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Abstract Background Uterine corpus endometrial carcinoma (UCEC) is a prevalent gynecologic malignancy with a favorable prognosis if detected early. However, there is a lack of accurate and reliable early detection tests for UCEC. This study aims to develop a precise and non-invasive diagnostic method for UCEC using circulating cell-free DNA (cfDNA) fragmentomics. Methods Peripheral blood samples were collected from all participants, and cfDNA was extracted for analysis. Low-coverage whole-genome sequencing was performed to obtain cfDNA fragmentomics data. A robust machine learning model was developed using these features to differentiate between UCEC and healthy conditions. Results The cfDNA fragmentomics-based model showed high predictive power for UCEC detection in training (n = 133; AUC 0.991) and validation cohorts (n = 89; AUC 0.994). The model manifested a specificity of 95.5% and a sensitivity of 98.5% in the training cohort, and a specificity of 95.5% and a sensitivity of 97.8% in the validation cohort. Physiological variables and preanalytical procedures had no significant impact on the classifier’s outcomes. In terms of clinical benefit, our model would identify 99% of Chinese UCEC patients at stage I, compared to 21% under standard care, potentially raising the 5-year survival rate from 84 to 95%. Conclusion This study presents a novel approach for the early detection of UCEC using cfDNA fragmentomics and machine learning showing promising sensitivity and specificity. Using this model in clinical practice could significantly improve UCEC management and control, enabling early intervention and better patient outcomes. Further optimization and validation of this approach are warranted to establish its clinical utility.

ObjectiveTo explore the value of combined radiomics and deep learning models using different machine learning algorithms based on mammography (MG) and magnetic resonance imaging (MRI) for predicting axillary lymph node metastasis (ALNM) in breast cancer (BC). The objective is to provide guidance for developing scientifically individualized treatment plans, assessing prognosis, and planning preoperative interventions.MethodsA retrospective analysis was conducted on clinical and imaging data from 270 patients with BC confirmed by surgical pathology at the Third Hospital of Shanxi Medical University between November 2022 and April 2024. Multiple sequence images from MG and MRI were selected, and regions of interest in the lesions were delineated. Radiomics and deep learning (3D-Resnet18) features were extracted and fused. The samples were randomly divided into training and test sets in a 7:3 ratio. Dimensionality reduction and feature selection were performed using the least absolute shrinkage and selection operator (LASSO) regression model, and other methods. Various machine learning algorithms were used to construct radiomics, deep learning, and combined models. These models were visualized and evaluated for performance using receiver operating characteristic curves, area under the curve (AUC), calibration curves, and decision curves.ResultsThe highest AUCs in the test set were achieved using radiomics-logistic regression (AUC = 0.759), deep learning-multilayer perceptron (MLP) (AUC = 0.712), and combined-MLP models (AUC = 0.846). The MLP model demonstrated strong classification performance, with the combined model (AUC = 0.846) outperforming both the radiomics (AUC = 0.756) and deep learning (AUC = 0.712) models.ConclusionThe multimodal radiomics and deep learning models developed in this study, incorporating various machine learning algorithms, offer significant value for the preoperative prediction of ALNM in BC.

Abstract Background Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality. Methods We collected a prospective study cohort of 110 stage I–II gastric cancer patients and 139 non-cancer individuals. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. With these differential profiles, we developed an ensemble model to detect gastric cancer signals. Further, we validated the assay in an in-house first validation cohort of 73 gastric cancer patients and 94 non-cancer individuals and an independent second validation cohort of 47 gastric cancer patients and 49 non-cancer individuals. Additionally, we evaluated the assay in a hypothetical 100,000 screening population by Monte Carlo simulation. Results Our cfDNA-based assay could distinguish early-stage gastric cancer from non-cancer at an AUROC of 0.962 (95% CI: 0.942–0.982) in the study cohort, 0.972 (95% CI: 0.953–0.992) in the first validation cohort and 0.937 (95% CI: 0.890–0.983) in the second validation cohort. The model reached a specificity of 92.1% (128/139) and a sensitivity of 88.2% (97/110) in the study cohort. In the first validation cohort, 91.5% (86/94) of non-cancer individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In the second validation cohort, 89.8% (44/49) of non-cancer individuals and 87.2% (41/47) of gastric cancer patients were accurately classified. Conclusions We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer. Trial registration This study was registered on ClinicalTrials.gov under the identifier NCT05269056 on March 7, 2022.

This case report describes a patient initially diagnosed with Gaucher disease (GD) with type I with homozygous mutation c.1448T > C p. (Leu483Pro) at age of 2, presenting with hepatosplenomegaly and cytopenia. Imiglucerase replacement therapy was initiated. At age 17, bilateral hearing loss developed, with subsequent Cranial MRI revealing thalamic damage, leading to a reclassification as type 3 GD. By age of 20, the patient presented with a range of symptoms, including abdominal pain, diarrhea, hypoproteinemia, multiple lymphadenopathy, edema, and Gaucher cell infiltration in the lymph nodes. Comprehensive diagnosis identifies Gaucher tumor and protein-losing enteropathy. Imiglucerase therapy at 90‐120 U/kg every 2 weeks significantly improved clinical symptoms, emphasizing the importance of tailored interventions for managing GD manifestations.

Anaplastic lymphoma kinase (ALK) inhibitors are the recommended treatment of ALK-rearranged non-small cell lung cancer but are prone to eventual drug resistance.Herein we report a 45-year-old Asian woman diagnosed with EML4-ALK rearranged lung adenocarcinoma. Small cell lung cancer-like phenotypic transformation occurred when resistance to crizotinib treatment. Next-generation sequencing was performed and detected an ALK rearrangement co-existent with a TP53 gene mutation in the small cell specimens. The patient had a good response to alectinib with a progression-free survival >7 months. After disease progression, newly emerged ALK p.G1269A and p.L1196 M gene mutations co-existent with ALK rearrangement were detected. The patient had a good initial response to ceritinib treatment, which last for >12 months. After ceritinib failure, however, more complicated mutations within the ALK kinase domain (p.G1269A, p.L1196 M, newly emerged p.D1203 N, and p.L1122V) were detected. Ultimately, due to terminal rapid progression and resistance to lorlatinib, the overall survival was nearly 3 years.Our case showed that next-generation ALK-tyrosine kinase inhibitors (TKIs) may be an appropriate choice after transformation to small cell lung cancer and failure to one ALK-TKI. Sequential biopsies and gene mutation monitoring are important to arrange the sequence of different generation ALK-TKIs. Appropriate sequential therapies may yield a prolonged response with a satisfactory quality of life in patients with advanced ALK-rearranged non-small cell lung cancer.

Abstract HER2-positive gastric cancer (GC) makes up 15–20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.

Abstract Background Although with the impressive efficacy, several patients showed intrinsic resistance or an unsatisfactory response to Osimertinib. We aim to explore the impact of clinical and molecular features on efficacy and outcome of patients with EGFR T790M-mutation non-small cell lung cancer (NSCLC) receiving second-line Osimertinib. Methods Patients with EGFR T790M-mutant NSCLC who had acquired resistance to the first-generation EGFR TKI and then received Osimertinib as second-line treatment were included. Patients’ demographic and clinical information, as well as molecular data were extracted from electronic medical records. The impact of clinical and molecular features on treatment response and patients’ outcome were assessed. Results Among the 99 patients, 60 patients were tissue/pleural effusion T790M positive and 69 patients were plasma positive with a median PFS of 12.1 m and 9.9 m (P = 0.25), respectively. In addition, median PFS were similar between patients of plasma T790M + and patients of plasma T790M- (P = 0.94). The Pearson correlation test showed no significant relationship between plasma T790M abundance and PFS (r = 0.074, P = 0.546). In subgroup analyses, PFS was significantly improved in elder patients (P = 0.009) and patients with longer PFS to the first-generation EGFR TKI (P = 0.0008), while smokers tended to have worse PFS compared with non-smokers (P = 0.064). PARP1 mutant-type patients had a worse PFS compared with wild-type group (P = 0.0003). Patients with MYC amplification also had a worse PFS than MYC wild-type patients (P = 0.016). A significant PFS shrinkage was observed in TMB-High group as 6.77 m, compared with 19.10 m in TMB-Low group. The multivariate Cox analysis revealed that years ≥ 65 was an independent positive feature for PFS, while PARP1 mutation and TMB-H were negative features for PFS. Conclusion In conclusion, our findings in this study demonstrated that clinical and molecular features can be served as predictive biomarkers to stratify patients with EGFR T790M-mutant NSCLC receiving second-line Osimertinib.

BackgroundThe circulating predictive factors for the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) remain elusive. We aimed to assess the predictive value of circulating cytokines for outcomes.MethodsSerum samples of 102 advanced-stage NSCLC patients who underwent immunotherapy were collected at baseline. The relative levels of 37 cytokines were detected. PD-L1 expression was also analyzed.ResultsHigher serum CXCL12 levels (top 33%) were a poor predictive biomarker for durable clinical benefit (DCB) (23.5% vs. 72.1%, p

Background: KMT2D mutation (KMT2DMT) was found to play an important role in cancer immunity and response to immune checkpoint inhibitors (ICIs). The present study aims to investigate the association between KMT2D exon 39 mutation (K-ex39MT) and molecular and clinical characteristics in colorectal adenocarcinoma (CRAD). Methods: We performed profiling of KMT2DMT and K-ex39MT via Kaplan–Meier analysis, cBioportal, Immune-related functional analysis and correlation analysis with TCGA and MSK cohorts to explore their effects on the prognosis, immune landscape, molecular characteristics and drug sensitivity in CRAD. Panel gene sequencing of 30 in-house CRAD tissues and multiple immunofluorescences (mIF) were also used. Results: In multi-cancer, patients with KMT2DMT have a worse overall survival (OS), and CRAD with K-ex39MT exhibited a greater degree of immune cellular infiltration. For CRAD, compared with KMT2D exon39 wild type (K-ex39WT), K-ex39MT patients had higher tumor mutational burden (TMB) and lower copy number alteration (CNA), and were accompanied by more immune cell infiltration including activated T cells, NK cells, Treg cells and exhausted T cells and enrichment of immune-related genes and pathways. In drug sensitivity prediction, K-ex39MT patients have a lower CTX-S score and IC50 of 5-Fluorouracil and irinotecan, and higher Tumor Immune Dysfunction and Rejection (TIDE) dysfunction score. Conclusions: CRAD patients with K-ex39MT have more abundant immune cell infiltration and enrichment of immune-related pathways and signatures. And they may be more sensitive to some chemotherapies but less to cetuximab.

Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As a dysregulated urea cycle is implicated in cancer development, the impact of GS’s ammonia clearance function has not been explored in cancer. Here, we show that oncogenic activation of β-catenin (encoded by CTNNB1) led to a decreased urea cycle and elevated ammonia waste burden. While β-catenin induced the expression of GS, which is thought to be cancer promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived nonessential amino acids, which subsequently stimulated mechanistic target of rapamycin complex 1 (mTORC1). Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While patients with hepatocellular carcinoma, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.

BackgroundLi-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma. The pathogenic variants underlying the majority of LFL cases remain to be explored.MethodsWe performed whole-exome sequencing (WES) on 13 core members of a large LFL family with highly aggregated incidences of cancers, including cases with sarcoma, non-small cell lung cancer and cardiac angiosarcoma, and conducted a comprehensive literature review of candidate gene associations in LFS/LFL syndromes or sarcoma to identify potential pathogenic germline variants.ResultsNo germline variants in the best-known LFL/LFS-associated gene TP53 were detected. Of all the genes associated with LFS/LFL or sarcoma that we have surveyed, we identified a novel p.P35L germline variant in POT1 (protection of telomeres 1). Germline and somatic alterations in POT1 have been implicated in a series of familial cancers, including angiosarcoma, glioma, melanoma and colorectal cancer. This particular variant is located in the telomere-binding OB1 domain, which is important in maintaining the proper telomere length, and showed high conservation across different POT1 orthologues. No record of the variant was found in any of the 1000 genomes, ExAC, gnomAD, dpSNP and COSMIC databases. Prediction algorithms and in silico structural analysis suggested completely disrupted protein structure and function of POT1 in the presence of this mutation.ConclusionsLeveraging WES, we identified a novel germline risk allele, p.P35L in POT1, that likely predisposes to LFL syndrome. Our results support the routine testing of POT1 and other LFL/LFS-associated genes in the risk populations to enable early cancer diagnosis, prevention and intervention.

ObjectiveThe aim of this study is to determine the clinical efficacy of bile-derived liquid biopsy compared with plasma and tumor tissue biopsy in patients with biliary tract carcinoma (BTC).MethodsA total of 13 patients with BTC were enrolled in this cohort. Tumor tissue, bile, and plasma samples were obtained and analyzed using next-generation sequencing for genomic profiling.ResultsBile and plasma samples were collected from all 13 patients, and 11 patients also had matched tumor tissues available. The cell-free DNA (cfDNA) concentration was significantly higher in the bile supernatant than in plasma (median: 1918 vs. 63.1 ng/ml, p = 0.0017). The bile supernatant and pellet had a significantly higher mean mutation allele frequency (MF) than plasma (median: 3.84% vs. 4.22% vs. 0.16%; p < 0.001). Genomic alterations were predominantly missense. Both bile supernatant and pellet had significantly more genomic alterations than plasma (average: 9.3 vs. 7.2 vs. 2.3 alterations per sample; p < 0.01). Among the top 10 most frequent genomic alterations, the consistency between bile supernatant and tumor tissue was 90.00% (18/20), that between bile pellet and tumor tissue was 85.00% (17/20), and that between the plasma and tissue was only 35.00% (7/20). MAF of both bile supernatant and pellet was positively correlated with that in tissue samples (ρ < 0.0001, spearman r = 0.777, and ρ < 0.0001, spearman r = 0.787, respectively), but no significant correlation with tissue was found in the plasma (ρ = 0.966, spearman r = 0.008). Furthermore, additional genomic alterations could be detected in bile supernatant and pellet than in tissue. Potential targets for targeted therapy were identified in bile supernatant and pellet. Regarding copy number variation (CNV) and chromosomal instability (CIN) detection, four additional CNVs from two patients were detected in the bile supernatant that was not detected in tissues (i.e., amplification of TERC, IL7R, RICTOR, and TERT). CIN was significantly higher in tumor tissue than in plasma. The CIN of the bile was also significantly higher than that of plasma. There was no significant difference in CIN between the tissue and the bile supernatant.ConclusionThe consistency of all genomic alterations and tumor tissue-determined genomic alteration in the bile supernatant/pellet was significantly higher than in plasma. Bile supernatants/pellets are better for genetic sequencing and may also have potential clinical value to guide targeted therapy and evaluate prognosis. Bile cfDNA may be a feasible substitute for tumor tissue in the genetic testing of patients with BTC.

Background and Aims: TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquitylating p62 and prevents its oligomerization and protein sequestration function. As redox homeostasis plays a pivotal role in many cancers including liver cancer, we sought to determine the role of TRIM21 in hepatocarcinogenesis. Methods: We examined the correlation between TRIM21 expression and the disease using publicly available data sets and 49 cases of HCC clinical samples. We used TRIM21 genetic knockout mice to determine how TRIM21 ablation impact HCC induced by the carcinogen DEN plus phenobarbital (PB). We explored the mechanism that loss of TRIM21 protects cells from DEN-induced oxidative damage and cell death. Results: There is a positive correlation between TRIM21 expression and HCC. Consistently, TRIM21-knockout mice are resistant to DEN-induced hepatocarcinogenesis. This is accompanied by decreased cell death and tissue damage upon DEN treatment, hence reduced hepatic tissue repair response and compensatory proliferation. Cells deficient in TRIM21 display enhanced p62 sequestration of Keap1 and are protected from DEN-induced ROS induction and cell death. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient mutant TRIM21 impedes the protection from DEN-induced oxidative damage and cell death in TRIM21-deficient cells. Conclusions: Increased TRIM21 expression is associated with human HCC. Genetic ablation of TRIM21 leads to protection against oxidative hepatic damage and decreased hepatocarcinogenesis, suggesting TRIM21 as a preventive and therapeutic target.

For the mmWave MIMO system using a partially-connected structure,in order to improve the spectral efficiency,the antenna composition of each subarray will be dynamically adjusted according to the channel conditions.However,the optimal grouping of antennas requires exhaustive searching for all possible antenna combinations according to certain criteri,which leads to unacceptable complexity.In response to the problem,a low-complexity sub-array dynamic allocation method was proposed.The core was to introduce certain rules when grouping array elements,thereby significantly reducing the number of combinations and reducing the search range.Specifically,two low-complexity antenna combination algorithms were proposed.Firstly,considering the strong correlation between mmWave antennas,multiple adjacent antennas were virtualized as an array element,thereby reducing the search space.Secondly,by dividing all antennas into upper and lower half areas,the antenna combination based on partition was realized,and the search space was also reduced.Simulation results show that the proposed method can achieve a good trade-off between performance and complexity.

The histological transformation from adenocarcinoma (ADC) to squamous cell carcinoma (SCC) is rare but recurrently occurs post TKI treatment in EGFR-mutated non-small cell lung cancer patients with a very limited number of clinical cases published. The outcome of patients after SCC onset is poor as no established treatment guidelines were available. Here we report a case who was initially diagnosed with lung ADC with EGFR L858R driver mutation and demonstrated a partial response (PR) to gefitinib for 27 months before disease progression. The rapidly progressive lung metastatic lesions were determined as an SCC histology with positive PD-L1 expression. Besides EGFR L858R, the metastatic SCC harbored the amplification of CD274 and PDCD1LG2 detected by targeted next-generation sequencing (NGS), which encode PD-L1 and PD-L2, respectively. The disease remained stable on the combination therapy of pembrolizumab plus chemotherapy for eight months until the primary ADC lesion progressed. After the failure of progressed primary ADC lesion with radiotherapy and immunotherapy, systemic ADC metastases were developed in multiple locations including kidney, liver, and chest wall with EGFR L858R mutation but negative PD-L1 expression. The patient then received the combination therapy of bevacizumab plus chemotherapy and the disease remained stable for five months. Since August 2021, afatinib has been administrated which led to a PR and the disease has remained stable up till present. This study demonstrated a primary lung ADC who developed systemic ADC metastases and local SCC transformation with distinct molecular features. The patient has achieved long-term clinical benefit upon multiple lines of chemotherapy and immunotherapy, which provided valuable insight into the treatment of advanced SCC-transformed lung ADC patients.

Esophageal squamous cell carcinoma (ESCC) is one of the most common and lethal malignant tumors. The incidence of malignant transformation of esophageal mucosa increases greatly due to long-term exposure to factors such as smoking, drinking, and poor eating habits. Furthermore, multiple primary tumors could occur synchronously or asynchronously in the upper aerodigestive tract, especially in the esophagus, adding difficulty to the treatment of ESCC. Genetic mutations are important during the malignant transformation from normal mucosa to esophageal cancer, but the underlying mechanism has not been fully elucidated. In this study, we used whole-exome sequencing (WES) to profile genetic variations in physiologically normal mucosa (PNM) and ESCC tumors, as well as PNM of non-ESCC subjects. We found significant differences in mutation frequencies of NOTCH1 and NOTCH2, copy number variations (CNVs) at both gene and chromosomal arm levels, and cancer-related HIPPO, WNT, and NRF2 signaling pathways between ESCC tumors and normal mucosa. Our analysis of both primary tumors and paired PNM in bifocal ESCC revealed three different primary tumor evolution modes, and the most common mode exhibited a complete genomic divergence in all the samples from the same patient. Furthermore, the mutation frequency of TP53 was significantly higher in ESCC cases than that in non-ESCC cases. Overall, our results provide important evidence for further elucidating the mechanisms of genetic mutations underlying the cause of ESCC.

BackgroundHigh PD-L1 expression in non-small cell lung cancer (NSCLC) is evident to predict elevated immunotherapy efficacy, to which NSCLC with onco-driver gene mutations is probed with poor responsiveness. Thus, it is of great interest to investigate how effective immune monotherapy is in the presence of concurrent high PD-L1 expression and driving gene mutation.Patients and methodsWe present a case of squamous lung cancer with high PD-L1 expression and HER2 exon 20 insertion (20Ins) who presented hyperprogressive disease (HPD) after being treated with PD-1 inhibitor.ResultsA 71-year-old female was diagnosed with advanced squamous lung cancer with 98% tumor proportion score of PD-1 and 20ins. She benefited from first-line docetaxel cisplatin followed by 2 months second-line afatinib. Third-line pembrolizumab monotherapy was then given. Unfortunately, she rapidly progressed with dramatically enlarged primary site as well as mediastinal lymph nodes and pleural effusion only 2 weeks later, presenting severe dyspnea and dysphagia. Re-biopsy was conducted, and we found that compared with the baseline, CD8+ T cells were largely recruited only in tumor stroma but not in tumor parenchyma. Tumor-associated macrophages were notably increased in both tumor stroma and parenchyma. Concomitantly, CD56dim NK cells in tumor parenchyma were decreased.ConclusionsApplication of immune monotherapy in patients with positive driver genes demands extreme caution, even harboring high PD-L1 expression. Abnormality of tumor microenvironment might be critically involved in immune checkpoint inhibitor-induced HPD. Further study in greater depth is required.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of large lymphoid B cell malignancy with distinct clinical and genetic features. Recently, NOTCH1 mutations were identified in DLBCL cases by Next-generation sequencing (NGS), but the clinical features and prognostic impact were not systematically studied. Here, NOTCH1 genes in 161 DLBCL samples were sequenced by NGS. The prognostic value of NOTCH1 mutations was assessed in the context of clinical and laboratory factors, such as international prognostic index (IPI), cell-of-origin classification, double expression of BCL2 and c-MYC. The combined data from three Western cohorts were used to validate these results. As a result, NOTCH1 mutations were found in 17(10.6%) patients, and three patients had a hotspot mutation of c.7541_7542delCT. The presence of NOTCH1 mutations was significantly associated with poor complete response and progression free survival(PFS), which was independent of established clinical and laboratory parameters. In addition, 30 (1.92%) of 1562 patients treated with R-CHOP regimen in those combined Western cohorts had NOTCH1 mutations. Meta-analysis of the Western cohorts confirmed that NOTCH1 mutations were also associated with poor PFS and OS. In conclusion, DLBCL patients with the NOTCH1 mutations have worse PFS and OS, and the NOTCH1 mutations can be used as an independent predictor for patients with DLBCL.

Background: Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage. Methods: Using TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin. Findings: TRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicin-induced cell death. Interpretation: Our study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity.

BackgroundThe therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy.Material and MethodsWe consecutively enrolled stage IV, EGFR-mutant, and EGFR-TKI–treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed.ResultsIn total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, P

BackgroundMicropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments.MethodsWe performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort.ResultsTumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (TTF1), brain-specific angiogenesis inhibitor 3 (BAI3), mammalian target of rapamycin (MTOR), and cyclin-dependent kinase inhibitor 2A (CDKN2A) were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including MET amplification and MTOR mutation, were correlated with increased PD-L1 expression.ConclusionWe identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy.

BackgroundInvasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear.MethodsWe collected 76 surgically resected primary tumors of invasive lung adenocarcinoma, including 51 IMA and 25 non-mucinous adenocarcinomas (non-IMA). IMA was further divided into pure-IMA (mucinous features≥90%) and mixed-IMA subgroups. Comprehensive genomic profiling based on targeted next-generation sequencing (NGS) of 425 genes was explored and genomic characteristics were evaluated for the correlation with postoperative disease-free survival (DFS).ResultsIMA had a unique genetic profile, with more diverse driver mutations and more tumor drivers/suppressors co-occurrence than that of non-IMA. The frequency of EGFR (72.0% vs. 40.0% vs. 23.1%, p=0.002) and ALK (undetected vs. 20.0% vs. 26.9%, p=0.015) alterations showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. The frequency of KRAS mutations in pure-IMA was higher than that in mixed-IMA, albeit statistically insignificant (23.1% vs. 4.0%, p=0.10). TP53 mutation was significantly less in pure-IMA compared to mixed-IMA and non-IMA (23.1% vs. 52.0% vs. 56.0%, p=0.03). Besides, IMA exhibited less arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, and the frequency of amplification and deletion also showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. Furthermore, prognosis analysis in stage III IMA patients showed that patients harboring alterations in EGFR (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) achieved prolonged DFS, while patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or with KRAS mutations (mDFS=13.0 vs. 20.0 months, HR=6.95, p=0.027) had shorter DFS. Multivariate analysis showed that KRAS mutations, PI3K pathway alterations, and tumor differentiation status were independent factors that have statistically significant influences on clinical outcomes of IMA patients.ConclusionOur study provided genomic insights into Chinese surgically resected lung IMA. We also identified several genomic features that may serve as potential biomarkers on postoperative recurrence in IMA patients with stage III disease.

BackgroundKinase domain duplication of EGFR (EGFR-KDD) is a rare oncogenic driver alteration and serves as a potential therapeutic target. Its effect on EGFR–tyrosine kinase inhibitors (TKIs), especially the third-generation drug Osimertinib, and immune checkpoint inhibitors (ICIs) remains inconclusive.Case PresentationA 45-year old male with lung adenocarcinoma progressed with liver metastasis after receiving pemetrexed and cisplatin as adjuvant chemotherapy. Targeted next-generation sequencing (NGS) identified an EGFR-KDD in the resected left upper lung. Icotinib was used in the following treatment and the liver metastasis was found to shrink but the progression-free survival (PFS) only lasted for 4 months with the appearance of right hepatic metastasis. Meantime, the same EGFR-KDD was identified in the left hepatic re-biopsy. Afterward, the patient benefited from the third-line therapy of Osimertinib with a PFS as long as 21 months. Then he progressed with enlarged mediastinal lymph nodes, and targeted NGS consistently identified EGFR-KDD, as well as a new RELN p.G1774E mutation. Given the continually increasing tumor mutation burden (TMB, 3.4 mutation/Mb) and PD-L1 expression-based tumor proportion score (TPS, 1%), Nivolumab was used as the fourth-line salvage therapy, which lead to considerable efficacy, with decreased blood carcinoembryonic antigen (CEA), regressed mediastinal lymph nodes, and reduced liver metastases.ConclusionsOur case provided direct evidence to support the role of Osimertinib in the treatment of EGFR-KDD, as well as added valuable insights into application of immune-based therapeutics in the specific subgroups bearing EGFR alteration(s).

Abstract Background While there have been encouraging preliminary clinical results for immune checkpoint inhibitors (ICIs) in BTCs, it remains a challenge to identify the subset of patients who may benefit. In this study, we evaluated the efficacy of ICI treatment in patients with advanced BTCs, and explored potential biomarkers that are predictive of response. Methods The study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with intrahepatic cholangiocarcinoma [ICCs]) who received ICI treatment. Targeted next‐generation sequencing (NGS) was performed on tumor tissue samples collected from 17 patients. Clinical and genomic characteristics were assessed for the correlation with clinical outcome. Results Analysis of the baseline clinical characteristics showed that performance score (PS) of 0 was associated with a better prognosis than PS of 1 (HR = 1.08 × 109; 95% CI, 0∼Inf; P = .002). No significant correlations were found between clinical outcome and inflammation‐related indicators. NGS profiling of the available tumor tissues, revealed largely non‐overlapping somatic alterations between GCs and ICCs. Mutations in LRP1B (HR = 0.26; 95% CI, 0.06‐1.21; P = .067), ERBB2 (HR = 0.15; 95% CI, 0.02‐1.19; P = .04), or PKHD1 (HR

Non–small cell lung cancer (NSCLC) with activating EGFR mutations in exon 19 and 21 typically responds to EGFR tyrosine kinase inhibitors (TKI); however, for some patients, responses last only a few months. The underlying mechanisms of such short responses have not been fully elucidated. Here, we sequenced the genomes of 16 short-term responders (SR) that had progression-free survival (PFS) of less than 6 months on the first-generation EGFR TKI and compared them to 12 long-term responders (LR) that had more than 24 months of PFS. All patients were diagnosed with advanced lung adenocarcinoma and harbored EGFR 19del or L858R mutations before treatment. Paired tumor samples collected before treatment and after relapse (or at the last follow-up) were subjected to targeted next-generation sequencing of 416 cancer-related genes. SR patients were significantly younger than LR patients (P < .001). Collectively, 88% of SR patients had TP53 variations compared to 13% of LR patients (P < .001). Additionally, 37.5% of SR patients carried EGFR amplifications compared to 8% of LR patients. Other potential primary resistance factors were also identified in the pretreatment samples of 12 SR patients (75%), including PTEN loss; BIM deletion polymorphism; and amplifications of EGFR, ERBB2, MET, HRAS, and AKT2. Comparatively, only three LR patients (25%) were detected with EGFR or AKT1 amplifications that could possibly exert resistance. The diverse preexisting resistance mechanisms in SR patients revealed the complexity of defining treatment strategies even for EGFR-sensitive mutations.

Abstract Background One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated the utility of ctDNA to reflect the efficacy of treatment and to monitor resistance mechanisms. Methods Targeted next‐generation sequencing (NGS) of 416 cancer‐relevant genes was performed on 41 plasma biopsy samples of 19 HER2+ and 12 HER2‐ BC patients. Longitudinal ctDNA samples were analyzed in three BC patients over the treatment course for detecting acquired mutations. Results In HER2+ BC patients, ERBB2 somatic copy numbers in ctDNA samples were significantly higher in patients progressed on HER2‐targeted therapy than those who were still responding to the treatment. Recurrent acquired mutations were detected in genes including ERBB2, TP53, EGFR, NF1, and SETD2, which may contribute to trastuzumab resistance. In longitudinal analyses, the observed mutation allele frequencies were tracked closely in concordance with treatment responses. A novel ERBB2 p.(Leu869Arg) mutation was acquired in one patient upon resistant to trastuzumab therapy, which was further validated as an oncogenic mutation in vitro and contributed to resistance. In HER2‐ BC patients with chemotherapy resistance, genetic alterations on TP53, PIK3CA, and DNA damage repair genes were frequently observed. Conclusions In summary, ctDNA monitoring, particularly longitudinal analyses, provides valuable insights into the assessment of targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2‐ BC patients, respectively.

The high accuracy and low overhead of elephant flows identification have a great meaning on solving the controller's single point of failure problem in SDN traffic management.Aiming at the problem of high overhead of the existing elephant flows identification method,a two-level method for elephant flows identification was proposed which included a suspicious elephant detection algorithm based on TCP write-queue in the first stage and areal elephant detection algorithm based on flow duration in the second stage.During the first stage,the suspicious elephant flows were identified in the end systems to reduce the amount of flows monitored by the SDN controller at the second stage.Analysis and simulation prove that, under the premise of ensuring the accuracy of elephant flow identification, the two-level method for elephant flows identification reduces about 85% overhead of identification compared with sampling identification method.

Congestion control algorithms of TCP protocol previously used in space communications are mostly based on TCP Vegas algorithm.They always require accurately measurement of RTT,but it's very difficult to achieve in deep space communication networks which have very long and variable delay channel characteristics.An errors tolerated congestion control algorithm is proposed based on packet loss rate measurement.The algorithm sends data in the form of data blocks and gives an errors tolerated degree based on the history data.It measures the congestion state based on the current packet loss rate measurement,so it can achieve a smaller overhead and higher transmission efficiency.In addition,the usage of mathematical modeling methods simplifies the networks and simulates the real network traffic.The mentioned algorithm is compared with the classical congestion control algorithm.Analysis and simulation prove that thethroughput of improved algorithm is 34 percent better than Tahoe and 22 percent better than Reno,so it gets a better performance.

Background: Patients with peritoneal metastasis (PM) from gastric cancer (GC) exhibit poor prognosis. Chemoimmunotherapy offers promising clinical benefits; however, its efficacy and predictive biomarkers in a conversion therapy setting remain unclear. The authors aimed to retrospectively evaluate chemoimmunotherapy efficacy in a conversion therapy setting for GC patients with PM and establish a prediction model for assessing clinical benefits. Materials and methods: A retrospective evaluation of clinical outcomes encompassed 55 GC patients with PM who underwent chemoimmunotherapy in a conversion therapy setting. Baseline PM specimens were collected for genomic and transcriptomic profiling. Clinicopathological factors, gene signatures, and tumor immune microenvironment were evaluated to identify predictive markers and develop a prediction model. Results: Chemoimmunotherapy achieved a 41.8% objective response rate and 72.4% R0 resection rate in GC patients with PM. Patients with conversion surgery showed better overall survival (OS) than those without the surgery (median OS: not reached vs 7.82 m, P<0.0001). Responders to chemoimmunotherapy showed higher ERBB2 and ERBB3 mutation frequencies, CTLA4 and HLA-DQB1 expression, and CD8+ T cell infiltration, but lower CDH1 mutation and naïve CD4+ T cell infiltration, compared to nonresponders. A prediction model was established integrating CDH1 and ERBB3 mutations, HLA-DQB1 expression, and naïve CD4+ T cell infiltration (AUC= 0.918), which were further tested using an independent external cohort (AUC= 0.785). Conclusion: This exploratory study comprehensively evaluated clinicopathological, genomic, and immune features and developed a novel prediction model, providing a rational basis for the selection of GC patients with PM for chemoimmunotherapy-involved conversion therapy. [ABSTRACT FROM AUTHOR]

Double pipe heat exchangers (DPHEs) are widely used in industrial fields, such as refrigeration, heat pumps, and chemical industry, owing to their efficient coupled heat transfer characteristics of evaporation and condensation. In this study, the effects of inner and outer tube diameter combinations and inlet velocity on heat transfer performance, pressure drop, and thermal performance are systematically analyzed through computational fluid dynamic simulation. Results show a significant difference in heat transfer performance under different conditions. At an inlet velocity of 2 ms−1, the total heat transfer coefficient of Case 5 is 66.1 % higher than that of Case 2. Case 3 has the lowest pressure drop among all the cases. Turbulence increases interface renewal, mixing efficiency, and heat transfer efficiency when the inlet velocity is 8 ms−1. When the velocity is 2 ms−1, turbulence is reduced, and the gravity effect dominates across, resulting in a drop in heat transfer efficiency. This study reveals the influence law of inner and outer tube diameters and flow velocity on the coupled heat transfer characteristics, which provides an important theoretical basis and a practical reference for optimizing the design of DPHEs and has significant application in heat-intensive industries.