Arm ; Asian Continental Ancestry Group ; Bias (Epidemiology) ; Carboplatin ; Disease-Free Survival ; Doxorubicin ; Drug Therapy ; Follow-Up Studies ; Humans ; Maintenance Chemotherapy ; Ovarian Neoplasms ; Prognosis ; Quality of Life ; Recombination, Genetic ; Sample Size

Objectives: An Asian Gynecologic Oncology Group phase III randomized trial was conducted to determine whether maintenance chemotherapy could improve progression-free survival (PFS) in stages III/IV ovarian cancer. Methods: Between 2007 and 2014, 45 newly-diagnosed ovarian cancer patients were enrolled after complete remission and randomized (1:1) to arm A (4-weekly carboplatin area under the curve 4 and pegylated liposomal doxorubicin [PLD] 30 mg/m2, n=24) for 6 cycles or arm B (observation, n=21). The primary end-point was PFS. A post hoc translational study was conducted to deep sequence BRCA/homologous recombination deficiency (HRD) genes, because BRCA/HRD mutations (BRCA/HRDm) are known to be associated with better prognosis. Results: Enrollment was slow, accrual was closed when 7+ years had passed. With a medianfollow-up of 88.9 months, the median PFS was significantly better in arm A (55.5 months) than arm B (9.2 months) (hazard ratio [HR]=0.40; 95% confidence interval [CI]=0.19–0.87; p=0.020), yet the median overall survival was not significantly different in arm A (not reached) than arm B (95.1 months) (p=0.148). Overall grade 3/4 adverse events were more frequent in arm A than arm B (60.9% vs 0.0%) (p<0.001). Quality of life was generally not significantly different. Distribution of BRCA1/2m or BRCA/HRDm was not significantly biased between the two arms. Wild-type BRCAon-HRD subgroup seemed to fare better with maintenance therapy (HR=0.35; 95% CI=0.11–1.18; p=0.091). Conclusions Despite limitations in small sample size, it suggests that maintenance carboplatin-PLD chemotherapy could improve PFS in advanced ovarian cancer.

Objective To explore the predictive value of INR in early stage of warfarin therapy (early INR)for anticoagulation intensity after 7 days of treatment. Methods The medical records of patients hospitalized in the Department of Cardiology,Linyi People′s Hospital,Shandong University from January 2012 to May 2015 were collected,who received warfarin anticoagulation therapy and underwent INR tests in the morning after 3 or 7 days of medication. The early INR meant INR after 3 days of warfarin treatment. According to INR after 7 days of warfarin treatment,the patients were divided into 2 groups, anticoagulation up to standard(INR 2. 0﹣3. 0)group and over﹣anticoagulation(INR﹥3. 0)group. The best critical value of early INR for predicting INR after 7 days of warfarin treatment was obtained by plotting ROC curve. The risk of over﹣anticoagulation after 7 days of warfarin treatment was compared in patients with early INR ≥critical value and﹤critical value. Univariate analysis was used to compare the clinical characteristics in the 2 groups. The indexes with P ﹤0. 100 were used as covariate and multivariate logistic regression analysis was performed. The odds ratio( OR)and its 95% confidence interval( CI)was calculated and independent risk factors of INR ﹥3. 0 after warfarin treatment were screened. Results A total of 75 patients with atrial fibrillation were enrolled in the study,including 38 males and 37 females,aged(64 ± 9),42 patients in the anticoagulation up to standard group and 33 patients in the over﹣anticoagulation group. There were significant differences in body weight,INR after 3 days of medication,and the number of patients with hypoproteinemia between the 2 groups(all P﹤0. 05),but no significant differences in other indicators (all P﹥0. 05). The results of ROC curve showed that the best critical value of anticoagulation intensity predicted by early INR was 1. 67,the area under the curve was 0. 915[95% CI:0. 828﹣0. 967],and the sensitivity and specificity were 0. 95 and 0. 82,respectively. The risk of over﹣anticoagulation in patients with 7 days of warfarin treatment in the group with early INR ≥1. 67 was significantly higher than that in the group with early INR ﹤1. 67[90. 0%(27/30)vs. 13. 3%(6/45),χ2 ＝39. 883,OR＝58. 50,95% CI:13. 45﹣254. 48,P﹤0. 001]. Multivariate logistic regression analysis showed that early INR≥1. 67 was an independent risk factor for over﹣anticoagulation after 7 days of treatment( OR＝48. 719,95% CI:10. 891﹣217. 940,P﹤0. 001). Conclusions The early INR can predict anticoagulation intensity after 7 days of treatment. Early INR≥1. 67 is an independent risk factor for over﹣anticoagulation after 7 days of warfarin treatment.

Objective To explore the predictive value of INR in early stage of warfarin therapy (early INR)for anticoagulation intensity after 7 days of treatment. Methods The medical records of patients hospitalized in the Department of Cardiology,Linyi People′s Hospital,Shandong University from January 2012 to May 2015 were collected,who received warfarin anticoagulation therapy and underwent INR tests in the morning after 3 or 7 days of medication. The early INR meant INR after 3 days of warfarin treatment. According to INR after 7 days of warfarin treatment,the patients were divided into 2 groups, anticoagulation up to standard(INR 2. 0﹣3. 0)group and over﹣anticoagulation(INR﹥3. 0)group. The best critical value of early INR for predicting INR after 7 days of warfarin treatment was obtained by plotting ROC curve. The risk of over﹣anticoagulation after 7 days of warfarin treatment was compared in patients with early INR ≥critical value and﹤critical value. Univariate analysis was used to compare the clinical characteristics in the 2 groups. The indexes with P ﹤0. 100 were used as covariate and multivariate logistic regression analysis was performed. The odds ratio( OR)and its 95% confidence interval( CI)was calculated and independent risk factors of INR ﹥3. 0 after warfarin treatment were screened. Results A total of 75 patients with atrial fibrillation were enrolled in the study,including 38 males and 37 females,aged(64 ± 9),42 patients in the anticoagulation up to standard group and 33 patients in the over﹣anticoagulation group. There were significant differences in body weight,INR after 3 days of medication,and the number of patients with hypoproteinemia between the 2 groups(all P﹤0. 05),but no significant differences in other indicators (all P﹥0. 05). The results of ROC curve showed that the best critical value of anticoagulation intensity predicted by early INR was 1. 67,the area under the curve was 0. 915[95% CI:0. 828﹣0. 967],and the sensitivity and specificity were 0. 95 and 0. 82,respectively. The risk of over﹣anticoagulation in patients with 7 days of warfarin treatment in the group with early INR ≥1. 67 was significantly higher than that in the group with early INR ﹤1. 67[90. 0%(27/30)vs. 13. 3%(6/45),χ2 ＝39. 883,OR＝58. 50,95% CI:13. 45﹣254. 48,P﹤0. 001]. Multivariate logistic regression analysis showed that early INR≥1. 67 was an independent risk factor for over﹣anticoagulation after 7 days of treatment( OR＝48. 719,95% CI:10. 891﹣217. 940,P﹤0. 001). Conclusions The early INR can predict anticoagulation intensity after 7 days of treatment. Early INR≥1. 67 is an independent risk factor for over﹣anticoagulation after 7 days of warfarin treatment.

Objective To evaluate the effectiveness of anticoagulation management by physician-clinical pharmacist team for patients with valvular atrial fibrillation. Methods One hundred and seventy two patients with valvular atrial fibrillation received warfarin therapy for anticoagulation during hospitalization in Linyi People′s Hospital from January 2014 to December 2016, the patients continued to receive warfarin therapy for>6 months after discharge. The patients were randomly assigned in two groups:the anticoagulation management was given by physician-clinical pharmacist team in 87 cases (trial group), while the dosage of wargarin was adjusted in outpatient department by physicians alone in 85 cases (control group). The goal attainment rate of international normalized ratio (INR), the proportion of patients with a stable warfarin dose, knowledge of anticoagulants, belief of medication, medication compliance were compared between two groups. Results There were no significant differences in age, sex, body weight, smoking and drinking habits, valvular disease type, comorbidities; and the initial INR, knowledge of anticoagulants, belief of medication and medication compliance at admission between two groups (all P>0.05). The goal attainment rate of INR (52.17％vs. 41.02％,χ2=8.178, P=0.004), the proportion of patients with a stable dose of warfarin (74.71％ vs. 56.47％,χ2=6.349, P=0.012), the knowledge of anticoagulants (11.03 ± 2.25 vs. 10.08 ± 1.86, t=3.018, P=0.003), the belief of medication[(12.23 ± 2.07) vs. (11.67 ± 1.48), t=2.042, P=0.043], and the medication compliance[(7.36 ± 0.89) vs. (7.04 ± 1.10), t=2.1128, P=0.036] in the trial group were significantly higher than those in control group. Conclusion Anticoagulation management by physician - clinical pharmacist team can improve the management level of anticoagulation and the knowledge of anticoagulans, enhance the medication belief, improve the goal attainment rate of INR and the compliance rate of medication in patients with valvular atrial fibrillation.

OBJECTIVE:To evaluate the effects of clinical pharmacists participating in clinical pathway management for chron-ic heart failure(CHF). METHODS:A total of 107 CHF adult inpatients in Linyi People's Hospital during Jan. 2014-Oct. 2015 were divided into control group(56 cases,3 withdrawal,53 in total)and trial group(58 cases,4 withdrawal,54 in total)accord-ing to random number table. Control group received routine clinical pathway management method of CHF;trial group received clin-ical pathway management with the participation of clinical pharmacists. Clinical efficacy,the utilization of heart failure drugs,eco-nomic indexes,medication compliance after discharge,re-hospitalization rate due to heart failure were compared between 2 groups. RESULTS:Total response rate of trial group was significantly higher than control group,with statistical significance(P<0.05). The utilization rate of ACEI/ARB,β-receptor blocker,target dose rate of ACEI/ARB in trial group were significantly higher than control group,with statistical significance(P<0.05);target dose rate of β-receptor blocker was higher than control group,without statistical significance(P>0.05). Hospitalization time,drug cost,total hospitalization cost and drug ratio of trial group were short-er or lower than control group,without statistical significance(P>0.05). One month after discharge,the proportion of medication compliance in trial group was significantly higher than control group,with statistical significance(P<0.05);re-hospitalization rate was lower than control group,without statistical significance(P>0.05). Three months after discharge,the proportion of medica-tion compliance in trial group was higher than control group,while re-hospitalization rate was lower than control group,with statis-tical significance(P<0.05). CONCIUSIONS:The participation of clinical pharmacists in clinical pathway management of CHF can significantly improve the utilization rate of recommended drugs by guideline,clinical efficacy and medication compliance,and reduce re-hospitalization rate.

Objective To select drugs inducing international normalized ratio (INR) elevation by concomitant use of warfarin in inpatients.Methods The data of inpatients with increased INR rise (INR>3.50) because of concomitant use of warfarin and other drugs in Linyi People′s Hospital, Shandong University from January 2012 to December 2016 were collected and analyzed retrospectively.The baseline conditions, combination drugs, INR rise during treatments, bleeding events, treatments and outcomes in inpatients were recorded.Drugs that could increase anticoagulant effect of warfarin were screened. Results A total of 100 patients were enrolled in this study, including 43 men and 57 women aged from 26 to 86 years with an average age of (64±13) years.Primary diseases in 64 patients were atrial fibrillation, in 15 patients were after heart valve replacements, in 10 patients were pulmonary embolism, in 7 patients were lower extremity venous thrombosis, and in 4 patients were myocardial infarction with left ventricular thrombus.Hospital stay were 5-39 d and the average time was (17±7) d;the time of warfarin treatments were 3-36 d and the average time was (11±5) d.Of the 302 kinds of drugs combined with warfarin in the 100 patients, 40 kinds of drugs were found to induce INR elevation, including 16 kinds of anti-infective drugs (66 cases), 7 kinds of endocrine system drugs (28 cases), 4 kinds of cardiovascular system drugs (30 cases), 4 kinds of nervous system drugs (5 cases), 3 kinds of proton pump inhibitors (21 cases), 3 kinds of blood system drugs (4 cases), 2 kinds of proprietary Chinese medicine preparations (10 cases), 1 kind of non-steroidal anti-inflammatory drugs (2 cases).According to the number of drug use, the top ten drugs were piperacillin sodium and tazobactam sodium (27 cases), methylprednisolone (22 cases), levofloxacin (20 cases), amiodarone (20 cases), omeprazole (19 cases), cefoperazone sodium and sulbactam sodium (11 cases), fluvastatin sodium (10 cases), compound liquorice preparations (9 cases), voriconazole (7 cases), latamoxef (4 cases), and moxifloxacin (4 cases).The number of drug combination was 1-5 kinds in each patient, combination drug was 1 kind in 31 cases, 2 kinds in 46 cases, 3 kinds in 18 cases, 4 kinds in 4 cases, and 5 kinds in 1 case.Of the 100 patients with INR elevation, 83 patients stopped taking warfarin and 13 patients were given intramuscular injection of vitamin K1 at the same time, 17 patients′warfarin dose was decreased from 1.25-3.75 mg to 0.75-3.00 mg, then the INR levels in all patients decreased to <3.0.Seven patients had mild bleeding before warfarin withdrawal, including 4 cases of subcutaneous hemorrhage, 1 case of subarachnoid hemorrhage, 1 case of hematochezia, and 1 case of blood in phlegm.Conclusions Many commonly used drugs in clinical practice, such as compound preparations of β-lactam antibiotics and β-lactamase inhibitors, quinolones, glucocorticoid, anti-arrhythmic drugs, and proton pump inhibitors, etc., could cause INR elevation and increase bleeding risk.

Objective To select drugs inducing international normalized ratio (INR) elevation by concomitant use of warfarin in inpatients.Methods The data of inpatients with increased INR rise (INR>3.50) because of concomitant use of warfarin and other drugs in Linyi People′s Hospital, Shandong University from January 2012 to December 2016 were collected and analyzed retrospectively.The baseline conditions, combination drugs, INR rise during treatments, bleeding events, treatments and outcomes in inpatients were recorded.Drugs that could increase anticoagulant effect of warfarin were screened. Results A total of 100 patients were enrolled in this study, including 43 men and 57 women aged from 26 to 86 years with an average age of (64±13) years.Primary diseases in 64 patients were atrial fibrillation, in 15 patients were after heart valve replacements, in 10 patients were pulmonary embolism, in 7 patients were lower extremity venous thrombosis, and in 4 patients were myocardial infarction with left ventricular thrombus.Hospital stay were 5-39 d and the average time was (17±7) d;the time of warfarin treatments were 3-36 d and the average time was (11±5) d.Of the 302 kinds of drugs combined with warfarin in the 100 patients, 40 kinds of drugs were found to induce INR elevation, including 16 kinds of anti-infective drugs (66 cases), 7 kinds of endocrine system drugs (28 cases), 4 kinds of cardiovascular system drugs (30 cases), 4 kinds of nervous system drugs (5 cases), 3 kinds of proton pump inhibitors (21 cases), 3 kinds of blood system drugs (4 cases), 2 kinds of proprietary Chinese medicine preparations (10 cases), 1 kind of non-steroidal anti-inflammatory drugs (2 cases).According to the number of drug use, the top ten drugs were piperacillin sodium and tazobactam sodium (27 cases), methylprednisolone (22 cases), levofloxacin (20 cases), amiodarone (20 cases), omeprazole (19 cases), cefoperazone sodium and sulbactam sodium (11 cases), fluvastatin sodium (10 cases), compound liquorice preparations (9 cases), voriconazole (7 cases), latamoxef (4 cases), and moxifloxacin (4 cases).The number of drug combination was 1-5 kinds in each patient, combination drug was 1 kind in 31 cases, 2 kinds in 46 cases, 3 kinds in 18 cases, 4 kinds in 4 cases, and 5 kinds in 1 case.Of the 100 patients with INR elevation, 83 patients stopped taking warfarin and 13 patients were given intramuscular injection of vitamin K1 at the same time, 17 patients′warfarin dose was decreased from 1.25-3.75 mg to 0.75-3.00 mg, then the INR levels in all patients decreased to <3.0.Seven patients had mild bleeding before warfarin withdrawal, including 4 cases of subcutaneous hemorrhage, 1 case of subarachnoid hemorrhage, 1 case of hematochezia, and 1 case of blood in phlegm.Conclusions Many commonly used drugs in clinical practice, such as compound preparations of β-lactam antibiotics and β-lactamase inhibitors, quinolones, glucocorticoid, anti-arrhythmic drugs, and proton pump inhibitors, etc., could cause INR elevation and increase bleeding risk.

Bone marrow mesenchymal stem cells (MSCs) are considered as a promising cell source to treat the acute myocardial infarction. However, over 90% of the stem cells usually die in the first three days of transplantation. Survival potential, migration ability and paracrine capacity have been considered as the most important three factors for cell transplantation in the ischemic cardiac treatment. We hypothesized that stromal-derived factor-1 (SDF-1)/CXCR4 axis plays a critical role in the regulation of these processes. In this study, apoptosis was induced by exposure of MSCs to H(2)O(2) for 2 h. After re-oxygenation, the SDF-1 pretreated MSCs demonstrated a significant increase in survival and proliferation. SDF-1 pretreatment also enhanced the migration and increased the secretion of pro-survival and angiogenic cytokines including basic fibroblast growth factor and vascular endothelial growth factor. Western blot and RT-PCR demonstrated that SDF-1 pretreatment significantly activated the pro-survival Akt and Erk signaling pathways and up-regulated Bcl-2/Bax ratio. These protective effects were partially inhibited by AMD3100, an antagonist of CXCR4.We conclude that the SDF-1/CXCR4 axis is critical for MSC survival, migration and cytokine secretion.
Animals ; Apoptosis ; Apoptosis Regulatory Proteins ; genetics ; metabolism ; Bone Marrow Cells ; metabolism ; physiology ; Cell Hypoxia ; Cell Movement ; Chemokine CXCL12 ; genetics ; pharmacology ; physiology ; Cytokines ; metabolism ; Gene Expression ; L-Lactate Dehydrogenase ; metabolism ; MAP Kinase Signaling System ; Male ; Mesenchymal Stem Cells ; metabolism ; physiology ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, CXCR4 ; metabolism

The aim of this paper is to report the study on gene silencing efficiency of siRNA targeted against mouse VEGFR2 (siVEGFR2) in vitro mediated by polyethyleneimine (PEI) and its anti-tumor effect in vivo. CY3-labeled siRNA was compounded into PEI and transfected into MS1 cells. Confocal microscopy was used to image the subcellular distribution of siRNA in MS1 cells. Semi-quantitative RT-PCR and Western blotting were used to evaluate VEGFR2 gene silencing induced by siVEGFR2/PEI complexes. A tumor-bearing nude mice model was established to compare the anti-tumor effect after delivered by local and systemic routes. siVEGFR2/PEI complex-transfected cells exhibited much fluorescence in cytoplasm with no evidence of nuclear accumulation. The expression levels of VEGFR2 mRNA and protein in PEI-transfected cells were significantly down-regulated compared with that in blank group, the silencing efficiency were 28.2% and 23.6% respectively. The tumor sizes in mice intratumorally injected with siVEGFR2/PEI complexes (189.429 +/- 17.562 mm3) were reduced definitely compared to that in mice injected with siVEGFR2/PEI complexes via vein route (315.507 +/- 20.491 mm3), or to saline groups (365.844 +/- 20.713 mm3). The study demonstrated that PEI could effectively transfect siRNA into cells and silence the VEGFR2 gene expression. Intratumoral delivery is more suitable for non-targeted modified PEI/siRNA complexes to inhibit the tumor growth in vivo. The present data lay a solid foundation to further study on the gene silencing mechanism for PEI-medicated RNAi and its anti-tumor efficiency in vivo.
Animals ; Cell Line, Tumor ; Cells, Cultured ; Endothelial Cells ; cytology ; metabolism ; Female ; Gene Silencing ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Polyethyleneimine ; chemistry ; RNA, Messenger ; metabolism ; RNA, Small Interfering ; genetics ; metabolism ; Spleen ; cytology ; Transfection ; Tumor Burden ; Vascular Endothelial Growth Factor Receptor-2 ; genetics ; metabolism