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"ABSTRAKLatar Belakang: Leukemia mieloid akut (LMA) mempunyai karakteristik heterogenisitas derajat tinggi yang ditandai dengan kelainan kromosom/sitogenetik, mutasi gen, dan perubahan eskpresi gen. Mutasi gen telah diketahui mempunyai peran penting sebagai biomarker prognostik dan prediktif terkait dengan kesintasan, dan juga sebagai sasaran terapi. Mutasi gen yang terlibat cukup penting dalam prognosis pasien LMA adalah FLT3-ITD, NPM1, dan CEBPA.Tujuan: Untuk mengetahui frekuensi imunofenotip, mutasi gen FLT3-ITD, NPM1, dan CEBPA serta untuk mengetahui hubungannya dengan kesintasan tiga bulan pada pasien LMA.Metode Penelitian: Penelitian dilakukan dengan menggunakan desain longitudinal prospektif terhadap pasien LMA dewasa rawat jalan dan rawat inap RS Kanker Dharmais (RSKD) pada bulan Juli 2014 sampai Februari 2015. Sampel berupa 20 mL aspirat sumsum tulang atau darah perifer dengan antikoagulan EDTA. Penelitian dilakukan di Laboratorium Patologi Klinik dan Bagian Penelitian dan Pengembangan RSKD. Deteksi mutasi gen FLT3-ITD dilakukan dengan metode elektroforesis. Deteksi mutasi NPM1 dan CEBPA dilakukan dengan metode DHPLC yang kemudian dilanjutkan dengan pemeriksaan sekuens DNA untuk mengetahui jenis mutasi. Variabel bebas berupa usia, jenis kelamin, jumlah leukosit, ekspresi imunofenotip (CD34 dan aberrant), dan mutasi gen (FLT3-ITD, NPM1, dan CEBPA), sedangkan variabel tergantung adalah luaran klinis kesintasan dalam tiga bulan.Hasil Penelitian dan Pembahasan: Didapatkan total 66 subjek dengan rerata usia relatif lebih muda yaitu 42,37 + 15,75 dan sebanyak 83,3 % di bawah 60 tahun. Sebanyak 54 % subjek mempunyai ekspresi CD34, dan hanya 15,2 % mempunyai ekspresi aberrant. Terdapat 40 subjek yang menjalani kemoterapi induksi (60,5 %). Hanya 37 dari 66 subjek yang dilakukan pemeriksaan mutasi gen FLT3-ITD, NPM1, dan CEBPA. Frekuensi mutasi gen FLT3-ITD, NPM1 dan CEBPA berturut-turut 16,2 %, 40,5 %, dan 35,1 %. Pada keseluruhan subjek (n = 66) ditemukan bahwa FLT3 wild type dan CEBPA mutasi berhubungan bermakna terhadap kesintasan dalam tiga bulan yang lebih pendek dengan adjusted RR berturut-turut 2,21 (p 0,022; IK95 % 1,50 - 3,26) dan 2,08 (p 0,036; IK95% 1,06 - 4,07). Pada kelompok subjek yang mendapat kemoterapi (n = 40), hanya mutasi FLT3-ITD yang secara klinis mempunyai kecenderungan memengaruhi kesintasan tiga bulan dengan RR 1,73 (p 0,273; IK95 % 1,18 - 2,54). Sebagai hasil tambahan, ditemukan bahwa mutasi NPM1 berhubungan dengan ekspresi CD34 negatif (p 0,018) dan mutasi CEBPA berhubungan dengan jumlah leukosit lebih besar dari 50 x103/μL (p 0,028).Kesimpulan: Usia LMA di Indonesia relatif lebih muda. Frekuensi mutasi FLT3-ITD relatif lebih rendah dan mutasi NPM1 dan CEBPA cenderung lebih tinggi. FLT3 wild type dan mutasi CEBPA berhubungan dengan kesintasan yang lebih pendek pada penelitian ini. Diperoleh data bahwa kejadian mutasi NPM1 behubungan dengan CD34 negatif dan mutasi CEBPA berhubungan dengan jumlah leukosit yang lebih tinggi.

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ABSTRACT

Background: Acute Myeloid Leukemia (AML) has high degree of heterogeneity characteristic signed with chromosome/cytogenetic abnormality, gene mutation, and gene expression changes. The importance of gene mutation has been known as prognostic and predictive biomarker associated with survival and also as a targeted therapy. Gene mutation that is considered important in AML patient prognosis are FLT3-ITD, NPM1 and CEBPA.

Purpose: To obtain frequency data of immunophenotype and gene mutation of FLT3-ITD, NPM1, and CEBPA, and its relationship with three-month overall survival.

Method: This research was a prospective longitudinal study on adult AML patients who were admitted as outpatient and inpatient in Dharmais National Cancer Center (DNCH) on July 2014 until February 2015. Samples used were 20 mL of bone marrow aspirate or peripheral blood using EDTA anticoagulant. Research was done in Pathological Laboratory and Research and Development of DNCH. FLT3-ITD gene mutation was detected using electrophoresis and NPM1 and CEBPA mutation was detected using DHLPC method continued with DNA sequencing examination to know the type of mutation. The independent variables were age, sex, leukocyte, immunophenotype (CD34 and aberrant), gene mutations (FLT3-ITD, NPM2 and CEBPA). The dependent variable was three-months overall survival.

Result and Discussion: a total of 66 subjects were collected with mean age relatively young, 39.78 years and 83.3 % of them were under 60 years. Fifty four percent subjects had positivity in CD34 expression and 15.2 % had aberrant expression. Forty subjects received induction chemotherapy (60.5 %). Only 37 of 66 subject were analyzed gene mutations. The frequency of FLT3, NPM1 and CEBPA mutation frequency was subsequently 16.2 %, 40.5 % and 35.1 %. From all subjects (n = 66), was found that wild type FLT3 and mutant CEBPA was statistically significant had twice mortality rate in three months than mutant FLT3-ITD (p 0,022; adjusted RR 2,21; IK95 % 1,50 - 3,26) and wild type CEBPA (p 0,036; adjusted RR 2,08; IK95 % 1,06 - 4,07). In treated groups (n = 40), there was no statistically significant association between independent variables with three-months survival. However, there was a clinically significant tendency that wild type FLT3 was consistently related with longer OS (RR 1.73, 95 % CI 1.18 - 2.54). As an additional result, it was found that the NPM1 mutation is associated with lack of CD34 expression (p 0.018) and CEBPA mutations were associated with leukocyte levels > 50 X103 / mL (p 0.028).

Conclusion: The age of AML patients in Indonesia are relatively younger. Proportion of FLT3-ITD gene mutation is relatively lower, whereas proportion of NPM1 and CEBPA mutations tend to be higher. FLT3-ITD wild type and CEBPA mutation are related with shorter survival in this research. Incidence of NPM1 gene mutation is related to lack of CD34 and CEBPA mutation is related to higher leukocyte count."

"Latar Belakang: Keberhasilan terapi Imatinib Mesylate (IM) pada pasien Leukemia Granulositik Kronik (LGK) di Indonesia berbeda dari yang dilaporkan di luar negeri. Diduga karena adanya faktor-faktor lain yang memengaruhi keberhasilan terapi tersebut. Salah satu faktor yang diduga berpengaruh adalah telah terjadinya mutasi gen BCR-Abl sebelum pemberian terapi. Adanya mutasi diperkirakan akan memengaruhi pencapaian CHR bulan ke-3, -6 dan -12, serta MMR bulan ke-18. Metoda: Penelitian nested case control yang dimulai sejak tanggal 1 September 2009 hingga setidaknya 18 bulan pengamatan (waktu untuk melakukan evaluasi, yaitu tercapai atau tidaknya MMR), dilakukan terhadap 88 pasien yang telah dinyatakan positif menderita LGK. Terhadap seluruh subjek penelitian diberikan terapi IM dengan dosis 400 mg sehari. Hasil Penelitian: Pada penelitian ini diikutsertakan 88 pasien, dengan subjek lelaki 55 orang (62,5 %) dan perempuan 33 orang (37,5 %). Untuk mendeteksi mutasi gen BCR-Abl dan selanjutnya dilakukan sekuensing, dari 88 pasien di atas yang berhasil diperiksa hanya 44 pasien. Kaitan antara mutasi gen BCR-Abl hanya bemakna dengan CHR bulan ke-6, tetapi sangat bermakna dengan MMR. Ditemukan 8 jenis mutasi pada 7 pasien pada daerah P-loop dan di luar P-loop, tidak terlihat adanya mutasi yang dominan. Rerata usia pasien adalah 39 tahun, 42 berusia ≥ 39 tahun dan 46 pasien < 39 tahun. Risiko Sokal pada saat pertama kali dilakukan diagnosis, adalah sebagai berikut: low 39,8 %, intermediate 22,7 %, dan high 37,5 %. Berdasarkan pemeriksaan BMP, perincian fase adalah sebagai berikut: kronik 72,7 %, akselerasi 23,9 % dan krisis blastik 3,4 %. Median lama sakit didapatkan nilai 2 bulan. Sebanyak 73,9 % pasien telah mendapat terapi awal dengan HU, sebelum mendapat IM. Berdasarkan lama pemberian HU sebelum terapi IM, sebanyak 27,3 % pasien mendapatkan terapi HU ≥ 6 bulan. Semua faktor-faktor di atas tidak tebukti mempunyai hubungan bermakna dengan pencapaian MMR. Setelah pemberian IM dilakukan evaluasi CHR 3 bulan, 6 bulan, dan 12 bulan. Terbukti adanya hubungan antara pencapaian CHR pada bulan ke-3, ke-6, dan ke-12, dan antara CHR bulan ke-3, ke-6, maupun ke-12 dengan MMR. Belum dapat diformulasikan faktor prediksi untuk pencapaian MMR bulan ke-18, namun mutasi gen BCR-Abl dan pencapaian CHR bulan ke-3 dan ke-12 sangat kuat keterkaitannya dengan pencapaian MMR, sehingga dapat digunakan sebagai prediktor keberhasilan terapi. Simpulan: Mutasi gen BCR-Abl yang dideteksi di awal terapi, cenderung berperan dalam perjalanan klinis pasien LGK di Indonesia. Keberhasilan pencapaian CHR bulan ke-3, dan ke-12 berperan sebagai faktor prediktor untuk tercapainya MMR bulan ke-18.

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Background: The success of Imatinib Mesylate (IM) therapy in patients with Chronic Myeloid Leukemia (CML) in Indonesia is different from abroad. Allegedly there are other factors that influence the success of the treatment. One of the factors suspected is the occurrence of mutation in BCR-Abl gene prior to therapy. Mutation is expected to affect the achievement of CHR in –the 3rd, -6th and -12th months, and MMR in the -18th month. Methods: nested case-control study, started September 1th 2009 until at least 18 months of observation (time to perform the evaluation, namely whether the MMR were achieved or failed), carried out to 88 patients who were proven positive suffered from CML through cytomorphology examination of bone marrow aspirate and qualitative PCR method. All research subjects were given IM therapy dosage 400 mg daily. Results: This study included 88 patients, with 55 male (62.5 %) and 33 female (37.5 %). To detect BCR-Abl gene mutations and continued with sequencing test, from 88 patients recruited, only 44 patients were succeeded performing the test. The correlation between mutation and CHR only significant for CHR 6 months, but the result from MMR was very significant. We found 8 mutations out of 7 patients at P-loop and outside P-loop region, no predominant mutation that was recorded. The mean age of patients was 39 years, 42 were aged ≥ 39 years and 46 were < 39 years. Sokal's risk at the first diagnosis, were as follows: low 39.8 %, intermediate 22.7 %, and high 37.5 %. Based on BMP examination, details of the phases were as follows: chronic 72.7 % patients, acceleration 23.9 % patients and blastic crisis of 3.4 %. Patients. Median duration of illness obtained at a value of 2 months 60.2 % patients had duration of illness ≥ 2 months and 39.8 % patients < 2 months. A total of 73.9 % patients had received initial therapy with hydroxyurea, before given IM. Based on the duration of HU prior IM therapy 27.3 % patients received hydroxyurea therapy ≥ 6 months. All the above mentioned factors were not proven to have significant relationship with the achievement of MMR. After IM administration, CHR evaluated every -3rd, -6th, and 12th months. It was proven that the achievement CHR in the -3rd, -6th, and - 12th month, besides between CHR in the -3rd, -6th and -12th month with MMR. Yet the achievement of CHR in the-3rd and -12th months were strongly related to the achievement of MMR, with the result it can be used as the single predictor of successful therapy. Conclusions: BCR-Abl’s gene mutation that was detected at the early of therapy, tend to play a role in the success therapy of IM in Indonesia. The success of the achievement of CHR of the -3rd and -12th month played a role as a factor of predictor for the achievement of MMR in the -18th month. "

"Kanker paru memiliki mortalitas tinggi dan sering terdiagnosis pada stage lanjut. Kelainan morfologis sel trakeobronkial dan biomolekuler mendahului proses karsinogenesis. Bronkoskopi gelombang cahaya spektrum sempit (GCSS) dikembangkan untuk meningkatkan akurasi diagnostik. Tujuan penelitian ini adalah untuk mengetahui akurasi diagnostik bronkoskopi GCSS dalam mendeteksi kelainan morfologis sel trakeobronkial dan hubungannya dengan mutasi gen p53.Studi ini merupakan studi diagnostik eksperimental yang dilakukan pada subjek kanker paru yang menjalani prosedur bronkoskopi di RS Persahabatan periode Januari-November 2023. Prosedur bronkoskopi GCSS dan biopsi forseps bronkus dilakukan di lesi non-tumor, dilanjutkan dengan pemeriksaan histopatologi hematoksilin dan eosin (HE), serta pemeriksaan Polymerase Chain Reaction (PCR) sekuensing sanger mutasi p53 pada titik R175L, R248W, dan R273C. Analisis kesesuaian juga dilakukan.Sebanyak 105 subjek diikutsertakan dalam analisis penelitian, dengan dominasi laki-laki, perokok, jenis kanker adenokarsinoma dan stage lanjut. Kelainan morfologis sel trakeobronkial ditemukan pada 34 subjek (32,4%) berupa metaplasi, sel atipik dan sel tumor. Mutasi p53 wild type pada titik R175L, R248W, dan R273C ditemukan pada seluruh jaringan biopsi. Satu jaringan metaplasi dengan mutasi p53 Kodon 267 heterozigot CT dan satu jaringan hiperplasi dengan mutasi p53 Kodon 180 heterozigot GC. Pola vaskular berliku didapatkan sebagai kriteria diagnostik paling baik dibandingkan dengan pola vaskular lainnya dengan area under the curve (AUC) 78,4%; sensitivitas 79,41%; spesifisitas 77,46%; nilai prediktif positif 62,8% dan nilai prediktif negatif 88,7%. Kesesuaian antar pengamat dalam menilai pola vaskular GCSS cukup baik dengan nilai kappa 0,88 (standar eror 0,06; nilai p <0,01). Mukosa edematosa berhubungan dengan pola vaskular berliku pada bronkoskopi GCSS dengan OR 3,6 (IK95% 1,53-8,46; nilai p <0,01). Subjek dengan pola vaskular berliku [OR 21,89 (IK95% 6,50-73,71; nilai p<0,01)] dan subjek dengan IB ³ 600 [OR 5,39 (IK95% 1,62-17,71; nilai p 0,01)] berhubungan dengan kelainan morfologis sel trakeobronkial.

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Lung cancer has high mortality and is often diagnosed at an advanced stage. Additionally, morphological abnormalities of tracheobronchial cells precede the carcinogenesis process and are based on molecular abnormalities. Moreover, Narrow-Band Imaging Bronchoscopy (NBI) has been developed to improve diagnostic accuracy. The objective of this study is to determine the diagnostic accuracy of NBI bronchoscopy in detecting morphological abnormalities of tracheobronchial cells and their relationship with p53 gene mutations.

This study is an experimental diagnostic study conducted on lung cancer subjects undergoing bronchoscopy procedures at RS Persahabatan from January to November 2023. NBI bronchoscopy procedures and bronchial forceps biopsies were performed on non-tumor lesions, followed by haematoxylin and eosin (HE) histopathological examination, as well as Polymerase Chain Reaction (PCR) Sanger sequencing for p53 mutations at the R175L, R248W, and R273C points. Reliability analysis was also performed.

A total of 105 subjects were included in the study analysis, predominantly male, smokers, with adenocarcinoma type cancer and advanced stage. Tracheobronchial cell morphological abnormalities were found in 34 subjects (32.4%), in the form of metaplasia, atypical cells, and tumor cells. Wild type p53 mutations at the R175L, R248W, and R273C points were found in all biopsy tissues. One metaplastic tissue had a p53 Codon 267 CT heterozygous mutation and one hyperplastic tissue had a p53 Codon 180 GC heterozygous mutation. The tortuous vascular pattern was identified as the best diagnostic criteria compared to other patterns with an area under the curve (AUC) of 78.4%; sensitivity 79.41%; specificity 77.46%; positive predictive value 62.8% and negative predictive value 88.7%. Inter-observer agreement in assessing vascular patterns was good with a kappa value of 0.88 (standard error 0.06; p-value <0.01). Edematous mucosa was associated with a tortuous vascular pattern on NBI bronchoscopy with an OR of 3.6 (95% CI 1.53-8.46; p-value <0.01). Subjects with a tortuous vascular pattern (OR of 21.89; 95% CI 6.50-73.71; p-value <0.01) and subjects with IB ≥ 600 (OR of 5.39; 95% CI 1.62-17.71; p-value 0.01) were associated with tracheobronchial cell morphological abnormalities."