We tested the efficacy of lapatinib, a dual tyrosine kinase inhibitor which interrupts the HER2 and epidermal growth factor receptor (EGFR) pathways, in a panel of triple-negative breast cancer (TNBC) cells, and examined the drug mechanism. Lapatinib showed an anti-proliferative effect in HCC 1937, MDA-MB-468, and MDA-MB-231 cell lines. Lapatinib induced significant apoptosis and inhibited CIP2A and p-Akt in a dose and time-dependent manner in the three TNBC cell lines. Overexpression of CIP2A reduced lapatinib-induced apoptosis in MDA-MB-468 cells. In addition, lapatinib increased PP2A activity (in relation to CIP2A inhibition). Moreover, lapatinib-induced apoptosis and p-Akt downregulation was attenuated by PP2A antagonist okadaic acid. Furthermore, lapatinib indirectly decreased CIP2A transcription by disturbing the binding of Elk1 to the CIP2A promoter. Importantly, lapatinib showed anti-tumor activity in mice bearing MDA-MB-468 xenograft tumors, and suppressed CIP2A as well as p-Akt in these xenografted tumors. In summary, inhibition of CIP2A determines the effects of lapatinib-induced apoptosis in TNBC cells. In addition to being a dual tyrosine kinase inhibitor of HER2 and EGFR, lapatinib also inhibits CIP2A/PP2A/p-Akt signaling in TNBC cells.

To investigate the incidence and risk factors for the occurrence of proven or probable invasive fungal infection (IFI) in adult patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 421 patients undergoing HSCT between 2002 and 2013 in our hospital. The risk factors for the occurrence of IFI were analyzed using Cox regression models. Thirty-one patients with the median age of 42 years (range, 19-60 years) developed IFI after HSCT. The post-HSCT IFI incidence was 7.4% and median time from HSCT to the diagnosis of IFI was 139 days (range, 2-1809 days). Of the pretransplant factors, European Group for Blood and Marrow Transplantation (EBMT) risk score > 2 (p = 0.001) and prior history of IFI (p = 0.006) or type 2 diabetes mellitus (DM; p = 0.042) were the significant predictors for post-HSCT IFI in univariate analyses. In multivariate analysis, EBMT risk score > 2 (p = 0.015) and prior history of IFI (p = 0.006) retained significance. Of the post-transplant factors, acute graft-versus-disease (GVHD) overall Grade III-IV (p < 0.001), extensive chronic GVHD (p = 0.002), development of post-transplant lymphoproliferative disorders (p = 0.005), and the use of high-dose steroids (p < 0.001) were statistically significant in univariate analyses. After multivariate analysis, high-dose steroids (p < 0.001) and acute GVHD overall Grade III-IV (p = 0.045) retained significance. These results suggest that risk group stratification prior to HSCT and monitoring of IFI in patients with severe GVHD receiving high-dose steroids is mandatory to reduce the mortality and morbidity of post-HSCT IFI, especially in those with prior history of IFI.

Background and Purpose. This study aimed to analyze survival, clinical responses, compliance, and adverse effects in locally advanced head and neck cancer (LAHNC) patients treated with split-dose cisplatin-based concurrent chemoradiation therapy (SD-CCRT) or cetuximab with concurrent radiation therapy (BioRT). Materials and Methods. We retrospectively evaluated 170 LAHNC patients diagnosed between January 1, 2009, and July 31, 2012: 116 received CCRT and 54 received BioRT. Results. Complete response rates were similar in the SD-CCRT and BioRT groups (63.8% versus 59.3%; ), and locoregional relapse rates were 18.1% and 13.0%, respectively (). The 3-year relapse-free survival rate was 65.8% in the SD-CCRT group and 65.5% in the BioRT group, respectively (). The 3-year overall survival rate was 78.5% in the SD-CCRT group and 70.9% in the BioRT group, respectively (). Hematologic side effects were significantly more frequent in the SD-CCRT than in the BioRT group. Mucositis frequency was similar. Conclusions. Primary SD-CCRT and BioRT both showed good clinical response and survival. Hematologic toxicities were more frequent, but tolerable, in the SD-CCRT group. Both groups showed good compliance.

Non-small cell lung cancer (NSCLC)-carrying specific epidermal growth factor receptor (EGFR) mutations can be effectively treated by a tyrosine kinase inhibitor such as gefitinib. However, the inevitable development of acquired resistance leads to the eventual failure of therapy. In this study, we show the combination effect of omega-3 fatty acid-enriched fish oil (FO) and selenium (Se) on reversing the acquired gefitinib-resistance of HCC827 NSCLC cells. The gefitinib-resistant subline HCC827GR possesses lowered proapoptotic CHOP (CCAAT/enhancer-binding protein homologous protein) and elevated cytoprotective GRP78 (glucose regulated protein of a 78 kDa molecular weight) endoplasmic reticulum (ER) stress response elements, and it has elevated β-catenin and cyclooxygenase-2 (COX-2) levels. Combining FO and Se counteracts the above features of HCC827GR cells, accompanied by the suppression of their raised epithelial-to-mesenchymal transition (EMT) and cancer stem markers, such as vimentin, AXL, N-cadherin, CD133, CD44, and ABCG2. Accordingly, an FO and Se combination augments the gefitinib-mediated growth inhibition and apoptosis of HCC827GR cells, along with the enhanced activation of caspase -3, -9, and ER stress-related caspase-4. Intriguingly, gefitinib further increases the elevated ABCG2 and cancer stem-like side population in HCC827GR cells, which can also be diminished by the FO and Se combination. The results suggest the potential of combining FO and Se in relieving the acquired resistance of NSCLC patients to targeted therapy.