High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines.

OBJECTIVE: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells. METHODS: Cell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting. RESULTS: High-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells. CONCLUSIONS: Ascorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.

Chemotherapy response in low-grade serous ovarian carcinoma at a comprehensive cancer center: Readdressing the roles of platinum and cytotoxic therapies.

BACKGROUND: Data on platinum sensitivity of low-grade serous ovarian carcinoma (LGSOC) in the upfront setting is lacking, and there is limited and contradictory information on chemotherapy responses in recurrent disease. METHODS: Patients with LGSOC seen at a comprehensive cancer center from January 1, 1998 to September 30, 2021 were identified from institutional databases. Response to neoadjuvant chemotherapy (NACT) or adjuvant platinum-based chemotherapy and to second- to fifth-line regimens was retrospectively characterized by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Wilcoxon rank-sum and two-tailed Fisher exact tests were employed. RESULTS: Of 50 patients, 12 received platinum doublets for suboptimal residual disease and 11 as NACT. Of 12 patients with suboptimal residual disease, seven (58%) achieved objective responses (five partial responses [PRs] and two complete responses); of the 11 patients who underwent NACT, one (9%) achieved a PR (p = .027). The 15 remaining patients had stable disease on first-line platinum chemotherapy. Of 44 patients who recurred, 20 had RECIST-evaluable responses to second-line and 27 to third-line chemotherapy. Objective response rates to platinum-based chemotherapy were 22% (two of nine) in the second line and 10% (one of 10) in the third. In second and third lines, highest response rates were observed with nonplatinum chemotherapy with bevacizumab, at 100% (two of two) and 30% (three of 10), respectively. CONCLUSIONS: Primary platinum-based chemotherapy has moderate activity in LGSOC and minimal activity in the recurrent setting, suggesting standard definitions of platinum sensitivity may not apply in LGSOC. In the second and third lines, nonplatinum chemotherapy/bevacizumab elicited the highest response rates.

Targeted Therapies in the Treatment of Uterine Serous Carcinoma.

OPINION STATEMENT: Despite the dismal prognosis of uterine serous carcinoma (USC), recent advances in molecular classification and targeted treatments have demonstrated improvements in survival outcomes for patients both in the upfront and recurrent treatment settings. After appropriate surgical staging and surgical cytoreduction as indicated, correct pathologic and molecular classification of USC is important to provide the most appropriate systemic adjuvant treatment. HER2-targeted agents are one of the most important advances in the treatment of USC in decades. Thus, for HER2-positive tumors, the addition of trastuzumab to conventional chemotherapy is indicated in those with advanced stage and/or recurrent disease. Treatment with pembrolizumab and lenvatinib suggests a 50% response rate in women with recurrent disease which serves as a promising targeted treatment strategy. Overall, emerging targeted therapeutic options with antibody-drug conjugates (i.e. targeting HER2, folic acid receptor alpha, or Trop-2), combinations of immunotherapies and tyrosine kinase inhibitors, PARP inhibitors, WEE1 inhibitors, and AKT inhibitors shed further promise in advancements of effective disease-modifying treatments for this unmet medical need for patients with USC. Several trials evaluating these targeted agents are ongoing, and those results are eagerly awaited. As such, enrollment of patients in clinical trials is highly recommended as it will provide patients with a higher level of personalized cancer care.

Molecular Mechanism of Gleditsiae Spina for the Treatment of High-Grade Serous Ovarian Cancer Based on Network Pharmacology and Pharmacological Experiments.

Background: Gleditsiae Spina, widely used in traditional Chinese medicine, has a good curative effect on malignant tumors such as ovarian cancer, but the mechanism is not clear. So, we aimed to analyze the pharmacological mechanism of Gleditsiae Spina in the treatment of high-grade serous ovarian cancer (HGSC) based on network pharmacology and biological experiments. Methods: The main active ingredients of Gleditsiae Spina were identified by high performance liquid chromatography (HPLC) and mass spectrometry (MS), and the active ingredients were performed by ADME screening. The component targets of Gleditsiae Spina were screened using the PharmMapper platform, and differentially expressed genes in normal and HGSC tissues were identified through the GEO database. Thereafter, the network of "active ingredient-targets" was constructed by cytoscape 3.7.2 software. The protein-protein interaction network was established by the BioGenet database to mine the potential protein function. Biological processes and pathways were analyzed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The binding ability of the core components of the Gleditsiae Spina and the core target of HGSC was verified by molecular docking and molecular dynamics simulation, and the therapeutic effect of Gleditsiae Spina was proved in vitro through cytotoxicity experiments. The effect of Gleditsiae Spina on the core pathway is obtained by western blotting. Results: Gleditsiae Spina had cytotoxicity on HGSC based on network pharmacology and biological experiments. Luteolin, genistein, D-(+)-tryptophan, ursolic acid, and berberine are the identified core active ingredients of Gleditsiae Spina for regulating HGSC, with HPSE, PI3KCA, AKT1, and CTNNB1as the ideal targets. The prediction results were verified by molecular docking, molecular dynamic simulation, cell viability, and western blot analysis. Conclusion: Gleditsiae Spina mainly downregulates the expression of heparanase and ß-catenin to affect the composition of tumor cytoplasmic matrix and can regulate the PI3K-AKT pathway, integrating multiple targets and multiple pathways to play a therapeutic role. It also provides a theoretical basis for the prevention of ovarian cancer and its treatment using traditional Chinese medicine in the future.

Cytoreductive Surgery and Intraperitoneal Chemotherapy in Advanced Serous Epithelial Ovarian Cancer: A 14-Year French Retrospective Single-Center Study of 124 Patients.

INTRODUCTION: Ovarian cancer (OC) is the most lethal gynecological cancer. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy appears to increase survival, and normothermic intraperitoneal chemotherapy (IPC) could improve overall survival (OS). Furthermore, intraperitoneal epinephrine could decrease the toxicity of chemotherapy by decreasing the systemic absorption of chemotherapy. The goal of this study was to assess the effects of CRS and IPC with intraperitoneal epinephrine, as first-line therapy, on the survival of patients with serous epithelial OC (EOC) with peritoneal metastases. METHODS: A prospective monocentric database was retrospectively searched for all patients with advanced serous EOC treated by interval or consolidative CRS plus IPC with intraperitoneal epinephrine after neoadjuvant chemotherapy. OS and disease-free survival (DFS), postoperative complications, and prognostic factors were analyzed. RESULTS: From January 2003 to December 2017, 124 patients with serous EOC were treated with interval (n = 58) or consolidative (n = 66) complete CRS plus IPC with intraperitoneal epinephrine. The median follow-up was 77.8 months, the median OS was 60.8 months, and the median DFS was 21.2 months. In our multivariate analysis, a higher Peritoneal Cancer Index (PCI) and positive lymph node status resulted in worse OS, while higher World Health Organization score, higher PCI score, and positive lymph node status were risk factors for worse DFS. Grade 3 or higher surgical morbidity occurred in 27.42% of cases; only 3.2% had grade 3 renal toxicity and mortality was 0.8%. CONCLUSION: CRS and IPC with intraperitoneal epinephrine in stage III EOC offer good OS and DFS with acceptable morbidity and mortality rates.

Artificial intelligence-based image analysis can predict outcome in high-grade serous carcinoma via histology alone.

High-grade extrauterine serous carcinoma (HGSC) is an aggressive tumor with high rates of recurrence, frequent chemotherapy resistance, and overall 5-year survival of less than 50%. Beyond determining and confirming the diagnosis itself, pathologist review of histologic slides provides no prognostic or predictive information, which is in sharp contrast to almost all other carcinoma types. Deep-learning based image analysis has recently been able to predict outcome and/or identify morphology-based representations of underlying molecular alterations in other tumor types, such as colorectal carcinoma, lung carcinoma, breast carcinoma, and melanoma. Using a carefully stratified HGSC patient cohort consisting of women (n = 30) with similar presentations who experienced very different treatment responses (platinum free intervals of either ≤ 6 months or ≥ 18 months), we used whole slide images (WSI, n = 205) to train a convolutional neural network. The neural network was trained, in three steps, to identify morphologic regions (digital biomarkers) that are highly associating with one or the other treatment response group. We tested the classifier using a separate 22 slide test set, and 18/22 slides were correctly classified. We show that a neural network based approach can discriminate extremes in patient response to primary platinum-based chemotherapy with high sensitivity (73%) and specificity (91%). These proof-of-concept results are novel, because for the first time, prospective prognostic information is identified specifically within HGSC tumor morphology.

MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy.

OBJECTIVE: Platinum compounds have been widely used as a primary treatment for many types of cancer. However, resistance is the major cause of therapeutic failure for patients with metastatic or recurrent disease, thus highlighting the need to identify novel factors driving resistance to Platinum compounds. Metadherin (MTDH, also known as AEG-1 and LYRIC), located in a frequently amplified region of chromosome 8, has been consistently associated with resistance to chemotherapeutic agents, though the precise mechanisms remain incompletely defined. METHODS: The mRNA of FANCD2 and FANCI was pulled down by RNA-binding protein immunoprecipitation. Pristimerin-loaded nanoparticles were prepared using the nanoprecipitation method. Immunocompromised mice bearing patient-derived xenograft tumors were treated with pristimerin-loaded nanoparticles, cisplatin and a combination of the two. RESULTS: MTDH, through its recently discovered role as an RNA binding protein, regulates expression of FANCD2 and FANCI, two components of the Fanconi anemia complementation group (FA) that play critical roles in interstrand crosslink damage induced by platinum compounds. Pristimerin, a quinonemethide triterpenoid extract from members of the Celastraceae family used to treat inflammation in traditional Chinese medicine, significantly decreased MTDH, FANCD2 and FANCI levels in cancer cells, thereby restoring sensitivity to platinum-based chemotherapy. Using a patient-derived xenograft model of endometrial cancer, we discovered that treatment with pristimerin in a novel nanoparticle formulation markedly inhibited tumor growth when combined with cisplatin. CONCLUSIONS: MTDH is involved in post-transcriptional regulation of FANCD2 and FANCI. Pristimerin can increase sensitivity to platinum-based agents in tumors with MTDH overexpression by inhibiting the FA pathway.

Pectasol-C Modified Citrus Pectin targets Galectin-3-induced STAT3 activation and synergize paclitaxel cytotoxic effect on ovarian cancer spheroids.

Here we sought to determine the relationship between STAT3 activity and Galectin-3 (Gal-3) and to investigate the cytotoxic effect of PectaSol-C Modified Citrus Pectin (Pect-MCP) as a specific competitive inhibitor of Galectin-3 (Gal-3) in combination with Paclitaxel (PTX) to kill the ovarian cancer cell SKOV-3 multicellular tumor spheroid (MCTS). To this order, SKOV-3 cells in 2D and 3D cultures were treated with exogenous Gal-3 for the assessment of STAT3 activity. Two-way ANOVA main effect and IC50 of each drug Paclitaxel (PTX) and Pect-MCP or in combination were obtained from MTT assay results. The phosphorylated STAT3 levels, migration, invasion, integrin mRNA and p-AKTser473 levels were assessed in the absence or presence of each drug alone or in combination. Gal-3 expression levels were assessed in human serous ovarian cancer (SOC) specimens and its correlation with different integrin mRNA levels was further assessed. Our results showed that Gal-3 expression level was significantly increased in MCTS compared to monolayer SKOV-3 cells which triggered STAT3 phosphorylation. Moreover, Pect-MCP synergized with PTX to kill SKOV3 MCTS through abrogation of STAT3 activity and reduced expression of its downstream target HIF-1α, reduced integrin mRNA levels, and subsequently decreased AKT activity. There were higher expression levels of Gal-3 in human high-grade SOC specimens compared to the normal ovary and borderline SOC which positively and significantly correlated with α5, ß2 and ß6 integrin mRNA levels. Together, these results revealed for the first time that Pect-MCP could be considered as a potential drug to enhance the PTX effect on ovarian cancer cells MCTS through inhibition of STAT3 activity.

Phosphorylation of STAT1 serine 727 enhances platinum resistance in uterine serous carcinoma.

Uterine serous carcinoma (USC) is a highly aggressive histological subtype of endometrial cancers harboring highly metastatic and chemoresistant features. Our previous study showed that STAT1 is highly expressed in USC and acts as a key molecule that is positively correlated with tumor progression, but it remains unclear whether STAT1 is relevant to the malicious chemorefractory nature of USC. In the present study, we investigated the regulatory role of STAT1 toward platinum-cytotoxicity in USC. STAT1 suppression sensitized USC cells to increase cisplatin-mediated apoptosis (p < 0.001). Furthermore, phosphorylation of STAT1 was prominently observed on serine-727 (pSTAT1-Ser727), but not on tyrosine-701, in the nucleus of USC cells treated with cisplatin. Mechanistically, the inhibition of pSTAT1-Ser727 by dominant-negative plasmid elevated cisplatin-mediated apoptosis by increasing intracellular accumulation of cisplatin through upregulation of CTR1 expression. TBB has an inhibitory effect on casein kinase 2 (CK2), which phosphorylate STAT1 at serine residues. Sequential treatment with TBB and cisplatin on USC cells greatly reduced nuclear pSTAT1-Ser727, enhanced intracellular accumulation of cisplatin, and subsequently increased apoptosis. Tumor load was significantly reduced by combination therapy of TBB and cisplatin in in vivo xenograft models (p < 0.001). Our results collectively suggest that pSTAT1-Ser727 may play a key role in platinum resistance as well as tumor progression in USC. Thus, targeting the STAT1 pathway via CK2 inhibitor can be a novel method for attenuating the chemorefractory nature of USC.

Predictors of Long-Term Survival among High-Grade Serous Ovarian Cancer Patients.

BACKGROUND: Relatively little is known about factors associated with long-term survival (LTS) following a diagnosis of ovarian cancer. METHODS: We conducted a retrospective study of high-grade serous ovarian cancer (HGSOC) to explore predictors of LTS (defined as ≥7 years of survival) using electronic medical record data from a network of integrated health care systems. Multivariable logistic regression with forward selection was used to compare characteristics of women who survived ≥7 years after diagnosis (n = 148) to those who died within 7 years of diagnosis (n = 494). RESULTS: Our final model included study site, age, stage at diagnosis, CA-125, comorbidity score, receipt of chemotherapy, BMI, and four separate comorbid conditions: weight loss, depression, hypothyroidism, and liver disease. Of these, only younger age, lower stage, and depression were statistically significantly associated with LTS. CONCLUSIONS: We did not identify any new characteristics associated with HGSOC survival. IMPACT: Prognosis of ovarian cancer generally remains poor. Large, pooled studies of ovarian cancer are needed to identify characteristics that may improve survival.

Molecular Characterization of Non-responders to Chemotherapy in Serous Ovarian Cancer.

Nearly one-third of patients with high-grade serous ovarian cancer (HGSC) do not respond to initial treatment with platinum-based therapy. Genomic and clinical characterization of these patients may lead to potential alternative therapies. Here, the objective is to classify non-responders into subsets using clinical and molecular features. Using patients from The Cancer Genome Atlas (TCGA) dataset with platinum-resistant or platinum-refractory HGSC, we performed a genome-wide unsupervised cluster analysis that integrated clinical data, gene copy number variations, gene somatic mutations, and DNA promoter methylation. Pathway enrichment analysis was performed for each cluster to identify the targetable processes. Following the unsupervised cluster analysis, three distinct clusters of non-responders emerged. Cluster 1 had overrepresentation of the stage IV disease and suboptimal debulking, under-expression of miRNAs and mRNAs, hypomethylated DNA, "loss of function" TP53 mutations, and the overexpression of genes in the PDGFR pathway. Cluster 2 had low miRNA expression, generalized hypermethylation, MUC17 mutations, and significant activation of the HIF-1 signaling pathway. Cluster 3 had more optimally cytoreduced stage III patients, overexpression of miRNAs, mixed methylation patterns, and "gain of function" TP53 mutations. However, the survival for all clusters was similar. Integration of genomic and clinical data from patients that do not respond to chemotherapy has identified different subgroups or clusters. Pathway analysis further identified the potential alternative therapeutic targets for each cluster.

P-MAPA immunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling.

BACKGROUND: Toll-like receptors (TLRs) are transmembrane proteins expressed on the surface of ovarian cancer (OC) and immune cells. Identifying the specific roles of the TLR-mediated signaling pathways in OC cells is important to guide new treatments. Because immunotherapies have emerged as the adjuvant treatment for patients with OC, we investigated the effect of a promising immunotherapeutic strategy based on protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) combined with cisplatin (CIS) on the TLR2 and TLR4 signaling pathways via myeloid differentiation factor 88 (MyD88) and TLR-associated activator of interferon (TRIF) in an in vivo model of OC. METHODS: Tumors were chemically induced by a single injection of 100 µg of 7,12-dimethylbenz(a)anthracene (DMBA) directly under the left ovarian bursa in Fischer 344 rats. After the rats developed serous papillary OC, they were given P-MAPA, CIS or the combination P-MAPA+CIS as therapies. To understand the effects of the treatments, we assessed the tumor size, histopathology, and the TLR2- and TLR4-mediated inflammatory responses. RESULTS: Although CIS therapy was more effective than P-MAPA in reducing the tumor size, P-MAPA immunotherapy significantly increased the expressions of TLR2 and TLR4. More importantly, the combination of P-MAPA with CIS showed a greater survival rate compared to CIS alone, and exhibited a significant reduction in tumor volume compared to P-MAPA alone. The combination therapy also promoted the increase in the levels of the following OC-related proteins: TLR4, MyD88, TRIF, inhibitor of phosphorylated NF-kB alpha (p-IkBα), and nuclear factor kappa B (NF-kB p65) in both cytoplasmic and nuclear sites. While P-MAPA had no apparent effect on tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6, it seems to increase interferon-γ (IFN-γ), which may induce the Thelper (Th1)-mediated immune response. CONCLUSION: Collectively, our results suggest that P-MAPA immunotherapy combined with cisplatin could be considered an important therapeutic strategy against OC cells based on signaling pathways activated by TLR4.

Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats.

Angiogenesis is a hallmark of ovarian cancer (OC); the ingrowth of blood vessels promotes rapid cell growth and the associated metastasis. Melatonin is a well-characterized indoleamine that possesses important anti-angiogenic properties in a set of aggressive solid tumors. Herein, we evaluated the role of melatonin therapy on the angiogenic signaling pathway in OC of an ethanol-preferring rat model that mimics the same pathophysiological conditions occurring in women. OC was chemically induced with a single injection of 7,12-dimethylbenz(a)anthracene (DMBA) under the ovarian bursa. After the rats developed serous papillary OC, half of the animals received intraperitoneal injections of melatonin (200 µg/100 g body weight/day) for 60 days. Melatonin-treated animals showed a significant reduction in OC size and microvessel density. Serum levels of melatonin were higher following therapy, and the expression of its receptor MT1 was significantly increased in OC-bearing rats, regardless of ethanol intake. TGFß1, a transforming growth factor-beta1, was reduced only after melatonin treatment. Importantly, vascular endothelial growth factor (VEGF) was severely reduced after melatonin therapy in animals given or not given ethanol. Conversely, the levels of VEGF receptor 1 (VEGFR1) was diminished after ethanol consumption, regardless of melatonin therapy, and VEGFR2 was only reduced following melatonin. Hypoxia-inducible factor (HIF)-1α was augmented with ethanol consumption, and, notably, melatonin significantly reduced their levels. Collectively, our results suggest that melatonin attenuates angiogenesis in OC in an animal model of ethanol consumption; this provides a possible complementary therapeutic opportunity for concurrent OC chemotherapy.

Expression of hypothalamic-pituitary-gonadal axis-related hormone receptors in low-grade serous ovarian cancer (LGSC).

BACKGROUND: The aim of our study was to investigate the clinical features and expression levels of hypothalamic-pituitary-gonadal axis-related hormone receptors in low-grade serous ovarian cancer (LGSC). METHODS: We retrospectively investigated the clinical features of 26 consecutive patients with LGSC who underwent primary staging or debulking surgery between April 2005 and June 2013 in our center; concomitant primary high-grade serous ovarian cancer (HGSC) patients were randomly selected at a 2:1 ratio for comparison. Tissue microarrays were constructed from the LGSC and HGSC specimens, and the expression levels of six hormone receptors in the hypothalamic pituitary-gonadal axis were analyzed by immunohistochemistry. RESULTS: The median (range) age of patients with LGSC was 54 (27-77) years. According to the FIGO staging system, the cases were distributed as follows: stage I, 6 (23.1%); stage II, 0 (0%); stage III, 19 (73.1%); and stage IV, 1 (3.8%). The 2-year and 5-year overall survival rates for LGSC were 91.8% and 67.5%, respectively. The expression levels of the hormone receptors were as follows: ER, 80.8%; PR, 34.6%; AR, 53.8%; FSHR, 84.0%; LHR, 65.4%; and GnRHR, 100%. Hormone receptor-positive patients had a better prognosis compared with hormone receptor-negative patients, but the difference was not significant. CONCLUSIONS: Our study presented a higher overall survival rate and distinctive hormone receptor expression levels of LGSC patients compared with the HGSC cohort. Patients with positive hormone receptor expression tended to have a better prognosis than the corresponding hormone receptor negative patients.

Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial.

AIM: To perform a subset analysis of patients with very platinum-sensitive recurrent ovarian cancer (ROC) enrolled in the phase III CALYPSO trial. PATIENTS AND METHODS: The international non-inferiority trial enrolled women with ROC that relapsed >6 months following first- or second-line platinum- and paclitaxel-based therapies. Patients were randomised to CD [carboplatin-pegylated liposomal doxorubicin (PLD)] or CP (carboplatin-paclitaxel) and stratified by treatment-free interval (TFI). In this analysis, patients with a TFI>24 months were analysed separately for progression free survival (PFS), the primary endpoint of CALYPSO, overall survival (OS) and safety. RESULTS: A total of 259 very platinum-sensitive patients were included (n=131, CD; n=128, CP). Median PFS was 12.0 months for the CD arm and 12.3 months for CP [HR=1.05 (95% CI, 0.79-1.40); P=0.73 for superiority] and median OS was 40.2 months for CD and 43.9 for CP [HR=1.18 (95% CI 0.85-1.63); P=0.33 for superiority]. Overall response rates were 42% and 38%, respectively (P=0.46). Toxicities were more common with CP versus CD, including grade 3/4 neutropenia (40.8% versus 27.5%; P=0.025), nausea (4.8% versus 3.1%; P=0.47), allergic reaction (8% versus 3.1%; P=0.082) sensory neuropathy (4.8% versus 2.3%; P=0.27) and grade 2 alopecia (88% versus 9.2%; P<0.001). Grade 3/4 thrombocytopenia (12.2% versus 3.2%; P=0.007) and mucositis (2.3% versus 0%; P=0.089) were more common with CD. Grade 3/4 hand-foot syndrome occurred rarely with CD (3 patients versus 0 in CP arm; P=0.089). CONCLUSION: CP and CD were equally effective treatment regimens for patients with very platinum-sensitive ROC. The favourable risk-benefit profile suggests carboplatin-PLD as treatment of choice for these patients.

[Hyperthermic intraperitoneal chemotherapy in the treatment for recurrent ovarian cancer].

There are presented data of literature and own observations of the treatment for recurrent ovarian cancer using hyperthermic intraperitoneal chemoperfusion. The possible complications during hyperthermic chemoperfusion are discussed and the effectiveness of the method is analyzed. Further studies are needed to obtain more certain criteria for abdominal chemotherapy in these patients.

A two-stage, single-arm, phase II study of EGCG-enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer.

OBJECTIVES: A two-stage, single-arm, phase II study was conducted to assess the effectiveness and safety of an epigallocatechin gallate (EGCG)-enriched tea drink, the double-brewed green tea (DBGT), as a maintenance treatment in women with advanced stage serous or endometrioid ovarian cancer (clinicaltrials.gov, NCT00721890). METHODS: Eligible women had FIGO stage III-IV serous or endometrioid ovarian cancer. They had to undergo complete response after debulking surgery followed by 6 to 8 cycles of platinum/taxane chemotherapy at the Centre Hospitalier Universitaire de Québec. They all had to drink the DBGT, 500 mL daily until recurrence or during a follow-up of 18 months. The primary endpoint was the absence of recurrence at 18 months. Statistical analyses were done according to the principle of intention to treat. Using a two-stage design, the first stage consisted of 16 enrolled patients. At the end of the follow-up, if 7 or fewer patients were free of recurrence, the trial stopped. Otherwise, accrual would continue to a total of 46 patients. RESULTS: During the first stage of the study, only 5 of the 16 women remained free of recurrence 18 months after complete response. Accordingly, the clinical trial was terminated. Women's adherence to DBGT was high (median daily intake during intervention, 98.1%, interquartile range: 89.7-100%), but 6 women discontinued the intervention before the end of their follow-up. No severe toxicity was reported. CONCLUSIONS: DBGT supplementation does not appear to be a promising maintenance intervention in women with advanced stage ovarian cancer after standard treatment.

Ex vivo 1H and 31P magnetic resonance spectroscopy as a means for tumor characterization in ovarian cancer patients.

We aimed to determine whether cells obtained from malignant ovarian tumors had different ex vivo 1H- and 31P (phosphorus-31)-magnetic resonance (MR) spectra compared to cells obtained from benign ovarian cysts. In addition, we aimed to assess the metabolic effects of chemotherapy on malignant cells obtained from peritoneal effusions of ovarian cancer patients. We included 20 ovarian cancer patients undergoing explorative laparotomy for tumor resection, 15 patients undergoing oophorectomy for benign ovarian cysts and 8 patients with advanced ovarian cancer with cancerous peritoneal effusion undergoing palliative percutaneous drainage. Ovarian and metastatic tissues were obtained from all patients undergoing laparotomy and analyzed using 1H magnetic resonance spectroscopy (MRS). Cancerous cells from peritoneal effusions were incubated with 3 different anti-mitotic drugs (paclitaxel, cisplatin and carboplatin) at LC50 and the consequent metabolic changes were monitored using 31P-MRS. 1H-MRS revealed significantly higher intracellular lactate levels in cells obtained from ovarian tumors, most prominently in the moderately to poorly differentiated histological types, while total choline (Chol) compounds were higher in the moderately to poorly differentiated subgroup only. Ovarian cancer cells obtained from peritoneal effusions showed a significantly decreased glycerophosphocholine (GPC), glycerophosphoethanolamine (GPE) and uridine diphospho-sugar (UDPS) levels following ex vivo exposure to all 3 anti-mitotic drugs. Ex vivo 1H-MRS identified significant metabolic differences between cells obtained from ovarian tumors compared to those originating in benign ovarian cysts, including increased lactate and total choline compound levels. The 31P-MRS technique allowed characterization and monitoring of metabolic changes occurring in ovarian cancer cells in response to chemotherapy.

Triptolide inhibits ovarian cancer cell invasion by repression of matrix metalloproteinase 7 and 19 and upregulation of E-cadherin.

Triptolide, a compound extracted from the traditional Chinese medicine preparation of Tripterygium wilfordii Hook F., has been reported to have anti-inflammatory and anti-cancer activities. However, its effect on ovarian cancer invasion is unknown. We observed that MMP7 and MMP19 expression increased in ovarian cancer tissue. Triptolide treatment inhibited the migration and invasion of ovarian cancer cells SKOV3 and A2780 at the concentration of 15 nM. We also observed that triptolide suppressed MMP7 and MMP19 promoter activity in a dose-dependent manner, down-regulating the expressions of these promoters on mRNA and protein level. Moreover, triptolide enhanced E-cadherin expression in ovarian cancer cells. In vivo, triptolide inhibited tumor formation and metastasis in nude mice, and suppressed MMP7 and MMP19 expression; it also enhanced E-cadherin expression in tumor in a dose-dependent manner. Over expression of MMP7 and MMP19, or suppression of E-cadherin expression partially abolished the inhibitory effect of triptolide on invasion of ovarian cancer cells. To summarize, triptolide significantly inhibited the migration and invasion of ovarian cancer cells by suppression of MMP7 and MMP19 and up-regulation of E-cadherin expression. This study shows that triptolide is a good candidate for the treatment of ovarian cancer and reduction of metastasis.

Triptolide inhibits ovarian cancer cell invasion by repression of matrix metalloproteinase 7 and 19 and upregulation of E-cadherin

Triptolide, a compound extracted from the traditional Chinese medicine preparation of Tripterygium wilfordii Hook F., has been reported to have anti-inflammatory and anti-cancer activities. However, its effect on ovarian cancer invasion is unknown. We observed that MMP7 and MMP19 expression increased in ovarian cancer tissue. Triptolide treatment inhibited the migration and invasion of ovarian cancer cells SKOV3 and A2780 at the concentration of 15 nM. We also observed that triptolide suppressed MMP7 and MMP19 promoter activity in a dose-dependent manner, down-regulating the expressions of these promoters on mRNA and protein level. Moreover, triptolide enhanced E-cadherin expression in ovarian cancer cells. In vivo, triptolide inhibited tumor formation and metastasis in nude mice, and suppressed MMP7 and MMP19 expression; it also enhanced E-cadherin expression in tumor in a dose-dependent manner. Over expression of MMP7 and MMP19, or suppression of E-cadherin expression partially abolished the inhibitory effect of triptolide on invasion of ovarian cancer cells. To summarize, triptolide significantly inhibited the migration and invasion of ovarian cancer cells by suppression of MMP7 and MMP19 and up-regulation of E-cadherin expression. This study shows that triptolide is a good candidate for the treatment of ovarian cancer and reduction of metastasis.