Effects of oral iron chelator deferasirox on human malignant lymphoma cells.

BACKGROUND: Iron is essential for cell proliferation and viability. It has been reported that iron depletion by a chelator inhibits proliferation of some cancer cells. Deferasirox is a new oral iron chelator, and a few reports have described its effects on lymphoma cells. The goal of this study was to determine the anticancer effects of deferasirox in malignant lymphoma cell lines. METHODS: Three human malignant lymphoma cell lines (NCI H28:N78, Ramos, and Jiyoye) were treated with deferasirox at final concentrations of 20, 50, or 100 µM. Cell proliferation was evaluated by an MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry. Western blot analysis was performed to determine the relative activity of various apoptotic pathways. The role of caspase in deferasirox-induced apoptosis was investigated using a luminescent assay. RESULTS: The MTT assay showed that deferasirox had dose-dependent cytotoxic effects on all 3 cell lines. Cell cycle analysis showed that the sub-G1 portion increased in all 3 cell lines as the concentration of deferasirox increased. Early apoptosis was also confirmed in the treated cells by Annexin V and PI staining. Western blotting showed an increase in the cleavage of PARP, caspase 3/7, and caspase 9 in deferasirox-treated groups. CONCLUSION: We demonstrated that deferasirox, a new oral iron-chelating agent, induced early apoptosis in human malignant lymphoma cells, and this apoptotic effect is dependent on the caspase-3/caspase-9 pathway.

Human feeder cells can support the undifferentiated growth of human and mouse embryonic stem cells using their own basic fibroblast growth factors.

In the culture system using human feeder cells, the mechanism through which these cells support undifferentiated growth of embryonic stem cells (ESCs) has not been well investigated. Here, we explored the mechanisms of 3 kinds of human feeder cells, including human placental cells from the chorionic plate, human bone marrow stromal cells, and human foreskin fibroblasts. First, we determined that undifferentiated growth of 2 kinds each of human (H1 and HSF6) and mouse (D3 and CE3) ESCs was possible in all human feeder cell types tested (human placental cells, human bone marrow stromal cells, and human foreskin fibroblasts), without the need for exogenous cytokine supplementation including basic fibroblast growth factor (bFGF) and leukemia inhibitory factor. We then prepared their corresponding endogenous bFGF-knockout feeders using siRNA and tried to maintain human and mouse ESCs in their undifferentiated state; however, neither human nor mouse ESCs could be maintained in bFGF-knockout human feeder cells. The expressions of stemness markers such as Oct-4 and Nanog were significantly decreased in the bFGF-knockout group compared with those in the controls, and differentiation had already occurred, despite the undifferentiated morphologic appearance of the ESCs. In conclusion, human feeder cells are able to support the undifferentiated growth of human and mouse ESCs via bFGF synthesis. Further, a bFGF-dependent pathway might be crucial for maintaining the undifferentiated characteristics of mouse and human ESCs.

Wernicke's encephalopathy following allogeneic hematopoietic stem cell transplantation.

Wernicke's encephalopathy is caused by thiamine deficiency, and is characterized by acute mental confusion, ataxia, and ophthalmoplegia. It is also a rare neurologic complication of hematopoietic stem cell transplantation (HSCT). However, because of its rare incidence, Wernicke's encephalopathy can easily be overlooked in HSCT patients, and a few misleading steps in the early stage of the disease may result in permanent neurologic disability or even mortality. We recently encountered a case of Wernicke's encephalopathy in a patient who underwent allogeneic HSCT. Based on our own experience and previously published documents, we suggest early radiologic surveillance and treatment for patients with findings compatible with Wernicke's encephalopathy following HSCT.

Treatment results including more than third-line chemotherapy for patients with advanced non-small cell lung cancer.

Recently, third-line chemotherapy for advanced non-small cell lung cancer (NSCLC) was accepted as a reasonable therapeutic option in patients with a favorable performance status. In practice, however, palliative chemotherapy has been performed for patients with a favorable performance status, even after third-line chemotherapy. Although multiple cycles of palliative chemotherapy were performed for these patients, there are little data of observation for courses of treatment from first-line to the last chemotherapy. We reviewed the courses of treatment for 82 patients with advanced NSCLC that had been admitted for platinum-based chemotherapy as a first-line treatment. Additional cycles of palliative chemotherapy were provided as monotherapy, based on the attending physician's decision considering patient performance status and toxicity after disease progression for previous chemotherapy. The median number of chemotherapy lines and cycles were 2 and 7, respectively, from first-line to the last chemotherapy. The median overall survival was 24 months in the response group of first-line chemotherapy, compared to 15 months for the entire study group. In the response group, the median number of chemotherapy cycles was 15 and patients received a median of 3 lines of chemotherapy. A total of 33 patients were candidate third-line chemotherapy or more. The median survival was 23 months for patients treated with more than third-line chemotherapy, compared to 7 months for patients treated with less than second-line chemotherapy. We conclude that long-standing chemotherapy is not beneficial to all NSCLC patients. However, patients with a favorable response to first-line chemotherapy tend to receive a higher number and more cycles of chemotherapy than the non-response group. Furthermore, multi-line chemotherapy appears to increase survival in the response group. Further studies will be needed to confirm these results.

The suggestion of a risk stratification system for febrile neutropenia in patients with hematologic disease.

We analyzed the prognostic factors from 259 cases of febrile neutropenia occurring in 137 patients with hematologic disease. Based on multivariate analysis, significant prognostic factors are recovery of neutropenia, respiratory infection, baseline serum albumin, baseline bicarbonate, baseline CRP, and CRP on the fifth day after antibiotic treatment. From these variables, we derived a predictive model for the prognosis of febrile neutropenia using baseline serum albumin, bicarbonate, and CRP, which could be easily checked before chemotherapy. Further studies in prospective setting are needed for the validation of this model.

Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy.

Rituximab is a monoclonal antibody that targets B-lymphocytes, and it is widely used to treat non-Hodgkin's lymphoma. However, its use has been implicated in HBV reactivation that's related with the immunosuppressive effects of rituximab. Although the majority of reactivations occur in hepatitis B carriers, a few cases of reactivation have been reported in HBsAg negative patients. However, reactivation in an HBsAg negative/HBsAb positive patient after rituximab treatment has never been reported in Korea. We present here an HBsAg-negative/HBsAb-positive 66-year-old female who displayed reactivation following rituximab plus CHOP chemotherapy for diffuse large B-cell lymphoma. While she was negative for HBsAg at diagnosis, her viral status was changed at the time of relapse as follows: HBsAg positive, HBsAb negative, HBeAg positive, HBeAb negative and an HBV DNA level of 1165 pg/ml. Our observation suggests that we should monitor for HBV reactivation during rituximab treatment when prior HBV infection or occult infection is suspected, and even in the HBsAg negative/HBsAb positive cases.

Clinical factors related to suspected second primary lung cancer development in patients with head and neck cancer.

PURPOSE: The rate of second primary lung cancer development for patients with head and neck cancer (HNC) has been noted. The aim of our study was to evaluate the incidence and clinical features of suspected second primary lung cancer that developed in patients with primary HNC. MATERIALS AND METHODS: We conducted a retrospective study of 469 patients who were newly diagnosed with HNC at the Korea University Medical Center between January 2000 and December 2006. RESULTS: A total of 469 patients were included (389 men and 80 women). Eighteen patients (3.8%) had suspected second primary lung cancers. Statistically significant clinical variables for lung cancer development included the origin site for the primary HNC (oro-hypopharynx and larynx) (p=0.048), abnormal chest x-ray findings (p=0.027) and the histological HNC type (squamous cell carcinoma) (p=0.032). When the second primary lung cancers were combined with HNCs, the adjusted overall survival of patients with a second primary lung cancer was 16 months (p<0.001). CONCLUSIONS: Considering the relative risk factors for a second primary lung cancer developing in patients with HNC, advanced diagnostic tools, such as chest CT or PET CT scan, should be applied for the early detection of a second primary lung cancer.

Association of single nucleotide polymorphisms in PIM-1 gene with the risk of Korean lung cancer.

PURPOSE: The expression of the PIM-1 gene, which is a proto-oncogene that encodes a serine/threonine kinase, is associated with multiple cellular functions such as proliferation, differentiation, apoptosis and tumorigenesis. In particular, several studies have reported that the PIM-1 gene is associated with the development of lymphoma, leukemia and prostate cancer. Therefore, this study was conducted to evaluate the association between the single nucleotide polymorphisms in the PIM-1 gene and the risk of lung cancer occurrence in the Korean population. MATERIALS AND METHODS: To evaluate the role of the PIM-1 gene in the development of lung cancer, the genotypes of the PIM-1 gene were determined in 408 lung cancer patients and 410 normal subjects. RESULTS: We found that the T-C-T-C haplotypes of the PIM-1 gene (-1196 T>C, IVS4 +55 T>C, IVS4 +1416 T>A and +3684 C>A) were associated with an increased risk of lung cancer [adjusted odds ratio (aOR): 3.98; 95% CI: 1.24 approximately 12.75, p-value: 0.020]. In particular, these haplotypes showed an increased risk of lung cancer in males (aOR: 5.67; 95% CI: 1.32~24.30, p-value: 0.019) and smokers (aOR: 7.82; 95% CI: 1.75 approximately 34.98, p-value: 0.007). CONCLUSIONS: The present results suggest that the T-C-T-C haplotype of the PIM-1 gene could influence the risk of developing smoking-related lung cancer in the Korean population. Additional functional studies with an larger sample sized analysis are warranted to reconfirm our findings.

Glucose transporter-1 expression in squamous cell carcinoma of the tongue.

PURPOSE: Tumor cells are known to express hypoxia-related proteins such as glucose transporter-1 (Glut-1). These hypoxia-induced changes may allow tumor cells to survive under sustained hypoxic microenvironments, and the surviving tumor cell under hypoxia may develop a more aggressive phenotype and so result in a poor prognosis. MATERIALS AND METHODS: The Glut-1 expression was analyzed by immunohistochemistry, and its association with the prognosis was assessed in 60 patients with squamous cell carcinoma of the tongue. RESULTS: The Glut-1 expression was diffuse with a membranous pattern, and the median percentage of Glut-1 positive tumor cells was 60% (range: 0.0 approximately 90.0%). A high Glut-1 expression (the percentage of positive tumor cells >or= the median value, 60%) was associated with the location of primary lesion, lymph node metastasis status and disease stage (p<0.05). The expression of Glut-1 was correlated with the Ki-67 expression (r=0.406, p=0.001). Microvessel density, as represented by CD31 staining, was also correlated with the Glut-1 expression although its significance is weak (r=0.267, p=0.039). On the univariate analysis, the group with a high Glut-1 expression showed poorer overall survival than the group with a low Glut-1 expression (p<0.05). However, the Glut-1 expression failed to show any independent prognostic significance on the multivariate analysis. CONCLUSION: The expression of Glut-1 may be useful for predicting the prognosis and determining the treatment strategy for the management of squamous cell carcinoma of the tongue.