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유건희 대한소아청소년과학회 2005 Clinical and Experimental Pediatrics (CEP) Vol.48 No.2
Purpose:The purpose of this study was to evaluate the outcome of children with juvenile myelomonocytic leukemia(JMML) treated with allogeneic hematopoietic stem cell transplantation(allo- HSCT). Methods:Eleven JMML patients aged 8-39 months underwent allo-HSCT. The sources of grafts were unrelated donors(n=7), HLA-matched siblings(n=3) and an HLA 1-antigen mismatched familial donor. All patients had received chemotherapy ± 13-cis-retinoic acid(CRA) before transplant, and CRA was used, posttransplant, in six patients. Results:Only three patients were in complete remission(CR) at the time of transplantation. Initial chimeric status revealed complete donor chimerism(CC) in five patients, mixed chimerism(MC) in five and autologous recovery(AR) in one. One patient with MC having persistent splenomegaly eventually turned to CC and CR after rapid tapering of cyclosporine, combined with daily use of CRA. An AR case relapsed shortly after transplant but was rescued with second, unrelated cord blood transplantation. Ultimately, six patients are alive, event-free, with a median follow-up of 15.5 months posttransplant. All three deaths occurred in patients who failed to achieve CC, leading to disease progression. Conclusion:We suggest that graft-versus-leukemia effect play an important role and CRA a possible role in posttransplant leukemic involution in JMML. In patients whose leukemic burden is still high with MC after transplant, early tapering of immunosuppressants and introduction of CRA might provide a chance of a cure for some patients 목 적 : JMML은 소아에서 발생하는 매우 드문 종류의 백혈병으로서 통상적인 항암화학요법만으로는 완치가 어려워 동종 조혈 모세포 이식을 시행하여야 한다. 아직 국내에서는 본 질환의 조혈 모세포 이식 성적에 대한 보고가 없어 저자들은 단일기관에서 경험한 JMML 환자의 동종 조혈 모세포 이식 성적을 보고하고자 하였다. 방 법 : 8개월에서 39개월 된 11명의 JMML 환자를 대상으로 동종 조혈 모세포 이식을 시행하였다. 조혈 모세포의 공급원으로 비혈연 골수 혹은 제대혈 7례, HLA 일치 형제 공여자 3례, HLA 1 항원 불일치 가족 공여자 1례 등을 이용하였다. 모든 환자들은 이식 전 항암화학요법을 시행 받았고 일부 환자에게는 13-cis-retinoic acid(CRA)를 사용하였다.결 과 : 총 11례 중 3례만이 이식 전 치료로 혈액학적 및 임상적 완전관해에 도달하였다. 이식 후 1개월째 첫 키메리즘 평가 결과 완전 공여자 키메리즘 5례, 혼합 키메리즘 5례, 자가회복 1례였다. 혼합 키메리즘 상태에서 비장종대가 해소되지 않았던 1례에서 면역억제제의 급속 감량과 함께 CRA를 지속적으로 투여한 결과 완전 공여자 키메리즘으로의 전환과 함께 완전관해가 유도되었다. 자가회복 되었던 1례는 이식 후 조기 재발하였으나 복합 항암화학요법과 CRA의 투여로 이차 완전관해가 유도되었다. 결과적으로 11례 중 6례가 이식 후 정중 추적기간 15.5개월간 무사건 생존 중이다. 사망한 3례는 모두 완전 공여자 키메리즘에 실패하였던 경우들로서 질병의 재발 혹은 진행이 사망의 원인이었다. 결 론:본 연구 결과 JMML의 근치에는 동종 조혈 모세포 이식 후 이식편대 백혈병 효과가 중요한 역할을 담당하며 CRA도 긍정적 역할을 가지는 것으로 사료된다. 이식 후에도 완전관해에 도달하지 못하고 혼합 키메리즘 양상을 보이는 경우, 면역억제제를 조기 감량하는 정책과 함께 CRA를 도입함으로써 완치의 가능성을 높일 수 있을 것으로 기대된다.
유건희,이계향,이수현,김성혜,김상종,유동길,황수정,조은주,구홍회 대한조혈모세포이식학회 2002 대한조혈모세포이식학회지 Vol.7 No.2
연구배경: 소아 자가 조혈모세포이식 환자를 대상으로 감염의 양상을 파악하여 이의 예방 및 치료를 위한 합리적인 대처 방안에 대해 모색하고자 하였다. 방법: 2001년 3월부터 2002년 4월까지 삼성서울병원 소아과에서 고용량 화학요법 및 자가 조혈모세포이식을 시행받은 27명을 대상으로 의무기록을 후향적으로 조사하여 발열 및 감염의 양상에 대한 전반적인 분석을 시행하였다. 결과: 이식 시 중앙연령은 60개월(16~195개월)이었고 남아가 18예, 여아가 9예이었다. 진단별로는 신경모세포종 12예, 급성골수성백혈병 3예, 비호지킨림프종 3예, 수모세포종 2예, 생식세포종 2예, 원시신경외배엽종양 2예, 기타가 3예이었다. 24예(88.9%)에서 발열이 있었고 총 32회의 새로운 발열이 있었다. 발열이 없이 감염 병소가 있었던 1예를 포함하여 25예(92.6%)에서 감염이 발생하였고 미생물학적으로 확인된 감염이 11.1%, 임상적으로 확인된 감염이 22.2%, 미확인 발열이 59.3%였다. 발열 기간 중 동반된 증상으로는 설사(70.8%)와 구내염(58.3%)이 가장 흔하였다. 총발열 기간은 중앙값 5일(0~13일)이었으며 전신방사선조사를 받은 경우 발열 기간이 더 길었다(P=0.0398). 발열의 65.6%는 ANC 500/μL 미만에서 발생하였으나 ANC 1,000/μL 이상에서도 31.3%가 발생하였다. 1차 경험적 항균요법의 성공률은 26%이었고 항생제 사용 일수는 중앙값 19일(7~50일)이었다. 진균 감염이 증명된 예는 없었다. 이식된 CD34 양성세포의 수가 5×10^(6)/kg 이상일 때 그 미만인 경우보다 항생제 투여 기간이 짧았다(15.5일 vs 18일, P=0.0182). 총 7예가 사망하였으나 감염이 사망의 직접 원인으로 작용한 예는 없었다. 결론: 본 연구 결과를 통해 소아 자가 조혈모세포이식 환자에서는 비교적 이른 시기에 발열이 시작되어 장기간의 항생제 투여가 필요하나 감염에 의한 사망은 드문 것으로 기대된다. 세균 이외의 발열 원인에 대한 쉽고 정확한 진단법의 개발이 필요하며, 항균요법의 방법을 개선하여 과거의 대조군과 비교하는 연구를 통해 더욱 효과적인 감염 예방과 치료방법을 모색해야 하겠다. Background: In this study, we intended to describe the infectious manifestations in children undergoing autologous peripheral blood stem cell transplantation (APBSCT) and to establish the proper methods of preventing and treating infectious complications in those patients. Methods: We retrospectively reviewed medical records of 27 patients who underwent APBSCT from March 2001 to April 2002 at Samsung Seoul Hospital and analyzed the general manifestations of infectious complications. Results: Median age at transplant was 60 months (16~195 Mo). Patients' diagnoses were neuroblastoma (n=12), acute myeloid leukemia (n=3), non-Hodgkin's lymphoma (n=3), medulloblastoma (n=2), germ cell tumor (n=2), primitive neuroectodermal tumor (n=2), and others (n=3). Fever developed in 24 patients (88.9%) with 32 febrile episodes. Infectious complications occurred in 25 patients (92.6%) including 1 afebrile patient having pneumonic infiltrates. The types of infection were microbiologically documented infection in 11.1%, clinically documented infection in 22.2%, and undefined fever in 59.3%. Diarrhea (70.8%) and oral mucositis (58.3%) were the leading symptom and sign accompanied by febrile episodes. The median duration of fever was 5 days (0~13 days), and it was longer in patients who received total body irradiation (P=0.0398). Fever developed at absolute neutrophil count (ANC) <500/μL in 65.6%, but 31.3% of fever developed at ANC >1,000/μL. The success rate to initial empirical antibiotics was only 26% of patients and the median duration of antibiotic treatment was 19 days (7~50 days), which was significantly shorter when infused CD34^(+) cell count exceeded 5×10^(6)/kg (P=0.0182). There was no proven fungal infection. There were 7 deaths but no patient died from infectious complication. Conclusion: Fever developed relatively earlier, which led to the prolonged use of antibiotics but, mortality rate from infectious complication was rare in children. More accurate and easy diagnostic methods to detect infectious organisms other than bacteria and prospective studies to determine optimal empirical antibiotics for the treatment of fever of unknown origin in APBSCT, would uncover more effective strategy of preventing and treating infectious complications in children undergoing APBSCT.
유전성 대사질환에서의 동종조혈모세포이식 : 단일 기관에서의 경험 A single center experience
유건희,김흥렬,이지은,이호영,천정미,성기웅,구홍회,이문향,진동규,김종원,김대원,김형록 대한조혈모세포이식학회 2001 대한조혈모세포이식학회지 Vol.6 No.2
배경: 유전성 대사질환의 치료로서 효소 요법 및 유전자 치료가 제한적인 현실에서 동종 조혈모세포이식이 현재로선 가장 중요한 치료가 될 수 있다. 본 연구에서는 단일 기관에서 유전성 대사질환에 대해 동종 조혈모세포이식을 시행한 경험을 보고하고자 하였다. 방법: 삼성서울병원 유전성 대사질환 조혈모세포이식팀에서는 1999년 12월부터 2001년 3월까지 총 6례의 유전성 대사질환을 대상으로 동종 조혈모세포이식을 시행하였다. 대상 질환은 Hunter 증후군 3례, galactosialidosis 1례, 이염성 백질이영양증 1례, 부신백질이영양증 1례였으며 성별 분포는 남아가 5명, 여아가 1명이었으며 연령 분포는 2년 9개월에서 15년 9개월이었다. 5례는 HLA 일치 혈연간 골수이식이었으며 1례는 HLA 불일치 T 림프구 제거 말초혈액 조혈모세포이식이었다. 전처치는 모두 BuCy를 사용하였으며 이식편대숙주반응의 예방에는 cyclosporine을 사용하였다. 이식된 세포는 유핵세포가 4.81×10^(8)(2.40~7.01×10^(8))/kg이었으며 CD34+ 세포는 3.65×10^(6)(0.88~10.72×10^(6))/kg이었다. 결과: 이식 후 조혈기능의 회복은 모두 조기에 달성되었으며(ANC>500: 정중 9.5일, 범위 9~14일; PLT>50K: 정중 32일, 범위 23~34일) 이식과 관련된 합병증은 Gr I의 aGVHD 3례, 국한성의 cGVHD 1례, 경증의 간정맥 폐쇄성 질환이 1례이었다. 모든 환자에서 직간접적으로 이식 후 효소의 생산이 증가함이 확인되었으며 임상적인 호전을 보인 경우가 4례, 질병 진행이 중단된 경우가 1례, 질병이 진행된 경우가 1례이었다. 질병 진행이 중단되었던 1례는 면역억제제 투여 중 수두 감염에 의한 폐출혈로 사망하였다. 결론: 유전성 대사질환에서 동종 조혈모세포이식이 가장 중요한 치료법으로 사용될 수 있고 중추신경계 증상이 나타나기 전, 가능한 조기에 조혈모세포이식을 시행하는 것이 바람직할 것이며 적극적인 지지 요법이 필요하다. 향후 더 많은 임상 경험이 필요하리라 사료된다. Background: Allogeneic hematopoietic stem cell transplantation (HSCT) may be the most important treatment modality to cure a number of genetic metabolic disorders because of the limitation of enzyme replacement or gene therapy. In this study, we report our single center experience about HSCT in several genetic metabolic disorders. Methods: We performed 6 cases of HSCT for genetic metabolic disorders from December 1999 to March 2001. Patients' diagnoses were Hunter syndrome (3), galactosialidosis (1), metachromatic leukodystrophy (1), and adrenoleukodystrophy (1). Stem cell sources were bone marrow from HLA matched sibling donors in 5 patients and mother's peripheral blood stem cells in one patient who did not have HLA matched donors. Busulfan and cyclophosphamide for conditioning, and cyclosporine for the prevention of graft versus host disease were used in all patients. Transplanted total nucleated cell counts were median 4.81×10^(8)(2.40~7.01×10^(8))/kg , and CD34+ cells 3.65×10^(6)(0.88~10.72×10^(6))/kg. Results: All patients achieved early hematologic recovery (median 9.5 days, range 9~14 days for ANC>500/μL; median 32 days, range 23~34 days for PLT>50,000/μL). Transplant-related complications were 3 cases of grade 1 acute GVHD, a case of limited chronic GVHD, and a case of mild hepatic veno-occlusive disease. Enzyme levels were normalized in 4 patients evaluated and there were indirect evidences of enzyme production in the other 2 patients after HSCT. Four of the 6 patients showed symptomatic improvement, 1 patient (galactosialidosis) experienced disease stabilization without progression before he eventually died due to pulmonary hemorrhage, and the other 1 patient deteriorated progressively even after HSCT. Conclusions: Allogeneic HSCT can be done as the only curative treatment in a number of genetic metabolic disorders. It seems desirable to perform HSCT as early as possible before the onset of central nervous system symptoms. More experience and long term follow up is needed to evaluate the efficacy and to monitor the long term transplant-related complications.
유건희,박한,김흥수,김재원,이강근,박동호,정창영,박선규 대한마취통증의학회 2019 Anesthesia and pain medicine Vol.14 No.1
Background: Dexmedetomidine, an α2-adrenergic agonist, can be used for sedation and as an adjuvant to anesthetics. This study aimed to evaluate the effects of preanesthetic administration of dexmedetomidine on the propofol and remifentanil requirement during general anesthesia and postoperative pain in patients undergoing laparoscopic cholecystectomy. Methods: Sixty patients were randomly assigned to group D or S (n = 30 each). Dexmedetomidine (0.5 μg/kg) and a comparable volume of saline were administered in groups D and S, respectively, over a 10 minutes period before induction. General anesthesia was induced and maintained with propofol and remifentanil; the bispectral index was maintained at 40–60. The intraoperative remifentanil and propofol dosages were recorded, and postoperative pain was assessed using a visual analog scale (VAS). Results: In groups S and D, propofol dosage was 8.52 ± 1.64 and 6.83 ± 1.55 mg/kg/h, respectively (P < 0.001), while remifentanil dosage was 7.18 ± 2.42 and 4.84 ± 1.44 μg/ kg/h, respectively (P < 0.001). VAS scores for postoperative pain were 6.50 (6–7) and 6.0 (6–7), respectively, at 30 minutes (P = 0.569), 5 (4–5) and 4 (3–5), respectively, at 12 hours (P = 0.039), and 2 (2–3) and 2 (1.25–2), respectively, at 24 hours (P = 0.044). The Friedman test revealed that VAS scores changed over time in both groups (P < 0.001). Conclusions: Preanesthetic single administration of a low dose of dexmedetomidine (0.5 μg/kg) can significantly decrease the remifentanil and propofol requirement during short surgeries and alleviate postoperative pain.
재발성/불응성 소아 급성림프모구백혈병 환자의 치료 경향 및 성적에 대한 다기관 후향적 관찰 연구
유건희,정낙균,조빈,강형진,신희영,임호준,서종진,임영탁,유철주,김순기,전인상,국훈,구홍회 대한소아혈액종양학회 2017 Clinical Pediatric Hematology-Oncology Vol.24 No.2
Background: Although the overall survival of childhood acute lymphoblastic leukemia (ALL) approaches 85-90%, the prognosis of relapsed or refractory (R/R) ALL is grave. This study aimed to identify the treatment pattern, treatment response, and overall survival of these patients. Methods: We reviewed data of 64 patients with R/R ALL whose initial diagnosis of ALL had been made between 1 and 21 years of age. Patients who received clofarabine as part of an induction regimen were excluded. Relapsed patients were limited to those who relapsed after ≥2 prior induction regimens. Treatment patterns, response rates, and overall survival were analyzed. Results: Patients’ median age was 15.0 years (range, 6.0-25.0) at the diagnosis of R/R ALL. The most frequently used agents other than steroid were vincristine (54.0%), cytarabine (44.6%), and idarubicin (36.5%), while L-asparaginase was used in only one patient. The complete remission (CR) and overall response (OR) rates were 38.1 and 42.9%, respectively. Sixteen patients (25.4%) underwent allogeneic hematopoietic stem cell transplantation (HSCT). The 5-year overall survival was 6.7%. The survival of patients with HSCT was significantly higher compared with those without HSCT (35.2% vs 0%, P=0.0097). Among 14 patients who achieved CR or CR without platelet recovery (CRp) before HSCT, the 3-year survival was 46.9%. Conclusion: The survival of Korean patients with R/R childhood ALL was dismal despite a reasonable CR rate, whereas that of those who received HSCT after CR or CRp was excellent. More treatment options are needed to improve the overall outcome of R/R childhood ALL.
유건희,이용재 한국미생물학회 1971 미생물학회지 Vol.9 No.4
Because of the cases of Japanese Encephalitis(J.E.) were reported every year in Korea. We, Dong-A Pharmaceutical Co., Ltd., produced J.E. virus vaccine, with lower price, since 1970 in order to prevent ourselves from being infected by the disease. And inoculated the J.E. virus vaccine for the children with a great success. We are going to report several questions which brought about in producing the J.E. virus vaccine by alcohol precipitation, protamine sulfate treatment method. The results obtained were as folows ; 1) In process treated with 40% alcohol, we used to ethanol made in Germany, but it was too expensive to use it. As the result which we had studied about it, we were satisfied with J.E. virus vaccine which produced with alcohol made in Korea, and then, we treated with accurate specific gravity of 40% ethanol for the precipitation of the virus. And also, we knew that it was the best method to be treated it for 3hrs, $13^{\circ}C$. 2) When we treated with protamine sulfate (0.025mg/ml), we acquired the highest potent titer, and suited into purpose for the nitrogen concentration. 3) The filtration of the purified J.E. virus vaccine, in case of millipore filter paper of large pore size was not suitable for the sterility. Therefore the pore size less than 0.8.$\mu$ (AA filter paper) in millipore filter paper was very suitable. But it seemed to be important subhects that the smaller was the pore size, the lower was the potent titer.
고위험 소아 고형종양에서의 반복적인 고용량 화학요법 및 자가말초혈 조혈모세포이식
유건희,성기웅,구홍회,김대원,김형록 대한조혈모세포이식학회 2001 대한조혈모세포이식학회지 Vol.6 No.2
배경: 고용량 화학요법 및 자가 조혈모세포이식으로 고위험 소아 고형 종양의 치료 성적이 현저히 향상되었으나 아직 다수의 환자에서 종양이 재발한다. 본 연구에서는 1회의 고용량 화학요법으로 완치가 어려울 것으로 판단되는 고위험 고형 종양에서 반복적인 고용량 화학요법을 시행함으로서 치료성적을 극대화하고자 하였다. 방법: 1998년 4월부터 2001년 6월까지 삼성서울병원 소아과에서 반복적인 고용량 화학요법 및 자가 말초혈 조혈모세포이식을 시행한 26명을 대상으로 하였으며 대상질환은 신경모세포종 15례, 수모세포종 3례, 뇌간교종 2례, 원시신경외배엽종양 1례, 교모세포종 1례, 털모양별세포종 1례, 악성섬유성조직세포종 1례, 투명세포종 1례, 횡문근육양종 1례이었다.. 1차 및 2차 조혈모세포이식의 혈액학적 회복과 합병증을 비교하였고 고용량 화학요법 전후의 치료반응, 생존율을 분석하였다. 결과: 진단시 중앙 연령은 3년 3개월(7개월~16년 6개월)이었고, 1차 이식 시 중앙 연령은 4년 2개월(16개월~16년 8개월), 1차 이식 후 2차 이식까지의 간격은 중앙값 76일(46일~329일)이었다. 1차, 2차 이식 후 절대호중구수가 500/μL에 도달하는데 각각 10일과 11일(P=0.06)이 소요되었으며 혈소판수가 50,000/μL에 도달하는데 각각 24일과 36.5일(P=0.0005)이 소요되었다. Grade 3 이상의 합병증은 1차 이식에서 구내염이 더 많았으며 간정맥 폐쇄성 질환, 구토, 황달, 신기능 저하 등은 통계적으로 유의하지는 않았으나 2차 이식에서 빈도가 높은 경향을 보였다. 1차 이식 후 부분 관해였던 21명 중 2차 이식 후 완전 관해가 된 경우가 13명이었다. 대상 환자의 3년 생존율은 62.9%였고, 3년 무병 생존율은 57.7%였다. 사망자 9명의 사인은 질병의 진행 4명, 간정맥 폐쇄성 질환 3명, 폐출혈 1명, RSV 폐렴 1명 순이었다. 결론: 2차 고용량 화학요법 및 자가 조혈모세포이식에서 조혈 기능의 회복이 느리고 합병증의 빈도가 더 높은 경향을 보였지만 부분 관해에서 완전 관해로의 전환이 다수에서 관찰되었다. 따라서, 향후 보다 적극적인 보존적 치료가 병행된다면 고위험 소아 고형 종양에서 반복적인 고용량 화학요법을 통해 치료 성적의 향상을 기대할 수 있을 것으로 사료된다. Background: The survival of the patients with pediatric solid tumors has been improved, but there are still many patients who relapse. In this study, double high dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (PBSCT) was applied to those who seem to have the least chance to be cured with single HDCT, so that maximize the cure rate of patients with high risk childhood cancers. Methods: Twenty six patients received double HDCT and autologous PBSCT from April 1998 to June 2001. Patients' diagnoses were neuroblastoma (15), medulloblastoma (3), brain stem glioma (2), primitive neuroectodermal tumor (1), glioblastoma (1), pilocytic astrocytoma (1), malignant fibrous histiocytoma (1), clear cell sarcoma (1), and rhabdoid tumor (1). We compared the hematologic recovery and the incidence of transplant-related complications after 1st and 2nd HDCT. Results: Median age at diagnosis and at 1st HDCT was 39 mo (7 mo~198 mo) and 50 mo (16 mo~200 mo), respectively. The interval between 1st and 2nd HDCT was median 76 days (46 d~329 d). The neutrophil recovery above ANC 500/μL after 1st and 2nd transplant was attained on day 10 and day 11, respectively (P=0.06). The platelet recovery above 50,000/μL without transfusion dependency was attained on day 24 and day 36.5 after 1st and 2nd transplant, respectively (P=0.0005). Grade 3 or 4 stomatitis was more common during 1st transplant (P=0.045), but other toxicities such as hepatic veno-occlusive disease (VOD), hyperbilirubinemia, and renal insufficiency were more common during 2nd transplant without statistical significances. Of the 21 patients who were in partial remission (PR) after 1st HDCT, 13 patients converted to complete remission (CR) after 2nd HDCT. Patients' 3 year overall survival and disease free survival were 62.9% and 57.7%, respectively. Nine patients died from disease progression (4), VOD (3), pulmonary hemorrhage (1), and RSV pneumonia (1). Conclusion: Delayed platelet recovery and various toxicities were more common after 2nd HDCT. But, many patients achieved CR after 2nd HDCT. Therefore, if delicate supportive cares are provided, double HDCT and autologous PBSCT might increase the cure rate of those patients with high risk pediatric solid tumors.
유건희,이수현,이지훈,성기웅,정혜림,구홍회,임도훈,김종현,신형진 대한의학회 2010 Journal of Korean medical science Vol.25 No.3
To determine the impact of treatment protocols on the outcome of central nervous system germ cell tumors (CNS-GCTs), we reviewed the medical records of 53 patients who received front-line chemotherapy from September 1997 to September 2006. Pure germinoma, normal alpha-fetoprotein level and beta-human chorionic gonadotropin level <50 mIU/mL were regarded as low-risk features and the others as high-risk. Patients from different time periods were divided into 3 groups according to the chemotherapy protocols. Group 1 (n=19) received 4 cycles of chemotherapy comprising cisplatin, etoposide and bleomycin. Group 2 (n=16) and group 3(n=18) received 4 cycles of chemotherapy with cisplatin, etoposide, cyclophosphamide and vincristine in the former and with carboplatin, etoposide, cyclophosphamide and bleomycin in the latter. In group 2 and group 3, high-risk patients received double doses of cisplatin, carboplatin and cyclophosphamide. Radiotherapy was given after chemotherapy according to the clinical requirements. The event-free survivals of groups 1, 2, and 3 were 67.0%, 93.8%, and 100%, respectively (group 1 vs. 2, P=0.06; group 2 vs. 3, P=0.29; group 1 vs. 3, P=0.02). Our data suggest that risk-adapted intensive chemotherapy may improve the outcome of patients with malignant CNS-GCTs.