Hyponatremia as a Prognostic Factor in Advanced Stage Ovarian Cancer Patients.

Background: hyponatremia represents one of the most commonly encountered conditions in hospitalized patients, multiple mechanisms being cited so far, neoplastic syndromes being an important cause. The aim of the current paper is to analyse the presence and influence of the short- and long-term outcomes of hyponatremia on ovarian cancer patients submitted to surgery for advanced stage ovarian cancer. Method: 57 patients diagnosed with advanced stage ovarian cancer were submitted to surgery between 2014-2020. The patients were further classified according to the preoperative value of sodium into two groups. Results: there were 21 cases with preoperative normal values of sodium and respectively 36 cases with hyponatremia. Patients with preoperative hyponatremia associated a significantly higher rate of early postoperative complications and a significantly poorer long-term outcome. Therefore, cases with hyponatremia reported a mean disease-free survival of 10.8 months and respectively a mean overall survival of 18.5 months while cases with normal natrium levels reported a mean disease-free survival of 31.4 months and respectively a mean overall survival of 49.7 months (p=0.0001 and p 0.001). Conclusions: patients with lower preoperative values of sodium have a higher risk of developing postoperative complications and a significantly poorer outcome when compared to cases presenting normal levels of sodium preoperatively.

Surgical and Anatomical Basics of Pelvic Debulking Surgery for Advanced Ovarian Cancer - the "Hudson Procedure" as a Cornerstone of Complete Cytoreduction.

Ovarian cancer (OC) is the fifth most common cause of death in women and accounts for more deaths than any other cancer of the female reproductive tract. OC usually spreads through peritoneal dissemination and direct invasion. Optimal cytoreduction (no macroscopic residual disease) and adjuvant platinum-based chemotherapy are the fundaments of OC treatment. OC is usually diagnosed at advanced stages, hence the obliteration of the Douglas pouch by the tumor as well as disseminated pelvic peritoneal carcinomatosis are commonly seen. Radical surgical cytoreduction typically requires a retroperitoneal approach to the pelvic masses and multivisceral resections in the upper abdomen. In 1968, Christopher Hudson introduced a new retroperitoneal surgical technique ("radical oophorectomy") for fixed ovarian tumors. Since then, numerous modifications have been described, including visceral peritonectomy, the "cocoon" technique, Bat-shaped en-bloc total peritonectomy (Sarta-Bat approach), or en-bloc resection of the pelvis. Although these modifications expanded the classical description in many ways, the concepts and key surgical steps are derived from the Hudson procedure. However, there are some gaps or disagreements regarding the anatomical or practical rationale for certain surgical steps. The purpose of this article is to outline the critical steps of radical pelvic cytoreduction ("Hudson procedure"), and to delineate the anatomical basis for the procedure in the proposed form. In addition, we discuss the controversies and address the perioperative morbidity associated with the procedure.

Novel approach of desensitization in allergic reaction to Olaparib.

INTRODUCTION: PARP (Poly ADP Ribose Polymerase) inhibitors are an effective maintenance therapy for various entities, such as BRCA (breast cancer gene) mutated or HRD (homologous recombination deficiency) positive primary platin-sensitive advanced ovarian cancer after platin induction therapy and in relapse after responding to carboplatin reinduction. Other entities are metastatic BRCA mutated pancreas, prostate and Her2-negative breast cancer. Therefore, patients with allergic reactions to PARP inhibitors should undergo a desensitization procedure to be able to receive this efficient therapy. CASE REPORT: We conducted a two-day desensitization on a 45-year-s old patient with advanced ovarian cancer who displayed symptoms of an allergic reaction to Olaparib. MANAGEMENT AND OUTCOME: Using an Olaparib tablet suspension, we orally administered increasing Olaparib doses, starting with 12.5 mg and reaching a cumulative dose of 387.5 mg on the first day and starting with 100 mg and reaching a cumulative dose of 600 mg on the second day, without concomitant antiallergic medication.Except for mild erythema on day one receding within the hour, no further allergic reactions appeared during desensitization. The patient has since received 300 mg of Olaparib twice a day without further complications or interruptions. CONCLUSION: Desensitization in a two-day suspension protocol is a safe method that ensures effective maintenance therapy for patients with allergic reactions to PARP inhibitors.

Research progress on anti-ovarian cancer mechanism of miRNA regulating tumor microenvironment.

Ovarian cancer is the most deadly malignancy among women, but its complex pathogenesis is unknown. Most patients with ovarian cancer have a poor prognosis due to high recurrence rates and chemotherapy resistance as well as the lack of effective early diagnostic methods. The tumor microenvironment mainly includes extracellular matrix, CAFs, tumor angiogenesis and immune-associated cells. The interaction between tumor cells and TME plays a key role in tumorigenesis, progression, metastasis and treatment, affecting tumor progression. Therefore, it is significant to find new tumor biomarkers and therapeutic targets. MicroRNAs are non-coding RNAs that post-transcriptionally regulate the expression of target genes and affect a variety of biological processes. Studies have shown that miRNAs regulate tumor development by affecting TME. In this review, we summarize the mechanisms by which miRNAs affect ovarian cancer by regulating TME and highlight the key role of miRNAs in TME, which provides new targets and theoretical basis for ovarian cancer treatment.

Fluorescence turn-on immunosensing of HE4 biomarker and ovarian cancer cells based on target-triggered metal-enhanced fluorescence of carbon dots.

Rapid and sensitive detection of tumor biomarkers and cancer cells is of crucial importance for the early diagnosis and prognosis prediction of cancer. The present report describes a target-induced fluorescence enhancement immunosensor that utilizes the optical property of carbon dots (CDs) and the metal-enhanced fluorescence effect (MEF) property of silver nanoparticles (AgNPs) for the sensitive detection of the cancer biomarker human epididymis protein 4 (HE4) and ovarian cancer cells. Nitrogen and sulfur co-doped CDs with a quantum yield of 85.6% were prepared and served as the fluorophore in MEF. The HE4 antibody (Ab) specific to the HE4 antigen was linked covalently to the surface of the synthesized CDs as the capture. The HE4 Ab-conjugated AgNPs (AgNPs-Ab) were prepared and utilized as signal amplification elements. In the presence of the target HE4, composite sandwich structures were formed between the labeled CDs-Ab and AgNPs-Ab, which brought the CDs and AgNPs into proximity, resulting in the fluorescence of CDs enhancement owing to MEF. The intensity of fluorescence enhancement was positively correlated with the HE4 concentration in the clinically important range of 0.01-200 nM with a limit detection of 2.3 pM. Moreover, the immunosensor was also successfully applied to specific fluorescence labeling and quantitative determination of HE4-positive ovarian cancer cells. The proposed target-triggered MEF sensor platform demonstrated high sensitivity, excellent anti-interference ability, along with successful validation in complex biological matrices, providing a new approach for HE4 detection in early diagnosis and therapeutic monitoring.

The Totality of Evidence and Use of ABP 215, a Biosimilar to Bevacizumab.

ABP 215 (MVASI™, Amgen, Thousand Oaks, CA; MVASI™, Amgen Europe B.V., Netherlands) is a biosimilar to bevacizumab (Avastin®, Genentech, South San Francisco, CA) reference product (RP), a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A). Here we provide a brief overview of the totality of evidence that supported the approval of ABP 215, along with practical considerations to ensure safe and effective administration.ABP 215 has been shown to be highly similar to the RP, with similar mechanism of action, analytical (structural and functional) characteristics, binding, and potency. The similarity of PK parameters of ABP 215 and bevacizumab RP has been confirmed in healthy volunteers.In a comparative clinical trial, patients with stage IV or recurrent non-squamous non-small cell lung cancer receiving carboplatin and paclitaxel were randomized to ABP 215 or bevacizumab RP. No clinically meaningful differences were found between ABP 215 and RP. The objective response rate (ORR) was 39% for ABP 215 and 41.7% for bevacizumab RP. The risk ratio for the ORR was 0.93 [90% confidence interval (CI), 0.80-1.09], which fell within the prespecified margin for equivalence of 0.67-1.5, indicating similar clinical efficacy.Similar to bevacizumab RP, ABP 215 is supplied as a clear to slightly opalescent, colorless to pale yellow, sterile solution in a glass vial. It should be diluted in 0.9% sodium chloride in polyvinylchloride or polyolefin bags before administering as an intravenous infusion. The ABP 215 solution should be stored at 2-8 °C (36-46°F) prior to use. Physicochemical stability studies showed that there were no meaningful changes in purity or potency and no loss of protein after storage at 2-8 °C for 35 days followed by storage at 30 °C for 48 h.

Prognostic Factors in Advanced Ovarian Cancer - A Clinical Trial.

Introduction: Ovarian cancer is one of most fatal gynecological condition. The number of patients diagnosed in advanced stages is very high, hence the recurrence rate is high, and the chance of survival at 5 years is less than 45%. Purpose: To evaluate correspondance between overall survival with clinical, paraclinical, tumor or treatment characteristics and to identify prognostic factors in patients with advanced ovarian cancer - stage III and IV FIGO. Material and Method: We performed a retrospective study in 65 patients with advanced ovarian cancer - stages III and IV FIGO operated during 2010-2018, with a follow-up period of at least one year. There were correlations with clinical and paraclinical charateristics, tumor or treatment characteristics and with overall survival. Results: In the univariate statistical analysis of survival, a significant statistical association is obtained by the presence of pelvic pain at presentation (p_value = 0.033744), with the stage III (p_value = 0.007595, respectively p_value = 0.022090), with the type of citoreduction (p_value = 0.035) , with postoperative complications (p_value = 0.000685) within the pathological subtypes (p_value = 0.046266), with adjuvant treatment (p_value = 0.000083). Cox multivariate regression analysis showed that adjuvant chemotherapy (HR = 0.046, 95% CI = (0.008, 0.261), (p_value = 0.000492), suboptimal cytoreduction (HR = 0.346, 95% CI = (0.140, 0.853), (p_value) = 0.021219) and postoperative complications (HR = 53,751, 95% CI = (4,672, 618,365), (p_value = 0.001389) are independent prognostic factors. Conclusions: Absence of pelvic pain at diagnosis, FIGO IIIC stage, suboptimal cytoreduction, presence of postoperative complications, inadequate adjuvant treatment and pathological type of clear cell cancer have been shown to be prognostic factors for overall survival. In patients with advanced ovarian cancer, the type of optimal citoreduction and adjuvant treatment are independent protective factors for overall survival, and the presence of postoperative complications has been shown to be an independent risk factor.

Ovarian cancer stem cells and targeted therapy.

BACKGROUND: Ovarian cancer has the highest ratio of mortality among gynecologic malignancies. Chemotherapy is one of the most common treatment options for ovarian cancer. However, tumor relapse in patients with advanced tumor stage is still a therapeutic challenge for its clinical management. MAIN BODY: Therefore, it is required to clarify the molecular biology and mechanisms which are involved in chemo resistance to improve the survival rate of ovarian cancer patients. Cancer stem cells (CSCs) are a sub population of tumor cells which are related to drug resistance and tumor relapse. CONCLUSION: In the present review, we summarized the recent findings about the role of CSCs in tumor relapse and drug resistance among ovarian cancer patients. Moreover, we focused on the targeted and combinational therapeutic methods against the ovarian CSCs.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Peritoneal Carcinomatosis: Our Initial Experience.

Introduction: Peritoneal carcinomatosis represents an advanced stage of tumor dissemination of abdominal cancers in general and colorectal cancer in particular. The only therapeutic methods currently available for the treatment of this pathology are systemic chemotherapy (palliative character) and cytoreductive surgery (CR) with intraperitoneal chemotherapy. After evaluation of evidence-based medical literature and current guide lines we can state that CR + HIPEC procedure is considered to be the treatment of choice in case of patients with peritoneal carcinomatosis of colorectal, ovarian and mucinous appendicular origin. Material and method: In the present study we prospectively analyzed the immediate postoperative results obtained in the first 50 patients that were treated by our team for peritoneal carcinomatosis of different origin. We described the protocol of selection, the patients characteristics that were included in our CR+HIPEC program and analyzed the complications and death rate. Results: From January 2015 till Dec 2018 we evaluated 98 patients with peritoneal carcinomatosis. From them, 51 received radical CR+HIPEC treatment, 33 were not suitable for surgery because of the exclusion criteria's and 15 had only exploratory laparotomies. In regard with the histopathological diagnosis, 30 patients had ovarian cancer and 19 had colorectal cancer or peritoneal pseudomixoma of appendicular origin. There was no 30 days postoperative mortality. The incidence of significant postoperative complications was 15%. Conclusions: Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy is a complex technique accompanied by an acceptable rate of complications and postoperative deaths, the results being optimized by a standardized perioperative management and patient selection. The initial results obtained by our team emphasize the feasibility of this procedure, with immediate good results, as a result of a standardization protocol of patient selection and perioperative care.

Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts.

Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.

An amplified comparative fluorescence resonance energy transfer immunosensing of CA125 tumor marker and ovarian cancer cells using green and economic carbon dots for bio-applications in labeling, imaging and sensing.

CA125, is a marker in the clinical diagnosis of several cancers and currently is the best serum-based tumor marker for ovarian cancer. Here, we developed an ultrasensitive antibody-ssDNA aptamer sandwich-type fluorescence immunosensor for CA125 detection. Based on a novel signal amplification strategy the carbon dots (CDs) functionalized with aptamer (CD-aptamer) used as detection probe and PAMAM-Dendrimers/AuNPs was used for covalent attachment of CA125-antibody and completing the sandwich assay method. By measuring of fluorescence resonance energy transfer (FRET) signals between CDs and AuNPs as nanoquenchers, the fluorescence signal quenched during sandwich complex formed between anti-CA125, CA125 and CDs-Aptamer and decreasing of fluorescence response signal is related to CA125 concentrations. Under optimal conditions, the immunosensor exhibited an extremely low calculated detection limit of 0.5fg/mL with wide linear range 1.0fg/mL to 1.0ng/mL of CA 125. The application of the immunosensor for CA125 detection in serum samples and measuring of ovarian-cancer cells was also investigated. The immunosensor revealed good sensitivity and specificity with ovarian cell concentrations from 2.5×103 to 2×104cells/mL with correlation coefficient of 0.9937 and detection limit of 400cells/mL (4 cell in 10µL), indicating potential application of immunosensor in clinical monitoring of tumor biomarkers. Furthermore, the cell viability was not changed upon treatment with CDs probe during 24h, showing the low cytotoxicity of the probe. More importantly, CDs-antibody hybrid was achieved in selective imaging of the cancer cells over the OVCAR-3 line cells, implying its potential applications in biosensing, as well as in cancer diagnosis.

Effect of 3 isoforms of Ikaros on proliferation of human ovarian cancer SKOV3 cells / 中国病理生理杂志

AIM:ToinvestigatetheeffectofIkarosisoformsontheproliferationofhumanovariancancerSK-OV3 cells.METHODS:Three isoforms of Ikaros, IK1, IK2 and IK6, were transfected into ovarian cancer SKOV3 cells. CCK-8 assay and cell counting were used to detect the effects of Ikaros isoforms on the proliferation of SKOV 3 cells.The cell cycle was analyzed by flow cytometry .The cell cycle-related proteins were detected by Western blot .RESULTS:IK1 and IK2 expression inhibited SKOV 3 cells proliferation .Flow cytometry analysis indicated that IK 1 and IK2 induced SK-OV3 cell cycle arrest at the G 1 phase.IK6 isoform exerted no obvious effect on the proliferation or cell cycle of SKOV 3 cells.Compared with control EV group , IK1 group and IK2 group showed a dramatic elevation in the expression of the cell cycle inhibitor p21, along with a substantial decrease in the expression of the cell cycle inducers cyclin D 1 and cyclin D2, which did not change in IK 6 group.CONCLUSION:IK1 and IK2 significantly inhibit the proliferation of ovarian cancer SKOV3 cells and induce cell cycle arrest at G 1 phase by regulation of cell cycle-related proteins cyclin D1, cyclin D2 and p21, while IK6 isoform exerts no obvious effect on the proliferation and cell cycle of SKOV 3 cells.

Inhibition effect of silencing EGFR gene by RNAi on tumorigenesis of xenograft tumor of ovarian cancer / 重庆医科大学学报

Objective: To investigate the inhibition effect of silencing EGFR gene by RNAi on tumorigenesis of ovarian cancer SKOV3 cells. Methods: The EGFR gene sequence-specific dsRNA expression vector was constructed,lipofectamine transfer SKOV3 cells and G418 were used for the selection of positive clones. Xenograft tumor models were established.The model mice were divided into positive interference group,negative control group,blank control group. The tumor volume was monitored;the tumor quality was measured;the expression of EGFR gene in the xenograft tumor was detected by RT-PCR,Western Blot and immunohistochemical. Results: The tumorigenesis of the positive interference group decreased significantly,EGFR mRNA and protein inhibition rates were 78.8% and 76.4%,respectively. Conclusion: The animal experiment was confirmed that Silencing of EGFR gene by RNAi can obviously inhibit the tumorigenesis of ovarian cancer.