Hyeon Jin Park

Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division

Cells expressing indoleamine 2,3‐dioxygenase (IDO), an enzyme which catabolizes tryptophan, prevent T‐cell proliferation in vitro, suppress maternal antifetal immunity during pregnancy and inhibit T‐cell‐mediated responses to tumour‐associated antigens. To examine the mechanistic basis of these phenomena we activated naïve murine T cells in chemically defined tryptophan‐free media. Under these conditions T cells expressed CD25 and CD69 and progressed through the first 12 hr of G0/G1 phase but did not express CD71, cyclin D3, cdk4, begin DNA synthesis, or differentiate into cytotoxic effector cells. In addition, activated T cells with their growth arrested by tryptophan deprivation exhibited enhanced tendencies to die via apoptosis when exposed to anti‐Fas antibodies. Apoptosis was inhibited by caspase inhibitor and was not observed when T cells originated from Fas‐deficient mice. These findings suggest that T cells activated in the absence of free tryptophan entered the cell cycle but cell cycle progression ceased in mid‐G1 phase and T cells became susceptible to death via apoptosis, in part though Fas‐mediated signalling. Thus, mature antigen‐presenting cells expressing IDO and Fas‐ligand may induce antigen‐specific T‐cell tolerance by blocking T‐cell cycle progression and by rapid induction of T‐cell activation induced cell death in local tissue microenvironments.

Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation: incidence, risk factors, and outcome

Four hundred and sixty-seven hematopoietic stem cell transplantations (HSCTs) (217 autologous and 250 allogeneic HSCT) were performed in 374 children at four pediatric HSCT centers in Korea from January 2005 to December 2007. Among 467 transplants, veno-occlusive disease (VOD) developed in 72 transplants (15.4%) at a median of 10 days after HSCT. Multivariate analysis showed that BU or TBI-containing regimen (P=0.002), VOD prophylaxis without lipo-prostaglandin E1 (PGE1) (P=0.012), number of previous HSCT (P=0.014), and pretransplant serum ferritin (P=0.018) were independent risk factors for developing VOD. Mean serum ferritin levels were significantly higher in HSCT with VOD (2109.6±2842.5 ng/ml) than in HSCT without VOD (1315.9±1094.4 ng/ml) (P<0.001). The relative risk of death within 100 days of HSCT in transplants with VOD compared with transplants without VOD was 3.39 (confidence interval: 1.78–6.45). Our results suggest that lipo-PGE1 might have a protective effect against the development of VOD, and pretransplant serum ferritin could act as a risk factor for VOD. A larger prospective study is needed to confirm a possible role of lipo-PGE1 and iron chelation therapy in reducing the incidence of VOD.

Statistics of hematologic malignancies in Korea: incidence, prevalence and survival rates from 1999 to 2008

Background The nationwide statistical analysis of hematologic malignancies in Korea has not been reported yet. Methods The Korea Central Cancer Registry and the Korean Society of Hematology jointly investigated domestic incidence rates and prevalence of hematologic malignancies occurred between 1999 and 2008, and analyzed survival rates of patients who were diagnosed between 1993 and 2008. Data of hematologic malignancies from 1993 to 2008 were obtained from the Korean National Cancer Incidence Data base. The crude incidence rates, age-specific incidence rates, age-standardized incidence rates, annual percentage change of incidence, and prevalence from 1999-2008 were calculated. Survival rates for patients diagnosed in 1993-2008 were estimated. Results In 2008, a total of 8,006 cases of hematologic malignancies were occurred, which comprised 4.5% of all malignancies. In all genders, non-Hodgkin lymphoma, myeloid leukemia, and multiple myeloma were most frequent diseases. In terms of age, ages between 60 and 69 were most prevalent. From 1999 to 2008, the age-standardized incidence rates increased from 10.2 to 13.7, and the annual percentage change was 3.9%. The 5-year survival rate increased from 38.2% during 1993-1995 to 55.2% during 2004-2008. As of January 2009, number of patients with 10-year prevalence was 33,130, and with 5- to 10-year prevalence was 10,515. Conclusion This is the first nationwide statistical report of hematologic malignancies in Korea. It could be used as the basic information to help investigate epidemiologic characteristics, evaluate progress during the past years, and establish future strategies for hematologic malignancies. Periodic statistical analysis of hematologic malignancies in Korea should be continued.

Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Young Children with Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System

The feasibility and effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) were evaluated in children younger than 3 yr of age with atypical teratoid/rhabdoid tumors (ATRT). Tandem HDCT/autoSCT was administered following six cycles of induction chemotherapy. Radiotherapy (RT) was administered if the tumor relapsed or progressed, otherwise, it was administered after 3 yr of age. Tumors relapsed or progressed during induction chemotherapy in 5 of 9 patients enrolled; 3 of these 5 received tandem HDCT/autoSCT as a salvage treatment. One patient died from sepsis during induction chemotherapy. The remaining 3 patients proceeded to tandem HDCT/autoSCT; however, 2 of these patients showed tumor relapse/progression after tandem HDCT/autoSCT. All 7 relapses/progressions occurred at primary sites even in patients with leptomeningeal seeding. Toxicities during tandem HDCT/autoSCT were manageable. A total of 5 patients were alive with a median follow-up of 20 (range 16-70) months from diagnosis. Four of 5 patients who received RT after relapse/progression are alive. The probability of overall survival at 3 yr from diagnosis was 53.3% ± 17.3%. Our tandem HDCT/autoSCT is feasible; however, early administration of RT prior to tandem HDCT/autoSCT should be considered to improve the outcome after tandem HDCT/autoSCT.

Controlled cyclopolymerisation of 1,7-octadiyne derivatives using Grubbs catalyst

Cyclopolymerisation of 1,6-heptadiyne derivatives by Grubbs catalysts gives the conjugated polymers containing a five-membered ring repeat unit. The first example of cyclopolymerisation of 1,7-octadiyne derivatives is demonstrated here to give a new class of conjugated polymer that contains six-memebered rings. This polymerisation was very challenging and efficient cyclopolymerisation was achieved only with monomers that showed a significant Thorpe–Ingold effect. By using a third-generation Grubbs catalyst, we obtained the polymers with excellent molecular weight control and narrow PDIs. This controlled polymerisation allowed the synthesis of diblock copolymers containing five- and six-membered rings, respectively, from 1,6-heptadiyne and the 1,7-octadiyne derivatives.

Cancer Incidence and Survival among Adolescents and Young Adults in Korea

Background In Korea, cancer is the third leading cause of death among adolescents and young adults (AYAs). However, cancer incidence and survival trends among AYAs (15–29 years) have never been studied in Korea. Therefore, this study aimed to investigate the incidence and relative survival rates and their trends among AYAs in Korea. Materials and Methods Cancer incidence data from 1999–2010 were obtained from the Korea Central Cancer Registry (KCCR). Each cancer was classified into subgroups according to the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) AYA site recode. Percent distributions, age-specific incidence rates, age-standardized incidence rates per million, and annual percent changes (APCs) were calculated for AYAs according to sex. Five-year relative survival rates were estimated for cases diagnosed between 1993 and 2010 and followed up to 2011. Results The age-standardized incidence rates of all cancers combined were 196.4 and 367.8 per million for males and females, respectively (male-to-female (M/F) ratio: 0.5). The age-standardized incidence rates increased from 208.7 per million in 1999 to 396.4 per million in 2010, and the APC was 6.3% (P<0.001). The five most common cancers among AYAs were thyroid carcinoma, non-Hodgkin lymphoma, stomach carcinoma, breast carcinoma, and acute myeloid leukemia. In males, the 5-year relative survival rate improved, from 46.5% in 1993–1995 to 75.9% in 2006–2010. In females, the 5-year relative survival rate also improved, from 66.7% in 1993–1995 to 89.1% in 2006–2010. Conclusions Our study showed increases in cancer incidence and improvements in the 5-year relative survival rate among Korean AYAs. This study also provides additional data regarding temporal and geographic trends in cancer that may enhance future efforts to identify factors affecting cancer incidence and responses to treatment among AYAs.

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

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.

Current status of pediatric umbilical cord blood transplantation in Korea: A multicenter retrospective analysis of 236 cases

We report the outcome of 236 pediatric umbilical cord blood transplantations (UCBT) performed in Korea. Given that the sources of the grafts were mostly unrelated donors (n = 226; 95.8%), only the results of unrelated UCBT were included for all statistics. The most frequent primary disease was acute leukemia (n = 167). In total, 91.7% of recipients were seropositive for cytomegalovirus (CMV). The median doses of nucleated cells and CD34+ cells were 4.84 × 107/kg and 2.00 × 105/kg, respectively. The median times to neutrophil (>0.5 × 109/L) and platelet recovery (>20 × 109/L) were 18 and 45 days, respectively. Grade 2–4 acute graft‐versus‐host‐disease (GVHD) and chronic GVHD developed in 41.1 and 36.1% of cases, respectively. Forty‐five patients developed CMV disease. The 5‐year overall and event‐free survival were 47.5 and 36.9%, respectively. Multivariate analysis revealed that adverse factors for survival of the whole cohort were total body irradiation‐based conditioning (P = 0.007), salvage transplant (P = 0.001), failure to achieve early complete chimerism (P < 0.0005), and CMV disease (P = 0.001). The outcomes of the single‐ and double‐unit UCBT (n = 64) were similar, while double‐unit recipients were heavier (P < 0.0005) and older (P < 0.0005). We conclude that double‐unit UCBT is a reasonable option for older or heavier children and that the thorough surveillance of CMV infection and the development of an effective CMV therapeutic strategy may be especially important for Korean children, whose CMV seroprevalence exceeds 90%. Am. J. Hematol., 2011.

Synthesis of Small and Large Fused Bicyclic Compounds by Tandem Dienyne Ring-Closing Metathesis

A tandem ring-closing metathesis reaction using ruthenium catalyst was carried out to synthesize various fused bicyclic compounds containing both small and large rings. Fast ring-closure of the small ring and slow ring-closure of the large ring resulted in the formation of only one isomer. Further manipulation such as the Diels-Alder reaction was carried out to prepare a complex molecule containing multiple rings of different sizes.

Proton beam therapy reduces the incidence of acute haematological and gastrointestinal toxicities associated with craniospinal irradiation in pediatric brain tumors.

Abstract Background. The benefits of proton beam craniospinal irradiation (PrBCSI) in children have been extensively reported in dosimetric studies. However, there is limited clinical evidence supporting the use of PrBCSI. We compared the acute toxicity of PrBCSI relative to that of conventional photon beam CSI (PhBCSI) in children with brain tumours. Material and methods. We prospectively evaluated the haematological and gastrointestinal toxicities in 30 patients who underwent PrBCSI between April 2008 and December 2012. As a reference group, we retrospectively evaluated the medical records of 13 patients who underwent PhBCSI between April 2003 and April 2012. The median follow-up time from starting CSI was 22 months (range 2–118 months). The mean irradiation dose was 32.1 Gy (range 23.4–39.6 Gy) and 29.4 CGE (cobalt grey equivalents; range 19.8–39.6), in the PrBCSI and PhBCSI groups, respectively (p = 0.236). Results. There was no craniospinal fluid space relapse after curative therapy in either group of patients. Thrombocytopenia was less severe in the PrBCSI group than in the PhBCSI group (p = 0.012). The recovery rates of leukocyte and platelet counts measured one month after treatment were significantly greater in the PrBCSI group than in the PhBCSI group (p = 0.003 and p = 0.010, respectively). Diarrhoea was reported by 23% of patients in the PhBCSI group versus none in the PrBCSI group (p = 0.023). Conclusions. The incidence rates of thrombocytopenia and diarrhoea were lower in the PrBCSI group than in the PhBCSI group. One month after completing treatment, the recovery from leukopenia and thrombocytopenia was better in patients treated with PrBCSI than in those treated with PhBCSI.