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"Pendahuluan: World Health Organization (WHO) mendefinisikan Giant Cell-Tumour (GCT) merupakan tumor tulang yang bersifat jinak, mempunyai sifat dan kecenderungan untuk agresif lokal. Tujuan tata laksana GCT adalah menghilangkan jaringan tumor, mempertahankan fungsi tulang yang terkena, serta mencegah rekurensi. Sampai saat ini belum ada konsensus seragam untuk tata laksana GCT primer. Denosumab merupakan antibodi monoklonal yang berikatan dengan RANKL. Dengan adanya ikatan antara denosumab dengan RANKL, ikatan antara RANKL dengan RANK tidak terjadi, sehingga diharapkan tidak terjadi pertumbuhan tumor. Akan tetapi masih ada beberapa masalah yang masih menjadi pertanyaan antara lain: apakah pemakaian denosumab menurunkan angka rekurensi dibandingkan tata laksana konvensional sebelumnya, bagaimana efikasi denosumab pada tata laksana GCT, serta berapa dosis dan lama terapi denosumab diberikan. Dengan belum adanya pedoman baku penggunaan denosumab, dan belum adanya telaah sistematis serta penelitiannya di Indonesia, maka meta-analisis ini dilakukan untuk menjawab pertanyaan-pertanyaan tersebut dalam membantu menyusun pedoman penggunaannya sehingga menghasilkan kebijakan baru dalam tata laksana GCT di Indonesia.Metode: Telah dilakukan pencarian dalam lima database menggunakan kata kunci ("DENOSUMAB" AND ("GIANT CELL TUMOR" OR "GCT") AND "OUTCOME"). Penilaian risiko bias studi dengan desain randomized controlled trial dilakukan dengan Cochrane Collaboration’s tool for assessing risk of bias, sedangkan penilaian risiko bias studi dengan desain nonrandomized controlled trial dan kohort dilakukan dengan Newcastle-Ottawa Quality Assessment Form for cohort study.Hasil Setelah diseleksi, didapatkan 21 studi yang dilakukan penilaian risiko bias. Meta-analisis menemukan bahwa terdapat 85,5% (IK95%: 74,9-96,0%) pasien mendapatkan perbaikan klinis; perbaikan radiologis pada 82.4% (95% IK: 73,3-91,4%) pasien; perubahan histopatologis pada 96,5% (95% IK: 93,6-99,3%) pasien; serta rekurensi sebesar 27,2% (95% IK: 18,7-35,7%) dan rekurensi pada denosumab dibanding kontrol yakni RR: 2,6 (95% CI: 1,66-4,09); total kejadian efek samping berat pada rahang sebesar 2,7% (95% IK: 1,4-4,0%).Kesimpulan: Administrasi Denosumab pada pasien GCT sebagai terapi sistemik memiliki efikasi yang baik dalam perbaikan klinis; perbaikan radiologis; penurunan aktivitas sel GCT; potensi efek samping yang rendah; akan tetapi angka kejadian rekurensi lebih tinggi dibanding kontrol. Meski demikian, studi komparatif eksperimen acak terkontrol dirasa perlu lebih banyak untuk meningkatkan kualitas hasil studi.

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Introduction: The World Health Organization (WHO) defines GCT as a benign bone tumor, with the nature and tendency for local aggressiveness. The goal of GCT management is to remove tumor tissue, maintain the function of the affected bone, and prevent recurrence. To date there has been no uniform consensus for primary GCT management. Denosumab is a monoclonal antibody that binds to RANKL. With the bond between denosumab and RANKL, the bond between RANKL and RANK does not occur, so that no tumor growth is expected. However, there are still a number of questions that remain questionable, among others: whether the use of denosumab reduces recurrence rates compared to previous conventional management, how the efficacy of denosumab in the management of GCT, and how much dose and duration of denosumab therapy is given. With no standard guidelines for using denosumab, and no systematic study and research in Indonesia. This meta-analitic study was conducted to answer these questions in helping to develop guidelines for their use so as to produce new policies in the management of GCT in Indonesia.

Methods: Five databases have been searched using keywords ("DENOSUMAB" AND ("GIANT CELL TUMOR" OR "GCT") AND "OUTCOME"). After being selected, 21 studies were carried out with a bias risk assessment with the Newcastle-Ottawa Quality Assessment Form for cohort studies for studies with cohort designs and nonrandomized controlled trials while for one study a randomized controlled trial was conducted with the Cochrane Collaboration's tool for assessing risk of bias with results 4 poor quality studies.

Results: The meta-analysis found that there were 85.5% (CI 95%: 74.9-96.0%) patients received clinical improvement, there was a reduction in VAS scale pain in 98.9% (CI 95%: 96.5-101.4% ) patient; radiological improvement in 85.5% 82.4% (95% CI: 73.3-91.4%) patients; histopathological changes in 96.5% (95% CI: 93.6-99.3%) patients; and recurrence of 27.2% (95% CI: 18.7-35.7%) and recurrence in denosumab compared to controls namely RR: 2.6 (95% CI: 1.66-4.09); the total incidence of severe side effects on the jaw was 2.7% (95% CI: 1.4-4.0%).

Conclusions: Denosumab administration in GCT patients as a systemic therapy has good efficacy in clinical improvement; radiological repair; decreased GCT cell activity; low potential for side effects; however the recurrence rate is higher than the control. However, comparative studies of randomized controlled trials are deemed necessary to improve the quality of study results."

"ABSTRAKLatar Belakang Giant cell tumor (GCT) merupakan tumor jinak yang bersifat lokal agresif destruksif. Tumor ini memiliki rekurensi yang tinggi sebanyak 25-50% setelah tindakan pembedahan. Berbagai macam pemberian zat kimia lokal sebagai terapi ajuvan, telah digunakan pada tatalaksana pembedahan. Namun perbandingan efektifitas untuk masing-masing zat kimia ini belum diketahui. Studi mengenai sitotoksisitas dan mekanisme kematian sel dengan membandingkan pemberian etanol dan H2O2 pada sel GCT tulang secara in vitro masih sedikit dan belum ada di Indonesia.Metode Penelitian ini merupakan studi in vitro eksperimental dengan mengambil empat sampel jaringan tumor dari pasien yang didiagnosis GCT tulang dan dilakukan isolasi-kultur sel. Cell line yang didapatkan dikarakterisasi melalui analisis morfologi serta pemeriksaan ekspresi penanda gen Nanog dan Oct 4 dengan Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). Sel yang telah 80% konfluens dilakukan terapi dengan H2O2 1%, 3%, 5% dan etanol 75%, 85%, 95% selama10 menit serta dosis in vitro H2O2 (0,003%, 0,005%, 0,01%, 0,03%, 0,1%, 0,3%) selama 5 menit serta inkubasi selama 24 jam. Morfologi sel dievaluasi dibawah mikroskop cahaya dengan membandingkan kontrol dan setelah pemberian zat kimia, viabilitas sel dihitung menggunakan automatic cell counter serta toksisitas sel dinilai dengan uji Annexin V dan Propidium Iodida (PI) pada flow cytometry.Hasil Kultur jaringan sel GCT dengan metode eksplan dan kolagenase mempunyai angka keberhasilan yang sama dalam mendapatkan cell line GCT. Namun metode eksplan membutuhkan waktu yang lebih cepat dan memiliki jumlah sel yang lebih banyak. Sel yang tumbuh dari jaringan GCT terkarakterisasi dengan analisis morfologi serta ekspresi gen Oct 4 dan Nanog. Viabilitas sel GCT menurun secara signifikan setelah paparan terhadap dosis klinis H2O2 1% (p = 0,046), H2O2 3% (p = 0,043), dan H2O2 5% (p = 0,043) selama 10 menit dibandingkan dengan kontrol. Tidak ada perbedaan yang bermakna untuk viabilitas sel antara konsentrasi H2O2 1%, 3% dan 5%. Sementara pada konsentrasi in vitro (0,003%, 0,005%, 0,01%, 0,03%, 0,1%, 0,3%), konsentrasi H2O2 0,3% (p < 0,001) selama 5 menit memiliki efektivitas paling baik dalam sterilisasi GCT secara in vitro. Terdapat fenomena fiksasi sel setelah pemberian etanol pada semua konsentrasi. Dari uji RT-PCR didapatkan penurunan ekspresi gen Oct 4 dan Nanog seiring dengan peningkatan konsentrasi H2O2 pada dosis in vitro. Flow cytometry dengan marker Annexin V dan propidium iodide (PI) didominasi oleh marker PI yang menunjukkan kematian sel akibat nekrosis dengan persentase terbesar pada konsentrasi 0,3%.Kesimpulan Eksplan merupakan metode terbaik dalam isolasi dan kultur sel GCT. Semua sel hasil isolasi dan kultur terkarekterisasi sebagai GCT. Pemberian ajuvan kimia lokal dengan dosis klinis H2O2 konsentrasi 1%, 3%, dan 5% selama 10 menit secara in vitro mempunyai efektivitas yang sama dalam membunuh sel GCT. Sedangkan konsentrasi H2O2 0,3% selama 5 menit merupakan terapi optimal dalam sterilisasi GCT secara in vitro dengan mekanisme kematian nekrosis sel.

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ABSTRACTBackground Giant cell tumor (GCT) is a benign, aggressive local tumor with high tendency to recur after surgery. Various chemicals have been used as an adjuvant treatment for GCT. However, the comparative effect of these chemicals remains unclear. To date, there are no studies about the cytotoxicity and mechanism of injury to etanol and H2O2 in GCT in Indonesia especially in vitro experiment. The present study aims to find the best method to isolation and culture of GCT from primary human patients, the optimal treatment of etanol and H2O2 for reducing GCT recurrence.Methods This is an experimental in vitro study that took four tumor tissue samples from patients diagnosed with bone GCT and conducted cell-culture isolation. Cell line characterized by morphology, gene markers Nanog and Oct 4 expression with Polymerase Chain Reaction (RT-PCR) Reverse Transcriptase was obtained. Cells that had 80% confluence were treated with H2O2 1%, 3%, 5% and etanol 75%, 85%, 95% for 10 minutes and in vitro doses of H2O2 (0.003%, 0.005%, 0.01%, 0.03 %, 0.1%, 0.3%) for 5 minutes and were incubated for 24 hours. Cell morphology was evaluated under a light microscope by comparing the morphology of controls and after exposure a chemical agents, cell viability was calculated using automatic cell counter and cell toxicity was assessed by Annexin V and Propidium Iodida (PI) on flow cytometry.Results Collagenase and explant methods had the same success rate in obtaining GCT cell line characterized by morphology, the gene expression Oct 4 and Nanog. But explants need a less time and had more cell than collagenase method. Viability of GCT cells decreased significantly after exposure to the clinical dose of H2O2 1% (p = 0,046), H2O2 3% (p = 0,043), and H2O2 5% (p = 0,043) for 10 minutes compared to controls. There was no significant difference for cell viability between 1%, 3% and 5% H2O2 concentrations. While in in vitro doses (0,003%, 0,005%, 0,01%, 0,03%, 0,1%, 0,3%), 0.3% H2O2 concentration for 5 minutes has the best effectivity in sterilizing GCT in vitro. There was a phenomenon of cell fixation after exposure of GCT cells to etanol in various concentrations, in which all cells die and its viability could not be analyzed. From the RT-PCR test it was found that there was a decrease in the expression of Oct 4 and Nanog genes along with an increase in the concentration of H2O2 in vitro. Flow cytometry using Annexin V in conjunction with propidium iodide (PI) was dominated with PI marker detection which showed cell death due to necrosis, with the highest concentration amounted to 0.3%Conclusion Explant was the best method for isolation and GCT cell culture. All of the cell from isolation and culture result had a characterization of GCT. Giving local a chemical adjuvants with clinical doses of H2O2 concentrations of 1%, 3%, and 5% for 10 minutes in vitro had the same effectiveness in killing GCT cells. While the concentration of 0.3% H2O2 for 5 minutes is the optimal therapy in GCT sterilization in vitro with necrosis cell death mechanism."

"[ABSTRAKPendahuluan: GCT tulang merupakan lesi jinak tetapi secara lokal dapat bersifat agresif pada daerah epifisis. Angka rekurensi yang tinggi, dilaporkan mencapai 75%. Tumor dapat bermetastasis ke paru (2-9%) dan tercatat 0-37% angka mortalitas akibat metastasis. Beberapa penelitian menghasilkan variasi berbeda penanganan tumor ini terhadap luaran onkologi dan fungsional serta angka kematian paska pembedahan. Penelitian ini bertujuan melaporkan pengalaman dalam penatalaksanaan pembedahan tumor ini dan untuk melihat adanya hubungan antara tatalaksana pembedahan dengan dampak klinis.Metode: Penelitian ini merupakan kohort retrospektif, sebanyak 99 pasien GCT tulang menjalani tindakan kuretase ataupun wide resection di Rumah Sakit Cipto Mangunkusumo pada 1995 - 2014. Luaran onkologi berdasarkan angka rekurensi lokal, metastasis tumor serta mortalitas dan luaran fungsional berdasarkan sistem penilaian Musculoskeletal Tumor Society (MSTS).Hasil: Lokasi tumor terutama di distal femur (25,2%). Rekurensi lokal terjadi pada 4 pasien, terutama di distal femur (50%). Rekurensi lokal terjadi seimbang pada wide resection dan kuretase dan secara statistik tidak bermakna (p 0.578, uji eksak Fischer). Tidak dijumpai kejadian rekurensi lokal pada seluruh pasien yang mengalami metastasis. Metastasis terjadi pada kelompok wide resection. Kematian terjadi pada 4 pasien yang mengalami metastasis. Sebagian besar pasien (51,1%) menunjukkan luaran fungsional kategori sangat baik (skor MSTS di atas 75%). Analisis kesintasan bebas rekurensi lokal secara statistik tidak bermakna (p 0.564). Analisis multivariat (regresi Cox) hanya faktor metastasis yang berpengaruh pada mortalitas (p. 0.001)Kesimpulan: Terdapat hubungan yang bermakna antara stadium tumor dengan metastasis dan jenis tindakan operasi. Tidak terdapat perbedaan bermakna antara kejadian rekurensi lokal dan metastasis serta luaran fungsional dengan jenis tindakan operasi.

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ABSTRACTIntroduction: Giant cell tumor of bone is benign lesion with ability to be locally aggressive in epiphysis. Its recurrence rate was reported as high as 75%. Tumor can metastasize to lungs (2-9%) and up to 37% mortality rate due to metastasis. Several studies have reported different rates of local recurrence, lung metastasis, mortality rate, and functional outcome. This study aims to report our experience and analyze the correlation between surgery and clinical findings.Methods: In this retrospective cohort, 99 patients GCT of bone undergone curettage or wide resection in Cipto Mangunkusumo Hospital during 1995-2014. Oncological outcome were analyzed according to local recurrence rate, metastasis, and mortality rate, while functional outcome were measured according to Musculoskeletal Tumor Society Score (MSTS).Results: Tumor location were predominantly in distal femur (25.2%). Local recurrence were observed in 4 patient and mainly in distal femur (50%). Local recurrence were evenly balanced between surgical curettage and wide resection (50% each) and thus not statistically significant (Exact Fischer, p=0.578). Metastasis were observed in patients who undergone wide resection, however, no significant correlation were found between metastasis incidence and types of surgical intervention (Exact Fischer, p=0.318). Four have died related to metastasis. No local recurrence were observed in patients suffering from metastasis. In more than half of patients (51.5%), the functional status were very good (MSTS >75. Recurrence-free survival analysis not significant statistically (p 0.564).Multivariate analysis (Cox regression) showed that only metastasis was found to be significantly correlated to mortality (p. 0.001).Conclusion: Tumor stage was correlated to metastasis, and type of surgical intervention. No significant correlation were found between local recurrence, metastasis, and functional outcome to types of surgical intervention., Introduction: Giant cell tumor of bone is benign lesion with ability to be locally aggressive in epiphysis. Its recurrence rate was reported as high as 75%. Tumor can metastasize to lungs (2-9%) and up to 37% mortality rate due to metastasis. Several studies have reported different rates of local recurrence, lung metastasis, mortality rate, and functional outcome. This study aims to report our experience and analyze the correlation between surgery and clinical findings.Methods: In this retrospective cohort, 99 patients GCT of bone undergone curettage or wide resection in Cipto Mangunkusumo Hospital during 1995-2014. Oncological outcome were analyzed according to local recurrence rate, metastasis, and mortality rate, while functional outcome were measured according to Musculoskeletal Tumor Society Score (MSTS).Results: Tumor location were predominantly in distal femur (25.2%). Local recurrence were observed in 4 patient and mainly in distal femur (50%). Local recurrence were evenly balanced between surgical curettage and wide resection (50% each) and thus not statistically significant (Exact Fischer, p=0.578). Metastasis were observed in patients who undergone wide resection, however, no significant correlation were found between metastasis incidence and types of surgical intervention (Exact Fischer, p=0.318). Four have died related to metastasis. No local recurrence were observed in patients suffering from metastasis. In more than half of patients (51.5%), the functional status were very good (MSTS >75. Recurrence-free survival analysis not significant statistically (p 0.564).Multivariate analysis (Cox regression) showed that only metastasis was found to be significantly correlated to mortality (p. 0.001).Conclusion: Tumor stage was correlated to metastasis, and type of surgical intervention. No significant correlation were found between local recurrence, metastasis, and functional outcome to types of surgical intervention.]"