Jun Suk Kim

Response to high-dose intravenous immune globulin as a valuable factor predicting the effect of splenectomy in chronic idiopathic thrombocytopenic purpura patients

This study was conducted to verify whether the response to high‐dose intravenous immune globulin (IVIG) was related to the effect of splenectomy in chronic idiopathic thrombocytopenic purpura (ITP) patients. A total of 79 patients over 16 years of age were enrolled in this study. The response to the treatment was classified on the basis of the platelet count as no response (NR, <50 × 109/l), incomplete response (IR, (50–150) × 109/l), and complete response (CR, >150 × 109/l). The response was evaluated after the infusion of high‐dose IVIG, within 2 weeks after splenectomy (immediate response), and during a follow‐up period of more than 6 months after splenectomy (sustained response), respectively. 58 patients (73.4%) showed responses (CR or IR) to high‐dose IVIG. After splenectomy, immediate responses were observed in 73 patients (92%). The response to high‐dose IVIG had no relationship with the immediate response to splenectomy (P = 0.333). A follow‐up evaluation was possible with 58 patients; 6 patients with NR in immediate responses did not show any response during the follow‐up period, and 17 patients relapsed within 6 months after immediate responses, so 35 patients (60.3%) had sustained responses. Responders to IVIG had significantly higher sustained response rates to splenectomy than non‐responders (62% vs. 38%, P = 0.001). These results indicate that the response to high‐dose IVIG could be a valuable factor predicting the sustained response to splenectomy in chronic ITP patients. Am. J. Hematol. 66:197–202, 2001.

Long-Term Engraftment Stability of Peripheral Blood Stem Cells Cryopreserved Using the Dump-Freezing Method in a −80°C Mechanical Freezer with 10% Dimethyl Sulfoxide

In this study, we summarize our long-term follow-up data of 24 patients who underwent autologous peripheral blood stem cell transplantation (PBSCT) using the dump-freezing method in a −80°C freezer. Collected peripheral blood mononuclear cells were mixed with a cryoprotectant solution consisting of autologous plasma and 20% dimethyl sulfoxide, then placed in a −80°C freezer. The recovery rate of mononuclear cells (MNCs), colony-forming unit—granulocyte/macrophage (CFU-GM) colonies, and CD34+ cells were calculated. Engraftment time (with neutrophil count > 0.5 × 109/L, platelet count > 50 ×109/L) and normal hemopoiesis (neutrophil count > 2 ×109/L, platelet count > 100 ×109/L) were evaluated. Median duration of cryopreservation was 76 days. The mean recovery rates of MNCs, CFU-GM colonies, and CD34+ cells were 93.4%, 78.4%, and 95.3%, respectively. The median engraftment times of neutrophils and platelets were 8 and 27 days, respectively. The median normal hemopoiesis times of neutrophil and platelet were 31 and 45 days, respectively. Nine patients are alive and in complete remission (CR). Seven patients in first CR sustained normal hemopoiesis with a median duration of 35 months. Two patients, who achieved second CR after salvage chemotherapy due to a leukemia relapse after PBSCT, maintained engraftment status for 24 and 28 months, and 1 reached normal hemopoiesis. These results demonstrate that PBSCT using the dump-freezing method in a −80°C freezer leads to acceptable long-term engraftment stability.

The cutoff value of serum ferritin for the diagnosis of iron deficiency in community-residing older persons

The serum ferritin assay is the best single blood test for the diagnosis of iron deficiency. Previous studies with elderly anemic patients have suggested that ferritin level less than 45xa0μg/L is indicative of iron deficiency. The subjects of these studies were hospitalized patients with anemia, however. We thus conducted a prospective study to determine the normal minimum level of serum ferritin of community-dwelling older adults by assessing the ratio of serum transferrin receptor to the log ferritin level (sTfR-F index). We conducted the anemia survey between October and November 2002. A total of 1,254 apparently healthy older adults, aged between 60 and 95 years, from three urban community dwellings participated in the survey. Among these individuals, 156 subjects who were anemic or whose serum ferritin level was less than 100xa0μg/L were selected. The soluble transferrin receptor assay was performed and the sTfR-F index was calculated. The receiver operating characteristic curve analysis was performed. Based on the data, serum ferritin level of 22xa0μg/L was selected as the cutoff value for the diagnosis of iron deficiency in community-dwelling older adults. Applying the serum ferritin cutoff of 22xa0μg/L and the sTfR-F index cutoff of 1.5, the sensitivity of the assay was 89.5% (34 of 38) and the specificity was 89.0% (105 of 118). In conclusion, for the diagnosis of iron deficiency of community-residing older adults, we suggest the serum ferritin cutoff value of 22xa0μg/L obtained by use of the sTfR-F index. The value is lower than the previous value established for hospitalized and anemic older adults.

Phase II study with a combination of epirubicin, cisplatin, UFT, and leucovorin in advanced hepatocellular carcinoma

Purpose: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Because HCC usually presents as an advanced disease and occurs in the background of liver cirrhosis, most patients are not suitable for treatment with curative intent, thus effective systemic chemotherapy is required. However, the outcome of systemic chemotherapy has been disappointing in advanced HCC. This study was conducted to test the efficacy and toxicity of the combined regimen of epirubicin, cisplatin, and UFT moderated by leucovorin in advanced or recurrent HCC. Patients and methods: All 53 patients received epirubicin (50xa0mg/m2 i.v.) on day 1 and cisplatin (60xa0mg/m2 i.v.) after epirubicin administration. Oral UFT 400–600xa0mg/day, determined by body surface area, and leucovorin 75xa0mg/day were administered for 21 consecutive days, followed by a 7-day drug free interval. Results: Nine had a partial response, representing 16.9% of response rate (95% confidence interval rate; 7.0–26.8%) with median response duration of 17.1xa0weeks (95% CI; 5.0–29.3xa0weeks, range; 7.1–51.7xa0weeks). Fifteen patients had stable disease and the disease progressed in 26 patients. The median overall survival for the patients was 24.6xa0weeks (95% CI; 17.3–31.9xa0weeks, range; 3.0–131.3xa0weeks). The main toxicities were hematologic toxicities including neutropenia, which reached grade 3/4 in 17 patients (38.5%), and grade 3 or 4 thrombocytopenia in five patients (9.4%). Conclusion: The combination of epirubicin, cisplatin, and UFT moderated by leucovorin showed modest anti-tumor activity with relatively tolerable toxicities. However, a randomized phase III trial based on this regimen is warranted to clarify its survival benefit in patients with advanced HCC.

Hematopoietic Differentiation of Embryoid Bodies Derived from the Human Embryonic Stem Cell Line SNUhES3 in Co-culture with Human Bone Marrow Stromal Cells

Human embryonic stem (ES) cells can be induced to differentiate into hematopoietic precursor cells via two methods: the formation of embryoid bodies (EBs) and co-culture with mouse bone marrow (BM) stromal cells. In this study, the above two methods have been combined by co-culture of human ES-cell-derived EBs with human BM stromal cells. The efficacy of this method was compared with that using EB formation alone. The undifferentiated human ES cell line SNUhES3 was allowed to form EBs for two days, then EBs were induced to differentiate in the presence of a different serum concentration (EB and EB/high FBS group), or co-cultured with human BM stromal cells (EB/BM co-culture group). Flow cytometry and hematopoietic colony-forming assays were used to assess hematopoietic differentiation in the three groups. While no significant increase of CD34+/CD45- or CD34+/CD38- cells was noted in the three groups on days 3 and 5, the percentage of CD34+/CD45- cells and CD34+/CD38- cells was significantly higher in the EB/BM co-culture group than in the EB and EB/high FBS groups on day 10. The number of colony-forming cells (CFCs) was increased in the EB/BM co-culture group on days 7 and 10, implying a possible role for human BM stromal cells in supporting hematopoietic differentiation from human ES cell-derived EBs. These results demonstrate that co-culture of human ES-cell-derived EBs with human BM stromal cells might lead to more efficient hematopoietic differentiation from human ES cells cultured alone. Further study is warranted to evaluate the underlying mechanism.

Mitomycin‐C, 5‐fluorouracil, and leucovorin as a salvage therapy in patients with metastatic colorectal adenocarcinoma

Aim:u2003 There is no further treatment option for metastatic colon patients who are refractory to standard chemotherapy and to whom novel biological agents are not available. We evaluated the outcomes of mitomycin‐C, 5‐fluorouracil (5‐FU) and leucovorin in patients with metastatic colon cancer previously treated with oxaliplatin/5‐FU/leucovorin and irinotecan/5‐FU/leucovorin.

Persistent anemia in a patient with diffuse large B cell lymphoma: Pure red cell aplasia associated with latent Epstein-Barr virus infection in bone marrow

We report a case of pure red cell aplasia (PRCA), which was initially suspected as a result of bone marrow involvement of diffuse large B cell lymphoma. Persistent anemia without an obvious cause was observed in a 47-yr-old man diagnosed with relapsed diffuse large B cell lymphoma. The bone marrow study showed only erythroid hypoplasia without the evidence of bone marrow involvement with lymphoma cells, thus PRCA was suggested. However, parvovirus infection was excluded as a potential cause of PRCA because of negative IgM anti-parvovirus B19 antibody and negative parvovirus PCR in the serum. Latent Epstein-Barr virus (EBV) infection of bone marrow was suggested by in situ hybridization with EBV-encoded small RNA (EBER) that showed a strong positive expression in bone marrow cells. Thus, PRCA was thought to be associated with latent EBV infection in bone marrow cells. Although the finding of unexplained anemia is a possible predictor of bone marrow involvement with lymphoma cells, PRCA as a result of a viral infection including EBV should be considered in lymphoma patients. This is the first report of the occurrence of PRCA associated with latent EBV infection in a patient with non-Hodgkins lymphoma.

Abstract 208: Metformin represses stem cell properties and induces apoptosis in human breast cancer cells and mouse mammary epithelial cells

Cancer stem cells (CSCs) are small portions of cancer cells that have important self-renewal and proliferation characteristics, and therefore, they play a significant role in cancer development and metastasis. Recently, several studies have revealed CSCs of several solid tumors. The identification and targeting of CSCs are expected to advance treatment outcomes, but until now, only a few drugs that specifically target CSCs have been developed. Metformin, an antidiabetic drug used for the treatment of type 2 diabetes mellitus, suppresses gluconeogenesis in the liver and increases insulin sensitivity and glucose uptake in peripheral tissues such as muscles. Moreover, the drug has shown an anti-cancer effect by inhibiting cellular proliferation and protein synthesis in several cancer cell lines. Additionally, many clinical and epidemiological studies have suggested that metformin might be associated with a decreased risk of cancer development and an increased response to chemotherapy. In addition to its anticarcinogenic effect, studies about the anti-cancer stem cell effect of metformin have been recently reported. Several reports revealed that metformin could preferentially kill cancer stem cells, including breast cancer stem cells. However, the mechanism of anti-cancer stem cell activity is not well known. Therefore, this study was planned to confirm the cytotoxicity of metformin, especially for breast cancer stem cells as well as breast cancer cells. To this end, several human breast cancer cell lines and normal mouse mammary epithelial cell lines were used. In this study, metformin showed cell growth inhibition in human breast cancer cells and mouse mammary epithelial cells by inducing cell cycle arrest and apoptosis. Moreover, metformin specifically killed breast cancer stem cells. Metformin showed reduced mammosphere formation in all cell lines. In addition, decreasing breast cancer stem cell population by metformin treatment was identified through FACS analysis. For the mechanism of anti-cancer stem cell activity, western blot assay was performed. We identified decreased levels of cyclin D and cycline E and increased levels of Bax in secondary mammaospheres according to metformin treatment. In conclusion, this present study show that metformin kills breast cancer stem cells as well as breast cancer cells, and these phenomena occur by the induction of cell cycle arrest and apoptosis. Citation Format: Eun Joo Kang, Jae Hong Seo, Jun Suk Kim, Ji Young Kim. Metformin represses stem cell properties and induces apoptosis in human breast cancer cells and mouse mammary epithelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 208. doi:10.1158/1538-7445.AM2014-208

Prevalence of iron deficiency anemia in community-dwelling older persons as measured by the transferrin receptor-ferritin index

community-dwelling older adults using the sTfR-F index. We conducted the anemia survey in three urban districts (Guro, Yangcheon and Gwanak) located in the southwestern part of Seoul in 2002. In this survey, a total of 1,254 subjects over the age of 60 years were selected from a cross-sectional study, the results of which have been published previously [2] . In brief, all the subjects lived in their own homes and were fully ambulatory with unlimited activities of daily living. Informed consent was obtained from all subjects, and then a complete medical history was taken and laboratory testing including a complete blood cell count with a reticulocyte count and iron profi les was performed. Anemia was defi ned according to the World Health Organization criteria, i.e. a hemoglobin level of ! 13 g/dl in men and ! 12 g/dl in women. In case of anemia, we performed the sTfR assay using a commercial kit based on a polyclonal antibody in a sandwich enzyme immunoassay (R&D Systems, Minneapolis, Minn., USA). According to the manufacturer, the central 95th percentile of the reference distribution of the sTfR concentration is 8.7–28.1 nmol/l. We then calculated the sTfR-F index (ratio of sTfR and log ferritin level). All the sTfR assays were performed in duplicate. IDA was considered present if the subject had anemia and the sTfR-F index was 1 1.5. Anemia is the most common hematologic problem encountered in older adults, and its prevalence increases with age [1, 2] . The common causes of anemia among older persons are anemia of chronic disease, iron defi ciency caused by gastrointestinal bleeding, cobalamin defi ciency, folate defi ciency and the myelodysplasia. Among these causes, the diagnosis of iron defi ciency anemia (IDA) is important because proper iron therapy can improve the symptoms, and treatment may help indicate an occult gastrointestinal pathology such as malignancy [3, 4] . There are few reports regarding the prevalence of IDA in older persons, and epidemiologic studies on East Asian populations are scarce. Moreover, the results of such studies have been variable according to the diagnostic criteria used. Previously published reports have used serum ferritin levels to diagnose IDA, but the cutoff levels were different in the various studies. The interpretation of the serum ferritin level in older adults is sometimes complicated because its level increases with age and with concomitant chronic illnesses [5, 6] . Therefore, we measured the soluble transferrin receptor (sTfR), which is not infl uenced by ageing or chronic diseases [7, 8] , and we calculated the ratio of sTfR to the log ferritin level (sTfR-F index) to make the test more specifi c. An index value of