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Abstrak :
[ABSTRAK
Latar Belakang: Karsinoma papiler tiroid (KPT) merupakan keganasan tersering organ endokrin dengan prognosis yang sangat baik, namun pada beberapa kasus dapat terjadi rekurensi dan mortalitas. Beberapa faktor prognostik dan mutasi Btype rapidly accelerated fibrosarcoma V600E (BRAF V600E) dikatakan berhubungan dengan prognosis yang lebih buruk. Pemeriksaan imunohistokimia protein BRAF V600E dipercaya dapat mendeteksi adanya mutasi dengan spesifisitas 100% dan sensitivitas 89%. Tujuan penelitian ini untuk mengetahui imunoekspresi BRAF V600E dan hubungannya dengan faktor-faktor prognostik. Bahan dan Cara: Penelitian dilakukan secara retrospektif, desain deskriptif analitik studi potong lintang. Sampel penelitian berasal dari RSCM berjumlah 50 kasus KPT yang dinilai ulang untuk menentukan faktor-faktor prognostik secara mikroskopik. Pemeriksaaan mutasi BRAF V600E menggunakan tehnik imunohistokimia dan penilaian menggunakan H score. Hasil: Nilai H score ³ 326,5 ditentukan sebagai mutasi BRAF V600E positif dan < 326,5 sebagai mutasi BRAF V600E negatif. Terdapat 17 (34%) kasus positif mengalami mutasi BRAF V600E. Rerata usia pada kasus dengan mutasi BRAF V600E positif adalah 44,71 tahun. Ukuran tumor pada kasus dengan mutasi BRAF V600E positif berkisar antara 0,1-4cm. Tujuh belas kasus yang mengalami mutasi, 6 dlaki-laki dan 11 perempuan. Tujuh kasus dengan perluasan keluar tiroid, 11 kasus dengan metastasis kelenjar getah bening (KGB), dan 8 kasus dengan varian histopatologik tall cell. Kesimpulan: Terdapat hubungan bermakna antara mutasi BRAF V600E dengan perluasan keluar tiroid, metastasis kelenjar getah bening (KGB), dan varian histopatologik tall cell. Tidak terdapat hubungan bermakna antara mutasi BRAF V600E dengan usia, jenis kelamin, dan ukuran tumor.

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ABSTRACT
Backgroud: Papillary Thyroid Carcinoma (PTC) is the most common malignant neoplasm of the endocrine organ with an excellent prognosis, but in some cases present with recurrency and mortality. There are prognostic factors and BRAF V600E mutation that related to worse prognosis. Immunohistochemical investigetion of BRAF V600E protein believe can detect mutation wth 100% specificity and 89% sensitivity. Recent study suggest PTC with BRAF V600E mutation do thyroidectomy with prophylactic lymph node dissection. BRAF V600E specific inhibitor effective to the patient with advance stadium, patient with metastases, and resistant to iodium radioactive. Aim of this study is to obtain BRAF V600E and the relation with prognostic factors. Material and Methods: This is a retrospective descriptive-analytic crosssectional study. Fifty patient with PTC comes from Ciptomangunkusumo Hospital and reviewed to determine prognostic factors microscopicaly. BRAF V600E mutation detected by immunohistochemical staining and assesed with H score. Result: H score ³ 326,5 determined as positive BRAF V600E mutation and < 326,5 as negative BRAF V600E mutation. BRAF V600E mutation was detected in 17 (34%) cases by immunohistochemistry. The mean age of the cases with positive BRAF V600E mutation was 44.71 years, while the negative 41.58. The size of the tumor in cases with BRAF V600E mutation positive range between 0,1-4cm, while negative 0,1-9cm. Seventeen cases have mutations, 6 of them sex male and 11 female. Seven cases with extrathyroidal extension (ETE), 11 cases with lymph node metastasis (KGB), and 8 cases with tall cell variant. Conclusion: There are significant correlation between BRAF V600E mutation with extrathyroidal extension, lymph node metastases, and tall cell variant. There are no significant correlation between BRAF V600E mutation with age, gender, and size of the tumor, Backgroud: Papillary Thyroid Carcinoma (PTC) is the most common malignant neoplasm of the endocrine organ with an excellent prognosis, but in some cases present with recurrency and mortality. There are prognostic factors and BRAF V600E mutation that related to worse prognosis. Immunohistochemical investigetion of BRAF V600E protein believe can detect mutation wth 100% specificity and 89% sensitivity. Recent study suggest PTC with BRAF V600E mutation do thyroidectomy with prophylactic lymph node dissection. BRAF V600E specific inhibitor effective to the patient with advance stadium, patient with metastases, and resistant to iodium radioactive. Aim of this study is to obtain BRAF V600E and the relation with prognostic factors. Material and Methods: This is a retrospective descriptive-analytic crosssectional study. Fifty patient with PTC comes from Ciptomangunkusumo Hospital and reviewed to determine prognostic factors microscopicaly. BRAF V600E mutation detected by immunohistochemical staining and assesed with H score. Result: H score ³ 326,5 determined as positive BRAF V600E mutation and < 326,5 as negative BRAF V600E mutation. BRAF V600E mutation was detected in 17 (34%) cases by immunohistochemistry. The mean age of the cases with positive BRAF V600E mutation was 44.71 years, while the negative 41.58. The size of the tumor in cases with BRAF V600E mutation positive range between 0,1-4cm, while negative 0,1-9cm. Seventeen cases have mutations, 6 of them sex male and 11 female. Seven cases with extrathyroidal extension (ETE), 11 cases with lymph node metastasis (KGB), and 8 cases with tall cell variant. Conclusion: There are significant correlation between BRAF V600E mutation with extrathyroidal extension, lymph node metastases, and tall cell variant. There are no significant correlation between BRAF V600E mutation with age, gender, and size of the tumor]

Abstrak :
ABSTRAK
V600E adalah perubahan genetik yang paling banyak terjadi pada kanker tiroid, dan telah menjadi penanda diagnostik penting pada jenis histopatologi ganas, khususnya karsinoma papiler. Tujuan dari penelitian ini adalah untuk mengembangkan dan memvalidasi teknik screnning BRAF V600E pada kanker tiroid menggunakan metode high resolution melting (HRM). Sebanyak 57 pasien dengan kelainan nodul tiroid dikumpulkan secara retrospektif di Rumah Sakit Kanker Dharmais yang dikoleksi dari tahun 2012-2014. Mutasi gen BRAF V600E dianalisis dari sampel fine needle aspiration biopsy (FNAB) menggunakan teknik HRM reagen MeltDoctor HRM Master Mix (Applied Biosystem) yang divalidasi dengan teknik Sanger Sequencing. Penelitian ini berhasil mengoptimalisasi metode HRM dengan membedakan melting curve sampel kontrol positif mutasi gen BRAF V600E dengan sampel normal. Berdasarkan hasil validasi dengan teknik Sanger Sequencing, diperoleh hasil gambaran elektroferogram pada gen BRAF ekson 15 yang mengalami mutasi titik pada basa nukleotida ke 1799 T>A (V600E). Hasil screening menunjukkan bahwa terdapat 13 sampel terdeteksi positif mutasi gen BRAF V600E pada jenis histopatologi ganas karsinoma tiroid papiler (12) dan karsinoma anaplastik (1). Tidak ditemukan satu pun mutasi gen BRAF V600E pada sampel dengan histopatologi jinak ataupun kontrol normal. Berdasarkan hasil tersebut, dapat disimpulkan bahwa teknik HRM dapat digunakan untuk screening mutasi gen BRAF V600E pada kanker tiroid.

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ABSTRACT
BRAF V600E gene mutation is the most common genetic alteration that found in thyroid cancer and has been an important diagnostic marker for malignant histopathology, specifically papillary carcinoma. The aim of this study is to develop and validate BRAF V600E gene mutation screening technique on thyroid cancer patients using high resolution melting (HRM) method. Retrospectively 57 patients with thyroid nodules abnormalities were collected in Dharmais Cancer Hospital collected in 2012-2014. Mutation in BRAF V600E gene were analyze from fine needles aspiration biopsy (FNAB) using MeltDoctor HRM Master Mix (Applied Biosystem) as the HRM reagen and validated using Sanger sequencing. This Study have optimalize HRM method by differentiating positive control BRAF V600E gene melting curve mutaion with normal sampel. Validation using Sanger sequencing depict electropherogram of BRAF gene on exon 15 point mutation on nucleotide 1799 T>A (V600E). Screening shows 13 samples detected positive on BRAF V600E gene mutation on malignant histopathology thyroid papillary carcinoma (12) and anaplastic carcinoma (1). No mutation found on benign histopathology samples and normal samples. The conclusion of this study is HRM technique can be use to screen mutation BRAF V600E on thyroid cancer.

Abstrak :
Tujuan. Penelitian ini dibuat untuk mengetahui peranan mutasi BRAF V600E dan TERT dalam kejadian metastasis kelenjar getah bening (KGB) leher pada pasien kanker tiroid papiler (KTP) Metode. Penelitian ini merupakan studi potong lintang, melibatkan pasien KTP di RSUPN Dr. Cipto Mangunkusumo, DKI Jakarta. Data-data diperoleh secara retrospektif berdasarkan catatan rekam medis, kecuali untuk mutasi BRAF V600E dan Promoter TERT. Spesimen jaringan tumor pasien kanker tiroid papiler ditransfer ke Laboratorium Terpadu FKUI. DNA diekstrasi menggunakan QIAamp DNA FFPE Tissue Kit sebanyak 3-8 potongan dengan ketebalan FFPE 5-10 mikrometer. Multiplikasi gen BRAF dilakukan dengan KOD One Polymerase Chain Reaction (PCR) Master Mix (Toyobo KMM–201), sementara multiplikasi gen TERT dilakukan dengan PCR Master Mix (2X MyTaq HS Red Mix, primer forward, reverse, dan Nuclear-free water). Analisis data dilakukan dengan SPSS versi 20. Hasil. Peneliti menginklusi 42 pasien KTP dengan 19 (45%) mengalami mutasi BRAF, 20 (48%) mengalami mutasi TERT, dan 20 (48%) mengalami metastasis KGB. Mutasi BRAF ditemukan berhubungan dengan kejadian metastasis KGB [p<0,001, OR = 25,333 (IK95% 4,924–130,340)], sementara mutasi TERT ditemukan tidak berhubungan. Pasien yang mengalami mutasi BRAF tanpa TERT memiliki risiko 18,000 (IK95% 2,012–161,051) lebih tinggi untuk mengalami metastasis KGB dibandingkan pasien tanpa kedua mutasi. Lebih lanjut, adanya mutasi TERT yang berbarengan dengan mutasi BRAF membuat risiko meningkat menjadi 60,000 (4,718–763,043) lebih tinggi dibandingkan pasien tanpa kedua mutasi. Kesimpulan. Mutasi BRAF berhubungan dengan metastasis KGB pasien KTP, namun tidak dengan mutasi TERT. Namun, kehadiran mutasi TERT pada pasien KTP dengan mutasi BRAF meningkatkan risiko metastasis KGB. ......Objective. This study was designed to determine the role of BRAF V600E and TERT mutations in the incidence of neck lymph node (LN) metastasis in patients with papillary thyroid cancer (PTC). Methods. This was a cross-sectional study, involving KTP patients at Dr. Cipto Mangunkusumo Hospital, DKI Jakarta. Data were obtained retrospectively based on medical records, except for BRAF V600E and TERT promoter mutation. Tumor tissue specimens of PTC’s patients were transferred to the Laboratorium Terpadu FKUI. DNA was extracted using QIAamp DNA FFPE Tissue Kit for 3-8 pieces with FFPE thickness of 5-10 micrometers. BRAF gene multiplication was performed with KOD One Polymerase Chain Reaction (PCR) Master Mix (Toyobo KMM-201), while TERT gene multiplication was performed with PCR Master Mix (2X MyTaq HS Red Mix, primers forward, reverse, and Nuclear-free water). Data analysis was performed with SPSS version 20. Results. We included 42 PTC’s patients with 19 (45%) patients had BRAF mutation, 20 (48%) patients had TERT mutation, and 20 (48%) patients had LN metastasis. BRAF mutation was associated with the LN metastasis [p<0.001, OR = 25.333 (95% CI 4.924-130.340)], while TERT mutation was not. Patients with BRAF+ and TERT- had an 18,000 (IK95% 2,012-161,051) higher risk of LN metastasis than patients with BRAF- and TERT-. Furthermore, the presence of TERT mutation along with BRAF mutation increased the risk to 60,000 (4,718-763,043) higher than patients with BRAF- and TERT-. Conclusion. BRAF mutation was associated with LN metastasis in PTC’s patients, but not TERT mutations. However, the presence of TERT mutation in PTC’s patients with BRAF mutation increased the risk of LN metastasis.

Abstrak :
ABSTRAK
Latar Belakang: Kanker tiroid merupakan keganasan endokrin yang paling sering ditemukan dan insidennya semakin meningkat. Meskipun metode biopsi aspirasi jarum halus memiliki sensitivitas yang baik dalam mendiagnosis nodul tiroid, sebanyak 10-40 masih memberikan hasil inkonklusif dalam penentuan keganasan. Hal ini sering merugikan pasien karena harus mengalami re-operasi apabila terdapat keganasan pada hasil histopatologi.Tujuan Penelitian: Mengetahui proporsi dan mendapatkan nilai diagnostik dari pemeriksaan mutasi BRAF, NRAS, dan promoter TERT pada spesimen BAJAH untuk meningkatkan akurasi diagnosis kanker tiroid.Metode Penelitian: Studi retrospektif dengan mengikutsertakan 50 pasien nodul tiroid yang memerlukan pembedahan. Spesimen diambil pada saat proses BAJAH atau pasca operasi. Deteksi mutasi BRAF, NRAS, dan promoter TERT menggunakan metode DNA sekuensing Sanger . Hasil mutasi akan dibandingkan dengan pemeriksaan baku emas histopatologi.Hasil: Dari 50 kasus yang ikut dalam analisis, terdapat 39 kasus 78 merupakan keganasan tiroid. Nilai proporsi mutasi BRAF, NRAS, dan pTERT berturut-turut sebesar 31 , 18 , dan 13 . Uji diagnostik mutasi BRAF menghasilkan sensitivitas, spesifisitas, nilai duga positif, dan nilai duga negatif berturut-turut 31 , 100 , 100 , 29 terhadap kanker tiroid. Untuk mutasi NRAS sebesar 18 , 100 . 100 , 26 . Sedangkan untuk mutasi pTERT sebesar 13 , 100 , 100 , 24 . Jika ketiga mutasi tersebut dikombinasikan, maka nilainya akan meningkat menjadi 49 , 100 , 100 , 35 . Kesimpulan: Pemeriksaan mutasi BRAF, NRAS dan promoter TERT pada kanker tiroid masing-masing memiliki spesifisitas yang tinggi. Jika ketiganya dikombinasikan maka akan meningkatkan sensitivitas untuk membantu dalam meningkatkan akurasi diagnosis keganasan tiroid.

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ABSTRACT
Background Thyroid cancer is the most common endocrine malignancy and it rsquo s incidence is on the rise. Although the fine needle aspiration biopsy FNAB has a good sensitivity in the diagnosis of thyroid nodules, as much as 10 40 still gives inconclusive results in malignant determination. This is often detrimental to patients having to undergo re surgery if there is a malignancy in the histopathologic outcome.Aim To establish the proportion and diagnostic value of BRAF, NRAS, and TERT promoter mutation detection on FNAB specimens to improve the accuracy of thyroid cancer diagnosis.Methods The retrospective study by involving 50 patients with thyroid nodules surgery. Specimens were taken during the FNAB or postoperative process. Detection of BRAF, NRAS, and TERT promoter mutation using DNA sequencing method Sanger . The mutation results will be compared with the histopathologic gold standard examination.Resuts Of the 50 cases involved in the analysis, there were 39 cases 78 of thyroid malignancies. The proportion of BRAF, NRAS, and pTERT mutations was 31 , 18 , and 13 , respectively. BRAF mutation diagnostic test results in sensitivity, specificity, positive predictive value, and negative predictive value were 31 , 100 , 100 , 29 respectively. For NRAS mutation were 18 , 100 . 100 , 26 . As for pTERT mutation were 13 , 100 , 100 , 24 . If the three mutations are combined, then the value will increase to 45 , 100 , 100 , 35 .Conclusion Detection mutations of BRAF, NRAS and TERT promoters in thyroid cancer have a high specificity. If all three are combined it will increase the sensitivity to improve the accuracy of the diagnosis in thyroid malignancy.

Abstrak :
Latar Belakang: Kanker tiroid adalah keganasan yang paling sering terjadi pada sistem endokrin. Kanker tiroid yang paling sering terjadi adalah karsinoma tiroid papiler (KTP), dengan sebagian besar kasus dapat disembuhkan dengan angka kesintasan >95% selama 20 tahun. Namun, apabila terjadi kekambuhan, maka angka mortalitasnya yang meningkat. Skoring prognostik penting sebagai penentu pengobatan yang bertujuan untuk mengelompokkan pasien ke dalam kelompok risiko yang sesuai sehingga memungkinkan pasien untuk mendapatkan optimalisasi modalitas pengobatan. Skoring prognosis yang umum digunakan adalah skoring AMES, MACIS, dan AGES. Mutasi gen BRAF V600E dihubungkan dengan prognosis yang buruk karena persistensi dan kekambuhan penyakit. Suatu studi menambahkan pemeriksaan mutasi BRAF V600E kedalam skoring prognosis dan bermakna secara statistik sedangkan studi lainnya tidak memiliki kemaknaan secara statistik. Metode: Studi ini merupakan studi potong lintang terhadap pasien KTP di RSUPN Cipto Mangunkusumo menggunakan data sekunder berupa status mutasi BRAF V600E dan data untuk mengkalkulasi skoring prognosis (Usia, USG preoperatif, CT-Scan atau MRI, data histopatologi, dan data laporan pembedahan). Parameter yang diukur meliputi proporsi dan hubungan antara mutasi BRAF V600E dengan skoring prognosis (AMES, MACIS, dan AGES). Hasil: Proporsi mutasi BRAF V600E pada skoring prognosis yaitu: Skoring AMES: High Risk: 71,4% dan Low Risk: 28,6%, Skoring MACIS: Skor ³ 8: 38,1%; Skor 7 – 7,99: 9,5%; Skor 6 – 6,99: 19%; dan Skor < 6: 33,3%, dan Skoring AGES: Skor ³ 6: 61,9%; Skor 5 – 5,99: 0%; Skor 4 – 4,99: 4,8%; dan Skor < 4: 33,3%. Analisis bivariat menunjukan mutasi BRAF V600E bermakna secara statistik dengan skoring MACIS dengan Odd Ratio (OR) 2,96 (p Value = 0,044, Confidence Interval (CI) 95% = 1,01 – 8,64), sedangkan skoring AMES dan AGES tidak bermakna secara statistik. Kesimpulan: Mutasi BRAF V600E dengan hasil positif meningkatkan prognosis buruk pada skoring MACIS sebanyak 2,96 kali. ......Introduction: Thyroid cancer is the most common malignancy of the endocrine system. The most common type of thyroid cancer is papillary thyroid carcinoma (PTC), and most cases are curable, with a 20-year survival rate of more than 95%. However, when it recurs, it has a high mortality rate. Prognostic scoring systems are important as treatment determinants that aim to classify patients into appropriate risk groups to optimize treatment modalities. Commonly used prognostic scoring systems are the AMES, MACIS, and AGES. Mutation of BRAF V600E is associated with a poor prognosis due to disease persistence and recurrence. One study added the BRAF V600E mutation to the prognosis scoring, and it was statistically significant, while another study showed no statistical significance. Methods: This study was a cross-sectional study of PTC patients at Cipto Mangunkusumo Hospital using secondary data, such as BRAF V600E mutation status and data to calculate prognosis scoring systems. Parameters measured included the proportion and association between the BRAF V600E mutation and prognosis scoring systems (AMES, MACIS, and AGES). Results: The proportion of BRAF V600E mutations in prognosis scoring systems was as follows: AMES - High Risk: 71.4% and Low Risk: 28.6%; MACIS Scoring - Score ≥ 8: 38.1%; Score 7–7.99: 9.5%; Score 6–6.99: 19%; and Score < 6: 33.3%; and AGES - Score ≥ 6: 61.9%; Score 5–5.99: 0%; Score 4–4.99: 4.8%; and Score < 4: 33.3%. Bivariate analysis showed that the BRAF V600E mutation was statistically significant with MACIS scoring, with an Odd Ratio (OR) of 2.96 (p Value = 0.044, Confidence Interval (CI) 95% = 1.01–8.64), while AMES and AGES scoring were not statistically significant. Conclusion: A positive BRAF V600E mutation result increases the poor prognosis on MACIS scoring by 2.96 times.