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Purpose This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. Materials and Methods This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. Results A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). Conclusion Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC. [ABSTRACT FROM AUTHOR]

Objective: Dyslipidemia can promote cell proliferation, malignant transformation, metastasis, and cancer recurrence. Moreover, it could also affect immune infiltration in the tumor microenvironment. Therefore, we aimed to explore the effects of lipid levels on tumor-infiltrating lymphocytes (TILs) and prognosis in patients with triple-negative breast cancer (TNBC). Methods: Samples from 222 patients with TNBC from July 2007 to December 2019 were obtained from the tissue specimen banks in 3 hospitals. The blood samples were used to detect the levels of lipid levels such as apolipoprotein B (Apo B), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C). The TILs in the 222 TNBC tissues were detected using hematoxylin and eosin (H&E) staining, and the relationship between the lipid levels, clinical characteristics, and prognosis was analyzed. Results: Among TNBC patients, the overall survival (OS) time and disease-free survival (DFS) time were lower in patients with high LDL-C levels than those with low LDL-C levels (p < 0.01, respectively). The DFS was shorter in patients with low stromal TIL (STIL) levels than those with moderate or high STIL levels (p = 0.023). Multifactor Cox regression analysis showed that LDL-C level, Apo B level, and lymphocyte-predominant breast cancer were independent risk factors for OS in TNBC patients. The number of positive lymph nodes, postoperative staging, and total amount of TILs were independent risk factors for DFS in TNBC patients. Conclusion: The LDL-C and STIL levels were correlated with survival and prognosis in patients with TNBC. [ABSTRACT FROM AUTHOR]

Purpose: To establish a model for predicting mild cognitive impairment (MCI) progression to Alzheimer's disease (AD) using morphological features extracted from a joint analysis of voxel-based morphometry (VBM) and surface-based morphometry (SBM). Methods: We analyzed data from 121 MCI patients from the Alzheimer's Disease Neuroimaging Initiative, 32 of whom progressed to AD during a 4-year follow-up period and were classified as the progression group, while the remaining 89 were classified as the non-progression group. Patients were divided into a training set (n = 84) and a testing set (n = 37). Morphological features measured by VBM and SBM were extracted from the cortex of the training set and dimensionally reduced to construct morphological biomarkers using machine learning methods, which were combined with clinical data to build a multimodal combinatorial model. The model's performance was evaluated using receiver operating characteristic curves on the testing set. Results: The Alzheimer's Disease Assessment Scale (ADAS) score, apolipoprotein E (APOE4), and morphological biomarkers were independent predictors of MCI progression to AD. The combinatorial model based on the independent predictors had an area under the curve (AUC) of 0.866 in the training set and 0.828 in the testing set, with sensitivities of 0.773 and 0.900 and specificities of 0.903 and 0.747, respectively. The number of MCI patients classified as high-risk for progression to AD was significantly different from those classified as low-risk in the training set, testing set, and entire dataset, according to the combinatorial model (P < 0.05). Conclusion: The combinatorial model based on cortical morphological features can identify high-risk MCI patients likely to progress to AD, potentially providing an effective tool for clinical screening. [ABSTRACT FROM AUTHOR]

Background: Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large‐scale Chinese BC patients. Methods: BC patients who had undergone genetic testing at the Sun Yat‐sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort. Results: A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high‐risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high‐risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non‐BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non‐BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes. Conclusions: Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non‐BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies. [ABSTRACT FROM AUTHOR]

The thermal deformation behavior of the Mg–Gd–Y–Zr–Ag alloy was studied by isothermal hot compression tests at high temperatures. The flow stress increased with increased strain rates and decreased temperatures, first increasing and finally remaining stable with increased strain. A hot processing map was built. Using the processing map and microstructural analysis, the temperature should remain at 673–773 K for this alloy to ensure the deformation quality. The primary softening mechanism is discontinuous dynamic recrystallization (DDRX). Rising temperatures and declining strain rates facilitated the emergence and growth of Dynamic recrystallization (DRX) grains. An original JC (O–JC) model and a modified JC (M–JC) model were established. The M–JC model indicated a better prediction than the O–JC model. Still, it was deficient in predicting flow stresses with insufficient coupling effects. Hence, based on the M–JC model, a newly modified JC (NM–JC) model, which further enhances the interaction between strain and strain rate as well as strain and temperature, is proposed. Its projected values can better align with the tested values. [ABSTRACT FROM AUTHOR]

The optimal therapeutic options, adding locoregional therapy (LRT) to systemic therapy (ST) or not, for patients with oligometastatic breast cancer (OMBC) have not been fully elucidated. Hence, we designed a retrospective observational study which enrolled patients with measurable extracranial OMBC having less than 5 metastatic lesions not necessarily in the same organ. We retrospectively reviewed a total of 199 patients diagnosed with extracranial OMBC, including 28 receiving ST followed by LRT (ST to LRT group), 44 receiving LRT followed by ST (LRT to ST group), and 127 receiving ST alone (ST alone group). After a median follow-up of 28.7 months, patients receiving both ST and LRT had a significantly better prognosis than those receiving ST alone: the median progression-free survival (PFS) was 16.3, 14.0, and 9.3 months (P < 0.001) and the median overall survival (OS) was 39.8, 70.5, and 26.7 months (P < 0.001) in the ST to LRT, LRT to ST, and ST alone groups, respectively. Sequence of ST and LRT had no significant impact on survival among patients receiving both. Further exploratory analysis identified ST plus LRT as an independent predictor for longer PFS. In conclusion, we demonstrated that adding LRT to ST was associated with survival benefits for patients with OMBC, and further prospective studies were warranted. [ABSTRACT FROM AUTHOR]

To investigate the effect of quenching rate on microstructure, residual stress (RS) and mechanical properties of a rare-earth wrought magnesium alloy Mg-Gd-Y-Zr-Ag-Er, RS in 20 °C water quenching (WQ (20 °C)), 100 °C water quenching (WQ (100 °C)) or air cooling (AC) conditions were measured and compared with the simulation results, corresponding mechanical properties and microstructure in quenching and aging state were studied. The decrease of quenching rate has little effect on the grain size but makes the twinning disappear, precipitates increase and the texture weakened, leading to easier brittle fracture after aging. WQ (100 °C) is the best quenching condition in this study, with a significant decline in RS and only 4.9% and 3.7% decrease in yield stress (YS) and hardness compared with WQ (20 °C). The results make it feasible to invent an appropriate quenching method of greatly reducing RS while maintaining mechanical properties. The research conclusions would be beneficial to the application of the alloy. [ABSTRACT FROM AUTHOR]

DC magnetization is generally considered to suppress the usual local magnetic permeability variation and increase the penetration depth for magnetizing-based eddy current testing (MB-ECT) of ferromagnetic materials. In fact, such simple explanations lead to rough nondestructive evaluation and cause new neglected non-uniform magnetic characteristics. Hence, the "perturbation" of the internal magnetic field variation is analyzed using a magnetic dipole model and the mechanism of magnetic permeability perturbation in MB-ECT is revealed. The theoretical analysis and simulations show that a significant permeability perturbation always appears around a defect and presents opposite features with strong and weak magnetization. Furthermore, experimental results indicate that the hidden signal component arising from the local permeability perturbation is critical for both far-side surface and near-side surface defects in the MB-ECT method. [ABSTRACT FROM AUTHOR]

Purpose: We attempted to explore the prognostic value of baseline inflammatory and nutritional biomarkers at diagnosis in patients with early-stage breast cancer and develop a novel scoring system, the inflammatory-nutritional prognostic score (INPS). Patients and Methods: We collected clinicopathological and baseline laboratory data of 1259 patients with early-stage breast cancer between December 2010 and November 2012 from Sun Yat-sen University Cancer Center. Eligible patients were randomly divided into training and validation cohorts (n = 883 and 376, respectively) in a 7:3 ratio. We selected the most valuable biomarkers to develop INPS by the least absolute shrinkage and selection operator (LASSO) Cox regression model. A prognostic nomogram incorporating INPS and other independent clinicopathological factors was developed based on the stepwise multivariate Cox regression method. Then, we used the concordance index (C-index), calibration plot, and time-dependent receiver operating characteristic (ROC) analysis to evaluate the prognostic performance and predictive accuracy of the predictive nomogram. Results: Four inflammatory-nutritional biomarkers, including neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), prognostic nutritional index (PNI), and albumin-alkaline phosphatase ratio (AAPR), were selected using the LASSO Cox analysis to construct INPS, which remained an independent prognostic indicator per the multivariate Cox regression analysis. Patients were stratified into low- and high-INPS groups based on the cutoff INPS determined by the maximally selected rank statistics. The prognostic model for overall survival consisting of INPS and other independent clinicopathological indicators showed excellent discrimination with C-indexes of 0.825 (95% confidence interval [CI]: 0.786– 0.864) and 0.740 (95% CI: 0.657– 0.822) in the training and validation cohorts, respectively. The time-dependent ROC curves showed a higher predictive accuracy of our prognostic nomogram than that of traditional tumor-node-metastasis staging. Conclusion: Baseline INPS is an independent indicator of OS in patients with early-stage breast cancer. The INPS-based prognostic nomogram could be used as a practical tool for individualized prognostic predictions. [ABSTRACT FROM AUTHOR]

Background: Aging, an inevitable process characterized by functional decline over time, is a significant risk factor for various tumors. However, little is known about aging-related genes (ARGs) in breast cancer (BC). We aimed to explore the potential prognostic role of ARGs and to develop an ARG-based prognosis signature for BC. Methods: RNA-sequencing expression profiles and corresponding clinicopathological data of female patients with BC were obtained from public databases in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). An ARG-based risk signature was constructed in the TCGA cohort based on results of least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis, and its prognostic value was further validated in the GSE20685 cohort. Results: A six ARG-based signature, including CLU, DGAT1, MXI1, NFKBI, PIK3CA and PLAU, was developed in the TCGA cohort and significantly stratified patients into low- and high-risk groups. Patients in the former group showed significantly better prognosis than those in the latter. Multivariate Cox regression analysis demonstrated that the ARG risk score was an independent prognostic factor for BC. A predictive nomogram integrating the ARG risk score and three identified factors (age, N- and M-classification) was established in the TCGA cohort and validated in the GSE20685 cohort. Calibration plots showed good consistency between predicted survival probabilities and actual observations. Conclusion: A novel ARG-based risk signature was developed for patients with BC, which can be used for individual prognosis prediction and promoting personalized treatment. [ABSTRACT FROM AUTHOR]

Lessons Learned: Fulvestrant 500 mg maintenance therapy showed a clinical benefit rate of 76% and median progression‐free survival of 16.1 months in patients who achieved objective responses or disease control after first‐line chemotherapy.Adverse events with fulvestrant maintenance therapy were consistent with the known safety profile of the drug. Background: Evidence for maintenance hormonal therapy after chemotherapy for estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer is scarce. This study aimed to evaluate the efficacy of fulvestrant 500 mg maintenance therapy in patients after first‐line chemotherapy. Methods: We enrolled postmenopausal women with ER‐positive/HER2‐negative advanced breast cancer who attained tumor responses or disease control with four to eight cycles of chemotherapy as first‐line treatment. Fulvestrant 500 mg was injected on days 1, 15, and 29 and every 28 (±3) days thereafter. The primary endpoint was the clinical benefit rate (CBR); the secondary endpoints included the objective response rate (ORR), progression‐free survival (PFS), and safety. Results: We included 58 patients; the median follow‐up duration was 32.6 months. The CBR since commencing fulvestrant maintenance therapy was 76% (95% confidence interval [CI], 63%–86%), and ORR was 14% (95% CI, 6%–25%); eight patients achieved partial response. The median PFS for fulvestrant maintenance therapy was 16.1 months (95% CI, 10.3–21.0 months). Thirty‐nine patients (67%) reported at least one adverse event, of which most were grade 1/2, whereas three patients (5%) reported grade 3 adverse events. Conclusion: Fulvestrant 500 mg is a feasible and promising hormonal maintenance strategy in patients with ER‐positive/HER2‐negative advanced breast cancer who have no disease progression after first‐line chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Tumor progression following endocrine therapy is considered to indicate resistance to endocrine drugs due to a variety of mechanisms. An insufficient dose of endocrine drugs is one of the causes for treatment failure in some patients with high hormone-receptor (HR)-expressing advanced breast cancer. This study aimed to explore the efficacy of high-dose tamoxifen (TAM) treatment in patients with advanced breast cancer with highly expressed HR. Materials & methods: This was a single-arm, phase II pilot study that enrolled patients with advanced breast cancer with high HR expression (estrogen receptor ⩾60% and/or progesterone receptor ⩾60%) following routine endocrine therapy. All enrolled patients received a high-dose of TAM (100 mg/day) until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Exploratory endpoints included the predictive value of 16α-18F-17β-fluoroestradiol quantitative positron emission tomography/computed tomography (18F-FES PET/CT) for treatment efficacy. Results: A total of 30 patients were enrolled between September 2017 and February 2019. The median PFS was 6 months [95% confidence interval (CI) 4.9–7.1] and the median OS was 15.6 months (95% CI 8.3–22.9). Five patients experienced a partial response (PR) and none experienced a complete response (CR), with an ORR of 16.7% and CBR of 33.3%. No severe adverse events were observed. Lesions with 18F-FES maximum standardized uptake value (SUVmax) ⩾4 had a significantly longer PFS [median 9.2 months, (95% CI 6.9–11.6)] compared with lesions with a 18F-FES SUVmax <4 [median 4.8 months, (95% CI 3.9–5.6); p = 0.022]. Conclusion: A high-dose of TAM is effective and safe for patients with advanced breast cancer with high HR expression. 18F-FES SUVmax values may predict the local clinical benefits of high-dose TAM. Trial Registration: [ClinicalTrials.gov identifier: NCT0304565] [ABSTRACT FROM AUTHOR]