of the patients, if primary debulking is performed in high volume centers. Nevertheless in a sub-group of patients optimal surgical outcome cannot be achieved. Until now there are no predictive biomarkers or clinical parameters for residual tumor mass. We analyzed the role of CA125 and HE4 in predicting surgical outcome in primary EOC. CA125 performed better than HE4 alone, but the combination of both biomarkers increased the sensitivity and specificity. When looking at different histological subtypes, we found out that in early stages, type I tumors have better survival rates, less extensive surgery, less extensive tumor spread. This was mostly due to diagnosis in early stages. Nevertheless when analyzing only the advanced FIGO stages, there was no differences in survival rates between type I and type II EOC. In advanced stages, tumor residuals together with positive lymph nodes and extrapelvic dissemination were independent prognostic factors for PFS and OS. If surgery is well accepted for primary situation, controversial discussions are surrounding the indication of secondary debulking surgery for ovarian cancer relapse. In our presented data, we analyzed the differences in surgical outcome and dissemination pattern in paired primary and relapse ovarian cancer patients. Complete tumor resection was significantly more often achieved in primary debulked patients as in first relapse. Residual mass at first surgery correlated with surgical outcome at relapse. No clinical parameters could predict surgical outcome in relapse situation. Dissemination pattern differed between primary and relapsed situation: with higher incidence of ascites at first diagnosis, and significant more involvement of upper abdomen in recurrent setting. In relapsed ovarian cancer diffuse mesenterial and peritoneal spread have been reported, leading to sub-optimal surgical outcome. There were no significant differences within postoperative complications. Looking for the classical biomarkers, HE4 and CA125, and their ability to predict surgical outcome, our study showed that both HE4 and CA125 are correlating with tumor residuals in patients with first platinum sensitive relapses. Nevertheless the sensitivity and specificity was poor, so further prospective multicentric studies evaluating biomarkers in combination with clinical parameters (eg. ECOG status, ascites, residual mass after primary debulking surgery) are needed. Furthermore, HE4 together with response to first platinum based chemotherapy were the only independent prognostic factors for OS. These data are the fundament for further validation and discovery studies towards personalized management of ovarian cancer patients.Obwohl in den letzten Jahren eine Vielzahl von Biomarkern und Ultraschallkriterien etabliert wurden, wird Eierstockkrebs noch immer meist in fortgeschrittenen Stadien diagnostiziert. Trotz Verbesserung der chirurgischen Techniken und des surgical outcome, bleibt Eierstockkrebs eine tödliche Erkrankung, während welcher die Patientinnen Rezidive und Platinresistenzen entwickeln. Obwohl in den letzten Jahren Fortschritte im Verständnis für die molekularen Zusammenhänge der Erkrankung verzeichnet wurden, konnten mittels gezielter Therapieansätze („targeted therapy“) keine Verbesserungen der Gesamtüberlebensraten bei Eierstockkrebspatientinnen erreicht werden. Die hier präsentierten Daten konzentrieren sich auf die drei Schwerpunkte einer multimodalen Therapiestrategie bei Eierstockkrebs: prädiktive Biomarker für eine frühzeitige Diagnosestellung, die Rolle und Limitationen von epigenetischen Veränderungen von BRCA1 und prädiktiver Biomarker sowie klinische Parameter für die Evaluation des klinischen Outcome. Borderlinetumoren des Ovars (BOT) sind eine spezielle Entität von epithelialen Tumoren, welche üblicherweise von benigner Dignität sind. Trotzdem ist ein optimales chirurgisches Staging unerlässlich, da die BOT Vorstufen des low grade serösen Eierstockkrebs darstellen können. Dabei sind BOT zusammen mit anderen benignen Tumoren am schwierigsten von allen Beckentumoren sonographisch zu diagnostizieren, da sie sowohl maligne als auch benigne Charakteristika tragen. In unserer Studie analysierten wir die Rolle des HE4 und CA125 allein und in Kombination mit dem ROMA Algorithmus, um das Vorliegen von BOT in Patientinnen mit unklarem Beckentumor zu prognostizieren. Unsere Ergebnisse zeigten, dass HE4 und ROMA sowohl einzeln als auch gemeinsam betrachtet eine schlechte Sensitivität und Spezifität aufzeigten. Daher besteht ein dringender Bedarf für die Etablierung neuer diagnostischer Strategien bezüglich des BOT. Weiterhin analysierten wir die Rolle von GLYCOV für die Diagnostik von Eierstockkrebs im Frühstadium. GLYCOV ist ein neu entwickelter Score, welcher aus 11 Bereichen (4 High- Mannose- und sieben fukosylierten N- Glykanen vom komplexen Typ) des N- glycan- Biomarker errechnet wird. Nach aktueller Datenlage ist CA125 in bis zu 80% der Ovarialkarzinompatientinnen erhöht, bei frühen Stadien jedoch nur in 50%. Daher bleibt CA125 ein schwacher Biomarker für die Krebsfrüherkennung. In unserer Studie wies GLYCOV eine bessere Sensitivität und Spezifität auf als CA125 allein mit einem AUC von 0.992 für die Erkennung von EOC in Frühstadien (FIGO- Studien I und II). Diese Studie umfasst 20 FIGO I und II Ovarialkarzinompatientinnen, sodass weitere Validierungsstudien notwendig sind. Ein Defizit in der der Homologen Rekombinationsreparatur (HRR) wurde in bis zu 50% der Patientinnen mit high grade serösem Ovarialkarzinom (HGSOC) berichtet. Dafür sind meist Mutationen des BRCA1 und 2- Gens verantwortlich. Epigenetische Veränderungen der BRCA1/2- Promoter sowie Funktionsverluste von Proteinen durch defiziente HRR zeigten ähnliches Verhaltensmuster wie Tumoren mit BRCA1/2- Mutationen. Aktuelle Studien zeigten, dass PARP- Inhibitoren das progressionsfreie Überleben in BRCA- mutierten Tumoren erhöhen. Daher ist das Verständnis bezüglich der Inaktivierungsmechanismen des BRCA1- Gens von hoher klinischer Relevanz. In unserer Studie zeigten wir, dass die Methylierung des BRCA- Promotorgens in HGSOC nicht mit der Platinsensitivität, der Verbesserung des Gesamtüberlebens oder des progressionsfreien Überlebens assoziiert ist. Es konnte weiterhin keine Korrelation zwischen Methylierungsstatus und chirurgischem Outcome festgestellt werden. Der Tumorrest nach primärem Tumordebulking ist ein wichtiger prognostischer Faktor. Diesbezüglich kann ein optimales Ergebnis in ca. 60-70% der Patientinnen erreicht werden, sofern das primäre Debulking in einem hierfür spezialisierten Tumorzentrum durchgeführt wird. Nichtsdestotrotz kann bei einem Teil der Patientinnen kein optimales Ergebnis erzielt werden. Bis heute gibt es keine prädiktiven Biomarker oder klinischen Parameter für den Verbleib von Tumorrest. Wir analysierten die prädiktive Rolle von CA125 und HE4 bezüglich des Surgical Outcomes bei primärem EOC. Dabei schnitt CA125 besser ab als HE4 und die Kombination aus beiden Biomarkern erhöhte die Sensitivität und Spezifität nochmals. Bei der Betrachtung der verschiedenen histologischen Subtypen konnten wir zeigen, dass in frühen Stadien die Typ I- Tumoren bessere Überlebensraten, weniger ausgedehnte Operationen und geringeren Tumorbefall aufwiesen. Bei der Analyse der fortgeschrittenen FIGO Stadien, zeigte sich kein Unterscheid in den Überlebensraten zwischen Typ I und Typ II EOC. Bei fortgeschrittenen Stadien stellten Tumorrest gemeinsam mit positivem Lymphknotenstatus und extrapelviner Tumorausbreitung unabhängige prognostische Faktoren für das progressionsfreie Überleben und das Gesamtüberleben dar. Im Gegensatz zur allgemein anerkannten Operation in der Primärsituation, bestehen Kontroversen bezüglich der Indikation zur sekundären Debulkingoperation bei Ovarialkarzinomrezidiv. Wir analysierten die Unterschiede im Surgical Outcome und Tumorbefallsmuster in gepaarten Patientinnen mit jeweils primärem und rezidiviertem Ovarialkarzinom. Tumorfreiheit konnte signifikant häufiger in primären Debulkingoperationen als bei Rezidivoperationen erreicht werden. Der Tumorrest korrelierte bei primärer Operation mit dem surgical outcome und Auftreten von Rezidiven. Es gab keine klinischen Parameter, welche das surgical outcome in der Rezidivsituation beurteilen konnten. Auch der Tumorbefall unterschied sich in der Primär- und Rezidivsituation, indem bei Ersterer ein höherer Aszitesanteil bei Erstdiagnose und ein signifikant höherer Tumorbefall des Oberbauches bestand. In der Rezidivsituation zeigten sich vermehrt eine diffuse mesenterielle und peritoneale Tumorausbreitung, welche zu einem suboptimalem surgical outcome führten. Es gab keine signifikanten Unterschiede bezüglich der postoperativen Komplikationen. Bezüglich der klassischen Biomarker HE4 und CA125 und deren prädiktiven Aussage bezüglich des surgical outcomes zeigte unsere Studie, das Beide mit dem Tumorrest bei Patientinnen mit erstem platinsensitivem Rezidiv korrelierten. Trotzdem war die Sensitivität und die Spezifität gering, sodass weitere prospektive multizentrische Studien zur Evaluation von Biomarkern in Kombination mit klinischen Parametern (z.B.- ECOG Status, Aszites, Tumorrest nach primärer Debulkingoperation) benötigt werden. HE4 stellte zusammen mit der Platinsensitivität der ersten Chemotherapie die einzigen unabhängigen prognostischen Faktoren für das Gesamtüberleben dar. Diese Daten stellen die Grundlage für weitere Validierungs- und Entwicklungsstudien hinsichtlich eines personalisierten Managements von Patientinnen mit Ovarialkarzinom dar

Immunoglobulin G Subclass-Specific Glycosylation Changes in Primary Epithelial Ovarian Cancer

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, IgG1, IgG2 and IgG3 isolated from sera of 87 EOC patients and 74 age-matched healthy controls. In order to separate IgG2 and IgG3, 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 IgG1 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, IgG1 was the only subclass that showed a significant decrease in sialylation and a significant increase in fucosylation in EOC patients. Interestingly, IgG2 and IgG3 that were often investigated collectively in previous studies, were found to have distinct glycosylation patterns. IgG3 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 IgG1 and IgG3 agalactosylation show the strongest association with CA125, the routine diagnostic marker. Additionally, our results show that simultaneous analyses of IgG2 and IgG3 might lead to wrong conclusions as these two subclasses exhibit noticeably different glycosylation phenotypes

Cancer-testis antigen cyclin A1 is broadly expressed in ovarian cancer and is associated with prolonged time to tumor progression after platinum-based therapy

Background Cyclin A1 is essential for male gametopoiesis. In acute myeloid leukemia, it acts as a leukemia-associated antigen. Cyclin A1 expression has been reported in several epithelial malignancies, including testicular, endometrial, and epithelial ovarian cancer (EOC). We analyzed Cyclin A1 expression in EOC and its correlation with clinical features to evaluate Cyclin A1 as a T-cell target in EOC. Methods Cyclin A1 mRNA expression in EOC and healthy tissues was quantified by microarray analysis and quantitative real-time PCR (qRT-PCR). Protein expression in clinical samples was assessed by immunohistochemistry (IHC) and was correlated to clinical features. Results Cyclin A1 protein was homogeneously expressed in 43 of 62 grade 3 tumor samples and in 1 of 10 grade 2 specimens (p < 0.001). Survival analysis showed longer time to progression (TTP) among patients with at least moderate Cyclin A1 expression (univariate: p = 0.018, multivariate: p = 0.035). FIGO stage, grading, age, macroscopic residual tumor after debulking, and peritoneal carcinomatosis / distant metastasis had no impact on TTP or overall survival (OS). Conclusion Cyclin A1 is highly expressed in most EOCs. The mechanism behind the prolonged TTP in patients with high Cyclin A1 expression warrants further investigation. The frequent, selectively high expression of Cyclin A1 in EOC makes it a promising target for T-cell therapies

In Silico Analysis Predicts Nuclear Factors NR2F6 and YAP1 as Mesenchymal Subtype-Specific Therapeutic Targets for Ovarian Cancer Patients

Background: Tumour heterogeneity in high-grade serous ovarian cancer (HGSOC) is a proposed cause of acquired resistance to treatment and high rates of relapse. Among the four distinct molecular subtypes of HGSOC, the mesenchymal subtype (MES) has been observed with high frequency in several study cohorts. Moreover, it exhibits aggressive characteristics with poor prognosis. The failure to adequately exploit such subtypes for treatment results in high mortality rates, highlighting the need for effective targeted therapeutic strategies that follow the idea of personalized medicine (PM). Methods: As a proof-of-concept, bulk and single-cell RNA data were used to characterize the distinct composition of the tumour microenvironment (TME), as well as the cell-cell communication and its effects on downstream transcription of MES. Moreover, transcription factor activity contextualized with causal inference analysis identified novel therapeutic targets with potential causal impact on transcription factor dysregulation promoting the malignant phenotype. Findings: Fibroblast and macrophage phenotypes are of utmost importance for the complex intercellular crosstalk of MES. Specifically, tumour-associated macrophages were identified as the source of interleukin 1 beta (IL1B), a signalling molecule with significant impact on downstream transcription in tumour cells. Likewise, signalling molecules tumour necrosis factor (TNF), transforming growth factor beta (TGFB1), and C-X-C motif chemokine 12 (CXCL12) were prominent drivers of downstream gene expression associated with multiple cancer hallmarks. Furthermore, several consistently hyperactivated transcription factors were identified as potential sources for treatment opportunities. Finally, causal inference analysis identified Yes-associated protein 1 (YAP1) and Nuclear Receptor Subfamily 2 Group F Member 6 (NR2F6) as novel therapeutic targets in MES, verified in an independent dataset. Interpretation: By utilizing a sophisticated bioinformatics approach, several candidates for treatment opportunities, including YAP1 and NR2F6 were identified. These candidates represent signalling regulators within the cellular network of the MES. Hence, further studies to confirm these candidates as potential targeted therapies in PM are warranted

Prevalence of human papillomavirus detection in ovarian cancer: a meta-analysis

We conducted a meta-analysis of published data to update and estimate the prevalence of HPV in ovarian cancer. A comprehensive literature search was performed according to the PRISMA guidelines. Eligible articles published from 1989 until 2020 by searching Web of Sciences, Pubmed, Embase, and the Cochrane Library Central databases were gathered. A pooled estimation of HPV prevalence with a 95% confidence interval (CI) was calculated based on a random effect model. Quantitative assessment of heterogeneity was explored using Cochrane test and I-2. Additionally, publication bias, sensitivity, meta-regression, and subgroup analyses were also performed. Twenty-nine studies involving 2280 patients with ovarian cancer were included. The statistical heterogeneity was high (I-2 = 88%, P<0.0001). The pooled prevalence of HPV in ovarian cancer cases was 15.9% (95% CI, 11-22). In subgroup analyses, the highest prevalence of HPV was reported by studies from Asia (30.9%; 95% CI, 20-44) and Eastern Europe (29.3%; 95% CI, 4.4-78). Furthermore, the most frequently detected HPV genotype was HPV16 (54%; 95% CI, 27.9-55), followed by HPV18 (23.2%; 95% CI, 18.8-28.2). Our meta-analysis suggests a great difference in the prevalence of HPV detected in ovarian cancer by different studies, which is not seen in strongly HPV-associated cancers such as cervical cancer. However, the prevalence varied markedly by geographic region. Considering the substantial heterogeneity found, more studies with control groups and precise assays measuring HPV mRNA expression are needed to further evaluate the link and causative aetiology between HPV and ovarian cancer

Sialic Acid Linkage Analysis Refines the Diagnosis of Ovarian Cancer

Epithelial ovarian cancer (EOC) is a rather rare but lethal disease that is usually diagnosed at an advanced stage; this is due to a lack of early diagnostic markers. At the time being, less than a quarter of patients are diagnosed when the tumor has not metastasized yet. In previous work, we demonstrated that antennarity, fucosylation, and sialylation increased in EOC patients and built a glycan-based score that was able to diagnose EOC better than CA125, the routine diagnostic marker, does. To date, little attention had been paid to the sialic acid linkages of N-glycans in the context of blood biomarker research. In this work, the sialic acid linkages of the serum glycome of ovarian cancer patients were investigated for the first time by MALDI-TOF-MS. To this end, we released N-glycans, derivatized sialic acids solely in a linkage-specific way and measured glycome profiles by MALDI-TOF mass spectrometry. A statistically significant decrease was observed between late stage patients and controls or early stage patients for high-mannose, hybrid-type, complex-type asialylated, bi, tri- and tetraantennary sialylated structures. A significant decrease of monosialylated monoantennary N-glycan structures was observed in early and late stage EOC when compared to healthy controls. Statistically significant increases were observed in early and late stage patients compared to controls for tri, tetraantennary fucosylated structures, afucosylated, and fucosylated triantennary structures taken as α-2,3-linked/α-2,6-linked sialic acid ratio. Moreover, all afucosylated and fucosylated structures taken as α-2,3-linked/α-2,6-linked sialic acid ratio and the α-2,3-linked/α-2,6-linked sialic acid ratio of all sialylated structures were increased significantly for early and late stage EOC patients when compared to healthy controls. Finally, ROC curves were built for the most significant glycan combinations and we were able to show that the serum glycome sialic acid ratio could enhance ovarian cancer diagnosis as sialic acid linkage modulations arise even in early stage ovarian cancer

Green and sustainable public procurement—an instrument for nudging consumer behavior. A case study on romanian green public agriculture across different sectors of activity

Green Public Procurement (GPP) became an efficient instrument to achieve the objectives of environmental policy expressed by the European Commission in its Communications. At the same time, it must be addressed by the public authorities as a complex process, in which all purchased goods and services must integrate perfectly into an entire puzzle-like system of legislation, the construction field, innovation, healthcare, food, and education. Scientific references published in the Web of Science (WoS) mainly between 2017 and 2020 were investigated, and they analyze the implications of green public procurement in various fields, as presented by scientific communities. This article brings as a novelty in this context the identification of some barriers in the adoption of these processes, so that they can be overcome. Based on good practices and international standards and trends, the article shows how aspects related to the implementation of green procurement in society can be taken into account. In the second stage, we added a case study on Romanian green agriculture and discussions regarding inter-correlation between different fields and GPP.info:eu-repo/semantics/publishedVersio

European Network of Gynaecological Oncological Trial Groups’ requirements for trials between academic groups and industry partners – a new Model D for drug and medical device development

No abstract available

Discovery and Validation of Novel Biomarkers for Detection of Epithelial Ovarian Cancer

Detection of epithelial ovarian cancer (EOC) poses a critical medical challenge. However, novel biomarkers for diagnosis remain to be discovered. Therefore, innovative approaches are of the utmost importance for patient outcome. Here, we present a concept for blood-based biomarker discovery, investigating both epithelial and specifically stromal compartments, which have been neglected in search for novel candidates. We queried gene expression profiles of EOC including microdissected epithelium and adjacent stroma from benign and malignant tumours. Genes significantly differentially expressed within either the epithelial or the stromal compartments were retrieved. The expression of genes whose products are secreted yet absent in the blood of healthy donors were validated in tissue and blood from patients with pelvic mass by NanoString analysis. Results were confirmed by the comprehensive gene expression database, CSIOVDB (Ovarian cancer database of Cancer Science Institute Singapore). The top 25% of candidate genes were explored for their biomarker potential, and twelve were able to discriminate between benign and malignant tumours on transcript levels (p < 0.05). Among them T-cell differentiation protein myelin and lymphocyte (MAL), aurora kinase A (AURKA), stroma-derived candidates versican (VCAN), and syndecan-3 (SDC), which performed significantly better than the recently reported biomarker fibroblast growth factor 18 (FGF18) to discern malignant from benign conditions. Furthermore, elevated MAL and AURKA expression levels correlated significantly with a poor prognosis. We identified promising novel candidates and found the stroma of EOC to be a suitable compartment for biomarker discovery

High-grade ovarian serous carcinoma patients exhibit profound alterations in lipid metabolism

Ovarian cancer is a very severe type of disease with poor prognosis. Treatment of ovarian cancer is challenging because of the lack of tests for early detection and effective therapeutic targets. Thus, new biomarkers are needed for both diagnostics and better understanding of the cellular processes of the disease. Small molecules, consisting of metabolites or lipids, have shown emerging potential for ovarian cancer diagnostics. Here we performed comprehensive lipidomic profiling of serum and tumor tissue samples from high-grade serous ovarian cancer patients to find lipids that were altered due to cancer and also associated with progression of the disease. Ovarian cancer patients exhibited an overall reduction of most lipid classes in their serum as compared to a control group. Despite the overall reduction, there were also specific lipids showing elevation, and especially alterations in ceramide and triacylglycerol lipid species were dependent on their fatty acyl side chain composition. Several lipids showed progressive alterations in patients with more advanced disease and poorer overall survival, and outperformed CA-125 as prognostic markers. The abundance of many serum lipids correlated with their abundance in tumor tissue samples. Furthermore, we found a negative correlation of serum lipids with 3-hydroxybutyric acid, suggesting an association between decreased lipid levels and fatty acid oxidation. In conclusion, here we present a comprehensive analysis of lipid metabolism alterations in ovarian cancer patients, with clinical implications.Peer reviewe