Preimplantation genetic testing for Aicardi-Goutières syndrome induced by novel compound heterozygous mutations of TREX1: an unaffected live birth.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare, autosomal recessive, hereditary neurodegenerative disorder. It is characterized mainly by early onset progressive encephalopathy, concomitant with an increase in interferon-α levels in the cerebrospinal fluid. Preimplantation genetic testing (PGT) is a procedure that could be used to choose unaffected embryos for transfer after analysis of biopsied cells, which prevents at-risk couples from facing the risk of pregnancy termination. METHODS: Trio-based whole exome sequencing, karyotyping and chromosomal microarray analysis were used to determine the pathogenic mutations for the family. To block the inheritance of the disease, multiple annealing and looping-based amplification cycles was used for whole genome amplification of the biopsied trophectoderm cells. Sanger sequencing and next-generation sequencing (NGS)-based single nucleotide polymorphism (SNP) haplotyping were used to detect the state of the gene mutations. Copy number variation (CNV) analysis was also carried out to prevent embryonic chromosomal abnormalities. Prenatal diagnosis was preformed to verify the PGT outcomes. RESULTS: A novel compound heterozygous mutation in TREX1 gene was found in the proband causing AGS. A total of 3 blastocysts formed after intracytoplasmic sperm injection were biopsied. After genetic analyses, an embryo harbored a heterozygous mutation in TREX1 and without CNV was transferred. A healthy baby was born at 38th weeks and prenatal diagnosis results confirmed the accuracy of PGT. CONCLUSIONS: In this study, we identified two novel pathogenic mutations in TREX1, which has not been previously reported. Our study extends the mutation spectrum of TREX1 gene and contributes to the molecular diagnosis as well as genetic counseling for AGS. Our results demonstrated that combining NGS-based SNP haplotyping for PGT-M with invasive prenatal diagnosis is an effective approach to block the transmission of AGS and could be applied to prevent other monogenic diseases.

Capecitabine in Combination with Standard (Neo)Adjuvant Regimens in Early Breast Cancer: Survival Outcome from a Meta-Analysis of Randomized Controlled Trials.

Capecitabine has been investigated in early breast cancer in several studies, but it was undefined that whether it could improve survival. To investigate whether the addition of capecitabine affected survival in patients with early breast cancer, a meta-analysis was conducted and overall survival (OS), disease-free survival (DFS), and toxicity were assessed. The PubMed, Embase databases and the Cochrane Central Register of Controlled Trials were searched for studies between January 2006 and April 2016. Hazard ratios (HRs) with their 95% confidence intervals (CIs), or data for calculating HRs with 95% CI were derived. Seven trials with 9097 patients, consisted of 4 adjuvant and 3 neoadjuvant studies, were included in this meta-analysis. Adding capecitabine showed no improvement in DFS (HR = 0.93; 95% CI, 0.85-1.02; P = 0.12), whereas a significant improvement in OS was observed (HR = 0.85; 95% CI, 0.75-0.96; P = 0.008). A sub-analysis of DFS showed that benefit of capecitabine derived from patients with triple negative subtype and with extensive axillary involvement. Safety profiles were consistent with the known side-effects of capecitabine, but more patients discontinued scheduled treatment in the capecitabine group. Combining capecitabine with standard (neo)adjuvant regimens in early breast cancer demonstrated a significantly superior OS, and indicated DFS improvement in some subtypes with high risk of recurrence. Selection of subtypes was a key to identify patients who might gain survival benefit from capecitabine.

Synchronous primary esophageal squamous cell carcinoma and gastric adenocarcinoma: analysis of 41 cases treated in a single institution.

The present study investigated the treatment and survival outcomes of patients with synchronous primary esophageal squamous cell carcinoma and gastric adenocarcinoma. The medical records of 10,783 patients with primary esophageal squamous cancer treated at our institution between 1995 and 2012 were retrospectively reviewed. Overall survival (OS) rates were calculated using the Kaplan-Meier method. The incidence was 0.38% (41/10,783). Of these 41 patients, 26 underwent curative surgery, ten received palliative chemotherapy or radiotherapy, and five received no treatment. The median OS of the surgery, palliative-therapy, and treatment-free groups was 17.1, 9.0, and 3.8 months, respectively. The 1-, 3-, 5-, and 10-year OS rates for the surgery group were 77%, 45%, 33%, and 19%, respectively. No significant differences in median OS were observed between the surgery group and the historical cohort of isolated esophageal cancer (n = 186) (17.1 vs. 21.0 months, P = 0.061) or isolated gastric cancer (n = 51) (17.1 vs. 28.9 months, P = 0.875), or between the palliative-therapy group and its corresponding historical cohort (n = 30) (9.0 vs. 8.3 months, P = 0.862). The survival outcomes of patients with synchronous primary esophageal squamous and gastric cancers were not worse than those of patients with isolated esophageal cancer or isolated gastric cancer.

Phase II trial of second-line chemotherapy with docetaxel and capecitabine in advanced esophageal squamous cell carcinoma.

We performed a phase II trial of docetaxel in combination with capecitabine to evaluate the antitumor response, toxicity, and survival in pre-treated patients with advanced esophageal squamous cell carcinoma. Patients with advanced esophageal squamous cell carcinoma who had failed first-line chemotherapy with cisplatin and 5-fluorouracil were enrolled in this study. Treatment consisted of oral capecitabine (825 mg/m(2) twice daily on days 1-14) plus 1-h intravenous docetaxel (60 mg/m(2) on day 1) every 3 weeks for up to 6 cycles. Between June 2008 and August 2011, thirty eligible patients with a median age of 58 years (range 38-68 years) were enrolled. Patients received a median of three cycles of treatment (range 1-6). The median follow-up was 15.4 months (range 1.0-31.5 months). Intent-to-treat efficacy analysis demonstrated an overall response rate of 23.3% (0 complete response and 7 partial response) and stable disease of 43.4 % (n = 13). The median time to progression was 3.0 months (95% CI 1.9-4.1 months). The median survival was 8.3 months (95% CI 6.8-9.8 months). Severe adverse events (grade 3/4) reported were as follows: neutropenia (33.3%, n = 10, including febrile neutropenia 6.7%, n = 2), anemia (16.7%, n = 5), thrombocytopenia (10 %, n = 3), hand-foot syndrome (13.3%, n = 4), and fatigue (10%, n = 3). Docetaxel plus capecitabine had a manageable adverse event profile and promising activity in advance esophageal squamous cell carcinoma as a second-line treatment.

[Study of sequence-dependent in vitro effects of zoledronic acid and paclitaxel upon human nasopharyngeal carcinoma cell line HNE1].

OBJECTIVE: To explore the in vitro effects of anti-proliferation and apoptosis-inducing with different sequence regimens of zoledronic acid plus paclitaxel in human nasopharyngeal carcinoma cell line HNE1 so as to explore the optimal sequence regimen of these two drugs and related mechanism. METHODS: The cytotoxic effects of different sequence schemes of zoledronic acid plus paclitaxel on HNE1 cells were detected by methyl-thiazol-tetrazolium (MTT) assay. Annexin V-FITC/PI double staining flow cytometry (FCM) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay were used to measure the effects of zoledronic acid plus paclitaxel upon apoptosis. The expressions of mRNA of Bcl-2, Bax, Caspase3 and Caspase9 gene were detected by real-time quantitative-polymerase chain reaction (PCR) and protein was detected by Western blot. RESULTS: All experiment groups enhanced the effect of anti-proliferation by MTT assay (P < 0.05); the treatment of zoledronic acid followed by paclitaxel was superior to the other two regimens (P < 0.05). As detected by FCM, the early apoptotic rate of control group was 2.59% ± 0.28% and the experiment groups were 13.89% ± 0.69%, 11.73% ± 0.54%, 23.97% ± 0.68%, 10.45% ± 0.16% and 8.59% ± 0.74% respectively (P < 0.05). TUNEL assay detected the late apoptosis of HNE1 cells and the experiment groups enhanced the effect of apoptosis-inducing (P < 0.05). The treatment of zoledronic acid followed by paclitaxel was superior to the other regimens (P < 0.05). Such an effect was due to the down-regulation of anti-apoptotic protein Bcl-2 and up-regulations of pro-apoptotic proteins Bax, Caspase3 and Caspase9 at the expression levels of mRNA and protein. There was a greater regulation in the group of zoledronic acid followed by paclitaxel. CONCLUSION: Zoledronic acid can enhance the in vitro effects of anti-proliferation and apoptosis-inducing for paclitaxel on HNE1 cell. The treatment of zoledronic acid followed by paclitaxel may be the optimal regimen. Synergistic induction of apoptosis is via the effects of Bcl-2 family and through the mitochondrial pathway.

Zoledronic acid inhibits human nasopharyngeal carcinoma cell proliferation by activating mitochondrial apoptotic pathway.

We investigated the apoptosis-inducing effect of zoledronic acid in human nasopharyngeal carcinoma cell HNE-1 and explore the potential mechanism. Human nasopharyngeal carcinoma cell HNE-1 was exposed to various concentrations (0-40 µmol/L) of zoledronic acid. Cell proliferation was studied by an MTT assay. Cell apoptosis was analyzed by flow cytometry and TdT-mediated dUTP nick-end labeling (TUNEL) assay. Cell cycle was analyzed by flow cytometry. Gene expressions were investigated by quantitative real-time PCR, and protein expressions were investigated by Western blot. The results showed zoledronic acid decreased cell proliferation not in a time- or dose-dependent fashion. TUNEL assay, together with Annexin V/propidium iodide FACS analysis, confirmed the increase in apoptotic HNE-1 cells treated with zoledronic acid. Cell cycle analysis showed a larger number of treated cells occupied the S-phase. Quantitative RT-PCR and Western blot revealed that the pro-apoptotic genes, Bad, Bax, and Caspase-9, were upregulated in treated HNE-1 cells, whereas the anti-apoptotic gene, Bcl-2, was downregulated in both mRNA and protein levels. In conclusion, zoledronic inhibits human nasopharyngeal carcinoma cell proliferation by inducing apoptosis via the mitochondrial apoptotic pathway.

[The efficacy of vinorelbine plus cisplatin in the treatment of 48 cases of advanced non-small cell lung cancer].

BACKGROUND: Chemotherapy is one of the important treatment methods for advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy of the combination of vinorelbine (NVB) and cisplatin (DDP) in the treatment of advanced NSCLC. METHODS: Forty-eight patients with stage IIIB and IV NSCLC were treated with NVB (25mg/m² ,iv,d1 and d8) and DDP (40mg/m², d1 and d2). RESULTS: The overall response rate (RR) was 48%, median survival time was 10 months, and 1-year survival rate was 35%. The RR of patients with first-line chemotherapy was 55%, median survival time was 11 months, the RR of patients with second-line chemotherapy was 35%, median survival time was 8 months; the RR of patients with stage IIIB was 54%, median survival time was 10 months, the RR of patients with stage IV was 41%, median survival time was 9 months. The main toxicities were myelosuppression, nausea, vomiting and phlebitis. CONCLUSIONS: The combination of NVB and DDP in the treatment of advanced NSCLC has a high response rate and tolerable side effects, which can be adopted as the first-line treatment of advanced NSCLC, or the second line treatment that still need further studies.