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

Knowledge and understanding risk factors and preventive measures for osteoporosis in women: results of a survey in 502 women with and without a migration background

Background: Osteoporosis is a disease of the skeletal system associated with loss of bone mass and an increased risk of fractures affecting women more often than men. Identification of the knowledge about osteoporosis and its preventive methods is the backbone of any awareness program. This study investigates the knowledge with a special focus on women with and without a migration background. Methods: Data from systematic patient interviews based on a questionnaire were collected at three different sites in Berlin between February and June 2021. The survey included questions assessing migrant background, demographic characteristics, lifestyle habits including physical exercise and smoking, prevention by vitamin D intake and bone densitometry, and information on personal and family medical history. According to the responses, a scale was created to assess the level of knowledge of preventive osteoporosis measures. The ethic committee of the Charite, Medical faculty has approved this study. SPSS (version 24.0) was used for the statistical analyses. Results: The survey of 502 female patients revealed that 25% had low and 34% no previous knowledge of osteoporosis. Older age and a better education level correlate with a higher knowledge. Patients with gynecologic cancer are less well informed. There is a significant difference in vitamin D intake between migrant and non-migrant women (57% vs. 49%). There were no significant differences regarding the use of bone densitometry. Conclusion: Knowledge of osteoporosis and the possibility of a bone densitometry as well as the implementation of preventive measures is low among women. Therefore, informing patients better should be a priority, with particular attention on the risks and needs of women with a migration background. Specific programs for women with and without migration background should be developed to increase the awareness of osteoporosis

Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation

BACKGROUND: Disulfiram (DSF) is a drug used for treatment of alcoholism that has also displayed promising anti-cancer activity. It unfolds its effects by inhibiting the enzyme activity of aldehyde dehydrogenase (ALDH) isoforms. METHODS: MTT assay, spheroid formation, clonogenicity assay, qRT-PCR, and ALDH enzyme activity analysis were performed using ovarian cancer cell lines IGROV1, SKOV3 and SKOV3IP1. Cell cycle analyses and measurement of intracellular reactive oxygen species (ROS) were carried out by flow cytometry. ALDH+ and ALDH- cells were isolated by FACS sorting. RESULTS: ALDH activity was inhibited in ovarian cancer stem cells (the proportion of ALDH+ cells was reduced from 21.7% to 0.391%, 8.4% to 0%, 6.88% to 0.05% in cell lines IGROV1, SKOV3, and SKOV3IP1, respectively). DSF with or without the cofactor copper (Cu2+) exhibited cytotoxicity dose- and time-dependent and enhanced cisplatin-induced apoptosis. DSF + Cu2+ increased intracellular ROS levels triggering apoptosis of ovarian cancer stem cells (CSC). Significantly more colony and spheroid formation was observed in ALDH+ compared with ALDH- cells (P < 0.01). Moreover, ALDH+ cells were more resistant to cisplatin treatment compared with ALDH-cells (P < 0.05) and also exhibited a lower basal level of ROS. However, no significant difference in ROS accumulation nor in cellular viability was observed in ALDH + cells in comparison to ALDH- cells after pre-treatment with DSF (0.08 μM). CONCLUSION: Our findings provide evidence that DSF might be employed as a novel adjuvant chemotherapeutic agent in combination with cisplatin for treatment of ovarian cancer

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

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

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

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 IC50 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

Primary Treatment Results in Patients with Ovarian, Fallopian or Peritoneal Cancer—Results of a Clinical Cancer Registry Database Analysis in Germany

Simple Summary: Diagnosis and treatment of ovarian cancers has changed significantly over the last years. However, the role of primary surgery and chemotherapy remain important parts of the multimodal treatment. Furthermore, real life data are often lacking but are very important for improving quality indicators and for hypothesis generation for future trials. The present work represents the first major analysis of federal cancer registry data of OC patients in Germany. Overall, 2771 primary OC cases were included. The results clearly elucidate quality measurements and treatment results and show good treatment outcomes in patients with primary OC compared to other internationally reported outcomes. Abstract: Background: The current therapy of ovarian cancer is based on the so-called "Three-Pillar-Model", consisting of surgery, chemotherapy and maintenance therapy. This study represents the first major analysis of a federal cancer database of OC patients from the states Berlin/Brandenburg in Germany. The primary objective was to evaluate the prevailing established quality indicators surgical outcome, adjuvant chemotherapy and integrity of surgical staging in early stages. Methods: Data from the Clinical Cancer Registry for Brandenburg and Berlin of the years 2009-2019 were analyzed. Objectives were defined by a working group of selected physicians. Descriptive statistics were performed, as well as survival analysis. Results: A total of 2771 primary OC cases were included. Results regarding histological subtype met the suspected allocation with predominantly high-grade serous OC in advanced stage. The rate of complete surgical staging in FIGO stages I-IIA was 57%, and the rate of macroscopic complete resection in >FIGO III was 53%. Five-year survival rate varied from 79% (FIGO I) to 40% (FIGO III). Rate of adjuvant chemotherapy was above 50%. Conclusion: The results elucidate quality measurements and treatment results and show good treatment outcomes in patients with primary diagnosis. However, they also indicate deficits and can help to establish new quality indicators to further improve the treatment

Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines

The chemotherapeutic agent cisplatin typically induces apoptosis by inhibiting the cell cycle. Cancer Stem Cells (CSCs), which are a proliferative quiescent and slowly-cycling cell population, are less sensitive and therefore frequently spared from toxic effects. Thus, it remains a priority to increase the sensitivity of CSCs to cisplatin-based chemotherapy, or to specifically target CSCs to improve the therapeutic outcome in breast cancer. Disulfiram (DSF) is a drug used clinically for alcoholism treatment that has displayed promising anti-cancer activity in vitro and in cancer xenografts in breast cancer. Our study provides evidence that DSF inhibits Aldehyde dehydrogenase (ALDH) enzyme activity, inhibits the expression of stemness-related transcription factors (Sox, Nanog, Oct) in CSC derived from breast cancer cell lines, and modulates intracellular reactive oxygen species (ROS) generation. Importantly, our research proved that ALDH + stem-like cells play important roles in the resistance to the conventional chemotherapeutic agent cisplatin. DSF enhances the cytotoxic effect of cisplatin through inhibiting the stemness and by overcoming cisplatin resistance of ALDH + stem-like cells. A quantitative measurement showed the synergistic effect of DSF and cisplatin. Further, we show that ALDH+ cancer stem-like cells and ALDH- bulk cancer cells have different intrinsic ROS levels, what may explain differences in susceptibility to cisplatin treatment. Importantly, this difference is eliminated by DSF treatment making both cell types similarly susceptible for cytotoxic effects by cisplatin. These findings may influence chemotherapeutic treatment approaches in the future

Improving the Antigenicity of SARS-CoV-2 Vaccine Genes by Merging Mutations from Different Variants of Concern

During the COVID-19 pandemic, the early emergence of viral variants repeatedly undermined the effects of vaccination. Our aim here is to explore strategies for improving spike vaccine gene antigenicity by merging mutations from different variants of concern (VOCs) in a single vaccine gene. To this end, newly developed recombinant vaccine genes were designed, cloned into adenoviral vectors, and applied to C57BL/6 mice; then, serum-neutralizing antibodies against the wildtype SARS-CoV-2 strains were determined in neutralization assays. The merger of mutations from different variants of concern (alpha, beta, gamma, and delta) in a single recombinant spike-based vaccine gene provided a substantial improvement in neutralizing immunity to all variants of concern, including the omicron strains. To date, only unmodified spike genes of the original SARS-CoV-2 Wuhan strain (B.1) or dominant variants (BA.1, BA.5, and XBB.1.5) have been used as vaccine genes. The employment of unmodified vaccine genes is afflicted by limited cross-protection among variant strains. In contrast, recombinant vaccine genes that combine mutations from different strains in a single gene hold the potential to broaden and improve immune protection and might help to reduce the need for frequent vaccine adaptations in the future

ECOG and BMI as preoperative risk factors for severe postoperative complications in ovarian cancer patients: results of a prospective study (RISC-GYN—trial)

Background: Accompanying co-morbidities in patients with ovarian cancer are of major relevance for scheduling debulking surgery, especially in the anesthesiological consultations. Aim of this study was to evaluate the impact of co-morbidities and patient characteristics on postoperative complications. Methods: Patients undergoing maximal cytoreductive surgery were prospectively enrolled from October 2015 to January 2017. Various variables were recorded, such as the Charlson comorbidity index, Eastern cooperative oncology group scale of performance status (ECOG PS) and the American society of anesthesiologists physical status classification system (ASA PS). Surgical complications were graded using the Clavien-Dindo criteria. Logistic regression models were used to analyze risk factors for severe postoperative complications. Results: Of 106 enrolled patients, 19 (17.9%) developed severe postoperative complications grade >= IIIb according to Clavien-Dindo criteria. In the multivariable regression analysis impaired (ECOG PS) > 1 (odds ratio OR) 13.34, 95% confidence interval (CI) 1.74-102.30, p = 0.01), body mass index (BMI) > 25 kg/m(2) (OR 10.48, 95% CI 2.38-46.02, p = 0.002) along with the use of intraoperative norepinephrine > 0.11 mu g/kg/min (OR 4.69, 95% CI 1.13-19.46, p = 0.03) and intraoperative fresh frozen plasma (FFP) > 17 units (OR 4.11, 95% CI 1.12-15.14, p = 0.03) appeared as significant predictors of severe postoperative complications. Conclusion: We demonstrated that neither the presence of a certain comorbidity nor the summation of the co-morbidities were associated with adverse outcome. Patient characteristics, such as ECOG PS > 1 and obesity (BMI > 25 kg/m(2)), are highly predictive factors for severe postoperative complications. The analysis of intraoperative data showed that the need for more than > 0.11 mu g/kg/min of norepinephrine and transfusions of FFPs more than 17 units were strongly associated with severe postoperative complications