Background: Immunotherapy is effective in treating unresectable esophageal squamous cell carcinoma (ESCC), but little is known about its role in the preoperative setting. The aim of this study was to evaluate the safety, feasibility and efficacy of neoadjuvant treatment with camrelizumab plus chemotherapy in locally advanced ESCC.Methods: Patients diagnosed with locally advanced ESCC were retrospectively included if they had received neoadjuvant camrelizumab plus nab-paclitaxel and S1 capsule followed by radical esophagectomy between November, 2019 and June, 2020 at Sun Yat-sen University Cancer Center. Primary endpoints were safety and feasibility. In addition, pathological response and the relationship between tumor immune microenvironment (TIME)/tumor mutational burden (TMB) and treatment response were also investigated.Results: Twelve patients were included and they all received three courses of preoperative treatment with camrelizumab plus nab-paclitaxel/S1. No grade 3 or higher toxicities occurred. No surgical delay or perioperative death was reported. Nine patients (75%) responded to the treatment, four with a complete pathological response (pCR) and five with a major pathological response (MPR). Neither programmed death-ligand 1 (PD-L1) expression nor TMB was correlated with treatment response. TIME analysis revealed that a higher abundance of CD56dim natural killer cells was associated with better pathological response in the primary tumor, while lower density of M2-tumor-associated macrophages was associated with better pathological response in the lymph nodes (LNs).Conclusions: Neoadjuvant camrelizumab plus nab-paclitaxel and S1 is safe, feasible and effective in locally advanced ESCC and is worth further investigation.
The aim of the present study was to identify the appropriate DNA sequence and design high-quality primers for methylation-specific polymerase chain reaction (MSP). These primers may be used to examine and identify patients with early-stage epithelial ovarian carcinoma (EOC). Opioid binding protein/cell adhesion molecule like (OPCML), Runt-related transcription factor 3 and tissue factor pathway inhibitor 2 were selected as possible molecular markers. MSP primer sets were designed to monitor the methylation of the three markers. Free circulating DNA (fcDNA) from 194 patients with epithelial ovarian carcinoma and healthy donors were templates in the nested MSP. OPCML MSP was effective with respect to screening methylated fcDNA. One-way ANOVA P-values indicated that the difference in cancer antigen 125 (CA125), a biomarker for EOC diagnosis, level between early EOC and healthy donors was not significant. The methylation of OPCML was significantly altered in early-stage EOC compared with healthy donors (P<0.0001), and this supported the hypothesis that specific fcDNA methylation was able to distinguish patients with early-stage EOC from healthy donors. With respect to detecting early EOC, compared with the results of the CA125 test, MSP increased the κ coefficient from 0.140 to 0.757. Therefore, OPCML combined with fcDNA may be used to establish an improved clinical assay compared with the current CA125 test.
Cisplatin resistance is still one of the main reasons for failure of clinical therapy for cervical cancer. But the underlying molecular mechanisms involved in cisplatin resistance of cervical cancer have still remained unclear. Recent studies reported that long noncoding RNAs (lncRNAs) are novel nonprotein-coding transcripts, which might play a key role in cancer biogenesis and prognosis. One of the lncRNAs, urothelial cancer associated 1 (UCA1), has been shown to promote different types of cancer cell proliferation, migration, and invasion. This study showed that overexpression of UCA1 confers cisplatin resistance by promoting cancer cell proliferation and inhibiting apoptosis. In addition, knockdown of UCA1 remarkably decreased cisplatin resistance in cervical cancer cells. Moreover, results also indicated that UCA1 was involved in signaling pathways modulating cell apoptosis and proliferation. UCA1 suppressed apoptosis by downregulating caspase 3 and upregulating CDK2, whereas enhanced cell proliferation by increased level of survivin and decreased level of p21. This study reports for the first time that UCA1 might play an important role in the cisplatin resistance in cervical cancer, and also explain partially how UCA1 promotes cisplatin resistance in cancer cells. These results provide evidence to support that UCA1 can be used as a potential target for a novel therapeutic strategy for cervical cancer.
Objective: To explore the application of multiplex nested methylated specific polymerase chain reaction (PCR) in the early diagnosis of epithelial ovarian carcinoma (EOC). Materials and Methods: Serum and fresh tissue samples were collected from 114 EOC patients. RUNX3, TFPI2 and OPCML served as target genes. Methylation levels of tissues were assessed by multiplex nested methylated specific PCR, the results being compared with those for carcinoma antigen 125 (CA125). Results: The serum free deoxyribose nucleic acid (DNA) methylation spectrum of EOC patients was completely contained in the DNA spectrum of cancer tissues, providing an accurate reflection of tumor DNA methylation conditions. Serum levels of CA125 and free DNA methylation in the EOC group were evidently higher than those in benign lesion and control groups (p<0.05). Patients with early EOC had markedly lower serum CA125 than those with advanced EOC (p<0.05), but there was no significant difference in free DNA methylation (p>0.05). The sensitivity, specificity and positive predicative value (PPV) of multiplex nested methylated specific PCR were significantly higher for detection of all patients and those with early EOC than those for CA125 (p<0.05). In the detection of patients with advanced EOC, the PPV of CA125 detection was obviously lower than that of multiplex nested methylated specific PCR (p>0.05), but there was no significant difference in sensitivity (p>0.05). Conclusions: Serum free DNA methylation can be used as a biological marker for EOC and multiplex nested methylated specific PCR should be considered for early diagnosis since it can accurately determine tumor methylation conditions.
Vitamin D, termed 1,25(OH)2D3 in it's active form, activity is associated with a reduced risk of hepatocellular carcinoma (HCC) and is an important immune regulator. However, the detail molecular mechanisms underlying the effects of 1,25(OH)2D3 on the progression of HCC are widely unknown. Histone deacetwylase 2 (HDAC2) is usually expressed at high levels in tumors, and its downregulation leads to high expression levels of cell cycle components, including p21(WAF1/Cip1), a well-characterized modulator, which is critical in cell senescence and apoptosis. The present study investigated whether vitamin D inhibits HCC via the regulation of HDAC2 and p21(WAF1/Cip1). Firstly, the toxic concentrations of 1,25(OH)2D3 were determined, according to trypan blue and [(3)H]thymidine incorporation assays. Secondly, HCC cells lines were treated with different concentrations of 1,25(OH)2D3. The expression of HDAC2 was either silenced via short hairpin (sh)RNA or induced by transfection of plasmids expressing the HDAC2 gene in certain HCC cells. Finally the mRNA and protein levels of HDAC2 and p21(WAF1/Cip1) were measured using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The results revealed that 1,25(OH)2D3 treatment reduced the expression of HDAC2 and increased the expression of p21(WAF1/Cip1), in a dose-dependent manner, resulting in the reduction of HCC growth. Elevated levels of HDAC2 reduced the expression of p21(WAF1/Cip1), resulting in an increase in HCC growth. HDAC2 shRNA increased the expression of p21(WAF1/Cip1), resulting in reduction in HCC growth. Thus, 1,25(OH)2D3 exerted antitumorigenic effects through decreasing the expression levels of HDAC2 and increasing the expression of p21(WAF1/Cip1), which inhibited the development of HCC and may indicate the possible underlying mechanism. These results suggest that vitamin D3 may be developed as a potential drug for effective therapy in the treatment of HCC.
The inhibitory effects of 1,25(OH)2D3 on the proliferation of a variety of cancer cell lines have been extensively reported. However, the underlying mechanisms remain largely unknown. In the present study, the effects of 1,25(OH)2D3 on the in vitro proliferation of human hepatocellular carcinoma HepG2 cells and the mechanism involved were investigated. Flow cytometry and MTT assay revealed that 1,25(OH)2D3 inhibited cell proliferation in vitro. Western blotting and real-time PCR indicated that 1,25(OH)2D3 upregulated the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and attenuated that of histone deacetylase 2 (HDAC2). Knockdown of HDAC2 completely mimicked the effects of 1,25(OH)2D3 on PTEN gene expression. The influence of 1,25(OH)2D3 on PTEN expression was reversed in the cells treated with a recombinant pEGFP-LV2-HDAC2 plasmid. Akt phosphorylation, which was downregulated by 1,25(OH)2D3 treatment, was promoted by HDAC2 overexpression. These findings revealed that 1,25(OH)2D3 inhibited cell growth possibly by HDAC2-mediated PTEN upregulation, Akt deactivation, and inhibition of the PI3K/Akt signaling pathway.
Background Two cycles of neoadjuvant PD-1 blockade plus chemotherapy induced favorable pathological response and tolerant toxicity in patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, approximately 25% of patients relapsed within 1 year after surgery, indicating that a short course of treatment may not be sufficient. Therefore, exploring the effects of intensive treatment is needed for optimal clinical outcomes. Methods Locally advanced ESCC patients were administered three cycles of camrelizumab plus nab-paclitaxel and capecitabine, followed by thoracoscopic esophagectomy. The primary endpoint was pathologic response. Secondary endpoints included safety, feasibility, radiologic response, survival outcomes, and immunologic/genomic correlates of efficacy. Results Forty-seven patients were enrolled in the study. Forty-two patients received surgery, and R0 resection was achieved in all cases. The complete and major pathological response rates were 33.3% and 64.3%, respectively, and the objective response rate was 80.0%. Three cycles of treatment significantly improved T down-staging compared to two cycles (P = 0.03). The most common treatment-related adverse events were grades 1–2, and no surgical delay was reported. With a median follow-up of 24.3 months, the 1-year disease-free survival and overall survival rates were both 97.6%, and the 2-year disease-free survival and overall survival rates were 92.3% and 97.6%, respectively. Three patients experienced disease recurrence or metastasis ranging from 12.5 to 25.8 months after surgery, and one patient died 6 months after surgery due to cardiovascular disease. Neither programmed death-ligand 1 expression nor tumor mutational burden was associated with pathological response. An increased infiltration of CD56dim natural killer cells in the pretreatment tumor was correlated with better pathological response in the primary tumor. Conclusions It seems probable that intensive cycles of neoadjuvant camrelizumab plus nab-paclitaxel and capecitabine increased tumor regression and improved survival outcomes. Randomized controlled trials with larger sample sizes and longer follow-up periods are needed to validate these findings. Trial registration Chinese Clinical Trial Registry, ChiCTR2000029807, Registered February 14, 2020, https://www.chictr.org.cn/showproj.aspx?proj=49459.
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