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"[ABSTRAK

Latar Belakang: Angka kesintasan LLA pada anak di negara berkembang masih tertinggal dibanding negara maju. Ketepatan diagnosis dan stratifikasi risiko pasien LLA merupakan hal penting yang perlu dievaluasi sebagai langkah awal untuk meningkatkan kesintasan. Di negara maju ketepatan diagnosis dan stratifikasi risiko didasarkan atas hasil pemeriksaan morfologi, imunofenotiping, sitogenetik, dan molekular. Di Indonesia, hal tersebut belum dapat dilakukan sepenuhnya karena keterbatasan biaya dan fasilitas. Untuk itu, perlu kriteria stratifikasi berdasarkan klinis dan laboratorium sederhana tetapi mampu mendekati stratifikasi molekular. Respons steroid merupakan faktor prognostik kuat dalam memprediksi kejadian relaps dan memengaruhi angka kesintasan. Penambahan variabel respons steroid pada stratifikasi RSCM (stratifikasi modifikasi) diharapkan dapat mendekati kemampuan stratifikasi molekular sebagai baku emas.

Metode: Penelitian kohort prospektif selama 6 bulan dilakukan di Departemen Ilmu Kesehatan Anak FKUI-RSCM pada Januari 2013 - September 2014. Subjek adalah pasienbaruterdiagnosis LLAkemudiandikelompokkanmenjadirisikobiasa(RB)danrisiko tinggi (RT) berdasarkan kriteria stratifikasi RSCM (usia, jumlah leukosit, massa mediastinum dan infiltrasi SSP). Subjek dengan RB mendapat prednison (60 mg/kgBB/hari) dan RT mendapat deksametason (6 mg/kgBB/hari) selama 7 hari. Respons steroid dievaluasi pada hari ke-8, dengan menghitung blas di darah tepi. Respons baik bila jumlah blas < 1.000/μL dan respons buruk bila jumlah blas > 1.000/μL. Subjek dengan respons buruk dikelompokkan RT sesuai stratifikasi risiko yang baru (stratifikasi modifikasi). Evaluasi remisi fase induksi dilakukan setelah 6 minggu pemberian kemoterapi berdasarkan persentase blas dan minimal residual disease (MRD) sumsum tulang. Kriteria risiko tinggi pada stratifikasi molekular bila terdapat fusi gen E2A-PBX1, MLL-AF4, dan BCR-ABL, sedangkan risiko biasa bila terdapat fusi gen TEL-AML1.

Hasil Penelitian: Pada penelitian ini diikutsertakan 73 subjek dengan rerata usia subjek 5,5 (SB ± 3,8) tahun. Subjek lelaki (65,8%) lebih banyak dibanding perempuan (34,2%). Gejala klinis yang sering ditemukan adalah pucat sebanyak 65 (89%), demam 53 (72,6%), nyeri tulang 51 (70%), dan hepatomegali 51 (70%) subjek. Hasil pemeriksaan imunofenotiping mendapatkan 77,1% sel B, 17,1% sel T, dan 5,7% sel campuran. Ketidaksesuaian remisi fase induksi berdasarkan morfologi dan MRD sebesar 15,2%. Stratifikasi RSCM maupun modifikasi tidak berkorelasi dengan stratifikasi molekular (r = 1,1; p = 0,6). Angka kesintasan berdasarkan stratifikasi molekular (79%) lebih tinggi dibandingkan stratifikasi RSCM (68,5%) maupun modifikasi (69,6%).

Simpulan: Stratifikasi modifikasi menunjukkan kemampuan yang sama dengan stratifikasi RSCM dibandingkan stratifikasi molekular. Angka kesintasan berdasarkan stratifikasi molekular lebih tinggi dibandingkan stratifikasi RSCM dan modifikasi.;

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ABSTRACT

Introduction: Survival rate of children with ALL in developing countries remains lower compared to developed countries. Diagnosis and risk stratification are important to determine survival rates. Diagnosis and risk stratification in developed countries are based on morphology, immunophenotyping, cytogenetic, and molecular examination of bone marrow while in Indonesia most of those examinations are not available due to financial and facilities limitation. Therefore, we need to develop stratification criteria based on clinical and laboratory assessment which is comparable to molecular stratification. Response to steroid is a strong predictor of relapse and survival rates in ALL. The aim of the study is to develop new stratification to improve accuracy in predicting relapse rate and increase survival rate, by adding steroid response variable to current CMH stratification, in comparison with molecular stratification as gold standard.

Methods: A prospective study was conducted at Pediatric Hematology-Oncology Division, Department of Child Health, FMUI-CMH on January 2013 ? September 2014. Morphology, immunophenotyping, cytogenetic and molecular assessment were performed. Patient was stratified into standard risk (SR) and high risk (HR) based on CMH stratification criteria (based on age, WBC, mediastinal mass and CNS infiltration) and given steroid (prednisone or dexamethasone) for 7 days. Steroid response was evaluated at day 8, good response if peripheral blast count < 1,000/μL and poor response if > 1,000/μL. Poor responders were moved to HR group in new stratification (modified stratification). Bone marrow aspiration and minimal residual disease (MRD) detection were perfomed after induction phase to evaluate remission and patient was observed for 6 months. High risk criteria based on molecular stratification are E2A-PBX1, MLL-AF4 and BCR-ABL fusion genes, while standard risk is TEL-AML1.

Results: A total of 73 newly diagnosed ALL patients were enrolled in this study. The mean age was 5.5 (SD ± 3.8) years. Incidence in male (65.8%) is higher than female (34.2%). Clinical characteristics are pale (89%), fever (72.6%), bone pain (70%), hepatomegaly (70%), bleeding (42.5%), lymphadenopathy (49.0%), and splenomegaly (46.6%). Immunophenotyping result was 77.1% for B-lineage; 17.1% T-lineage; and 5.7% mixed lineage. Minimal residual disease detection from 33 patients showed no difference in remission between CMH and modified stratification. Four patients were moved to HR after evaluation of steroid response. We found discrepancy of remission induction results based on morphology and MRD in 15.2% subjects. Survival rate for CMH, modified, and molecular stratification were 68.5%, 69.6%, and 75.5%, respectively. Cipto Mangunkusumo Hospital and modified stratification were not correlated with molecular stratification as the gold standard (r = 1.1 ; p = 0.6).

Conclusions: Modified stratification had similar accuracy with CMH stratification compare to molecular stratification in predicting survival rate of ALL children. Remission based on MRD detection between the two stratification was also similar. Survival rate by molecular stratification was higher compared to CMH or modified stratification.;Introduction: Survival rate of children with ALL in developing countries remains lower compared to developed countries. Diagnosis and risk stratification are important to determine survival rates. Diagnosis and risk stratification in developed countries are based on morphology, immunophenotyping, cytogenetic, and molecular examination of bone marrow while in Indonesia most of those examinations are not available due to financial and facilities limitation. Therefore, we need to develop stratification criteria based on clinical and laboratory assessment which is comparable to molecular stratification. Response to steroid is a strong predictor of relapse and survival rates in ALL. The aim of the study is to develop new stratification to improve accuracy in predicting relapse rate and increase survival rate, by adding steroid response variable to current CMH stratification, in comparison with molecular stratification as gold standard.

Methods: A prospective study was conducted at Pediatric Hematology-Oncology Division, Department of Child Health, FMUI-CMH on January 2013 ? September 2014. Morphology, immunophenotyping, cytogenetic and molecular assessment were performed. Patient was stratified into standard risk (SR) and high risk (HR) based on CMH stratification criteria (based on age, WBC, mediastinal mass and CNS infiltration) and given steroid (prednisone or dexamethasone) for 7 days. Steroid response was evaluated at day 8, good response if peripheral blast count < 1,000/μL and poor response if > 1,000/μL. Poor responders were moved to HR group in new stratification (modified stratification). Bone marrow aspiration and minimal residual disease (MRD) detection were perfomed after induction phase to evaluate remission and patient was observed for 6 months. High risk criteria based on molecular stratification are E2A-PBX1, MLL-AF4 and BCR-ABL fusion genes, while standard risk is TEL-AML1.

Results: A total of 73 newly diagnosed ALL patients were enrolled in this study. The mean age was 5.5 (SD ± 3.8) years. Incidence in male (65.8%) is higher than female (34.2%). Clinical characteristics are pale (89%), fever (72.6%), bone pain (70%), hepatomegaly (70%), bleeding (42.5%), lymphadenopathy (49.0%), and splenomegaly (46.6%). Immunophenotyping result was 77.1% for B-lineage; 17.1% T-lineage; and 5.7% mixed lineage. Minimal residual disease detection from 33 patients showed no difference in remission between CMH and modified stratification. Four patients were moved to HR after evaluation of steroid response. We found discrepancy of remission induction results based on morphology and MRD in 15.2% subjects. Survival rate for CMH, modified, and molecular stratification were 68.5%, 69.6%, and 75.5%, respectively. Cipto Mangunkusumo Hospital and modified stratification were not correlated with molecular stratification as the gold standard (r = 1.1 ; p = 0.6).

Conclusions: Modified stratification had similar accuracy with CMH stratification compare to molecular stratification in predicting survival rate of ALL children. Remission based on MRD detection between the two stratification was also similar. Survival rate by molecular stratification was higher compared to CMH or modified stratification.;Introduction: Survival rate of children with ALL in developing countries remains lower compared to developed countries. Diagnosis and risk stratification are important to determine survival rates. Diagnosis and risk stratification in developed countries are based on morphology, immunophenotyping, cytogenetic, and molecular examination of bone marrow while in Indonesia most of those examinations are not available due to financial and facilities limitation. Therefore, we need to develop stratification criteria based on clinical and laboratory assessment which is comparable to molecular stratification. Response to steroid is a strong predictor of relapse and survival rates in ALL. The aim of the study is to develop new stratification to improve accuracy in predicting relapse rate and increase survival rate, by adding steroid response variable to current CMH stratification, in comparison with molecular stratification as gold standard.

Methods: A prospective study was conducted at Pediatric Hematology-Oncology Division, Department of Child Health, FMUI-CMH on January 2013 ? September 2014. Morphology, immunophenotyping, cytogenetic and molecular assessment were performed. Patient was stratified into standard risk (SR) and high risk (HR) based on CMH stratification criteria (based on age, WBC, mediastinal mass and CNS infiltration) and given steroid (prednisone or dexamethasone) for 7 days. Steroid response was evaluated at day 8, good response if peripheral blast count < 1,000/μL and poor response if > 1,000/μL. Poor responders were moved to HR group in new stratification (modified stratification). Bone marrow aspiration and minimal residual disease (MRD) detection were perfomed after induction phase to evaluate remission and patient was observed for 6 months. High risk criteria based on molecular stratification are E2A-PBX1, MLL-AF4 and BCR-ABL fusion genes, while standard risk is TEL-AML1.

Results: A total of 73 newly diagnosed ALL patients were enrolled in this study. The mean age was 5.5 (SD ± 3.8) years. Incidence in male (65.8%) is higher than female (34.2%). Clinical characteristics are pale (89%), fever (72.6%), bone pain (70%), hepatomegaly (70%), bleeding (42.5%), lymphadenopathy (49.0%), and splenomegaly (46.6%). Immunophenotyping result was 77.1% for B-lineage; 17.1% T-lineage; and 5.7% mixed lineage. Minimal residual disease detection from 33 patients showed no difference in remission between CMH and modified stratification. Four patients were moved to HR after evaluation of steroid response. We found discrepancy of remission induction results based on morphology and MRD in 15.2% subjects. Survival rate for CMH, modified, and molecular stratification were 68.5%, 69.6%, and 75.5%, respectively. Cipto Mangunkusumo Hospital and modified stratification were not correlated with molecular stratification as the gold standard (r = 1.1 ; p = 0.6).

Conclusions: Modified stratification had similar accuracy with CMH stratification compare to molecular stratification in predicting survival rate of ALL children. Remission based on MRD detection between the two stratification was also similar. Survival rate by molecular stratification was higher compared to CMH or modified stratification., Introduction: Survival rate of children with ALL in developing countries remains lower compared to developed countries. Diagnosis and risk stratification are important to determine survival rates. Diagnosis and risk stratification in developed countries are based on morphology, immunophenotyping, cytogenetic, and molecular examination of bone marrow while in Indonesia most of those examinations are not available due to financial and facilities limitation. Therefore, we need to develop stratification criteria based on clinical and laboratory assessment which is comparable to molecular stratification. Response to steroid is a strong predictor of relapse and survival rates in ALL. The aim of the study is to develop new stratification to improve accuracy in predicting relapse rate and increase survival rate, by adding steroid response variable to current CMH stratification, in comparison with molecular stratification as gold standard.

Methods: A prospective study was conducted at Pediatric Hematology-Oncology Division, Department of Child Health, FMUI-CMH on January 2013 – September 2014. Morphology, immunophenotyping, cytogenetic and molecular assessment were performed. Patient was stratified into standard risk (SR) and high risk (HR) based on CMH stratification criteria (based on age, WBC, mediastinal mass and CNS infiltration) and given steroid (prednisone or dexamethasone) for 7 days. Steroid response was evaluated at day 8, good response if peripheral blast count < 1,000/μL and poor response if > 1,000/μL. Poor responders were moved to HR group in new stratification (modified stratification). Bone marrow aspiration and minimal residual disease (MRD) detection were perfomed after induction phase to evaluate remission and patient was observed for 6 months. High risk criteria based on molecular stratification are E2A-PBX1, MLL-AF4 and BCR-ABL fusion genes, while standard risk is TEL-AML1.

Results: A total of 73 newly diagnosed ALL patients were enrolled in this study. The mean age was 5.5 (SD ± 3.8) years. Incidence in male (65.8%) is higher than female (34.2%). Clinical characteristics are pale (89%), fever (72.6%), bone pain (70%), hepatomegaly (70%), bleeding (42.5%), lymphadenopathy (49.0%), and splenomegaly (46.6%). Immunophenotyping result was 77.1% for B-lineage; 17.1% T-lineage; and 5.7% mixed lineage. Minimal residual disease detection from 33 patients showed no difference in remission between CMH and modified stratification. Four patients were moved to HR after evaluation of steroid response. We found discrepancy of remission induction results based on morphology and MRD in 15.2% subjects. Survival rate for CMH, modified, and molecular stratification were 68.5%, 69.6%, and 75.5%, respectively. Cipto Mangunkusumo Hospital and modified stratification were not correlated with molecular stratification as the gold standard (r = 1.1 ; p = 0.6).

Conclusions: Modified stratification had similar accuracy with CMH stratification compare to molecular stratification in predicting survival rate of ALL children. Remission based on MRD detection between the two stratification was also similar. Survival rate by molecular stratification was higher compared to CMH or modified stratification.]"

"ABSTRAKLatar belakang: Pada semua sindrom epilepsi, epilepsi lobus temporal ELT memiliki kemungkinan paling besar untuk menjadi resisten terhadap obat.Polimorfisme gen multidrug resistant-1 MDR1 C3435T dicurigai sebagai salahsatu penyebabnya. Di RS Cipto Mangunkusumo RSCM , sebagai pusat rujukannasional, prevalensi ELT potensial resisten obat adalah 84.51 dan duapertiganya dalam terapi karbamazepin KBZ .Tujuan: Mengetahui polimorfisme dan ekspresi gen MDR1 C3435T serta kadarplasma KBZ pada penderita epilepsi yang responsif dan resisten terhadap obat.Metode: Penelitian potong lintang komparatif dilakukan di RSCM dari Juni 2015sampai Desember 2016. Penderita ELT dipilih secara konsekutif. Kelompokkontrol terdiri dari subjek sehat tanpa riwayat epilepsi. Identifikasi genotipemenggunakan teknik restriction Fragment Length Polymorphism PCR denganenzim restriksi Mbo1. Pemeriksaan kadar plasma KBZ menggunakan HighPerformance Liquid Chromatography. Ekspresi mRNA dengan metodesequencing and real time quantitative PCR.Hasil: Didapatkan 61 subjek dan 25 kontrol. Sebaran genotipe TT 71,43 danalel T genotipe CT dan TT lebih tinggi pada grup resisten x= 10,41; p =0,001 . Terdapat korelasi sangat kuat antara dosis dan kadar plasma KBZ padagrup responsif r = 0,75; p = 0,000 dengan rerata dosis 405,21 226,50mg dankadar plasma 7,59 2,32mcg/mL. Ekspresi kuantitatif relatif Rq mRNA palingtinggi pada grup kontrol diikuti resisten dan responsif. Genotipe TT menunjukkanRq yang berbeda pada tiap grup. Terdapat perbedaan bermakna antara dosis dankadar plasma KBZ pada masing-masing genotipe tiap grup, terutama antaragenotipe CT reponsif dengan semua genotipe grup resisten.Kesimpulan: Genotipe TT dan alel T MDR1 C3435T secara statistik berhubungandengan dosis dan kadar plasma KBZ yang lebih tinggi pada ELT resisten obat.

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ABSTRACTBackground Among epilepsy syndrome, temporal lobe epilepsy TLE has thehighest probability to become drug resistant. Multidrug resistant 1 MDR1 C3435T polymorphism was suspected to be one of the caused. In CiptoMangunkusumo hospital RSCM , as the national reference hospital, potentialdrug resistant epilepsy prevalence was 84.51 and carbamazepine CBZ usagein two third of the patients.Objective This study was performed to learn about MDR1 C3435T polymorphismand expressions, and CBZ plasma concentration in drug responsive and resistanttemporal lobe epilepsy patients.Methods A comparative cross sectional study was performed in RSCM. TLEpatients were selected consecutively. Healthy people were also selected as thecontrol group. Restriction Fragment Length Polymorphism PCR technique withMbo1 restriction enzyme was used to identify the genes. High Performance LiquidChromatography method was used to determine CBZ concentration in plasma.mRNA expressions identification were using sequencing and real timequantitative PCR methods.Result There were 61 subjects in study group and 25 in control group. Frequencyof TT genotype 71.43 and T allele CT and TT genotype were higher inresistant one x2 10.41, p 0.001 . There was a very strong correlationsbetween CBZ plasma concentration in drug responsive epilepsy r 0.75, p 0.000 in mean dosage of 405,21 226,50mg and plasma concentration of 7,59 2,32mcg mL. mRNA expressions were highest in control group followed byresistant and responsive ones. TT genotype expression was relatively different ineach group. There were signifant differences between genotype in each groupwith CBZ dosage and plasma concentration, especially in CT responsivecompare to all genotypes in resistant group.Conclusion TT genotype and T allele of MDR1 C3435T statistically associatedwith higher CBZ dosage and plasma concentration in drug resistant TLE patients."

"Latar Belakang. Kadar antibodi antikardiolipin (ACA) yang tinggi pada penderita thalassemia dewasa telah dijumpai di Jakarta. Hal ini belum pernah dilaporkan di Indonesia. Publikasi ilmiah internasional mengenai hal inipun sangat sedikit. Bahkan, belum ada tulisan ilmiah yang mengupas mekanisme fenomena ini. Di samping itu, telah dijumpai berbagai kejadian trombosis pada penderita thalassemia dewasa dengan kadar ACA yang tinggi. Namun, sampai saat ini belum ada satupun tulisan yang menghubungkan gangguan hemostasis pada thalassemia dengan kadar ACA yang tinggi. Thalassemia dan Sindrom Antifosfolipid (APS) masuk dalam kondisi hiperkoagulabilitas. Pertanyaannya adalah: Selain ACA, apakah LA dan anti-|32GPl juga tinggi? Mengapa ACA tinggi? Bagaimana gambaran klinis dan laboratoris gangguan hernostasis yang terjadi? Apakah sama dengan yang ditemukan pada thalassemia dan APS, pada umumnya? Apakah ada hubungan antara gangguan hemostasis, baik klinis maupm laboratoris, dengan ACA yang tinggi?Metodologi. Dilakukan Studi potong lintang yang bersifat eksploratif dan analitik pada 41 penderita thalassemia B dewasa, di beberapa rumah sakit dan klinik di Jakarta, dalam kurun waktu 2 tahun 8 bulan, mulai Maret 2002 sampai dengan Oktober 2004. Pemeriksaan sampel darah dilakukan di beberapa laboratorium di Jakarta dan di Bangkok, mencakup ACA IgG dan IgM, anti-|32GP1 IgG dan IgM, LA, annexin V (ekspresi fosfatidilserin eritrosit), mikrovesikel eritrosit, VCAM-1 (disfungsi endotel), bilirubin indirk, LDH, feritin serum, untuk menentukan mengapa ACA tinggi, dan TAT komplel-zs, F1+2, D-dimer, agregasi trombosit, AT Ill, protein C,protein S, PAI-1 untuk menentukan adakah hubungan antara ACA yang tinggi dengan gangguan hemostasis.Hasil Penelitian. Penderita thalassemia B dewasa menunjukkan: (a) proporsi yang lebih besar secara bermakna dalam hal kadar ACA IgG dan ACA IgM yang tinggi, namun proporsinya tidak berbeda bermakna dalam hal anti-|32GPl IgG dan IgM yang tinggi serla LA yang posilif, (b) annexin V, mikrovesikel, bilirubin indirek, LDH, feritln serum, dan VCAM-1 yang tinggi (c) ACA IgG yang tinggi secara klinis memiliki hubungan dengan VCAM-l, bilirubin indirek dan LDI-I yang tinggi; VCAM-1 merupakan variabel paling baik untuk mcmprediksi ACA yang tinggi, (cl) VCAM-I yang tinggi memiliki hubungan bermakna dengan feritin serum yang tinggi, (e) annexin V yang tinggi memiliki hubungan dengan mikrovesikel eritrosit dan LDH yang tinggi; LDH yang tinggi merupakan variabel paling bermakna dalam memprudiksi annexin V yang tinggi, (f) episiaksis, gusi berdarah, dan purpura memiliki hubungan bermakna dengan ACA IgG yang tinggi; ACA IgG IgG secara klinis meningkatkan risiko keluhan di mata dan telinga; ACA IgM yang tinggi seoara klinis meningkalkan keluhan di kepala, tungkai, dada, serta mata dan telinga, (g) ACA IgG yang tinggi memiliki hubungan bermakna dengan aktifitas protein S dan AT III yang rendah; secara klinis meningkatkan risiko untuk tenjadinya D-dimer yang tinggi, dan (h) kelainan hemostasis pada penderita thalassemia dengan ACA yang tinggi banyak kesamaannya dengan thalasssemia dan APS pada umumnya, kecuali pada subyek penelitian dijumpai adanya hiporeaktif agregasi trombosit dan PAI-1 yang tidak tinggi.Simpulan. Desain penelitian yang bersifat studi potong lintang ini menghasilkan konsep yang didasarkan atas hubungan dua variabel, sehingga hasil penelitian ini harus ditindak Ianjuti dengan studi lanjutan, mencakup konsep: pada penderita thalassemia [3 dewasa (a) muatan besi berlebih menimbulkan kerusakan endotel vaskular, sehingga fosfolipid anionik terpajan ke luar, kemudian merangsang pembentukan ACA IgG, (b) hemolisis menyebabkan pajanan berlebih fosfolipid anionik pada lapisan luar eritrosit, yang kemudian merangsang pembentukan ACA IgG."