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.

HER2 IHC Expression and Gene Amplification in p53-aberrant High-grade Endometrial Endometrioid Carcinoma Suggests That This Population May Benefit From HER2 Testing and Targeted Therapy.

Among gynecologic cancers, uterine serous carcinoma (USC) has been shown to be human epidermal growth factor receptor 2 (HER2) amplified and trastuzumab has been included in the recent National Comprehensive Cancer Network (NCCN) guidelines for treatment of advanced stage or recurrent USC with HER2 overexpression/amplification. There is limited literature suggesting that a subset of high-grade endometrioid carcinomas with aberrant p53 expression may also be HER2 amplified and these patients could benefit from the addition of targeted therapy. We identified 59 p53-aberrant (mismatch repair proficient) FIGO 3 endometrioid carcinomas of the uterus. HER2 immunohistochemistry was performed in all 59 tumors and HER2 fluorescence in situ hybridization (FISH) was performed in 52 of the 59 cases. Four of the 59 cases were HER2 3+ by immunohistochemistry (6.7%), using the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2007, 2013, and 2018 criteria. HER2 FISH was performed in 3 of the 4 cases and was amplified in all 3. Nine, 8, and 7 tumors showed 2+ HER2 staining when applying 2018, 2013, and 2007 criteria, respectively, FISH was performed in 7 tumors and none were amplified. An additional 4 cases did not perfectly meet the 2018 ASCO/CAP criteria but were assigned a score of 2+, none were amplified by HER2 FISH. The remaining 42 cases showed 1+ or no staining for HER2, FISH was successfully performed in 38 tumors and none showed amplification. Approximately half of the tumors fulfilled criteria for HER2-low or HER2-very low (10 HER2-low and 20 HER2-very low). Our data shows that a subset of p53-aberrant high-grade endometrial endometrioid carcinoma express HER2 and these patients may benefit from the addition of targeted therapy. The role of targeted therapy in HER2-low gynecologic carcinoma is currently unexplored.

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.

Rare clinical manifestations of primary peritoneal serous carcinoma presenting as colorectal cancer: A report of two cases.

OBJECTIVE: To report two cases of for primary peritoneal serous carcinoma (PPSC) to present with gastrointestinal manifestations that mimic colorectal cancer. CASE REPORT: There were two patients with initial presentations of fatigue with iron deficiency anemia, and tenesmus with bloody stool. Tumors of the ascending colon and rectum were detected by colonofiberoscope, and pathologic reports of tumor biopsies revealed adenocarcinoma of suspected gynecologic origin. Both patients underwent optimal debulking surgery without macroscopic residual tumor, and then received adjuvant carboplatin and paclitaxel chemotherapy with bevacizumab. CONCLUSIONS: PPSC can clinically present like primary colorectal carcinoma. The differential diagnosis requires special staining of several markers for tumor tissues.

HER2 Testing in Endometrial Serous Carcinoma: Time for Standardized Pathology Practice to Meet the Clinical Demand.

CONTEXT.­: Endometrial serous carcinoma is an aggressive subtype of endometrial cancer with the highest rate of recurrence and mortality among all histotypes. A recent clinical trial showed prolonged progression-free survival in advanced-stage and recurrent human epidermal growth factor receptor 2 (HER2)-positive endometrial serous carcinoma when trastuzumab was added to the standard chemotherapy regimen. This targeted therapeutic approach was recently endorsed by the National Comprehensive Cancer Network clinical guidelines. There is a growing interest among clinicians to obtain HER2 testing in endometrial serous carcinoma, and pathologists need to be prepared to recognize the unique characteristics of HER2 protein expression and gene amplification in these tumors and apply specific HER2 scoring criteria. OBJECTIVE.­: To provide a historical overview of targeted HER2 therapy in endometrial serous carcinoma and to summarize key findings from recent studies on the specific features of HER2 protein expression and gene amplification relative to other tumor types. Endometrial carcinoma-specific HER2 testing criteria are proposed based on evidence in the existing literature. DATA SOURCES.­: Sources comprise review of the literature and personal experience of the author. CONCLUSIONS.­: HER2 protein overexpression and/or gene amplification is present in approximately 25% to 30% of endometrial serous carcinomas, providing an opportunity for targeted therapy. Pathologists play a key role in tumor HER2 testing and scoring to ensure appropriate patient selection and successful clinical outcome.

Network Pharmacology-Based and Clinically Relevant Prediction of the Potential Targets of Chinese Herbs in Ovarian Cancer Patients.

Reports increasingly suggest that Chinese herbal medicine (CHM) has been used to treat ovarian cancer (OvCa) with a good curative effect; however, the molecular mechanisms underlying CHM are still unclear. In this retrospective study, we explored CHM's molecular targets for the treatment of OvCa based on clinical data and network pharmacology. We used the Kaplan-Meier method and Cox regression analysis to verify the survival rate of 202 patients with CHM-treated OvCa. The association between CHM and survival time was analyzed by bivariate correlation. A target network of CHM active ingredients against OvCa was established via network pharmacology. Cox regression analysis showed that CHM is an independent favorable prognostic factor. The median survival time was 91 months in the CHM group and 65 months in the non-CHM group. The survival time of FIGO stage III patients in the two groups was 91 months and 52 months, and the median survival period of FIOG stage IV patients was 60 months and 22 months, respectively (p < 0.001). Correlation analysis demonstrated that 12 herbs were closely associated with prognosis, especially in regard to the long-term benefits. Bioinformatics analysis indicated that the anti-OvCa activity of these 12 herbs occurs mainly through the regulation of apoptosis-related protein expression, which promotes OvCa cell apoptosis and inhibits OvCa development. They also regulate the progress of OvCa treatment by promoting or inhibiting protein expression on the p53 signaling pathway and by inhibiting the NF-κB signaling pathway by directly inhibiting NF-κB.

HIPEC plus EPIC paclitaxel for maximal perioperative treatments of advanced epithelial ovarian cancer. Long-term results of a pilot study.

BACKGROUND: A unique time in which to effectively treat an intraabdominal malignancy is the time at which the surgeon attempts complete removal of the malignant process. Although surgery is effective for visible disease, micrometastases or multiple small cancer nodules are not amenable to resection. Alternative interventions to deal with residual disease disseminated on peritoneal surfaces are needed. MATERIALS AND METHODS: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be combined with early postoperative intraperitoneal chemotherapy (EPIC) in order to maximally treat gross disease within the abdomen and pelvis and also the minimal residual disease that exists in many patients after resection. The third component of this treatment for ovarian malignancy was EPIC paclitaxel in this study. The clinical features, pharmacologic assessments, and survival were determined in ovarian cancer patients in whom EPIC was added to the perioperative treatment plan. RESULTS: Patients with high grade serous ovarian cancer underwent CRS, HIPEC with cisplatin/doxorubicin, and EPIC paclitaxel. These treatments combined as a single intervention were studied in 10 patients. The median number of peritonectomy procedures was 1, the median number of visceral resections was 5, and the median time required in the operating room was 8 h. Two patients had a class 3 adverse event. The median survival of patients was 50 months. Pharmacokinetic analysis of the intraperitoneal paclitaxel showed 252 ± 153 times exposure of peritoneal surfaces as compared to intravenous exposure when the drug was instilled into the peritoneal space. CONCLUSIONS: EPIC paclitaxel was successfully combined with CRS and HIPEC in 10 patients with ovarian cancer. The treatment was tolerated approximately the same as other major cytoreductive surgical procedures for ovarian cancer or other malignancies. Survival of these ovarian cancer patients seemed unusually prolonged as compared to other patients with stage 3b or recurrent disease. In this pilot study CRS, HIPEC and EPIC were safe and effective.

Prognostic impact of Dynamin related protein 1 (Drp1) in epithelial ovarian cancer.

BACKGROUND: The mitochondrial fission protein, Dynamin related protein 1 (Drp1), and its upstream protein calcium/calmodulin-dependent protein kinase I (CaMKI) play a critical role in chemoresistance in ovarian cancer (OVCA). Thus, we examined the expression of Drp1, CaMKI and their phosphorylated forms and their prognostic impact in epithelial OVCA patients. METHODS: Expression analysis was performed by immunohistochemistry (IHC) of paraffin-embedded tumor samples from 49 patients with epithelial OVCA. Staining intensity and the percentage of positively stained tumor cells were used to calculate an immunoreactive score (IRS) of 0-12. The expression scores calculated were correlated with clinicopathological parameters and patient survival. RESULTS: High immunoreactivity of phospho-Drp1Ser637 was significantly correlated with high-grade serous carcinoma (HGSC) (p = 0.034), residual postoperative tumor of > 1 cm (p = 0.006), and non-responders to adjuvant chemotherapy (p = 0.007), whereas high expression of CaMKI was significantly correlated with stage III/IV [International Federation of Gynecologists and Obstetricians (FIGO)] (p = 0.011) and platinum-resistant recurrence (p = 0.030). ROC curve analysis showed that Drp1, phospho-Drp1Ser637 and CaMKI could significantly detect tumor progression with 0.710, 0.779, and 0.686 of area under the curve (AUC), respectively. The Kaplan-Meier survival curve showed that patients with high Drp1, phospho-Drp1Ser637 and CaMKI levels had significantly poorer progression free survival (PFS) (p = 0.003, p < 0.001 and p = 0.017, respectively). Using multivariate analyses, phospho-Drp1Ser637 was significantly associated with PFS [p = 0.043, hazard ratio (HR) 3.151, 95% confidence interval (CI) 1.039-9.561]. CONCLUSIONS: Drp1 and CaMKI are novel potential candidates for the detection and prognosis of epithelial OVCA and as such further studies should be performed to exploit their therapeutic significance.

LGR4 overexpression is associated with clinical parameters and poor prognosis of serous ovarian cancer.

OBJECTIVE: LGR4 expression in serous ovarian cancer paraffin-embedded tissues and fresh tissues were investigated, and its expression associated with clinicopathological parameters and prognosis in serous ovarian cancer was explored. METHODS: From Dec, 2009 to Jan, 2020, 122 paraffin-embedded serous ovarian cancer patients and 41 paired paratumor tissues who were both diagnosed and operated at the memorial hospital of Sun Yat-sen University and Integrated Hospital of Traditional Chinese Medicine, Southern Medical University were selected in this research, respectively, and all of these tissues were performed by immunohistochemistry (IHC) with a polyclonal antibody for LGR4. Meanwhile, from Aug, 2013 to Mar, 2019, 15 cases of serous ovarian cancer fresh tissues and 15 cases of paratumor fresh tissues who were operated at Integrated Hospital of Traditional Chinese Medicine, Southern Medical University were performed with Quantitative Real-time PCR to detect the mRNA expression of LGR4, respectively. RESULTS: LGR4 expression was much higher both in paraffin-embedded and fresh cancer tissues than that in paratumor tissues, respectively, and its expression was associated with recurrence free survival and overall survival in serous ovarian cancer patients. Moreover, in a multivariate model LGR4 was an indeed independent predictor of poor survival in serous ovarian cancer patients. CONCLUSION: LGR4 is upregulated in serous ovarian cancer, and LGR4 is an indeed useful independent prognostic predictor in serous ovarian cancer, and it may provide important clinical value of serous ovarian cancer.

Disparities in care among patients with low-grade serous ovarian carcinoma.

OBJECTIVE: Low-grade serous carcinoma (LGSC) is a rare histotype of ovarian cancer with a unique disease course. Little data exist regarding the influence of sociodemographic factors on diagnosis and outcomes in this disease. Our objective was to evaluate the associations between these factors and the clinical characteristics, treatment approaches, and survival in LGSC. METHODS: The National Cancer Database (NCDB) was queried for data between 2004 and 2015 on patients with LGSC. LGSC was inclusive of invasive, grade 1, serous carcinoma of the ovary, fallopian tube, or peritoneum. Patient demographics, insurance status, disease characteristics, treatment approach, and survival were evaluated. ANOVA, Chi Square, Kaplan-Meier, and Cox regression were used in the analysis. RESULTS: 3221 patients with LGSC were evaluated (89.5% White, 6.2% Black; 7.2% Hispanic, 92.8% non-Hispanic). Compared to Whites, Blacks were diagnosed younger (50.4 vs. 55.9 years, p < 0.01), received less chemotherapy (61.8% vs 67.0%, p = 0.04), and had less CA-125 elevation (OR 4.14 [1.26-13.57], p = 0.02). Compared to non-Hispanics, Hispanics were younger (49.5 vs. 55.8 years, p < 0.01) and received less chemotherapy (55% vs 67%, p < 0.001). In contrast to private insurance, government insurance was associated with a higher 30-day mortality (1.5% vs 0.01%, p < 0.001). Race/ethnicity were not predictive of OS, while older age (HR 1.013 [1.002-1.024], p = 0.03), advanced stage (HR 3.09 [2.15-4.43], p < 0.001), and government insurance (HR 2.33 [1.65-3.30], p < 0.001) were all independently associated with worse OS. CONCLUSIONS: Significant differences exist in the clinical characteristics, treatments, and outcomes of LGSC by sociodemographics, with Blacks and Hispanics being diagnosed younger and receiving less chemotherapy. Age, stage, and insurance status were predictive of overall survival.

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.

Upfront debulking surgery versus interval debulking surgery for advanced tubo-ovarian high-grade serous carcinoma and diffuse peritoneal metastases treated with peritonectomy procedures plus HIPEC.

BACKGROUND: Whether patients with advanced tubo-ovarian high-grade serous cancer (HGSC) fare better after upfront debulking surgery (UDS) or neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) remains controversial. METHODS: We studied patients with HGSC who underwent UDS or NACT-IDS between July 2000 and December 2015, with peritonectomy procedures combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Clinical reports were included peritoneal cancer index (PCI), NACT responses, surgical complexity score (SCS), completeness of cytoreduction (CC), complete follow-up with timing, site, and treatment of recurrence. Outcome measures were morbidity, progression-free survival (PFS), PFS2, and overall survival during a mean 5-year follow-up. RESULTS: A total of 34 patients (23.6%) underwent UDS and 110 (76.4%) NACT-IDS both combined with HIPEC. At a median 66.3-month follow-up, patients who underwent UDS or NACT-IDS had similar outcomes. NACT subgroup responses correlated with PCI, SCS, morbidity, and CC. Patients who underwent UDS had lower recurrence rates than those who responded partly or poorly to NACT (PFS, P < .04; PFS2, P < .01). Despite HIPEC, the peritoneal disease recurred in 42.5% of the overall patients. CONCLUSION: In patients with primary HGSC who undergo UDS or NACT-IDS, despite similar outcomes, peritonectomy procedures combined with HIPEC seem unable to prevent peritoneal recurrence.

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.