Neoadjuvant therapy in triple-negative breast cancer: A systematic review and network meta-analysis.

BACKGROUND: Evidence for the preferred neoadjuvant therapy regimen in triple-negative breast cancer (TNBC) is not yet established. METHODS: Literature search was conducted from inception to February 12, 2022. Phase 2 and 3 randomized controlled trials (RCTs) investigating neoadjuvant therapy for TNBC were eligible. The primary outcome was pathologic complete response (pCR); the secondary outcomes were all-cause treatment discontinuation, disease-free survival or event-free survival (DFS/EFS), and overall survival. Odd ratios (OR) with 95% credible intervals (CrI) were used to estimate binary outcomes; hazard ratios (HR) with 95% CrI were used to estimate time-to-event outcomes. Bayesian network meta-analysis was implemented for each endpoint. Sensitivity analysis and network meta-regression were done. RESULTS: 41 RCTs (N = 7109 TNBC patients) were eligible. Compared with anthracycline- and taxane-based chemotherapy (ChT), PD-1 inhibitor plus platinum plus anthracycline- and taxane-based ChT was associated with a significant increased pCR rate (OR 3.95; 95% CrI 1.81-9.44) and a higher risk of premature treatment discontinuation (3.25; 1.26-8.29). Compared with dose-dense anthracycline- and taxane-based ChT, the combined treatment was not associated with significantly improved pCR (OR 2.57; 95% CrI 0.69-9.92). In terms of time-to-event outcomes, PD-1 inhibitor plus platinum plus anthracycline- and taxane-based ChT was associated with significantly improved DFS/EFS (HR 0.42; 95% CrI 0.19-0.81). CONCLUSIONS: PD-1 inhibitor plus platinum and anthracycline- and taxane-based ChT was currently the most efficacious regimen for pCR and DFS/EFS improvement in TNBC. The choice of chemotherapy backbone, optimization of patient selection with close follow-up and proactive symptomatic managements are essential to the antitumor activity of PD-1 inhibitor.

Neoadjuvant docetaxel plus carboplatin vs epirubicin plus cyclophosphamide followed by docetaxel in triple-negative, early-stage breast cancer (NeoCART): Results from a multicenter, randomized controlled, open-label phase II trial.

Previous studies have shown that the addition of carboplatin to neoadjuvant chemotherapy improved the pathologic complete response (pCR) rate in patients suffering from triple-negative breast cancer (TNBC) and patients who obtained a pCR could achieve prolonged event-free survival (EFS) and overall survival (OS). However, no studies have assessed the effects of the combination of docetaxel and carboplatin without anthracycline with taxane-based and anthracycline-based regimens. The NeoCART study was designed as a multicenter, randomized controlled, open-label, phase II trial to assess the efficacy and safety of docetaxel combined with carboplatin in untreated stage II-III TNBC. All eligible patients were randomly assigned, at a 1:1 ratio, to an experimental docetaxel plus carboplatin (DCb) for six cycles group (DCb group) or an epirubicin plus cyclophosphamide for four cycles followed by docetaxel for four cycles group (EC-D group). PCR (ypT0/is ypN0) was evaluated as the primary outcome. Between 1 September 2016 and 31 December 2019, 93 patients were randomly assigned and 88 patients were evaluated for the primary endpoint (44 patients in each group). In the primary endpoint analysis, 27 patients in the DCb group (61.4%, 95% CI 47.0-75.8) and 17 patients in the EC-D group achieved a pCR (38.6%, 95% CI 24.3-53.0; odds ratio 2.52, 95% CI 2.4-43.1; Pnoninferiority = .004). Noninferiority was met, and the DCb regimen was confirmed to be superior to the EC-D regimen (P = .044, superiority margin of 5%). At the end of the 37-month median follow-up period, OS and EFS rates were equivalent in both groups.

Peritoneal Metastasis After Treated With Abemaciclib Plus Fulvestrant for Metastatic Invasive Lobular Breast Cancer: A Case Report and Review of the Literature.

Peritoneal metastases from invasive lobular carcinoma (ILC) of breast are uncommon and usually related to poor prognosis due to difficulty of detection in clinical practice and drug resistance. Therefore, recognizing the entities of peritoneal metastases of ILC and the potential mechanism of drug resistance is of great significance for early detection and providing accurate management. We herein report a case of a 60-year-old female who presented with nausea and vomiting as the first manifestation after treated with abemaciclib (a CDK4/6 inhibitor) plus fulvestrant for 23 months due to bone metastasis of ILC. Exploratory laparotomy found multiple nodules in the peritoneum and omentum, and immunohistochemistry confirmed that the peritoneal metastatic lesions were consistent with ILC. Palliative therapy was initiated, but the patient died two months later due to disease progression with malignant ascites. Whole exome sequencing (WES) was used to detect the tumor samples and showed the peritoneal metastatic lesions had acquired ESR1 and PI3KCA mutations, potentially explaining the mechanism of endocrine therapy resistance. We argue that early diagnosis of peritoneal metastasis from breast cancer is crucial for prompt and adequate treatment and WES might be an effective supplementary technique for detection of potential gene mutations and providing accurate treatment for metastatic breast cancer patients.

Tumor Microenvironment Characterization in Breast Cancer Identifies Prognostic and Neoadjuvant Chemotherapy Relevant Signatures.

Immune response which involves distinct immune cells is associated with prognosis of breast cancer. Nonetheless, less study have determined the associations of different types of immune cells with patient survival and treatment response. In this study, A total of 1,502 estrogen receptor(ER)-negative breast cancers from public databases were used to infer the proportions of 22 subsets of immune cells. Another 320 ER-negative breast cancer patients from Guangdong Provincial People's Hospital were also included and divided into the testing and validation cohorts. CD8+ T cells, CD4+ T cells, B cells, and M1 macrophages were associated with favourable outcome (all p <0.01), whereas Treg cells were strongly associated with poor outcome (p = 0.005). Using the LASSO model, we classified patients into the stromal immunotype A and B subgroups according to immunoscores. The 10 years OS and DFS rates were significantly higher in the immunotype A subgroup than immunotype B subgroup. Stromal immunotype was identified as an independent prognostic indicator in multivariate analysis in all cohorts and was also related to pathological complete response(pCR) after neoadjuvant chemotherapy. The nomogram that integrated the immunotype and clinicopathologic features showed good predictive accuracy for pCR and discriminatory power. The stromal immunotype A subgroup had higher expression levels of immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) and cytokines (IL-2, INF-γ, and TGF-ß). In addition, patients with immunotype A and B diseases had distinct mutation signatures. Therefore, The stromal immunotypes could predict survival and responses of ER-negative breast cancer patients to neoadjuvant chemotherapy.

Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR-positive, HER2-negative early breast cancer: A meta-analysis of randomized clinical trials.

BACKGROUND: The benefit of adjuvant cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) in hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) early breast cancer (EBC) is uncertain. Hence, we performed a meta-analysis to determine the efficacy and safety of adjuvant CDK4/6 inhibitors plus ET and to identify potential preferred subpopulations for this regimen. METHODS: A literature search was conducted in PubMed, Embase, Cochrane databases up to Jan 15, 2021. Hazard ratios (HRs) for invasive disease-free survival (IDFS) and risk ratios (RRs) for grade 3/4 adverse events (AEs) and treatment discontinuation were extracted. Analysis with predefined subgroup variables was done. Trial sequential analysis (TSA) was performed to assess the conclusiveness of survival outcomes. RESULTS: Three trials were eligible (N = 12647). Compared with ET, adjuvant CDK4/6 inhibitors with ET prolonged IDFS in patients with HR+/HER2- EBC (HR 0.87, 95% CI 0.76-0.98, p = 0.03, I2 = 19%), with positive therapeutic responses observed in patients with N2/N3 nodal status (HR 0.83, 95% CI 0.71-0.97, p = 0.02, I2 = 0%). None of the cumulative z-curves crossed the trial monitoring boundaries in TSA, and no reliable conclusion could be drawn. The combination treatment carried a higher risk of grade 3/4 AEs (RR 4.14, 95% CI 3.33-5.15, p < 0.00001) and an increase in treatment discontinuation due to AEs (RR 19.16, 95% CI 9.27-39.61, p < 0.00001). CONCLUSIONS: Adjuvant CDK4/6 inhibitors with ET might provide survival benefit in HR+/HER2- EBC. A statistically significantly improved IDFS was only observed in N2/N3 subgroup. However, overall evidence favoring the use of this combination regimen was inadequate.

Anthracycline-containing versus carboplatin-containing neoadjuvant chemotherapy in combination with trastuzumab for HER2-positive breast cancer: the neoCARH phase II randomized clinical trial.

BACKGROUND: Although dual blockade HER2-based neoadjuvant chemotherapy is associated with excellent outcomes for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, pertuzumab is not available to all patients due to cost. The optimal neoadjuvant chemotherapy for HER2-positive breast cancer in the presence of a single HER2 blockade is unknown. This study aimed to compare the efficacy and safety of epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (EC-TH) with docetaxel/carboplatin/trastuzumab (TCH) neoadjuvant setting for HER2-positive breast cancer under the single HER2 blockade. METHODS: Patients with stage II-IIIC HER2-positive breast cancer were randomly assigned to either eight cycles of EC-TH every 3 weeks during all chemotherapy cycles, or six cycles of TCH every 3 weeks. The primary endpoint was pathological complete response (pCR) (defined as the absence of invasive tumor cells in breast and axilla, ypT0/is ypN0). RESULTS: From May 2017 to November 2019, 140 patients were randomly assigned, and 135 patients were ultimately found evaluable for the primary endpoint. The pCR was recorded in 25 of 67 patients [37.3%; 95% confidence interval (CI), 25.8-50.0] in the EC-TH group and in 38 of 68 patients (55.9%, 95% CI, 43.3-67.9) in the TCH group (p = 0.032). The most common adverse events (AEs) were neutropenia in 24 of 67 (35.8%) patients in the EC-TH group versus 27 of 68 (39.7%) in the TCH group (p = 0.642), anemia in 33 of 67 (49.3%) patients in the EC-TH group versus 34 of 68 (50.0%) in the TCH group (p = 0.931), and thrombocytopenia in five of 67 (7.5%) patients in the EC-TH group versus 17 of 68 (25.0%) in the TCH group (p = 0.006). CONCLUSION: For patients receiving the single HER2 blockade trastuzumab for HER2-positive breast cancer, TCH regimen might be a preferred neoadjuvant therapy. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov identifier: NCT03140553) on 2 May 2017.

The role of adjuvant chemotherapy in stage I-III male breast cancer: a SEER-based analysis.

BACKGROUND AND AIMS: Male breast cancer is an uncommon disease. The benefit of adjuvant chemotherapy in the treatment of male breast cancer patients has not been determined. The aim of this study was to explore the value of adjuvant chemotherapy in men with stage I-III breast cancer, and we hypothesized that some male patients may safely skip adjuvant chemotherapy. METHODS: Male breast cancer patients between 2010 and 2015 from the Surveillance Epidemiology and End Results database were included. Univariate and multivariate Cox analyses were used to analyse the factors associated with survival. The propensity score matching method was adopted to balance baseline characteristics. Kaplan-Meier curves were used to evaluate the impacts of adjuvant chemotherapy on survival. The primary endpoint was survival. RESULTS: We enrolled 514 patients for this study, including 257 patients treated with chemotherapy and 257 patients without. There was a significant difference in overall survival (OS) but not in breast cancer-specific survival (BCSS) between the two groups (p < 0.001 for OS and p = 0.128 for BCSS, respectively). Compared with the non-chemotherapy group, the chemotherapy group had a higher 4-year OS rate (97.5% versus 95.2%, p < 0.001), while 4-year BCSS was similar (98% versus 98.8%, p = 0.128). The chemotherapy group had longer OS than the non-chemotherapy group among HR+, HER2-, tumour size >2 cm, lymph node-positive male breast cancer patients (p < 0.05). Regardless of tumour size, there were no differences in OS or BCSS between the chemotherapy and non-chemotherapy cohorts for lymph node-negative patients (OS: p > 0.05, BCSS: p > 0.05). Adjuvant chemotherapy showed no significant effects on both OS and BCSS in patients with stage I (OS: p = 0.100, BCSS: p = 0.858) and stage IIA breast cancer (OS: p > 0.05, BCSS: p > 0.05). CONCLUSION: For stage I and stage IIA patients, adjuvant chemotherapy could not improve OS and BCSS. Therefore, adjuvant chemotherapy might be skipped for stage I and stage IIA male breast cancer patients.

Adjuvant chemotherapy could benefit early-stage ER/PR positive mucinous breast cancer: A SEER-based analysis.

PURPOSE: The aim of this study was to explore the value of adjuvant chemotherapy in patients with early-stage ER/PR-positive mucinous carcinoma. METHODS: We identified early-stage ER/PR-positive mucinous carcinoma patients in the Surveillance, Epidemiology, and End Results (SEER) database. We used propensity-score matching (PSM) analysis to eliminate selection bias and differences in baseline characteristics. Univariate and multivariate analyses were performed to identify significant prognostic factors. The primary outcomes were overall survival (OS) and breast cancer-specific survival (BCSS), which were evaluated with the Kaplan-Meier method. RESULTS: After propensity score matching, 805 pairs were selected. Patients with early-stage ER/PR-positive mucinous adenocarcinoma in the chemotherapy group had a better OS, but not BCSS, than those in the nonchemotherapy group after PSM (OS: p < 0.001; BCSS: p = 0.285). After stratifying by tumor size and lymph node status, adjuvant chemotherapy could significantly improve the OS of early-stage ER/PR-positive patients with tumors larger than 3 cm (p = 0.004) if they had negative lymph nodes (LNs). For patients positive LNs, the OS was significantly different between the chemotherapy group and the non-chemotherapy group when the tumors were larger than 1 cm (T = 1-2.9 cm, p = 0.006; T＞3 cm, p = 0.049, respectively). CONCLUSION: Adjuvant chemotherapy maybe improves prognosis in patients with negative LNs and tumors larger than 3 cm, or patients with LNs metastasis and tumors larger than 1 cm. We suggest considering clinical characteristics meanwhile when deciding chemotherapy or not. Randomized controlled trials (RCT) are expected to confirm our results in the future.

Risk of breast cancer-related death in women with a prior cancer.

The overall risk of developing a second primary cancer is increasing. The purpose of this study was to analyze the survival of patients with breast cancer diagnosed after a prior cancer and identify risk factors of breast cancer death in this population. Using the SEER database, we identified 1,310 woman diagnosed with breast cancer between 2010 and 2015 after a prior cancer as the primary cohort. Clinicopathological characteristics were compared using the Student t-test and chi-square test. Fine and Gray's regression was used to evaluate the effect of treatments on breast cancer death. After propensity score matching (PSM), 9,845 pairs of patients with breast cancer as the prior or second cancer diagnosed between 2010 and 2011 were included as a second cohort. PSM-adjusted Kaplan-Meier and Cox hazards models were used to evaluate the impact of prior cancer on survival. The results showed that survivors of gynecologic cancers (e.g., ovarian cancer) had a higher risk of developing breast cancer than survivors of gastrointestinal and urinary tract cancers. More patients died of breast cancer than of prior urinary cancer (53.3% vs. 40%, P < 0.05) and melanoma (66.7% vs. 33.3%, P < 0.05). The ratio of breast cancer deaths to prior cancer deaths was significantly higher in patients with diagnoses interval ≥ 3 years than in those with the interval < 3 years (2.67 vs. 0.69, P < 0.001). Breast cancer-specific survival and overall survival rates were significantly lower in women with breast cancer as the second primary cancer than in those with breast cancer as the prior cancer, especially among hormone receptor-positive women. However, breast cancer treatment decreased the risk of breast cancer -specific death (hazard ratio = 0.695, 95% confidence interval: 0.586-0.725, P < 0.001). Breast cancer patients with prior cancers must be carefully considered for clinical trials.

The Role of Sharp Dissection in Nipple-Sparing Mastectomy: A Safe Procedure with No Necrosis of the Nipple-Areolar Complex.

BACKGROUND: Nipple-sparing mastectomy (NSM) is becoming increasingly accepted as a treatment for breast disease; however, nipple-areolar complex (NAC) necrosis, a frequent severe postoperative complication, inhibits the popularity of this procedure. This study reports the technical aspects and short-term postoperative outcomes of NSM. METHODS: A single-center, retrospective review of 110 patients treated with NSM at our institution from November 2015 to September 2018 was performed. The primary outcome was the incidence of NAC necrosis. RESULTS: A total of 130 NSMs performed on 110 patients were included in our study. Median patient age was 42 years. We performed a sharp dissection by using a scalpel, raising 3-5 mm thick flaps, and continuing onto the undersurface of the NAC. None of the 110 patients appeared to have NAC necrosis or mastectomy skin flap necrosis. However, discoloration or ischemia of the NAC with eschar formation presented between postoperative days 3 and 7 in six nipples; four nipples were ischemic, and two were discolored. No infection was detected in any of the 110 patients. All NACs were intact after an average follow-up of 30 months, and no local or systemic recurrence was detected in those breast cancer cases. CONCLUSION: NSM can be safely performed in properly selected patients. Nipple necrosis was avoided using a special surgical technique, and other complications occurred at an acceptable rate.

Tumor location of the central and nipple portion is associated with impaired survival for women with breast cancer.

BACKGROUND: Tumor location in the breast varies, with the highest frequency in the upper outer quadrant and lowest frequency in the lower inner quadrant. Nevertheless, tumors in the central and nipple portion (TCNP) are poorly studied types of breast cancer; therefore, we aimed to clarify the clinicopathological characteristics and prognostic features of TCNP. METHODS: Using the Surveillance, Epidemiology, and End Results database, we identifed 105,037 patients diagnosed with tumor in the breast peripheral quadrant (TBPQ) (n=97,046) or TCNP (n=7,991). The chi-squared test was used to compare categorical variables across TCNP and TBPQ. Cox proportional hazard models with hazard ratios were applied to estimate the factors associated with prognosis. RESULTS: The median follow-up was over 43 months. Compared with TBPQ, TCNP patients were signifcantly older (age ≥66 years: 40.4% vs 34.1%, P<0.001), with larger tumor sizes (>20 mm size: 46.9% vs 37.3%, P<0.001), higher proportions of TNM stage II-III (18.6% vs 9.9%, P<0.001), and more mastectomies (58.1% vs 37.8%, P<0.001). The breast cancer-specifc survival (BCSS)/overall survival (OS) rate was signifcantly worse for TCNP than for TBPQ. Multivariate Cox analysis showed a higher hazard ratios for TCNP over TBPQ (BCSS: hazard ratios =1.160, P=0.005, 95% CI: 1.046-1.287; OS: hazard ratios =1.301, P<0.001, 95% CI: 1.211-1.398). A subgroup analysis revealed inferior outcomes for TCNP in TNM stage II-III and breast subtype subgroup. Multivariate logistic regression indicated that TCNP was an independent contributing factor to LN metastasis. CONCLUSIONS: TCNP was associated with older age, larger tumor size, higher TNM stage, and lymph node metastasis. Compared with TBPQ, TCNP had adverse impacts on BCSS and OS.

Comparison of Oncoplastic Breast-Conserving Surgery and Breast-Conserving Surgery Alone: A Meta-Analysis.

PURPOSE: The use of oncoplastic reconstruction for breast-conserving surgery (BCS) extends benefits beyond merely minimizing poor cosmetic results. However, the feasibility and oncological safety of oncoplastic surgery (OPS) are controversial. METHODS: This meta-analysis aimed to compare the short-term and long-term oncological outcomes of BCS alone and BCS plus OPS. Relevant studies published before July 2017 in the Embase, the Cochrane Library, PubMed, and Web of Science databases were screened and collected. The meta-analysis was performed using STATA software (Stata Corp.). RESULTS: A total of 3,789 patients from 11 studies were included, with 2,691 patients in the BCS-alone group and 1,098 patients in the BCS plus OPS group. The demographics were similar between both groups, and no significant difference was observed in pathological T and N stages between the two groups. Re-excision was less common (relative risk [RR], 0.66; p=0.009) and the positive-margin rate was lower, but not significantly (RR, 0.83; p=0.191), in the BCS plus OPS group than in the BCS-alone group. The local and distal recurrence rates were similar in both groups. Both disease-free survival (hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.96-1.49; p=0.112) and overall survival (HR, 1.14; 95% CI, 0.76-1.69; p=0.527) did not differ between the two groups. CONCLUSION: A combination of BCS and OPS is preferred over BCS alone for decreasing re-excisions and provides similar long-term survival as BCS alone in patients with breast cancer.

Prognostic Significance of Mesenchymal-Epithelial Transition in Triple-Negative Breast Cancers.

INTRODUCTION: The prognostic value of the mesenchymal-epithelial transition (MET) in triple-negative breast cancers (TNBCs) remains controversial. A meta-analysis of the impact of MET in TNBCs was performed by searching published data. METHODS: PubMed and Embase databases were searched for eligible literature. The principal outcome measures were hazard ratios (HRs) for recurrence-free survival or overall survival according to MET expression. Combined HRs were calculated using fixed- or random-effects models according to heterogeneity. RESULTS: Six studies involving 785 patients met our selection criteria. The meta-analysis results showed that MET overexpression was associated with a 1.29-fold increased risk of recurrence (combined HR 1.29; 95% confidence interval, 1.04-1.60; P = .020) in the TNBCs. Three studies provided the related overall survival data (488 cases). The results showed that MET overexpression was associated with a 1.38-fold increased risk of mortality (HR, 1.38; 95% confidence interval, 1.08-1.76; P = .009). CONCLUSION: MET is an adverse prognostic marker for TNBCs. The results strengthen the rationale for targeted therapy of TNBCs using MET inhibitors in future clinical trials.

Characterization of Fc gamma receptor IIb expression within abdominal aortic aneurysm.

OBJECTIVE: To evaluate protein profiles and Fc gamma receptor IIb (FCGRIIB) expression in abdominal aortic aneurysm (AAA) compared to the expression in normal aortas. METHODS: We performed a protein array to study the protein expression profiles within AAA and normal aortic tissues. FCGRIIB was found to be significantly elevated in AAA samples. Quantitative PCR and Western blot analyses were performed to study the expression of FCGRIIB in AAA compared to that in normal aortic tissue. Immunohistochemistry was used to locate FCGRIIB and the B cell marker CD19 in AAA and normal aortas specimens. RESULTS: FCGRIIB was significantly elevated in AAA tissues in both mRNA (AAA vs. normal control: about 5.8 folds, p < 0.001) and protein levels (AAA vs. normal control: about 6.3 folds, p < 0.001). In AAA specimens, immunohistochemistry revealed that FCGRIIB localized to the area of inflammatory infiltrates, which consisted of CD 19+ B cells and other inflammatory cells. FCGRIIB and CD19 were undetectable in normal aortas. CONCLUSIONS: FCGRIIB was significantly elevated in AAA tissues compared to normal aortas. FCGRIIB may be involved in the pathogenesis of AAA by regulation of inflammatory reactions.

The -A2518G polymorphism in the MCP-1 gene and inflammatory bowel disease risk: A meta-analysis.

OBJECTIVE: The monocyte chemoattractant protein-1 (MCP-1) -A2518G gene polymorphism has been found to be involved in the susceptibility to inflammatory bowel disease (IBD); however, the results of existing studies are controversial. The aim of this meta-analysis was to assess the relationship between the MCP-1 -A2518G polymorphism and the risk of IBD. METHODS: PubMed, EMBASE and MEDLINE were searched for studies assessing the relationship between the -A2518G polymorphism in MCP-1 gene and the risk of IBD. Available data were extracted and statistically analyzed using STATA 12.0. RESULTS: A total of five publications involving 3137 individuals (1818 IBD cases and 1319 controls) were included in the meta-analysis. A combined analysis revealed that the MCP-1 -A2518G polymorphism in was a protective factor for GG + AG vs AA (OR 0.76, 95% CI 0.67-0.87, P = 0.000). Subgroup analysis by ethnicity showed that among European patients the AG + GG homozygote, unlike the AA homozygote, had a protective effect against IBD (OR 0.73, 95% CI 0.63-0.84, P = 0.000), but did not do so among Asian and African patients. Subgroup analysis by disease subtype suggested the -A2518G polymorphism in MCP-1 had a protective effect against Crohn's disease (OR 0.69, 95% CI 0.58-0.81, P = 0.000), but not against ulcerative colitis. CONCLUSIONS: Our meta-analysis suggested that the -A2518G polymorphism in MCP-1 may be a protective factor for IBD in European populations. Further studies are required to confirm these findings.

MCP-1 stimulates MMP-9 expression via ERK 1/2 and p38 MAPK signaling pathways in human aortic smooth muscle cells.

OBJECTIVE: We investigated the molecular mechanism underlying the role of monocyte chemoattractant protein-1 (MCP-1) in the formation and development of human abdominal aortic aneurysm (AAA). METHODS: We examined protein expression profiles using a protein array and found that MCP-1 was the most highly expressed protein in AAA tissues compared with normal aortas. To investigate the potential mechanism of MCP-1 involvement in the pathogenesis of AAA, we treated human aortic smooth muscle cells (HASMCs) with human recombinant MCP-1. RESULTS: MCP-1 was the most highly expressed protein in AAA tissues compared with normal aorta; matrix metalloproteinase-9 (MMP-9) expression was also significantly increased. Treatment with MCP-1 significantly increased the expression and activation of MMP-9 and activated the three major mitogen activated protein kinases (MAPKs) extracellular signal regulated kinase (ERK), c-Jun amino terminal kinase (JNK1/2) and p38 MAPK. Furthermore, MCP-1-induced secretion of MMP-9 was inhibited by U0126 (inhibitor of the ERK 1/2 pathway) and SB203580 (inhibitor of the p38 MAPK pathway), but not SP600125 (inhibitor of the JNK1/2 pathway). CONCLUSION: These data demonstrate that MCP-1 stimulates secretion of MMP-9 directly through the ERK1/2 and p38 MAPK mediated pathways in HASMCs. Thus, inhibition of this molecular mechanism might be a potential therapeutic target in the non-surgical treatment of AAA.