Eribulin plus carboplatin combination for HER2-negative metastatic breast cancer: a multicenter, real-world cohort study.

BACKGROUND: Pre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC. PATIENTS AND METHODS: This multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. RESULTS: From March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 - mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 - subtype. The median treatment was 6 cycles (range, 2 - 8 cycles). In the full cohort, TNBC, and HR + HER2 - subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed. CONCLUSION: ErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment.

Development of a prediction model for suicidal ideation in patients with advanced cancer: A multicenter, real-world, pan-cancer study in China.

BACKGROUND: Patients diagnosed with advanced stage cancer face an elevated risk of suicide. We aimed to develop a suicidal ideation (SI) risk prediction model in patients with advanced cancer for early warning of their SI and facilitate suicide prevention in this population. PATIENTS AND METHODS: We consecutively enrolled patients with multiple types of advanced cancers from 10 cancer institutes in China from August 2019 to December 2020. Demographic characteristics, clinicopathological data, and clinical treatment history were extracted from medical records. Symptom burden, psychological status, and SI were assessed using the MD Anderson Symptom Inventory (MDASI), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9), respectively. A multivariable logistic regression model was employed to establish the model structure. RESULTS: In total, 2814 participants were included in the final analysis. Nine predictors including age, sex, number of household members, history of previous chemotherapy, history of previous surgery, MDASI score, HADS-A score, HADS-D score, and life satisfaction were retained in the final SI prediction model. The model achieved an area under the curve (AUC) of 0.85 (95% confidential interval: 0.82-0.87), with AUCs ranging from 0.75 to 0.95 across 10 hospitals and higher than 0.83 for all cancer types. CONCLUSION: This study built an easy-to-use, good-performance predictive model for SI. Implementation of this model could facilitate the incorporation of psychosocial support for suicide prevention into the standard care of patients with advanced cancer.

Pyrotinib and trastuzumab plus palbociclib and fulvestrant in HR+/HER2+ breast cancer patients with brain metastasis.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients are at a high risk of developing metastases in the brain. However, research focusing on treatment strategies for hormonal receptor positive (HR+), HER2+ BC patients with brain metastases (BM) remains limited. Thus, a multi-center, prospective trial was conducted in China. Women over the age of 18 who were naive to whole brain radiotherapy and had estrogen receptor (ER)/progesterone-receptor (PgR) positive, HER2+ BM were treated with palbociclib, fulvestrant, trastuzumab and pyrotinib, until disease progression or the development of intolerable side effects. The primary endpoint was objective response rate (ORR) in the central nervous system (CNS). This ongoing study is still recruiting participants and is registered with ClinicalTrials.gov (NCT04334330). This report presents the findings from an interim analysis. From December 4, 2020, to November 2, 2022, 15 patients were enrolled. Among the 14 patients who were evaluable for clinical response, the ORR was 35.7% (95% CI: 12.8-64.9%), with a CNS-ORR of 28.6% (95% CI: 8.4-58.1%). The median follow-up period was 6.3 months (range, 2.1-14.3 months), during which the median progression-free survival (PFS) was 10.6 months (95% CI: 4.3-16.9 months), and the median time to CNS progression was 8.5 months (95% CI: 5.9-11.1 months). The most common adverse event was diarrhea (93%), with 33% having grade 3 and 6.7% having grade 4. The study suggests that the combination of palbociclib, trastuzumab, pyrotinib and fulvestrant offers a promising chemo-free treatment strategy for HR+, HER2+ BC patients with BM.

Association between anxiety, depression, and symptom burden in patients with advanced colorectal cancer: A multicenter cross-sectional study.

OBJECTIVES: Patients with advanced colorectal cancer (CRC) have multiple concurrent physical and psychological symptoms. This study aimed to explore the relationship between anxiety, depression, and symptom burden in advanced CRC. METHODS: A multicenter cross-sectional study was conducted in 10 cancer centers from geographically and economically diverse sites in China. A total of 454 patients with advanced CRC completed the Hospital Anxiety and Depression Scale and the MD Anderson Symptom Inventory. Multiple regression analysis was applied to explore the relationship between anxiety, depression and symptom burden. RESULTS: About one-third of the patients showed symptoms of anxiety or depression. Patients with anxiety or depression reported significantly higher symptom burden than those without (p < 0.001). Patients with anxiety or depression reported a higher proportion of moderate-to-severe (MS) symptom number than those without (p < 0.001). About 52% of the patients with anxiety or depression reported at least three MS symptoms. The prevalence of MS symptoms was ranging from 7.3% (shortness of breath) to 22% (disturbed sleep), and in patients with anxiety or depression was 2-10 times higher than in those without (p < 0.001). Disease stage (ß = -2.55, p = 0.003), anxiety (ß = 15.33, p < 0.001), and depression (ß = 13.63, p < 0.001) were associated with higher symptom burden. CONCLUSIONS: Anxiety and depression in patients with advanced cancer correlated with higher symptom burden. Findings may lead oncology professionals to pay more attention to unrecognized and untreated psychological symptoms in symptom management for advanced cancer patients.

Suicidal ideation in Chinese patients with advanced breast cancer: a multi-center mediation model study.

PURPOSE: The pathways underpinning suicide ideation (SI) and certain physical and psychological factors in patients with advanced breast cancer remain unclear. This study develops and validates a mediation model that delineates the associations between several multidimensional variables and SI in Chinese patients with advanced breast cancer. METHODS: Patients with advanced breast cancer (n = 509) were recruited as study participants from 10 regional cancer centers across China from August 2019 to December 2020. Participants were required to complete five questionnaires using an electronic patient-reported outcomes (ePRO) system: 9 item- Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), Insomnia Severity Index (ISI), 5-level EQ-5D (EQ-5D-5L), and MD Anderson Symptom Inventory (MDASI). Risk factors for SI were identified using multivariable logistic regression, and inputted into serial multiple mediation models to elucidate the pathways linking the risk factors to SI. RESULTS: SI prevalence was 22.8% (116/509). After adjusting for covariates, depression (odds ratio [OR] = 1.384), emotional distress (OR = 1.107), upset (OR = 0.842), and forgetfulness (OR = 1.236) were identified as significant independent risk factors (all p < 0.05). The ORs indicate that depression and distress have the strongest associations with SI. Health status has a significant indirect effect (OR=-0.044, p = 0.005) and a strong total effect (OR=-0.485, p < 0.001) on SI, mediated by insomnia severity and emotional distress. CONCLUSIONS: There is a high SI prevalence among Chinese patients with advanced breast cancer. Our analysis revealed predictive pathways from poor health to heightened SI, mediated by emotional distress and insomnia. Regular management of distress and insomnia can decrease suicide risk in this vulnerable population.

Physical symptoms and anxiety and depression in older patients with advanced cancer in China: a network analysis.

BACKGROUND: Little is understood about the association between psychosomatic symptoms and advanced cancer among older Chinese patients. METHODS: This secondary analysis was part of a multicenter cross-sectional study based on an electronic patient-reported outcome platform. Patients with advanced cancer were included between August 2019 and December 2020 in China. Participants (over 60 years) completed the MD Anderson Symptom Inventory (MDASI) and Hospital Anxiety and Depression Scale (HADS) to measure symptom burden. Network analysis was also conducted to investigate the network structure, centrality indices (strength, closeness, and betweenness) and network stability. RESULTS: A total of 1022 patients with a mean age of 66 (60-88) years were included; 727 (71.1%) were males, and 295 (28.9%) were females. A total of 64.9% of older patients with advanced cancer had one or more symptoms, and up to 80% had anxiety and depression. The generated network indicated that the physical symptoms, anxiety and depression symptom communities were well connected with each other. Based on an evaluation of the centrality indices, 'distress/feeling upset' (MDASI 5) appears to be a structurally important node in all three networks, and 'I lost interest in my own appearance' (HADS-D4) had the lowest centrality indices. The network stability was relatively high (> 0.7). CONCLUSION: The symptom burden remains high in older patients with advanced cancer in China. Psychosomatic symptoms are highly interactive and often present as comorbidities. This network can be used to provide targeted interventions to optimize symptom management in older patients with advanced cancer in China. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900024957), registered on 06/12/2020.

Phase II study of apatinib plus exemestane in estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer.

PURPOSE: Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR)-2. This study was conducted to assess the efficacy and safety of apatinib combined with exemestane in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). METHODS: This single-center, single-arm phase II study enrolled patients with ER+/HER2- MBC progressed on previous letrozole or anastrozole. Stratified analysis was performed according to the number of chemotherapy regimens for metastatic disease. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and toxicity. Patients received apatinib at a starting dose of 500 mg/d and exemestane 25 mg/d on days 1-28 of each 4-week cycle. RESULTS: Thirty patients were enrolled with median four prior anticancer therapies. Eighty percent of patients received chemotherapy for metastatic disease. The median PFS (mPFS) and OS were 5.6 (95%CI: 4.3-6.9) months and 15.7 (95% CI: 9.7-21.7) months, respectively. The ORR, DCR, and CBR were 21.4%, 71.4%, and 46.4%, respectively. Patients with 0-1 line chemotherapy for MBC showed a slightly longer mPFS compared to those with ≥2 lines chemotherapy (mPFS: 6.4 months vs 4.8 months, P = .090). Most of the AEs were grade 1/2. One patient (3.3%) who suffered bone marrow metastases experienced grade 4 thrombocytopenia, and 14 experienced grade 3 AEs. Fifty percent of patients were given reduced dose for apatinib. CONCLUSIONS: Apatinib plus exemestane exhibited objective efficacy in patients with ER+/HER2- MBC who have failed multiple lines of treatment. The AEs of apatinib required close monitoring and most of patients were well tolerated.

Suicidal ideation in advanced cancer patients without major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) is associated with an increased risk of suicide and suicide attempt among cancer patients. However, we do not know how many cancer patients without MDD have suicidal ideation (SI). OBJECTIVES: This study aimed to investigate the prevalence, characteristics and correlated factors of SI among advanced cancer patients without MDD. METHODS: This is a multi-center, cross-sectional study based on an electronic patient-reported outcome systems in patients who were diagnosed with advanced lung, liver, gastric, esophageal, colorectal or breast cancer, the top six prevalent cancers in China. A total of 2930 advanced cancer patients were recruited from 10 regional representative cancer centers across China from August 2019 to December 2020. Patients completed the Patient Health Questionnaire-9 regarding if they had thoughts of being better off dead or of hurting themselves in some way in the previous 2 weeks. Patients also completed the symptom inventory and quality of life assessment. Generalized estimating equation model was performed to explore the correlated factors associated with SI among the patients without MDD. RESULTS: The overall prevalence of SI among advanced cancer patients without MDD was 13.1%. The prevalence was higher in older patients. After adjusted for existing conditions, patients with vomiting symptom (p < 0.001), poorer life quality (p < 0.001), and middle education level (p = 0.031) were correlated factors of SI. CONCLUSIONS: The suicidal ideation is common in advanced cancer patients without MDD. Patients with vomiting, poor quality of life, and middle education level should be screened and monitored for suicidal ideation even without MDD. CLINICAL TRIAL INFORMATION: ChiCTR1900024957.

Perceived Importance of Breast Cancer Risk Factors: A Survey on 386 Physicians in China.

There are varying definitions of women at high risk of breast cancer across different institutions, and there are reports suggesting that the breast cancer risk assessment tools have not been well integrated into clinical practice. In this study, we tried to investigate the perceived importance of different breast cancer risk factors by physicians in China. A cross-sectional survey involving 386 anonymous physicians was conducted using a 20-item, 5-point Likert scale questionnaire. The Kruskal-Wallis test and post-hoc pairwise comparisons were used to compare the differences in response. Most of the respondents were either breast surgeons/specialists (n=161; 41.7%) or medical oncologists (n=151; 39.1%), and the results showed that the breast cancer risk factors were not perceived as equally important. The weighting of each risk factor also varied depending on the physician's medical specialty, location of practice, and the number of years of clinical experience.  This study provides a more updated insight into the perceptions of physicians in China toward the breast cancer risk factors, as well as underlines the potential improvements in breast cancer risk assessment strategies that can be done.

Efficacy and safety of continuous infusion of Rh-endostatin combined with platinum-based chemotherapy for advanced triple-negative breast cancer.

BACKGROUND: This study aimed to prospectively evaluate and investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with platinum-based regimens for advanced triple-negative breast cancer (TNBC) patients. METHODS: This study was a prospective, single-arm, single-center, open-label trial. From January 2017 to August 2019, 21 women aged 18-70 years with histologically confirmed advanced TNBC were enrolled. Rh-endostatin at 30 mg/d was continuously pumped for 7 days and used synchronously with the chemotherapy cycle. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and toxicity. RESULTS: The median PFS (mPFS) was 8.8 months (95% CI: 7.2-10.4 months), and the median OS was 13.3 months (95% CI: 11.6-15.0 months). The ORR and CBR for the whole population were 47.6% and 52.4%, respectively. Patients sensitive to anthracycline and taxane drugs showed a significantly longer mPFS compared to those who were resistant to anthracycline and taxane drugs (mPFS: 8.8 vs. 5.3 months, P=0.038). For patients who received first- and second-line therapy or beyond, the mPFS was 8.8 and 5.3 months, respectively, with a significant difference (P=0.025). No statistically significant differences in the mPFS between pemetrexed combined with platinum and gemcitabine/taxanes combined with platinum were observed. The most common grade 3-4 hematologic toxicities were neutropenia (14.3%) and anemia (14.3%). One patient (4.8%) experienced febrile neutropenia. No grade 3-4 non-hematologic toxicities were observed, and no treatment-related deaths were reported in this study. CONCLUSIONS: This study revealed that Rh-endostatin might enhance the antitumor effects of platinum-based chemotherapy for advanced TNBC patients with well-tolerated toxicities, which may provide a new basis and novel idea for the treatment of TNBC. However, further investigations and validation of its long-term efficacy and toxicity are warranted in the future.

A three-gene signature based on tumour microenvironment predicts overall survival of osteosarcoma in adolescents and young adults.

Evidences shows that immune and stroma related genes in the tumour microenvironment (TME) play a key regulator in the prognosis of Osteosarcomas (OSs). The purpose of this study was to develop a TME-related risk model for assessing the prognosis of OSs. 82 OSs cases aged ≤25 years from TARGET were divided into two groups according to the immune/stromal scores that were analyzed by the Estimate algorithm. The differentially expressed genes (DEGs) between the two groups were analyzed and 122 DEGs were revealed. Finally, three genes (COCH, MYOM2 and PDE1B) with the minimum AIC value were derived from 122 DEGs by multivariate cox analysis. The three-gene risk model (3-GRM) could distinguish patients with high risk from the training (TARGET) and validation (GSE21257) cohort. Furthermore, a nomogram model included 3-GRM score and clinical features were developed, with the AUC values in predicting 1, 3 and 5-year survival were 0.971, 0.853 and 0.818, respectively. In addition, in the high 3-GRM score group, the enrichment degrees of infiltrating immune cells were significantly lower and immune-related pathways were markedly suppressed. In summary, this model may be used as a marker to predict survival for OSs patients in adolescent and young adults.

Mesenchymal Stem Cell-Secreted Exosome Promotes Chemoresistance in Breast Cancer via Enhancing miR-21-5p-Mediated S100A6 Expression.

Emerging evidence has shown the role of mesenchymal stem cell-derived exosome (MSC-exo) in inducing resistance of cancer cells to chemotherapy. However, it remains unclear whether the change of MSC-exo in response to chemotherapy also contributes to chemoresistance. In this study, we investigated the effect of a standard-of-care chemotherapeutic agent, doxorubicin (Dox), on MSC-exo and its contribution to the development of Dox resistance in breast cancer cells (BCs). We found that the exosome secreted by Dox-treated MSCs (Dt-MSC-exo) induced a higher degree of Dox resistance in BCs when compared with non-treated MSC-exo. By analysis of the MSC-exo-induced transcriptome change in BCs, we identified S100A6, a chemoresistant gene, as a top-ranked gene induced by MSC-exo in BCs, which was further enhanced by Dt-MSC-exo. Furthermore, we found that Dox induced the expression of miR-21-5p in MSCs and MSC-exo, which was required for the expression of S100A6 in BCs. Importantly, silencing of miR-21-5p expression in MSCs and MSC-exo abolished the resistance of BCs to Dox, indicating an exosomal miR-21-5p-regulated S100A6 in chemoresistance. Our study thus uncovered a novel mechanistic insight into the role of MSC-secreted exosome in the development of chemoresistance in the tumor microenvironment.

Leptin promotes bone metastasis of breast cancer by activating the SDF-1/CXCR4 axis.

Obesity is associated with an increased risk of tumorigenesis, and increased leptin levels can promote tumor metastasis. However, the effects of leptin on bone metastasis in breast cancer are not fully understood. Here, we examined leptin receptor expression and bone metastasis in tissue samples from 96 breast cancer patients. In addition, we investigated the effects of leptin on the metastatic capacity of breast cancer cells invitro using a transwell assays. The results indicated that higher leptin receptor levels in breast cancer cells are associated with increased incidence of bone metastasis in breast cancer patients. Additionally, leptin promoted migration and invasion of breast cancer cells. The SDF-1/CXCR4 axis activated by leptin also promoted bone metastasis of breast cancer. Finally, increased CXCR4 expression was accompanied by high leptin receptor expression in bone metastatic tissues from breast cancer patients. These results indicate that leptin induces bone metastasis of breast cancer by activating the SDF-1/CXCR4 axis.

Aspirin alleviates hepatic fibrosis by suppressing hepatic stellate cells activation via the TLR4/NF-κB pathway.

Hepatic fibrosis arises from a sustained wound-healing response to chronic liver injury. Because the occurrence and development of hepatic fibrosis is always associated with chronic inflammation, controlling inflammation within the liver may be an effective means of controlling the development and progression of hepatic fibrosis. Aspirin is a non-steroidal anti-inflammatory drug used to relieve both inflammatory symptoms and pain. The results of our study showed that aspirin significantly attenuated hepatic inflammation and fibrosis. Aspirin effectively inhibited the activation and proliferation of hepatic stellate cells (HSCs), which led to downregulation of inflammatory factors, including IL-6 and TNF-α in those cells. Aspirin also downregulated expression of Toll-like receptor-4 (TLR4) on HSCs, as well as its downstream mediators, MyD88 and NF-κB. The results of our study demonstrate aspirin's potential to inhibit the development of hepatic fibrosis and the molecular mechanism by which it acts. They suggest aspirin may be an effective therapeutic agent for the treatment of hepatic fibrosis.

Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma.

Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies.Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR12 weeks).Results: A total of 166 patients were included in the final analysis. Overall, the PFR12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%-18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR12 weeks, median PFS and OS were: 58%, 4.1 and 11 months for UPS (n = 19); 63%, 5.6 and 13 months for LPS (n = 13); 75%, 11 and 15 months for LMS (n = 26); 75%, 7.7 and 12 months for SS (n = 47); 81%, 5.6 and 12 months for FS (n = 18); 77%, 21 and not reached for ASPS (n = 13); 54%, 11 and 16 months for CCS (n = 7); and 44%, 2.8 and 8.8 months for other sarcoma (n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred.Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233-8. ©2018 AACR.

Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression.

Ovarian cancer have a poor overall survival rate in patients, and late disease presentation and chemoresistance are the main factors that lead to the mortality of ovarian cancer. Cancer stem cells (CSCs), a small subpopulation of cancer cells, have been associated with resistance to chemo- and radio-therapy in cancer treatment. Hypoxia is a common characteristic of many malignant tumors, and increased HIF-1α expression predicts the poor prognosis of ovarian cancer. In this study, we reported the relationship between hypoxia and cancer stem cells-like properties in human ovarian cancer cell lines SKOV3 and HO8910, we found that hypoxia induced cancer stem cells-like properties in ovarian cancer cells. Moreover, SIRT1 was found to be the downstream target gene of HIF-1α, which was involved in the promotion of cancer stem cells-like features in ovarian cancer cells by hypoxia, and NF-κB signaling pathway was involved in hypoxia-induced SIRT1 up-regulation. Our results hinted that HIF1α and SIRT1 might serve as potential therapeutic targets for ovarian cancer.

Gene polymorphisms of TLR2 and TLR3 in HBV clearance and HBV-related hepatocellular carcinoma in a Chinese male population.

BACKGROUND: The Toll-like receptor plays an essential role in controlling immunity and inflammation. This study was to investigate the relationships of genetic variants in TLR2 and TLR3 with hepatitis B virus (HBV) natural clearance and HBV-related hepatocellular carcinoma (HCC) risk in a Chinese male population. METHODS: We analyzed 5 polymorphisms of TLR2 (rs3804099 and rs3804100) and TLR3 (rs5743305, rs3775296 and rs3775291) in a population consisting of 686 participants with HBV natural clearance, 293 chronic HBV carriers and 395 HBV-positive HCC patients, using the improved multiplex ligase detection reaction method. RESULTS: After adjustment for age and smoking and drinking status, no associations were observed either between the 5 single-nucleotide polymorphisms (SNPs) and the HBV natural clearance participants, or between the 5 SNPs and HCC patients. Whereas the stratified analysis showed that under the dominant models, nondrinkers with TLR2 rs3804100 and participants younger than 40 years old with TLR3 rs3775291 were significantly associated with HCC risk when compared with persistent HBV carriers (adjusted odd ratio [OR] = 0.49, 95% confidence interval [95% CI], 0.31-0.78, p = 0.003; and adjusted OR = 0.50, 95% CI, 0.29-0.86, p = 0.013, respectively). Furthermore, the TTTCT haplotype was found to promote the progress of HBV clearance and inhibit development of HBV-related HCC (OR = 0.77, 95% CI, 0.61-0.97, p = 0.029; and OR = 0.72, 95% CI, 0.55-0.94, p = 0.016, respectively). And the CCACC and CCTCT haplotypes were observed to decrease susceptibility to HCC (OR = 0.64, 95% CI, 0.40-1.00, p = 0.048; and OR = 0.43, 95% CI, 0.28-0.68, p<0.001, respectively). CONCLUSIONS: This study revealed that TLR2 rs3804100 and TLR3 rs3775291 polymorphisms may be protective factors for HBV-related HCC.

Mesenchymal stem cells with Sirt1 overexpression suppress breast tumor growth via chemokine-dependent natural killer cells recruitment.

Mesenchymal stem cells (MSCs) are generally used in regenerative medicine, tissue engineering and therapy for immune disorder diseases. However, due to the immunosuppressive function of MSCs, the application of MSCs in breast cancer therapy remains limited. Sirt1 is the closest mammalian homologue of the yeast enzyme Sir2 which has an established capacity to influence yeast replicative lifespan. In this study, we demonstrated the effect of MSCs with Sirt1 overexpression (MSCs-Sirt1) in mice bearing 4T1 breast cancer and investigated the underlying mechanism. Firstly, we found that MSCs could accelerate breast tumor growth with promoted proliferation and inhibited apoptosis, whereas MSCs-Sirt1 significantly suppressed tumor growth with proliferation inhibition and apoptosis promotion. Moreover, we detected that NK cells were the prominent antitumor effectors for the MSCs-Sirt1-induced antitumor activity. Besides that, CXCL10 and IFN-γ showed the high level expression in MSCs-Sirt1 treatment group. The impulsive effect of MSCs-Sirt1 on 4T1 cells in vivo could be reversed by inhibition of CXCL10 and IFN-γ. Overall, our results suggest that MSCs-Sirt1 can effectively inhibit breast tumor growth via the recruitment of NK cells in tumor inflammatory microenvironment.

Inhibition of autophagy enhances the radiosensitivity of nasopharyngeal carcinoma by reducing Rad51 expression.

Radiotherapy has long been considered as the mainstay of treatment for nasopharyngeal carcinoma (NPC). However, locoregional recurrence or distant metastasis may occur in some patients due to the radiation resistance of cancer cells. Autophagy plays a vital role in protecting cells against radiation. However, the mechanism of autophagy in radiation therapy remains obscure. In the present study, we demonstrated that suppression of autophagy related 5 (Atg5) aggravated ionizing radiation (IR)-induced DNA damage and apoptosis in human NPC cells without accelerating the cell cycle, whereas regulation of the cell cycle has been widely regarded as the most important determinant of IR sensitivity. Further study showed that inhibition of autophagy suppressed the mRNA expression of Rad51, a key protein of homologous recombination that has been demonstrated to play a critical role in the repair of DNA double-strand breaks induced by radiation. Moreover, suppression of Atg5 had no impact on the radiosensitivity when cells were pre-treated by the Rad51 inhibitor, and the enhanced radiosensitivity by Atg5 suppression was reversed by overexpression of Rad51 in human NPC cells. Our results suggest that inhibition of autophagy enhances the susceptibility of NPC cells to radiation by reducing Rad51 expression. Therefore, Rad51 targeted therapy may be investigated as a potential novel agent for the adjuvant treatment of traditional radiation of NPC.

Human epidermal growth factor receptor 2 expression in breast cancer: correlation with clinical pathological features.

The overexpressed HER2 (human epidermal growth factor receptor 2) is a valuable therapeutic target. Precise assessment of HER2 status is thus crucial in the treatment of breast cancer. In this study, formalin-fixed, paraffin-embedded samples of tumors from 304 breast cancer patients who underwent curative surgery procedures between 2011 and 2014 were tested by immunohistochemistry (IHC) as a primary estimate of HER2 status, followed by fluorescence in situ hybridization (FISH). Concordance rate between IHC and FISH was evaluated. The Χ(2) test was used to evaluate the correlation between HER2 gene amplification status and different clinical pathological features including: (estrogen receptor) ER and (progesterone receptor) PR expression, age, menopausal status and tumor size. The results show that 84.8% of IHC score 3+ cases and 6.2% of IHC score 0/1+ cases were amplified by FISH. After exclusion of group IHC 2+, the concordance rate between FISH and IHC was 87.4%. There was a significant inverse association between expression of hormone receptors (ER and PR) and HER2 amplification (P < 0.001) among the patients studied. However, no relationship was observed between HER2 amplification and age, menopausal status and tumor size (P > 0.05). The data demonstrate a relatively high level of concordance rate for HER2 testing between FISH and IHC, and HER2 overexpression was associated with the levels of ER and PR.