I-Chun Chen

Lovastatin Modulates Glycogen Synthase Kinase-3β Pathway and Inhibits Mossy Fiber Sprouting after Pilocarpine-Induced Status Epilepticus

This study was undertaken to assay the effect of lovastatin on the glycogen synthase kinase-3 beta (GSK-3β) and collapsin responsive mediator protein-2 (CRMP-2) signaling pathway and mossy fiber sprouting (MFS) in epileptic rats. MFS in the dentate gyrus (DG) is an important feature of temporal lobe epilepsy (TLE) and is highly related to the severity and the frequency of spontaneous recurrent seizures. However, the molecular mechanism of MFS is mostly unknown. GSK-3β and CRMP-2 are the genes responsible for axonal growth and neuronal polarity in the hippocampus, therefore this pathway is a potential target to investigate MFS. Pilocarpine-induced status epilepticus animal model was taken as our researching material. Western blot, histological and electrophysiological techniques were used as the studying tools. The results showed that the expression level of GSK-3β and CRMP-2 were elevated after seizure induction, and the administration of lovastatin reversed this effect and significantly reduced the extent of MFS in both DG and CA3 region in the hippocampus. The alteration of expression level of GSK-3β and CRMP-2 after seizure induction proposes that GSK-3β and CRMP-2 are crucial for MFS and epiletogenesis. The fact that lovastatin reversed the expression level of GSK-3β and CRMP-2 indicated that GSK-3β and CRMP-2 are possible to be a novel mechanism of lovatstain to suppress MFS and revealed a new therapeutic target and researching direction for studying the mechanism of MFS and epileptogenesis.

Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF

Obesity is associated with chronic, low-grade inflammation, which can disrupt homeostasis within tissue microenvironments. Given the correlation between obesity and relative risk of death from cancer, we investigated whether obesity-associated inflammation promotes metastatic progression. We demonstrate that obesity causes lung neutrophilia in otherwise normal mice, which is further exacerbated by the presence of a primary tumour. The increase in lung neutrophils translates to increased breast cancer metastasis to this site, in a GM-CSF- and IL5-dependent manner. Importantly, weight loss is sufficient to reverse this effect, and reduce serum levels of GM-CSF and IL5 in both mouse models and humans. Our data indicate that special consideration of the obese patient population is critical for effective management of cancer progression.

Predictors of bloodstream infection associated with permanently implantable venous port in solid cancer patients

BACKGROUND The purpose of this study is to characterize the risk factors of bloodstream infection (BSI) associated with the use of permanent implantable venous ports (Port-A) in solid cancer patients. METHODS Solid cancer patients implanted with a Port-A were prospectively observed for the occurrence of Port-A-associated BSI (PABSI), defined as BSI without other identifiable infection foci. A PABSI risk score was developed using the Cox proportional hazards model. RESULTS A total of 415 patients were registered; 88 PABSI episodes occurred in 58 patients (incidence1.05 per 1000 catheter-days). All but one patient had stage IV cancer. Independent predictors of PABSI occurrence included neutropenia, total parenteral nutrition (TPN), chronic steroid use, invasive procedures, postoperative antibiotics, and preoperative antibiotics. A PABSI risk score with a cut-off value of 0 (sensitivity 88.5%, specificity 64.3%) was defined for stage IV cancer patients as follows: neutropenia, +1.350; TPN, +1.256; chronic steroid use, +1.947; preoperative antibiotics, -0.970; postoperative antibiotics, +0.959; and invasive procedures, +1.098. The median PABSI-free survival was 4.47 months for patients with scores ≥ 0 but not reached for patients with scores <0 (P < 0.0001). CONCLUSION The PABSI risk score can assist in identifying high-risk solid cancer patients and may assist in designing future preventive strategies.BACKGROUND The purpose of this study is to characterize the risk factors of bloodstream infection (BSI) associated with the use of permanent implantable venous ports (Port-A) in solid cancer patients. METHODS Solid cancer patients implanted with a Port-A were prospectively observed for the occurrence of Port-A-associated BSI (PABSI), defined as BSI without other identifiable infection foci. A PABSI risk score was developed using the Cox proportional hazards model. RESULTS A total of 415 patients were registered; 88 PABSI episodes occurred in 58 patients (incidence1.05 per 1000 catheter-days). All but one patient had stage IV cancer. Independent predictors of PABSI occurrence included neutropenia, total parenteral nutrition (TPN), chronic steroid use, invasive procedures, postoperative antibiotics, and preoperative antibiotics. A PABSI risk score with a cut-off value of 0 (sensitivity 88.5%, specificity 64.3%) was defined for stage IV cancer patients as follows: neutropenia, +1.350; TPN, +1.256; chronic steroid use, +1.947; preoperative antibiotics, -0.970; postoperative antibiotics, +0.959; and invasive procedures, +1.098. The median PABSI-free survival was 4.47 months for patients with scores ≥0 but not reached for patients with scores <0 (P < 0.0001). CONCLUSION The PABSI risk score can assist in identifying high-risk solid cancer patients and may assist in designing future preventive strategies.

Bevacizumab might potentiate the chemotherapeutic effect in breast cancer patients with leptomeningeal carcinomatosis.

BACKGROUND/PURPOSE Patients with leptomeningeal carcinomatosis (LC) from breast cancer is generally resistant to systemic chemotherapy. Bevacizumab may increase intratumor concentration of the chemotherapeutic agents through vascular normalization, although the overall clinical benefit of bevacizumab for metastatic breast cancer is under debate. METHODS Successful treatment of two breast cancer patients who developed LC after whole brain irradiation treatment for the brain metastases is reported here. Both patients have refractory disease to taxane and anthracycline, and both of them have disease progression under intrathecal methotrexate treatment for LC. RESULTS The two patients received systemic chemotherapy with bevacizumab (7.5 mg/kg infusion on Day 1), cisplatin (80 mg/m(2) infusion for 24 hours on Day 2), and etoposide (80 mg/m(2) infusion for 2 hours on Days 2-4) at 21-28 day intervals. Both patients achieved best response of negative cerebral spinal fluid cytology study and dramatic improvement of neurologic deficit after treatment. Their overall survival after development of LC was 8 months and 7.5 months respectively. CONCLUSION Bevacizumab plus etoposide and cisplatin might be a new option for breast cancer patients with LC. Further prospective study is warranted.

Clinical Relevance of Liver Kinase B1(LKB1) Protein and Gene Expression in Breast Cancer.

Liver kinase B1 (LKB1) is a tumor suppressor, and its loss might lead to activation of the mammalian target of rapamycin (mTOR) and tumorigenesis. This study aimed to determine the clinical relevance of LKB1 gene and protein expression in breast cancer patients. LKB1 protein expression was evaluated using immunohistochemistry in tumors from early breast cancer patients in two Taiwanese medical centers. Data on LKB1 gene expression were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set. The correlations between LKB1 expression, clinicopathologic factors, and patient outcome were analyzed. LKB1 expression was significantly associated with estrogen receptor (ER) expression in 2 of the 4 cohorts, but not with other clinicopathologic factors. LKB1 expression was not a predictor for relapse-free survival, overall survival (OS), or breast cancer-specific survival. In a subgroup analysis of the two Taiwanese cohorts, high LKB1 protein expression was predictive of high OS in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients (P = 0.013). Our study results indicate that LKB1 expression is not prognostic in the whole population of breast cancer patients, but it is a potential predictor of OS in the subset of HER2-positive patients

High Prevalence of the BIM Deletion Polymorphism in Young Female Breast Cancer in an East Asian Country.

Background A rapid surge of female breast cancer has been observed in young women in several East Asian countries. The BIM deletion polymorphism, which confers cell resistance to apoptosis, was recently found exclusively in East Asian people with prevalence rate of 12%. We aimed to evaluate the possible role of this genetic alteration in carcinogenesis of breast cancer in East Asians. Method Female healthy volunteers (n = 307), patients in one consecutive stage I-III breast cancer cohort (n = 692) and one metastatic breast cancer cohort (n = 189) were evaluated. BIM wild-type and deletion alleles were separately genotyped in genomic DNAs. Results Both cancer cohorts consistently showed inverse associations between the BIM deletion polymorphism and patient age (≤35 y vs. 36-50 y vs. >50 y: 29% vs. 22% vs. 15%, P = 0.006 in the consecutive cohort, and 40% vs. 23% vs. 13%, P = 0.023 in the metastatic cohort). In healthy volunteers, the frequencies of the BIM deletion polymorphism were similar (13%-14%) in all age groups. Further analyses indicated that the BIM deletion polymorphism was not associated with specific clinicopathologic features, but it was associated with poor overall survival (adjusted hazard ratio 1.71) in the consecutive cohort. Conclusions BIM deletion polymorphism may be involved in the tumorigenesis of the early-onset breast cancer among East Asians.

Phosphatidylinositol-3 Kinase Inhibitors, Buparlisib and Alpelisib, Sensitize Estrogen Receptor-positive Breast Cancer Cells to Tamoxifen

Tamoxifen is the standard first-line hormonal therapy for premenopausal women with estrogen receptor (ER)-positive metastatic breast cancer (BC). One of the crucial mechanisms underlying hormonal therapy resistance is the collateral activation of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We explored whether PI3K inhibitors, buparlisib and alpelisib, enhance the efficacy of tamoxifen against ER-positive BC cells. We have observed a synergism between alpelisib or buparlisib and tamoxifen in the treatment for ER-positive BC cell lines harboring different PI3K alterations. Immunoblotting analysis showed alpelisib, buparlisib, or either drug in combination with tamoxifen downregulated the PI3K downstream targets in the MCF-7 and ZR75-1 cells. In the MCF-7 cells transfected with a constitutive active (myristoylated) AKT1 construct or mutant ER, the synergistic effect between alpelisib and tamoxifen was markedly attenuated, indicating that synergism depends on AKT inhibition or normally functioning ER. Combining alpelisib or buparlisib with tamoxifen also attenuated MCF-7 tumor growth in Balb/c nude mice. Our data suggest that additional PI3K blockade might be effective in enhancing the therapeutic effect of tamoxifen in ER-positive BC and support the rationale combination in clinical trials.

Adiposity, Inflammation, and Breast Cancer Pathogenesis in Asian Women

Obesity is associated with white adipose tissue (WAT) inflammation in the breast, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that predispose to breast cancer development. We examined whether WAT inflammation and its associated systemic effects correlate with body fat levels in an Asian population where body mass index (BMI) is not an accurate assessment of obesity and cancer risk. We also investigated whether biologic differences could account for the greater proportion of premenopausal estrogen receptor (ER)–positive breast cancer in Asian versus Western countries. Breast WAT and fasting blood were prospectively collected from Taiwanese women undergoing mastectomy for breast cancer treatment. Body composition was measured in a subgroup using bioelectrical impedance analysis. WAT inflammation was defined by the presence of crown-like structures of the breast, which are composed of dead or dying adipocytes surrounded by macrophages. Findings were compared with U.S. Caucasian women. In the Taiwanese cohort (n = 72), breast WAT inflammation was present in 31 (43%) women and was associated with elevated BMI (P < 0.01) and increased levels of body fat (P < 0.01), C-reactive protein (P = 0.02), triglycerides (P < 0.01), insulin resistance scores (P = 0.04), and lower HDL cholesterol (P < 0.01). ER+ tumors were associated with greater body fat versus other subtypes (P = 0.03). Compared with U.S. Caucasians (n = 267), Taiwanese women had larger breast adipocytes despite lower BMI after adjusting for BMI and menopausal status (P = 0.01). A subclinical inflammatory state associated with increased adiposity and metabolic dysfunction could contribute to breast cancer pathogenesis in Asian women. Cancer Prev Res; 11(4); 227–36. ©2017 AACR.

Significant Clinical Factors Associated with Long-term Mortality in Critical Cancer Patients Requiring Prolonged Mechanical Ventilation

Studies about prognostic assessment in cancer patients requiring prolonged mechanical ventilation (PMV) for post-intensive care are scarce. We retrospectively enrolled 112 cancer patients requiring PMV support who were admitted to the respiratory care center (RCC), a specialized post-intensive care weaning facility, from November 2009 through September 2013. The weaning success rate was 44.6%, and mortality rates at hospital discharge and after 1 year were 43.8% and 76.9%, respectively. Multivariate logistic regression showed that weaning failure, in addition to underlying cancer status, was significantly associated with an increased 1-year mortality (odds ratio, 6.269; 95% confidence interval, 1.800–21.834; P = 0.004). Patients who had controlled non-hematologic cancers and successful weaning had the longest median survival, while those with other cancers who failed weaning had the worst. Patients with low maximal inspiratory pressure, anemia, and poor oxygenation at RCC admission had an increased risk of weaning failure. In conclusion, cancer status and weaning outcome were the most important determinants associated with long-term mortality in cancer patients requiring PMV. We suggest palliative care for those patients with clinical features associated with worse outcomes. It is unknown whether survival in this specific patient population could be improved by modifying the risk of weaning failure.

Abstract 4490: Comparisons of genetic alterations of breast cancer between East and West: Special emphases on young patients with ER+/HER2- tumors

A rapid surge of female breast cancer has been observed in young East Asians. As a first step toward understanding this phenomenon, we compared the genetic alterations between breast cancer form Taiwan (East) and Western countries (West). Under the same array platforms, the differences in gene copy number alterations (n = 120 in East and 1,948 in West) and gene expressions (n = 327 in East and 423 in West) were analyzed as further stratified by age and estrogen receptor (ER)/ HER2 status. Gene-gene interaction networks were explored by analyzing the overlapping gene with ingenuity pathway analysis. The ingenuity pathway analysis revealed the common differences between East and West in NFkB, PI3K, Akt, MAPK, ERK, IFNα, and Jnk networks. Among the patients Citation Format: Ching-Hung Lin, Tzu-Pin Lu, Ruby Yun-Ju Huang, Yen-Shen Lu, Ko-Yun Lo, Kuan-Ting Kuo, Eric Y. Chuang, Pei-Fang Wu, I-Chun Chen, Jean Paul Thiery, Chiun-Sheng Huang, Ann-Lii Cheng. Comparisons of genetic alterations of breast cancer between East and West: Special emphases on young patients with ER+/HER2- tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4490.