Chemokines are key factors that influence the migration and maintenance of relevant immune cells into an infected tissue or a tumor microenvironment. Therefore, it is believed that the controlled administration of chemokines in the tumor microenvironment may be an effective immunotherapy against cancer. Previous studies have shown that CCL3, also known as macrophage inflammatory protein 1-alpha, facilitates the recruitment of dendritic cells (DCs) for the presentation of tumor Ags and promotes T cell activation. Here, we investigated the role of CCL3 in regulating the tumor microenvironment using a syngeneic mouse tumor model. We observed that MC38 tumors overexpressing CCL3 (CCL3-OE) showed rapid regression compared with the wild type MC38 tumors. Additionally, these CCL3-OE tumors showed an increase in the proliferative and functional tumor-infiltrating T cells. Furthermore, PD-1 immune checkpoint blockade accelerated tumor regression in the CCL3-OE tumor microenvironment. Next, we generated a modified CCL3 protein for pre-clinical use by fusing recombinant CCL3 (rCCL3) with a non-cytolytic hybrid Fc (HyFc).Administering a controlled dose of rCCL3-HyFc via subcutaneous injections near tumors was effective in tumor regression and improved survival along with activated myeloid cells and augmented T cell responses. Furthermore, combination therapy of rCCL3-HyFc with PD-1 blockade exhibited prominent effect to tumor regression. Collectively, our findings demonstrate that appropriate concentrations of CCL3 in the tumor microenvironment would be an effective adjuvant to promote anti-tumor immune responses, and suggest that administering a long-lasting form of CCL3 in combination with PD-1 blockers can have clinical applications in cancer immunotherapy.

Chemokines are key factors that influence the migration and maintenance of relevant immune cells into an infected tissue or a tumor microenvironment. Therefore, it is believed that the controlled administration of chemokines in the tumor microenvironment may be an effective immunotherapy against cancer. Previous studies have shown that CCL3, also known as macrophage inflammatory protein 1-alpha, facilitates the recruitment of dendritic cells (DCs) for the presentation of tumor Ags and promotes T cell activation. Here, we investigated the role of CCL3 in regulating the tumor microenvironment using a syngeneic mouse tumor model. We observed that MC38 tumors overexpressing CCL3 (CCL3-OE) showed rapid regression compared with the wild type MC38 tumors. Additionally, these CCL3-OE tumors showed an increase in the proliferative and functional tumor-infiltrating T cells. Furthermore, PD-1 immune checkpoint blockade accelerated tumor regression in the CCL3-OE tumor microenvironment. Next, we generated a modified CCL3 protein for pre-clinical use by fusing recombinant CCL3 (rCCL3) with a non-cytolytic hybrid Fc (HyFc).Administering a controlled dose of rCCL3-HyFc via subcutaneous injections near tumors was effective in tumor regression and improved survival along with activated myeloid cells and augmented T cell responses. Furthermore, combination therapy of rCCL3-HyFc with PD-1 blockade exhibited prominent effect to tumor regression. Collectively, our findings demonstrate that appropriate concentrations of CCL3 in the tumor microenvironment would be an effective adjuvant to promote anti-tumor immune responses, and suggest that administering a long-lasting form of CCL3 in combination with PD-1 blockers can have clinical applications in cancer immunotherapy.

PURPOSE: In this study, we compared the treatment outcomes for an alpha-blocker between 2 groups of men, one with high sympathetic activity (HSA) and another with low sympathetic activity (LSA) or normal sympathetic activity. METHODS: A total of 159 men (> or =50 years of age) with lower urinary tract symptoms resulting from benign prostatic hyperplasia were analyzed. We assigned patients to groups according to their sympathetic activity, which was evaluated by heart ratevariability measurements. HSA was defined as a low frequency/high frequency ratio greater than 1.6. All patients received 10mg of alfuzosin once a day for 12 weeks. The primary end point was a change in the total International Prostate SymptomScore (IPSS) at 12 weeks from baseline. RESULTS: Sixty-seven men were assigned to the HSA group and 92 men were assigned to the LSA group. The baseline characteristics were not significantly different between the 2 groups, and the response to alfuzosin was good in both groups. Themean total IPSS change was not different between the groups. Both groups were not significantly different with respect to the changes in maximal flow rate, IPSS voiding or storage symptom subscores, quality of life, and rates of adverse drug events. TheHSA group showed a similar willingness to continue treatment compared to the LSA group, although their treatment satisfaction rating was lower. CONCLUSIONS: The therapeutic effects of alfuzosin did not differ in regards to the differences in sympathetic activity, but treatment satisfaction ratings were lower in the HSA group.
Drug-Related Side Effects and Adverse Reactions ; Heart ; Heart Rate ; Humans ; Lower Urinary Tract Symptoms* ; Male ; Observational Study* ; Prospective Studies* ; Prostate ; Prostatic Hyperplasia ; Quality of Life ; Sympathetic Nervous System

This study investigated the baseline predictors of best corrected visual acuity (BCVA) and central retinal thickness (CRT) at 6 months in patients with treatment-naive branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). This multicenter, interventional case series included 208 BRVO and 123 CRVO patients with follow-up period of 6 months or more. Outcome measures of BCVA (logMAR) included absolute change from baseline and a gain or loss of > or = 0.3 from baseline. Outcome measures of CRT included absolute change from baseline and a measurement of < or = 250 microm or > or = 400 microm at 6 months. Univariate and multiple regression analyses were done to find baseline predictors. For BRVO, younger age, worse baseline BCVA, and shorter duration of symptom were associated with more gain in BCVA. For CRVO, worse baseline BCVA was associated with more gain in BCVA. For CRT outcomes, higher baseline CRT predicted greater decrease at 6 months in both BRVO and CRVO. Younger age and better baseline BCVA were associated with an increased likelihood of measurement of a < or = 250 microm outcome for BRVO and CRVO, respectively. For CRVO, smoking was associated with greater decrease from baseline and decreased likelihood of measurement of a CRT > or = 400 microm at 6 months. In conclusion, several baseline factors including age, symptom duration, and baseline BCVA and CRT are associated with BCVA and CRT outcomes at 6 months, which may help to predict disease course for RVO patients.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Retina/*pathology ; Retinal Vein Occlusion/pathology/*physiopathology ; *Visual Acuity

PURPOSE: The measurement of serum human epidermal growth factor receptor 2 (HER2) extracellular domain levels is a well-established method for evaluating whether a metastatic HER2-positive breast cancer patient will respond to HER2-targeted treatment. However, little is known about the value of serum HER2 for detecting disease relapse following curative surgical treatment in breast cancer patients. The purpose of this study was to evaluate the sensitivity of serum HER2, carcinoembryonic antigen (CEA), and carcinoma antigen 15-3 (CA 15-3) for the detection of disease recurrence in postoperative breast cancer patients with a primary HER2-positive tumor. METHODS: Serial measurements were taken of serum HER2, CEA, and CA 15-3 levels in patients with primary invasive HER2-positive breast cancer who underwent curative surgical treatment between January 2008 and December 2010. Following treatment, serum HER2 levels were monitored every 6 months using a chemiluminescence immunoassay. RESULTS: Overall, 264 patients were analyzed in this retrospective study. The median follow-up period was 27.7 months, and 24 patients relapsed during follow-up. The sensitivity of serum HER2, CEA, and CA 15-3 for the detection of disease recurrence was 37.5%, 25.1%, and 12.5%, respectively. Sensitivity increased to 45.8% when all three tumor markers were combined in the analysis. In a subgroup of patients without liver disease, the sensitivity of serum HER2, CEA, and CA 15-3 was 57.1%, 21.4%, and 14.3%, respectively. Of the 264 patients in this study, 80 patients had chronic hepatitis, liver cirrhosis, or abnormal aspartate aminotransferase or alanine aminotransferase levels during the follow-up period. Following the exclusion of these patients, the sensitivity of serum HER2 for the detection of disease recurrence increased to 57.1%. CONCLUSION: Serial serum HER2 measurement may be useful for the detection of disease relapse in patients with HER2-positive breast cancer. Abnormal liver function can result in elevated serum HER2 in the absence of disease recurrence.
Alanine Transaminase ; Aspartate Aminotransferases ; Breast Neoplasms* ; Breast* ; Carcinoembryonic Antigen ; Follow-Up Studies ; Hepatitis, Chronic ; Humans ; Immunoassay ; Liver ; Liver Cirrhosis ; Liver Diseases ; Luminescence ; Receptor, Epidermal Growth Factor ; Recurrence* ; Retrospective Studies ; Biomarkers, Tumor

We investigated the demographic characteristics and risk factors of Korean patients with naIve central or branch retinal vein occlusion (CRVO or BRVO). This study enrolled 41 clinical sites throughout Korea and included 557 consecutive patients with retinal vein occlusion (RVO) from May through November 2010. A total of 557 patients with new-onset RVO participated in this study. Two hundred and three (36.4%) patients were diagnosed with CRVO and 354 (63.6%) patients were diagnosed with BRVO. Comparisons between the two groups showed that the prevalence of diabetes mellitus was significantly higher in CRVO patients and hypertension was significantly higher in BRVO patients (P = 0.001 and 0.002, respectively). Poor baseline visual acuity was significantly associated with female and old age in BRVO patients (P = 0.002 and 0.013, respectively), whereas the wide intraretinal hemorrhage (CRVO, P = 0.029; BRVO, P < 0.001) and the macular ischemia (CRVO, P < 0.001; BRVO, P < 0.001) were associated with both groups. The study results show the clinical features of RVO in Korean patients. Hypertension is strongly associated with BRVO and diabetes mellitus is more strongly associated with CRVO in Korean patients with RVO. As the first nationwide study performed by the Korean Retinal Society, the results of this study can be applied to future studies on RVO.
Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group ; Child ; Child, Preschool ; Demography ; Diabetes Complications ; Female ; Humans ; Hypertension/complications ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Regression Analysis ; Republic of Korea ; Retinal Hemorrhage/complications ; Retinal Vein Occlusion/complications/*diagnosis ; Risk Factors ; Sex Factors ; Young Adult

PURPOSE: To validate whether FAM70B, which was found in our micro-array profiling as a prognostic marker for cancer survival, could accurately predict prognosis in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: A total of 124 patients with MIBC were enrolled in this study. The FAM70B expression level was analyzed by real-time polymerase chain reaction by using RNA from tumor tissues. The prognostic effect of FAM70B was evaluated by Kaplan-Meier analysis and a multivariate Cox regression model. RESULTS: Kaplan-Meier estimates showed a significant difference in progression-free survival (log-rank test, p=0.011) and cancer-specific survival (log-rank test, p=0.017) according to FAM70B gene expression level. By multivariate Cox regression analysis, high FAM70B expression was predictive of cancer progression (hazard ratio [HR], 2.115, p=0.013) and cancer-specific death (HR, 1.925; p=0.033). In the subgroup analysis, high expression of FAM70B was associated with poor cancer-specific survival, progression-free survival, and overall survival in the patients who underwent cystectomy (log-rank test, p=0.013, p=0.036, p=0.005, respectively). In the chemotherapy group, FAM70B expression was associated with cancer-specific survival and progression-free survival (log-rank test, p=0.013, p=0.042, respectively). Moreover, high FAM70B expression was associated with shorter cancer-specific survival in localized or locally advanced tumor stages (log-rank test, p=0.016). CONCLUSIONS: We confirmed the significance of FAM70B as a prognostic marker in a validation cohort. Therefore, we propose that the FAM70B gene could be used to more precisely predict cancer progression and cancer-specific death in patients with MIBC.
Cohort Studies ; Cystectomy ; Disease-Free Survival ; Gene Expression ; Gene Expression Profiling ; Humans ; Kaplan-Meier Estimate ; Prognosis ; Real-Time Polymerase Chain Reaction ; RNA ; Urinary Bladder ; Urinary Bladder Neoplasms

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia occurring in Western nations. In CLL it is well known that the risk of a secondary malignancy is higher than in the normal population. But in Korea, CLL is a rare type of leukemia, so there have been only a few reported cases with a secondary malignancy. CLL is characterized by progressive defects in both cell-mediated and humoral immunity. It is known that defects in the immune system of patients with CLL contribute to the development of a secondary malignancy. We experienced a case of a 71-year-old man who suffered from a chronic cough and was diagnosed with small cell lung cancer coexisting with CLL. Until this case, there was no reported case in Korea of small cell lung cancer coexisting with CLL. We now report a case of small cell lung cancer coexisting with CLL and present a literature review.
Aged ; Cough ; Humans ; Immune System ; Immunity, Humoral ; Korea ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell ; Small Cell Lung Carcinoma

PURPOSE: S100A8 is a member of the S100 protein family containing 2EF-hand calcium-binding motifs. S100 proteins are involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. Altered expression of this protein is associated with various diseases and cancers. The present study aimed to evaluate whether S100A8 has prognostic value for non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: A total of 103 primary NMIBC samples obtained by transurethral resection were evaluated. mRNA levels were examined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The results were compared with clinico-pathological parameters. The Kaplan-Meier method was applied to plot the curves for progression-free survival. The multivariate Cox regression model was used to identify the independent prognostic factors for progression. RESULTS: mRNA expression levels of S100A8 were significantly related to the progression of NMIBC. Kaplan-Meier estimates demonstrated significant differences in tumor progression according to the level of S100A8 expression (log-rank test, p<0.001). The multivariate Cox regression model revealed that the S100A8 mRNA expression level (hazard ratio: 12.538; 95% confidence interval: 2.245-70.023, p=0.004) was an independent predictor for disease progression of NMIBC. CONCLUSIONS: Expression levels of S100A8 might be a useful prognostic marker for disease progression of NMIBC.
Calgranulin A ; Cell Cycle ; Disease Progression ; Disease-Free Survival ; Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger ; S100 Proteins ; Biomarkers, Tumor ; Urinary Bladder ; Urinary Bladder Neoplasms

BACKGROUND/AIMS: The reflow disturbance phenomenon is associated with poor functional and clinical outcomes for patients suffering with acute myocardial infarction (AMI). In the era of primary coronary intervention (PCI), accurately identifying those lesions that are at a high risk of no-reflow is of crucial importance. Therefore, we investigated the risk factors of the reflow disturbance phenomenon in AMI patients who underwent PCI. METHODS: From February 2003 to June 2005, the clinical and angiographic characteristics of 475 patients who had undergone PCI were reviewed retrospectively. RESULTS: 65 patients (13.7%) showed the reflow disturbance phenomenon and the reperfusion times of the reflow disturbance group ranged from 1 hour to 142 hours. On univariate analysis, an older age (p<0.001), low systolic blood pressure (p=0.01), no thrombolysis followed by PCI (p<0.001), primary PCI (p<0.001), less time to PCI (p=0.001), a high peak serum CK-MB level (p=0.013), angiographically visible thrombus (p=0.016), a low pre-TIMI grade (p=0.021) and ST segment elevation on the ECG (p=0.002) were the significant risk factors of the reflow disturbance phenomenon. An older age, a low systolic BP and angiographically visible thrombus were significant risk factors on multivariate analysis. CONCLUSION: An older age, low systolic blood pressure and angiographically visible thrombus were the independent risk factors for the reflow disturbance phenonmenon in AMI patients who undergo PCI.
Blood Pressure ; Electrocardiography ; Humans ; Multivariate Analysis ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Reperfusion ; Retrospective Studies ; Risk Factors ; Stress, Psychological ; Thrombosis