Jusun Kim

The efficacy of cefazolin plus macrolide (erythromycin or clarithromycin) versus cefazolin alone in neonatal morbidity and placental inflammation for women with preterm premature rupture of membranes.

INTRODUCTION Although the use of broad-spectrum antibiotics in women with preterm premature rupture of membranes (PPROM) is recommended to prolong pregnancy and decrease short-term neonatal complications, the optimal regimen remains undetermined. The objective of this study was to compare the efficacy of cefazolin plus macrolide (erythromycin or clarithromycin) versus cefazolin alone in reducing neonatal morbidity and placental inflammation for women with PPROM. METHODS This prospective study included singleton pregnancies with PPROM (23-33 weeks gestation). The primary outcome was neonatal composite morbidity and the secondary outcomes were the incidence of abnormal brain sonography and infant neurological outcome at one year of age. The presence and the stage of acute histological chorioamnionitis and funisitis were also reviewed blinded to all clinical information. RESULTS 102 women were randomly assigned to cefazolin (n = 35), cefazolin plus erythromycin (n = 31), or cefazolin plus clarithromycin (n = 36). The neonatal composite morbidity, the incidence of abnormal brain sonography, and infant neurological outcome at one year of age were similar between the comparison treatments (combination of cefazolin plus erythromycin or clarithromycin) and cefazolin. However, the presence and stage of histological funisitis showed significant difference between cefazolin plus clarithromycin versus cefazolin alone (p = 0.023). DISCUSSION This study is the first clinical trial of the use of cefazolin with either clarithromycin or erythromycin compared to cefazolin alone in the management of PPROM in which the primary and secondary analyses showed no difference among the three antibiotic regimens. The only noted difference was from a lesser degree of histological funisitis associated with clarithromycin exposure. CONCLUSION Our data suggests that clarithromycin may be an alternative worth considering with potentially beneficial effects compared to erythromycin in PPROM.

Performance Analysis of Underwater Acoustic Communication Systems Using Underwater Channel Simulation Tool

The performance of underwater acoustic communication system is sensitive to the Doppler shift and ISI(Inter-Symbol Interference). Therefore, the simulation algorithm needs to consider time-spread due to multipath arrivals which cause the ISI, and time-varying Doppler shift along with moving source and receiver. For this purpose, VirTEX(Virtual Time series EXperiment) based on Ray model has been developed. In this paper, VirTEX is used to compare the characteristics of ocean waveguide from the experimental data and illustrate the performance. The CIR(Channel Impulse Response) that characterizes the multipath arrivals with representative time-spread due to multipath arrivals is compared between numerically simulated and experimental probe signal. Also, the communication performance analysis for BER(Bit Error Rate) is compared between numerically simulated and experimental data signal. As a result, VirTEX can be useful as a simulation tool for evaluating the performance of underwater acoustic communication system.

Acquired resistance to LY2874455 in FGFR2 -amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion

Background Fibroblast growth factor 2 (FGFR2) amplification, occurring in ~2–9% of gastric cancers (GC), is associated with poor overall survival. Results RNA sequencing identified a novel FGFR2-ACSL5 fusion in the resistant tumor that was absent from the matched pre-treatment tumor. The FGFR2-amplified PDC line was sensitive to FGFR inhibitors whereas the PDC line with concomitant FGFR2 amplification and FGFR2-ACSL5 fusion exhibited resistance. Additionally, the FGFR2-amplified GC PDC line, which was initially sensitive to FGFR2 inhibitors, subsequently also developed resistance. Materials and Methods We identified an FGFR2-amplified patient with GC, who demonstrated a dramatic and long-term response to LY2874455, a pan-FGFR inhibitor, but eventually developed an acquired LY2874455 resistance. Following resistance development, an endoscopic biopsy was performed for transcriptome sequencing and patient-derived tumor cell line (PDC) establishment to elucidate the underlying molecular alterations. Conclusions FGFR inhibitors may function against FGFR2-amplified GC, and a novel FGFR2-ACSL5 fusion identified by transcriptomic characterization may underlie clinically acquired resistance. Implications for Practice Poor treatment response represents a substantial concern in patients with gastric cancer carrying multiple FGFR2 gene copies. Here, we show the utility of a general FGFR inhibitor for initial response prior to treatment resistance and report the first characterization of a potential resistance mechanism involving an FGFR2-ACSL5 fusion protein.

Loss of Tuberous Sclerosis Complex 2 (TSC2) as a Predictive Biomarker of Response to mTOR Inhibitor Treatment in Patients with Hepatocellular Carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally. Mechanistic target of rapamycin (mTOR) is frequently up-regulated in HCC and plays an important role in HCC tumorigenesis. Tumors with loss of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR signaling, tend to respond well to mTOR inhibitors. We analyzed TSC2 expression status in Korean patients with HCC and evaluated the correlation between TSC2 loss and response to the mTOR inhibitor, everolimus. METHODS: We retrospectively assessed 36 patients with advanced HCC who had received sorafenib at a single center in Korea between 2008 and 2014, and for whom tumor specimens were available for TSC2 immunohistochemical analysis (IHC). Three patient-derived tumor cell lines (PDCs) were analyzed by western blotting to determine TSC2 expression and drug sensitivity to mTOR. RESULTS: Twelve of 36 patients (33.3%) showed low to undetectable levels of TSC2 expression. No significant differences were observed in progression-free survival (PFS) or overall survival with sorafenib treatment based on TSC2 expression status. Two patients were treated with everolimus after sorafenib failure; one patient, with moderate TSC2 expression, experienced stable disease with a PFS of 5.8 months; the other, with high TSC2 expression, experienced rapid progression. PDC models demonstrated that the TSC2-low HCC PDC line was significantly more sensitive to everolimus than the TSC2-high HCC PDC lines. CONCLUSION: Loss of TSC2 may predict improved response to everolimus in HCC patients, but further studies are needed to confirm the predictive role of TSC2 expression for everolimus treatment.

Placental deposition of C-reactive protein is a common feature of human pregnancy

This study examined the occurrence of placental C-reactive protein (CRP) in normal pregnancy with term delivery, spontaneous preterm delivery (sPTD), preeclampsia, and miscarriage. CRP immunoreactivity was detected in the syncytiotrophoblast. The immunopositive rate was significantly higher in sPTD than preeclampsia. The CRP immunopositive rate was also higher in acute chorioamnionitis than those without and showed a good correlation with the maternal serum CRP concentration. CRP mRNA expression was not detected in human and mouse placentas or choriocarcinoma cells. CRP may play a role in the pathological and physiological states of pregnancy.

3-Dimensional micropillar drug screening identifies FGFR2-IIIC overexpression as a potential target in metastatic giant cell tumor

We established two patient derived tumor cells (PDCs) from right and left pulmonary metastatic lesions respectively of a patient with giant cell tumor. At that time, patient-derived tumor cells from right and left surgical specimens were collected and cultured. High-throughput screening (HTS) for 24 drugs was conducted with a micropillar/microwell chip platform using giant cell tumor PDCs. Using 6 doses per drug in 6 replicates for giant cell tumor PDCs, the dose response curves and corresponding IC50 values were calculated from the scanned images using the S+ Chip Analyzer. A sensitive response was more significantly achieved for AZD4547 (FGFR2 inhibitor) in giant cell tumor PDCs originated from the right pulmonary nodule under the micropillar/microwell chip platform using 3D culture. This sensitivity was consistent with the target expression patterns of giant cell tumor PDCs (FGFR2-IIIC mRNA expression in giant cell tumor PDCs originated from the right pulmonary nodule was increased significantly as compared to those originated from left). However, in a conventional 2D cultured MTT assay, there was no difference for IC50 values of AZD4547 between giant cell tumor PDCs originated from right and left pulmonary nodules. An HTS platform based on 3D culture on micropillar/microwell chips and PDC models could be applied as a useful preclinical tool to evaluate the intrapatient tumor/response heterogeneity. This platform based on 3D culture might reflect far better the relation between the tumor-biology and the matched targeted agent as compared to a conventional 2D cultured MTT assay.

Abstract P3-10-25: The Prognosis of Metaplastic Breast Cancer Patients Compare to Triple-Negative Breast Cancer Patients

Background: Metaplastic breeast cancer (MBC) is a rare, heterogenous cancer characterized by admixture of adenocarcinoma with metaplastic elements, low hormone receptor expression and poor outcome. This study was planned to assess the clinicopathological chacteristics and immunohistochemical findings of MBC compared to invasive ductal carcinoma (IDC) including the triple-negative subtype (TN-IDC). Material and Methods: We retrospectively reviewed the medical records of 47 MBC and 1,346 IDC patients. Two hundred eighteen TN-IDC patients were included in the 1,346 IDC patients. Between 2005 and 2009, these patients were undergone surgical treatment at the Samsung Medical Center. Patients were reviewed clinicopathologic factors, immunohistochemistry of biologic factors such as ER, PR, HER-2, p53, Ki67, cytokeratine (CK) 5/6, epidermal growth factor receptor (EGFR), and treatment modalities (type of operation, use of chemotherapy, radiotherapy and hormone therapy). Result: The MBC patients presented with a larger tumor size (>T1, 66.0% vs. 44.3.%, P = 0.008), lower lymph node involvement (N0, 73.3% vs. 55.6%, P = 0.03), higher histologic (HG) and nuclear grade (NG) (HG3, 70.0% vs. 41.5%, P = 0.001; NG3,82.6% vs. 46.9%, P P P P P P P P P = 0.017). In follow-up duration (median 30 months, range 2-56 months), seven (14.9%) MBC patients and 98 (7.2%) IDC patients recurred. The 3-year disease-free survival (DFS) rate was 78.1% in the MBC group and 91.1% in IDC group (P P = 0.114). However, in patients with lymph node metastasis who underwent adjuvant chemotherapy, the 3-year DFS rate was 44.4% in MBC group and 72.5% in TN-IDC group (P = 0.025). Discussion: In our result, MBC show poorer clinical outcome than IDC. It is not shown significant difference between MBC and TN-IDC. However, MBC patients with nodal metastasis have poorer prognosis than TN-IDC patients with metastasis despite adjuvant chemotherapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-25.