Prediction of cardiovascular adverse events in newly diagnosed multiple myeloma: Development and validation of a risk score prognostic model.

Background: Multiple myeloma (MM) is the second most common hematological malignancy, and the treatments markedly elevate the survival rate of the patients in recent years. However, the prevalence of cardiovascular adverse events (CVAEs) in MM had been increasing recently. CVAEs in MM patients are an important problem that we should focus on. Clinical tools for prognostication and risk-stratification are needed. Patients and methods: This is a retrospective study that included patients who were newly diagnosed with multiple myeloma (NDMM) in Shanghai Changzheng Hospital and Affiliated Jinhua Hospital, Zhejiang University School of Medicine from June 2018 to July 2020. A total of 253 patients from two medical centers were divided into training cohort and validation cohort randomly. Univariable analysis of the baseline factors was performed using CVAEs endpoints. Multivariable analysis identified three factors for a prognostic model that was validated in internal validation cohorts. Results: Factors independently associated with CVAEs in NDMM were as follows: age>61 years old, high level of baseline office blood pressure, and left ventricular hypertrophy (LVH). Age contributed 2 points, and the other two factors contributed 1 point to a prognostic model. The model distinguished the patients into three groups: 3-4 points, high risk; 2 points, intermediate risk; 0-1 point, low risk. These groups had significant difference in CVAEs during follow-up days in both training cohort (p<0.0001) and validation cohort (p=0.0018). In addition, the model had good calibration. The C-indexes for the prediction of overall survival of CVAEs in the training and validation cohorts were 0.73 (95% CI, 0.67-0.79) and 0.66 (95% CI, 0.51-0.81), respectively. The areas under the receiver operating characteristic curve (AUROCs) of the 1-year CVAEs probability in the training and validation cohorts were 0.738 and 0.673, respectively. The AUROCs of the 2-year CVAE probability in the training and validation cohorts were 0.722 and 0.742, respectively. The decision-curve analysis indicated that the prediction model provided greater net benefit than the default strategies of providing assessment or not providing assessment for all patients. Conclusion: A prognostic risk prediction model for predicting CVAEs risk of NDMM patients was developed and internally validated. Patients at increased risk of CVAEs can be identified at treatment initiation and be more focused on cardiovascular protection in the treatment plan.

Overexpression of pressure-responsive miRNA-5703 inhibits pressure-induced growth and metastasis of liver cancer.

A vast majority of liver cancers coexist with cirrhosis and/or portal hypertension. A high-pressure tumour microenvironment may lead to malignant progression of liver cancer. Through quantitative reverse transcription-polymerase chain reaction, we found that miRNA-5703 was expressed at low levels in HepG2 and Huh-7 cells and pressure-treated MHCC97H implanted mouse cancer tissues, while its potential target gene, sarcoma gene (SRC), was highly expressed. The expression of miRNA-5703 was higher in liver cancer tissues from Barcelona Clinic Liver Cancer (BCLC) stage A1 patients than those from BCLC stage A2-D patients, whereas SRC showed the opposite expression pattern. Bioinformatics analysis, luciferase reporter assay, and western blotting were performed to verify the relationship between miRNA-5703 and its potential target SRC. Using intravital imaging and immunohistochemistry, we demonstrated that pressure promotes tumour growth in subcutaneous tumourigenesis nude mice, and overexpression of miRNA-5703 significantly downregulated Ki67 and upregulated NM23 in tumour tissues of mice, implying the blockage of tumour growth and metastasis. The activation of proliferation, migration, and invasion of HepG2 and Huh-7 cells by pressure, and inhibition by overexpressing miRNA-5703 were observed by cell counting kit-8 assay, flow cycle assay, transwell assay, and wound healing assay. After the intervention of pressure, inhibitor, and lentivirus to hepatoma cells, SRC, focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), serum/glucocorticoid regulated kinase-3 (SGK3), phosphoinositide dependent protein kinase 1 (PDK1), and paxillin were upregulated, and forkhead box O1 (FOXO1) and cyclin dependent kinase inhibitor 1B (P27Kip1) were downregulated in pressure-loaded hepatoma cells, which could be reversed by overexpression of miRNA-5703 or SRC knockdown. In conclusion, upregulation of miRNA-5703 inhibited pressure-induced growth and metastasis by suppressing the SRC-FAK-FOXO1 axis and SRC-paxillin axis. This novel perspective may be conducive to the mechano-inspired anticancer drugs of liver cancer.

The Effect of Laminectomy with Instrumented Fusion Carried into the Thoracic Spine on the Sagittal Imbalance in Patients with Multilevel Ossification of the Posterior Longitudinal Ligament.

OBJECTIVE: To determine if there is a difference in either the cervical alignment or the clinical outcomes in cervical ossification of the posterior longitudinal ligament (OPLL) patients who underwent laminectomy with instrumented fusion (LIF) ending at C6 , C7 , or proximal thoracic spine for the treatment of multilevel OPLL, and to find out the appropriate distal fusion level. METHODS: This was a single-center retrospective study. In total, 36 patients with cervical OPLL who underwent three or more level LIF in our institution between January 2015 and January 2017 were enrolled. They were divided into three groups according to their distal ends: C6 (nine females and 11 males, 60.45 ± 9.68 years old), C7 (four females and six males, 61.60 ± 10.29 years old), and T-group (two females and four males, 64.33 ± 8.12 years old). Radiographic (compression level, classification of OPLL, occupying rate, C2-7 cobb angle, C2-7 sagittal vertical axis, and fusion level) and clinical outcomes (NDI score, operative time, and blood loss) were compared. Predictors of postoperative sagittal imbalance were also identified according to if the postoperative C2-7 SVA was greater than 40 mm. The sensitivity and specificity of preoperative parameters predicting postoperative cervical stability were evaluated via the receiver operating characteristic (ROC) curve. RESULTS: All patients were followed up at least 1 year. The blood loss in T group was significantly more than C6 or C7 group. The length of fusion level became significantly longer when the caudal level extended to the thoracic spine. The age, preoperative SVA, and NDI score at follow-up were significantly greater in the imbalance group. At the final follow-up, the cervical lordosis tended to be straight and the C2-7 SVA tended to be greater when the caudal level of fusion was extended to upper thoracic segment. Further ROC curve analysis suggested that patients' age had a sensitivity of 75.00%, specificity of 79.17% for cervical stability, and the AUC was 0.844 (P < 0.01), with the cutoff value for age being 66.5 years old. For preoperative SVA, the sensitivity was 58.30%, and specificity was 91.70%, with the AUC of 0.778 (P < 0.01). The cutoff value for preoperative SVA was 30.4 mm. CONCLUSION: Although posterior fusion terminating in the thoracic spine was not superior to the cervical spine for patients with multilevel OPLL, for elderly patients (>67 years) with great preoperative SVA (>30 mm), terminating at C6 was recommended to limit the invasion of cervical extensor muscles, provided the decompression was adequate.