Sacituzumab govitecan in HR+HER2- metastatic breast cancer: the randomized phase 3 EVER-132-002 trial.

Sacituzumab govitecan (SG) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2-) metastatic breast cancer (mBC) in the global TROPiCS-02 study. TROPiCS-02 enrolled few Asian patients. Here we report results of SG in Asian patients with HR+HER2- mBC from the EVER-132-002 study. Patients were randomized to SG (n = 166) or chemotherapy (n = 165). The primary endpoint was met: PFS was improved with SG versus chemotherapy (hazard ratio of 0.67, 95% confidence interval 0.52-0.87; P = 0.0028; median 4.3 versus 4.2 months). OS also improved with SG versus chemotherapy (hazard ratio of 0.64, 95% confidence interval 0.47-0.88; P = 0.0061; median 21.0 versus 15.3 months). The most common grade ≥3 treatment-emergent adverse events were neutropenia, leukopenia and anemia. SG demonstrated significant and clinically meaningful improvement in PFS and OS versus chemotherapy, with a manageable safety profile consistent with prior studies. SG represents a promising treatment option for Asian patients with HR+HER2- mBC (ClinicalTrials.gov identifier no. NCT04639986 ).

Abemaciclib combined with endocrine therapy as adjuvant treatment for hormone-receptor-positive, HER2-, high-risk early breast cancer: 5-year Chinese population analysis of the phase III randomized monarchE study.

Background: Abemaciclib was the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved globally in the adjuvant setting for high-risk hormone-receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) early breast cancer (EBC), based on the phase III monarchE trial. Objective: To report an exploratory Chinese population analysis based on the preplanned overall survival (OS) interim analysis with 5-year efficacy results of monarchE. Design and methods: Patients with HR+/HER2-, high-risk (⩾4 positive lymph nodes, or 1-3 nodes and either tumor size ⩾5 cm, histologic grade 3, or Ki-67 ⩾20%) EBC were randomized (1:1) to abemaciclib (150 mg twice daily for 2 years) plus endocrine therapy (ET), or ET alone. This analysis included Chinese patients enrolled in mainland China, Hong Kong, and Taiwan. The primary endpoint was invasive disease-free survival (IDFS); key secondary endpoints included distant relapse-free survival (DRFS), safety, and patient-reported outcomes (PROs). Results: Overall, 501 Chinese patients were included (abemaciclib + ET, n = 259; ET, n = 242). With a median follow-up of 53 months, the addition of abemaciclib to ET resulted in improvements in IDFS (estimated 5-year IDFS rate: 85.9% vs 79.1%; hazard ratio (HR), 0.65 (95% confidence interval (CI) 0.41-1.03)) and DRFS (estimated 5-year DRFS rate: 88.4% vs 82.3%; HR, 0.65 (95% CI, 0.39-1.07)). The most common grade ⩾3 treatment-emergent adverse events in the abemaciclib + ET versus ET groups were neutropenia (24.7% vs 0.8%) and leukopenia (22.4% vs 0.4%). Generally, no clinically meaningful difference in PROs (endocrine symptoms and fatigue) was observed between groups, except for diarrhea. Conclusion: At this prespecified OS interim analysis, which provides 5-year data, the addition of abemaciclib to ET in Chinese patients with high-risk HR+, HER2- EBC was associated with sustained and clinically meaningful improvements in IDFS and DRFS, with acceptable safety and tolerability profiles and minimal impact on PROs. These results represent the first full report of a CDK4/6 inhibitor in Chinese patients with EBC and support the positive benefit-risk profile of adjuvant abemaciclib + ET in Chinese patients. Trial registration: ClinicalTrials.gov identifier: NCT03155997 (first posted: May 16, 2017).

Adipocytes promote metastasis of breast cancer by attenuating the FOXO1 effects and regulating copper homeostasis.

BACKGROUND: Obesity and the forkhead box O1(FOXO1) affect the survival of breast cancer patients, but the underlying mechanism remains unclear. We aimed to investigate the role of FOXO1 in obesity-associated-breast cancer. METHODS: We screened 383 breast disease patients from the first affiliated hospital with Nanjing Medical University in 2020. We performed wound healing, transwell, matrigel assays to assess the metastatic ability of cancer cells. We adopted mRNAs sequencing to select the differentially expressed transcripts in breast cancer. We applied immunohistochemistry, western blot, tissue microarrays to assess the level of FOXO1 and epithelial-mesenchymal transition (EMT) pathways. We conducted bioinformatic analysis to investigate interactions between FOXO1 and miR-135b. We used fluorescence in situ hybridization, RT-qPCR to confirm the characteristics of circCNIH4. We conducted luciferase reporter assay, rescue experiments to investigate interactions between circCNIH4 and miR-135b. RESULTS: Obesity was positively correlated with the incidence and progression of breast cancer. Adipocytes enhanced the migration of breast cancer and attenuated the effects of FOXO1. MiR-135b was a binding gene of FOXO1 and was regulated by circCNIH4. CircCNIH4 exhibited antitumor activity in vitro and in vivo. CONCLUSION: Adipocytes might accelerate the progression of breast cancer by modulating FOXO1/miR-135b/ circCNIH4 /EMT axis and regulating copper homeostasis.

tRF-27 competitively Binds to G3BPs and Activates MTORC1 to Enhance HER2 Positive Breast Cancer Trastuzumab Tolerance.

About 20% of breast cancer patients are positive for HER2. The efficacy of current treatments is limited by primary and secondary resistance to trastuzumab. tRNA-derived fragments (tRFs) have shown crucial regulatory roles in various cancers. This study aimed to evaluate the role of tRF-27 in regulating the resistance of HER2-positive breast cancer against trastuzumab. tRF-27 was highly expressed in trastuzumab-resistant cells, and its expression level could predict the resistance to trastuzumab. High expression of tRF-27 promoted the growth and proliferation of trastuzumab-exposed cells. RNA-pulldown assay and mass spectrometry were performed to identify Ras GTPase-activating protein-binding proteins 1 and 2 (G3BPs) (two proteins targeted by tRF-27); RNA-immunoprecipitation (RIP) to confirm their bindings; co-immunoprecipitation (co-IP) and RNA-pulldown assay to determine the binding domains between G3BPs and tRF-27.tRF-27 bound to the nuclear transport factor 2 like domain(NTF2 domain) of G3BPs through a specific sequence. tRF-27 relied on G3BPs and NTF2 domain to increase trastuzumab tolerance. tRF-27 competed with lysosomal associated membrane protein 1(LAMP1) for NTF2 domain, thereby inhibiting lysosomal localization of G3BPs and tuberous sclerosis complex (TSC). Overexpression of tRF-27 inhibited phosphorylation of TSCs and promoted the activation of mechanistic target of rapamycin complex 1(MTORC1) to enhance cell proliferation and entice the resistance of HER2-positive breast cancer against trastuzumab.

Systematic characterization of the expression, prognosis and immune characteristics of PLOD family genes in breast cancer.

BACKGROUND: The expression patterns and prognostic value of Procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) family genes in breast cancer remain to be elucidated. METHODS: The expression levels, prognostic value, and biological function of PLODs were determined using Oncomine, cBioPortal, GEPIA, Timer, UALCAN, PrognoScan, GeneMANIA, Metascape, and breast cancer tissue microarrays. RESULTS: The expressions of PLOD1 and PLOD3 were upregulated in breast cancer tissues, indicating worse clinical stages. High expression levels of PLOD family genes were associated with worse disease-free survival and distant metastasis-free survival, while high expression levels of PLOD1 and PLOD3 were related to worse overall survival in all breast cancer patients. The levels of PLOD family genes were all significantly higher in the age ≤51 y group, HR-negative patients, and triple negative breast cancer (TNBC) patients. They are associated with tumor-infiltrating immune cells (TIICs), including CD4+ T cells, CD8+ T cells, B cells, macrophages, neutrophils, and dendritic cells. According to co-expression gene analysis and functional enrichment, they are associated with protein hydroxylation, collagen biosynthesis and modifying enzymes, collagen metabolism, RNA splicing, extracellular matrix organization, VEGFA-VEGFR2 signaling pathway, and skeletal system development. Immunohistochemistry showed that the expressions of all PLOD family genes were significantly elevated in breast cancer tissues. PLOD1 expression was positively correlated with ER, TNBC status, and tumor grade. PLOD2 expression was positively connected with Ki-67 status. PLOD3 expression was positively related with age and tumor grade. CONCLUSIONS: PLOD family genes are novel potential prognostic biomarkers for breast cancer, and targeting PLOD inhibitors might be an effective strategy for breast cancer therapy.

The relationship between prognosis and temporal muscle thickness in 102 patients with glioblastoma.

Temporal muscle thickness measured on 3D MRI has recently been linked to prognosis in glioblastoma patients and may serve as an independent prognostic indicator. This single-center study looked at temporal muscle thickness and prognosis in patients with primary glioblastoma. Overall survival was the major study outcome. For a retrospective analysis from 2010 to 2020, clinical data from 102 patients with glioblastoma at the Department of Oncology Radiotherapy of the First Affiliated Hospital of Dalian Medical University were gathered. Fifty-five cases from 2016 to 2020 contained glioblastoma molecular typing data, of which 45 were IDH wild-type glioblastomas and were analysed separately. TMT was measured on enhanced T1-weighted magnetic resonance images in patients with newly diagnosed glioblastoma.Overall patient survival (OS) was calculated by the Kaplan-Meier method and survival curves were plotted using the log-rank-sum test to determine differences between groups, and multifactorial analyses were performed using a Cox proportional-risk model.The median TMT for 102 patients was 6.775 mm (range: 4.95-10.45 mm). Patients were grouped according to median TMT, and the median overall survival (23.0 months) was significantly longer in the TMT > median group than in the TMT median group (P 0.001; Log-rank test). Analysing 45 patients with IDH wild type alone, the median overall survival (12 months) of patients in the TMT > median group was significantly longer than that of patients in the TMT ≤ median group (8 months) (P < 0.001; Log-rank test).TMT can serve as an independent prognostic factor for glioblastoma.

Effect of adjuvant radiotherapy on overall survival and breast cancer-specific survival of patients with malignant phyllodes tumor of the breast in different age groups: a retrospective observational study based on SEER.

PURPOSE: Malignant phyllodes tumor of the breast (MPTB) is a rare type of breast cancer, with an incidence of less than 1%. The value of adjuvant radiotherapy (RT) for MPTB has been controversial. The aim of the study was to explore the effect of radiotherapy on the long-term survival of female patients with MPTB at different ages. METHODS: Female MPTB patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2020. A Kaplan-Meier survival analysis was conducted to investigate the value of RT for the long-term survival of MPTB patients in different age groups. Additionally, univariate and multivariate Cox regression analyses were performed for overall survival (OS) and breast cancer-specific survival (BCSS) of MPTB patients. Furthermore, propensity score matching (PSM) was also performed to balance the differences in baseline characteristics. RESULTS: 2261 MPTB patients were included in this study, including 455 patients (20.12%) with RT and 1806 patients (79.88%) without RT. These patients were divided into four cohorts based on their ages: 18-45, 46-55, 56-65, and 65-80. Before adjustment, there was a statistically significant difference in long-term survival between RT-treated and non-RT-treated patients in the younger age groups (age group of 18-45 years: OS P = 0.019, BCSS P = 0.016; age group of 46-55 years: OS P < 0.001, BCSS P < 0.001). After PSM, no difference was found in long-term survival of patients in both younger and older groups regardless of whether they received RT (age group of 18-45 years: OS P = 0.473, BCSS P = 0.750; age group of 46-55 years: OS P = 0.380, BCSS P = 0.816, age group of 56-65 years: OS P = 0.484, BCSS P = 0.290; age group of 66-80 years: OS P = 0.997, BCSS P = 0.763). In multivariate COX regression analysis, RT did not affect long-term survival in patients with MPTB. CONCLUSION: There is no evidence that long-term survival of MPTB patients in specific age groups can benefit from RT.

IFI30 as a key regulator of PDL1 immunotherapy prognosis in breast cancer.

BACKGROUND: IFI30 is a lysosomal thiol reductase involved in antigen presentation and immune regulation in various cancers, including breast cancer. Despite its known involvement, the precise mechanism, function, and relationship with the PD-L1 axis and immune response remain unclear. METHODS: We conducted an extensive investigation into IFI30 mRNA expression in breast cancer utilizing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Furthermore, we characterized IFI30 mRNA expression across various cell types using publicly available single-cell RNA sequencing datasets, and assessed protein expression through immunohistochemistry using an in-house breast cancer tissue microarray. Functional experiments were performed to elucidate the effects of IFI30 overexpression on PD-L1 expression and inhibitory efficacy in both macrophages and breast tumor cells. RESULTS: Our study unveiled a marked upregulation of IFI30 expression in breast cancer tissues compared to their normal counterparts, with notable associations identified with tumor stage and prognosis. Additionally, IFI30 expression demonstrated significant correlations with various immune-related signaling pathways, encompassing peptide antigen binding, cytokine binding, and MHC class II presentation. Notably, breast cancer samples exhibiting high IFI30 expression in tumor cells displayed high PD-L1 expression on corresponding cells, alongside a diminished ratio of CD8 + T cell infiltration within the tumor microenvironment. Furthermore, ectopic knockdown of IFI30 in both tumor cells and macrophages resulted in a reduction of PD-L1 expression, while conversely, overexpression of IFI30 led to an increase in PD-L1 expression. CONCLUSIONS: This study offers new insights into the involvement of IFI30 in breast cancer, elucidating its interplay with the PD-L1 axis and immune response dynamics. Our findings suggest that modulation of the IFI30-PD-L1 axis could serve as a promising strategy for regulating T cells infiltration in breast cancer thus treating breast cancer.

Pitavastatin induces autophagy-dependent ferroptosis in MDA-MB-231 cells via the mevalonate pathway.

Triple-negative breast cancer (TNBC) is more prone to recurrence and metastasis relative to other subtypes of breast cancer, leading to an extremely poor prognosis. The increasing potential chemoresistance of TNBC patients is mainly due to that tumor cells escape from apoptosis. In recent years, statins have demonstrated extensive anti-tumor effects. It is worth noting that statins have more effective anti-tumor effects on TNBC cells and drug-resistant breast cancer cells. Therefore, this study examines the superior cytotoxic effects of statins on TNBC cell lines and further explores their potential therapeutic mechanisms. We detected different cell phenotypes and found that statins significantly reduced the cell viability of TNBC cells. Specifically, pitavastatin showed an obvious induction in cell death, cell cycle arrest and oxidative stress in TNBC MDA-MB-231 cells. The reversal effect of iron chelator desferrioxamine (DFO) on the morphological and molecular biological changes induced by pitavastatin has revealed a new mode of cell death induced by pitavastatin: ferroptosis. This ferroptotic effect was strengthened by the decreased expression of glutathione peroxidase 4 (GPx4) as well as newly discovered ferroptosis suppressor protein 1 (FSP1). The data showed that ferroptotic death of MDA-MB-231 cells is autophagy-dependent and mediated by the mevalonate pathway. Finally, we found that therapeutic oral doses of statins can inhibit the growth of transplanted tumors, which establishes statins as a potential treatment for TNBC patients. In conclusion, we found pitavastatin could induce autophagy-dependent ferroptosis in TNBC cells via the mevalonate pathway which may become a potential adjuvant treatment option for TNBC patients.

Inhibitory Impact Of Cinobufagin In Triple-Negative Breast Cancer Metastasis: Involvements Of Macrophage Reprogramming Through Upregulated MME and Inactivated FAK/STAT3 Signaling.

BACKGROUND: Cinobufagin (CBG), a key bioactive component in cinobufacini, exhibits antitumor properties. This study explores CBG's impact on triple-negative breast cancer (TNBC) metastasis and elucidates the underpinning mechanism. METHODS: Murine xenograft and orthotopic metastatic TNBC models were generated and treated with CBG. The burden of metastatic tumor in the mouse lung, the epithelial to mesenchymal transition (EMT) markers, and macrophage polarization markers within the tumors were examined. The phenotype of tumor-associated macrophages (TAMs) and mobility of TNBCs in vitro in a macrophage-TNBC cell coculture system were analyzed. Physiological targets of CBG were identified by bioinformatics analyses. RESULTS: CBG treatment significantly alleviated lung tumor burden and EMT activity. It triggered an M2-to-M1 shift in TAMs, resulting in decreased TNBC cell migration, invasion, and EMT in vitro. CBG upregulated membrane metalloendopeptidase (MME) expression, suppressing FAK and STAT3 phosphorylation. Silencing of MME, either in mice or TAMs, counteracted CBG effects, reinstating M2 TAM predominance and enhancing TNBC cell metastasis. Cotreatment with Defactinib, a FAK antagonist, reversed M2 TAM polarization and TNBC cell metastasis. Notably, MME silencing in TNBC cells had no impact on CBG-suppressed malignant properties, indicating MME's indirect involvement in TNBC cell behavior through TAM mediation. CONCLUSION: This study unveils CBG's ability to enhance MME expression, deactivate FAK/STAT3 signaling, and inhibit TNBC metastasis by suppressing M2-skewed macrophages.

Efficacy, Safety, and Population Pharmacokinetics of MW032 Compared With Denosumab for Solid Tumor-Related Bone Metastases: A Randomized, Double-Blind, Phase 3 Equivalence Trial.

Importance: The bioequivalence of denosumab biosimilar has yet to be studied in a 53-week, multicenter, large-scale, and head-to-head trial. A clinically effective biosimilar may help increase access to denosumab in patients with solid tumor-related bone metastases. Objectives: To establish the biosimilarity of MW032 to denosumab in patients with solid tumor-related bone metastases based on a large-scale head-to-head study. Design, Setting, and Participants: In this 53-week, randomized, double-blind, phase 3 equivalence trial, patients with solid tumors with bone metastasis were recruited from 46 clinical sites in China. Overall, 856 patients were screened and 708 eligible patients were randomly allocated to receive either MW032 or denosumab. Interventions: Patients were randomly assigned (1:1) to receive MW032 or reference denosumab subcutaneously every 4 weeks until week 49. Main Outcomes and Measures: The primary end point was percentage change from baseline to week 13 of natural logarithmic transformed urinary N-telopeptide/creatinine ratio (uNTx/uCr). Results: Among the 701 evaluable patients (350 in the MW032 group and 351 in the denosumab group), the mean (range) age was 56.1 (22.0-86.0) years and 460 patients were women (65.6%). The mean change of uNTx/uCr from baseline to week 13 was -72.0% (95% CI, -73.5% to -70.4%) in the MW032 group and -72.7% (95% CI, -74.2% to -71.2%) in the denosumab group. These percent changes corresponded to mean logarithmic ratios of -1.27 and -1.30, or a difference of 0.02. The 90% CI for the difference (-0.04 to 0.09) was within the equivalence margin (-0.13 to 0.13); the mean changes of uNTx/uCr and bone-specific alkaline phosphatase (s-BALP) at each time point were also similar during 53 weeks. The differences of uNTx/uCr change were 0.015 (95% CI, -0.06 to 0.09), -0.02 (95% CI, -0.09 to 0.06), -0.05 (95% CI, -0.13 to 0.03) and 0.001 (95% CI, -0.10 to 0.10) at weeks 5, 25, 37, and 53, respectively. The differences of s-BALP change were -0.006 (95% CI, 0.06 to 0.05), 0.00 (95% CI, -0.07 to 0.07), -0.085 (95% CI, -0.18 to 0.01), -0.09 (95% CI, -0.20 to 0.02), and -0.13 (95% CI, -0.27 to 0.004) at weeks 5, 13, 25, 37 and 53, respectively. No significant differences were observed in the incidence of skeletal-related events (-1.4%; 95% CI, -5.8% to 3.0%) or time to first on-study skeletal-related events (unadjusted HR, 0.86; P = .53; multiplicity adjusted HR, 0.87; P = .55) in the 2 groups. Conclusions and Relevance: MW032 and denosumab were biosimilar in efficacy, population pharmacokinetics, and safety profile. Availability of denosumab biosimilars may broaden the access to denosumab and reduce the drug burden for patients with advanced tumors. Trial Registration: ClinicalTrials.gov Identifier: NCT04812509.

TH-4000, a hypoxia-activated pan-HER inhibitor, shows excellent preclinical efficacy for the treatment of HER2+ breast cancer.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is correlated with poor prognosis, the current treatment of which is still based on surgery and adjuvant targeted therapy with monoclonal antibody. Problems of drug resistance hinder the use of monoclonal antibodies. Subsequently, tyrosine kinase inhibitors (TKIs) have been noticed, TKIs have the advantages of multi-targets and reduced drug resistance. However, TKIs that target HER family proteins often cause adverse effects such as liver damage and diarrhea. Thus, TKIs with high selectivity are being developed. TH-4000, a prodrug that generated an active form TH-4000Effector (TH-4000E) under hypoxic condition, was evaluated in this research. We found that TH-4000E ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium) (1-1000 nM) had potent and highly selective toxic effects on HER2+ breast cancer cells and inhibited the phosphorylation of HER family kinases at lower doses than that of Lapatinib and Tucatinib. TH-4000E activated Caspase-3 and induced apoptosis through a reactive oxygen species (ROS)-dependent pathway. The prodrug TH-4000 ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide) (50 mg/kg) effectively suppressed the tumor growth with less liver damage in mouse tumor models. This hypoxia-targeted strategy has possessed advantage in avoiding drug-induced liver damage, TH-4000 could be a promising drug candidate for the treatment of HER2+ breast cancer.

Systematic review and metanalysis of neutrophil to lymphocyte ratio and prognosis in patients with nasopharyngeal carcinoma.

Background: Hematological parameters have been associated with prognosis in patients with nasopharyngeal carcinoma (NPC). The present meta-analysis investigated the utility of neutrophil-lymphocyte ratio (NLR) in the prognosis of patients with NPC. Methods: Multiple electronic databases, including PubMed, Embase, the Cochrane Library, and the Web of Science, were systematically searched for studies assessing the association between NLR and NPC from 2011 to 2021. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized to estimate effect size. Use of a fixed effect or random effect model was based on heterogeneity stability was tested by sensitivity analysis, and the risk of bias was assessed by funnel plots. Random effects models were used based on the actual results. Because the NLR grouping criteria for the included studies differed, subgroup analyses were performed. Results: A search of the electronic databases identified 14 studies, encompassing 6693 patients, that met the selection criteria. NLR higher than the cutoff value was significantly associated with poorer OS [HR 1.760, 95% CI 1.470-2.120, p <0.00001] and PFS [HR 1.850, 95% CI 1.430-2.390, p = .006]. Sensitivity analysis showed that the results of the meta-analysis were relatively stable, and funnel plots were used to exclude the risk of bias. Conclusions: Elevated pretreatment NLR in peripheral blood is predictive of poorer OS and PFS in patients with NPC. NLR is an easily measured and important prognostic factor in patients with NPC.

Accuracy of Thoracic Ultrasonography for the Diagnosis of Pediatric Pneumonia: A Systematic Review and Meta-Analysis.

As an emerging imaging technique, thoracic ultrasonography (TUS) is increasingly utilized in the diagnosis of lung diseases in children and newborns, especially in emergency and critical settings. This systematic review aimed to estimate the diagnostic accuracy of TUS in childhood pneumonia. We searched Embase, PubMed, and Web of Science for studies until July 2023 using both TUS and chest radiography (CR) for the diagnosis of pediatric pneumonia. Two researchers independently screened the literature based on the inclusion and exclusion criteria, collected the results, and assessed the risk of bias using the Diagnostic Accuracy Study Quality Assessment (QUADAS) tool. A total of 26 articles met our inclusion criteria and were included in the final analysis, including 22 prospective studies and four retrospective studies. The StataMP 14.0 software was used for the analysis of the study. The overall pooled sensitivity was 0.95 [95% confidence intervals (CI), 0.92-0.97] and the specificity was 0.94 [95% CI, 0.88-0.97], depicting a good diagnostic accuracy. Our results indicated that TUS was an effective imaging modality for detecting pediatric pneumonia. It is a potential alternative to CXR and a follow-up for pediatric pneumonia due to its simplicity, versatility, low cost, and lack of radiation hazards.

RelB-activated GPX4 inhibits ferroptosis and confers tamoxifen resistance in breast cancer.

Tamoxifen (TAM) resistance remains a major obstacle in the treatment of advanced breast cancer (BCa). In addition to the competitive inhibition of the estrogen receptor (ER) signaling pathway, damping of mitochondrial function by increasing reactive oxygen species (ROS) is critical for enhancing TAM pharmacodynamics. Here, we showed that RelB contributes to TAM resistance by inhibiting TAM-provoked ferroptosis. TAM-induced ROS level promoted ferroptosis in TAM-sensitive cells, but the effect was alleviated in TAM-resistant cells with high constitutive levels of RelB. Mechanistically, RelB inhibited ferroptosis by transcriptional upregulating glutathione peroxidase 4 (GPX4). Consequently, elevating RelB and GPX4 in sensitive cells increased TAM resistance, and conversely, depriving RelB and GPX4 in resistant cells decreased TAM resistance. Furthermore, suppression of RelB transcriptional activation resensitized TAM-resistant cells by enhancing ferroptosis in vitro and in vivo. The inactivation of GPX4 in TAM-resistant cells consistently resensitized TAM by increasing ferroptosis-mediated cell death. Together, this study uncovered that inhibition of ferroptosis contributes to TAM resistance of BCa via RelB-upregulated GPX4.

Integration of bioinformatics and machine learning strategies identifies APM-related gene signatures to predict clinical outcomes and therapeutic responses for breast cancer patients.

BACKGROUND: Tumor antigenicity and efficiency of antigen presentation jointly influence tumor immunogenicity, which largely determines the effectiveness of immune checkpoint blockade (ICB). However, the role of altered antigen processing and presentation machinery (APM) in breast cancer (BRCA) has not been fully elucidated. METHODS: A series of bioinformatic analyses and machine learning strategies were performed to construct APM-related gene signatures to guide personalized treatment for BRCA patients. A single-sample gene set enrichment analysis (ssGSEA) algorithm and weighted gene co-expression network analysis (WGCNA) were combined to screen for BRCA-specific APM-related genes. The non-negative matrix factorization (NMF) algorithm was used to divide the cohort into different clusters and the fgsea algorithm was applied to investigate the altered signaling pathways. Random survival forest (RSF) and the least absolute shrinkage and selection operator (Lasso) Cox regression analysis were combined to construct an APM-related risk score (APMrs) signature to predict overall survival. Furthermore, a nomogram and decision tree were generated to improve predictive accuracy and risk stratification for individual patients. Based on Tumor Immune Dysfunction and Exclusion (TIDE) method, random forest (RF) and Lasso logistic regression model were combined to establish an APM-related immunotherapeutic response score (APMis). Finally, immune infiltration, immunomodulators, mutational patterns, and potentially applicable drugs were comprehensively analyzed in different APM-related risk groups. IHC staining was used to assess the expression of APM-related genes in clinical samples. RESULTS: In this study, APMrs and APMis showed favorable performances in risk stratification and therapeutic prediction for BRCA patients. APMrs exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. APMrs was closely associated with distinct mutational patterns, immune cell infiltration and immunomodulators expression. Furthermore, the two APM-related gene signatures were independently validated in external cohorts with prognosis or immunotherapeutic responses. Potential applicable drugs and targets were mined in the APMrs-high group. APM-related genes were further validated in our in-house samples. CONCLUSION: The APM-related gene signatures established in our study could improve the personalized assessment of survival risk and guide ICB decision-making for BRCA patients.

Advances in the relationship between temporal muscle thickness and prognosis of patients with glioblastoma: a narrative review.

The most dangerous variety of glioma, glioblastoma, has a high incidence and fatality rate. The prognosis for patients is still bleak despite numerous improvements in treatment approaches. We urgently need to develop clinical parameters that can evaluate patients' conditions and predict their prognosis. Various parameters are available to assess the patient's preoperative performance status and degree of frailty, but most of these parameters are subjective and therefore subject to interobserver variability. Sarcopenia can be used as an objective metric to measure a patient's physical status because studies have shown that it is linked to a bad prognosis in those with cancers. For the purpose of identifying sarcopenia, temporal muscle thickness has demonstrated to be a reliable alternative for a marker of skeletal muscle content. As a result, patients with glioblastoma may use temporal muscle thickness as a potential marker to correlate with the course and fate of their disease. This narrative review highlights and defines the viability of using temporal muscle thickness as an independent predictor of survival in glioblastoma patients, and it evaluates recent research findings on the association between temporal muscle thickness and prognosis of glioblastoma patients.

Tumor-derived small extracellular vesicles promote breast cancer progression by upregulating PD-L1 expression in macrophages.

BACKGROUND: The metastasis of breast cancer (BC) is a complex multi-step pathological process, strictly dependent on the intrinsic characteristics of BC cells and promoted by a predisposing microenvironment. Although immunotherapy has made important progress in metastasis BC, the heterogeneity of PD-L1 in tumor associated macrophages (TAMs) in BC and the underlying mechanisms in the metastasis development of BC are still not completely elucidated. Small extracellular vesicles (sEVs) represent essential interaction mediators between BC cells and TAMs. It is worth noting to explore the underlying mechanisms typical of sEVs and their role in the metastasis development of BC. METHODS: The structure of sEVs was identified by TEM, while the particle size and amounts of sEVs were detected by BCA and NTA analysis. The specific PD-L1 + CD163 + TAM subpopulation in metastasis BC was identified by scRNA-seq data of GEO datasets and verified by IHC and IF. The function of TAMs and sEVs in metastasis BC was explored by RT-qPCR, WB, IF, flow cytometry and in vivo experiment. The expression profiles of plasma sEVs-miRNA in relation to BC metastasis was analyzed using next-generation sequencing. Further detailed mechanisms of sEVs in the metastasis development of BC were explored by bioinformatics analysis, RT-qPCR, WB and luciferase reporter assay. RESULTS: In this study, we identified that the immunosuppressive molecule PD-L1 was more abundant in TAMs than in BC cells, and a specific PD-L1 + CD163 + TAM subpopulation was found to be associated with metastasis BC. Additionally, we found that BC cells-derived sEVs can upregulate the PD-L1 expression and induce the M2 polarization, enhancing the metastasis development both in vitro and in vivo. Also, Clinical data showed that sEV-miR-106b-5p and sEV-miR-18a-5p was in relation to BC metastasis development and poor prognosis of BC patients. Further mechanistic experiments revealed that BC-derived sEV-miR-106b-5p and sEV-miR-18a-5p could synergistically promoted the PD-L1 expression in M2 TAMs by modulating the PTEN/AKT and PIAS3/STAT3 pathways, resulting in the enhancement of the BC cells invasion and metastasis. CONCLUSIONS: Our study demonstrated that BC-derived sEVs can induce metastasis in BC through miR-106b-5p/PTEN/AKT/PD-L1 and miR-18a-5p/PIAS3/STAT3/PD-L1 pathways in TAMs. Therefore, the inhibition of these specific interactions of signaling pathways would represent a promising target for future therapeutic strategies for treatment of BC.

A simplified non-coplanar volumetric modulated arc therapy for the whole brain radiotherapy with hippocampus avoidance.

Purpose: To evaluate the feasibility of using a simplified non-coplanar volumetric modulated arc therapy (NC-VMAT) and investigate its dosimetric advantages compared with intensity modulated radiation therapy (IMRT) and coplanar volumetric modulated arc therapy (C-VMAT) for hippocampal-avoidance whole brain radiation therapy (HA-WBRT). Methods: Ten patients with brain metastase (BM) were included for HA-WBRT. Three treatment plans were generated for each case using IMRT, C-VMAT, and NC-VMAT, respectively. Results: The dosimetric results of the three techniques complied roughly with the RTOG 0933 criteria. After dose normalization, the V30Gy of whole brain planned target volume (WB-PTV) in all the plans was controlled at 95%. Homogeneity index (HI) of WB-PTV was significantly reduced in NC-VMAT (0.249 ± 0.017) over IMRT (0.265 ± 0.020, p=0.005) and C-VMAT (0.261 ± 0.014, p=0.020). In terms of conformity index (CI), NC-VMAT could provide a value of 0.821 ± 0.010, which was significantly superior to IMRT (0.788 ± 0.019, p<0.001). According to D2% of WB-PTV, NC-VMAT could provide a value of 35.62 ± 0.37Gy, significantly superior to IMRT (36.43 ± 0.65Gy, p<0.001). According to D50% of WB-PTV, NC-VMAT can achieve the lowest value of 33.18 ± 0.29Gy, significantly different from IMRT (33.47 ± 0.43, p=0.034) and C-VMAT (33.58 ± 0.37, p=0.006). Regarding D2%, D98%, and Dmean of hippocampus, NC-VMAT could control them at 15.57 ± 0.18Gy, 8.37 ± 0.26Gy and 11.71 ± 0.48Gy, respectively. D2% and Dmean of hippocampus for NC-VMAT was significantly lower than IMRT (D2%: 16.07 ± 0.29Gy, p=0.001 Dmean: 12.18 ± 0.33Gy, p<0.001) and C-VMAT (D2%: 15.92 ± 0.37Gy, p=0.009 Dmean: 12.21 ± 0.54Gy, p<0.001). For other organs-at-risk (OARs), according to D2% of the right optic nerves and the right lenses, NC-VMAT had the lowest values of 31.86 ± 1.11Gy and 7.15 ± 0.31Gy, respectively, which were statistically different from the other two techniques. For other organs including eyes and optic chiasm, NC-VMAT could achieve the lowest doses, different from IMRT statistically. Conclusion: The dosimetry of the three techniques for HA-WBRT could roughly comply with the proposals from RTOG 0933. After dose normalization (D95%=30Gy), NC-VMAT could significantly improve dose homogeneity and reduce the D50% in the brain. Besides, it can reduce the D2% of the hippocampus, optic nerves, and lens. With this approach, an efficient and straightforward plan was accomplished.