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

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

Pyrotinib plus capecitabine for trastuzumab-resistant, HER2-positive advanced breast cancer (PICTURE): a single-arm, multicenter phase 2 trial.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer and primary resistance to trastuzumab have a poor clinical outcome and lack good evidence to inform clinical decision. This study investigated the efficacy and safety of pyrotinib plus capecitabine in this population. METHODS: This phase 2 trial was conducted at 16 sites in China. Patients received oral pyrotinib 400 mg once daily and capecitabine 1000 mg/m2 twice a day on days 1-14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: Between June 2019 and September 2021, 100 patients were enrolled with a median age of 51 years (range, 24-69). All patients had been treated with trastuzumab and 21 (21.0%) patients had prior use of pertuzumab. As of August 31, 2022, the median follow-up duration was 20.1 months (range, 1.3-38.2). The median PFS was 11.8 months (95% confidence interval [CI], 8.4-15.1), which crossed the pre-specified efficacy boundary of 8.0 months. The objective response rate was 70.0% (70/100), with a median duration of response of 13.8 months (95% CI, 10.2-19.3). The disease control rate was 87.0% (87/100). The median overall survival was not reached. The most common grade ≥ 3 treatment-emergent adverse event was diarrhea (24 [24.0%]). No treatment-related deaths occurred. CONCLUSIONS: Pyrotinib plus capecitabine can be considered to be a treatment option in HER2-positive advanced breast cancer patients who have shown primary resistance to trastuzumab. Even in the era of modern anti-HER2 treatments, this clinical setting warrants more investigations to meet unmet needs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04001621. Retrospectively registered on June 28, 2019.

Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment. FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Layered Clay Minerals in Cancer Therapy: Recent Progress and Prospects.

Cancer is one of the deadliest diseases, and current treatment regimens suffer from limited efficacy, nonspecific toxicity, and chemoresistance. With the advantages of good biocompatibility, large specific surface area, excellent cation exchange capacity, and easy availability, clay minerals have been receiving ever-increasing interests in cancer treatment. They can act as carriers to reduce the toxic side effects of chemotherapeutic drugs, and some of their own properties can kill cancer cells, etc. Compared with other morphologies clays, layered clay minerals (LCM) have attracted more and more attention due to adjustable interlayer spacing, easier ion exchange, and stronger adsorption capacity. In this review, the structure, classification, physicochemical properties, and functionalization methods of LCM are summarized. The state-of-the-art progress of LCM in antitumor therapy is systematically described, with emphasis on the application of montmorillonite, kaolinite, and vermiculite. Furthermore, the property-function relationships of LCM are comprehensively illustrated to reveal the design principles of clay-based antitumor systems. Finally, foreseeable challenges and outlook in this field are discussed.

Survival outcomes for breast conserving surgery versus mastectomy among elderly women with breast cancer.

PURPOSE: Elderly patients have different physical condition and tumor biology of breast cancer. Surgical choices for older patients are complicated and several studies have reported that breast conserving surgery (BCS) had better survival than mastectomy in different patient population. The major objective of this study was to compare the efficacy of BCS and mastectomy in the whole elderly cohort in SEER database. METHODS: Female patients aged over 70 years old and diagnosed with breast cancer between 2010 and 2015 were included from SEER database. Propensity score matching (PSM) was used to establish a cohort composing of similar characteristics. We compared the overall survival (OS) among patients undergoing BCS and mastectomy. Kaplan-Meier analysis and Cox proportional regression model were used to evaluate the associated factors of survival outcome. RESULTS: Of 44,755 eligible patients, 30,375 (67.9%) patients underwent BCS and 14,380 (32.1%) patients underwent mastectomy. After PSM, 7222 patients in each group were analyzed and there was no significant difference between BCS and mastectomy in terms of the OS rate (85.8% in BCS group and 85.0% in mastectomy group, p = 0.135). Multivariable analysis also indicated that no significant difference between two surgical procedures after adjusting for covariates in matched cohort (HR 1.062, 95% CI 0.997-1.132, p = 0.063). Subgroup analysis demonstrated that postoperative radiotherapy and chemotherapy contributed to the survival benefit of BCS compared to mastectomy (p < 0.05). CONCLUSION: For elderly breast cancer patients, BCS and mastectomy appeared to be comparable in terms of OS after being matched by clinicopathologic features. While our findings suggested that there was statistically survival benefit of BCS in some subsets of patients, including radiotherapy, chemotherapy, and 80-84 year-old subgroups, these results were likely to be related to selection bias and should be interpreted with caution. Thus, for this elderly patient population, BCS should be considered as an equivalent and less aggressive alternative to mastectomy.

HOXD9 aggravates the development of cervical cancer by transcriptionally activating HMCN1.

BACKGROUND: To detect HOXD9 levels in cervical cancer species and to explore the relationship between HOXD9 level and prognosis in cervical cancer patients. We also verify the influence of HOXD9 on metastatic abilities in cervical cancer. METHODS: HOXD9 levels in cervical cancer species were detected. Its influence on clinical features and prognosis in cervical cancer patients was analyzed. Regulatory effects of HOXD9 on migratory and invasive capacities in C33-A and HeLa cells were evaluated by Transwell assay. Subsequently, the downstream gene of HOXD9 was predicted by bioinformatics analysis and confirmed by luciferase assay. The involvement of HMCN1 in regulating metastatic ability in cervical cancer cells was finally explored by rescue experiments. RESULTS: HOXD9 was upregulated in cervical cancer species and its level was positively correlated to rates of lymphatic metastasis and distant metastasis. High level of HOXD9 in cervical cancer patients predicted a poor prognosis. Overexpression of HOXD9 promoted migratory and invasive capacities in cervical cancer cells. HMCN1 was identified to be the downstream gene binding HOXD9. It was responsible for HOXD9-regulated metastasis in cervical cancer. CONCLUSIONS: HOXD9 is upregulated in cervical cancer species. Its level is closely linked to metastasis rate and poor prognosis in cervical cancer patients. Through positively regulating HMCN1 level, HOXD9 stimulates migratory and invasive capacities in cervical cancer cells.

Oncolytic adenoviruses synergistically enhance anti-PD-L1 and anti-CTLA-4 immunotherapy by modulating the tumour microenvironment in a 4T1 orthotopic mouse model.

Effective therapeutic strategies for triple-negative breast cancer (TNBC) are still lacking. Clinical data suggest that a large number of TNBC patients cannot benefit from single immune checkpoint inhibitor (ICI) treatment due to the immunosuppressive tumour microenvironment (TME). Therefore, combination immunotherapy is an alternative approach to overcome this limitation. In this article, we combined two kinds of oncolytic adenoviruses with ICIs to treat TNBC in an orthotopic mouse model. Histopathological analysis and immunohistochemistry as well as multiplex immunofluorescence were used to analyse the TME. The immunophenotype of the peripheral blood and spleen was detected by using flow cytometry. Oncolytic adenovirus-mediated immune activity in a coculture system of lytic supernatant and splenocytes supported the study of the mechanism of combination therapy in vitro. Our results showed that the combination of oncolytic adenoviruses with anti-programmed cell death-ligand 1 (anti-PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (anti-CTLA-4) (aPC) can significantly inhibit tumour growth and prolong survival in a TNBC model. The combination therapy synergistically enhanced the antitumour effect by recruiting CD8+ T and T memory cells, reducing the number of regulatory T cells and tumour-associated macrophages, and promoting the polarization of macrophages from the M2 to the M1 phenotype to regulate the TME. The rAd.GM regimen performed better than the rAd.Null treatment. Furthermore, aPC efficiently blocked oncolytic virus-induced upregulation of PD-L1 and CTLA-4. These findings indicate that oncolytic adenoviruses can reprogramme the immunosuppressive TME, while ICIs can prevent immune escape after oncolytic virus therapy by reducing the expression of immune checkpoint molecules. Our results provide a mutually reinforcing strategy for clinical combination immunotherapy.

Prognostic value of long non-coding RNA MALAT1 in hepatocellular carcinoma: A study based on multi-omics analysis and RT-PCR validation.

Background: This study aimed to explore the relationship between MALAT1 and the prognosis of patients with hepatocellular carcinoma (HCC). Methods: We constructed a MALAT1 protein-protein interaction network using the STRING database and a network of competing endogenous RNAs (ceRNAs) using the StarBase database. Using data from the GEPIA2 database, we studied the association between genes in these networks and survival of patients with HCC. The potential mechanisms underlying the relationship between MALAT1 and HCC prognosis were studied using combined data from RNA sequencing, DNA methylation, and somatic mutation data from The Cancer Genome Atlas (TCGA) liver cancer cohort. Tumor tissues and 19 paired adjacent non-tumor tissues (PANTs) from HCC patients who underwent radical resection were analyzed for MALAT1 mRNA levels using real-time PCR, and associations of MALAT1 expression with clinicopathological features or prognosis of patients were analyzed using log-rank test and Gehan-Breslow-Wilcoxon test. Results: Five interacting proteins and five target genes of MALAT1 in the ceRNA network significantly correlated with poor survival of patients with HCC (p < 0.05). High MALAT1 expression was associated with mutations in two genes leading to poor prognosis and may upregulate some prognostic risk genes through methylation. MALAT1 was significantly co-expressed with various signatures of genes involved in HCC progression, including the cell cycle, DNA damage repair, mismatch repair, homologous recombination, molecular cancer m6A, exosome, ferroptosis, infiltration of lymphocyte (p < 0.05). The expression of MALAT1 was markedly upregulated in HCC tissues compared with PANTs. In Kaplan-Meier analysis, patients with high MALAT1 expression had significantly shorter progression-free survival (PFS) (p = 0.033) and overall survival (OS) (p = 0.023) than those with low MALAT1 expression. Median PFS was 19.2 months for patients with high MALAT1 expression and 52.8 months for patients with low expression, while the corresponding median OS was 40.5 and 78.3 months. In subgroup analysis of patients with vascular invasion, cirrhosis, and HBsAg positive or AFP positive, MALAT1 overexpression was significantly associated with shorter PFS and OS. Models for predicting PFS and OS constructed based on MALAT1 expression and clinicopathological features had moderate predictive power, with areas under the receiver operating characteristic curves of 0.661-0.731. Additionally, MALAT1 expression level was significantly associated with liver cirrhosis, vascular invasion, and tumor capsular infiltration (p < 0.05 for all). Conclusion: MALAT1 is overexpressed in HCC, and higher expression is associated with worse prognosis. MALAT1 mRNA level may serve as a prognostic marker for patients with HCC after hepatectomy.

Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial.

Blockade of the cyclin-dependent kinase 4 and 6 pathway has been shown to be effective in the treatment of hormone receptor-positive advanced breast cancer (ABC). We report the interim results of DAWNA-1 ( NCT03927456 ), a double-blind, randomized, phase 3 trial of dalpiciclib (a new cyclin-dependent kinase 4 and 6 inhibitor) plus fulvestrant in hormone receptor-positive, HER2-negative ABC with disease progression after endocrine therapy. A total of 361 patients were randomized 2:1 to receive dalpiciclib plus fulvestrant or placebo plus fulvestrant. The study met the primary end point, showing significantly prolonged investigator-assessed progression-free survival with dalpiciclib plus fulvestrant versus placebo plus fulvestrant (median = 15.7, 95% confidence interval (CI) = 11.1-not reached versus 7.2, 95% CI = 5.6-9.2 months; hazard ratio = 0.42, 95% CI = 0.31-0.58; one-sided P < 0.0001 (boundary was P ≤ 0.008)). The most common grade 3 or 4 adverse events with dalpiciclib plus fulvestrant were neutropenia (84.2%) and leukopenia (62.1%). The incidence of serious adverse events was 5.8% with dalpiciclib plus fulvestrant versus 6.7% with placebo plus fulvestrant. Our findings support dalpiciclib plus fulvestrant as a new treatment option for pretreated hormone receptor-positive, HER2-negative ABC.

Potentiality of α-fetoprotein (AFP) and soluble intercellular adhesion molecule-1 (sICAM-1) in prognosis prediction and immunotherapy response for patients with hepatocellular carcinoma.

ABSTRCTThe α-fetoprotein (AFP) and soluble intercellular adhesion molecule-1 (sICAM-1) have certain diagnostic value, but their potential value in prognosis prediction, especially immunotherapy response prediction, remains unclear in liver cancer. Through the tumor-free survival (TFS) and overall survival (OS) rates analyses of serum AFP and sICAM-1 levels in 87 patients with primary hepatocellular carcinoma (HCC), the patients whose AFP and sICAM-1 levels were normal (AFP < 20 µg/L or sICAM-1 < 1000 µg/L) before surgery or recovered to normal after surgery exhibited a lower tumor recurrence rate and better OS than patients with elevated serum levels of the two markers. Combined analysis showed that patients with synchronously elevated levels of AFP and sICAM-1 showed the lowest TFS and OS. In addition, the RNA-seq data and clinical information of The Cancer Genome Atlas Liver Hepatocellular Carcinoma were collected to analyze the predictive values of AFP and ICAM-1 in the diagnosis, prognosis and immunotherapy of HCC. The results indicated that the combined application of the two indicators had higher accuracy in both the diagnosis and prognostic prediction of HCC by receiver operating characteristic curves. AFP and ICAM-1 were significantly correlated with multiple immune cells in HCC samples but not in normal samples. The patients with low expression of the two indicators were most likely to benefit from the immune checkpoint blockade therapy. In conclusion, AFP and ICAM-1 play vital roles in the diagnosis, prognostic prediction, and immunotherapy of HCC, suggesting that they are considered as prognostic predictors in clinical practice.

Hypomethylation-driven overexpression of HJURP promotes progression of hepatocellular carcinoma and is associated with poor prognosis.

Our previous studies have initially identified HJURP, which encodes a Holliday junction recognizing protein, as a hepatocellular carcinoma (HCC) susceptibility gene. In this report, we showed that the HJURP is highly expressed in HCC tissues compared to adjacent normal tissues. Overexpression of HJURP in HCC tissues is mainly due to the hypomethylation of HJURP promoter region. Clinically, high expression of HJURP is significantly associated with poor overall survival and disease-free survival of patients with HCC, as well as in multiple other types of cancer. Gain- and loss-of functional studies demonstrated that HJURP promotes HCC cell proliferation, clone formation, migration and invasion. Additionally, HJURP enhances HCC tumorigenesis via reducing G0/G1 arrest and apoptosis. Mechanistically, by gene set enrichment analysis (GSEA) analysis, HJURP was identified as a modulator involved in CENPA-mediated centromere maintenance. Our results provide evidence of HJURP as an important oncogene that promotes HCC progression, and the HJURP pathway may be a potential target for the treatment of HCC.

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.

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.

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.

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.

Medium- and long-term effects of endovascular treatments for severely stenotic basilar arteries supported by multimodal imaging.

BACKGROUND: To evaluate the medium-and long-term effect of intravascular interventional therapy for symptomatic severe basilar artery stenosis supported by multimodal imaging. METHOD: After strict screening of 67 patients with symptomatic severe basilar artery stenosis (70-99%) with atherosclerotic stenosis, 67 patients with symptomatic recurrence after intensive drug treatment were treated with intravascular balloon dilatation and Enterprise stent implantation. Any stroke or death within 30 days after operation and any stroke and restenosis during medium-and long-term follow-up were recorded. RESULTS: ①The mean age of 67 patients (67lesions) was 57 ± 8 years old, and the technical success rate was 100%; ②Preoperative angiography showed that the collateral circulation was poor, and TICI was 1-2a while postoperative angiography showed that TICI was significantly improved to 2b-3; ③The average preoperative stenosis rate was 82 ± 9%, and the postoperative stenosis rate was reduced to 17 ± 10%; ④Before surgery, abnormal perfusion was found in the posterior circulation CTP; After the postoperative re-examination, the posterior circulation of CTP perfusion was significantly improved; ⑤Postoperative symptoms and neurological conditions improved significantly; ⑥Complications of perforating branch event occurred in 1 case after operation, and symptoms were relieved after more than 1 month of medication treatment, and mild neurological dysfunction remained. 1 case developed subacute thrombosis in the stent, which improved after active intra-arterial thrombolysis, and there was no residual neurological dysfunction; and 1 case of micro-guide wire being trapped by the distal vasospasm. ⑦67 patients were followed up by telephone, WeChat or imaging for 36-66 months. CONCLUSIONS: In summary intravascular balloon dilation + Enterprise stent implantation is safe and effective for the treatment of symptomatic severe atherosclerotic stenosis of the basilar artery, with high technical success rate, low perioperative complications, and good mid-term and long-term effects.

Expression and Clinical Significance of ERCC1 and XPF in Human Hepatocellular Carcinoma.

OBJECTIVE: To investigate the correlation between the ERCC1 and XPF expression and the clinicopathological parameters of hepatocellular carcinoma (HCC) patients through assessment of the expression of the DNA repair genes ERCC1 and XPF. METHODS: ERCC1 and XPF mRNA expression in HCC (n= 177) and adjacent para-cancer tissues (n=21) were assessed by RT-PCR. The correlation between ERCC1 and XPF expression, clinicopathological features and HCC prognosis were compared. RESULTS: ERCC1 expression in liver cancer tissues was significantly lower than that of adjacent tissues (9.5% (2/21) vs 38.1% (8/21); P<0.05). The positive expression rates of XPF in liver cancer tissues was lower than that of adjacent tissues (14.3% (3/21) vs 71.4% (15/21); P<0.05). ERCC1 and XPF expression were associated with hepatic capsular invasion and microvascular invasion. HCC patients with hepatic capsular invasion and microvascular tumor embolus formation had significantly lower levels of ERCC1 and XPF mRNA than those without hepatic capsular invasion and microvascular tumor embolus formation (P<0.05). In addition, ERCC1 expression was associated with TNM staging of HCC. The expression of ERCC1 mRNA in patients with stage II and III HCC were lower than that of patients with stage I HCC (P<0.05). The low levels of ERCC1 and XPF mRNA significantly correlated with relapse-free survival times (RFS) in HCC patients. The median RFS of the low ERCC1 expression group and low XPF expression group were shorter than those of the high expression group (15.0 months vs 32.0 months, P<0.05) and (19.0 months vs 33.0 months, P<0.05). The decrease in XPF mRNA expression was significantly associated with the overall survival (OS) of HCC patients. The median OS in the low XPF expression group was shorter than that of the high expression group (46.0 months vs 78.0 months, P<0.05). However, no significant difference in OS between the low ERCC1 expression group and the high ERCC1 expression groups were observed (63.0 months vs 64.0 months, P>0.05). Multivariate analysis showed that tumor size and the extent of differentiation were independent factors affecting the RFS in HCC patients (P<0.05). The extent of differentiation and XPF were independent factors affecting the OS in HCC (P<0.05). CONCLUSION: The expression in ERCC1 and XPF were low in HCC and associated with early relapse after HCC surgery. Low XPF expression may be a potential indicator of a high risk of death.

First-line chemotherapy regimens for locally advanced and metastatic pancreatic adenocarcinoma: a Bayesian analysis.

BACKGROUND: Systemic chemotherapy is the standard treatment for locally advanced and metastatic pancreatic cancer, but there is no consensus on the optimum regimen. We aimed to compare and rank the locally advanced and metastatic pancreatic adenocarcinoma chemotherapy regimens evaluated in randomized controlled trials (RCTs) in the past 15 years. MATERIALS AND METHODS: PubMed, Embase, Cochrane Collaboration database, and ClinicalTrials.gov were searched for RCTs comparing chemotherapy regimens as first-line treatment for locally advanced and metastatic pancreatic adenocarcinomas. By using Bayesian network meta-analysis, we compared and ranked all included chemotherapy regimens in terms of overall survival, progression-free survival, response rate, and hematological toxicity. RESULTS: The analysis included 68 RCTs, with 14,908 patients and 63 treatment strategies. For overall survival, NSC-631570 (hazard ratio [HR] vs gemcitabine monotherapy 0.44, 95% credible interval: 0.24-0.76) and gemcitabine+NSC-631570 (HR 0.45, 0.24-0.86) were the two top-ranked chemotherapy regimens. For progression-free survival, PEFG (cisplatin + epirubicin + fluorouracil + gemcitabine) ranked first (HR 0.51, 0.34-0.77). PG (gemcitabine + pemetrexed) (odds ratio [OR] 4.68, 2.24-9.64) and FLEC (fluorouracil + leucovorin + epirubicin + carboplatin) (OR 4.52, 1.14-24.00) were ranked the most hematologically toxic, with gastrazole having the least toxicity (OR 0.03, 0.00-0.46). CONCLUSION: The chemotherapy regimens NSC-631570 and gemcitabine+NSC-631570 were ranked the most efficacious for locally advanced and metastatic pancreatic adenocarcinomas in terms of overall survival, which warrants further confirmation in large-scale RCTs.

Germline Duplication of SNORA18L5 Increases Risk for HBV-related Hepatocellular Carcinoma by Altering Localization of Ribosomal Proteins and Decreasing Levels of p53.

BACKGROUND & AIMS: Single nucleotide polymorphisms could affect risk for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We performed a germline copy number variation (CNV)-based genome-wide association study (GWAS) in populations of Chinese ancestry to search for germline CNVs that increase risk of HCC. METHODS: We conducted a CNV-based GWAS of 1583 HCC cases (persons with chronic HBV infection and HCC) and 1540 controls (persons with chronic HBV infection without HCC) in Chinese populations. Identified candidates were expressed in L-02, HepG2, or TP53-/- or wild-type HCT116 cells, and knocked down with short hairpin RNAs in HepG2, Bel-7402, and SMMC-7721 cells; proliferation, colony formation, and apoptosis were measured. Formation of xenograft tumors from cell lines was monitored in nude mice. Subcellular localization of ribosome proteins and levels or activity of p53 were investigated by co-immunoprecipitation, immunofluorescence, and immunoblot analyses. Levels of small nucleolar RNA H/ACA box 18-like 5 (SNORA18L5) were quantified by quantitative reverse transcription polymerase chain reaction. RESULTS: We identified a low-frequency duplication at chromosome 15q13.3 strongly associated with risk of HBV-related HCC (overall P = 3.17 × 10-8; odds ratio, 12.02). Copy numbers of the 15q13.3 duplication correlated with the expression of SNORA18L5 in liver tissues. Overexpression of SNORA18L5 increased HCC cell proliferation and growth of xenograft tumors in mice; knockdown reduced HCC proliferation and tumor growth. SNORA18L5 overexpression in HepG2 and SMMC-7721 cells inhibited p53-dependent cell cycle arrest and apoptosis. Overexpression of SNORA18L5 led to hyperactive ribosome biogenesis, increasing levels of mature 18S and 28S ribosomal RNAs and causing the ribosomal proteins RPL5 and RPL11 to stay in the nucleolus, which kept them from binding to MDM2. This resulted in increased MDM2-mediated ubiquitination and degradation of p53. Levels of SNORA18L5 were increased in HCC tissues compared with nontumor liver tissues and associated with shorter survival times of patients. CONCLUSIONS: In a CNV-based GWAS, we associated duplication at 15q13.3 with increased risk of HBV-related HCC. We found SNORA18L5 at this location to promote HCC cell proliferation and tumor growth in mice. SNORA18L5 increases ribosome biogenesis, facilitates ribosomal RNA maturation, and alters localization of RPL5 and RPL11, allowing for increased MDM2-mediated proteolysis of p53 and cell cycle arrest.

Smoking and risk of cholangiocarcinoma: a systematic review and meta-analysis.

Previous studies evaluating the association between smoking and risk of cholangiocarcinoma (CCA) have yielded controversial results. We conducted a meta-analysis to evaluate the association based on available evidence. We searched the databases of Embase, PubMed and Cochrane Central Register of Controlled Trials from inception to April 11, 2017. Studies that investigated the association between smoking and risk of CCA were included. Pooled odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated using either a random-effects or a fixed-effects model. A total of 22 studies involving 324,333 participants were identified. The summary OR of CCA was 1.31 (95% CI, 1.15 to 1.51) for smokers versus nonsmokers. The increased risk was independent of diabetes mellitus, bilious tract stone disease, and liver cirrhosis. Smokers also had increased risk of intrahepatic CCA (12 studies; OR, 1.31; 95% CI, 1.06 to 1.63) and extrahepatic CCA (12 studies; OR, 1.32; 95% CI, 1.10 to 1.59) compared with nonsmokers. The results of our meta-analysis support the hypothesis that there is a moderate association between cigarette smoking and risk of CCA.