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The use of liquid biopsy in cancer research has grown exponentially, offering potential for early detection, treatment stratification, and monitoring residual disease and recurrence. Exosomes, released by cancer cells, contain tumor-derived materials and are stable in biofluids, making them valuable biomarkers for clinical evaluation. Bibliometric research on osteosarcoma (OS) and exosome-derived diagnostic biomarkers is scarce. Therefore, we aimed to conduct a bibliometric evaluation of studies on OS and exosome-derived biomarkers. Using the Web of Science Core Collection database, Microsoft Excel, the R “Bibliometrix” package, CiteSpace, and VOSviewer software, quantitative analyses of the country, author, annual publications, journals, institutions, and keywords of studies on exosome-derived biomarkers for OS from 1995 to 2023 were performed. High-quality records (average citation rate ≥ 10/year) were filtered. The corresponding authors were mainly from China, the USA, Australia, and Canada. The University of Kansas Medical Center, National Cancer Center, Japan, and University of Kansas were major institutions, with limited cooperation reported by the University of Kansas Medical Center. Keyword analysis revealed a shift from cancer progression to mesenchymal stem cells, exosome expression, biogenesis, and prognostic biomarkers. Qualitative analysis highlighted exosome cargo, including miRNAs, circRNAs, lncRNAs, and proteins, as potential diagnostic OS biomarkers. This research emphasizes the rapid enhancement of exosomes as a diagnostic frontier, offering guidance for the clinical application of exosome-based liquid biopsy in OS, contributing to the evolving landscape of cancer diagnosis.

IntroductionLung cancer is one of the major causes of cancer-related mortality worldwide. High-throughput RNA sequencing (RNA-seq) of surgically removed tumors has been used to identify new biomarkers of lung cancer; however, contamination by non-tumor cells in the tumor microenvironment significantly interferes with the search for novel biomarkers. Tumor organoids, as a pre-clinical cancer model, exhibit similar molecular characteristics with tumor samples while minimizing the interference from other cells.Methods and ResultsHere we analyzed six RNA-seq datasets collected from different organoid models, in which cells with oncogenic mutations were reprogrammed to mimic lung adenocarcinoma (LUAD) tumorigenesis. We uncovered 9 LUAD-specific biomarker genes by integrating transcriptomic data from multiple sources, and identified IRAK1BP1 as a novel predictor of LUAD disease outcome. Validation with RNA-seq and microarray data collected from multiple patient cohorts, as well as patient-derived xenograft (PDX) and lung cancer cell line models confirmed that IRAK1BP1 expression was significantly lower in tumor cells, and had no correlation with known markers oflung cancer prognosis. In addition, loss of IRAK1BP1 correlated with the group of LUAD patients with worse survival; and gene-set enrichment analysis using tumor and cell line data implicated that high IRAK1BP1 expression was associated with suppression of oncogenic pathways.DiscussionIn conclusion, we demonstrate that IRAK1BP1 is a promising biomarker of LUAD prognosis.

PurposeTo assess the effectiveness and safety of transcatheter arterial sclerosing embolization (TASE) for the treatment of subglottic hemangiomas that did not respond appreciably to propranolol.Materials and MethodsThis study was a retrospective analysis. Of the 101 patients with subglottic hemangiomas admitted to our center, 10 (4 male and 6 female) patients were included in this study. All these patients underwent arterial embolization using Pingyangmycin and polyvinyl alcohol particles (300–500 μm). All patients were examined 1 month after the last treatment and monthly thereafter.ResultsTASE treatment was technically successful in all patients. Ten lesions were located in the subglottic region. The blood supply included the superior thyroid artery, brachiocephalic trunk, facial artery, and ascending pharyngeal arteries. The median maximal diameter of the hemangiomas significantly decreased from 8.5 mm before treatment to 2 mm after TASE (P

BackgroundThe effect of type 2 diabetes mellitus (T2DM) on survival of patients with hepatocellular carcinoma (HCC) after laparoscopic liver resection (LLR) has not been reported. This study aimed to explore the relationship between preoperative T2DM and long-term prognosis in HCC patients undergoing LLR.MethodsHCC patients receiving LLR as initial treatment at four cancer centers were retrospectively included in this study. Clinicopathological factors associated with the prognosis of HCC patients were identified using univariate and multivariate Cox regression analysis. Recurrence-free survival (RFS) and overall survival (OS) curves between different cohorts of patients were generated using the Kaplan-Meier method and compared using the log-rank test.ResultsOf 402 HCC patients included, 62 patients had T2DM and 340 patients did not have T2DM. The OS and RFS of patients with T2DM were significantly worse compared to those without T2DM (P = 0.001 and 0.032, respectively). In Cox multivariate analysis, T2DM was identified as an independent risk factors for OS (HR = 2.31, 95% CI = 1.38–3.85, P = 0.001) and RFS (HR = 1.66, 95% CI = 1.08–2.55, P = 0.020).ConclusionsFollowing laparoscopic surgical approach, HCC patients with T2DM had poorer prognoses than those without T2DM. Preoperative T2DM was an independent risk factor for HCC patients. Thus, patients with concurrent HCC and T2DM should be closely monitored after LLR.

Gastric cancer (GC) is a cancer with a high mortality rate. lncRNAs play a role in regulating GC tumorigenesis. In this paper, we analyzed differentially expressed lncRNAs between GC and adjacent normal tissues using multiple bioinformatics tools to identify new potential targets in GC. Cell viability and migration ability were detected using the Cell Counting Kit-8 (CCK-8) and transwell assays, MIR4435-2HG was negatively correlated with the survival rate of GC patients, and by inhibiting the activity of MIR4435-2HG, the viability and migration ability of GC cells could be reduced. In addition, RT- qPCR and western blot to detect gene and protein level expression, transmission electron microscopy and nanoparticle tracking analysis (NTA) to study the efficiency of exosome isolation, and flow cytometry to observe cell differentiation were employed, delivery of MIR4435-2HG shRNA via MKN45 cell-derived exosomes significantly reversed the MKN45 exosome-induced M2 polarization in macrophages. Furthermore, the low expression of MIR4435-2HG in MKN45 cell-derived exosomes inhibited the Jagged1/Notch and JAK1/STAT3 pathways in macrophages; MIR4435-2HG downregulated exosomes were found to significantly inhibit GC tumor growth in vivo by establishing a mouse model. In short, MKN45 cell-derived exosomes deliver lncRNA MIR4435-2HG, which promotes gastric carcinogenesis by inducing macrophage M2 polarization.

BackgroundIntralesional injection of lauromacrogol has proven to be an efficient treatment method for infantile hemangioma. This study aims to explore a novel injection therapy and evaluate its efficacy and complications.MethodsThe medical records of 368 children with infantile hemangioma who received a lauromacrogol injection from January 2021 to April 2022 were retrospectively analyzed. All patients were reviewed every 4 weeks, and their condition was assessed according to symptoms and medical records. The patient’s age, lesion type, location, size and thickness, lesion photographs, ultrasound, and complications were recorded.ResultsAmong the 368 infants who accept sclerotherapy with lauromacrogol, 226(61.4%)achieved excellent regression. In total, 108(29.4%)cases achieved good regression. 24(6.5%)achieved complete moderate regression. 10(2.7%)achieved poor regression. The reported incidence of adverse events was 4.9% and severe complications were not observed. Before and after three courses of treatment, the median vascular endothelial growth factor levels were 104.12 pg/ml and 28.982 pg/ml. There was a significant difference between the two groups (P=0.0043).ConclusionsThe results showed that this novel injection therapy a safe and effective treatment method. The therapy accelerated the regression of infantile hemangiomas without serious complications.

ObjectivesTo assess the utility of Dual-layer spectral-detector CT (DLCT) in predicting the pT stage and histologic grade for colorectal adenocarcinoma (CRAC).MethodsA total of 131 patients (mean 62.7 ± 12.9 years; 72 female, 59 male) with pathologically confirmed CRAC (35 pT1-2, 61 pT3, and 35 pT4; 32 high grade and 99 low grade), who received dual-phase DLCT were enrolled in this retrospective study. Normalized iodine concentration (NIC), slope of the spectral HU curve (λHU), and effective atomic number (Eff-Z) were measured for each lesion by two radiologists independently. Intraobserver reliability and interobserver agreement were assessed. The above values were compared between three pT-stage and two histologic-grade groups. The correlation between the pT stages and above values were assessed. Receiver operating characteristic (ROC) curves were calculated to evaluate the diagnostic efficacy.ResultsIntra-class correlation coefficients were ranged from 0.856 to 0.983 for all measurements. Eff-Z [7.21(0.09) vs 7.31 (0.10) vs 7.35 (0.19)], NICAP [0.11 (0.05) vs 0.15 (0.08) vs 0.15 (0.08)], NICVP [0.27 (0.06) vs 0.34 (0.11) vs 0.35 (0.12)], λHUAP [1.20 (0.45) vs 1.93 (1.18) vs 2.37 (0.91)], and λHUVP [2.07 (0.68) vs 2.35 (0.62) vs 3.09 (1.07)] were significantly different among pT stage groups (all P

Brain metastasis from intrahepatic cholangiocarcinoma (iCCA) is extremely rare, and no standard therapeutic strategy has been established. Camrelizumab is a programmed cell death protein 1 (PD-1) inhibitor that has been widely studied in treating liver cancer. Combined immunotherapy and targeted therapy are a promising approach for treating advanced iCCA. Despite that immune checkpoint inhibitor (ICI)-based neoadjuvant therapy on iCCA has shown a significant response rate and resection rate, few reports have shown the therapeutic efficacy of immunotherapy in treating brain metastasis from iCCA. Although PD-1 inhibitors such as pembrolizumab, nivolumab, or camrelizumab are increasingly applied in clinic practice to treat multiple malignancies, to the best of our knowledge, we report the first case of an iCCA patient with brain metastasis successfully treated with a combined immunotherapy and targeted therapy. The patient is a 54-year-old man with metastatic iCCA in brain treated though camrelizumab plus lenvatinib therapy with a complete response (CR). By the time of writing, he has had a progression-free survival of 17.5 months and did not experience any severe side effects related to this therapy. Camrelizumab plus lenvatinib therapy showed favorable efficacy and manageable toxicity for this patient with advanced iCCA and could be of interest for more prospective randomized trials to further verify the potential clinical benefits.

BackgroundIntra-tumor heterogeneity (ITH) plays a vital role in drug resistance and recurrence of lung cancer. We used a mutant-allele tumor heterogeneity (MATH) algorithm to assess ITH and investigated its association with clinical and molecular features in advanced lung adenocarcinoma.MethodsTissues from 63 patients with advanced lung adenocarcinoma were analyzed by next-generation sequencing (NGS) using a panel targeting 520 cancer-relevant genes. We calculated the MATH values from NGS data and further investigated their correlation with clinical and molecular characteristics.ResultsAmong the 63 patients with advanced lung adenocarcinoma, the median value of MATH was 33.06. Patients with EGFR mutation had higher level of MATH score than those with wild-type EGFR status (P = 0.008). Patients with stage IV disease showed a trend to have a higher MATH score than those with stage III (P = 0.052). MATH was higher in patients with disruptive TP53 mutations than in those with non-disruptive mutations (P = 0.036) or wild-type sequence (P = 0.023), but did not differ between tumors with non-disruptive mutations and wild-type TP53 (P = 0.867). High MATH is associated with mutations in mismatch repair (MMR) pathway (P = 0.026) and base excision repair (BER) pathway (P = 0.008). In addition, MATH was found to have a positive correlation with tumor mutational burden (TMB) (Spearman ρ = 0.354; P = 0.004). In 26 patients harboring EGFR mutation treated with first generation EGFR TKI as single-agent therapy, the objective response rate was higher in the Low-MATH group than in the High-MATH group (75% vs. 21%; P = 0.016) and Low-MATH group showed a significantly longer progression-free survival than High-MATH group (median PFS: 13.7 months vs. 10.1 months; P = 0.024).ConclusionsFor patients with advanced lung adenocarcinoma, MATH may serve as a clinically practical biomarker to assess intratumor heterogeneity.

The application and promotion of 125I seed implantation technology have increased the safety and effectiveness of the clinical treatment of advanced hepatocellular carcinoma (HCC). Epirubicin (EPI) is a traditional anthracycline chemotherapy agent that has minimal side effects and has been widely used in the clinical treatment of HCC. We hypothesized that EPI would enhance the anti-cancer effects of 125I seeds via the JAK/STAT1 signaling pathway. Thus, we aimed to investigate whether EPI could enhance the radiosensitivity of HCC cells to 125I and determine the underlying molecular mechanism. This basic study was conducted in an animal laboratory at Shandong University. BALB/C male nude mice were used, and all animals were fed and treated according to the standards of the Institutional Animal Care and Use Committee of Shandong University. Both in vitro and in vivo models of 125I irradiation of HCC cells were created. The anti-cancer effects of 125I and the role of EPI in promoting these effects were evaluated using flow cytometry for apoptosis and cell cycle, CCK-8 assay for EPI drug cytotoxicity, and transwell assays for migration and invasion. The potential mediating effect of the JAK/STAT1 pathway was assessed using an isobaric tag for relative and absolute quantitation analysis to identify differentially expressed proteins after 125I treatment. Transfection of HCC cells with STAT1-RNAi were performed to determine the effect of STAT1 downregulation on 125I and EPI treatment effects. The radiosensitivity concentration of EPI promoted 125I-induced anti-cancer effects, including apoptosis, anti-proliferation, and inhibition of migration and invasion. These effects were mediated via the JAK/STAT1 pathway. Downregulation of STAT1 compromised measured anti-cancer effects, which were both confirmed in the in vivo and in vitro models. EPI can promote 125I-induced anti-cancer effects in HCC. The JAK/STAT1 pathway may be a potential target for 125I seed implantation in the treatment of HCC.

The RE1 Silencing Transcription Factor (REST) is a major regulator of neurogenesis and brain development. Medulloblastoma (MB) is a pediatric brain cancer characterized by a blockade of neuronal specification. REST gene expression is aberrantly elevated in a subset of MBs that are driven by constitutive activation of sonic hedgehog (SHH) signaling in cerebellar granular progenitor cells (CGNPs), the cells of origin of this subgroup of tumors. To understand its transcriptional deregulation in MBs, we first studied control of Rest gene expression during neuronal differentiation of normal mouse CGNPs. Higher Rest expression was observed in proliferating CGNPs compared to differentiating neurons. Interestingly, two Rest isoforms were expressed in CGNPs, of which only one showed a significant reduction in expression during neurogenesis. In proliferating CGNPs, higher MLL4 and KDM7A activities opposed by the repressive polycomb repressive complex 2 (PRC2) and the G9A/G9A-like protein (GLP) complex function allowed Rest homeostasis. During differentiation, reduction in MLL4 enrichment on chromatin, in conjunction with an increase in PRC2/G9A/GLP/KDM7A activities promoted a decline in Rest expression. These findings suggest a lineage-context specific paradoxical role for KDM7A in the regulation of Rest expression in CGNPs. In human SHH-MBs (SHH-α and SHH-β) where elevated REST gene expression is associated with poor prognosis, up- or downregulation of KDM7A caused a significant worsening in patient survival. Our studies are the first to implicate KDM7A in REST regulation and in MB biology.

BackgroundExtensive and complex head and neck lymphatic malformations (LMs) are challenging to manage through traditional therapy. The purpose of this retrospective study was to assess the efficacy and safety of sirolimus in infants with refractory head and neck LMs.MethodsSirolimus was administered orally on a continuous dosing schedule. Patients were seen every month for the first three months and then subsequently every three months. The primary endpoints were safety and efficacy based on clinical and radiological evaluations.ResultsEight patients, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, the response and safety to medication was evaluated: all patients experienced reductions in LMs bulk, ranging from modest to significant. Some minor adverse effects were reported: mouth sores, eczema, gastrointestinal reaction, dyslipidemia, and neutropenia.ConclusionSirolimus was efficient in children with refractory head and neck LMs and was well tolerated.

BackgroundA large proportion of patients with Lynch syndrome (LS) have MSH2 abnormalities, but genotype-phenotype studies of MSH2 mutations in LS are still lacking. The aim of this study was to comprehensively analyze the clinicopathological characteristics and molecular basis of colorectal cancer (CRC) in patients with uncommon MSH2 cytoplasmic expression.MethodsWe retrospectively reviewed 4195 consecutive cases of CRC patients diagnosed between January 2015 and December 2017 at the Cancer Hospital Chinese Academy of Medical Sciences. Of the 4195 patients with CRC, 69 were indicated to have abnormal MSH2 expression through tumor immunohistochemical staining. Genetic tests, such as next-generation sequencing, large genomic rearrangement (LGR) analysis, microsatellite instability status analysis and genomic breakpoint analysis, were performed. Clinicopathological and molecular characteristics and clinical immunotherapy response were analyzed.ResultsForty-five of 69 patients were identified to have LS with pathogenic germline mutations in MSH2 and/or EPCAM. Of these LS patients, 26.7% were confirmed to harbor large genomic rearrangements (LGRs). Of note, three tumors from two unrelated family pedigrees exhibited a rare cytoplasmic MSH2 staining pattern that was found in LS patients with EPCAM/MSH2 deletions. RNA analysis showed that two novel mRNA fusions of EPCAM and MSH2 resulted in the predicted protein fusion with MSH2 cytoplasmic localization. Analyses of genomic breakpoints indicated that two novel deletions of EPCAM and MSH2 originated from Alu repeat-mediated recombination events. Our study also provides clinical evidence for the beneficial effect of the PD-1 inhibitor pembrolizumab for CRC patients that exhibit cytoplasmic MSH2 staining.ConclusionOur study demonstrates that the rare cytoplasmic MSH2 staining pattern should be fully recognized by pathologists and geneticists. Given the specific genotype-phenotype correlation in LS screening, we advocate that all CRC patients with cytoplasmic MSH2 staining in histology should be screened for LGRs of EPCAM and MSH2.

BackgroundLung adenocarcinoma (LUAD), as the most common histological subtype of lung cancer, is a high-grade malignancy and a leading cause of cancer-related death globally. Identification of biomarkers with prognostic value is of great significance for the diagnosis and treatment of LUAD. Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an RNA-binding protein “reader” of N6-methyladenosine (m6A) methylation, and is related to the progression of various cancers; however, its role in LUAD is unclear. The aims of this study aims were to study the expression and prognostic value of HNRNPC in LUAD.MethodsThe Oncomine database and gene expression profiling interactive analysis (GEPIA) were used for preliminary exploration of HNRNPC expression and prognostic value in LUAD. LUAD cases from The Cancer Genome Atlas (TCGA) (n = 416) and the Kaplan-Meier plotter database (n = 720) were extracted to study the differential expression and prognostic value of HNRNPC. HNRNPC expression in the National Cancer Center of China (NCC) cohort was analyzed by immunohistochemical staining, and the relationship between HNRNPC expression and survival rate evaluated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. Several pathways that were significantly enriched in the HNRNPC high expression group were identified by Gene Set Enrichment Analysis (GSEA).ResultsFive data sets from the Oncomine and GEPIA databases all supported that HNRNPC expression is significantly higher in LUAD than in normal lung tissue. In TCGA cohort, HNRNPC was highly expressed in LUAD tissues and significantly related to age, sex, smoking history, ethnicity, lymph node metastasis, and TNM staging (P < 0.001). High HNRNPC expression was significantly correlated with poor prognosis in the three cohorts (NCC, TCGA, and K-M plotter) (P < 0.05). Multivariate Cox regression analysis showed that HNRNPC expression was an independent prognostic factor in both TCGA and NCC cohorts (P < 0.05). Further, 10 significantly enriched pathways were identified from TCGA data and 118 lung cancer cell lines in CCLE, respectively.ConclusionsHigh HNRNPC expression is significantly related to poor overall survival in patients with LUAD, suggesting that HNRNPC may be a cancer-promoting factor and a potential prognostic biomarker in LUAD.

BackgroundSIGLEC family genes can also be expressed on tumor cells in different cancer types, and though it has been found that SIGLEC genes expressed by immune cells can be exploited by tumors to escape immune surveillance, functions of tumor derived SIGLEC expression in tumor microenvironment (TME) were barely investigated, which could play roles in cancer patients’ survival.MethodsUsing bioinformatic analysis, mutation status of SIGLEC family genes was explored through the cBioPortal database, and expression of them in different tumors was explored through the UALCAN database. The GEPIA database was used to compare SIGLEC family genes’ mRNA between cancers and to generate a highly correlated gene list in tumors. A KM-plotter database was used to find the association between SIGLEC genes and survival of patients. The associations between SIGLEC family genes’ expression, immune infiltration, and immune regulators’ expression in TME were generated and examined by the TIMER 2.0 database; the differential fold changes of SIGLEC family genes in specific oncogenic mutation groups of different cancer types were also yielded by TIMER 2.0. The networks of SIGLEC family genes and highly correlated genes were constructed by the STRING database, and gene ontology and pathway annotation of SIGLEC family highly correlated genes were performed through the DAVID database.ResultsSIGLEC family genes were highly mutated and amplified in melanoma, endometrial carcinoma, non-small cell lung cancer, bladder urothelial carcinoma, and esophagogastric adenocarcinoma, while deep deletion of SIGLEC family genes was common in diffuse glioma. Alteration of SIGLEC family genes demonstrated different levels in specific tumors, and oncogenic mutation in different cancer types could influence SIGLEC family genes’ expression. Most SIGLEC family genes were related to patients’ overall survival and progression free survival. Also, tumor derived SIGLEC family genes were related to tumor immune cell infiltration and may regulate TME by influencing chemokine axis.ConclusionOur computational analysis showed SIGLEC family genes expressed by tumor cells were associated with tumor behaviors, and they may also influence TME through chemokine axis, playing vital roles in patients’ survival. Further experiments targeting tumor derived SIGLEC family genes are needed to confirm their influences on tumor growth, metastasis, and immune environment regulation.

Background: KDM5C is a histone H3K4-specific demethylase, which has multiple biological functions during development and disease. However, the role of KDM5C in intrahepatic cholangiocarcinoma (ICC) remains unknown.Methods: Expression levels of KDM5C in ICC patients were determined by qRT-PCR, western blotting and immunohistochemical assay. The functions of KDM5C in cell proliferation and invasion were determined in human ICC cells and mouse xenograft model using KDM5C overexpression and knockdown strategies in vivo. RNA-seq analysis was applied to investigate the transcriptional program of KDM5C. In addition, ChIP-qPCR was used to determine the regulation of FASN by KDM5C.Results: Here, we show that KDM5C was downregulated in human ICC, where its diminished expression was associated with poor prognosis. ICC cell proliferation and invasion were inhibited by KDM5C overexpression. Moreover, KDM5C suppressed ICC proliferation and metastasis in vivo. RNA-sequencing showed that KDM5C inhibits key signal pathways of cell proliferation, cell invasion and fatty acid metabolism. ChIP-qPCR revealed that overexpression of KDM5C led to the reduction of H3K4me3 on the promoter and the corresponding downregulation of the expression of FASN, which represents the major target gene of KDM5C to mediate the proliferation and invasion of ICC cells.Conclusions: Our results revealed the role of KDM5C as a novel tumor suppressor in ICC largely by repressing FASN-mediated lipid acid metabolism and thus KDM5C may contribute to the pathogenesis of ICC.

Background: Pyrotinib, an irreversible pan-ERBB inhibitor, has shown promising antitumour activity, and acceptable tolerability. This research was conducted to evaluate the actual use and effectiveness of pyrotinib in China, therefore, contributed to solve the problem of real-world data scarcity.Methods: In this retrospective study, 168 patients who received pyrotinib treatment for HER2-positive metastatic breast cancer (MBC) in Hunan Province from June 2018 to August 2019 were included. Progression-free survival (PFS), tumor mutation burden (TMB), and drug-related adverse events (AEs) after pyrotinib administration were analyzed.Results: The median PFS (mPFS) time in the 168 participants was 8.07 months. The mPFS times in patients with pyrotinib in second-line therapy (n = 65) and third-or-higher-line therapy (n = 94) were 8.10 months and 7.60 months, respectively. Patients with brain metastases achieved 8.80 months mPFS time. In patients with pyrotinib in third-or-higher-line therapy, patients who had previously used lapatinib still got efficacy but showed a shorter mPFS time (6.43 months) than patients who had not (8.37 months). TMB was measured in 28 patients, K-M curve (P = 0.0024) and Multivariate Cox analysis (P = 0.0176) showed a significant negative association between TMB and PFS. Diarrhea occurred in 98.2% of participants (in any grade) and 19.6% in grade 3–4 AEs.Conclusion: Pyrotinib is highly beneficial to second-or-higher-line patients or HER2-positive MBC patients with brain metastases. Pyrotinib seems to be a feasible strategy both in combination of chemotherapeutic drugs or as a replacement of lapatinib if diseases progressed. TMB could be a potential predictor for evaluating pyrotinib's effectiveness in HER2-positive MBC.