Chemotherapy For Epithelial Ovarian Cancer Research Articles

Peritumoral MRI Radiomics Features Increase the Evaluation Efficiency for Response to Chemotherapy in Patients With Epithelial Ovarian Cancer.

It remains unclear whether extracting peritumoral volume (PTV) radiomics features are useful tools for evaluating response to chemotherapy of epithelial ovarian cancer (EOC). To evaluate MRI radiomics signatures (RS) capturing subtle changes of PTV and their added evaluation performance to whole tumor volume (WTV) for response to chemotherapy in patients with EOC. Retrospective. 219 patients aged from 15 to 79 years were enrolled. 3.0 or 1.5T, axial fat-suppressed T2-weighted imaging (FS-T2WI), diffusion-weighted imaging (DWI), and contrast enhanced T1-weighted imaging (CE-T1WI). MRI features were extracted from the four axial sequences and six different volumes of interest (VOIs) (WTV and WTV + PTV (WPTV)) with different peritumor sizes (PS) ranging from 1 to 5 mm. Those features underwent preprocessing, and the most informative features were selected using minimum redundancy maximum relevance and least absolute shrinkage and selection operator to construct the RS. The optimal RS, with the highest area under the curve (AUC) of receiver operating characteristic was then integrated with independent clinical characteristics through multivariable logistic regression to construct the radiomics-clinical model (RCM). Mann-Whitney U test, chi-squared test, DeLong test, log-rank test. P < 0.05 indicated a significant difference. All the RSs constructed on WPTV exhibited higher AUCs (0.720-0.756) than WTV (0.671). Of which, RS with PS = 2 mm displayed a significantly better performance (AUC = 0.756). International Federation of Gynecology and Obstetrics (FIGO) stage was identified as the exclusive independent clinical evaluation characteristic, and the RCM demonstrated higher AUC (0.790) than the RS, but without statistical significance (P = 0.261). The radiomics features extracted from PTV could increase the efficiency of WTV radiomics for evaluating the chemotherapy response of EOC. The cut-off of 2 mm PTV was a reasonable value to obtain effective evaluation efficiency. 4 TECHNICAL EFFICACY: Stage 2.

SLFN11 is a BRCA Independent Biomarker for the Response to Platinum-Based Chemotherapy in High-Grade Serous Ovarian Cancer and Clear Cell Ovarian Carcinoma.

BRCA1/2 mutations are robust biomarkers for platinum-based chemotherapy in epithelial ovarian cancers. However, BRCA1/2 mutations in clear cell ovarian carcinoma (CCC) are less frequent compared with high-grade serous ovarian cancer (HGSC). The discovery of biomarkers that can be applied to CCC is an unmet need in chemotherapy. Schlafen 11 (SLFN11) has attracted attention as a novel sensitizer for DNA-damaging agents including platinum. In this study, we investigated the utility of SLFN11 in HGSC and CCC for platinum-based chemotherapy. SLFN11 expression was analyzed retrospectively by IHC across 326 ovarian cancer samples. The clinicopathologic significance of SLFN11 expression was analyzed across 57 advanced HGSC as a discovery set, 96 advanced HGSC as a validation set, and 57 advanced CCC cases, all of whom received platinum-based chemotherapy. BRCA1/2 mutation was analyzed using targeted-gene sequencing. In the HGSC cohort, the SLFN11-positive and BRCA mutation group showed significantly longer whereas the SLFN11-negative and BRCA wild-type group showed significantly shorter progression-free survival and overall survival. Moreover, SLFN11-positive HGSC shrunk significantly better than SLFN11-negative HGSC after neoadjuvant chemotherapy. Comparable results were obtained with CCC but without consideration of BRCA1/2 mutation due to a small population. Multivariate analysis identified SLFN11 as an independent factor for better survival in HGSC and CCC. The SLFN11-dependent sensitivity to platinum and PARP inhibitors were validated with genetically modified non-HGSC ovarian cancer cell lines. Our study reveals that SLFN11 predicts platinum sensitivity in HGSC and CCC independently of BRCA1/2 mutation status, indicating that SLFN11 assessment can guide treatment selection in HGSC and CCC.

Effectiveness of nab-paclitaxel versus traditional paclitaxels in the treatment of ovarian cancer

Purpose: To evaluate the effect of four taxane drugs, namely, paclitaxel, docetaxel, paclitaxel liposomes (Lipusu), and nab-paclitaxel (Keaili) on ovarian cancer cells both in vivo and in vitro.&#x0D; Methods: BALB/c-nu/nu female mice were used to develop mouse xenograft models. The mice were randomized to 5 groups (4 in each group), namely, control (PBS) group, paclitaxel group, docetaxel group, liposomal paclitaxel group and nab-paclitaxel group. The effect of four taxane drugs were determined via cell proliferation and toxicity tests. Mouse xenograft models were employed to assess the efficacy of four taxane drugs in inhibiting tumor growth.&#x0D; Results: Nab-paclitaxel has a significant ovarian growth-reducing effect in vitro. In vivo, no significant differences were observed in tumor volume among the four groups (p &lt; 0.05). Nab-paclitaxel produced the lowest animal toxicity when compared with other three drugs as the mice in nab- paclitaxel treatment group showed no significant alterations in body weight (p &lt; 0.05). Hematoxylin and eosin (H &amp; E) staining revealed the lowest degree of liver tissue damage in mice treated with nab-paclitaxel compared to mice administered the other three paclitaxels.&#x0D; Conclusion: Nab-paclitaxel is more effective in mice with ovarian cancer than traditional paclitaxels. Thus, it promises to offer a viable alternative as first- line chemotherapy for epithelial ovarian cancer in humans, as it has low systemic toxicity and fewer hypersensitivity reactions. However, further investigations, including clinical trials in humans, are required.

Analyses of tumor microenvironment affecting the survival in patients with ovarian cancer receiving intraperitoneal chemotherapy: Translational research from the phase 3 trial of intraperitoneal therapy for ovarian cancer with carboplatin (TRiPocc).

5555 Background: The iPocc trial is a randomized, global phase (P) 3 study of intraperitoneal (IP) versus intravenous (IV) carboplatin with dose-dense paclitaxel chemotherapy in epithelial ovarian cancer (EOC) patients that demonstrated an improved progression-free survival (PFS) but not overall survival (OS) in the former. IP chemotherapy induces an antitumor immune response and increases survival in a murine xenograft model. This study aimed to assess whether immunological background affected the clinical outcomes of patients receiving IP chemotherapy. Methods: Fresh frozen tumor samples at the time of primary surgery were obtained from 116 patients who joined the iPocc P3 trial for microarray analysis. Cell-type deconvolution was performed using MCP counter. Single sample Gene Set Enrichment Analysis was performed to evaluate the tumor immune microenvironment. Clinical data were obtained from the iPocc P3 trial. We stratified 116 patients according to the high or low values of each factor determined by the median values. The Kaplan-Meier method and log-rank test were used to analyze PFS and OS. Results: A total of 116 patients were assigned to either the IP (n=59) or IV (n=57) group. The most common histologic type was serous (58.6%), followed by endometrioid (17.2%) and clear cell (12.1%). The patients who received IP therapy had longer OS than those who received IV therapy in the group with a high infiltration of T cells, NK cells, or cytotoxic lymphocytes in the MCP counter (median OS: not reached (NR) vs 75.0 months, P=0.041, NR vs. 75.0 months, P=0.042, NR vs 65.2 months, P=0.031), but not in the group with a low infiltration. Similarly, the IP therapy improved OS in the patients with high expression of immune-related genes such as CD8A, FOXP3 or PDCD1 (median OS; NR vs 65.2 months, P=0.035, NR vs 65.2 months P=0.030, NR vs 53.1 months, P=0.016), but not in the patients with low expression of those genes. In addition, a multifaceted evaluation was conducted because of the limitations of evaluating the interaction between cancer and immunity using a single factor. When the patients were divided into two groups, “Immune Hot” and “Immune Cold” based on the hierarchical clustering analysis with 4 parameters representing “Innate immunity,” “T cells,” “Interferon gamma response” and “Inhibitory molecules,” the IP therapy increased both PFS and OS compared to the IV therapy in the “Immune Hot” group (median PFS; 35.5 vs 23.4 months, P=0.024, median OS; NR vs 75.0 months, P=0.040), but not in the “Immune Cold” group. Conclusions: IP therapy may improve the survivals in EOC patients with a high immunological background. Further studies are warranted to validate this hypothesis and to clarify the impact of IP therapy on the tumor immune microenvironment. Clinical trial information: NCT01506856 / GOTIC-001/ JGOG3019.

Impact of obesity on chemotherapy dosing of carboplatin and survival of women with ovarian cancer.

The study objective is to examine the impact of obesity on frontline carboplatin dosing in the neoadjuvant and adjuvant settings and to evaluate the association of dosing with survival among epithelial ovarian cancer (EOC) patients. We selected 1527 women diagnosed with EOC from January 1, 2011 to October 20, 2021 from a nationwide electronic health record-derived de-identified database. The dose reduction of frontline carboplatin was defined as a relative dose intensity (RDI) < 0.85. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of RDI with survival overall and by histology. Women with a BMI ≥ 30 kg/m2 versus <30 kg/m2 were more likely to be underdosed (RDI < 0.85) with frontline carboplatin. Underdosing of carboplatin in the neoadjuvant setting was associated with worse survival among women with serous tumours (HR = 1.98, 95% CI = 1.15, 3.42). Underdosing of carboplatin in the adjuvant setting was not associated with survival. In the real-world setting, underdosing of carboplatin in the neoadjuvant setting was associated with inferior survival among women with serous tumours. With the increasing utilisation of neoadjuvant chemotherapy in EOC, actual weight-based dosing of carboplatin may be important to improve outcomes in this patient population.

Association between CT-based body composition assessment and patient outcomes during neoadjuvant chemotherapy for epithelial ovarian cancer

ObjectiveThe aim of this study was to characterize the body composition of patients undergoing neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC), identify factors associated with sarcopenia at diagnosis, and evaluate the impact of pretreatment sarcopenia and changes in body composition parameters during therapy on perioperative and disease-related outcomes. MethodsPatients undergoing NACT for EOC between 2008 and 2020 were identified. Pre-treatment and post-treatment contrast-enhanced CT scans were reviewed to determine skeletal muscle index (SMI) and visceral adipose tissue (VAT) area at the mid-fourth lumbar vertebral level. SMI and VAT were analyzed for association with clinical and treatment variables. Results174 patients were identified. Mean pretreatment SMI and VAT were 38.3 cm2/m2 ± 7.9 and 51.2 cm2/m2 ± 34.3, respectively. Comparatively, mean post-treatment SMI and VAT were 37.8 cm2/m2 ± 7.9 and 43.7 cm2/m2 ± 29.7, respectively. Most patients exhibited an overall decrease in SMI from pretreatment to posttreatment scans. Caucasian race, older age, and lower body mass index at diagnosis were associated with lower pretreatment SMI. Lower pre-treatment SMI was associated with lower surgical complexity scores (p < 0.001) and estimated blood loss (p = 0.029). Decrease in SMI after NACT was associated with increased rates of ICU admissions and length of stay. While there was no association between SMI and overall survival (OS) or progression-free survival (PFS), >2% decrease per 100 days in VAT was significantly associated with worse OS. ConclusionsPatients with lower pretreatment SMI tend to undergo less complex surgery than those with higher SMI despite NACT. Decrease in VAT may be a potential indicator of worse OS. Information on body composition can aid in clinical decision making in patients with EOC.

Cost-effectiveness of poly-(ADP-ribose) polymerase (PARP)-inhibitors for the maintenance treatment after responding to first- and second-line chemotherapy in advanced ovarian cancer.

The introduction of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of women with epithelial ovarian cancers (EOC) has radically changed the treatment in maintenance setting after responding to first- and second-line chemotherapy. The aim of this paper was to assess the pharmacological costs of PARP inhibitors (olaparib, niraparib, rucaparib and veliparib) in maintenance treatment after responding to first-line chemotherapy in EOC. Incremental cost-effectiveness ratio (ICER) was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (progression-free survival (PFS)). We have considered the pivotal phase III randomized controlled trials (RCTs). Three different populations were considered: the overall population, patients with germline BRCA mutation (gBRCA) and homologous recombination deficiency (HRD) patients non-gBRCA mutation. Three thousand four hundred and twenty patients and 1209 patients were considered in maintenance treatment after responding to first- and second-line chemotherapy in EOC, respectively. At the actual price, the treatment with PARP inhibitors is not cost-effective in maintenance treatment after responding to first-line and second-line chemotherapy in EOC. A reduction in pharmacological costs is mandatory.

192P Human epididymis protein 4 as a predictor of response to neoadjuvant chemotherapy in epithelial ovarian cancer

Neoadjuvant chemotherapy is the best option for most epithelial ovarian cancers as they present in stage III & IV.The important determinants of survival in ovarian cancer include complete cytoreduction and response to platinum based chemotherapy . HE4, a novel biomarker was found to be better predictor of optimal cytoreduction and platinum sensitivity compared to CA 125 which has low sensitivity and specificity in premenopausal women. This study is done to assess the role of serum marker HE4 in predicting response to chemotherapy in epithelial ovarian cancer.

IDO1 Modulates the Sensitivity of Epithelial Ovarian Cancer Cells to Cisplatin through ROS/p53-Dependent Apoptosis.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase that may play a part in chemoresistance in ovarian cancer. However, its role in cisplatin (DDP) resistance is unclear. Here, the expression level of IDO1 in tumors in platinum-resistant (n = 22) and -sensitive (n = 46) ovarian cancer patients was determined, and then how IDO1 modulated DDP resistance was explored in vitro and in vivo. The IDO1 expression level in platinum-resistant patients was higher than that in -sensitive patients, and a higher IDO1 level was correlated with poor prognosis in type II cancer patients. Up-regulating IDO1 decreased DDP-induced apoptosis in SKOV3 cells via inhibiting the ROS/p53 cell-death pathway, thereby attenuating cytotoxicity of DDP. Silencing IDO1 enhanced p53-dependent apoptosis by increasing ROS accumulation, thereby enhancing DDP against SKOV3 cells. Down-knocking IDO1 augmented the action of DDP in vivo. These data demonstrated that silencing IDO1 enhanced the efficacy of DDP by intensifying p53-dependent apoptosis, and that targeting IDO1 can be a strategy to modulate DDP-based chemotherapy for epithelial ovarian cancer.

Does protracted chemotherapy have an influence on the clinical outcomes in advanced epithelial ovarian cancer?

In epithelial ovarian cancer, first-line adjuvant chemotherapy is necessary, and patients sometimes require protraction; however, there are only a few recent studies to show its influence. In this study, we investigated whether the protraction of the total period of first-line chemotherapy has a negative influence on the survival outcomes.Of the 101 patients we recruited from February 2011 to February 2021, 70 (69.3%) and 31 (30.7%) were classified into the not protracted and protracted groups, respectively. They underwent surgery and adjuvant chemotherapy for epithelial ovarian cancer. Protraction was defined as the overall duration of the first-line chemotherapy being more than 20 days longer than intended. Number of patients who underwent additional treatments such as bevacizumab or poly(adenosine diphosphate ribose) polymerase inhibitors or pembrolizumab was compared between both groups. Kaplan–Meier survival analysis and Cox regression analysis were used for survival outcomes.There was no significant difference for additional treatments. The progression-free survival (PFS) in the total follow-up period in the protracted group was significantly shorter than that in the not protracted group (P = .037); however, the difference in the overall survival between the 2 groups was not significant (P = .223). For the PFS, the hazard ratio of protraction was 1.646 in the univariate analysis (95% confidence interval, 1.020–2.658; P = .041).Excessive protraction of chemotherapy over 20 days or more can result in significantly shorter PFS within 5 years. A better therapeutic strategy is required for patients requiring protracted first-line chemotherapy in advanced epithelial ovarian cancer.

Estimating the Risk for Secondary Cancer After Targeted α-Therapy with 211At Intraperitoneal Radioimmunotherapy.

Intraperitoneal 211At-based targeted α-therapy (TAT) may hold great promise as an adjuvant therapy after surgery and chemotherapy in epithelial ovarian cancer to eradicate any remaining undetectable disease. This implies that it will also be delivered to patients possibly already cured by the primary treatment. An estimate of long-term risks is therefore sought to determine whether the treatment is justified. Methods: Baseline data for risk estimates of α-particle irradiation were collected from published studies on excess cancer induction and mortality for subjects exposed to either 224Ra treatments or Thorotrast contrast agent (25% ThO2 colloid, containing 232Th). Organ dosimetry for 224Ra and Thorotrast irradiation were taken from the literature. These organ-specific risks were then applied to our previously reported dosimetry for intraperitoneal 211At-TAT patients. Results: Risk could be estimated for 10 different organ or organ groups. The calculated excess relative risk per gray (ERR/Gy) could be sorted into 2 groups. The lower-ERR/Gy group, ranging up to a value of approximately 5, included trachea, bronchus, and lung, at 0.52 (95% CI, 0.21-0.82); stomach, at 1.4 (95% CI, -5.0-7.9); lymphoid and hematopoietic system, at 2.17 (95% CI, 1.7-2.7); bone and articular cartilage, at 2.6 (95% CI, 2.0-3.3); breast, at 3.45 (95% CI, -10-17); and colon, at 4.5 (95% CI, -3.5-13). The higher-ERR/Gy group, ranging from approximately 10 to 15, included urinary bladder, at 10.1 (95% CI, 1.4-23); liver, at 14.2 (95% CI, 13-16); kidney, at 14.9 (95% CI, 3.9-26); and lip, oral cavity, and pharynx, at 15.20 (95% CI, 2.73-27.63). Applying a typical candidate patient (female, age 65 y) and correcting for the reference population mortality rate, the total estimated excess mortality for an intraperitoneal 211At-monoclonal antibody treatment amounted to 1.13 per 100 treated. More than half this excess originated from urinary bladder and kidney, 0.29 and 0.34, respectively. Depending on various adjustments in calculation and assumptions on competing risks, excess mortality could range from 0.11 to 1.84 per 100 treated. Conclusion: Published epidemiologic data on lifelong detriment after α-particle irradiation and its dosimetry allowed calculations to estimate the risk for secondary cancer after 211At-based intraperitoneal TAT. Measures to reduce dose to the urinary organs may further decrease the estimated relative low risk for secondary cancer from 211At-monoclonal antibody-based intraperitoneal TAT.

Optimizing regional chemotherapy for epithelial ovarian cancer.

The response with intravenous chemotherapy using cisplatin and paclitaxel in patients with advanced ovarian cancer is often substantial. However, this regression of the malignancy is not durable, and a majority of patients succumb to this disease process. It is possible that alternative types of chemotherapy and alternative routes of chemotherapy administration can improve the results of treatment and perhaps, reduce the morbidity and mortality that patients experience. Regional chemotherapy treatments previously presented in the ovarian cancer literature were reviewed and critically analyzed. New methods for chemotherapy delivery for both advanced primary and recurrent ovarian cancer were reviewed. This included hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC), and normothermic intraperitoneal chemotherapy (NIPEC) long-term. An important addition to perioperative chemotherapy delivery is the simultaneous use of heat with intraperitoneal drug delivery after a complete cytoreductive surgery. Drugs to be considered for HIPEC are cisplatin, gemcitabine, and melphalan. For EPIC, chemotherapy agents to consider include paclitaxel, pemetrexed, gemcitabine, and liposomal doxorubicin. For NIPEC, paclitaxel is the drug of choice usually combined with a systemic agent as bidirectional chemotherapy. Also, pemetrexed, gemcitabine, and liposomal doxorubicin are drugs to be considered for NIPEC in phase I/II trials. Innovative regimens of regional chemotherapy may improve the outcome of patients with advanced ovarian cancer. These chemotherapy treatments must be integrated with complete cytoreductive surgery and the availability of peritoneal access for repeated delivery of chemotherapy solutions.

Bruceine D Sensitizes Human Ovarian Cancer Cells to Paclitaxel Through JNK and STAT3 Signal Regulation

Exploring novel regimens is essential to ensure the efficacy of paclitaxel-based chemotherapy in epithelial ovarian cancer. Brucea javanica (L.) Merr., Simaroubaceae, oil emulsion benefits the patients who received sequential chemotherapy, and bruceine D is identified as the major active tetracyclic quassinoid. On this premise, we explored the potential effects and related molecular mechanisms of bruceine D on epithelial ovarian cancer cells. Our study indicated an inhibitory effect of bruceine D treatment in epithelial ovarian cancer cells. Increased cell apoptosis and cancer stem cell elimination were observed with combined treatment of bruceine D and paclitaxel in ovarian cancer cells. Mechanism study indicated that JNK and STAT3 signaling regulation contributed to the synergistic effects of bruceine D in paclitaxel-based chemotherapy. Our study revealed a synergistic effect of bruceine D in paclitaxel-based chemotherapy. Our investigation provided a valuable strategy to enhance the efficiency of chemotherapy in ovarian cancer.Graphical abstract

The Role of Prophylactic Application of Granulocyte Colony Stimulating Factor in Adjuvant Chemotherapy for Epithelial Ovarian Cancer

The goal of this study was to investigate the relative merits of granulocyte colony stimulating factor (G-CSF) prophylaxis for patients with epithelial ovarian cancer (EOC). The Institutional Review Board of the Women's Hospital, Zhejiang University School of Medicine has approved this study (No. IRB-20200132-R) with a waiver of informed consent. Patients with EOC who received the combination of a platinum drug and paclitaxel (TP) chemotherapy regimens in the hospital from January 1, 2016, to November 30, 2020, were included in this retrospective cohort study. To assess clinical effectiveness, patients were categorized into groups who received either long-acting G-CSF or short-acting G-CSF prophylaxis with and without prophylaxis. The incidence of neutropenia and adverse events were compared between groups. All results of chemotherapy were pooled for analysis. Of the identified cases, 128 patients were evaluated. Long-acting G-CSF and short-acting G-CSF were applied in 51 and 41 patients, respectively. The absolute neutrophil count at the nadir was significantly lower in patients with G-CSF prophylaxis than those without G-CSF (p = 0.001). The duration of ANC levels < 2.0 x 109/L in cycles using short-acting G-CSF was longer than that in those receiving long-acting G-CSF (p = 0.045). There were no serious adverse events observed in patients with G-CSF. No significant differences in the incidence of febrile neutropenia (FN) and duration of grade 2 - 4 neutropenia were observed between groups receiving G-CSF prophylaxis and those without. Primary prophylaxis with G-CSF in chemotherapy for epithelial ovarian cancer appears to be of low value in terms of its relationship to the incidence of FN and prognosis.

Survival Outcomes With Reduced Doses of Adjuvant Chemotherapy in Advanced Epithelial Ovarian Cancer.

There have not been enough recent studies investigating the incidence or efficacy of dose reduction in adjuvant chemotherapy for epithelial ovarian cancer. This study examined whether patients who needed dose reduction showed poorer survival outcomes. From 2011 to 2021, 102 patients were included in the study. Patients who underwent neoadjuvant chemotherapy and those with early-stage disease were excluded. Patients were divided into two groups: those who had a ≥60% dose reduction during the whole period of first-line adjuvant chemotherapy, and those with dose reductions <60%. Of the 102 patients, 38 (37.3%) underwent dose reduction ≥60%. PFS was significantly longer in the group whose dose reductions were ≥60%, whereas OS was not significant. A dose reduction of ≥60%, determined by patients' medical conditions, during first-line of adjuvant chemotherapy does not negatively influence survival outcomes, such as OS and PFS, in advanced epithelial ovarian cancer.

Hyperthermic Intraperitoneal Chemotherapy for Epithelial Ovarian Cancer: A Systemic Review and Meta-Analysis

Hyperthermic Intraperitoneal Chemotherapy for Epithelial Ovarian Cancer: A Systemic Review and Meta-Analysis

Differential Benefit from Fractionated Dose-Dense First-Line Chemotherapy for Epithelial Ovarian Cancer (EOC) According to Kelim-Evaluated Tumour Primary Chemosensitivity: Exploratory Analysis of Icon-8 Trial

Differential Benefit from Fractionated Dose-Dense First-Line Chemotherapy for Epithelial Ovarian Cancer (EOC) According to Kelim-Evaluated Tumour Primary Chemosensitivity: Exploratory Analysis of Icon-8 Trial

Hymenialdisine is Cytotoxic Against Cisplatin-Sensitive but Not Against Cisplatin-Resistant Cell Lines.

ObjectivesNew compounds are needed to overcome the resistance to commonly used cytotoxic chemotherapy for epithelial ovarian cancer. Marine sponges are a rich source of diverse chemical compounds and hymenialdisine has been found to have antiproliferative effects. This study aimed to investigate the cytotoxic effect of hymenialdisine in cisplatin-sensitive and cisplatin resistant ovarian cancer cell lines.MethodsThis study took place at Sultan Qaboos University, Muscat, Oman between August and November, 2019. The anti-cancer effects of hymenialdisine or cisplatin were assessed using treating cells with different concentrations of hymenialdisine and cisplatin. Cell viability was determined using the AlamarBlue® Assay.ResultsThe half-maximal inhibitory concentration (IC50) of cisplatin was estimated at 31.4 μM for A2780S and 76.9 μM for A2780CP, whereas the IC50 of hymenialdisine was evaluated at 146.8 μM for A2780S cells. Despite the higher concentrations of hymenialdisine (up to 300 μM), IC50 could not be determined for the A2780CP cell line.ConclusionWhen compared to cisplatin, hymenialdisine was less toxic against both A2780S and A2780CP ovarian cancer cell lines.

LDLR-mediated lipidome-transcriptome reprogramming in cisplatin insensitivity

Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptor-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularities, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients' disease prognosis. In vitro and in vivo add-in/silencing LDLR was introduced to determine cisplatin sensitivity and cancer growth. Results revealed that knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR→LPC (Lyso-phosphatidylcholine)→FAM83B (phospholipase-related)→FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR→LPC→FAM83B→FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs. Significance: this study describes the role of LDLR in the development of insensitivity to platinum-based chemotherapy in epithelial ovarian cancer. The lipidome (e.g., LPC) and transcriptome (e.g., FAM38B) interactions revealed using trans-omics approaches an LDLR→LPC→FAM83B→FGFRs regulatory axis in cancer cells, in an animal model, and in patients.

Diffusion-weighted MRI and PET/CT reproducibility in epithelial ovarian cancers during neoadjuvant chemotherapy

PurposeTo investigate the reproducibility of diffusion-weighted (DW) MRI and 18F-Fluorodeoxyglucose (18F-FDG)-Positron emission tomography/CT (PET/CT) in monitoring response to neoadjuvant chemotherapy in epithelial ovarian cancer. Materials and methodsTen women (median age, 67 years; range: 41.8–77.3 years) with stage IIIC-IV epithelial ovarian cancers were included in this prospective trial (NCT02792959) between 2014 and 2016. All underwent initial laparoscopic staging, four cycles of carboplatine-paclitaxel-based chemotherapy and interval debulking surgery. PET/CT and DW-MRI were performed at baseline (C0), after one cycle (C1) and before surgery (C4). Two nuclear physicians and two radiologists assessed five anatomic sites for the presence of ≥1 lesion. Target lesions in each site were defined and their apparent diffusion coefficient (ADC), maximal standardized uptake value (SUV-max), SUV-mean, SUL-peak, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were monitored (i.e., 10 patients ×5 sites ×3 time-points). Their relative early and late changes were calculated. Intra/inter-observer reproducibilities of qualitative and quantitative analysis were estimated with Kappa and intra-class correlation coefficients (ICCs). ResultsFor both modalities, inter- and intra-observer agreement percentages were excellent for initial staging but declined later for DW-MRI, leading to lower Kappa values for inter- and intra-observer variability (0.949 and 1 at C0, vs. 0.633 and 0.643 at C4, respectively) while Kappa values remained>0.8 for PET/CT. Inter- and intra-observer ICCs were>0.75 for SUV-max, SUL-peak, SUV-mean and their change regardless the time-point. ADC showed lower ICCs (range: 0.013–0.811). ANOVA found significant influences of the evaluation time, the measurement used (ADC, SUV-max, SUV-mean, SUV-max, SUL-peak, MTV or TLG) and their interaction on ICC values (P=0.0023, P<0.0001 and P =0.0028, respectively). ConclusionWhile both modalities demonstrated high reproducibility at baseline, only SUV-max, SUL-peak, SUV-mean and their changes maintained high reproducibility during chemotherapy.