Impact of Platelets to Lymphocytes Ratio and Lymphocytes during Radical Concurrent Radiotherapy and Chemotherapy on Patients with Nonmetastatic Esophageal Squamous Cell Carcinoma.

Purpose: This study examined the importance of hematological parameters as prognostic markers for people with esophageal cancer receiving radical concurrent chemoradiation. Methods: 106 patients with esophageal cancer are included in this study. Cox regression analysis, Kaplan-Meier method, and chi-square test were used to analyze our data. Results: The median follow-up time for patients was 15.5 months (3-55). Univariate and multivariate analyses showed that age, the change of platelet-to-lymphocyte ratio (ΔPLR), and the change rate of circulating lymphocyte count (ΔCLC%) were independent influencing factors of OS and DFS. The patients were grouped according to the median of ΔPLR and ΔCLC%, and analysis showed that a higher ΔPLR and a higher ΔCLC% was related to poor OS and DFS (P < 0.001, P < 0.001 and P < 0.001, P < 0.001). By subgroup analysis, the OS of T1-4N1-2 were better in the low ΔPLR group than the high one (P = 0.03, P < 0.001, P = 0.001, P < 0.001, and P = 0.008). DFS of T3-4N1-2 in the low ΔPLR group were better than the high one (P < 0.001, P = 0.016 and P < 0.001, P = 0.022). For patients with T1-4N0-2, the OS in the low ΔCLC% group were better than in the high ΔCLC% group (P = 0.01, P < 0.001, P < 0.002, P = 0.012, P < 0.001, and P = 0.024). For T1-4N1-2, the DFS were better in the low ΔCLC% group than others (P = 0.042, P < 0.001, P < 0.001, P < 0.001, and P = 0.006). Conclusion: ΔPLR and ΔCLC% are independent factors of OS and DFS, and a lower ΔPLR and ΔCLC% are associated with a better OS and DFS. And T3-4N1-2 patients in the low ΔPLR group and low ΔCLC% group have greater survival benefit.

miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A.

MicroRNAs (miRNAs) are considered important in the pathogenesis of colon cancer. But the mechanism of their role in colon cancer is still largely unknown. Here, we aimed to explore the function of miR-503-5p in the pathogenesis of colon cancer. This study analyzed miRNA microarray of colon cancer. Then, we performed EdU, CCK-8, flow cytometry, Transwell invasion assays and in vivo assays to explore the exact role of miR-503-5p in colon cancer. We observed considerable downregulation of miR-503-5p expression in colon cancer cells and tissues and significant correlation with the TNM stage, differentiation grade and lymph node metastasis of colon cancer. Overexpression of miR-503-5p promoted the apoptosis and G1 arrest of colon cancer cells, and inhibited migration, proliferation, invasion and colony formation. Interestingly, ectopic miR-503-5p overexpression could significantly inhibit vascular endothelial growth factor (VEGF)-A expression and reduce the activity of a luciferase reporter containing the VEGF-A 3'-untranslated region. Furthermore, overexpressed miR-503-5p in human umbilical vein endothelial cells (HUVECs) and colon cancer cells resulted in lower expression levels of VEGFR-2, and subsequently inhibited AKT signaling pathway. Additionally, overexpression of miR-503-5p suppressed both lymphangiogenesis and angiogenesis in vivo and significantly inhibited the tumorigenicity of HT-29 cells in nude mice. In summary, our study shows downregulation of miR-503-5p at least partially contributes to the tumorigenesis of colon cancer through modulating the angiogenesis and lymphangiogenesis by targeting VEGF-A while stimulating AKT signaling pathways. Therapeutic strategies to restore miR-503-5p in colon cancer could be useful to inhibit tumor progression.

Chinese breast cancer patients with CYP2D6*10 mutant genotypes have a better prognosis with toremifene than with tamoxifen.

PURPOSE: To evaluate the prognosis of estrogen receptor-positive breast cancer patients with CYP2D6*10 mutant genotypes under tamoxifen or toremifen therapy. METHODS: Estrogen receptor-positive breast cancer patients were selected and CYP2D6*10 genotypes (C/C, C/T, and T/T) were determined by Sanger sequencing. Patients were divided into tamoxifen, toremifene, or tamoxifen + toremifene groups according to prior therapy. The correlation between CYP2D6*10 genotype and disease-free survival was analyzed. RESULTS: In total, 293 estrogen receptor-positive breast cancer patients treated with tamoxifen or toremifene between 2008 and 2017 were studied. Median follow-up was 39 months (10-141). Of these, 107 (36.52%), 112 (38.23%), and 74 (25.26%) patients had C/C, C/T, and T/T genotypes, respectively. Genotype was significantly associated with disease-free survival in tamoxifen patients. Patients with C/T and T/T genotypes showed worse disease-free survival than patients with a C/C genotype. Genotype and disease-free survival in toremifene and tamoxifen+toremifene patients were not correlated. Of patients with a C/T genotype, toremifene or tamoxifen+toremifene groups showed better disease-free survival than tamoxifen patients. Although disease-free survival of patients with a T/T genotype in the three groups was not statistically different, tamoxifen patients showed worse disease-free survival. There was no correlation between different treatments and disease-free survival in patients with a C/C genotype. Cox proportional hazard analysis revealed toremifene patients had a better prognosis than tamoxifen patients; toremifene was an independent protective factoremifene for disease-free survival. CONCLUSIONS: Tamoxifen was less effective in patients with CYP2D6*10 C/T and T/T genotypes. Estrogen receptor-positive breast cancer patients with a CYP2D6*10 mutation genotype have a better prognosis with toremifen than tamoxifen.

Sleep-disordered breathing and risk of the breast cancer: A meta-analysis of cohort studies.

BACKGROUND: Sleep-disordered breathing (SDB) has been related to a higher risk of breast cancer whereas the results of previous studies are inconsistent. We, therefore, performed a meta-analysis to evaluate the association between SDB and subsequent risk of breast cancer in women. METHODS: Cohort studies that investigated the temporal relationship between SDB and breast cancer incidence were obtained via search of PubMed, Embase and Web of Science from inception to 30 January 2021. Only studies with multivariate analyses were included. A fixed or a randomised effect model was applied according to the heterogeneity. RESULTS: Eight cohort studies with 1 398 113 women were included. Pooled results with a randomised-effect model showed that compared with women without SDB at baseline, women with SDB had a significantly increased risk of breast cancer (risk ratio [RR]: 1.36, 95% confidence interval [CI]: 1.08 to 1.71, P = .01) with significant heterogeneity (P for Cochrane's Q test < .001, I2  = 95%). Subgroup analyses showed that SDB seemed to confer a more remarkably increased risk of breast cancer in elderly women (RR: 3.00, 95% CI: 1.33 to 6.76, P = .008) than that in non-elderly women (RR: 1.15, 95% CI: 1.02 to 1.29, P = .02; P for subgroup difference = .04). However, the association was not significantly affected by country of the study, study design, diagnostic strategy for SDB or adjustment of obesity (P for subgroup analyses all > .05). CONCLUSIONS: SDB may be an independent risk factor for breast cancer in women, particularly in elderly females.

Impact of Postmastectomy Radiotherapy on Locoregional Control and Disease-Free Survival in Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy.

BACKGROUND: The impact of postmastectomy radiotherapy (PMRT) in patients receiving neoadjuvant chemotherapy (NAC) is unclear. The purpose of this study is to identify the patients who may benefit from PMRT. METHODS: We retrospectively analysed patients with clinical stage II-III breast cancer who underwent NAC and modified radical mastectomy at our centre from 2007 to 2015. We investigated the relationship amongst locoregional recurrence rate (LRR), disease-free survival (DFS), and clinical pathological characters. RESULTS: A total of 554 patients were analysed in this study. The median follow-up time was 65 months. Amongst the patients, 58 (10.5%) had locoregional recurrence, 138 (24.9%) had distant metastasis, and 72 (13.0%) patients died. The 5-year cumulative incidence of LRR and DFS was 9.2% and 74.2%, respectively. A total of 399 (72%) patients received PMRT and 155 (28%) did not. The 5-year LRR of the patients with PMRT (7.3% vs. 14.1%, P=0.01) decreased significantly. We found that PMRT was an independent prognostic factor of LRR and DFS. Patients with the persistent involvement of 1-3 lymph nodes (ypN1) and more than 4 positive lymph nodes (ypN2-3) had a better outcome after PMRT than those without. However, the LRR and DFS of patients with negative lymph nodes at the time of surgery (ypN0) and who received PMRT showed no significant benefits. Amongst all patients with the three molecular subtypes of breast cancer, patients with triple-negative breast cancer had the highest pathological complete response rate but the worst prognosis (P=0.001). CONCLUSION: Results showed that PMRT significantly reduced the LRR of patients with clinical stage II-III breast cancer after receiving NAC and mastectomy. YpN0 patients derived no local control or survival benefit after receiving PMRT, whereas those with ypN1 and ypN2-3 could obviously benefit from PMRT.

Prognostic factors for breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes and the role of postmastectomy radiotherapy in these patients.

PURPOSE: The purpose of this study was to identify independent prognostic factors for breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes, and discuss the role of postmastectomy radiotherapy(PMRT) in these patients. METHODS: Between January 2005 and December 2015, the data on 840 eligible patients with breast cancer were retrospectively reviewed. Of these patients, 368 women received PMRT and 472 did not. The endpoints were locoregional recurrence (LRR) and distant metastasis (DM). RESULTS: With a median follow-up of 62.0 months, multivariate analysis identified the following independent risk factors for increased LRR: tumor size ≥ 4 cm (HR: 2.994, 95% CI: 1.190-7.535, P = 0.020), ER- and PR-negative tumor (HR: 2.540, 95% CI: 1.165-5.537, P = 0.019), preoperative high neutrophil-to-lymphocyte ratio (NLR) (HR: 4.716, 95% CI: 1.776-12.528, P = 0.002)and low neutrophil-to-monocyte ratio (NMR) (HR: 0.231, 95% CI: 0.084-0.633, P = 0.004). And independent risk factors for increased DM: ER- and PR-negative tumor (HR: 2.540, 95% CI: 1.880-5.625, P = 0.000), high NLR (HR: 2.693, 95% CI: 1.426-5.084, P = 0.002) and low NMR (HR: 0.460, 95% CI: 0.257-0.824, P = 0.009). The high-risk patients (≥ 2 risk factors) had worse LRRFS and DFS than low-risk patients (0-1 risk factor) (all, P < 0.05). In the subgroup analysis, both low- and high-risk patients received PMRT had better LRRFS and DFS than those who without PMRT (all, P < 0.05), and the high-risk patients received PMRT had similar 5-year rates of LRRFS and DFS than low-risk patients who without PMRT (94.5 vs. 94.3%, P = 0.402; 83.4 vs.87.4%, P = 0.877, respectively). CONCLUSIONS: Tumor size, ER/PR status, preoperative NLR and NMR were independent predictors of risk of recurrence. PMRT could improve locoregional control even in low-risk subgroup of breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes significantly.

MicroRNA-582-5p promotes triple-negative breast cancer invasion and metastasis by antagonizing CMTM8.

Triple-negative breast cancer (TNBC) commonly have aggressive properties. microRNA-582-5p (miR-582-5p) modulates the progression of several cancers. Yet, the role of miR-582-5p in TNBC progression is undetermined. In the current study, we investigated miR-582-5p expression levels and clinical significance in TNBC. The impact of miR-582-5p modulation on the biological behaviors of TNBC cells were measured. The downstream gene(s) regulated by miR-582-5p in TNBC was explored. We showed that compared to adjacent normal breast tissues, the miR-582-5p level was elevated in TNBC samples. The upregulation of miR-582-5p correlated with lymph node metastasis. Overexpression of miR-582-5p enhanced TNBC cell migration and invasion, whereas knockdown of miR-582-5p had an adverse impact on aggressive phenotype. In vivo xenograft mouse studies demonstrated that miR-582-5p overexpression accelerated TNBC growth and metastasis. Mechanistically, miR-582-5p selectively inhibited CMTM8, leading to a reduction of CMTM8 expression. CMTM8 showed suppressive effects on TNBC cell migration and invasion. Rescue experiments revealed that overexpression of CMTM8 impaired miR-582-5p-induced migration and invasion in TNBC cells. Overall, our data uncover an oncogenic role for miR-582-5p in TNBC metastasis through inhibition of CMTM8. We suggest miR-582-5p as a promising target for managing TNBC.

MicroRNA-125a-5p modulates radioresistance in LTEP-a2 non-small cell lung cancer cells by targeting SIRT7.

BACKGROUND: Micro(mi)RNAs are a series of 20-24 nt non-coding small-molecule single-stranded RNAs that are believed to be closely related to tumor occurrence, development and other biological processes. MicroRNA-125a modulates radiochemotherapy sensitivity. However, the mechanism by which miRNA-125a regulates radiation resistance by lung cancer cells is yet to be elucidated. OBJECTIVE: The present study was designed to explore the biological role of miR-125a in regulating radioresistance in non-small cell lung carcinoma (NSCLC). METHODS AND RESULTS: The expression of miR-125a was assessed by quantitative real-time PCR in the human lung cancer cell lines, A549 and LTEP-a2. Notably, we found that miRNA-125a-5p regulated lung cancer radiosensitivity. We found that miRNA-125a-5p was more highly expressed in LTEP-a2 cells, which showed radiosensitivity compared to A549 cells with lower expression of miRNA-125a-5p. In addition, we up-regulated or down-regulated miR-125a-5p expression using an miR-125a-5p mimic or inhibitor, respectively, to reverse radioresistance. Flow cytometry revealed that the mimic increased the apoptotic rate as well as the expression of the apoptosis-related protein, cleaved poly ADP-ribose polymerase (PARP). Gene detection by luciferase reporter showed that sirtuin (SIRT)7 is a direct target of miR-125a-5p. Inhibiting SIRT7 using a small interfering RNA (siSIRT) abrogated resistance to radiation. In addition, the overexpression of SIRT7 decreased radiation-induced cell apoptosis. CONCLUSION: Our results indicated that the miR-125a level varies in NSCLC cell lines with different radiosensitivities. We demonstrated that miR-125a-5p upregulated SIRT7 and further upregulated apoptosis in lung cancer cells to increase their radiosensitivity. Our findings provide new directions for improving radiosensitivity in malignant lung tumors.

LncRNA LINC00963 Promotes Tumorigenesis and Radioresistance in Breast Cancer by Sponging miR-324-3p and Inducing ACK1 Expression.

Upregulation of long non-coding RNA LINC00963 has been observed in several cancer types. In this study, we analyzed the clinical and biological significance of LINC00963 in breast cancer. The key microRNA (miR) mediating the action of LINC00963 was identified. We show that LINC00963 upregulation is correlated with aggressive parameters of breast cancer. Silencing of LINC00963 suppresses the proliferation and tumorigenesis of breast cancer cells, whereas LINC00963 overexpression exerts an opposite effect. Knockdown of LINC00963 enhances DNA damage and oxidative stress and sensitizes breast cancer cells to radiation. Mechanistically, LINC00963 antagonizes the repressive activity of miR-324-3p on ACK1 expression. Clinically, there is a negative correlation between miR-324-3p and LINC00963 expression in breast cancer tissues. Overexpression of LINC00963 or ACK1 rescues the inhibitory effects of miR-324-3p on breast cancer cell proliferation and radiosensitivity. In addition, knockdown of ACK1 attenuates LINC00963-dependent breast cancer growth and tumorigenesis. Taken together, LINC00963 promotes tumorigenesis and radioresistance in breast cancer through interplay with miR-324-3p and derepression of ACK1. LINC00963 may represent a potential target for the treatment of breast cancer.