Radiomic signatures associated with tumor immune heterogeneity predict survival in locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The prognostic value of traditional clinical indicators for locally recurrent nasopharyngeal carcinoma (lrNPC) is limited due to their inability to reflect intratumor heterogeneity. We aimed to develop a radiomic signature to reveal tumor immune heterogeneity and predict survival in lrNPC. METHODS: This multicenter, retrospective study included 921 patients with lrNPC. A machine learning signature and nomogram based on pretreatment MRI features were developed for predicting overall survival (OS) in a training cohort and validated in two independent cohorts. A clinical nomogram and an integrated nomogram were constructed for comparison. Nomogram performance was evaluated by concordance index (C-index) and receiver operating characteristic curve analysis. Accordingly, patients were classified into risk groups. The biological characteristics and immune infiltration of the signature were explored by RNA sequencing (RNA-seq) analysis. RESULTS: The machine learning signature and nomogram demonstrated comparable prognostic ability to a clinical nomogram, achieving C-indexes of 0.729, 0.718, and 0.731 in the training, internal, and external validation cohorts, respectively. Integration of the signature and clinical variables significantly improved the predictive performance. The proposed signature effectively distinguished patients between risk groups with significantly distinct OS rates. Subgroup analysis indicated the recommendation of local salvage treatments for low-risk patients. Exploratory RNA-seq analysis revealed differences in interferon response and lymphocyte infiltration between risk groups. CONCLUSIONS: An MRI-based radiomic signature predicted OS more accurately. The proposed signature associated with tumor immune heterogeneity may serve as a valuable tool to facilitate prognostic stratification and guide individualized management for lrNPC patients.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Bioinformatics analysis of MMP14+ myeloid cells affecting endothelial-mesenchymal transformation and immune microenvironment in glioma.

Background: Gliomas, known for their complex and aggressive characteristics, are deeply influenced by the tumor microenvironment. Matrix metalloproteinases (MMPs) play a vital role in shaping this environment, presenting an opportunity for novel treatment strategies. Methods: We collected six bulk RNA datasets, one single-cell RNA sequencing (scRNA-seq) dataset, and gene sets related to Matrix Metalloproteinases (MMPs), Endothelial-Mesenchymal Transformation (EndMT), and sprouting angiogenesis. We computed enrichment scores using Gene Set Variation Analysis (GSVA) and Single-sample Gene Set Enrichment Analysis (ssGSEA). To analyze immune infiltration, we employed the CIBERSORT method. Data analysis techniques included the log-rank test, Cox regression, Kruskal-Wallis test, and Pearson correlation. For single-cell data, we utilized tools such as Seurat and CellChat for dimensionality reduction, clustering, and cell communication analysis. Results: 1. MMP14 was identified as an independent prognostic marker, highly expressed in myeloid cells in recurrent glioblastoma, highlighting these cells as functionally significant. 2. C-C Motif Chemokine Ligand (CCL) signaling from MMP14+ myeloid cells was identified as a critical immune regulatory pathway, with high C-C Motif Chemokine Receptor 1 (CCR1) expression correlating with increased M2 macrophage infiltration and PD-L1 expression. 3. Patients with high MMP14 expression showed better responses to bevacizumab combined chemotherapy. 4. Signaling pathways involving Visfatin, VEGF, and TGFb, emanating from myeloid cells, significantly impact endothelial cells. These pathways facilitate EndMT and angiogenesis in gliomas. 5. Nicotinamide Phosphoribosyltransferase (NAMPT) showed a strong link with angiogenesis and EndMT, and its association with chemotherapy resistance and differential sensitivity to bevacizumab was evident. Conclusions: MMP14+ myeloid cells are critical in promoting tumor angiogenesis via EndMT and in mediating immunosuppression through CCL signaling in glioblastoma. MMP14 and NAMPT serve as vital clinical indicators for selecting treatment regimens in recurrent glioma. The study suggests that a combined blockade of CCR1 and CD274 could be a promising therapeutic strategy.

Single-Cell Analysis Reveals Malignant Cells Reshape the Cellular Landscape and Foster an Immunosuppressive Microenvironment of Extranodal NK/T-Cell Lymphoma.

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive type of lymphoma associated with Epstein-Barr virus (EBV) and characterized by heterogeneous tumor behaviors. To better understand the origins of the heterogeneity, this study utilizes single-cell RNA sequencing (scRNA-seq) analysis to profile the tumor microenvironment (TME) of NKTCL at the single-cell level. Together with in vitro and in vivo models, the study identifies a subset of LMP1+ malignant NK cells contributing to the tumorigenesis and development of heterogeneous malignant cells in NKTCL. Furthermore, malignant NK cells interact with various immunocytes via chemokines and their receptors, secrete substantial DPP4 that impairs the chemotaxis of immunocytes and regulates their infiltration. They also exhibit an immunosuppressive effect on T cells, which is further boosted by LMP1. Moreover, high transcription of EBV-encoded genes and low infiltration of tumor-associated macrophages (TAMs) are favorable prognostic indicators for NKTCL in multiple patient cohorts. This study for the first time deciphers the heterogeneous composition of NKTCL TME at single-cell resolution, highlighting the crucial role of malignant NK cells with EBV-encoded LMP1 in reshaping the cellular landscape and fostering an immunosuppressive microenvironment. These findings provide insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.

Characteristics and classification of first primary cancer patients with second primary cancer: a population-based cohort study.

Cancer survivors have an increased risk of developing subsequent primary tumors. However, the characteristics of first primary cancers (FPCs) with various types of second primary cancers (SPCs) are poorly understood, which hinders screening strategies. We analyzed data from 1,893,258 patients from the Surveillance, Epidemiology, and End Results (SEER) database to characterize and classify of FPC patients with subsequent SPCs at the pan-cancer level. In total, 3% of patients had SPC, with varied incidence rates observed depending on the types of FPC. Their onset patterns of SPC and diversity of SPC varied. Based on the diversity of the high-incidence sites of SPC, we classified FPCs into two categories: FPCs that require whole-body screening and those that need screening of particular body parts. Moreover, according to the different timing of high incidence of SPCs, our system classifies FPCs into two subtypes: FPCs that require long-term monitoring for the occurrence of SPCs and those that require screening at specific time points for SPCs. Furthermore, we identified 11 anatomical sites where over half of FPC types are prone to SPC occurrence at these locations. The risk factors for SPC occurrence in different FPC types and prognostic factors were also elucidated. Overall, we characterize and classify of FPC patients with subsequent SPCs at the pan-cancer level, which can guide the development of distinct screening strategies for each FPC type.

New Staging System and Prognostic Model for Malignant Phyllodes Tumor Patients without Distant Metastasis: A Development and Validation Study.

PURPOSE: To build a new staging system and new prognostic models for MPTB. METHODS: We performed a comprehensive analysis of the data from the SEER database. RESULTS: We discussed the characteristics of MPTB by comparing 1085 MPTB cases with 382,718 invasive ductal carcinoma cases. We established a new stage- and age-stratification system for MPTB patients. Furthermore, we built two prognostic models for MPTB patients. The validity of these models was confirmed through multifaceted and multidata verification. CONCLUSIONS: Our study provided a staging system and prognostic models for MPTB patients, which can not only help to predict patient outcomes, but also enhance the understanding of the prognostic factors associated with MPTB.

Pan-cancer analysis identifies DDX56 as a prognostic biomarker associated with immune infiltration and drug sensitivity.

DDX56, a member of the RNA helicase family, is upregulated in colon adenocarcinoma, lung squamous cell carcinoma, and osteosarcoma. However, the relationships between DDX56 and other tumors are not clear, and the molecular mechanism of its action is not fully understood. Here, we explore the biological functions of DDX56 in 31 solid tumors and clarify that DDX56 can promote oncogenesis and progression in multiple tumor types based on multi-omics data. Bioinformatics analysis revealed that the cancer-promoting effects of DDX56 were achieved by facilitating tumor cell proliferation, inhibiting apoptosis, inducing drug resistance, and influencing immune cell infiltration. Furthermore, we found that copy number alterations and low DNA methylation of DDX56 were likely to be related to aberrantly high DDX56 expression. Our results suggest that DDX56 is a potential pan-cancer biomarker that could be used to predict survival and response to therapy, as well as a potential novel therapeutic target. We validated some of our results and illustrated their reliability using CRISPR Screens data. In conclusion, our results clarify the role of DDX56 in the occurrence and development of multiple cancers and provide insight into the molecular mechanisms involved in the process of pathogenesis, indicating a direction for future research on DDX56 in cancers.

Development and validation of a prognostic model and gene co-expression networks for breast carcinoma based on scRNA-seq and bulk-seq data.

Background: Breast carcinoma is the most common malignancy among women worldwide. It is characterized by a complex tumor microenvironment (TME), in which there is an intricate combination of different types of cells, which can cause confusion when screening tumor-cell-related signatures or constructing a gene co-expression network. The recent emergence of single-cell RNA sequencing (scRNA-seq) is an effective method for studying the changing omics of cells in complex TMEs. Methods: The Dysregulated genes of malignant epithelial cells was screened by performing a comprehensive analysis of the public scRNA-seq data of 58 samples. Co-expression and Gene Set Enrichment Analysis (GSEA) analysis were performed based on scRNA-seq data of malignant cells to illustrate the potential function of these dysregulated genes. Iterative LASSO-Cox was used to perform a second-round screening among these dysregulated genes for constructing risk group. Finally, a breast cancer prognosis prediction model was constructed based on risk grouping and other clinical characteristics. Results: Our results indicated a transcriptional signature of 1,262 genes for malignant breast cancer epithelial cells. To estimate the function of these genes in breast cancer, we also constructed a co-expression network of these dysregulated genes at single-cell resolution, and further validated the results using more than 300 published transcriptomics datasets and 31 Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screening datasets. Moreover, we developed a reliable predictive model based on the scRNA-seq and bulk-seq datasets. Conclusions: Our findings provide insights into the transcriptomics and gene co-expression networks during breast carcinoma progression and suggest potential candidate biomarkers and therapeutic targets for the treatment of breast carcinoma. Our results are available via a web app (https://prognosticpredictor.shinyapps.io/GCNBC/).

An immune and epithelial-mesenchymal transition-related risk model and immunotherapy strategy for grade II and III gliomas.

Grade II and III gliomas are heterogeneous and aggressive diseases. More efficient prognosis models and treatment methods are needed. This study aims to construct a new risk model and propose a new strategy for grade II and III gliomas. The data were downloaded from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), gene set enrichment analysis (GSEA), and the EMTome website for analysis. The Human Cell Landscape website and the Genomics of Drug Sensitivity in Cancer website were used for single-cell analysis and drug susceptibility analysis. Gene set enrichment analysis, gene function enrichment analysis, univariate and multivariate Cox regression analyses, Pearson's correlation analysis, log-rank test, Kaplan-Meier survival analysis, and ROC analysis were performed. We constructed an immune-related prognostic model associated with the isocitrate dehydrogenase 1 (IDH1) mutation status. By analyzing the immune microenvironment of patients with different risk scores, we found that high-risk patients were more likely to have an inflammatory immune microenvironment and a higher programmed death ligand-1 (PD-L1) expression level. Epithelial-mesenchymal transition (EMT)-related gene sets were significantly enriched in the high-risk group, and the epithelial-mesenchymal transition phenotype was associated with a decrease in CD8+ T cells and an increase in M2 macrophages. Transforming growth factor-ß (TGF-ß) signaling was the most important signaling in inducing epithelial-mesenchymal transition, and TGFB1/TGFBR1 was correlated with an increase in CD8+ T cytopenia and M2 macrophages. Survival analysis showed that simultaneous low expression of TGFBR1 and PD-L1 had better survival results. Through single-cell analysis, we found that TGFB1 is closely related to microglia and macrophages, especially M2 macrophages. Finally, we discussed the sensitivity of TGFB1 inhibitors in gliomas using cell line susceptibility data. These results demonstrated a potential immunotherapy strategy in combination with the TGFB1/TGFBR1 inhibitor and PD-1/PD-L1 inhibitor for grade II and III gliomas.

Tumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution.

The heterogeneous nature of tumour microenvironment (TME) underlying diverse treatment responses remains unclear in nasopharyngeal carcinoma (NPC). Here, we profile 176,447 cells from 10 NPC tumour-blood pairs, using single-cell transcriptome coupled with T cell receptor sequencing. Our analyses reveal 53 cell subtypes, including tumour-infiltrating CD8+ T, regulatory T (Treg), and dendritic cells (DCs), as well as malignant cells with different Epstein-Barr virus infection status. Trajectory analyses reveal exhausted CD8+ T and immune-suppressive TNFRSF4+ Treg cells in tumours might derive from peripheral CX3CR1+CD8+ T and naïve Treg cells, respectively. Moreover, we identify immune-regulatory and tolerogenic LAMP3+ DCs. Noteworthily, we observe intensive inter-cell interactions among LAMP3+ DCs, Treg, exhausted CD8+ T, and malignant cells, suggesting potential cross-talks to foster an immune-suppressive niche for the TME. Collectively, our study uncovers the heterogeneity and interacting molecules of the TME in NPC at single-cell resolution, which provide insights into the mechanisms underlying NPC progression and the development of precise therapies for NPC.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.

A Phase II Study of Fulvestrant 500 mg as Maintenance Therapy in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Patients with Advanced Breast Cancer After First-Line Chemotherapy.

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

Safety and Efficacy of Long-Term Zoledronic Acid in Advanced Breast Cancer with Bone Metastasis in South China.

BACKGROUND: This retrospective study aimed to characterize the long-term (>24 months) safety profile of zoledronic acid (ZA). We aimed to investigate whether long-term ZA treatment had greater benefits than short-term treatment in patients from southern China with advanced breast cancer (ABC) with bone metastasis. Patients and Methods. A total of 566 metastatic breast cancer cases were included and divided into two groups according to the duration of ZA treatment. The included patients had at least one lytic bone lesion and had no skeletal-related events (SREs) prior to ZA therapy. The primary endpoint was to analyze the safety and long-term adverse effects, which covered osteonecrosis of jaws (ONJ), renal impairment, and hearing impairment. The second objective was to determine the efficacy of long-term ZA treatment by the incidence of SREs. RESULTS: Fifteen patients were diagnosed with ONJ (2.7%): nine in the short-term group (3.1%) and six in the long-term group (2.2%, P = 0.606). Five cases (0.9%) had renal function impairment: two in the short-term group (0.7%) and four in the long-term group (1.1%, P = 0.676). One patient (0.2%) in the long-term group had hearing impairment after 23 months of ZA treatment (0.4%, P = 0.482). In total, 103 cases in the short-term group (35.2%) and 138 cases in long-term group (50.5%) developed SREs (P < 0.001). The mean annual SRE rate was 0.3 in the short-term group (range, 0-3.1) versus 0.2 in the long-term group (0-1.0, P = 0.269). Subgroup analysis suggested that cases with non-load-bearing bone involvement and those who received systematic anticancer therapy without chemotherapy might benefit from long-term ZA treatment. Cox regression analysis indicated poor performance status, and nonvisceral organ involvement predicted high risk for SRE. CONCLUSIONS: The extension of ZA treatment did not increase the long-term adverse events and reduced the annual incidence of SREs beyond 24 months. Although longer treatment of ZA over 24 months appeared to be safe, further prospective investigation is required.

First-line cetuximab improves the efficacy of subsequent bevacizumab for RAS wild-type left-sided metastatic colorectal cancer: an observational retrospective study.

The optimal targeted therapy sequence in patients of RAS wild-type left-sided metastatic colorectal cancer (mCRC) remains controversial, and few studies focus on the impact of first-line targeted agents on second-line ones. We enrolled 101 left-sided mCRC patients with RAS wild-type status, of which 50 cases received bevacizumab plus chemotherapy in both first-line and second-line therapies (Group A) and 51 cases received first-line cetuximab plus chemotherapy followed by second-line bevacizumab-containing regimens (Group B). The progression free survival (PFS) and overall survival (OS) from start of first-line (PFS 1nd and OS 1nd) and second-line (PFS 2nd and OS 2nd) therapy were compared between the two groups. PFS 1nd was comparable (10.0 vs 10.4 months; p = 0.402), while PFS 2nd (4.6 vs 7.9 months; p = 0.002), OS 1nd (26.8 vs 40.0 months; p = 0.011), and OS 2nd (15.2 vs 22.3 months; p = 0.006) were all poorer in group A compared with group B. Our study in combination with previous clinical data suggest that first-line application of cetuximab may provide a favorable condition for promoting the effect of subsequent bevacizumab, thus representing the optimal targeted therapy sequence in patients of RAS wild-type left-sided mCRC.

The Effects of Ganglioside-Monosialic Acid in Taxane-Induced Peripheral Neurotoxicity in Patients with Breast Cancer: A Randomized Trial.

BACKGROUND: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting adverse effect. Ganglioside-monosialic acid (GM1) functions as a neuroprotective factor. We assessed the effects of GM1 on the prevention of TIPN in breast cancer patients. METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 206 patients with early-stage breast cancer planning to receive taxane-based adjuvant chemotherapy with a follow-up of more than 1 year. Subjects were randomly assigned to receive GM1 (80 mg, day -1 to day 2) or placebo. The primary endpoint was the Functional Assessment of Cancer Treatment Neurotoxicity subscale score after four cycles of chemotherapy. Secondary endpoints included neurotoxicity evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and the Eastern Cooperative Oncology Group neuropathy scale. All statistical tests were two-sided. RESULTS: In 183 evaluable patients, the GM1 group reported better mean Functional Assessment of Cancer Treatment Neurotoxicity subscale scores than patients in the placebo group after four cycles of chemotherapy (43.27, 95% confidence interval [CI] = 43.05 to 43.49 vs 34.34, 95% CI = 33.78 to 34.89; mean difference = 8.96, 95% CI = 8.38 to 9.54, P < .001). Grade 1 or higher peripheral neurotoxicity in Common Terminology Criteria for Adverse Events v4.0 scale was statistically significantly lower in the GM1 group (14.3% vs 100.0%, P < .001). Additionally, the GM1 group had a statistically significantly lower incidence of grade 1 or higher neurotoxicity assessed by Eastern Cooperative Oncology Group neuropathy scale sensory neuropathy (26.4% vs 97.8%, P < .001) and motor neuropathy subscales (20.9% vs 81.5%, P < .001). CONCLUSIONS: The treatment with GM1 resulted in a reduction in the severity and incidence of TIPN after four cycles of taxane-containing chemotherapy in patients with breast cancer.

Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations.

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.

Genome sequencing analysis identifies Epstein-Barr virus subtypes associated with high risk of nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) infection is ubiquitous worldwide and is associated with multiple cancers, including nasopharyngeal carcinoma (NPC). The importance of EBV viral genomic variation in NPC development and its striking epidemic in southern China has been poorly explored. Through large-scale genome sequencing of 270 EBV isolates and two-stage association study of EBV isolates from China, we identify two non-synonymous EBV variants within BALF2 that are strongly associated with the risk of NPC (odds ratio (OR) = 8.69, P = 9.69 × 10-25 for SNP 162476_C; OR = 6.14, P = 2.40 × 10-32 for SNP 163364_T). The cumulative effects of these variants contribute to 83% of the overall risk of NPC in southern China. Phylogenetic analysis of the risk variants reveals a unique origin in Asia, followed by clonal expansion in NPC-endemic regions. Our results provide novel insights into the NPC endemic in southern China and also enable the identification of high-risk individuals for NPC prevention.

Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies.

Rationale: Epstein-Barr virus (EBV) is associated with multiple malignancies with expression of viral oncogenic proteins and chronic inflammation as major mechanisms contributing to tumor development. A less well-studied mechanism is the integration of EBV into the human genome possibly at sites which may disrupt gene expression or genome stability. Methods: We sequenced tumor DNA to profile the EBV sequences by hybridization-based enrichment. Bioinformatic analysis was used to detect the breakpoints of EBV integrations in the genome of cancer cells. Results: We identified 197 breakpoints in nasopharyngeal carcinomas and other EBV-associated malignancies. EBV integrations were enriched at vulnerable regions of the human genome and were close to tumor suppressor and inflammation-related genes. We found that EBV integrations into the introns could decrease the expression of the inflammation-related genes, TNFAIP3, PARK2, and CDK15, in NPC tumors. In the EBV genome, the breakpoints were frequently at oriP or terminal repeats. These breakpoints were surrounded by microhomology sequences, consistent with a mechanism for integration involving viral genome replication and microhomology-mediated recombination. Conclusion: Our finding provides insight into the potential of EBV integration as an additional mechanism mediating tumorigenesis in EBV associated malignancies.