Publications by authors named "Jalid Sehouli"

505 Publications

HE4 as a serum biomarker for the diagnosis of pelvic masses: a prospective, multicenter study in 965 patients.

BMC Cancer 2022 Jul 30;22(1):831. Epub 2022 Jul 30.

Department of Gynecology with Center of Oncological Surgery, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.

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.
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http://dx.doi.org/10.1186/s12885-022-09887-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338568PMC
July 2022

Survey on implementation of molecular testing in ovarian cancer and PARP inhibitor: a national North-Eastern German Society of Gynecologic Oncology/Young Academy of Gynecologic Oncology/Arbeitsgemeinschaft Gynäkologische Onkologie intergroup analysis.

Int J Gynecol Cancer 2022 Jul 27. Epub 2022 Jul 27.

Young Academy of Gynecologic Oncology (JAGO), Berlin, Germany.

Background: Since the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors, BRCA testing has evolved as a standard management in epithelial ovarian cancer.

Objective: To analyze the implementation of molecular testing and PARP inhibitor therapy in Germany.

Methods: The questionnaire contained 40 questions covering real-life data on genetic testing and the use of PARP inhibitors. It was divided into three main parts: basic demographics of respondents, genetic counseling and testing, and treatment with PARP inhibitors. The questionnaire was distributed via mail between August 2020 and May 2021.

Results: A total of 315 physicians participated in the survey, of whom 54.9% were specialized in the field of gynecologic oncology. Two-thirds of respondents (67.4%) stated that they tested more than 80% of patients with primary epithelial ovarian cancer for BRCA mutation; however, only 42.5% of gynecologists who performed genetic counseling had an additional qualification in subject-specific genetic counseling, which is mandatory for predictive genetic testing in Germany. The main reasons for failure of BRCA testing were patient refusal (54.6%) and organizational or logistical issues (31.7%). Only 13.7% of respondents felt sufficiently equipped with supportive information material on patient counseling, whereas a high need for information material was indicated by 86.3% of the respondents. Molecular tumor profiling to infer homologous recombination (HR) deficiency status was provided by only 53.3% of institutions. PARP inhibitors were applied on a regular basis by 62.1% of respondents. The most important criteria for selection of appropriate PARP inhibitor therapy were the side effect profile (78.2%) and efficacy (71.2%). The majority of respondents (66.5%) preferred a combination of olaparib and bevacizumab over PARP inhibitors alone in the frontline setting.

Conclusion: Adequate structure for BRCA/HR deficiency testing, and systematic education programs are needed to prevent delay in counseling and undertreatment of women with epithelial ovarian cancer. In Germany, a combination of olaparib and bevacizumab seems to be the preferred treatment in the first-line setting.
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http://dx.doi.org/10.1136/ijgc-2022-003637DOI Listing
July 2022

Influence of appropriate emergency department utilization and verbal communication on physicians' (dis)satisfaction with doctor-patient interactions with special consideration of migrational backgrounds.

Wien Med Wochenschr 2022 Jul 18. Epub 2022 Jul 18.

Campus Virchow Clinic, Clinic for Gynecology with Center for Oncological Surgery, Charité University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

In recent years, utilization of emergency departments (EDs) has increased continuously, both in Germany and internationally. Inappropriate use of EDs is believed to be partly responsible for this trend. The topic of doctor-patient interaction (DPI) has received little attention in research. However, successful DPI is not only important for adherence and treatment success, but also for the satisfaction of medical staff. This non-interventionl cross-sectional study attempts to identify factors influencing physicians' satisfaction with DPIs, with a particular focus on the appropriate utilization of EDs and verbal communication. We carried out tripartite data collection in three EDs of major referral hospitals in Berlin between July 2017 and July 2018. Migration experience, communication and language problems, level of education, and a large gap between physicians' and patients' perceived urgency regarding the utilization of EDs influence the quality of the doctor-patient relationships and interactions.
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http://dx.doi.org/10.1007/s10354-022-00948-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294758PMC
July 2022

Myths and fake messages about human papillomavirus (HPV) vaccination: answers from the ESGO Prevention Committee.

Int J Gynecol Cancer 2022 Jul 12. Epub 2022 Jul 12.

Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.

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http://dx.doi.org/10.1136/ijgc-2022-003685DOI Listing
July 2022

Chronic Pelvic Pain in Endometriosis: Cross-Sectional Associations with Mental Disorders, Sexual Dysfunctions and Childhood Maltreatment.

J Clin Med 2022 Jun 27;11(13). Epub 2022 Jun 27.

Endometriosis Centre Charité, Department of Gynaecology with Center for Oncological Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

The aim of this cross-sectional study was to compare the rates of mental disorders, sexual dysfunctions and childhood maltreatment (CM) in women with endometriosis with either chronic pelvic pain (CPP) or minimal to no pelvic pain. Additionally, two models to predict a current mental disorder were tested, including pelvic-pain-related or psychosocial predictor variables. We examined 100 women with confirmed endometriosis (group CPP, = 50; group NOPAIN, = 50). Participants responded to a comprehensive questionnaire and the Childhood Trauma Questionnaire. The Diagnostic Interview for Mental Disorders was used to assess mental disorders according to DSM-5 and to screen for sexual dysfunctions. The mean age was 28.8 ± 5.6 (CPP)/2.7 ± 6.3 (NOPAIN). Participants with CPP had higher rates of current mental disorders ( = 0.019), lifetime mental disorders ( = 0.006) and sexual dysfunctions ( < 0.001), but not CM ( = 0.074). In two binary-logistic regression analyses, a greater need for pain relief (aOR = 4.08, = 0.026) and a sexual dysfunction (aOR = 2.69, = 0.031) were significant predictors for a current mental disorder. Our findings confirmed the crucial role of pelvic pain for mental and sexual well-being in endometriosis. They highlight the need for pain relief and interdisciplinary care in the treatment of endometriosis.
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http://dx.doi.org/10.3390/jcm11133714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267229PMC
June 2022

Outcomes of gynecologic cancer surgery during the COVID-19 pandemic: an international, multicenter, prospective CovidSurg-Gynecologic Oncology Cancer study.

Am J Obstet Gynecol 2022 Jun 30. Epub 2022 Jun 30.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom. Electronic address:

Background: The CovidSurg-Cancer Consortium aimed to explore the impact of COVID-19 in surgical patients and services for solid cancers at the start of the pandemic. The CovidSurg-Gynecologic Oncology Cancer subgroup was particularly concerned about the magnitude of adverse outcomes caused by the disrupted surgical gynecologic cancer care during the COVID-19 pandemic, which are currently unclear.

Objective: This study aimed to evaluate the changes in care and short-term outcomes of surgical patients with gynecologic cancers during the COVID-19 pandemic. We hypothesized that the COVID-19 pandemic had led to a delay in surgical cancer care, especially in patients who required more extensive surgery, and such delay had an impact on cancer outcomes.

Study Design: This was a multicenter, international, prospective cohort study. Consecutive patients with gynecologic cancers who were initially planned for nonpalliative surgery, were recruited from the date of first COVID-19-related admission in each participating center for 3 months. The follow-up period was 3 months from the time of the multidisciplinary tumor board decision to operate. The primary outcome of this analysis is the incidence of pandemic-related changes in care. The secondary outcomes included 30-day perioperative mortality and morbidity and a composite outcome of unresectable disease or disease progression, emergency surgery, and death.

Results: We included 3973 patients (3784 operated and 189 nonoperated) from 227 centers in 52 countries and 7 world regions who were initially planned to have cancer surgery. In 20.7% (823/3973) of the patients, the standard of care was adjusted. A significant delay (>8 weeks) was observed in 11.2% (424/3784) of patients, particularly in those with ovarian cancer (213/1355; 15.7%; P<.0001). This delay was associated with a composite of adverse outcomes, including disease progression and death (95/424; 22.4% vs 601/3360; 17.9%; P=.024) compared with those who had operations within 8 weeks of tumor board decisions. One in 13 (189/2430; 7.9%) did not receive their planned operations, in whom 1 in 20 (5/189; 2.7%) died and 1 in 5 (34/189; 18%) experienced disease progression or death within 3 months of multidisciplinary team board decision for surgery. Only 22 of the 3778 surgical patients (0.6%) acquired perioperative SARS-CoV-2 infections; they had a longer postoperative stay (median 8.5 vs 4 days; P<.0001), higher predefined surgical morbidity (14/22; 63.6% vs 717/3762; 19.1%; P<.0001) and mortality (4/22; 18.2% vs 26/3762; 0.7%; P<.0001) rates than the uninfected cohort.

Conclusion: One in 5 surgical patients with gynecologic cancer worldwide experienced management modifications during the COVID-19 pandemic. Significant adverse outcomes were observed in those with delayed or cancelled operations, and coordinated mitigating strategies are urgently needed.
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http://dx.doi.org/10.1016/j.ajog.2022.06.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9242690PMC
June 2022

Prognostic value of regulatory T cells and T helper 17 cells in high grade serous ovarian carcinoma.

J Cancer Res Clin Oncol 2022 Jun 28. Epub 2022 Jun 28.

Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany.

Purpose: In recent years the tumor microenvironment and its interaction with the tumor has emerged into research focus with increased attention to the composition of Tumor-infiltrating lymphocytes. We wanted to quantify the composition of Regulatory T cells (Tregs) and T helper 17 cells (Th17 cells) and their prognostic impact in high-grade serous tubo-ovarian carcinoma.

Methods: Tregs and Th17 cells were determined by immunohistochemical analysis of CD25 FoxP3 and RORγt, respectively on tissue microarrays of a cohort of 222 patients with reviewed histology and available clinical data. Expression was analyzed with Qupath for quantification and integration with clinical data enabled calculation of prognostic impact. For validation FOXP3 and RORC mRNA expression levels from 502 patients with HGSC in publicly available datasets were evaluated.

Results: An average percentage of 0.93 Tregs and of 0.06 Th17 cells was detected per cells in overall tissue. Optimal cut-offs were determined and higher Tregs were associated with a better overall survival in stroma (p = 0.006), tumor area (p = 0.0012) and overall tissue (p = 0.02). After accounting for well-known prognostic factors age at diagnosis, residual tumor and FIGO stage, this association remained significant for stromal Tregs with overall survival (p = 0.02). Survival analysis for Th17 cells revealed no significant association with survival rates. Moreover, lower Th17/Treg ratios had a positive impact on patient overall survival (p = 0.025 tumor, p = 0.049 stroma and p = 0.016 overall tissue).

Conclusion: Our results outline a positive prognostic effect for higher Tregs but not for Th17 in high grade serous tubo-ovarian carcinoma.
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http://dx.doi.org/10.1007/s00432-022-04101-2DOI Listing
June 2022

A Promising Approach for Primary Cytoreductive Surgery for Advanced Ovarian Cancer: Survival Outcomes and Step-by-Step Description of Total Retroperitoneal en-Bloc Resection of Multivisceral-Peritoneal Packet (TROMP).

J Pers Med 2022 May 29;12(6). Epub 2022 May 29.

Department of Gynecology with Center for Oncological Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Virchow Campus Clinic, Charité Medical University, 13353 Berlin, Germany.

(1) Background: A complete tumor resection during primary cytoreductive surgery has been reported to be the most important and perhaps the only independent prognostic factor in advanced ovarian cancers. The goal of complete cytoreduction needs to be weighed against the potential morbidities and long-term survival outcomes. (2) Methods: in this retrospective analysis of a prospectively obtained database, 208 consecutive patients with advanced ovarian cancer who underwent a conventional primary cytoreductive surgery (150 patients) or TROMP technique (58 patients) were included. Progression-free and overall survival rates were calculated using Kaplan-Meier analysis as well as the 95% confidence interval of the hazard ratio between treatment groups. (3) Results: After a median follow-up phase of more than 3 years (range 1-72 months), there are no statistically significant differences between both groups in progression-free and overall survival rates. Albeit, the TROMP group included statistically significant more advanced-stage cases compared to the conventional surgery group. (4) Conclusions: the TROMP technique is a promising tool for successful primary cytoreductive surgery in a selected group of patients with high tumor burdens in order to achieve optimal surgical results and survival outcomes without introducing any additional risks or complications.
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http://dx.doi.org/10.3390/jpm12060899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225245PMC
May 2022

Predictive biomarker for surgical outcome in patients with advanced primary high-grade serous ovarian cancer. Are we there yet? An analysis of the prospective biobank for ovarian cancer.

Gynecol Oncol 2022 Aug 21;166(2):334-343. Epub 2022 Jun 21.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Gynecology, Augustenburger Platz 1, 13353 Berlin, Germany; Tumor Bank Ovarian Cancer, ENGOT Biobank, Charité Medizinische Universität Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Obstetrics and Gynaecology, Division of Gynaecologic Oncology, Stanford University School of Medicine, Stanford, CA, USA.

Background: High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer and is associated with high mortality rates. Surgical outcome is one of the most important prognostic factors. There are no valid biomarkers to identify which patients may benefit from a primary debulking approach.

Objective: Our study aimed to discover and validate a predictive panel for surgical outcome of residual tumor mass after first-line debulking surgery.

Study Design: Firstly, "In silico" analysis of publicly available datasets identified 200 genes as predictors for surgical outcome. The top selected genes were then validated using the novel Nanostring method, which was applied for the first time for this particular research objective. 225 primary ovarian cancer patients with well annotated clinical data and a complete debulking rate of 60% were compiled for a clinical cohort. The 14 best rated genes were then validated through the cohort, using immunohistochemistry testing. Lastly, we used our biomarker expression data to predict the presence of miliary carcinomatosis patterns.

Results: The Nanostring analysis identified 37 genes differentially expressed between optimal and suboptimal debulked patients (p < 0.05). The immunohistochemistry validated the top 14 genes, reaching an AUC Ø0.650. The analysis for the prediction of miliary carcinomatosis patterns reached an AUC of Ø0.797.

Conclusion: The tissue-based biomarkers in our analysis could not reliably predict post-operative residual tumor. Patient and non-patient-associated co-factors, surgical skills, and center experience remain the main determining factors when considering the surgical outcome at primary debulking in high-grade serous ovarian cancer patients.
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http://dx.doi.org/10.1016/j.ygyno.2022.06.010DOI Listing
August 2022

Measure of Ovarian Symptoms and Treatment concerns (MOST) indexes and their associations with health-related quality of life in recurrent ovarian cancer.

Gynecol Oncol 2022 Aug 17;166(2):254-262. Epub 2022 Jun 17.

University of Sydney, Faculty of Science, School of Psychology, Australia.

Purpose: The Measure of Ovarian Symptoms and Treatment (MOST) concerns is a validated patient-reported symptom assessment tool for assessing symptom benefit and adverse effects of palliative chemotherapy in women with recurrent ovarian cancer (ROC). We aimed to examine (i) how symptoms within MOST symptom indexes track together (i.e. co-occur) and (ii) the association between MOST symptom indexes and key aspects of health-related quality of life (HRQL).

Method: A prospective cohort of women with ROC completed the MOST-T35, EORTC QLQ-C30 and EORTC QLQ-OV28 at baseline and before each cycle of chemotherapy. Analyses were conducted on baseline and end-of-treatment data. Exploratory factor analysis and hierarchical cluster analysis identified groups of co-occurring symptoms. Path models examined associations between MOST symptom indexes and HRQL.

Results: Data from 762 women at baseline and 681 at treatment-end who completed all 22 symptom-specific MOST items and at least one HRQL measure were analysed. Four symptom clusters emerged at baseline and treatment-end: abdominal symptoms, symptoms associated with peripheral neuropathy, nausea and vomiting, and psychological symptoms. Psychological symptoms (MOST-Psych) and symptoms due to disease (ovarian cancer) or treatment (MOST-DorT) were associated with poorer scores on QLQ-C30 and OV28 functioning domains and worse overall health at both time points.

Conclusion: Four MOST symptom clusters were consistent across statistical methods and time points. These findings suggest that routine standardized assessment of psychological and physical symptoms in clinical practice with MOST plus appropriate symptom management referral pathways is an intervention for improving HRQL that warrants further research.
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http://dx.doi.org/10.1016/j.ygyno.2022.05.024DOI Listing
August 2022

Blockade of ALDH in Cisplatin-Resistant Ovarian Cancer Stem Cells In Vitro Synergistically Enhances Chemotherapy-Induced Cell Death.

Curr Oncol 2022 04 16;29(4):2808-2822. Epub 2022 Apr 16.

Department of Gynecology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-related death. The high mortality and morbidity associated with EOC are mostly due to late diagnosis and chemotherapy drug resistance. Currently, the standard first-line chemotherapy regimen is systemic administration of platinum-based chemotherapy combined with a taxane. A major problem besides cisplatin resistance (occurring in nearly one-third of patients) is the greater toxicity of the drug combinations. A synergistic treatment with drug supporting activity could maximize the cytotoxic effects of chemotherapeutic agents on tumor cells while decreasing the dosage of each drug to potentially reduce toxicity. The ALDH-blocking agent Disulfiram (DSF), a clinically approved drug used for alcoholism treatment, has displayed promising anti-cancer activity. We previously described that blocking ALDH activity enhances the induction of apoptosis, especially in ovarian cancer stem cells treated with chemotherapeutic agents. In this study, we further investigated the synergistic effect of DSF in combination with cytotoxic chemotherapeutic drugs. The concentration of each chemotherapeutic agent could be significantly reduced with sustained efficacy on tumor cell apoptosis in cell lines in vitro (Dose-Reduction Index at IC from 1 to 50). Moreover, the potential chemo-sensitizing effects of DSF on ALDH-associated cisplatin-resistant ovarian cancer stem cells were also investigated and shown that in contrast to its high resistance to cisplatin, the cisplatin-resistant cells remain very sensitive to DSF-induced cytotoxicity (apoptosis and necrosis: cisplatin-resistant cells vs. parental cells: 60.4% vs. 20.5%). In combination with DSF and cisplatin, relatively more apoptosis and necrosis were induced in cisplatin-resistant cells than in their parental cells (apoptosis and necrosis: cisplatin-resistant cells vs. parental cells: 81.5% vs. 50.1%). A transcriptome analysis identified that ALDH was mainly enriched in the cancer-associated fibroblasts and showed that ALDH plays roles in responding to oxidative stress, metabolisms, and energy transition in the ALDH-associated cisplatin-resistant ovarian cancer stem cells. In conclusion, our data demonstrate a key role of ALDH-associated cisplatin-resistant cancer stem cells and identifies DSF as a potential adjuvant for a rational protocol design by computational quantitative assessment in vitro on ovarian cancer cell lines. Our work contributes to resolving the ALDH-associated cisplatin resistance and provides a resource for the development of novel chemotherapeutic regimens.
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http://dx.doi.org/10.3390/curroncol29040229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031660PMC
April 2022

Biomarker-Based Models for Preoperative Assessment of Adnexal Mass: A Multicenter Validation Study.

Cancers (Basel) 2022 Mar 31;14(7). Epub 2022 Mar 31.

Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria.

Ovarian cancer (OC) is the most lethal genital malignancy in women. We aimed to develop and validate new proteomic-based models for non-invasive diagnosis of OC. We also compared them to the modified Risk of Ovarian Malignancy Algorithm (ROMA-50), the Copenhagen Index (CPH-I) and our earlier Proteomic Model 2017. Biomarkers were assessed using bead-based multiplex technology (Luminex) in 356 women (250 with malignant and 106 with benign ovarian tumors) from five European centers. The training cohort included 279 women from three centers, and the validation cohort 77 women from two other centers. Of six previously studied serum proteins (CA125, HE4, osteopontin [OPN], prolactin, leptin, and macrophage migration inhibitory factor [MIF]), four contributed significantly to the Proteomic Model 2021 (CA125, OPN, prolactin, MIF), while leptin and HE4 were omitted by the algorithm. The Proteomic Model 2021 revealed a c-index of 0.98 (95% CI 0.96, 0.99) in the training cohort; however, in the validation cohort it only achieved a c-index of 0.82 (95% CI 0.72, 0.91). Adding patient age to the Proteomic Model 2021 constituted the Combined Model 2021, with a c-index of 0.99 (95% CI 0.97, 1) in the training cohort and a c-index of 0.86 (95% CI 0.78, 0.95) in the validation cohort. The Full Combined Model 2021 (all six proteins with age) yielded a c-index of 0.98 (95% CI 0.97, 0.99) in the training cohort and a c-index of 0.89 (95% CI 0.81, 0.97) in the validation cohort. The validation of our previous Proteomic Model 2017, as well as the ROMA-50 and CPH-I revealed a c-index of 0.9 (95% CI 0.82, 0.97), 0.54 (95% CI 0.38, 0.69) and 0.92 (95% CI 0.85, 0.98), respectively. In postmenopausal women, the three newly developed models all achieved a specificity of 1.00, a positive predictive value (PPV) of 1.00, and a sensitivity of >0.9. Performance in women under 50 years of age (c-index below 0.6) or with normal CA125 (c-index close to 0.5) was poor. CA125 and OPN had the best discriminating power as single markers. In summary, the CPH-I, the two combined 2021 Models, and the Proteomic Model 2017 showed satisfactory diagnostic accuracies, with no clear superiority of either model. Notably, although combining values of only four proteins with age, the Combined Model 2021 performed comparably to the Full Combined Model 2021. The models confirmed their exceptional diagnostic performance in women aged ≥50. All models outperformed the ROMA-50.
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http://dx.doi.org/10.3390/cancers14071780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997061PMC
March 2022

Reconstructive Surgery versus Primary Closure following Vulvar Cancer Excision: A Wide Single-Center Experience.

Cancers (Basel) 2022 Mar 26;14(7). Epub 2022 Mar 26.

Department of Gynecology with Center for Oncological Surgery, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Virchow Campus Clinic, Charité Medical University, 13353 Berlin, Germany.

(1) Background: plastic reconstruction in vulvar surgery can lead to a better treatment outcome than primary closure. This study aims to compare the preoperative parameters (co-morbidities and tumor size) and postoperative results (tumor free margins and wound healing) between the primary closure and reconstructive surgery after vulvar cancer surgery; (2) Methods: this is a retrospective analysis of prospectively collected data from 2009 to 2021 at a tertiary cancer institution; (3) Results: 177 patients were included in the final analysis (51 patients had primary closure PC and 126 had reconstructive surgery RS). About half (49%) of the PC patients had no co-morbidities ( = 0.043). The RS group had a 45 mm median maximal tumor diameter compared to the PC group's 23 mm ( = 0.013). More than 90% of RS and 80% of PC had tumor-free margins ( = 0.1). Both groups had anterior vulvar excision as the most common surgery (52.4% RS vs. 23.5% PC; = 0.001). Both groups had identical rates of wound healing disorders. In a median follow-up of 39 months; recurrent disease was found in 23.5% of PC vs. 10.3% in RS ( = 0.012). In terms of overall survival there was no significant difference between the both groups; (4) Conclusions: reconstructive vulvar surgery enables enhanced complete resection rates of larger vulvar tumors with better anatomical restoration and a comparable wound recovery in comparison to primary closure. This results in a lower recurrence rate despite the increased tumor volume.
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http://dx.doi.org/10.3390/cancers14071695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997096PMC
March 2022

Ten years of live surgical broadcast at Charité-MAYO conferences (2010-2019): a systematic evaluation of the surgical outcome.

Int J Gynecol Cancer 2022 06 6;32(6):746-752. Epub 2022 Jun 6.

Department of Gynecology with Center of Oncological Surgery, Charité Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany.

Objective: The international Charité-MAYO Conference aims to promote international dialog on diagnostics, management, scientific breakthroughs, and state-of-the-art surgical procedures in gynecology and gynecologic oncology and senology. Live surgeries are a fundamental tool of interdisciplinary and international exchange of experts in their respective fields. Currently, there is a controversial and emotional debate about the true value, risks, and safety of live surgical broadcasts. The aim of the current study is to analyze peri-operative risks in patients who were operated live during the Charité-MAYO Conferences.

Methods: Live surgeries were performed by the core Charité team consisting of gynecologic oncologic surgeons, breast and plastic surgeons, partly in collaboration with visiting gynecologic oncologic surgeons. We performed a retrospective analysis of live surgeries performed during seven Charité-MAYO Conferences from 2010 to 2019 held in Berlin, Germany. Patients' files and tumor databases were analyzed as required and patients were contacted to update their long-term follow-up.

Results: Sixty-nine patients who were operated live were included. The types of surgery were as follows: urogynecologic procedures (n=13), breast surgery (n=21), and gynecologic oncology surgery for ovarian, uterine, vulvar or cervical cancer (n=35). Peri-operative complications were assessed according to the Clavien-Dindo classification. Despite a high rate of complete resection and the high frequency of multivisceral procedures, the rate of peri-operative complications was within the range published in the literature. Time of surgery and length of intensive unit care and hospital stay did not differ from data acquired at the home institution.

Conclusions: Based on our analysis, live surgeries appear to be safe when performed within a multidisciplinary setting without an increase in surgical morbidity and mortality compared with historical controls and without compromise of patients' outcome. This is the first analysis of its kind to set the basis for patient information and consent for this type of surgeries.
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http://dx.doi.org/10.1136/ijgc-2021-003173DOI Listing
June 2022

Genotype-specific high-risk human papillomavirus infections and risk factors for cervical dysplasia in women with human immunodeficiency virus in Germany: results from a single-center cross-sectional study.

Int J Gynecol Cancer 2022 06 6;32(6):716-723. Epub 2022 Jun 6.

Department of Gynecology with Center for Oncological Surgery, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

Objective: Women living with HIV have an increased risk of human papillomavirus (HPV) infection and cervical cancer. Little is known about genotype-specific HPV prevalence, the impact of antiretroviral therapy, immunological status, and additional risk factors in women living with HIV in Germany. The goal of this study was to characterize the risk profile for cervical dysplasia in these women.

Methods: Patients with HIV infection presenting at Charité-Universitätsmedizin Berlin from October 2017 to September 2020 were included and underwent gynecological examination, colposcopy, cervical cytology and HPV genotype testing. HPV genotypes were stratified by carcinogenicity. Atypical squamous cells of undetermined significance or higher were considered abnormal cytology. Data were analyzed by SPSS software (version 26, 2019). A two-tailed p-value ≤0.05 was considered statistically significant.

Results: A total of 84 women were evaluated. The majority (95.2%) received antiretroviral therapy. Median CD4 cell count was 564 cells/µl (range 20-1969). 95.2% were previously screened for cervical cancer. High-risk HPV prevalence was 44%. High-high-risk HPV subtypes (16, 18, 31, 33, 45, 52, 58) were significantly associated with abnormal cytology (p<0.001). HPV16 was the most common genotype (23%), was significantly associated with abnormal cytology (p=0.002) and was the main risk factor for abnormal cytology (OR 8.55, 95% CI 2.15 to 34.13, p=0.002), followed by age <35 years (OR 4.96, 95% CI 1.23 to 19.61, p=0.033) and cigarette smoking (OR 3.944, 95% CI 0.98 to 15.88, p=0.053).

Conclusions: Antiretroviral therapy and adherence to cervical cancer screening was high. High-high-risk HPV, especially HPV16, coincided with high incidence of cytological abnormalities. Women living with HIV in Germany have adequate immune status and are often pre-screened for cervical cancer, and therefore have a different risk profile for cervical dysplasia than in low-income or medium-income countries. Adapted screening programs should be defined.
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http://dx.doi.org/10.1136/ijgc-2021-003327DOI Listing
June 2022

Polycomb Protein BMI-1 as a Potential Therapeutic Target in Mucinous Ovarian Cancer.

Anticancer Res 2022 04;42(4):1739-1747

Tumorbank Ovarian Cancer Network, Charité Universitätsmedizin Berlin, Corporate Μember of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background/aim: Mucinous ovarian carcinoma (mOC) is a rare subtype with distinct clinical characteristics and biological behavior that differentiate them from other epithelial ovarian cancers. This study aimed to evaluate BMI-1 expression as a potential target for therapeutic approaches in advanced stage mOC.

Materials And Methods: We performed gene set, as well as transcription factor enrichment analysis and immunohistochemistry assessing of the BMI-1 protein levels in tissue specimens of eighteen mucinous ovarian cancer patients. To validate the clinical relevance of the findings, we performed cell viability assays and western blot analysis utilizing high-grade serous (HGSC) and mOC cell lines.

Results: BMI1 expression was not significantly associated with patient age, FIGO stage, lymph node status, and family history. With regard to progression-free survival, there was also no significant association (p=0.418). Cell viability was significant decreased in response to carboplatin in HGSC cells TYK-nu and OVHASO, and in mOC cell lines COV644 and EFO-27. Western blot analysis demonstrated various expression levels across all cell lines.

Conclusion: BMI-1 could be a useful potential therapeutic target in some ovarian cancer patients, including mOC patients.
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http://dx.doi.org/10.21873/anticanres.15650DOI Listing
April 2022

Clinical value of pre-operative scoring systems to predict leiomyosarcoma: results of a validation study in 177 patients from the NOGGO-REGSA Registry.

Int J Gynecol Cancer 2022 05 3;32(5):619-625. Epub 2022 May 3.

Department of Gynecology with Center for Oncological Surgery, Charite University Hospital Berlin, Berlin, Germany.

Objectives: Benign leiomyomas are the most common uterine tumors. In contrast, uterine leiomyosarcomas are malignancies with a poor prognosis due to difficulties in early diagnosis and inappropriate surgical treatment. Most often they are diagnosed incidentally after surgery performed for treatment of leiomyoma. As the appropriate surgical treatment is crucial for survival of the patient, there is a high demand to predict leiomyosarcoma pre-operatively. Available scoring systems to discriminate leiomyoma from leiomyosarcoma are based on retrospective studies with limited numbers of patients and are not implemented in routine clinical practice.

Methods: The aim of our study was to evaluate a recently published score-the pre-operative leiomyosarcoma (pLMS) score-to determine whether it would have been predictive of leiomyosarcoma in 177 patients from the NOGGO-REGSA study, a German register of histologically proven gynecological sarcoma detected during routine clinical investigation.

Results: The threshold of the pLMS score for 'leiomyosarcoma not probable' (< -3) failed for 7.5% of the patients and the threshold 'indicator for leiomyosarcoma' (>+1) was true for 39.1% of the patients. 53.4% of the patients were attributed to the group 'additional investigations are recommended' (-3 to +1). The most relevant parameters in our analysis were suspicious sonography and rapid growth, but neither have been quantitatively defined.

Conclusion: In our validation cohort, the pLMS score seems not to be a reliable tool to predict leiomyosarcoma and therefore we do not recommend its clinical implementation to identify leiomyosarcoma.
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http://dx.doi.org/10.1136/ijgc-2021-003334DOI Listing
May 2022

Genomic Instability Is Defined by Specific Tumor Microenvironment in Ovarian Cancer: A Subgroup Analysis of AGO OVAR 12 Trial.

Cancers (Basel) 2022 Feb 25;14(5). Epub 2022 Feb 25.

AGO & Evangelische Kliniken Essen Mitte (KEM), 45136 Essen, Germany.

Background: Following disappointing results with PD-1/PD-L1 inhibitors in ovarian cancer, it is essential to explore other immune targets. The aim of this study is to describe the tumor immune microenvironment (TME) according to genomic instability in high grade serous ovarian carcinoma (HGSOC) patients receiving primary debulking surgery followed by carboplatin-paclitaxel chemotherapy +/- nintedanib.

Methods: 103 HGSOC patients' tumor samples from phase III AGO-OVAR-12 were analyzed. A comprehensive analysis of the TME was performed by immunohistochemistry on tissue microarray. Comparative genomic hybridization was carried out to evaluate genomic instability signatures through homologous recombination deficiency (HRD) score, genomic index, and somatic copy number alterations. The relationship between genomic instability and TME was explored.

Results: Patients with high intratumoral CD3 T lymphocytes had longer progression-free survival (32 vs. 19.6 months, = 0.009) and overall survival (OS) (median not reached). High HLA-E expression on tumor cells was associated with a longer OS (median OS not reached vs. 52.9 months, = 0.002). HRD profile was associated with high HLA-E expression on tumor cells and an improved OS. In the multivariate analysis, residual tumor, intratumoral CD3, and HLA-E on tumor cells were more predictive than other parameters.

Conclusions: Our results suggest HLA-E/CD94-NKG2A/2C is a potential immune target particularly in the HRD positive ovarian carcinoma subgroup.
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http://dx.doi.org/10.3390/cancers14051189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909387PMC
February 2022

In Situ -Glycosylation Signatures of Epithelial Ovarian Cancer Tissue as Defined by MALDI Mass Spectrometry Imaging.

Cancers (Basel) 2022 Feb 17;14(4). Epub 2022 Feb 17.

BIH Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.

The particularly high mortality of epithelial ovarian cancer (EOC) is in part linked to limited understanding of its molecular signatures. Although there are data available on in situ -glycosylation in EOC tissue, previous studies focused primarily on neutral -glycan species and, hence, still little is known regarding EOC tissue-specific sialylation. In this proof-of-concept study, we implemented MALDI mass spectrometry imaging (MALDI-MSI) in combination with sialic acid derivatization to simultaneously investigate neutral and sialylated -glycans in formalin-fixed paraffin-embedded tissue microarray specimens of less common EOC histotypes and non-malignant borderline ovarian tumor (BOT). The applied protocol allowed detecting over 50 species, many of which showed differential tissue distribution. Most importantly, it could be demonstrated that α2,6- and α2,3-sialylated -glycans are enriched in tissue regions corresponding to tumor and adjacent tumor-stroma, respectively. Interestingly, analogous -glycosylation patterns were observed in tissue cores of BOT, suggesting that regio-specific -glycan distribution might occur already in non-malignant ovarian pathologies. All in all, our data provide proof that the combination of MALDI-MSI and sialic acid derivatization is suitable for delineating regio-specific -glycan distribution in EOC and BOT tissues and might serve as a promising strategy for future glycosylation-based biomarker discovery studies.
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http://dx.doi.org/10.3390/cancers14041021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870006PMC
February 2022

Neurofilament proteins as a potential biomarker in chemotherapy-induced polyneuropathy.

JCI Insight 2022 03 22;7(6). Epub 2022 Mar 22.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Klinik und Hochschulambulanz für Neurologie, Berlin, Germany.

BACKGROUNDPaclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. Given that sensory symptoms are challenging to assess objectively in clinical practice, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as a translational surrogate marker for CIPN.METHODSNFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell-derived sensory neurons (iPSC-DSNs) to paclitaxel. Patients with breast or ovarian cancer undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy, and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced (TNSr), which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFLs) concentrations were measured at both visits with single-molecule array technology.RESULTSNFL was released from iPSC-DSNs upon paclitaxel incubation in a dose- and time-dependent manner and was inversely correlated with iPSC-DSN viability. NFLs strongly increased in paclitaxel-treated patients with CIPN, but not in patients receiving chemotherapy without CIPN or controls, resulting in an 86% sensitivity and 87% specificity. An NFLs increase of +36 pg/mL from baseline was associated with a predicted CIPN probability of more than 0.5.CONCLUSIONNFLs was correlated with CIPN development and severity, which may guide neurotoxic chemotherapy in the future.TRIAL REGISTRATIONClinicalTrials.gov NCT02753036.FUNDINGDeutsche Forschungsgemeinschaft (EXC 257 NeuroCure), BMBF (Center for Stroke Research Berlin, 01 EO 0801), Animalfree Research, EU Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking (TransBioLine, 821283), Charité 3R - Replace - Reduce - Refine.
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http://dx.doi.org/10.1172/jci.insight.154395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986065PMC
March 2022

Cell-free tumor DNA, CA125 and HE4 for the objective assessment of tumor burden in patients with advanced high-grade serous ovarian cancer.

PLoS One 2022 7;17(2):e0262770. Epub 2022 Feb 7.

NEO New Oncology GmbH, Cologne, Germany.

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0262770PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820624PMC
February 2022

Symptom burden and quality of life with chemotherapy for recurrent ovarian cancer: the Gynecologic Cancer InterGroup-Symptom Benefit Study.

Int J Gynecol Cancer 2022 06 6;32(6):761-768. Epub 2022 Jun 6.

Australia New Zealand Gynaecological Oncology Group (ANZGOG), Camperdown, New South Wales, Australia

Objective: The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with ≥3 lines of chemotherapy (PPS-ROC ≥3).

Methods: Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated ≥4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of ≤3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores ≥10 points above baseline in the QLQ-C30 summary score scale (range 0-100).

Results: Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC ≥3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC ≥3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC ≥3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline.

Conclusion: Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants.
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http://dx.doi.org/10.1136/ijgc-2021-003142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9185817PMC
June 2022

Risk for Pelvic Metastasis and Role of Pelvic Lymphadenectomy in Node-Positive Vulvar Cancer-Results from the AGO-VOP.2 QS Vulva Study.

Cancers (Basel) 2022 Jan 14;14(2). Epub 2022 Jan 14.

Department of Gynecology and Gynecologic Oncology, University Medical Center Bonn, 53127 Bonn, Germany.

The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b.
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http://dx.doi.org/10.3390/cancers14020418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773532PMC
January 2022

Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression.

J Exp Clin Cancer Res 2022 Jan 19;41(1):28. Epub 2022 Jan 19.

Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University. No, 18 Daoshan Road, Fuzhou, 350001, China.

Background: Estrogen-related receptor α (ERRα) has been reported to play a critical role in endometrial cancer (EC) progression. However, the underlying mechanism of ERRα-mediated lipid reprogramming in EC remains elusive. The transcription factor EB (TFEB)-ERRα axis induces lipid reprogramming to promote progression of EC was explored in this study.

Methods: TFEB and ERRα were analyzed and validated by RNA-sequencing data from the Cancer Genome Atlas (TCGA). The TFEB-ERRα axis was assessed by dual-luciferase reporter and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The mechanism was investigated using loss-of-function and gain-of-function assays in vitro. Lipidomics and proteomics were performed to identify the TFEB-ERRα-related lipid metabolism pathway. Pseudopods were observed by scanning electron microscope. Furthermore, immunohistochemistry and lipidomics were performed in clinical tissue samples to validate the ERRα-related lipids.

Results: TFEB and ERRα were highly expressed in EC patients and correlated to EC progression. ERRα is the direct target of TFEB to mediate EC lipid metabolism. TFEB-ERRα axis mainly affected glycerophospholipids (GPs) and significantly elevated the ratio of phosphatidylcholine (PC)/sphingomyelin (SM), which indicated the enhanced membrane fluidity. TFEB-ERRα axis induced the mitochondria specific phosphatidylglycerol (PG) (18:1/22:6) + H increasing. The lipid reprogramming was mainly related to mitochondrial function though combining lipidomics and proteomics. The maximum oxygen consumption rate (OCR), ATP and lipid-related genes acc, fasn, and acadm were found to be positively correlated with TFEB/ERRα. TFEB-ERRα axis enhanced generation of pseudopodia to increase the invasiveness. Mechanistically, our functional assays indicated that TFEB promoted EC cell migration in an ERRα-dependent manner via EMT signaling. Consistent with the in vitro, higher PC (18:1/18:2) + HCOO was found in EC patients, and those with higher TFEB/ERRα had deeper myometrial invasion and lower serum HDL levels. Importantly, PC (18:1/18:2) + HCOO was an independent risk factor positively related to ERRα for lymph node metastasis.

Conclusion: Lipid reprogramming induced by the TFEB-ERRα axis increases unsaturated fatty acid (UFA)-containing PCs, PG, PC/SM and pseudopodia, which enhance membrane fluidity via EMT signaling to promote EC progression. PG (18:1/22:6) + H induced by TFEB-ERRα axis was involved in tumorigenesis and PC (18:1/18:2) + HCOO was the ERRα-dependent lipid to mediate EC metastasis.
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http://dx.doi.org/10.1186/s13046-021-02211-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767755PMC
January 2022

Cell-Free-DNA-Based Copy Number Index Score in Epithelial Ovarian Cancer-Impact for Diagnosis and Treatment Monitoring.

Cancers (Basel) 2021 Dec 30;14(1). Epub 2021 Dec 30.

Department for Gynecology with the Center for Oncologic Surgery Charité Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 12169 Berlin, Germany.

Background: Chromosomal instability, a hallmark of cancer, results in changes in the copy number state. These deviant copy number states can be detected in the cell-free DNA (cfDNA) and provide a quantitative measure of the ctDNA levels by converting cfDNA next-generation sequencing results into a genome-wide copy number instability score (CNI-Score). Our aim was to determine the role of the CNI-Score in detecting epithelial ovarian cancer (EOC) and its role as a marker to monitor the response to treatment.

Methods: Blood samples were prospectively collected from 109 patients with high-grade EOC. cfDNA was extracted and analyzed using a clinical-grade assay designed to calculate a genome-wide CNI-Score from low-coverage sequencing data. Stored data from 241 apparently healthy controls were used as a reference set.

Results: Comparison of the CNI-Scores of primary EOC patients versus controls yielded sensitivities of 91% at a specificity of 95% to detect OC, respectively. Significantly elevated CNI-Scores were detected in primary (median: 87, IQR: 351) and recurrent (median: 346, IQR: 1891) blood samples. Substantially reduced CNI-Scores were detected after primary debulking surgery. Using a cut-off of 24, a diagnostic sensitivity of 87% for primary and recurrent EOC was determined at a specificity of 95%. CNI-Scores above this threshold were detected in 21/23 primary tumor (91%), 36/42 of platinum-eligible recurrent (85.7%), and 19/22 of non-platinum-eligible recurrent (86.3%) samples, respectively.

Conclusion: ctDNA-quantification based on genomic instability determined by the CNI-Score was a biomarker with high diagnostic accuracy in high-grade EOC. The applied assay might be a promising tool for diagnostics and therapy monitoring, as it requires no a priori information about the tumor.
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http://dx.doi.org/10.3390/cancers14010168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750971PMC
December 2021

Association of a Combined Cancer Exhaustion Score with Circulating Tumor Cells and Outcome in Ovarian Cancer-A Study of the OVCAD Consortium.

Cancers (Basel) 2021 Nov 23;13(23). Epub 2021 Nov 23.

Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria.

We investigated the prognostic role of systemic characteristics for cancer exhaustion and the presence of circulating tumor cells (CTCs) in primary epithelial ovarian cancer (EOC) patients. We included 185 patients in this multicenter study with a median follow-up time of 10.25 years. Albumin, c-reactive protein (CRP) and the kynurenine to tryptophan ratio (Kyn/Trp) as well as the CTC-related marker cyclophilin C (PPIC) were obtained before primary therapy and were correlated to the respective clinical and outcome data. The information provided by albumin and Kyn/Trp was integrated in a combined score for cancer exhaustion (CCES). A high CCES characterized by hypoalbuminemia and a high Kyn/Trp was associated with both decreased overall and progression-free survival, independent from other known prognostic factors in a multivariable analysis. The presence of PPIC-positive CTCs was significantly associated with a high CCES, highlighting that the interplay between the systemic microenvironment and CTCs should be considered in "liquid biopsy" biomarker assessment.
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http://dx.doi.org/10.3390/cancers13235865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657288PMC
November 2021

Neurogenic Inflammation in the Context of Endometriosis-What Do We Know?

Int J Mol Sci 2021 Dec 3;22(23). Epub 2021 Dec 3.

Department of Gynecology Charité with Center of Oncological Surgery, Endometriosis Research Center Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.
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http://dx.doi.org/10.3390/ijms222313102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658724PMC
December 2021

Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer.

N Engl J Med 2021 12;385(23):2123-2131

From the Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen (P. Harter, A.B.), the Department of Gynecology with Center for Oncological Surgery, Charité Berlin, Berlin (J.S.), the Coordinating Center for Clinical Trials (A. Reuss) and Department of Gynecology (P. Harter), Philipps University, Marburg, the Department of Obstetrics and Gynecology, Heinrich-Heine-University, Duesseldorf (W.M.), the Department of Gynecology and Obstetrics, Hannover Medical School, Hannover (P. Hillemanns), the University Medical Center Mainz, Department of Gynecology and Obstetrics, Mainz (A.H.), and Mammazentrum Hamburg at Jerusalem Hospital, Hamburg (F.H.) - all in Germany; the Department of Gynecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium (I.V.); the Department of Surgical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer, Toulouse (G.F.), the Department of Medical Oncology, Groupe Hospitalier Diaconesses Croix Saint-Simon (F.S.), and Institut Curie, Oncologie Gynécologique and Université de Paris (F.L.), Paris, the Department of Surgical Oncology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux (F.G.), the Department of Surgical Oncology, Jean Perrin Cancer Center, Clermont-Ferrand (C.P.), and Institut de Cancerologie de l'Ouest, Université de Médecine, Nantes (J.-M.C.) - all in France; the Gynecologic Oncology Unit, Istituto Nazionale Tumori di Napoli, Fondazione IRCCS Pascale, Naples (S.G.), and Fondazione IRCCS Istituto Nazionale Tumori, Milan (F.R.) - both in Italy; the Gyne-Oncology Department of Gynecology (B.J.M.), Copenhagen University Hospital Rigshospitalet (M.R.M.), Copenhagen, the Department of Gynecology, Aarhus University Hospital and Aarhus University, Institute of Clinical Medicine, Faculty of Health, Aarhus (P.J.), and Aalborg University Hospital, Aalborg (B.L.) - all in Denmark; the Ovarian Cancer Program, Department of Gynecologic Oncology, Fudan University Zhongshan Hospital, Shanghai, China (R.Z.); the Department of Oncology-Pathology, Karolinska Institutet, Stockholm (E.A.-L.); the Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea (J.-W.K.); University Hospital of Bellvitge, Barcelona (J.P.), and the Gynecologic Oncology Unit, La Fe University Hospital, Valencia (A.S.) - both in Spain; the Department of Gynecologic Oncology and Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo (G.K.); the Department of Surgery and Cancer, Imperial College London (S.G.-M.), and the Department of Gynaecological Oncology, University College London Hospital (A.O.) - both in London; and the Department of Gynecology and Gynecological Oncology, Medical University of Vienna, Vienna (A. Reinthaller).

Background: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear.

Methods: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival.

Results: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery.

Conclusions: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).
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http://dx.doi.org/10.1056/NEJMoa2103294DOI Listing
December 2021

Deciphering the Role of Humoral and Cellular Immune Responses in Different COVID-19 Vaccines-A Comparison of Vaccine Candidate Genes in Roborovski Dwarf Hamsters.

Viruses 2021 11 16;13(11). Epub 2021 Nov 16.

Department of Gynecology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, 13353 Berlin, Germany.

With the exception of inactivated vaccines, all SARS-CoV-2 vaccines currently used for clinical application focus on the spike envelope glycoprotein as a virus-specific antigen. Compared to other SARS-CoV-2 genes, mutations in the spike protein gene are more rapidly selected and spread within the population, which carries the risk of impairing the efficacy of spike-based vaccines. It is unclear to what extent the loss of neutralizing antibody epitopes can be compensated by cellular immune responses, and whether the use of other SARS-CoV-2 antigens might cause a more diverse immune response and better long-term protection, particularly in light of the continued evolution towards new SARS-CoV-2 variants. To address this question, we explored immunogenicity and protective effects of adenoviral vectors encoding either the full-length spike protein (S), the nucleocapsid protein (N), the receptor binding domain (RBD) or a hybrid construct of RBD and the membrane protein (M) in a highly susceptible COVID-19 hamster model. All adenoviral vaccines provided life-saving protection against SARS-CoV-2-infection. The most efficient protection was achieved after exposure to full-length spike. However, the nucleocapsid protein, which triggered a robust T-cell response but did not facilitate the formation of neutralizing antibodies, controlled early virus replication efficiently and prevented severe pneumonia. Although the full-length spike protein is an excellent target for vaccines, it does not appear to be the only option for future vaccine design.
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http://dx.doi.org/10.3390/v13112290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625836PMC
November 2021

Correction to: Preoperative quality of life as prediction for severe postoperative complications in gynecological cancer surgery: results of a prospective study.

Arch Gynecol Obstet 2021 Nov 19. Epub 2021 Nov 19.

Department of Gynecology with Center of Surgical Oncology, Charité University Hospital of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

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http://dx.doi.org/10.1007/s00404-021-06333-yDOI Listing
November 2021
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