Fertility-Sparing Surgery in Early Epithelial Ovarian Cancer: A Viable Option?

Epithelial ovarian cancer (EOC) continues to represent one of the most lethal conditions in women in the western countries. With the shifting of childbearing towards higher age, EOC increasingly affects women with active childbearing wish, resulting in major impacts on treatment management. Next to the optimal therapeutic treatment strategies, gynecologic oncologists are being asked to incorporate into their decision-making processes the patients' wish for fertility preserving alternatives ideally without compromising oncologic safety. Nowadays, fertility-sparing surgery represents an effective alternative to conventional radical cytoreduction in younger women with early stages of the disease. As such, this paper considers indications for fertility sparing surgery in EOC, reflects on outcomes from the oncologic and reproductive data of the largest and most relevant series outcomes data, reporting on fertility sparing techniques in EOC, reviews medicamentous efforts to prevent chemotherapy induced gonadotoxicity, and discusses future aspects in the gynecologic cancer management

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

Noncoding RNAs in Lung Cancer Angiogenesis

Lung cancer is the major death-related cancer in both men and women, due to late diagnostic and limited treatment efficacy. The angiogenic process that is responsible for the support of tumor progression and metastasis represents one of the main hallmarks of cancer. The role of VEGF signaling in angiogenesis is well‐established, and we summarize the role of semaphorins and their related receptors or hypoxia‐related factors role as prone of tumor microenvironment in angiogenic mechanisms. Newly, noncoding RNA transcripts (ncRNA) were identified to have vital functions in miscellaneous biological processes, including lung cancer angiogenesis. Therefore, due to their capacity to regulate almost all molecular pathways related with altered key genes, including those involved in angiogenesis and its microenvironment, ncRNAs can serve as diagnosis and prognosis markers or therapeutic targets. We intend to summarize the latest progress in the field of ncRNAs in lung cancer and their relation with hypoxia‐related factors and angiogenic genes, with a particular focus on ncRNAs relation to semaphorins

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

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

Prediction of clinical response to drugs in ovarian cancer using the chemotherapy resistance test (CTR-test)

Background In order to validate if the test result of the Chemotherapy Resistance Test (CTR-Test) is able to predict the resistances or sensitivities of tumors in ovarian cancer patients to drugs, the CTR-Test result and the corresponding clinical response of individual patients were correlated retrospectively. Results were compared to previous recorded correlations. Methods The CTR-Test was performed on tumor samples from 52 ovarian cancer patients for specific chemotherapeutic drugs. Patients were treated with monotherapies or drug combinations. Resistances were classified as extreme (ER), medium (MR) or slight (SR) resistance in the CTR-Test. Combination treatment resistances were transformed by a scoring system into these classifications. Results Accurate sensitivity prediction was accomplished in 79% of the cases and accurate prediction of resistance in 100% of the cases in the total data set. The data set of single agent treatment and drug combination treatment were analyzed individually. Single agent treatment lead to an accurate sensitivity in 44% of the cases and the drug combination to 95% accuracy. The detection of resistances was in both cases to 100% correct. ROC curve analysis indicates that the CTR-Test result correlates with the clinical response, at least for the combination chemotherapy. Those values are similar or better than the values from a publication from 1990. Conclusions Chemotherapy resistance testing in vitro via the CTR-Test is able to accurately detect resistances in ovarian cancer patients. These numbers confirm and even exceed results published in 1990. Better sensitivity detection might be caused by a higher percentage of drug combinations tested in 2012 compared to 1990. Our study confirms the functionality of the CTR-Test to plan an efficient chemotherapeutic treatment for ovarian cancer patients

Transfusion of red blood cells does not impact progression‐free and overall survival after surgery for ovarian cancer

BACKGROUND: Allogeneic red blood cells (RBCs) have the potential to impact the immunosurveillance of the recipient and may therefore increase the risk of recurrence after cancer surgery. In this article the relationship between perioperative RBC transfusion and the risk of recurrence after ovarian cancer surgery is examined. STUDY DESIGN AND METHODS: This is a retrospective cohort analysis of a prospective database of patients who underwent surgery due to primary ovarian cancer between 2006 and 2014 and who had no residual disease after surgery. Patients who did and did not receive perioperative RBC transfusion were compared. The primary endpoint was progression-free survival (PFS). Propensity score matching (PSM) and Cox proportional hazards regression (CPH) was used to control for between-group differences of prognostic determinants. RESULTS: A total of 529 patients with a median follow-up of 51.4 months (95% CI, 46.1-56.5) were eligible for analysis. Of those, 408 patients (77.1%) received allogeneic, leukoreduced RBCs with a median of 4 units (IQR, 2-6) per patient. There was a strong selection bias of prognostic determinants between patients with and without transfusion. In unadjusted analysis, transfusion of RBCs was associated with an increased risk of cancer recurrence (hazard ratio [HR] of PFS 2.71 [95% CI, 1.94-3.77], p < 0.001). After bias reduction, transfusion of RBCs was no longer associated with an increased risk of cancer recurrence, neither in PSM-adjusted (HR 1.03 [95% CI, 0.59-1.80], p = 0.91), nor in multivariable CPH-adjusted analysis (HR 1.26 [95% CI, 0.85-1.86], p = 0.23). CONCLUSION Perioperative transfusion of RBCs did not increase the risk of recurrence after ovarian cancer surgery

Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To- Mesenchymal-Transition and Tumor Cell Migration

Background: Ovarian cancer (OvCa) is a highly aggressive malignoma with a tumor-promoting microenvironment. Infiltration of polymorphonuclear neutrophils (PMN) is frequently seen, raising the question of their impact on tumor development. In that context, effects of PMN on human ovarian cancer cells were assessed. Methods: Human epithelial ovarian cancer cells were incubated with human PMN, lysate of PMN, or neutrophil elastase. Morphological alterations were observed by time-lapse video-microscopy, and the underlying molecular mechanism was analyzed by flow cytometry and Western blotting. Functional alternations were assessed by an in vitro wound healing assay. In parallel, a large cohort of n=334 primary OvCa tissue samples of various histological subtypes was histologically evaluated. Results: Co-cultivation of cancer cells with either PMN or PMN lysate causes a change of the polygonal epithelial phenotype of the cells towards a spindle shaped morphology, causing a cribriform cell growth. The PMN-induced alteration could be attributed to elastase, a major protease of PMN. Elastase-induced shape change was most likely due to the degradation of membranous E-cadherin, which results in loss of cell contacts and polarity. Moreover, in response to elastase, epithelial cytokeratins were downmodulated, in parallel with a nuclear translocation of β-catenin. These PMN-elastase induced alterations of cells are compatible with an epithelial-to-mesenchymal transition (EMT) of the cancer cells. Following EMT, the cells displayed a more migratory phenotype. In human biopsies, neutrophil infiltration was seen in 72% of the cases. PMN infiltrates were detected preferentially in areas with low E-cadherin expression. Conclusion: PMN in the microenvironment of OvCa can alter tumor cells towards a mesenchymal and migratory phenotype

The Relationships Between Biological Activities and Structure of Flavan-3-Ols

Flavan-3-ols are involved in multiple metabolic pathways that induce inhibition of cell proliferation. We studied the structure-activity relationship of gallic acid (GA) and four flavan-3-ols: epigallocatechin gallate (EGCG), epigallocatechin (EGC), catechin (C), and epicatechin (EC). We measured the cell viability by the MTT assay and we determined the concentration of testing compound required to reduce cell viability by 50% (IC50). All tested compounds showed a dose-dependent and time-dependent inhibitory antiproliferative effect on Hs578T cells; IC50 values varying from the 15.81 to 326.8 μM. Intracellular ROS (reactive oxygen species) were quantified using a fluorescent probe 2′,7′-dichlorofluorescin diacetate (DCFH-DA). Only the treatment with 10 μM EGC and EGCG was able to induce a significant decrease of ROS concentration and increased levels of ROS were registered for 100 μM EGCG, EGC and GA. Flavans-3-ols and GA induced apoptosis in a dose- and time-dependent manner, which indicated that the induction of apoptosis mediated their cytotoxic activity at least partially. The galloylated catechins have shown a stronger antiproliferative activity and apoptotic effect than the one produced by non galloylated catechins. The galloylated flavan-3-ols are potential therapeutic agents for patients with triple negative breast cancer via induction of apoptosis