Showing papers by "Soo Hyun Lee published in 2014"

Gene expression profiles of human adipose tissue-derived mesenchymal stem cells are modified by cell culture density

Abstract: Previous studies conducted cell expansion ex vivo using low initial plating densities for optimal expansion and subsequent differentiation of mesenchymal stem cells (MSCs). However, MSC populations are heterogeneous and culture conditions can affect the characteristics of MSCs. In this study, differences in gene expression profiles of adipose tissue (AT)-derived MSCs were examined after harvesting cells cultured at different densities. AT-MSCs from three different donors were plated at a density of 200 or 5,000 cells/cm(2). After 7 days in culture, detailed gene expression profiles were investigated using a DNA chip microarray, and subsequently validated using a reverse transcription polymerase chain reaction (RT-PCR) analysis. Gene expression profiles were influenced primarily by the level of cell confluence at harvest. In MSCs harvested at ∼90% confluence, 177 genes were up-regulated and 102 genes down-regulated relative to cells harvested at ∼50% confluence (P 2). Proliferation-related genes were highly expressed in MSCs harvested at low density, while genes that were highly expressed in MSCs harvested at high density (∼90% confluent) were linked to immunity and defense, cell communication, signal transduction and cell motility. Several cytokine, chemokine and growth factor genes involved in immunosuppression, migration, and reconstitution of damaged tissues were up-regulated in MSCs harvested at high density compared with MSCs harvested at low density. These results imply that cell density at harvest is a critical factor for modulating the specific gene-expression patterns of heterogeneous MSCs.

Clinical features and treatment outcomes of Langerhans cell histiocytosis: a nationwide survey from Korea histiocytosis working party.

Abstract: A nationwide survey was conducted to clarify the clinical features and outcomes of Korean children with Langerhans cell histiocytosis (LCH). Korea Histiocytosis Working Party analyzed the data of 603 patients who were diagnosed with LCH between 1986 and 2010 from 28 institutions in Korea. Median age at diagnosis was 65 months (range, 0 to 276 mo). Bone was the most frequently affected organ (79.6%) followed by skin (19.2%). Initially, 419 patients (69.5%) had single-system involvement (SS), 85 (14.1%) with multisystem (MS) disease without risk organ involvement (MS-RO), and 99 (16.4%) multisystem disease with risk organ involvement (MS-RO). The 5-year overall survival (OS) rates in the SS, MS-RO, and MS-RO groups were 99.8%, 98.4%, and 77.0%, respectively (P<0.001), and the 5-year reactivation rates were 17.9%, 33.5%, and 34.3%, respectively (P<0.001). The OS rate was lower in patients with RO involvement (P=0.025) and lack of response to initial treatment (P=0.001). MS involvement (P=0.036) was an independent risk factor for reactivation. Permanent consequences were documented in 99 patients (16.4%). Reactivation of disease, MS involvement, and age at diagnosis ≤ 2 years were associated with higher incidence of permanent consequences. This study emphasized that further efforts are required to improve survival of MS-RO patients and reduce reactivation in younger patients with MS involvement.

Clinical outcome of relapsed or refractory burkitt lymphoma and mature B-cell lymphoblastic leukemia in children and adolescents.

Abstract: PURPOSE: Despite the rapid improvement in survival rate from Burkitt lymphoma and mature B-cell lymphoblastic leukemia (B-ALL) in children, a small subset of patients do not respond to first-line chemotherapy or experience relapse (RL). Herein, we report the clinical characteristics and outcomes of these patients. MATERIALS AND METHODS: RL or refractory Burkitt lymphoma and mature B-ALL in 125 patients diagnosed from 1990 to 2009 were retrospectively analyzed. RESULTS: Nineteen patients experienced RL or progressive disease (PD). Among them, 12 patients had PD or RL less than six months after initial treatment and seven had late RL. Seven patients achieved complete response (CR), 11 had PD, and one had no more therapy. Six patients who achieved CR survived without evidence of disease and four of them underwent high-dose chemotherapy (HDC) followed by stem cell transplantation (SCT). However, 11 patients who failed to obtain CR eventually died of their disease. Five-year overall survival (OS) was 31.6±10.7%. OS of patients with late RL was superior to that of patients with early RL (57.1±18.7%, vs. 16.7±10.8%, p=0.014). Achievement of CR after reinduction had significant OS (p < 0.001). OS for patients who were transplanted was superior (p < 0.01). In multivariate analysis, achievement of CR after reinduction chemotherapy showed an association with improved OS (p=0.05). CONCLUSION: Late RL and chemotherapy-sensitive patients have the chance to achieve continuous CR using HDC/SCT, whereas patients who are refractory to retrieval therapy have poor prognosis. Therefore, novel salvage strategy is required for improvement of survival for this small set of patients.

Toxicity of tandem high-dose chemotherapy and autologous stem cell transplantation using carboplatin-thiotepa-etoposide and cyclophosphamide-melphalan regimens for malignant brain tumors in children and young adults.

Abstract: The number of studies examining the use of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) to treat high-risk or recurrent brain tumors is increasing. However, studies addressing the toxicity associated with tandem HDCT/auto-SCT, particularly during the second HDCT/auto-SCT, are very limited. For this reason, we retrospectively evaluated the toxicity of tandem HDCT/auto-SCT with carboplatin-thiotepa-etoposide (CTE) and cyclophosphamide-melphalan (CM) regimens when used to treat high-risk or recurrent brain tumors. A total of 109 patients who received a first HDCT/auto-SCT and 100 who proceeded to a second HDCT/auto-SCT between May 2005 and December 2013 were included. Hematologic recovery was rapid during both the first and second HDCT/auto-SCT. In the first HDCT/auto-SCT, mucositis-related gastrointestinal toxicity was frequent, and two (1.8 %) patients died from toxicity [one hepatic veno-occlusive disease (VOD) and one sepsis]. In the second HDCT/auto-SCT, mucositis-related toxicity was milder than in the first round. However, hepatic VOD frequency was high (20.0 %), and six (6.0 %) patients died from toxicity (four hepatic VODs, one asphyxia, and one sepsis). Multivariate analysis indicated that age younger than 8 years was the only significant predictor for hepatic VOD. All six patients who died from toxicity during the second HDCT/auto-SCT were younger than 9 years of age. This study demonstrates that tandem HDCT/auto-SCT using CTE/CM regimens was generally feasible. However, dose reduction during the second HDCT/auto-SCT in young children might be needed to decrease the death rate from toxicity.

Intensive chemotherapy followed by reduced-dose radiotherapy for biopsy-proven CNS germinoma with elevated beta-human chorionic gonadotropin

Abstract: In this study, 10 patients with biopsy-proven germinoma with a beta-human chorionic gonadotropin (β-HCG) level >50 mIU/ml received intensive chemotherapy followed by reduced-dose radiotherapy (RT) to reduce late effects from RT. CSF β-HCG levels were >200 mIU/ml in five patients. After endoscopic or stereotactic biopsy, four cycles of induction chemotherapy were administered prior to RT. A CEB regimen (carboplatin + etoposide + bleomycin) and a CyEB regimen (cyclophosphamide + etoposide + bleomycin) were alternated. No residual tumor remained after induction chemotherapy in six patients, only cystic lesions were present at the primary tumor site in three, and a small solid residual tumor was observed in the remaining patient; however, all these patients had normal β-HCG levels. If complete response was achieved before initiation of RT, 19.5 Gy craniospinal RT (CSRT) + 10.8 Gy local RT was administered to the tumor bed. If residual lesion was suspected, the dose of RT was selected according to the presence/absence of tumor dissemination at diagnosis (19.5 Gy CSRT + 19.8 Gy local RT for localized tumors and 24.0 Gy CSRT + 16.2 Gy local RT for disseminated tumors). Eight patients, including four patients with a β-HCG level >200 mIU/ml, received 19.5 Gy CSRT. All patients remain disease free at a median follow-up of 58 (range 35–94) months from diagnosis. Our data suggest that pathologically pure germinoma with a significantly elevated β-HCG level might be cured with reduced-dose RT if intensive chemotherapy is provided.

Unrelated donor cord blood transplantation for non-malignant disorders in children and adolescents

Abstract: This study analyzes the data reported to the Korean Cord Blood Registry between 1994 and 2008, involving children and adolescents with non-malignant diseases. Sixty-five patients were evaluated in this study: SAA (n = 24), iBMFS, (n = 16), and primary immune deficiency/inherited metabolic disorder (n = 25). The CI of neutrophil recovery was 73.3% on day 42. By day 100, the CI of acute grade II-IV graft-versus-host disease was 32.3%. At a median follow-up of 71 months, five-yr OS was 50.7%. The survival rate (37.5%) and CI of neutrophil engraftment (37.5%) were lowest in patients with iBMFS. Deaths were mainly due to infection, pulmonary complications, and hemorrhage. In a multivariate analysis, the presence of >3.91 × 10(5) /kg of infused CD34 + cells was the only factor consistently identified as significantly associated with neutrophil engraftment (p = 0.04) and OS (p = 0.03). UCBT using optimal cell doses appears to be a feasible therapy for non-malignant diseases in children and adolescents for whom there is no appropriate HLA-matched related donor. Strategies to reduce transplant-related toxicities would improve the outcomes of UCBT in non-malignant diseases.

Acute lymphoblastic leukemia with mature B-cell phenotype and t(9;11;11)(p22;q23;p11.2): a case study and literature review.

Abstract: Patients with infantile ALL are fundamentally different from adult patients in that infants have a worse prognosis, which is attributed to the increased relative incidence of MLL gene rearrangements [1, 2]. MLL is located on chromosome 11q23 and is a frequent target of chromosome translocations in hematopoietic malignancies. Patients with ALL and MLL rearrangements usually have distinct characteristics, such as organomegaly, marked leukocytosis, and a high incidence of central nervous system leukemia [3, 4]. Most importantly, regardless of the age at presentation, MLL rearrangement in ALL is associated with a poor response to therapy and a poor prognosis [5]. In contrast to lymphoblastic leukemias with MLL rearrangements, B-lineage acute leukemias with surface immunoglobulin expression are generally associated with leukemic manifestation of Burkitt lymphoma. Leukemic cells typically have a deeply basophilic and vacuolated cytoplasm and a t(8;14) translocation or its variants, which can be generally identified by using conventional cytogenetic or FISH analysis [6]. However, a series of cases of B-cell lymphoblastic leukemia with surface immunoglobulin expression and without features of Burkitt lymphoma have been reported [7-16]. Among these cases, a small number of patients presented with MLL gene rearrangements, especially the t(9;11) [10-16]. We describe an infant with ALL with surface immunoglobulin expression and MLL gene rearrangements including the t(9;11). The patient was a 4-month-old boy who presented with fever for 5 days. At admission, the patient had leukocytosis (white blood cells, 117.2×109/L), anemia (Hb, 9.4 g/dL), and thrombocytopenia (platelets, 54×109/L). The results of physical examination were unremarkable. There was no lymphadenopathy or organomegaly. The serum uric acid (10.7 mg/dL) and lactate dehydrogenase (1,186 µmol/L) levels were elevated. Radiographic evaluation revealed no thoracic or abdominal masses. In the sample collected at admission, approximately 90% of the white blood cells were blasts having small to medium size, high nuclear-cytoplasmic ratio, round nuclei with fine chromatin and inconspicuous nucleoli, and pale blue cytoplasm without granules or vacuoles (Fig. 1A). The cellular elements of bone marrow aspirates and biopsies consisted almost entirely of blasts with a similar morphology. Immunophenotypic analysis by flow cytometry performed on bone marrow aspirate showed blasts expressing CD19, cytoplasmic CD79a, CD10, cytoplasmic CD22, and surface immunoglobulin λ light chain. CD34 and terminal deoxynucleotidyl transferase (TdT) were not expressed (Fig. 1B). All other markers including myelomonocytic markers were not expressed. Conventional karyotyping of uncultured bone marrow aspirate showed a 3-way t(9;11;11) translocation among 9p22, 11q23, and 11p11.2 in 20 metaphase cells (Fig. 2A). FISH studies performed on bone marrow aspirates revealed a MLL translocation (Fig. 2B). In additional studies, there was no evidence of MYC rearrangements. Molecular analysis by reverse transcription (RT)-PCR also revealed a 367-bp sized amplicon corresponding to the MLL ex8-MLLT3 (AF9) ex9 fusion transcript (Fig. 2C). Fig. 1 (A) Blasts of the patient exhibit non-FAB-L3 morphology. (B) Scatter plots of flow cytometric immunophenotyping show blasts with CD19+, CD10+, CD34-, terminal deoxynucleotidyl transferase (TdT)-, and surface immunoglobulin (sIg) λ+. Fig. 2 (A) Conventional karyotyping indicates the karyotype of t(9;11;11)(p22;q23;p11.2). The arrows indicate chromosomes showing abnormalities. (B) FISH analysis indicates the MLL break-apart signals. LSI MLL(B-A) probe refers to the locus specific identifier ... The patient received induction chemotherapy for ALL. A rapid response was observed with the resolution of leukocytosis, and complete remission (CR) was documented after the induction phase. Sibling peripheral blood stem cell transplantation (PBSCT) was performed after the consolidation phase. Minimal residual disease (MRD) evaluation at this time was negative and no evidence of relapse has been found during 8 months of follow-up. The majority of B-lineage lymphoblastic leukemia cases present B cells of the pre-pre-B and pre-B stages, without surface immunoglobulin light chain expression. Mature B-cell phenotype is found in less than 2% of cases [13]. MLL translocation, particularly t(9;11), exists in a small number of these patients. To date, more than 50 different translocation fusion partners of MLL have been identified [5]. Regardless of the variety of cytogenetic abnormalities, ALL with MLL gene rearrangement forms a distinct subset of acute leukemias. The three most frequent MLL rearrangements are t(4;11), t(9;11), and t(11;19) [17, 18]. However, the t(9;11), although common in de novo AML and therapy-related AML, is only rarely seen in B-cell lymphoblastic leukemias (B-ALL) [19, 20]. We found 13 previously reported cases of B-ALL with surface light chain expression and MLL rearrangements in children and the characteristics are summarized in Table 1. Among the 14 cases including the present case, 13 patients were children, and 9 had t(9;11). Interestingly, none of these patients showed t(4;11)(q21;q23), the most frequent MLL rearrangement found in B-ALL of children [18]. Rather, the t(9;11) was most frequently observed. In the present case, the three-way translocation t(9;11;11)(p22;q23;p11.2) bearing the MLL-AF9 fusion gene was detected by FISH and RT-PCR analyses. Table 1 Lymphoblastic leukemia with surface light chain immunoglobulin expression and MLL rearrangement including t(9;11) The frequent association between the t(9;11) and surface light chain restriction suggests that ALL with this profile is a distinct subset of MLL-positive B-ALL. Reported cases showed variable response to treatment. Some patients showed poor prognosis with multiple relapses (like most patients with MLL+B-ALL), while others showed CR with no evidence of relapse. The patient described here received chemotherapy and PBSCT, and has so far shown no evidence of relapse. However, leukemias with MLL rearrangement are typically associated with a poor prognosis owing to the recurrent relapses, and Blin et al. [16] reported a rapid response to chemotherapy contrasted by the high incidence of relapse and poor overall prognosis in patients with this profile. Future identification of patients with this profile will allow us to expand our knowledge regarding prognostic significance and optimal treatment for this rare subgroup of patients.

Optimal Time to Start Peripheral Blood Stem Cell Collection in Children with High-Risk Solid Tumors

Abstract: In order to clarify the optimal timing for peripheral blood stem cell (PBSC) collection, PBSC collection records of 323 children who were scheduled to undergo autologous stem cell transplantation from two study periods differing in the timing of PBSC collection were analyzed. In the early study period (March 1998 to August 2007, n=198), PBSC collection was initiated when the peripheral WBC count exceeded 1,000/µL during recovery from chemotherapy. Findings in this study period indicated that initiation of PBSC collection at a higher WBC count might result in a greater CD34(+) cell yield. Therefore, during the late study period (September 2007 to December 2012, n=125), PBSC collection was initiated when the WBC count exceeded 4,000/µL. Results in the late study period validated our conclusion from the early study period. Collection of a higher number of CD34(+) cells was associated with a faster hematologic recovery after transplant in the late study period. Initiation of PBSC collection at WBC count > 4,000/µL was an independent factor for a greater CD34(+) cell yield. In conclusion, PBSC collection at a higher WBC count is associated with a greater CD34(+) cell yield, and consequently a faster hematologic recovery after transplant.

Standard Induction Followed by Low Dose Cytarabine for the Treatment of Acute Myeloid Leukemia of Down Syndrome

Abstract: Background: Although acute myeloid leukemia occurring in patients with Down syndrome (AML-DS) is generally chemosensitive, these patients are more susceptible to regimen-related toxicities, and the optimal post-remission therapy for AML-DS is unknown. This study aimed to evaluate the outcome of post-remission chemotherapy using low dose cytarabine for AML-DS. Methods: We reviewed the medical records of 142 patients who were newly diagnosed as de novo AML between 1996 and 2011. Among them, 8 patients (5.6%) had Down syndrome. Seven patients received standard induction therapy composed of cytarabine (or behenoyl cytarabine) and anthracycline. Once complete remis sion (CR) was achieved, repetitive courses of low dose cytarabine were given. Results: Patients ’ median age at diagnosis was 1.3 years (range, 0.4-1.9). All but one showed French-American-British (FAB) M7 morphology. Six patients achieved CR (75%) after induction therapy and then received 9 to 20 courses (median, 14) of low dose cytarabine. One patient had 2 episodes of neutropenic fever, whereas the other 5 patients did not suffer from any complication. All six patients are alive event-free with a median follow-up of 118 months (range, 33-208). The estimated 5-year overall survival of all 8 AML-DS patients was 87.5%, while that of non-DS de novo AML patients was 58.6% (P=0.18). Conclusion: Low dose cytarabine was safe and effective as a post-remission therapy for AML-DS. Due to the rarity of AML-DS, a multicenter cooperative study is essential to identify the optimal duration of treatment and to further determine the feasibility of low dose cytarabine for these patients.