Assessment of Drug Susceptibility for Patient-Derived Tumor Models through Lactate Biosensing and Machine Learning.

A patient-derived tumor model (PDM) is a practical tool to rapidly screen chemotherapeutics for individual patients. The evaluation method of cell viability directly determines the application of PDMs for drug susceptibility testing. As one of the metabolites of "glycosis", the lactate content was used to evaluate cell viability, but these assays were not specific for tumor cells. Based on the "Warburg effect", wherein tumor cells preferentially rely on "aerobic glycolysis" to produce lactate instead of pyruvate in "anaerobic glycolysis" of normal cells, we reported a gold lactate sensor (GLS) to estimate the cell viability of PDMs in drug susceptibility testing. It demonstrated high consistency between the GLS and commercial cell viability assay. Unlike either imaging or cell viability assay, the GLS characterizes the cell viability, enables dynamic monitoring, and distinguishes tumor cells from other cells. Moreover, machine learning (ML) was employed to perform a multi-index assessment for drug susceptibility of PDMs, which proved to be accurate and practical for clinical application. Therefore, the GLS provides an ideal drug susceptibility testing tool for individualized medicine.

Expression and Prognostic Value of Glucose Transporter 3 in Diffuse Large B Cell Lymphoma.

BACKGROUND: Several reports have suggested that glucose transporter 3 (GLUT-3) promotes tumor metastasis. The aim of this study was to examine the relationship between the expression level of GLUT-3 and the prognosis of patients with diffuse large B cell lymphoma (DLBCL). METHODS: The GLUT-3 expression levels in 91 DLBCL patients were evaluated by immunohistochemistry. The relationships between GLUT-3 expression level and clinicopathological characteristics and progression-free survival (PFS) of DLBCL patients were analyzed. The use of validation cohorts confirmed the predictive value of GLUT-3 expression. The correlation between GLUT-3 and immune cell infiltration was investigated using the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts system and the analysis of the infiltrating score was obtained by single sample Gene Set Enrichment Analysis. RESULTS: Expression of GLUT-3, which is highly expressed in DLBCL patients, was significantly associated with elevated serum LDH level, recurrence and Ki-67 status. Kaplan-Meier analysis showed that high GLUT-3 expression levels in DLBCL were related to poor PFS. Univariate and multivariate analyses results showed that low GLUT-3 expression level was significantly but independently associated with favorable PFS in DLBCL patients. GLUT-3 expression was also correlated with immune cell infiltration and the analysis of the infiltrating score. CONCLUSION: Our results indicate that GLUT-3 may act as a potential independent prognostic factor in DLBCL patients. The difference of the immune microenvironment in DLBCL patients may be predicted by the expression level of GLUT-3.

TMEM139 prevents NSCLC metastasis by inhibiting lysosomal degradation of E-cadherin.

Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and has the highest mortality rate among all solid tumors. It is characterized by early metastasis, and investigations of the molecular mechanisms underlying the progression and metastasis of NSCLC are urgently needed for the development of therapeutic targets. Here, we report that the transmembrane protein TMEM139 is significantly downregulated in NSCLC and that reduced expression of TMEM139 is correlated with a poor prognosis in NSCLC patients. Mechanistically, we found that TMEM139 directly interacts with E-cadherin at the plasma membrane and at focal adhesion sites. Moreover, TMEM139 can prevent the lysosomal degradation of E-cadherin, which inhibits epithelial-mesenchymal transition, migration and invasion of NSCLC cells both in vitro and in vivo. Our study not only expands our understanding of NSCLC metastasis but also provides a foundation to develop novel therapeutic strategies.

Body Composition as a Predictor of Toxicity and Prognosis in Patients with Diffuse Large B-Cell Lymphoma Receiving R-CHOP Immunochemotherapy.

BACKGROUND: Our study measured the body composition of Diffuse large B-cell lymphoma (DLBCL) patients receiving rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimen by computed tomographic (CT) and assessed their correlation with treatment-related toxicity and other adverse outcomes. METHODS: We retrospectively analyzed 201 DLBCL patients who underwent pre-treatment abdominal CT examination. CT images were used to assess body composition metrics at the third lumbar vertebrae including fat tissues and muscle. Based on the skeletal muscle area (SMA) and density (SMD), skeletal muscle index (SMI), skeletal muscle gauge (SMG = SMI × SMD) and lean body mass (LBM) were calculated. Also analyzed were the toxicity, adverse events and survival. RESULTS: We found that SMG, SMD, SMI and LBM were correlated with any grade 3-4 toxicity, dose reduction, hospitalization or termination of the treatment due to immunochemotherapy and worse survival. However, multivariate analysis demonstrated SMG [progression-free survival (PFS): hazard ratio (HR), 2.889; 95% CI, 1.401-5.959; p = 0.004; overall survival (OS): HR, 2.655; 95% CI, 1.218-5.787; p = 0.014] was the best predictor of poor prognosis. CONCLUSIONS: SMG, SMD, SMI and LBM were identified as predictors of adverse reactions and poor survival. SMG was an innovative and valuable indicator of immunochemotherapy toxicity and other adverse outcomes. Additionally, it can be used to individualize antineoplastic drug dosing.

The clinical implication of soluble PD-L1 (sPD-L1) in patients with breast cancer and its biological function in regulating the function of T lymphocyte.

This work investigated the clinical prognostic implications and biological function of plasma soluble programmed cell death ligand 1 in breast cancer patients. Plasma sPD-L1 levels of recurrent/metastatic breast cancer patients were determined, and the association of sPD-L1 levels and metastatic progression-free survival and metastatic overall survival was assessed. The PD-L1 expression on breast cancer cells was analyzed by flow cytometry, and the level of sPD-L1 in the supernatant of breast cancer cells was determined by enzyme-linked immunosorbent assay. Furthermore, the effect of sPD-L1 on the proliferation and apoptosis of T lymphocytes was detected by WST-1 assay and flow cytometry. The plasma sPD-L1 levels in 208 patients with recurrent/metastatic breast cancer before receiving first-line rescue therapy were measured. The optimal cutoff value of plasma sPD-L1 for predicting disease progression was 8.774 ng/ml. Univariate and multivariate analyses identified high sPD-L1 level (≥ 8.774 ng/ml) and visceral metastasis were independent factors associated with poor prognosis. Relevance analysis showed that the plasma sPD-L1 level was weaklyassociated with some systemic inflammation markers, including white cell count (WBC), absolute monocytecount, and absolute neutrophil count. Furthermore, we found sPD-L1 could be found in supernatant of culture with breast cancer cell line expressing PD-L1 on the cell surface and inhibit T lymphocyte function, playing a negative regulatory role in cellular immunity. sPD-L1 was a good tumor predictive maker in breast cancer and it may play a potentially important role in immune tolerance.

The prognostic value of preoperative fibrinogen-to-prealbumin ratio and a novel FFC score in patients with resectable gastric cancer.

BACKGROUND: Chronic inflammation is considered as a hallmark of gastric cancer (GC) and plays a critical role in GC progression and metastasis. This study aimed to explore the prognostic values of preoperative fibrinogen-to-prealbumin ratio (FPR), fibrinogen-to-albumin ratio (FAR), and novel FPR-FAR-CEA (FFC) score in patients with GC undergoing gastrectomy. METHODS: A total of 273 patients with resectable GC were included in this retrospective study. We performed Kaplan-Meier and Cox regression analyses to assess the prognostic role of preoperative FPR, FAR, and FFC score in patients with GC and analyze their relationships with clinicopathological features. RESULTS: Receiver operating characteristic curve (ROC) analysis revealed that the optimal cutoff values for FPR and FAR were 0.0145 and 0.0784, respectively. The FFC score had a higher area under the ROC curve than FAR and CEA. Elevated FPR (≥ 0.0145) and FAR (≥ 0.0784) were significantly associated with old age, large tumor size, tumor invasion depth, lymph nodes metastasis, advanced TNM stage, large Borrmann type, and anemia status. Kaplan-Meier analysis showed that high FPR, FAR, and FFC score were related to poor survival. Multivariate analyses indicated that FPR, FFC score, TNM stage, and tumor size were significant independent factors for survival. CONCLUSIONS: Preoperative FPR and FFC score could be used as prospective noninvasive prognostic biomarkers for resectable GC.

High Expression of Plakoglobin Promotes Metastasis in Invasive Micropapillary Carcinoma of the Breast via Tumor Cluster Formation.

Invasive micropapillary carcinoma of the breast (IMPC) is a rare subtype of breast cancer that has a high frequency of lymph node (LN) involvement and metastasis to distant organs. IMPC is characterized by distinct histomorphology and unfavorable prognosis when compared with invasive ductal carcinoma no special type (IDC-NST). However, the underlying molecular mechanisms remain unclear. We reported here that plakoglobin, as a key component in cell adhesion, can promote collective metastasis through facilitating IMPC clusters formation. In comparing the clinicopathological features of 451 IMPC patients and 282 IDC-NST patients, our results showed that tumor emboli were significantly higher in IMPC patients and were associated with a high frequency of metastasis. Both in vitro and in vivo data showed overexpression of plakoglobin in both the cell membrane and the cytoplasm of IMPC clusters. When plakoglobin was knocked down in IMPC cell models, the tumor cell clusters were depolymerized. Using mouse models, we validated the metastatic potential of tumor clusters was higher than single cells in vivo. Further analysis showed that higher expression of plakoglobin was able to promote activation of the PI3K/Akt/Bcl-2 pathway, which might protect the clusters from anoikis. Our data indicate that plakoglobin promotes tumor cluster formation in IMPC and downregulates apoptosis in the cell clusters through activation of PI3K/Akt/Bcl-2 signaling. These results provide a convincing rationale for the high metastatic propensity seen in IMPC.

Combination of the preoperative albumin to globulin ratio and neutrophil to lymphocyte ratio as a novel prognostic factor in patients with triple negative breast cancer.

Background: The pretreatment albumin to globulin ratio (AGR) and neutrophil to lymphocyte ratio (NLR) were the inflammation-associated factors which were related to the disease-free survival in various malignancies. The aim of this study was to evaluate the clinical significance of the pretreatment AGR combined with NLR for patients with triple negative breast cancer (TNBC). Method: This retrospective study included 286 cases of pathologically diagnosed patients with TNBC. The relationships of AGR and NLR with clinicopathologic characteristics and prognosis were analyzed by Kaplan-Meier and Cox regression methods. Results: An AGR of 1.63 and a NLR of 2.93 were identified as the optimal cut-off points for distinguishing patients with good versus poor prognosis. The area under the receiver operating characteristic curves of combined with AGR and NLR (CO-AN) was increased compared with AGR and NLR individually. Kaplan-Meier analysis showed that low AGR/high NLR was related to poor survival. The prognosis of patients can be predicted well by the CO-AN. Univariate and multivariate analyses revealed that high AGR levels, low NLR levels, and CO-AN<1 were significantly and independently associated with favorable disease-free survival. Conclusions: Our study suggested that AGR and NLR levels can be prognostic biomarkers for disease-free survival in patients with TNBC. The CO-AN may have greater predictive value than AGR and NLR in patients with TNBC.

Systemic immune response associated with radiation therapy in B­cell non­Hodgkin's lymphoma of Waldeyer's ring.

Radiation therapy (RT) is one of the most effective therapeutic modalities for B­cell non­Hodgkin's lymphoma of Waldeyer's ring (WR­B­NHL). However, the responsiveness of RT remains controversial and clinical biomarkers are required to predict survival in RT­treated patients with WR­B­NHL. Previous studies have suggested an association between RT and systemic immune responses. In the present retrospective study, the lymphocyte to monocyte ratio (LMR) was identified as a systemic immune indicator in RT­treated patients with WR­B­NHL, and the prognostic value of the LMR with RT and systemic immune responses were evaluated. The optimal cut­off value of the LMR was selected as 3.14, and a high LMR demonstrated improved prognosis and was considered an independent prognostic indicator in RT­treated patients, particularly in patients with distant non­irradiated lesions. Furthermore, reverse transcription­quantitative polymerase chain reaction and ELISA analysis of irradiated lymphoma cell lines and serum samples from patients with WR­B­NHL demonstrated the upregulated expression levels of 4­1BB ligands, calreticulin and high mobility group box 1 compared with non­irradiated groups. Additionally, CD8+ T cells and expression levels of interferon­Î³ in T cells co­cultured with irradiated cells were significantly increased compared with non­irradiated cells. The results indicated that the anti­programmed cell death protein 1 (PD­1) antibody may serve a role in lymphoma therapy when combined with RT. The results of the present study demonstrated the prognostic significance of the LMR associated with RT in patients with WR­B­NHL and acknowledged the potential use of PD­1 antibody in RT­treated lymphomas.

Lymphocyte-Activation Gene-3 Expression and Prognostic Value in Neoadjuvant-Treated Triple-Negative Breast Cancer.

PURPOSE: In this study, we aimed to evaluate lymphocyte-activation gene-3 (LAG-3) expression and its prognostic value in neoadjuvant-treated triple-negative breast cancer (TNBC). METHODS: LAG-3, programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), and CD8+ tumor-infiltrating lymphocyte (TILs) levels were examined using immunohistochemistry in 148 preand 114 post-neoadjuvant chemotherapy (NACT) specimens of human TNBC tissue. Correlations between expression levels and clinicopathological features were analyzed. Prognostic values for combined detection in TNBC following NACT were evaluated. RESULTS: In pre-NACT specimens, LAG-3 expression showed a significant association with pathological complete response (pCR, p=0.038) and was correlated with PD-1 (p<0.001) and PD-L1 (p=0.008). In post-NACT specimens, high expression of LAG-3 showed significant effects on nodal status (p=0.023) and PD-1 (p<0.001). The expression of immune markers on TILs significantly increased following NACT. Multivariate analysis indicated that only nodal status (odds ratio [OR], 0.226; 95% confidence interval [CI], 0.079-0.644; p=0.005) and high quantities of CD8+TILs (OR, 3.186; 95% CI, 1.314-7.721; p=0.010) are independent predictors of pCR. Nodal status (hazard ratio [HR], 2.666; 95% CI, 1.271-5.594; p=0.010), CD8+TILs (HR, 0.313; 95% CI, 0.139-0.705; p=0.005), and the LAG-3-high/PD-L1-high group (HR, 2.829; 95% CI, 1.050-7.623; p=0.040) provided prognostic values for patients with TNBC following NACT. CONCLUSION: CD8+TILs were sensitive predictive markers in response to NACT. High expression of LAG-3 in residual tissues, especially in combination with PD-L1, was associated with poor prognosis.

Ratio of Immune Response to Tumor Burden Predicts Survival Via Regulating Functions of Lymphocytes and Monocytes in Diffuse Large B-Cell Lymphoma.

BACKGROUND/AIMS: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, and is the most common type of lymphoma in adults. Although significant progress in treatment has been made using chemotherapy combinations, there exist a large amount of relapse or refractory cases. Thus, effective clinical biomarkers for DLBCL are urgently needed. Our study aims to explore the predictive significance of using the immune response to tumor burden ratio [defined as the lymphocyte to monocyte ratio (LMR)/lactate dehydrogenase (LDH) levels] in 184 DLBCL patients and the potential mechanism underlying the use of the LMR to tumor burden ratio in predicting patient survival. METHODS: The correlation between serum LDH levels and tumor levels assessed by PET-CT was determined using Spearman's correlation analysis. Clinical data from 184 DLBCL patients was assessed using receiver operating characteristic curve analysis and survival analysis. The potential correlation between tumor burden and lymphocytes or monocytes was analyzed by immunohistochemical staining, flow cytometry, and ELISA analysis of patient samples. In addition, we performed in vitro studies to further determine the effects of tumor burden on the anti-tumor activity of T lymphocytes. RESULTS: We observed that serum LDH was an excellent surrogate marker of tumor burden in DLBCL patients, and that the ratio of LMR to LDH was an independent prognostic biomarker capable of predicting survival in DLBCL patients. Further analysis showed that a high tumor burden was correlated with decreased Ki67 expression in T cells, either in the solid tumor tissue or in the circulating blood. In addition, based on an in vitro co-culture study, a higher tumor burden led to the suppression of the anti-tumor response of T cells. Furthermore, we found that a higher tumor burden was correlated with the differentiation of monocytes to tumor associated macrophages in the tumor micro-environment. Both results demonstrate the importance of considering both the immune system and tumor burden for prognostic analysis. CONCLUSION: Our study has identified a novel clinical biomarker, namely, the immune response to tumor burden ratio, that can be used to distinguish survival outcomes in DLBCL patients, and demonstrated the potential mechanism underlying the use of this biomarker, that incorporates both the immune system and tumor burden, for use in future clinical applications.

CD44+/CD24- phenotype predicts a poor prognosis in triple-negative breast cancer.

Cancer stem cells are enriched in triple-negative breast cancer (TNBC) tumor tissues, which present strong capacities of proliferation and tumorigenicity. The present study detected the distribution of cancer stem cell markers cluster of differentiation (CD)44/CD24 and analyzed the clinical outcomes of different CD44/CD24 phenotypes in patients with TNBC. Multivariate Cox regression analyses were performed with regard to the prognostic value of cancer stem cell markers CD44/CD24, aldehyde dehydrogenase 1 and other baseline clinical characteristics, including tumor size, lymph node involved, adjuvant chemotherapy, Ki-67, breast cancer susceptibility gene 1, cellular tumor antigen p53, vimentin and basal-like status. The multivariate analyses showed that three of these factors, CD44/CD24 phenotype, basal-like status and number of lymph nodes involved, had an impact on overall survival. Furthermore, patients with CD44+/CD24- phenotype, basal-like tumors and ≥4 lymph nodes involved had a significantly worse prognosis. The expression of CD44 and CD24 was detected by double-staining immunohistochemistry, which can locate cancer stem cells individually. Overall, the present results indicated that CD44/CD24 status evaluated by double-staining immunohistochemistry constitutes an independent prognostic factor for TNBC.

Tumor LDH-A expression and serum LDH status are two metabolic predictors for triple negative breast cancer brain metastasis.

There are limited therapeutic methods for triple negative breast cancer in the clinic, which is easy to progress into the brain to form metastatic lesions and evolve into the terminal stage. Because both the primary cancer and the brain metastasis have high glycolysis, we hypothesize that lactate dehydrogenase (LDH), which catalyzes the final step of glycolysis, may be a predictor, as well as a treatment target, for breast cancer brain metastasis. Therefore, the expression of LDH-A was detected on 119 triple negative breast cancer tissues with immunohistochemistry, and the serum LDH levels were also measured. Our results showed that the LDH-A expression inside the tumor was significantly higher than the matched normal tissues. Tumor LDH-A expression, serum LDH status, and the slope of serum LDH status were closely associated with triple negative breast cancer brain metastasis and brain metastasis free survival. This study indicates that tumor LDH and serum LDH status are two predictors for triple negative breast cancer brain metastasis.

Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients.

PURPOSE: Endocrine resistance limits the efficacy of anti-estrogen therapies. Notch signaling is involved in modulating tumor-associated macrophage (TAM) differentiation and is upregulated in endocrine-resistant breast cancer cells. Here, we analyzed the role of Jagged1 in the regulation of TAM polarization to investigate whether the Jagged1-Notch pathway promotes the acquisition of aromatase inhibitor (AI) resistance by upregulating TAM infiltration. METHODS: The Jagged1 expression levels and M2 TAM infiltration density, in 203 tumor samples from ER-positive postmenopausal patients, who received AI treatment, were evaluated by immunohistochemical staining and the results were compared with clincopathological parameters and survival. The Jagged1 protein and mRNA levels were analyzed in MCF-7 and long-term endocrine-depleted (LTED) cell lines. The phenotypes of macrophage after macrophages were co-cultured with either MCF-7 or LTED cells, were evaluated using flow cytometry. Cell migration assay was performed to evaluate the mobility of cancer cells. Notch gama secretase inhibitor (GSI) RO4929097 was employed to investigate whether modulation of Notch signaling affects M2 polarization. RESULTS: In the tumor samples, Jagged1 expression was found to be associated with a large tumor size, high histological grade, lymphatic invasion, and high Ki67 expression. Jagged1 expression was also correlated with reduced disease-free and overall survival and was positively associated with the stromal M2 TAM infiltration density in primary tumor tissues. In AI-resistance patients, M2 TAM infiltration was denser in metastatic lesions than in primary tumors. Higher Jagged1 protein and mRNA levels were also found in LTED cells, which model AI-resistant conditions in patients, compared with MCF-7 cells. Macrophages co-cultured with LTED cells expressed higher levels of M2 marker and IL-10. M2 TAM proportion was reduced when macrophages were pre-treated with GSI before co-culture. CONCLUSIONS: The Jagged1-Notch pathway showed elevated expression in AI-resistant breast cancer cells, resulting in macrophage differentiation towards M2 TAMs and there contributing to the acquisition of AI resistance.

The Relationship Between Tamoxifen-associated Nonalcoholic Fatty Liver Disease and the Prognosis of Patients With Early-stage Breast Cancer.

PURPOSE: To investigate the relationship between tamoxifen-associated nonalcoholic fatty liver disease (NAFLD) and survival outcomes in patients with breast cancer. METHODS: Patients with early-stage invasive breast cancer after curative resection from January 2009 to June 2011 were selected. A total of 646 patients who were treated with tamoxifen were included. Patients diagnosed with NAFLD on ultrasonography were classified into the NAFLD and non-NAFLD groups. RESULTS: The NAFLD group included 221 patients, and the non-NAFLD group included 425 patients. Patients in the NAFLD group had significantly higher body mass index than those in the non-NAFLD group (P < .001). Disease-free survival was significantly longer in the non-NAFLD group than the NAFLD group (P = .006). However, there were no significant statistical differences between these 2 groups on overall survival (P = .387). With regard to body mass index, total cholesterol, triglyceride, low-density lipoprotein cholesterol, alanine aminotransferase, and high-density lipoprotein cholesterol, the optimal cutoff points were 21.06, 4.28, 1.22, 3.13, 27.50 and 1.29, respectively, which can be identified as risk factors for distinguishing patients who developed NAFLD from those who did not (P < .05). Moreover, a risk score ≥ 3 indicated a high risk of development of NAFLD (odds ratio, 3.03; 95% confidence interval, 1.11-8.28; P = .037). CONCLUSION: NAFLD development had a negative effect on survival outcomes of patients with breast cancer. The risk score created ≥ 3 had a high-level risk of developing NAFLD, and it might be used for physicians to evaluate each patient and give instructive advice for further treatment.

Lymphocyte-to-monocyte ratio is associated with prognosis of diffuse large B-cell lymphoma: correlation with CD163 positive M2 type tumor-associated macrophages, not PD-1 positive tumor-infiltrating lymphocytes.

The research aims to examine the prognostic value of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to- lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in diffuse large B-cell lymphoma (DLBCL). The relation of these hematologic indicators to poor antitumor immunity and prognosis must be investigated. Clinicopathologic data and survival information of 355 patients with DLBCL was retrospectively analyzed. Univariate analysis revealed that lower LMR (<2.71), higher NLR (≥2.81), CD163+ M2 tumor-associated macrophages (TAM) content ≥9.5% and programmed cell death 1 (PD-1)+ tumor-infiltrating lymphocytes (TILs) content < 4.5 cells per high power field(HPF) were significantly related to unfavorable overall survival (OS) and progression free survival (PFS). When considering the prognostic indexes of IPI, multivariate analysis confirmed that LMR of <2.71 and CD163+ M2 TAM content ≥9.5% significantly affected the prognosis of DLBCL. Spearman correlation test showed LMR was negatively correlated with CD163+ M2 TAM content. However, there were no correlation was found between LMR and PD-1+ TIL as well as between NLR and PD-1+ TIL content. These results indicated that decreased LMR lead to a weak anti-tumor immunity and could be used as a bad prognosis biomarker of DLBCL.

The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients.

The prognostic value of programmed death-ligand 1 (PD-L1) in gastric cancer (GC) remains controversial. To clarify this problem, we performed a meta-analysis of research studies identified in the PubMed, EMBASE and the Cochrane Library databases. A total of 1,901 patients in 10 studies were enrolled in this meta-analysis, and the pooled hazard ratio (HR) of 1.64 (95% CI 1.11 to 2.43; P = 0.01) indicated that PD-L1 expression is associated with a shorter overall survival (OS). The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with tumour size (OR = 1.87, 95% CI 1.25 to 2.78; P = 0.002) and lymph node status (OR = 2.17, 95% CI 1.04 to 4.52; P = 0.04). However, PD-L1 had no correlation with gender, age, cancer location, differentiation, depth of invasion, and tumour stage. This meta-analysis indicates that PD-L1 expression is a valuable predictor of the prognosis of patients with GC. PD-L1 expression could be used for identifying a subgroup of patients, who would potentially benefit from targeted therapy against PD-1 or PD-L1. Well-designed large-cohort studies are needed to confirm these findings.

Adherence to Needed Adjuvant Therapy Could Decrease Recurrence Rates for Rural Patients With Early Breast Cancer.

PURPOSE: The purpose of this study was to evaluate the differences in stage upon diagnosis, adherence to adjuvant treatment, and recurrence between rural and urban patients with early breast cancer. METHODS: This retrospective study included 3640 patients with primary breast cancer recruited from 2000 to 2009. Patients who developed recurrence or metastasis were verified by adequate diagnostic imaging modalities and pathology. The χ2 test was used to compare groups with respect to variables (recurrence and clinicopathologic features). A multivariable Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for breast cancer recurrence risk. RESULTS: Compared with tumors in urban patients, those in rural patients showed higher histologic grade, larger size, more lymphatic metastasis, and higher Ki-67 index; therapy adherence was strongly associated with recurrence in both. Compared with urban patients, the female rural patients had a higher recurrence rate. However, no significant difference in recurrence rates was observed between urban and rural patients following guideline adherence. CONCLUSIONS: The results of our study suggest that the later stage upon diagnosis and nonadherence to treatment contribute toward worse breast cancer outcomes among rural patients with breast cancer. Adherence to needed adjuvant therapy could decrease recurrence rates for rural patients with early breast cancer.

The prognostic and predictive value of the lymphocyte to monocyte ratio in luminal-type breast cancer patients treated with CEF chemotherapy.

Several reports have suggested that peripheral blood-based parameters are associated with host immunity response, which is an essential component of the pathogenesis and progression of cancer. The purpose of the present study was to identify the prognostic significance of various peripheral blood-based biomarkers and to determine the optimal cut-off value suitable for luminal breast cancer patients. We found that lymphocyte-to-monocyte ratio (LMR) was significant prognostic predictors. And the patients with a CEF regimen and LMR ratio ≥ 5.2 gained a good prognosis. This study suggested that the LMR could be regarded as an independent prognostic factor in luminal breast cancer patients. The elevated LMR level also had enhanced 5-fluorouracil sensitivity in luminal breast cancer patients.

Altered glycometabolism affects both clinical features and prognosis of triple-negative and neoadjuvant chemotherapy-treated breast cancer.

Glycometabolism is a distinctive aspect of energy metabolism in breast cancer, and key glycometabolism enzymes/pathways (glycolysis, hexosamine biosynthetic pathway, and pentose phosphate pathway) may directly or indirectly affect the clinical features. In this study, we analyzed the particular correlation between the altered glycometabolism and clinical features of breast cancer to instruct research and clinical treatment. Tissue microarrays containing 189 hollow needle aspiration samples and 295 triple-negative breast cancer tissues were used to test the expression of M2 isoform of pyruvate kinase (PKM2), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose-6-phosphate dehydrogenase (G6PD), and p53 by immunohistochemistry and the intensity of these glycometabolism-related protein was evaluated. Chi-square test, Kaplan-Meier estimates, and Cox proportional hazards model were used to analyze the relationship between the expression of these factors and major clinical features. PKM2, GFPT1, and G6PD affect the pathologic complete response rate of neoadjuvant chemotherapy patients in different ways; pyruvate kinase muscle isozyme 2 (PKM2) and G6PD are closely associated with the molecular subtypes, whereas GFPT1 is correlated with cancer size. All these three factors as well as p53 have impacts on the progression-free survival and overall survival of triple-negative breast cancer patients. Cancer size shows significant association with PKM2 and GFPT1 expression, while the pN stage and grade are associated with PKM2 and G6PD expression. Our study support that clinical characteristics are reflections of specific glycometabolism pathways, so their relationships may shed light on the orientation of research or clinical treatment. The expression of PKM2, GFPT1, and G6PD are hazardous factors for prognosis: high expression of these proteins predict worse progression-free survival and overall survival in triple-negative breast cancer, as well as worse pathologic complete response rate in neoadjuvant chemotherapy breast cancer. However, p53 appears as a protective factor only in the patients receiving neoadjuvant chemotherapy. All the four proteins, PKM2, GFPT1, G6PD and p53, are prognostic markers of breast cancer. The correlation among them suggests that there may be crosstalk of the four proteins in breast cancer.