Amaç: Kemik iliði infiltrasyonu (KÝÝ), lenfoma evresini, saðkalýmý ve tedaviyi etkiler. Lenfoma hastalarýnda KÝÝ’yi saptamada kemik iliði biyopsisi (KÝB) ve pozitron emisyon tomografi-bilgisayarlý tomografinin (PET/BT) performanslarýný deðerlendirmek istedik.
Gereç ve Yöntem: Ýki yüz altmýþ dokuz non-Hodgkin lenfoma (NHL) ve 110 hodgkin lenfoma (HL) hastasý retrospektif olarak deðerlendirildi. KÝÝ’yi saptamada PET/BT ve KÝB için duyarlýlýk, negatif prediktif deðer (NPD) ve doðruluk hesaplandý.
Bulgular: NHL olgularýnda KÝÝ’yi saptamada PET/BT için duyarlýlýk, NPD ve doðruluk sýrasýyla %65, %78 ve %84,4 iken KÝB için %55, %73,4 ve %79,9 idi. Diffüz büyük B-hücreli lenfoma ve folliküler lenfoma için PET/BT performansý KÝB’den daha iyi iken; mantle-cell lenfoma, Burkitt’s lenfoma ve primer mediastinal B-hücreli lenfomada KÝB performansý daha iyiydi. HL olgularýnda PET/BT için duyarlýlýk, NPD ve doðruluk sýrasýyla %91,3, %97,75 ve %98,18 iken KÝB için %56,52, %89,69 ve %90,91 idi. KÝB yapýlmasý ile NHL grubunda 43 (%15,9), HL grubunda ise 2 (%1,8) olgunun düþük evrelenmesinden korunmuþ olundu.
Sonuç: KÝÝ’yi saptamada NHL alt tiplerine göre deðiþmekle birlikte PET/BT ve KÝB birbirini tamamlayýcý yöntemlerdir. HL’de ise KÝÝ’yi saptamak için PET/BT önemli bir taný aracýdýr ve KÝB olgularýn önemli kýsmýnda gerekli deðildir.

Objective: Bone marrow infiltration (BMI) affects the stage diagnosis, and treatment of lymphoma. We aimed to evaluate the performance of bone marrow biopsy (BMB) and positron emission tomographycomputed tomography (PET/CT) in detecting BMI in lymphoma patients.
Materials and Methods: A total of 269 non-Hodgkin’s lymphoma (NHL) and 110 Hodgkin’s lymphoma (HL) patients were evaluated retrospectively. Sensitivity, negative predictive value (NPV), and accuracy were calculated for PET/CT and BMB in detecting BMI.
Results: Sensitivity, NPV, and accuracy for PET/CT in detecting BMI in NHL cases were 65%, 78%, and 84.4%, respectively, while they were 55%, 73.4%, and 79.9% for BMB. PET/CT performance for diffuse large B-cell lymphoma and follicular lymphoma was better than that of BMB, whereas the performance of BMB was better for mantlecell lymphoma, Burkitt’s lymphoma, and primary mediastinal B-cell lymphoma. Sensitivity, NPV, and accuracy for PET/CT in HL cases were 91.3%, 97.75%, and 98.18%, respectively, while they were 56.52%, 89.69%, and 90.91% for BMB. Due to BMB, 43 (15.9%) patients in the NHL group and 2 (1.8%) patients in the HL group were protected from downstaging.
Conclusion: Although their results vary according to NHL subtypes, PET/CT and BMB are complementary methods in determining BMI. In HL, PET/CT is an important diagnostic tool for detecting BMI, and BMB is not necessary in a significant proportion of cases.

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Amaç: T-hücreli akut lenfoblastik lösemi (T-ALL), T-hücrelerinin geliþimini etkileyen genetik deðiþikliklerin birikmesinden kaynaklanan agresif bir hastalýktýr. Bugüne kadar lymphoid enhancer-binding factor 1’in (LEF1) hem inaktive edici mutasyonlarý hem de aþýrý ekspresyonu bildirildiðinden T-ALL geliþiminde rolü tartýþmalýdýr. Bu çalýþmada, insan T hücreli lösemi hücre soyu olan Jurkat hücrelerinde LEF1’in potansiyel hedef genleri araþtýrýldý.
Gereç ve Yöntem: Jurkat hücrelerinde küçük engelleyici RNA (siRNA) teknolojisi ile LEF1 baskýlandý ve mikroarray analizi ile LEF1 baskýlanmýþ hücrelerdeki gen ekspresyon seviyeleri, negatif kontrol siRNA (hedefsiz siRNA) ile transfekte edilmiþ hücrelerdeki gen ekspresyon seviyeleri ile karþýlaþtýrýldý.
Bulgular: LEF1 baskýlanmýþ hücrelerde en önemli seviyede expresyonu azalan gen tümör baskýlayýcý DHRS2 geni olarak belirlendi. Ayrýca bu bulgu hem mRNA seviyesinde gerçek zamanlý kantitatif polimeraz zincir reaksiyonu (qRT-PCR) ile hem de protein seviyesinde western blot ile doðrulandý.
Sonuç: Bu bulgular DHRS2’nin Jurkat hücrelerinde LEF1 tarafýndan pozitif olarak düzenlendiðini göstererek LEF1’in tümör baskýlayýcý kapasitesi olduðuna iþaret etmektedir ve daha önceki çalýþmalarda bildirilen sonuçlarla birlikte, LEF1’in hem onkojenik hedefleri hem de tümör baskýlayýcý hedefleri aracýlýðýyla T-ALL’de düzenleyici bir rol oynadýðýný ileri sürmektedir.

Objective: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease resulting from the accumulation of genetic changes that affect the development of T-cells. The precise role of lymphoid enhancerbinding factor 1 (LEF1) in T-ALL has been controversial since both overexpression and inactivating LEF1 mutations have been reported to date. Here, we investigate the potential gene targets of LEF1 in the Jurkat human T-cell leukemia cell line.
Materials and Methods: We used small interfering RNA (siRNA) technology to knock down LEF1 in Jurkat cells and then compared the gene expression levels in the LEF1 knockdown cells with nontargeting siRNA-transfected and non-transfected cells by employing microarray analysis.
Results: We identified DHRS2, a tumor suppressor gene, as the most significantly downregulated gene in LEF1 knockdown cells, and we further confirmed its downregulation by real-time quantitative polymerase chain reaction (qRT-PCR) in mRNA and at protein level by western blotting.
Conclusion: Our results revealed that DHRS2 is positively regulated by LEF1 in Jurkat cells, which indicates the capability of LEF1 as a tumor suppressor and, together with previous reports, suggests that LEF1 exhibits a regulatory role in T-ALL via not only its oncogenic targets but also tumor suppressor genes.

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Amaç: Relaps/refrakter CD19-pozitif B-hücreli akut lenfoblastik lösemi (ALL) ve Hodgkin dýþý lenfoma (NHL), hematolojik kanserlerle ilgili çalýþmalarýn odak noktasýdýr. Bu malignitelerin tedavisi, daha güvenilir ve iyi tolere edilen terapötik yaklaþýmlar olan, yeni gen terapisi ve moleküler biyoloji tekniklerinin geliþtirilmesi ile son zamanlarda dönüþüm geçirmiþtir. CD19 antijeni, bu hematolojik kanserlerde en çok çalýþýlan terapötik hedeftir. Bu çalýþma, Türkiye’de relaps/refrakter ALL ve NHL hastalarýnda, ilk akademik klinik deneme için kullanýlmasý amacýyla, CD19 eksprese eden B hücrelerini hedefleyen CAR-T (ISIKOK-19) hücrelerinin klinik sýnýf üretimi, kalite kontrolü ve in vivo etkinlik süreçlerinin sonuçlarýný bildirmektedir.
Gereç ve Yöntem: Bu çalýþmada, insan T-lenfositleri (CAR-T) üzerinde kesilmiþ EGFR (EGFRt) formu ile birlikte kimerik bir antijen reseptörü (CAR) olarak CD8-CD28-CD3ζ sekansý ile konjuge CD19 antijene özgü antikor baþýný (FMC63) eksprese eden bir lentiviral vektör kullandýk.Hem saðlýklý donörlerin hem de ALL/NHL hastalarýnýn periferal kan mononükleer hücrelerinden üretilen CAR-T (ISIKOK-19) hücrelerinin etkinliðini ve güvenliðini klinik öncesi olarak deðerlendirdik.
Bulgular: CAR-T hücre üretiminin maliyetini düþürmek için sinyal molekülü TBK1/IKKƐ’nýn bir inhibitörü olan BX-795 kullanarak T-hücrelerinde CAR lentivirüs transdüksiyon etkinliðinin önemli ölçüde arttýðýný gösterdik. Ek olarak, ISIKOK-19 CAR-T hücrelerinin, NOD/SCID farelerinde özellikle bir CD19 + Blenfosit kanser modeli olan RAJI hücrelerine karþý önemli ölçüde ve yüksek seviyede sitotoksisite gösterdiðini deðerlendirdik.
Sonuç: Bu çalýþma, Türkiye’de relaps/refrakter ALL ve NHL hastalarýnda CD19 eksprese eden B-hücrelerini hedefleyen CAR-T hücrelerinin ilk akademik klinik çalýþmasý olarak ISIKOK-19 hücrelerinin klinik sýnýf üretimi, kalite kontrolü ve in vivo etkinlik süreçlerinin sonuçlarýný bildirmektedir.

Objective: Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biology techniques, which are safer and well-tolerated therapeutic approaches. The CD19 antigen is the most studied therapeutic target in these hematological cancers. This study reports the results of clinical-grade production, quality control, and in vivo efficacy processes of ISIKOK-19 cells as the first academic clinical trial of CAR-T cells targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey.
Materials and Methods: We used a lentiviral vector encoding the CD19 antigen-specific antibody head (FMC63) conjugated with the CD8-CD28-CD3ζ sequence as a chimeric antigen receptor (CAR) along with a truncated form of EGFR (EGFRt) on human T-lymphocytes (CAR-T). We preclinically assessed the efficacy and safety of the manufactured CAR-T cells, namely ISIKOK-19, from both healthy donors’ and ALL/NHL patients’ peripheral blood mononuclear cells.
Results: We showed significant enhancement of CAR lentivirus transduction efficacy in T-cells using BX-795, an inhibitor of the signaling molecule TBK1/IKKƐ, in order to cut the cost of CAR-T cell production. In addition, ISIKOK-19 cells demonstrated a significantly high level of cytotoxicity specifically against a CD19+ B-lymphocyte cancer model, RAJI cells, in NOD/SCID mice.
Conclusion: This is the first report of preclinical assessment of efficacy and safety analysis of CAR-T cells (ISIKOK-19) targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey.

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Amaç: Çalýþmalar göstermiþtir ki serum circRNA pekçok tümör için biyobelirteç olarak kullanýlabilir. Ancak, multiple myelomlu (MM) hastalarda eksozomal circRNA’nýn rolü belirsizdir. Bu çalýþmada dolaþan eksozomal circMYC’nin MM’li hastalarýn nüks ve prognozundaki rolünü analiz etmeyi hedefledik.
Gereç ve Yöntem: MM’li 122 hasta ve 54 saðlýklý kiþiden dolaþan eksozomlar izole edildi. Kantitatif polimeraz reaksiyonu circMYC eksozomal ekspresyonunu ölçmek için uygulandý. Saðkalým oranýnýn önemini tahmin etmek için log-rank testiyle beraber Kaplan-Meier saðkalým eðrileri kullanýldý. Tek deðiþkenli ve çok deðiþkenli analiz için Cox regresyon modeli kullanýldý.
Bulgular: Saðlýklý kiþilerle karþýlaþtýrýldýðýnda MM’li hastalarda serum eksozomal circMYC ekspresyon düzeyleri anlamlý ölçüde artmýþtý. Ýlaveten, dolaþan eksozomlarda circMYC ekspresyonu bortezomibe dirençli hastalarda dirençli olmayanlara göre anlamlý ölçüde yüksekti. Eksozomal circMYC ekspresyon düzeyi delesyon 17p, t(4;14), Durie- Salmon evrelemesi ve Uluslararasý Evreleme Sistemi ile baðlantýlýydý. Tek deðiþkenli ve çok deðiþkenli Cox regresyon analizi yüksek eksozomal circMYC düzeyinin MM’li hastalarda kötü prognozun baðýmsýz göstergesi olduðunu gösterdi. Yüksek eksozom circMYC ekspresyonu olan hastalarda daha yüksek nüks ve mortalite oraný vardý. Yüksek eksozomal circMYC ekspresyonu olan MM’lu hastalarýn genel saðkalým ve ilerlemesiz saðkalým oraný düþük eksozomal circMYC ekspresyonu olan hastalardan daha düþüktü.
Sonuç: Bu bulgular dolaþan eksozomal circMYC’nin MM taný ve prognozu için biyobelirteç olma potansiyeli olduðunu düþündürmektedir.

Objective: Studies have shown that serum circRNA can be used as a biomarker for many tumors. However, the role of exosomal circRNA in prognostic evaluation in patients with multiple myeloma (MM) remains unclear. In this study, we aimed to analyze the role of circulating exosomal circMYC in the relapse and prognosis of patients with MM.
Materials and Methods: Circulating exosomes from 122 patients with MM and 54 healthy people were isolated. Quantitative polymerase chain reaction was performed to measure circMYC exosomal expression. Kaplan-Meier survival curves with log-rank testing were used for estimating significance in survival rates. A Cox regression model was used for univariate and multivariate analysis.
Results: Compared with healthy people, the expression level of serum exosomal circMYC was significantly increased in patients with MM. In addition, the expression of circMYC in circulating exosomes in bortezomib-resistant patients was significantly higher than that in non-resistant patients. The expression level of exosomal circMYC was correlated with deletion 17p, t(4;14), Durie-Salmon staging, and the International Staging System. Univariate and multivariate Cox regression analysis found that a high exosomal circMYC level was an independent predictor of poor prognosis in patients with MM. The patients with high exosome circMYC expression had higher relapse rates and higher mortality rates. The overall survival rate and progression-free survival rate of MM patients with high exosomal circMYC expression were lower than those of patients with low exosomal circMYC expression.
Conclusion: These findings suggest that circulating exosomal circMYC has great potential as a biomarker for the diagnosis and prognosis of MM.

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Amaç: Ekstramedüller (EM) plazmasitom ile iliþkili multipl myelom (MM), geleneksel kemoterapi ile tedavi edildiðinde zayýf bir terapötik yanýta ve kötü sonuçlara sahiptir. EM plazmasitoma iki gruba ayrýlýr: ilk grup doðrudan osteolitik kemik lezyonlarýndan uzanan tümörlerden oluþurken, ikincisi yumuþak dokulara plazmasitom infiltrasyonundan, kemikle iliþkisi olmayan plasmasitomdur. Bu çalýþma, kemikle iliþkili yada yumuþak doku ile iliþkili olan ve taný anýnda plazmasitomu olmayan MM hastalarýnýn genel özelliklerini ve saðkalým sonuçlarýný karþýlaþtýrmayý amaçladý.
Gereç ve Yöntem: Bu çalýþma retrospektif olarak yapýlmýþtýr. Ocak 2003-Ocak 2017 tarihleri arasýnda üçüncü basamak merkezimizde tedavi gören MM hastalarý taný anýnda plazmasitom varlýðý açýsýndan retrospektif olarak deðerlendirildi.
Bulgular: Bu çalýþmaya plazmositom olmayan 141 (%78,3) MM, kemik plasmasitomu olan 22 (%12,2) ve taný anýnda yumuþak doku plasmasitomu olan 17 (%9,4) MM hastasý alýndý. Beþ yýllýk genel saðkalým, kemik plasmasitomu olan hastalarda %63, yumuþak doku plasmasitomu olan hastalarda %63 ve plazmositom olmayan hastalarda %80 saptandý (p=0,02). Beþ yýllýk hastalýksýz saðkalým ise kemik plasmasitomu olanlarda %47, yumuþak doku plasmasitomu olanlarda %35 ve plazmasitom olmayan MM hastalarýnda %54 saptandý (p=0,15).
Sonuç: Sonuç olarak, bu bulgular bizi, taný anýnda EM plazmasitomu olan MM hastalarýnýn, kök hücre nakli yapýlsa bile, plazmasitomu olmayan hastalara göre kötü prognoza sahip olduðunu düþündürmektedir. EM tutulumunun varlýðý saðkalým sonuçlarýný olumsuz etkilemektedir.

Objective: Multiple myeloma (MM) associated with extramedullary (EM) plasmacytoma has a poor therapeutic response and poor outcomes when treated with conventional chemotherapy. EM plasmacytoma is divided into two groups: the first group comprises tumors that are extending directly from osteolytic bone lesions (EM-B, bone-related), while the second results from plasmacytoma infiltration into soft tissues with no relationship to the bone (EM-S, soft tissuerelated). This study aimed to compare the general characteristics and survival outcomes of transplant-eligible MM patients who had EM-S or EM-B and MM patients who did not have plasmacytoma at the time of diagnosis.
Materials and Methods: This study was performed in a retrospective manner. The MM patients who were treated at our tertiary care center between January 2003 and January 2017 were evaluated retrospectively for the presence of plasmacytoma at diagnosis.
Results: There were 141 (78.3%) MM patients who did not have plasmacytoma, 22 (12.2%) MM patients who had EM-B, and 17 (9.4%) MM patients who had EM-S at the time of diagnosis in this study. The 5-year overall survival was 63% in patients who had bone EM-B, 63% in patients who had EM-S, and 80% in patients who did not have plasmacytoma (p=0.02). The 5-year disease-free survival was 47% in patients who had EM-B, 35% in patients who had EM-S, and 54% in MM patients who did not have plasmacytoma (p=0.15).
Conclusion: These findings lead us to suggest that MM patients with EM plasmacytoma at the time of diagnosis have poorer prognosis than patients without plasmacytoma, even if autologous stem cell transplantation is performed. The presence of EM involvement negatively affects survival outcomes.

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Amaç: Çocukluk çaðý lösemisinde aþýrý demir yükünü manyetik rezonans görüntüleme (MRG) ile deðerlendiren sýnýrlý sayýda çalýþma vardýr. Bu çalýþmanýn amacý, akut lenfoblastik lösemisi (ALL) olan ve tedavisini tamamlamýþ olan çocuklarda R2 MRI yöntemiyle karaciðer demir içeriðini (LIC) belirlemek ve serum demir parametreleriyle karþýlaþtýrmaktýr.
Gereç ve Yöntem: Çalýþmaya ALL tedavisini tamamlayan 7-18 yaþlarý arasýnda toplam 30 hasta alýndý. Serum demir parametreleri (serum demir, serum ferritin [SF] ve toplam demir baðlama kapasitesi), karaciðer fonksiyon testleri çalýþýldý. LIC’yi belirlemek için R2 MRG yöntemi kullanýldý.
Bulgular: Olgularýn 22’sinde (%63,4) normal LIC saptandý. Yedi (%23,3) olguda hafif ve 1 (%3,3) olguda orta derecede karaciðerde demir birikimi mevcuttu. Buna karþýlýk, hiçbir olguda ciddi derecede demir birikimi tespit edilmedi. LIC seviyeleri, pRBC transfüzyonu sayýsý (r=0,637, p<0,001), pRBC transfüzyon miktarý (r=0,449, p<0,013), SF seviyeleri (r=0,561, p=0,001) ve transferrin (r=0,353, p=0,044) ile korele saptandý. Ek olarak, pRBC transfüzyonlarýnýn sayýsý ile SF seviyeleri arasýnda pozitif korelasyon bulundu (r=0,595, p<0,001).
Sonuç: Çocukluk çaðý ALL hastalarýnda tedavi bitiminden sonra karaciðer demir birikiminin sýklýðýnýn düþük ve klinik olarak daha az önemli olduðunu gösterdik. Ayrýca, LIC’nin SF ve transfüzyon öyküsü ile iliþkili olduðunu gösterdik. Bu bulgular, SF ve transfüzyon geçmiþinin demir birikimini izlemek veya MRG gibi ileri tetkikin gerekli olduðu olgularý belirlemek açýsýndan referans olarak kullanýlabileceðini desteklemektedir.

Objective: There are a limited number of studies evaluating iron overload in childhood leukemia by magnetic resonance imaging (MRI). The aim of this study was to determine liver iron content (LIC) by MRI in children with acute lymphoblastic leukemia (ALL) who had completed treatment and to compare those values with serum iron parameters.
Materials and Methods: A total of 30 patients between the ages of 7 and 18 who had completed ALL treatment were included in the study. Serum iron parameters (serum iron, serum ferritin [SF], and total ironbinding capacity) and liver function tests were studied. R2 MRI was performed for determining LIC.
Results: Normal LIC was detected in 22 (63.4%) of the cases. Seven (23.3%) had mild and 1 (3.3%) had moderate liver iron deposition. In contrast, severe iron overload was not detected in any of the cases. LIC levels were correlated with the numbers of packed red blood cell (pRBC) transfusions (r=0.637, p<0.001), pRBC transfusion volume (r=0.449, p<0.013), SF levels (r=0.561, p=0.001), and transferrin saturation (r=0.353, p=0.044). In addition, a positive correlation was found between the number of pRBC transfusions and SF levels (r=0.595, p<0.001).
Conclusion: We showed that the frequency of liver iron deposition was low and clinically less significant after the end of treatment in childhood ALL patients. LIC was demonstrated to be related to SF and transfusion history. These findings support that SF and transfusion history may be used as references for monitoring iron accumulation or identifying cases for further examinations such as MRI.

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Amaç: Wiskott-Aldrich Sendromu (WAS) X’e baðlý geçen mikrotrombositopeni, egzema ve tekrarlayan enfeksiyonlarla karakterize bir primer immün yetmezliktir.
Gereç ve Yöntemler: 1982-2019 yýllarý arasýnda izlediðimiz toplam 23 WAS’li hastanýn klinik seyirleri, immünolojik özellikleri ve nakil yapýlan 11 hastanýn nakil iliþkili verileri retrospektif olarak deðerlendirildi.
Bulgular: Baþvurudan önce 11 hasta yanlýþlýkla immün trombositopeni tanýsý almýþtý. WAS skoru çoðunlukla 4 ve 5 puandý. On bir hastaya nakil yapýldý ve ortanca 8,5 yýl (8 ay-20 yýl) izlem süresinde hayatta kalma oraný %100 oldu. Nakil yapýlamayan 5 hasta ortanca 7 yýlda (2- 26 yýl) kaybedildi. Nakil yapýlmayan hastalar çoðunlukla otoimmünite, kanama ve enfeksiyonlarýn neden olduðu organ hasarlarý nedeniyle yüksek morbiditeye sahipti. Ayrýca, iki yeni mutasyon tanýmlandý.
Sonuç: Mikrotrombositopenisi olan tüm erkek bebekler WAS açýsýndan deðerlendirilmelidir. Hematopoetik kök hücre nakli mümkün olan en iyi donörlerle en erken yaþta yapýlmalýdýr.

Objective: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency characterized by microthrombocytopenia, eczema, and recurrent infections. We aimed to evaluate the clinical features and outcomes of a WAS cohort.
Materials and Methods: We retrospectively evaluated the clinical courses, immunological features, treatments, and outcomes in a total of 23 WAS patients together with data related to 11 transplanted cases among them between 1982 and 2019.
Results: Before admission, 11 patients (48%) were misdiagnosed with immune thrombocytopenia. WAS scores were mostly 4 or 5. Eleven patients were transplanted and they had an overall survival rate of 100% during a median follow-up period of 8.5 years (range: 8 months to 20 years). Five patients who were not transplanted died at a median of 7 years (range: 2-26 years). Nontransplanted patients had high morbidity due to organ damage, mostly caused by autoimmunity, bleeding, and infections. Two novel mutations were also defined.
Conclusion: All male babies with microthrombocytopenia should be evaluated for WAS. Hematopoietic stem cell transplantation should be performed at the earliest age with the best possible donors.

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