Efficacy and safety of an oral combination therapy of niraparib and etoposide in platinum resistant/refractory ovarian cancer: a single arm, prospective, phase II study.

OBJECTIVE: Non-platinum chemotherapy is used in platinum resistant/refractory ovarian cancer patients but offers limited efficacy, especially in those who develop platinum resistance after ≤2 lines of platinum based chemotherapy. This phase II study aimed to evaluate the efficacy and safety of oral niraparib plus etoposide in platinum resistant/refractory ovarian cancer. METHODS: Platinum resistant/refractory ovarian cancer patients after ≤2 lines of platinum based chemotherapy, histologically confirmed as non-mucinous epithelial ovarian cancer, regardless of biomarker status, were eligible. Patients received niraparib with a starting dose of 200 mg/100 mg alternate once a day, and oral etoposide of 50 mg once a day, on days 1-20 of 30 days per cycle for a maximum of 6-8 cycles, followed by niraparib until disease progression or intolerable toxicity. The primary endpoint was investigator assessed progression free survival. RESULTS: 29 patients were enrolled from 22 May 2020 to 3 February 2023; 26 patients were included in the efficacy analysis set as per protocol. Median progression free survival was 4.2 months (95% confidence interval (CI) 3.9 to 4.4). Overall response rate was 26.9% (95% CI 8.7 to 45.2). Disease control rate was 57.7% (95% CI 37.3 to 78.0). Overall response rate in patients with a BRCA mutation and homologous recombination deficiency was 50% and 41.7%, respectively. Median progression free survival in patients with primary platinum resistance was 4.5 months (95% CI 3.6 to 5.3). 29 patients were included in the safety analysis set, and 8 (28%) patients experienced treatment related adverse events of grade ≥3. There was no treatment related discontinuation. CONCLUSIONS: Niraparib combined with etoposide showed evidence of antitumor activity in platinum resistant/refractory ovarian cancer after ≤2 lines of platinum based chemotherapy, particularly in patients with a BRCA mutation, homologous recombination deficiency, or primary platinum resistance. This once-a-day oral combination was a convenient option. TRIAL REGISTRATION NUMBER: NCT04217798.

The prognostic implication of slug in all tumour patients - a systematic meta-analysis.

BACKGROUND: E-cadherin is an invasion suppressor molecule which counteracts tumour metastasis and progression. Slug, one of the crucial transcriptional repressors of E-cadherin gene, has been widely reported on its prognostic role in patients with carcinoma, but the results are controversial. Thus, it is necessary to conduct a meta-analysis to draw a convincing conclusion. DESIGN: PubMed, Embase and Web of Science databases were searched for studies published until August 1st, 2015. Studies using immunohistochemistry (IHC) to detect the protein expression level in tumour tissues were set as protein group, while studies applying real-time quantitative polymerase chain reaction (RT-qPCR) to probe mRNA transcriptional level were set as mRNA group. Pooled hazard ratio (HR) and their corresponding 95% confidence interval (95% CI) were extracted to evaluate the prognostic role. Funnel plots, Begg's test and Egger's test were used to evaluate the publication bias. Sensitivity and heterogeneity analysis were also conducted. RESULTS: The pooled HR of 23 studies in the protein group was 1·85 (95% CI: 1·51-2·28, I(2)  = 55·4%, P = 0·001), including 1·98 ((95% CI: 1·53-2·58, I(2)  = 55·9%, P = 0·004) for overall survival (OS) and 1·46 (95% CI: 1·18-1·82, I(2)  = 52·0%, P = 0·012) for progression-free/ recurrence-free/ disease-free/ cancer-free survival (PFS/RFS/DFS/CFS). The high expression of Slug in the protein group indicated poor prognosis of the tumour patients. However, the pooled HR of 6 studies in the mRNA group was 0·85 (95% CI: 0·48-1·53, I(2)  = 77·2%, P = 0·001), suggesting no statistical significance. Subgroup analysis was performed to avoid heterogeneity caused by tumour types. Besides, publication bias was not observed in all studies except for the mRNA transcription studies. CONCLUSIONS: The protein expression rather than mRNA transcription of Slug should be considered as a potent biomarker for poor prognosis of tumours, particularly head and neck cancer as well as lung and urinary carcinomas.

Responses of the structure and function of microbes in Yellow River Estuary sediments to different levels of mercury.

The health and stability of the estuary of the Yellow River ecosystem have come under increasing pressure from land-based inputs of heavy metals. While it is known that heavy metals affect the function and health of the microbial community, there remains little knowledge on the responses of the microbial community to heavy metals, particularly highly toxic mercury. The research aimed to characterize the responses of the sediment microbial community of the estuary of the Yellow River to different levels of mercury stress. Estuary sediment samples were collected for microbial community analysis, measurement of mercury [including total mercury (THg) and methylmercury (MeHg)], and measurement of other physicochemical factors, including pH, total organic carbon (TOC), sulfide, iron ratio (Fe3+/Fe2+), ammonium salt (NH4+), and biochemical oxygen demand (BOD). The application of 16S rRNA sequencing identified 60 phyla of bacteria, dominated by Proteobacteria, Firmicutes, and Bacteroidetes. Stations with higher THg or MeHg and lower microbial abundance and diversity were generally distributed further outside of the estuary. Besides mercury, the measured physicochemical factors had impacts on microbial diversities and distribution. Metagenomics assessment of three stations, representative of low, moderate, and high mercury concentrations and measured physicochemical factors, revealed the abundances and functions of predicted genes. The most abundant genes regulating the metabolic pathways were categorized as metabolic, environmental information processing, and genetic information processing, genes. At stations with high levels of mercury, the dominant genes were related to energy metabolism, signal transport, and membrane transport. Functional genes with a mercury-resistance function were generally in the mer system (merA, merC, merT, merR), alkylmercury lyase, and metal-transporting ATPase. These results offer insight into the microbial community structure of the sediments in the Yellow River Estuary and the microbial function of mercury resistance under mercury stress.

What predicts the clinical benefits of PARP inhibitors in platinum-sensitive recurrent ovarian cancer: A real-world single-center retrospective cohort study from China.

Objective: This study assessed the real-world application, effectiveness, and safety of olaparib and niraparib as maintenance therapies in patients with platinum-sensitive recurrent ovarian cancer (PSROC) in China and investigated clinical factors associated with prolonged benefits of poly ADP-ribose polymerase (PARP) inhibitors to help guide clinician treatment-decision making in daily practice. Methods: This real-world single-center retrospective cohort study was conducted at the Shandong Cancer Hospital and Institute. Archival data of consecutive patients diagnosed with PSROC who achieved a complete response (CR) or partial response (PR) after the last platinum-based chemotherapy and treated with olaparib or niraparib as maintenance therapy from August 2018 to September 2021 were collected. Results: Overall, 106 women were included in the cohort. Seventy-two (68%) patients were treated with olaparib, while 34 (32%) received niraparib; 99.1% of the patients were diagnosed with high-grade serous carcinoma, and 73.6% had FIGO stages III-IV. Approximately 71.7% of the patients had received PARP inhibitors after the second platinum-based line and 44.3% of the patients achieved a CR in their last platinum-based therapy. The median platinum-free interval (PFI) after the penultimate platinum-based therapy was 10 (95% CI: 10-13.6) months. The median PFS was 21 (95% CI: 13-24.5) months and the median CFI was 22 (95% CI: 16-26.5) months. Consistent with the univariate analysis, the multivariate analysis identified three independent factors associated with prolonged progression-free survival (PFS) and chemotherapy-free interval (CFI): breast cancer susceptibility gene (BRCA) mutant type (p = 0.005 and p = 0.003); PFI ≥12 months (p = 0.01 and p = 0.006); and CR to last platinum-based therapy (p = 0.016 and p = 0.019). It was found that there was no appreciable difference in any grade 3-4 hematological AE between patients who received olaparib and niraparib. Conclusion: Maintenance treatment with olaparib and niraparib is effective and well tolerated for PSROC patients in real-world clinical practice. Three clinical factors were identified that predicted prolonged survival under maintenance therapy with PARP inhibitors: BRCA mutant type, PFI ≥12 months, and CR to last platinum-based therapy. These findings should be further confirmed with an appropriately powered analysis in studies with larger sample sizes.

Prognostic Value of ß-catenin Expression in Breast Cancer Patients: a Meta-analysis.

BACKGROUND: ß-catenin plays a crucial role in the progression of breast cancer (BC) and a prognostic role of in BC patients has been widely reported. However, controversy still remains. MATERIALS AND METHODS: Identical search strategies were used to search relevant literature in electronic databases updated to July 1, 2014. Individual hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled HRs with 95%CIs were used to evaluate the strength of association between positive ß-catenin expression in different subcellular locations and survival results of BC patients. Subgroup and meta-regression analyses were performed to explore heterogeneity. Funnel plots of Begg's and Egger's linear regression test were used to investigate publication bias. Heterogeneity and sensitivity were also assessed. All the work was completed using STATA. RESULTS: A total of 2,204 patients from 12 evaluative studies were finally included. Pooled HRs and 95%CIs suggested that ß-catenin expression in cytoplasm/nucleus had an unfavorable impact on both overall survival (OS) (HR: 1.93, 95%CI: 1.40-2.65) and disease free survival (DFS)/ recurrent free survival (RFS) (HR: 1.60, 95%CI: 1.20-2.13) in BC patients. However, here was no significant association between ß-catenin expression in the membranes with OS (HR: 0.65, 95%CI: 0.42-1.02) or DFS/RFS (HR: 0.66, 95%CI: 0.38-1.13). Publication bias was absent in all of the four outcomes. Sensitivity analysis revealed that the results of this meta-analysis were robust. CONCLUSIONS: Positive ß-catenin expression in cytoplasm/nucleus rather than in membrane is a significant prognostic factor in patients with BC who have been surgically treated.

The impact of matrix metalloproteinase 2 on prognosis and clinicopathology of breast cancer patients: a systematic meta-analysis.

BACKGROUNDS: Matrix metalloproteinase 2 (MMP-2) plays a crucial role in the progression of breast cancer (BC). The prognostic role of MMP-2 expression in BC patients has been widely reported, but the results were inconsistent. Thus, a meta-analysis was conducted to gain a better insight into the impact of MMP-2 expression on survival and clinicopathological features of BC patients. METHODS: Identical search strategies were used to search relevant literatures in electronic databases update to August 1, 2014. Individual hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were extracted and pooled to evaluate the strength of the association between positive MMP-2 expression and survival results and clinicopathological features of BC patients. Begg's tests, Egger's tests and funnel plots were used to evaluate publication bias. Heterogeneity and sensitivity analysis were also assessed. All the work was completed using STATA. RESULTS: Pooled HRs and 95% CIs suggested that MMP-2 expression had an unfavorable impact on both OS (HR: 1.53, 95% CI: 1.29-1.82) and DFS/RFS/DDFS (HR: 1.41, 95% CI: 1.07-1.86) in BC patients. Furthermore, MMP-2 expression was significantly associated with lymph node metastasis (positive vs negative: OR 1.91, 95% CI 1.17-3.12). CONCLUSION: In conclusion, positive MMP-2 expression might be a significant predictive factor for poor prognosis in patients with BC.

GABAergic signaling facilitates breast cancer metastasis by promoting ERK1/2-dependent phosphorylation.

The present study aims to determine the role of γ-aminobutyric acid (GABA) signaling molecules in breast cancer metastasis. Our results reveal that GABAergic system exists in breast cancer cells. Both the GABA synthetic enzyme. (GAD65/67) and GABAB receptor are expressed in 4T1 mouse breast cancer cells, MCF-7 human breast cancer cells and human breast cancer tissue. Baclofen, a GABABR agonist, significantly promoted 4T1 cells invasion and migration in vitro and metastasis in vivo, an event that was attenuated by GABABR antagonist CGP55845. Baclofen-induced breast cancer metastasis was mediated by ERK1/2 pathway.