Effect of 1 H-NMR serum lipoproteins on immunotherapy response in advanced triple-negative breast cancer patients.

We previously reported the results of a phase II trial of anti-PD-1 antibody plus anti-vascular endothelial growth factor receptor 2 inhibitors and eribulin in heavily pretreated advanced triple-negative breast cancer with a favorable objective response rate (ORR) of 37.0% (NCT04303741). Here we report updated survival outcomes and serum metabolite changes of the study. Proton nuclear magnetic resonance spectroscopy was used to detect metabolite dynamics and explore biomarkers for response. We found that treatment-sensitive patients had higher very low-density lipoprotein-related metabolite expression at baseline. A lipid proteomics model consisting of six metabolites predicted ORR and progression-free survival at 6 months with area under the receiver operating characteristic curves of 0.88 and 0.87, respectively. Serum asparagine and sarcosine concentrations were significantly higher after treatment in treatment-resistant patients. In conclusion, we constructed a model consisting of six metabolites to identify patients who benefit more from the triplet treatment, and asparagine and sarcosine may be associated with treatment resistance.

Autophagy-associated circRNA circCDYL augments autophagy and promotes breast cancer progression.

BACKGROUND: Although both circular RNAs (circRNAs) and autophagy are associated with the function of breast cancer (BC), whether circRNAs regulate BC progression via autophagy remains unknown. In this study, we aim to explore the regulatory mechanisms and the clinical significance of autophagy-associated circRNAs in BC. METHODS: Autophagy associated circRNAs were screened by circRNAs deep sequencing and validated by qRT-PCR in BC tissues with high- and low- autophagic level. The biological function of autophagy associated circRNAs were assessed by plate colony formation, cell viability, transwells, flow cytometry and orthotopic animal models. For mechanistic study, RNA immunoprecipitation, circRNAs pull-down, Dual luciferase report assay, Western Blot, Immunofluorescence and Immunohistochemical staining were performed. RESULTS: An autophagy associated circRNA circCDYL was elevated by 3.2 folds in BC tissues as compared with the adjacent non-cancerous tissues, and circCDYL promoted autophagic level in BC cells via the miR-1275-ATG7/ULK1 axis; Moreover, circCDYL enhanced the malignant progression of BC cells in vitro and in vivo. Clinically, increased circCDYL in the tumor tissues and serum of BC patients was associated with higher tumor burden, shorter survival and poorer clinical response to therapy. CONCLUSIONS: circCDYL promotes BC progression via the miR-1275-ATG7/ULK1-autophagic axis and circCDYL could act as a potential prognostic and predictive molecule for breast cancer patients.

Incorporating MicroRNA into Molecular Phenotypes of Circulating Tumor Cells Enhances the Prognostic Accuracy for Patients with Metastatic Breast Cancer.

BACKGROUND: The molecular phenotype of circulating tumor cells (CTCs) was associated with clinical outcome of patients with breast cancer. CTCs isolated from patients with metastatic breast cancer (MBC) display a unique microRNA (miRNA) expression profile. The aim of this study was to enhance the prognostic accuracy of the CTC phenotype in patients with MBC, by incorporating miRNA into a combined prediction model. SUBJECTS, MATERIALS, AND METHODS: CTCs were detected by CellSearch and enriched by magnetic cell sorting. miRNA deep sequencing and quantitative polymerase chain reaction were used to screen and verify potentially CTC-specific miRNA candidates. Patients with MBC were enrolled from two independent cohorts, and overall survival (OS) and chemotherapy response were analyzed. RESULTS: We screened and identified that miR-106b was an upregulated molecule in patients with MBC with CTC ≥5/7.5 mL (n = 16) compared with patients with CTC = 0/7.5 mL (n = 16) and healthy donors (n = 8). The expression of CTC-specific miR-106b correlated with vimentin and E-cadherin in CTC and acted as an independent factor for predicting OS (hazard ratio 2.157, 95% confidence interval [CI] 1.098-4.239, p = .026). Although CTC-specific miR-106b, E-cadherin, and vimentin showed a prognostic potential independently, the prognostic performance for OS based on the combination of three markers was significantly enhanced in Cohort 1 (area under the curve [AUC] 0.752, 95% CI 0.658-0.847, n = 128) and further validated in Cohort 2 (AUC 0.726, 95% CI 0.595-0.856, n = 91). Besides, a combined model incorporating miR-106b was associated with therapy response. CONCLUSION: The phenotypic assemblies of CTC incorporating miR-106b show enhanced prognostic accuracy of overall survival in patients with MBC. IMPLICATIONS FOR PRACTICE: In order to enhance the prognostic accuracy of the circulating tumor cell (CTC) phenotype in patients with metastatic breast cancer (MBC), this study screened and identified a CTC-specific microRNA (miRNA), miR-106b, as an upregulated molecule based on the comparison of miRNA profile between CTCs, primary tumors, and healthy blood donors. By incorporating miR-106b into a combined prediction model, the prognostic accuracy of the CTC phenotype for patients with MBC was greatly improved in both the training and validation cohorts. This work provides clinical evidence supporting the prognostic potential of CTC-specific miRNA for patients with MBC. These results indicate that developing CTC-specific miRNAs as new biomarkers will help to further optimize personalized therapy.

MACHINE LEARNING FOR PREDICTING HEMODYNAMIC DETERIORATION OF PATIENTS WITH INTERMEDIATE-RISK PULMONARY EMBOLISM IN INTENSIVE CARE UNIT.

ABSTRACT: Background: Intermediate-risk pulmonary embolism (PE) patients in the intensive care unit (ICU) are at a higher risk of hemodynamic deterioration than those in the general ward. This study aimed to construct a machine learning (ML) model to accurately identify the tendency for hemodynamic deterioration in the ICU patients with intermediate-risk PE. Method: A total of 704 intermediate-risk PE patients from the MIMIC-IV database were retrospectively collected. The primary outcome was defined as hemodynamic deterioration occurring within 30 days after admission to ICU. Four ML algorithms were used to construct models on the basis of all variables from MIMIC IV database with missing values less than 20%. The extreme gradient boosting (XGBoost) model was further simplified for clinical application. The performance of the ML models was evaluated by using the receiver operating characteristic curve, calibration plots, and decision curve analysis. Predictive performance of simplified XGBoost was compared with the simplified Pulmonary Embolism Severity Index score. SHapley Additive explanation (SHAP) was performed on a simplified XGBoost model to calculate the contribution and impact of each feature on the predicted outcome and presents it visually. Results: Among the 704 intermediate-risk PE patients included in this study, 120 patients experienced hemodynamic deterioration within 30 days after admission to the ICU. Simplified XGBoost model demonstrated the best predictive performance with an area under the curve of 0.866 (95% confidence interval, 0.800-0.925), and after recalibrated by isotonic regression, the area under the curve improved to 0.885 (95% confidence interval, 0.822-0.935). Based on the simplified XGBoost model, a web app was developed to identify the tendency for hemodynamic deterioration in ICU patients with intermediate-risk PE. Conclusion: A simplified XGBoost model can accurately predict the occurrence of hemodynamic deterioration for intermediate-risk PE patients in the ICU, assisting clinical workers in providing more personalized management for PE patients in the ICU.

Multicenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer.

In the later-line setting or for patients with PD-L1-negative tumors, immunotherapy-based regimens remain ineffective against advanced triple-negative breast cancer (TNBC). In this multicentered phase II trial (NCT04303741), 46 patients with pretreated advanced TNBC were enrolled to receive camrelizumab 200 mg (day 1), and apatinib 250 mg daily, plus eribulin 1.4 mg/m2 (day 1 and 8) on a 21-day cycle until progression, or unacceptable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included toxicities, disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), and 1-year overall survival. With a median of 3 lines of prior chemotherapy in the advanced setting, 17.4% had received PD-1/PD-L1 blockade plus chemotherapy for advanced disease. The ORR was 37.0% (17/46, 95% CI 23.2-52.5). The DCR was 87.0% (40/46, 95% CI 73.7-95.1). Median PFS was 8.1 (95% CI 4.6-10.3) months. Tertiary lymphoid structure was associated with higher ORR. Patients with lower tumor PML or PLOD3 expression had favorable ORR and PFS. PD-L1 status was not associated with ORR/PFS. Grade 3/4 treatment-related adverse events occurred in 19 (41.3%) of 46 patients. Camrelizumab plus apatinib and eribulin shows promising efficacy with a measurable safety profile in patients with heavily pretreated advanced TNBC.

Prognostic and predictive value of the combination of TOP2A and HER2 in node-negative tumors 2 cm or smaller (T1N0) breast cancer.

BACKGROUND: We aim to evaluate the prognostic and predictive value of TOP2A and HER2 expression in T1N0 breast cancer patients. METHODS: 299 cases with T1N0 breast cancer were obtained from the Oncomine database (Cohort 1) and 963 of T1N0 breast cancer patients from Sun Yat-sen Memorial Hospital (Cohort 2) were retrospectively enrolled. Kaplan-Meier product was applied to estimate survival curve. Cox proportional hazard models was used to identify prognostic factors. We used PSM (propensity score matching) to balance clinicopathologic characteristics among four groups of different HER2/TOP2A status. Survival between groups and chemotherapy regimens were analyzed, before and after PSM. RESULTS: In Cohort 1, we found that the group with HER2+ and higher expression of TOP2A mRNA was associated with poor breast cancer-specific survival (BCSS) compared to the group of HER2- with lower expression of TOP2A mRNA. In Cohort 2, HER2+ patients with higher TOP2A protein expression had greater risk of recurrence and distant recurrence compared to HER2- patients with lower expression of TOP2A protein. Among the patients who developed both HER2+ and higher expression of TOP2A protein and received chemotherapy, patients who received an anthracycline-based regimen had a significantly better recurrence-free survival (RFS) than those with a non-anthracycline-based regime. CONCLUSION: Patients with both HER2+ and high expression level of TOP2A protein predicts poor prognosis in T1N0 breast cancer patients. Patients with double positive for TOP2A protein and HER2 may benefit from anthracycline-based regimens.

The Effect of Low and High Vacuum Drainage on the Postoperative Drainage of Breast Cancer: Insights from a Prospective, Non-Inferiority, Randomized Clinical Trial.

BACKGROUND: Vacuum drains have been extensively applied to prevent seroma formation after breast surgery. However, the usage of negative suction drainage is mainly determined by surgeon's experience and preferences. The aim of this study is to prospectively compare the drain effect after breast surgery between the low and high vacuum drains. METHODS: This prospectively randomized trial (from January 2018 to June 2019) involved 188 patients who were subjected to modified radical mastectomy (group A, n=128) or immediate breast reconstruction with implants (group B, n=60). In each group, patients were randomized to receive high vacuum drain (pressure=-98 kPa) or low vacuum drain (pressure=-12 kPa) after surgery. Days of drain permanence, which means the duration of drainage, was the primary endpoint. RESULTS: According to the comparison of days of drain permanence, the effect of a low vacuum drain is not inferior to a high vacuum drain in group A (pectoral drain, P<0.001; axillary drain, P<0.001) or group B (submuscular drain, P=0.002). The complications frequently occurred on patients with high vacuum drain (11.7%), such as seroma formation. The expense of low vacuum drain was significantly lower than high vacuum drain in both groups (P<0.01). CONCLUSION: The drain effect of the low vacuum drain is not inferior to a high vacuum drain in both group A and group B. The low vacuum drain was effective, relatively cheap, and did not increase the incidence of complications; it is therefore more recommended after breast surgery.

Serum anion gap on admission predicts intensive care unit mortality in patients with aortic aneurysm.

It has been widely reported that the serum anion gap is significantly associated with mortality in intensive care unit (ICU); however, it remains unknown whether the association is present in aortic aneurysm (AA) patients. The present study aimed to investigate the association between the admission serum anion gap and ICU mortality in AA patients. Data extracted from a publicly accessible clinical database using a modifiable data mining technique were analyzed retrospectively, mainly by employing multivariable logistic regression analysis. The primary study outcome was ICU mortality. A total of 273 patient records were analyzed. The ICU mortality was 8.79% (24/273). The median serum anion gap was significantly higher in non-survivors [17.50 mEq/l, interquartile range (IQR) 15.75-22.50 mEq/l] compared with survivors [13.00 mEq/l, IQR 11.00-15.00 mEq/l, P<0.001]. Multivariate analysis resulted in identification of a clear association between admission serum anion gap and ICU mortality in AA patients [odds ratio (OR) 1.38 per 1 mEq/l increase, 95% confidence interval (CI) 1.08-1.76]. The area under the receiver operating characteristic curve showed an outstanding discrimination ability in predicting ICU mortality (area under curve 0.8513, 95% CI 0.7698-0.9328). In conclusion, admission serum anion gap may serve as a strong predictor of ICU mortality for AA patients.