Risk of Gastrointestinal Events During Lapatinib Therapy: A Meta-Analysis From 12,402 Patients With Cancer.

Lapatinib, a tyrosine kinase inhibitor used as an anticancer therapeutic agent, has adverse events associated with treatment resulting in noncompliance and withdrawal from the therapy. Here, we performed meta-analysis of published clinical trials to determine relative risk (RR) and incidence of gastrointestinal events during lapatinib therapy in patients with cancer. A comprehensive literature search was performed and summary incidence, RR, and 95% confidence intervals (CI) were calculated using fixed-effects or random-effects models, depending on the heterogeneity of trials. Thirty-six trials with 12,402 patients were included; summary incidences of all-grade gastrointestinal events in patients with cancer were diarrhea 57.8%, nausea 30.8%, and vomiting 19.6%. Lapatinib combination with chemotherapy or any anti-HER2 mAbs were associated with significant risk of all-grade diarrhea [(RR 3.64, 95% CI, 2.96-4.49), (RR 2.89, 95% CI, 2.21-3.79), respectively] and high-grade diarrhea [(RR 11.25, 95% CI, 7.31-17.33), (RR 9.96, 95% CI, 7.23-13.72), respectively], and lapatinib combination with chemotherapy group showed a significantly increased risk of all-grade nausea (RR 1.54, 95% CI, 1.25-1.89). Lapatinib combination with chemotherapy or any anti-HER2 mAbs were associated with significant risk of all-grade vomiting [(RR 1.47, 95% CI, 1.12-1.93), (RR 1.30, 95% CI, 1.11-1.52), respectively]. Lapatinib combination with any anti-HER2 mAbs was associated with a significant risk of high-grade vomiting (RR 2.25, 95% CI, 1.41-3.61). This study revealed a significantly increased risk of diarrhea, nausea, and vomiting in patients with cancer receiving lapatinib, suggesting that appropriate clinical intervention and gastrointestianal protective agents should be emphasized.

Knockdown of Long Non-Coding RNA-ZFAS1 Protects Cardiomyocytes Against Acute Myocardial Infarction Via Anti-Apoptosis by Regulating miR-150/CRP.

ZFAS1 is one of cardiac-specific or cardiac-related lncRNAs. This study was to explore the functional involvement of ZFAS1 and its regulatory role in AMI. In this study, the models of AMI rat and myocardial cell cultured under hypoxia were made. The expression of ZFAS1 and miR-150 of myocardial infarction tissue or cardiac myocytes was determined by quantitative real time PCR. The regulatory role of ZFAS1 on miR-150 was examined by RNA pull down assay. The effect of miR-150 or ZFAS1 expression on cell viability was analyzed by MTT assay. The relative expression of ZFAS1 in the myocardium infracted zone and border zone was significantly upregulated at 1-48 h of AMI rats, but it downregulated at 1 week and 2 weeks; miR-150 was significantly downregulated at AMI-1-48 h and upregulated at 1 and 2 weeks after model establishment. The result of RNA pull down assay indicated that ZFAS1 could interact directly with miR-150. C-reactive protein (CRP) was regulated by ZFAS1/miR-150 axis and negatively targeted by miR-150. Hypoxia caused the decrease of cell viability and the upregulation of CRP at mRNA and protein levels; whereas this upregulation could be attenuated by miR-150 mimic or si-ZFAS1 in H9C2 cells and cardiomyocytes. Knockdown of ZFAS1 or miR-150 overexpression effectively relieved AMI-induced myocardial infarction in AMI-1 week rats. The ZFAS1/miR-150 axis was involved in the molecular mechanism of AMI induced cardiomyocytes apoptosis via regulating CRP. J. Cell. Biochem. 118: 3281-3289, 2017. © 2017 Wiley Periodicals, Inc.

Risk of Gastrointestinal Events During Vandetanib Therapy in Patients With Cancer: A Systematic Review and Meta-analysis of Clinical Trials.

Vandetanib, a tyrosine kinase inhibitor used as an anticancer therapeutic agent, has adverse events associated with treatment resulting in noncompliance and withdrawal from the therapy. Here, we performed meta-analysis of published clinical trials to determine relative risk (RR) and incidence of gastrointestinal events during vandetanib therapy in patients with cancer. A comprehensive literature search was performed and summary incidence, RR, and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models, depending on the heterogeneity of trials. Twenty-two trials with 6382 patients were included summary incidences of all-grade gastrointestinal events in patients with cancer were anorexia 24% (95% CI, 20%-28%), constipation 17% (95% CI, 13%-20%), diarrhea 46% (95% CI, 40%-53%), nausea 29% (95% CI, 25%-33%), and vomiting 17% (95% CI, 14%-21%). Incidences of vandetanib-associated gastrointestinal events stratified by tumor histology were statistically insignificant. Vandetanib was associated with a significant risk of all-grade diarrhea (RR 1.75, 95% CI, 1.42-2.16) and high-grade diarrhea (RR 1.94, 95% CI, 1.43-2.64) and significantly decreased risk of all-grade constipation (RR 0.80, 95% CI, 0.71-0.91). Summary RR showed a significant risk of vandetanib-associated constipation (RR 0.82, 95% CI, 0.72-0.93) and diarrhea (all-grade: RR 1.68, 95% CI, 1.31-2.14 and high-grade: RR 1.57, 95% CI, 1.14-2.17) in patients with non-small-cell lung cancer. This study revealed a significantly increased risk of diarrhea and a reduced risk of constipation in patients with cancer receiving vandetanib, suggesting that appropriate and frequent clinical monitoring should be emphasized.

Risk of Hypertension With Sorafenib Use in Patients With Cancer: A Meta-Analysis From 20,494 Patients.

Sorafenib is a new multikinase inhibitor; the incidence of hypertension (HTN) with sorafenib has been reported to vary substantially among clinical trials. We searched multiple databases to investigate the risk of sorafenib-induced HTN in patients with cancer. A total of 93 trials involving 20,494 patients were selected for this meta-analysis. The relative risks (RRs) of all-grade and high-grade HTN associated with sorafenib were 3.06 (P < 0.001) and 3.33 (P < 0.001). There are no significantly RRs of all-grade, 0.81 (P = 0.047), and high-grade HTN, 0.64 (P = 0.075), in sorafenib monotherapy versus other multitargeted antiangiogenic tyrosine kinase inhibitors. The incidence of sorafenib-associated all-grade and high-grade HTN was 21.3% (P < 0.001) and 5.9% (P < 0.001), respectively. The patients with renal cell carcinoma (RCC) and thyroid cancer have high incidence (≥20%) of sorafenib-associated all-grade HTN and high incidence (≥5%) of sorafenib-associated high-grade HTN. The trials with median treatment duration ≥ 4, 5, and 7 months were 21.0% (P < 0.001), 25.4% (P < 0.001), and 27.6% (P < 0.001); progression-free survival ≥ 6, 9, and 12 months were 24.5% (P < 0.001), 26.8% (P < 0.001), and 32.8% (P < 0.001); and overall survival ≥ 12, 18, and 24 months were 18.5% (P < 0.001), 22.5% (P < 0.001), and 25.9% (P < 0.001), respectively. There is a significantly high risk of sorafenib-induced HTN. In comparison between sorafenib and other multitargeted antiangiogenic tyrosine kinase inhibitors, RRs had no significance. The patients with RCC and thyroid cancer have significantly higher incidence of HTN. With prolonged treatment duration, progression-free survival, and overall survival, the incidence of all-grade HTN may increase.

Effect of Interventional Therapy Unexplained Dizziness and Relationship Between Dizziness Handicap Inventory and Right-to-Left Shunt Grading.

Objective: Unexplained dizziness remains a clinical challenge. Our previous studies have shown that unexplained dizziness may be related to patent foramen ovale (PFO). This study aims to explore whether the degree of shunt is correlated with the degree of unexplained dizziness and looking for the possible clinical intervention for patients with unexplained dizziness. Methods: This study was a large single-center, prospective, controlled study. From March 2019 to March 2022, patients with unexplained dizziness and explained dizziness and healthy controls were recruited. Contrast-enhanced transcranial Doppler sonography (c-TCD) was performed to detect the existence of right-to-left shunt (RLS) and shunt grading. The dizziness handicap inventory (DHI) was completed to evaluate the dizziness. Unexplained dizziness patients with large amount of PFO were volunteered to receive medication treatment and transcatheter PFO closure and followed up six months. Results: A total of 387 patients (132 unexplained, 123 explained and 132 controls) were enrolled. There was a statistical difference in the RLS grading with three groups (p < 0.001). The Spearman correlation coefficient of RLS grading and DHI scores in unexplained dizziness patients (r=0.122, p=0.163) and explained dizziness patients (r=0.067, p=0.460). In the unexplained group, there were 49 cases with massive grading RLS. Of which 25 patients received percutaneous PFO closure treatment and 24 cases received medication treatment. Followed up six months after treatment, the amount of DHI scores change in patients who received the percutaneous PFO closure was significantly higher than that in the medication treatment group (p < 0.001). Conclusion: RLS may play an important role in unexplained dizziness. For unexplained dizziness patients, PFO closure may contribute to better outcomes. In the future, large-scale randomized controlled studies are still needed.

Characteristics, treatments and survival of pulmonary arterial hypertension associated with congenital heart disease in China: Insights from a national multicenter prospective registry.

BACKGROUND: The purpose of this registry was to provide insights into the characteristics, treatments and survival of patients with PAH-CHD in China. METHODS: Patients diagnosed with PAH-CHD were enrolled in this national multicenter prospective registry. Baseline and follow-up data on clinical characteristics, PAH-targeted treatments and survival were collected. RESULTS: A total of 1060 PAH-CHD patients (mean age 31 years; 67.9% females) were included, with Eisenmenger syndrome (51.5%) being the most common form and atrial septal defects (37.3%) comprising the most frequent underlying defect. Approximately 33.0% of the patients were in World Health Organization functional class III to IV. The overall mean pulmonary arterial pressure and pulmonary vascular resistance were 67.1 (20.1) mm Hg and 1112.4 (705.9) dyn/s/cm5, respectively. PAH-targeted therapy was utilized in 826 patients (77.9%), and 203 patients (19.1%) received combination therapy. The estimated 1-, 3-, 5-, and 10-year survival rates of the overall cohort were 96.9%, 92.9%, 87.6% and 73.0%, respectively. Patients received combination therapy had significantly better survival than those with monotherapy (p = 0.016). NT-proBNP >1400 pg/ml, SvO2 ≤ 65% and Borg dyspnea index ≥ 3 and PAH-targeted therapy were independent predictors of mortality. Hemoglobin > 160g/L was a unique predictor for mortality in Eisenmenger syndrome. CONCLUSIONS: Chinese PAH-CHD patients predominantly exhibit Eisenmenger syndrome and have significantly impaired exercise tolerance and right ventricular function at diagnosis, which are closely associated with long-term survival. PAH-targeted therapy including combination therapy showed a favorable effect on survival in PAH-CHD. The long-term survival of Chinese CHD-PAH patients remains to be improved.

Molecular mechanisms of Ellis­van Creveld gene variations in ventricular septal defect.

The Ellis-van Creveld (EVC) gene is associated with various congenital heart diseases. However, studies on EVC gene variations in ventricular septal defect (VSD) and the underlying molecular mechanisms are sparse. The present study detected 11 single­nucleotide polymorphisms (SNPs) in 65 patients with VSD and 210 control patients from the Chinese Han population. Of the identified SNPs only the c.1727G>A SNP site was positively associated with the development of VSD (P<0.007). A known mutation, c.343C>G, was also identified, which causes a leucine to valine substitution at amino acid 115 of the EVC protein (p.L115V). The results of functional prediction indicated that c.343C>G may be a pathogenic mutation. In addition, in NIH3T3 mouse embryonic fibroblast cells, the EVC c.343C>G mutation significantly decreased cell proliferation and increased apoptosis. Further investigation demonstrated that in NIH3T3 cells, overexpression of EVC c.343C>G mutation reduced the binding between EVC and smoothened, which further downregulated the activity of the hedgehog (Hh) signaling pathway and the expression of downstream cyclin D1 and B­cell lymphoma 2 proteins with SAG. The c.1727G>A SNP of the EVC gene increased VSD susceptibility in patients from the Chinese Han population. The molecular mechanism underlying the development of VSD induced by the EVC c.343C>G mutation may be due to a reduction in the anti­apoptotic and proliferative abilities of cardiomyocytes via downregulation of Hh pathway activity. The results of the present study may provide novel targets for the diagnosis and treatment of patients with VSD.

Risk of treatment-related mortality with sorafenib in cancer patients: a meta-analysis of 20 randomly controlled trials : Risk of sorafenib-associated death.

BACKGROUND: Sorafenib is a relatively new multi-kinase inhibitor used to treat a wide range of cancers. As fatal adverse events from sorafenib therapy are rare, their investigation requires a meta-analysis. Aim of the review To provide a meta-analysis of sorafenib-associated fatal adverse events with the most expansive and current data. METHOD: We searched Medline, EMBASE, Web of Science and Cochrane Library databases. We also searched abstracts from a number of conferences. Twenty trials of sorafenib were found in 9434 cancer patients, tested against placebos and against other drugs. We calculated relative risks and incidences for sorafenib-associated mortality. RESULTS: Overall incidence of sorafenib-associated mortality was 3.3 %. Patients with renal cell carcinoma (RCC) and thyroid cancer had treatment-related mortality ≥5 %. Patients treated with sorafenib had a significantly greater risk of mortality than those in placebo/control groups, with an RR of 1.75. Subgroup analyses also showed significant differences in sorafenib versus placebo (RR 1.87, 95 % CI 1.23-2.86; I (2) = 0.0 %, P = 0.865); and sorafenib + platinum-based chemotherapy (RR 2.03, 95 % CI 1.15-3.59; I (2) = 0.0 %, P = 0.654). However, sorafenib had lower risk than other multi-targeted antiangiogenic tyrosine kinase inhibitors. Patients with RCC and non-small-cell lung carcinoma were significantly more vulnerable. CONCLUSION: Sorafenib presents a significant risk of fatal adverse events (FAEs) in patients with cancer, especially for RCC or non-small-cell lung carcinoma, and in patients treated with sorafenib + platinum-based chemotherapy. However, compared with other multi-targeted antiangiogenic tyrosine kinase inhibitors, sorafenib has a lower risk of FAEs.