Byoung Kook Kim

Structural integrity of the cyclin-dependent kinase inhibitor genes, p15, p16 and p18 in myeloid leukaemias.

Summary The cyclin‐dependent kinase inhibitors known as p15, p16 and p18 have been suggested as candidates for tumour suppressor genes. We examined these genes for their alterations in 46 myeloid leukaemias and 15 myeloid leukaemia cell lines, p16 mRNA expression was studied in 41 myeloid leukaemias. The p15 and p16 genes were either deleted or mutated in myeloid leukaemia lines at a high frequency [6/15 (40%) for p15; 8/15 (53%) for p16] but alterations in primary myeloid leukaemias are much less frequent [2/46 (4%) for p15; 3/46 (6%) for p16]. Alterations of p18 were not found in any of the samples. 13 primary myeloid leukaemia samples had negligible levels of p16 mRNA. In summary, the deletions of p15 and p16 genes identified in the myeloid leukaemia cell lines probably occurred during their in vitro immortalization. Alterations of the pl6 or pl5 gene only occurred in primary acute myeloid leukaemia samples that were of mixed myeloid/ lymphoid lineage (CD19/CD20‐positive acute myeloid leukaemia [AML], CD2/CD19‐positive AML, and lymphoid blastic crisis of chronic myeloid leukaemia). Further studies are required to determine if the absence of mRNA expression results from inactivation of the p16 gene.

Glutathione S-transferase A1 polymorphisms and acute graft-vs.-host disease in HLA-matched sibling allogeneic hematopoietic stem cell transplantation

Abstract:  Busulfan and the metabolites of cyclophosphamide are conjugated with glutathione and catabolized by enzymes of the cytosolic glutathione S‐transferases family. There are clearly linked single nucleotide polymorphisms in the promoter region of the glutathione S‐transferase A1 gene (i.e., GSTA1*A, −567T, −69C and −52G; GSTA1*B, −567G, −69T and −52A). We assessed whether the clinical outcomes, including acute graft‐vs.‐host disease, of 61 patients with hematological malignancies, following HLA‐matched sibling allogeneic stem cell transplantation using busulfan/cyclophosphamide conditioning are altered by glutathione S‐transferase A1 genotypes. Globally, grade II–IV acute graft‐vs.‐host disease developed in 13 patients (21%). Grade II–IV acute graft‐vs.‐host disease developed in 15.2% of 46 patients with GSTA1*A/*A diplotype and in 40.0% of 15 patients with GSTA1*A/*B or GSTA1*B/*B diplotype (p = 0.04). Moreover, this relationship between GSTA1*A/*A diplotypes and lower incidence of acute graft‐vs.‐host disease was independent of the age, gender, stem cell source, and disease status. The incidences of acute skin graft‐vs.‐host disease were 7% (3/46) in patients with GSTA1*A/*A and 27% (4/15) in patients without GSTA1*A/*A (p = 0.009, univariate; p = 0.01, multivariate). Acute hepatic graft‐vs.‐host disease developed in 6 (13%) of 46 patients with the GSTA1*A/*A diplotype and in 4 (27%) of 15 patients without this diplotype (p = 0.09, univariate; p = 0.12, multivariate). Ten patients (16%) developed hepatic veno‐occlusive disease. No significant difference was found in the incidence of hepatic veno‐occlusive disease between patients with and without the GSTA1*A/*A diplotype (19.6% vs. 6.7%; p = 0.24). We conclude that the GSTA1*A/*A diplotype is an independent protective factor against acute graft‐vs.‐host disease, especially for skin graft‐vs.‐host disease, and probably for hepatic graft‐vs.‐host disease, in patients using busulfan/cyclophosphamide conditioning. The identification of glutathione S‐transferase A1 genotypes prior to allogeneic stem cell transplantation could allow conditioning regimens and graft‐vs.‐host disease prophylaxis to be modified to improve outcome.

Blockage of interleukin-6 signaling with 6-amino-4-quinazoline synergistically induces the inhibitory effect of bortezomib in human U266 cells.

The transcription factor nuclear factor-kappa B (NF-κB) regulates the transcription of a number of genes involved in a variety of cellular responses, including cell survival, inflammation, and differentiation. NF-κB is activated by a variety of stimuli, proinflammatory cytokines, mitogens, growth factors, and stress-inducing agents. Aberrant NF-κB expression is considered to be one of the oncogenic factors of cancer and the constitutive activation of NF-κB is observed in several hematologic disorders [classic Hodgkins lymphoma, diffuse large B cell lymphoma, and multiple myeloma (MM)], and the modulation of NF-κB activation is emerging as a promising novel anticancer therapeutic strategy.Therefore, we focused on the regulation of NF-κB activation in MM. When U266 cells were treated with 6-amino-4-quinazoline, an NF-κB activation inhibitor, we determined that it most effectively blocked the interleukin (IL)-6-induced activation of MAPK and JAK/STAT pathways among different signaling inhibitors. The results of the luciferase assay indicated that 6-amino-4-quinazoline inhibited NF-κB activation with diminished NF-κB protein bound to NF-κB DNA binding sites. In addition, 6-amino-4-quinazoline suppressed the production of IL-6, which affected MM cell proliferation. Furthermore, combined treatment with bortezomib and 6-amino-4-quinazoline effectively inhibited the IL-6 and soluble IL-6R-induced activation of STAT3 and extracellular signal-regulated kinase phosphorylation. Our data showed that the inhibition of NF-κB activation abrogated MM cell proliferation induced by the IL-6 pathway, and might represent a promising therapeutic strategy for the treatment of MM.

Pneumatosis intestinalis with pneumoperitoneum mimicking intestinal perforation in a patient with myelodysplastic syndrome after hematopoietic stem cell transplantation.

Pneumatosis intestinalis (PI) is an uncommon disorder characterized by an accumulation of gas in the bowel wall, and has been associated with a variety of disorders and procedures. We describe a 35-year-old man who undertook hematopoietic stem cell transplantation due to myelodysplastic syndrome. An abdominal X-ray demonstrated extensive PI with pneumoperitoneum mimicking hollow organ perforation. However, the patient had no abdominal symptoms and there was no evidence of peritoneal inflammation. After two weeks of conservative management, including bowel rest and antibiotics, his pneumoperitoneum resolved spontaneously without any complications. Of the many factors that affect the gastrointestinal tract mucosal integrity, intramural pressure, and bacterial flora-produced intraluminal gas interact to produce PI. If the condition is accompanied by bowel ischemia, portomesenteric venous gas, metabolic acidosis, and abdominal sepsis, or if PI is severe in extent immediate surgical intervention is indicated. The described case supports that a mechanical rather than a bacterial etiology underlies the pathogenesis of PI.

Cost Analysis of Iron-Related Complications in a Single Institute

Background/Aims The financial burden of caring for iron-related complications (IRCs) is an emerging medical problem in Korea, as in Western countries. We produced a preliminary estimate of the costs of treating patients for IRCs. Methods The medical records of patients who had received multiple transfusions were reviewed. Newly developed cardiomyopathy, heart failure, diabetes mellitus, liver cirrhosis, and liver cancer were defined as IRCs. The costs of laboratory studies, medication, oxygenation, intervention, and education were calculated using working criteria we defined. Costs that had a definite causal relationship with IRCs were included to produce as accurate an estimate as possible. Results Between 2002 and 2006, 650 patients with hematologic diseases, including 358 with acute leukemia, 102 with lymphoma, 58 with myelodysplastic syndrome or myeloproliferative disease, 46 with multiple myeloma, and 31 with chronic leukemia, received more than 10 units of red blood cells. Nine patients developed IRCs. The primary diagnoses of eight patients were aplastic anemia and that of one patient was chronic lymphocytic leukemia. Two patients who had diabetes were excluded because one was treated at another hospital and the other was diagnosed as oxymetholone-induced diabetes. Of the seven patients included, liver cirrhosis developed in two, heart failure in four, and diabetes mellitus in three. Some of them had two diagnoses. The total cost attributed to IRCs for the seven patients was 47,388,241 KRW (approximately 50,000 USD). Conclusions The medical costs of IRCs are considerable, and more effective iron-chelating therapy is necessary to save medical resources and improve patient care. More in the way of comprehensive health and economic studies of IRCs are needed to allow both clinicians and health-policy makers to make better decisions.

Combination of SK-7041, one of novel histone deacetylase inhibitors, and STI571-induced synergistic apoptosis in chronic myeloid leukemia.

Although STI571 still plays a key role in the treatment of chronic myeloid leukemia, emergence of resistance to STI571 is a major obstacle to successful outcome. Therefore, new agents that increase the sensitivity of chronic myeloid leukemia cells to STI571 are urgently required. SK-7041 is a novel hybrid synthetic histone deacetylase inhibitor derived from the hydroxamic acid of trichostatin A and pyridyl ring of MS-275. Its cytotoxic effects were examined both as a single agent and in combination with STI571 in acute and chronic myeloid leukemia. SK-7041 exhibited growth inhibition of leukemia cells by downregulation of CDK4, cyclin E and cyclin B1 expression, and by upregulation of p21CIP1=WAF1 expression with subsequent activation of the mitochondria-mediated caspase pathway. SK-7041 showed synergism on growth inhibition, cell cycle arrest and induction of apoptosis in chronic myeloid leukemia (K562) when combined with STI571. The synergistic effect was mediated through the same mechanism as in SK-7041 alone, involving reduction of cyclin D1 and induction of p21CIP1=WAF1. Taken together, our findings suggest that SK-7041 is active against leukemia and offers new prospects for overcoming STI571 resistance in chronic myeloid leukemia.

Patient HSP70-hom TG haplotype is associated with decreased transplant-related mortality and improved survival after sibling HLA-matched hematopoietic stem cell transplantation.

Kim I, Kim JH, Rhee JY, Kim JW, Cho HJ, Cho E‐Y, Lee J‐E, Hong Y‐C, Park SS, Yoon S‐S, Park MH, Park S, Kim BK. Patient HSP70‐hom TG haplotype is associated with decreased transplant‐related mortality and improved survival after sibling HLA‐matched hematopoietic stem cell transplantation.
Clin Transplant 2010: 24: 459–466.
© 2009 John Wiley & Sons A/S.

Topical Recombinant Human Epidermal Growth Factor for Oral Mucositis Induced by Intensive Chemotherapy with Hematopoietic Stem Cell Transplantation: Final Analysis of a Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial

The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for oral mucositis (OM) induced by intensive chemotherapy with hematopoietic stem cell transplantation. In this phase 2 study, patients were randomized to either rhEGF (50 microg/mL) or placebo in a 1:1 ratio. The primary endpoint was incidence of National Cancer Institute (NCI) grade ≥2 OM. A total of 138 patients were enrolled in this study. In the intention-to-treat analysis, rhEGF did not reduce the incidence of NCI grade ≥2 OM (p = 0.717) nor reduce its duration (p = 0.725). Secondary endpoints including the day of onset and duration of NCI grade ≥2 OM, the incidence of NCI grade ≥3 OM and its duration, and patient-reported quality of life were also similar between the two groups. In the per-protocol analysis, however, the duration of opioid analgesic use was shorter in the rhEGF group (p = 0.036), and recipients in the rhEGF group required a lower cumulative dose of opioid analgesics than those in the placebo group (p = 0.046), among patients with NCI grade ≥2 OM. Adverse events were mild and transient. This study found no evidence to suggest that rhEGF oral spray reduces the incidence of OM. However, further studies are needed to investigate the effect of rhEGF on OM-induced pain reduction after intensive chemotherapy.

Comparative outcomes of reduced intensity and myeloablative allogeneic hematopoietic stem cell transplantation in patients under 50 with hematologic malignancies.

Abstract:  We have conducted a direct comparison of the outcomes of reduced intensity and myeloablative conditioning in younger adults with hematological malignancies <50 yr. One hundred and five patients received transplants from human leukocyte antigen (HLA)‐matched donors, via either reduced intensity (n = 35) or myeloablative conditioning (n = 70). The median ages of the reduced intensity and myeloablative groups were 36 and 33 yr (p = 0.014). Neutrophil engraftment (i.e. time to absolute neutrophil count >0.5 × 109/L) occurred more rapidly in the reduced intensity group (median: 10 d; range: 0–21 d) than in the myeloablative group (median: 18 d; range: 11–38 d; p < 0.0001). The incidence of grades 2–4 acute graft‐vs.‐host disease were similar between the reduced intensity and myeloablative groups, at 17% vs. 24% respectively (p = 0.40). The cumulative incidence of day 100 non‐relapse mortality was 18% in the reduced intensity group, and 21% in the myeloablative group (p = 0.88). The overall two‐yr survival rates were 43% in the reduced intensity group, and 35% in the myeloablative group (p = 0.72). In conclusion, reduced intensity transplantation yielded outcomes comparable with those of myeloablative transplantation in patients under 50 with hematological malignancies.