Efforts have been made to develop bromodomain inhibitors as cancer treatments. Sub-pathways, particularly in ovarian cancer, affected by bromodomain-containing protein (BRD) remain unclear. This ...study verified the antitumor effects of a new drug that can overcome OPT-0139-chemoresistance to treat ovarian cancer. A mouse xenograft model of human ovarian cancer cells, SKOV3 and OVCAR3, was used in this study. Cell viability and proliferation were assessed using MTT and ATP assays. Cell cycle arrest and apoptosis were determined using flow cytometry. BRD4 and c-Myc expression and apoptosis-related molecules were detected using RT-PCR and real-time PCR and Western blot. We confirmed the OPT-0139 effect and mechanism of action in epithelial ovarian cancer. OPT-0139 significantly reduced cell viability and proliferation and induced apoptosis and cell cycle arrest. In the mouse xenograft model, significant changes in tumor growth, volume, weight, and BRD4-related gene expression were observed, suggesting the antitumor effects of BRD4 inhibitors. Combination therapy with cisplatin promoted apoptosis and suppressed tumor growth in vitro and in vivo. Our results suggest OPT-0139, a BRD4 inhibitor, as a promising anticancer drug for the treatment of ovarian cancer by inhibiting cell proliferation, decreasing cell viability, arresting cell cycle, and inducing apoptosis.
Objectives
The objective is to evaluate the prognostic value of serum human epididymis protein 4 (HE4) as a tumor marker in patients with cervical cancer.
Methods
Sixty-seven patients with cervical ...cancer treated at Seoul National University Bundang Hospital from September 2014 to May 2018 were retrospectively reviewed. Serum HE4 levels were measured by immunoassay before starting primary treatment. A mean serum HE4 level of 72.6 pmol/L was used to divide the patients into low and high HE4 groups. Patient characteristics, clinicopathological variables, and survival outcomes were compared between the two groups.
Results
The low and high HE4 groups included 55 (82.1%) and 12 (17.9%) patients at diagnosis, respectively. Higher HE4 levels were significantly associated with older age at diagnosis (age <50: .0% vs age ≥50: 100.0%; P = .002), menopause (premenopause: 8.3% vs postmenopause: 91.7%; P = .009), higher FIGO stage (stage I–II: 33.3% vs III–IV: 66.7%; P = .017), large tumor size (<4.0 cm: 41.7% vs ≥4.0 cm: 58.3%; P = .029), positive lymph node metastasis (negative: 41.7% vs positive: 58.3%; P = .049), and involvement of the parametrium (negative: 25.0% vs positive: 75.0%; P = .002). Higher HE4 level was a predictive factor for worse overall survival but not for progression-free survival. Elevated HE4 levels were not independent factors for the prediction of either overall survival or progression-free survival. Subgroup analysis by histological type revealed similar results for patients with squamous cell carcinoma.
Conclusions
High levels of HE4 expression correlated with poor overall survival, indicating that elevated HE4 levels are associated with a poor prognosis for patients with cervical cancer.
The prognostic significance of positive peritoneal cytology in patients with early-stage endometrial cancer (Stage 1 or 2) is controversial and perhaps depends on the presence of other factors. The ...relationship of other prognostic factors with positive peritoneal cytology remains unclear. This study aimed to investigate the association between positive peritoneal cytology and prognostic factors and the influence of positive peritoneal cytology on survival in patients with early-stage endometrial cancer.
We identified 351 articles on the PubMed, Cochrane and Embase databases using a combination of the following search terms: endometrial cancer, endometrial carcinoma, positive peritoneal cytology and positive peritoneal washing. When filtered for studies comparing positive peritoneal cytology with negative peritoneal cytology in early-stage endometrial cancer, 11 retrospective studies met the selection criteria. Meta-analyses were performed using Review Manager 5.3 software.
In patients with surgical stage 1 or 2 early-stage endometrial cancer, the incidence of Grade 3 was higher and 5-year overall survival was worse in patients with positive peritoneal cytology compared with negative peritoneal cytology. However, the incidence of Grade 1 was lower in those with positive peritoneal cytology compared with negative peritoneal cytology. In patients with surgical stage 1 early-stage endometrial cancer, the incidence of myometrial invasion ≥1/2 tended to be higher and 5-year progression-free survival was worse in the positive peritoneal cytology group than the negative peritoneal cytology group. However, the incidence of myometrial invasion <1/2 was lower in the positive peritoneal cytology group than the negative peritoneal cytology group.
This study demonstrates that positive peritoneal cytology in patients with early-stage endometrial cancer is significantly associated with other prognostic factors and survival, suggesting its potential as a prognostic factor.
Pancreatic cancer is a highly metastatic tumor with an extremely low 5-year survival rate. Lack of efficient diagnostics and dearth of effective therapeutics that can target the cancer as well as the ...microenvironment niche are the reasons for limited success in treatment and management of this disease. Cell invasion through extracellular matrix (ECM) involves the complex regulation of adhesion to and detachment from ECM and its understanding is critical to metastatic potential of pancreatic cancer. To understand the characteristics of these cancer cells and their ability to metastasize, we compared human pancreatic cancer cell line, PANC-1 and its invading phenotype (INV) collected from transwell inserts. The invasive cell type, INV, exhibited higher resistance to Carbon-ion radiation compared to whole cultured (normally dish-cultured) PANC-1 (WCC), and had more efficient in vitro spheroid formation capability. Invasiveness of INV was hampered by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide (NO) plays a cardinal role in PANC-1 invasion. In addition, in vitro studies indicated that a MEK-ERK-dependent, JAK independent mechanism through which NOS/NO modulate PANC-1 invasiveness. Suspended INV showed enhanced NO production as well as induction of several pro-metastatic, and stemness-related genes. NOS inhibitor, l-NAME, reduced the expression of these pro-metastatic or stemness-related genes, and dampened spheroid formation ability, suggesting that NO can potentially influence pancreatic cancer aggressiveness. Furthermore, xenograft studies with INV and WCC in NSG mouse model revealed a greater ability of INV compared to WCC, to metastasize to the liver and l-NAME diminished the metastatic lesions in mice injected with INV. Overall, data suggest that NO is a key player associated with resistance to radiation and metastasis of pancreatic cancer; and inhibition of NOS demonstrates therapeutic potential as observed in the animal model by specifically targeting the metastatic cells that harbor stem-like features and are potentially responsible for relapse.
To evaluate the diagnostic performance of circulating tumor cells (CTCs) using tapered-slit membrane filter (TSF)-based chipsets for the differential diagnosis of adnexal tumors. A total of 230 women ...with indeterminate adnexal tumors were prospectively enrolled. The sensitivity, specificity, and accuracy of the CTC-detecting chipsets were analyzed according to postoperative pathological results and compared with those of cancer antigen (CA)-125 and imaging tests. Eighty-one (40.3%) benign tumors, 31 (15.4%) borderline tumors, and 89 (44.3%) ovarian cancers were pathologically confirmed. The sensitivity, specificity, and accuracy of CTC-detecting chipsets (75.3%, 58.0%, and 67.1%) for differentiating ovarian cancer from benign tumors were similar to CA-125 (78.7%, 53.1%, and 66.5%), but lower than CT/MRI (94.2%, 77.9%, and 86.5%). "CTC or CA125" showed increased sensitivity (91.0%) and "CTC and CA-125" revealed increased specificity (77.8%), comparable to CT/MRI. CTC detection rates in stage I/II and stage III/IV ovarian cancers were 69.6% and 81.4%, respectively. The sensitivity to detect high-grade serous (HGS) cancer from benign tumors (84.6%) was higher than that to detect non-HGS cancers (68.0%). Although the diagnostic performance of the TSF platform to differentiate between ovarian cancer and benign tumors did not yield significant results, the combination of CTC and CA-125 showed promising potential in the diagnostic accuracy of ovarian cancer.
Survival outcomes for patients with recurrent or advanced cervical cancer are poor. Pembrolizumab has been approved for the treatment of recurrent or metastatic cervical cancer, with an overall ...response rate of 14·3%. GX-188E vaccination has been shown to induce human papillomavirus (HPV) E6-specific and E7-specific T-cell responses and cervical lesion regression in patients with cervical precancer. We aimed to investigate whether a combination of GX-188E therapeutic DNA vaccine plus pembrolizumab showed antitumour activity against recurrent or advanced cervical cancer.
In this open-label, single-arm, phase 2 trial, patients with recurrent or advanced, inoperable cervical cancer, who were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically confirmed recurrent or advanced HPV-positive (HPV-16 or HPV-18) cervical cancer, and who had progressed after available standard-of-care therapy were recruited from seven hospitals in South Korea. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, and 19, with one optional dose at week 46 that was at the investigator's discretion, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was the overall response rate within 24 weeks assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 in patients who received at least 45 days of treatment 45 days of treatment with at least one post-baseline tumour assessment, and this is the report of a planned interim analysis. This trial is registered with ClinicalTrials.gov, NCT03444376.
Between June 19, 2018, and March 20, 2020, 36 patients were enrolled and received at least one dose of the study treatment. 26 patients were evaluable for interim activity assessment, with at least one post-baseline tumour assessment at week 10. At the data cutoff date on March 30, 2020, median follow-up duration was 6·2 months (IQR 3·5–8·1). At 24 weeks, 11 (42%; 95% CI 23-63) of 26 patients achieved an overall response; four (15%) had a complete response and seven (27%) had a partial response. 16 (44%) of 36 patients had treatment-related adverse events of any grade and four (11%) had grade 3–4 treatment-related adverse events. Grade 3 increased aspartate aminotransferase, syncope, pericardial effusion, and hyperkalaemia, and grade 4 increased alanine aminotransferase were reported in one patient each. No treatment-related deaths were reported.
Treatment with GX-188E therapeutic vaccine plus pembrolizumab for patients with recurrent or advanced cervical cancer was safe and treatment-related adverse events were manageable. This combination therapy showed preliminary antitumour activity in this interim analysis, which could represent a new potential treatment option for this patient population. This trial is ongoing.
National OncoVenture.
Vitamin D deficiency is a worldwide health issue especially in women. Serum vitamin D concentrations vary depending on the weather. However, the ideal vitamin D supplementation strategy related to ...weather remains uncertain. We aimed to investigate the relationship between climate factors and serum 25-hydroxy vitamin D 25(OH)D concentrations. This study included 11,272 women aged 20-79 who visited a health promotion center for annual checkups between January 2013 and December 2015. We reviewed medical records and collected daily meteorological data. We analyzed the association between serum 25(OH)D concentration and climate factors using simple and multiple regression models and then predicted serum 25(OH)D concentration using multiple fractional polynomial models. The median age of the participants was 51 years (20-79 years), and the mean serum 25(OH)D level was 17.4 ± 8.6 ng/mL. The serum 25(OH)D concentration was lower in young women than in older women. The proportions of women with adequate 25(OH)D levels were 14.9% and 47.0% in the age groups 20-29 and 70-79, respectively. The maximum level of predicted log 25(OH)D was found in September, and the minimum was found in January. In multiple regression analysis, age and monthly mean temperature were associated with 25(OH)D concentrations. Serum 25(OH)D level was predicted using the following formula: log (25(OH)D) = 2.144 + 0.009 × age + 0.018 × ((temperature + 12.4)/10)2 (P < 0.001, adjusted R2 = 0.091). Serum 25(OH)D concentrations changed according to air temperature. An adequate strategy for vitamin D supplementation, based on air temperature, is necessary to maintain healthy serum 25(OH)D levels.
We aimed to identify the effect of an extended number of neoadjuvant chemotherapy (NAC) cycles on prognosis and surgical morbidity after interval debulking surgery (IDS) in patients with newly ...diagnosed advanced ovarian cancer.
Medical records of patients with advanced ovarian cancer treated with NAC and having undergone IDS were retrospectively reviewed. Clinicopathological factors were compared between two groups: conventional (≤4 cycles) and extended (≥5 cycles) NAC groups. Kaplan-Meier analysis was performed to evaluate progression-free survival (PFS) and overall survival (OS).
A total of 156 patients were included, 112 patients in the conventional group and 44 patients in the extended NAC group. The extended NAC group had a significantly higher frequency of cancer antigen (CA)-125 normalization after NAC (59.1% vs. 33.9%, P = 0.004), a lower rate of bowel surgery (18.2% vs. 34.8%, P = 0.042), and a lower rate of transfusion during or after IDS (36.4% vs. 59.8%, P = 0.008) as compared to the conventional group. The complete cytoreduction rate after IDS was similar between the groups. In multivariate Cox regression analysis for PFS, radiologically stable and progressive disease after NAC (Hazard ratio HR, 1.983; 95% Confidence interval CI, 1.141-3.446; P = 0.015) and gross residual tumor after IDS (HR, 2.054; 95% CI, 1.414-2.983; P < 0.001) were independent risk factors for poor PFS. However, extended NAC cycles were not significantly associated with poor PFS. The median PFS was 19.5 and 16.9 months (P = 0.830), and the 5-year OS was 71.4 and 63.2% (P = 0.677) in the conventional and extended NAC groups, respectively.
Our study showed that extended NAC cycles were not inferior to conventional NAC cycles in terms of survival in patients with advanced ovarian cancer and reduced surgical morbidity such as bowel surgery and transfusion during or after IDS.
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