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"Receptor activator of nuclear factor-kappa (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL) signaling helps putative cancer stem cells (CSC) to maintain their stemness. Expression of CD44 and RANKL was analyzed in oral squamous cell carcinoma specimen (n = 191). Moreover, RANKL expression was measured in cancer cell lines (BICR3, BICR56) by immunohistochemistry and western blot analysis. Scanned images were digitally analyzed using ImageJ and the immunomembrane plug-in. CD44 and RANKL expression on protein level was correlated with clinical characteristics and impact on survival. RANKL was co-labeled with CD44 in immunohistochemical and immunofluorescence double labeling experiments. Although high CD44+/RANKL+ co-expression was significantly associated with clinicopathological factors and worse survival, multivariate analysis did not demonstrate high CD44+/RANKL+ co-expression as independent prognostic factor. Immunohistochemical and immunofluorescence double labeling experiments revealed RANKL expression by CD44+ cancer cells. RANKL specificity was confirmed by western blot analysis. For the first time, this study provides evidence that RANKL expression in OSCC might be associated with disease recurrence and a cell compartment measured by CD44+/RANKL+ co-expression within the mucosal epithelial basal layer cells."

"Because the concept and discoveries of cancer stem cells are relatively new, scientists and researchers need an introduction to this dynamic area. Cancer Stem Cells presents a consolidated account of the research done to date and recent progresses in the studies of cancer stem cells. Such a presentation facilitates a better understanding of and draws attention to stem cell and cancer biology, two fields that enhance, move, and evolve into each other continuously. It provides an informative study in designing approaches to apply stem cell principles to cancer biology while offering an overview of the challenges in developing combination stem and cancer biology targets for therapeutics. "

"In recent years, cancer stem cells have been recognized as important component in carcinogenesis and they seem to form the basis of many (if not all) tumor types. Cancer stem cells or "cancer cell like stem cells" have been isolated from various cancers of different origin (blood, breast, brain, skin, head and neck, thyroid, cervix, lung, retina, colon, pancreas and so on). Cancer stem cells - rare cells with indefinite proliferative potential that drive the formation and growth of tumours- seem to show intriguing relationships with physiological stem cells. Specifically, these cancer cells show significant similarities in the mechanisms that regulate self-renewal of normal stem cells. Moreover, tumour cells might directly arise from normal stem cells. Further, the cellular biology of cancer stem cells show a lot of similarities with normal stem cells."

"ABSTRAKFungi Emericella nidulans strain MFW39 yang diisolasi dari ascidia Aplidiumlongithorax dari Taman Nasional Laut Wakatobi, Sulawesi Tenggara memiliki aktivitassitotoksik terhadap beberapa sel lestari kanker. Senyawa yang berhasil diisolasi danbersifat sitotoksik adalah senyawa emestrin yang memiliki gugus ETP(epipolithiodioxopiperazine). Senyawa emestrin memiliki beberapa jenis derivat. Padapenelitian ini bertujuan untuk mengisolasi, mengidentifikasi dan menguji bioaktivitasantikanker terhadap salah satu derivat senyawa emestrin. Dari hasil penelitiandidapatkan jenis derivat senyawa emestrin adalah emestrin B. Proses elusidasi strukturdilakukan dengan metode HPLC, UPLC-MS, 1H-NMR dan 13C-NMR. Hasil ujiaktivitas sitotoksik dengan metode MTT (Microculture Tetrazolium Technique)menunjukan IC50 fraksi emestrin B berkisar pada 0,18 􀂱 4,21 µg/mL. Urutan aktivitassitotoksik fraksi emestrin B terhadap sel lestari T47D [kanker payudara] (0,18 µg/mL) >WiDr [kanker usus] (1,21 µg/mL) > HeLa [kanker serviks] (1,91 µg/mL). Fraksiemestrin B juga bersifat sitotoksik terhadap sel lestari normal [Vero] (4,21 µg/mL). Olehkarena itu fraksi emestrin yang berhasil diisolasi adalah emestrin B dengan rumusstruktur C27H22N2O10S3 dan memiliki potensi aktivitas antikanker.

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ABSTRACTEmericella nidulans marine fungi strain MFW39 was isolated from ascidia Aplidiumlongithorax collected from Wakatobi Marine National Park, South East Sulawesi has abiological activities to cancer cell lines. Emestrin was a compound with an ETP(epipolithiodioxopiperazine) group that found in Emericella nidulans marine fungi havecytotoxicity properties. Emestrin and another compound that related have the ETPgroup. The research include isolation, identification and cytotoxicity assay of compoundthat related with emestrin. Elucidation structure of molecule with HPLC, UPLC-MS,1H-NMR and 13C-NMR. The fraction emestrin B have bioactivity to cancer cell lines inrange 0,18 􀂱 4,21 µg/mL with MTT (Microculture Tetrazolium Technique) assay method.Order of anticancer activity was breast cancer cell line [T47D] (0,18 µg/mL) > coloncancer cell line [WiDr] (1,21 µg/mL) > cancer cervic cell line [HeLa] (1,91 µg/mL). Thefraction of emestrin B have a toxicity to normal cell line [Vero] (4,21 µg/mL). The resultshows compound fraction that succeed to isolated was emestrin B (C27H22N2O10S3) andhave a potency anticancer activity."

"Pemahaman karakteristik sel punca kanker merupakan salah satu cara untuk menemukan terapi yang tepat untuk mengobati penyakit kanker. Penelitian ini bertujuan untuk menemukan pengaruh lingkungan mikro yang dihasilkan oleh sel fibroblas normal dan kanker terhadap pluripotensi sel punca kanker payudara. Sel fibroblas dan sel punca kanker payudara masing-masing dikultur dengan menggunakan medium kultur DMEM high glucose. Kemudian sel punca kanker diko-kultur dengan sel fibroblas, baik sel fibroblas normal maupun kanker. Pengukuran pluripotensi dilakukan dengan 2 cara, yaitu pengukuran ekspresi penanda permukaan CD44+/CD24+ dengan spektrofluorometer dan pengukuran ekspresi SOX2 dengan menggunakan reverse transcription-polymerase chain reaction. Hasil pengukuran menunjukkan bahwa pluripotensi sel punca kanker payudara menurun pada sel punca kanker yang diko-kultur dengan sel fibroblas, baik fibroblas normal maupun kanker, namun, ekspresi penanda permukaan dan SOX2 pada sel punca kanker yang diko-kultur dengan sel fibroblas kanker lebih tinggi dibandingkan dengan yang diko-kultur dengan sel fibroblas normal. Dari hasil ini, kami menyimpulkan bahwa lingkungan mikro yang dihasilkan sel fibroblas normal dan kanker mampu menurunkan tingkat pluripotensi sel punca kanker payudara sehingga lingkungan mikro dapat dimanfaatkan sebagai sarana untuk menghilangkan sel punca kanker.

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Understanding and figuring out the characteristics of cancer stem cells is believed as a way to find a perfect therapy in treating cancer disease. This research aims to find out the effect of the microenvironment provided by either normal fibroblast cells or cancer fibroblast cells toward the pluripotent characteristics of breast cancer stem cells. Both the fibroblast cells and the cancer stem cells were cultured independently using DMEM high glucose. The cancer stem cells were then cocultured into the fibroblast cells, both normal and cancer cells. The pluripotent characteristics were measured using two methods; expression of CD44+/CD24+ cell surface markers using fluorescent spectroscopy and expression of SOX2 using reverse transcription - polymerase chain reaction. Results showed that the expression of both CD44+/CD24+ cell surface markers and SOX2 decreased in breast cancer stem cells co-cultured with the fibroblast cells, whereas the expression in the cancer stem cells co-cultured with cancer fibroblast cells were higher than those co-cultured with the normal fibroblast cells. From the results, we suggest that the microenvironment created by either normal fibroblast cells or cancer fibroblast cells could decrease the pluripotent characteristics of breast cancer stem cells, hence microenvironment can be used as a tool to eradicate cancer stem cells."

"ABSTRAKLatar Belakang. Sel punca kanker (SPK) osteosarkoma didefinisikan sebagai sebagian kecil populasi sel osteosarkoma yang mempunyai kemampuan memperbaharui diri, menunjukan proliferasi dan mampu berdifferensiasi. SPK diduga bertanggung jawab terhadap resistensi kemoterapi, rekurensi dan metastasis. Studi ini bertujuan untuk melakukan isolasi, kultur dan karakterisasi secara in vitro SPK osteosarkoma manusiaMetode. Penelitian ini merupakan studi in vitro sebagai lanjutan yang memisahkan SPK osteosarkoma dari sel osteosarkoma manusia yang berhasil dikultur secara in vitro. Prosedur isolasi dan kultur SPK osteosarkoma dilakukan dengan metode sphere-forming assay pada ultra low well attachment surface plate. Setelah koloni sarcosphere terbentuk, dilakukan penanaman koloni tersebut pada tissue culture plate dan dilakukan karakterisasi pewarnaan Alizarin Red S, ekspresi penanda gen Nanog, Oct ¾, STAT3 dan CD133 dengan Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) dan ekspresi penanda protein alkali fosfatase, osteokalsin dan CD133 dengan Immunofluorescence Analysis (IFA).Hasil. Dengan prosedur sphere forming assay dapat ditumbuhkan koloni sarcosphere yang berbentuk bulat, tiga dimensi serta tidak melekat pada substrat. Pada tissue culture plate didapatkan bentuk koloni sarcosphere berbentuk spindel dan melekat pada substrat. Pemeriksaan karakterisasi pewarnaan alizarin red s positif, ekspresi gen Nanog, Oct ¾ dan STAT3 yang dibuktikan dengan RT-PCR serta ekspresi protein alkali fosfatase, osteokalsin dan CD133 dengan metode IFA.Simpulan. SPK osteosarkoma dapat diisolasi dan dikultur secara in vitro dari sel osteosarkoma manusia dengan metode sphere forming assay.

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ABSTRACTIntroduction. Osteosarcoma cancer stem cells (CSCs) are defined as a subpopulation of osteosarcoma cells which have the ability of self-renewal, proliferate and differentiate. CSCs may be responsible for chemotherapy resistance, recurrence and metastasis. This study aims to do isolation, culture and characterization of human osteosarcoma CSCs in vitro.Method. This study was an in vitro study which extend the differentiation of osteosarcoma CSCs from human osteosarcoma cells that had been successfully cultured in vitro. Osteosarcoma CSCs had been isolated and cultured with sphere-forming assay method on an ultra low well attachment surface plate. After sarcosphere colonies formed, the planting of the colony on the tissue culture plate and Alizarin Red S staining characterization was performed, the expression of marker genes Nanog, Oct ¾, STAT3 and CD133 was obtained by Reverse Transcriptase Poslymerase Chain Reaction (RT-PCR) where as the expression of protein markers alkaline phosphatase, osteocalcin and CD133 was obtained by Immunofluorescence Analysis (IFA).Result. Sphere-forming assay procedure could develop sarcosphere colonies which were rounded, three-dimensional and not attached to the subtsrate. In tissue culture plate, spindle-shaped sarcosphere colonies attached to the substrate. Alizarin Red S staining characterization was positive, the expression of Nanog, Oct ¾ and STAT3 gene was demonstrated by RT-PCR and protein expression of alkaline phosphatase, osteocalcin and CD133 was demostrated by IFA method.Consclusion. CSCs in osteosarcoma can be isolated and cultured in vitro from human osteosarcoma cells by sphere-forming assay method."

"Breast cancer stem cells (BCSCs) dengan petanda Aldehida dehidrogenase 1-positif (ALDH1+) merupakan populasi minor dari sel-sel tumor dengan kemampuan tumorigenik yang tinggi dan bertahan terhadap stres oksidatif. Manganese superoksida dismutase (MnSOD) merupakan pertahanan utama terhadap superoksida yang diekspresikan spesifik di mitokondria, yang merupakan salah satu sumber utama stres oksidatif di dalam sel.  Sejauh ini, belum diketahui peranan MnSOD terhadap ketahanan hidup dan kepuncaan BCSC. Transfeksi in vitro pada BCSC (ALDH1+) dilakukan dengan menggunakan siRNA MnSOD spesifik dalam kondisi kultur standar. Total RNA dan protein diekstraksi dengan menggunakan TriPure® Isolation Reagent dan RIPA® lysis buffer. Viabilitas sel diukur dengan menggunakan trypan exclusion assay. Ekspresi relatif mRNA MnSOD dan OCT4 dianalisis dengan menggunakan one-step qRT-PCR. Aktivitas MnSOD diukur dengan menggunakan uji inhibisi xantin oksidase (RanSOD® kit). Kadar superoksida sel diukur dengan menggunakan uji dihidroetidium dan tumorigenik diukur dengan menggunakan mammosphere-forming unit. Setelah diinkubasi selama 48 jam dengan menggunakan siRNA dengan menggunakan dosis 80 pmol. Ekspresi relatif mRNA MnSOD mengalami penekanan sejumlah 0,17-kali (p<0,01), penurunan aktivitas spesifik MnSOD sebesar 70,4 %, peningkatan kadar superoksida sel menjadi 1,13-kali, penurunan ekspresi OCT4 menjadi 1,08-kali (p<0,05) dan penurunan mamosphere forming unit efficiency menjadi 36,5 % (p<0,05) dibandingkan dengan kontrol negatif. Viabilitas BCSC (ALDH1+) menurun sebanyak 75 %(p<-0,05) dibandingkan kontrol negatif. Hasil penelitian ini menunjukkan bahwa penekanan ekspresi MnSOD dapat menjadi target yang menjanjikan untuk menurunkan kepuncaan dan tumorigenitas BCSC (ALDH1+).

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Aldehyde dehydrogenase 1-positive (ALDH1+) breast cancer stem cells (BCSCs) are a small population of tumor cells with high capacity of tumorigenicity and oxidative stress. Manganese superoxide dismutase (MnSOD) is specifically expressed in mitochondria as the primary defense against superoxides, which are one of the causes of oxidative stress in cells. The aim of this study was to determine the impact of suppressing MnSOD expression using small interfering RNA (siRNA) on the stemness, tumorigenicity, and viability of BCSCs. In vitro transfection of ALDH1+ BCSCs was performed using 33 and 66 µM specific MnSOD siRNA under standard culture conditions. Total RNA and protein were extracted from the transfected cells using TriPure® Isolation Reagent and RIPA® lysis buffer. Cell viability was measured using a trypan blue exclusion assay. The relative expression of MnSOD and OCT4 mRNAs was analyzed by one step qRT-PCR. MnSOD activity was determined by xanthine oxidase inhibition assay (RanSOD® kit). Cellular superoxides were measured using a dihydroethidium assay and tumorigenicity was observed with mammosphere-forming unit.  After siRNA incubation for 48 hours, MnSOD was suppressed by 0.176-fold (p<0.01), MnSOD enzyme specific activity was reduced 70.4%, cellular superoxide levels increased by 1.13-fold, OCT4 expression was suppressed by 1.98-fold (p<0.05), and mammosphere-forming unit decreased by 36.5% (p<0.05) compared with the corresponding negative controls. The viability of the ALDH1+ BCSCs was reduced 75% (p< 0.05). Our results suggest that suppression of MnSOD expression may be a promising target to reduce stemness and tumorigenicity of ALDH1+ BCSCs."

"Latar Belakang: Sel punca kanker merupakan populasi sel minor yang memiliki kemampuan self-renewal dan proliferasi tak terbatas sehingga bersifat tumorigenik dan diduga berperan dalam penurunan sensitivitas terhadap berbagai terapi kanker. Tamoksifen merupakan terapi lini pertama pada kanker payudara ER positif namun penggunaan jangka panjangnya menimbulkan masalah resistensi. Beberapa faktor yang diduga berperan dalam penurunan sensitivitas sel terhadap Tamoksifen yakni modulasi pensinyalan estrogen melalui ERα66; dan ERα36 (yang diketahui memperantarai pensinyalan non-genomik), serta ekspresi transporter effluks seperti MRP2 yang berperan dalam penurunan kadar Tamoksifen intraseluler. Penelitian ini bertujuan untuk menganalisis efek pemaparan Tamoksifen berulang pada sel punca kanker payudara CD24-/CD44+, dalam kaitannya mengenai sensitivitas terapi melalui perubahan ekspresi estrogen reseptor alfa dan transporter efluks MRP2.Metode: Selpunca kanker payudara CD24-/CD44+ dipaparkan Tamoksifen 1 μM selama 21 hari dengan DMSO sebagai kontrol negatif. Viabilitas sel setelah pemaparan Tamoksifen diuji dengan metode trypan blue exclusion. Sifat tumorigenik sel setelah pemaparan (CD24-/CD44+(T)) diuji dengan mammossphere formation assay dan dibandingkan dengan sel CD24-/CD44+(0) yang belum dipaparkan Tamoksifen. Ekspresi mRNA Oct4, c-Myc, ERα66, ERα36 dan MRP2 dianalisis dengan one step quantitative RT-PCR.Hasil: Terjadi penurunan sensitivitas sel punca kanker payudara CD24-/CD44+(T) yang dipaparkan Tamoksifen selama 21 hari yang ditunjukkan dengan kenaikan viabilitas sel hingga 125,2%. Tamoksifen tidak dapat menekan sifat tumorigenik sel CD24-/CD44+(T) yang dibuktikan melalui jumlah mammosfer yang tidak berbeda bermakna dibandingkan dengan CD24-/CD44+(0). Penurunan sensitivitas sel CD24-/CD44+(T) juga dibuktikan melalui peningkatan ekspresi Oct4 dan c-Myc; keduanya merupakan petanda pluripotensi dan c-Myc juga dikenal sebagai petanda keganasan. Parameter penurunan sensitivitas seperti ERα66, ERα36 dan MRP2 juga menunjukkan peningkatan ekspresi pada hari ke-15 namun menurun kembali pada hari ke-21 yang menunjukkan adanya mekanisme regulasi lain yang mungkin terlibat dalam penurunan sensitivitas sel punca kanker payudara terhadap Tamoksifen.Kesimpulan: Pemaparan Tamoksifen berulang dapat menurunkan sensitivitas sel punca kanker payudara CD24-/CD44+ melalui perubahan ekspresi estrogen reseptor alfa dan transporter efluks MRP2.

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Background: Cancer stem cells are minor population of cells possessing self-renewal and unlimited proliferation abilities which support their tumorigenicity and role in decreased sensitivity to many cancer therapies. Tamoxifen is a first line therapy for breast cancer patients with positive ER status. Nonetheless, after 5 years of its long term use eventually leads to recurrence and resistance in 50% of patients receiving tamoxifen therapy. Among some factors that might play role in decreased sensitivity to tamoxifen are modulation of estrogen signaling through ERα66 and ERα36 (the latter known for its non-genomic estrogen signaling), and expression of efflux transporter such as MRP2 responsible for decreased intracellular tamoxifen level. The objective of this study is to analyze the effects of repeated tamoxifen exposure toward decreased sensitivity of the breast cancer stem cells CD24-/CD44+ through changes in expression of estrogen receptor alpha and efflux transporter MRP2.

Methods: Breast cancer stem cells CD24-/CD44+ were exposed to 1 μM tamoxifen for 21 days with DMSO as negative control. After exposure with 1 μM tamoxifen, the cell viability were tested by the trypan blue exclusion method. Cell tumorigenicity of tamoxifen-exposed CD24-/CD44+(T) and CD24-/CD44+(0) (before treatment) were tested by the mammosphere formation assay. The expression of Oct4, c-Myc, ERα66, ERα36 andMRP2 mRNAs were analyzed by one step quantiative RT-PCR.

Results: A decreased sensitivity of the breast cancer stem cells CD24-/CD44+ exposed with 1 μM tamoxifen for 21 days was observed as indicated by an increased cell viability up to 125.2%. In the presence of tamoxifen, breast cancer stem cells CD24-/CD44+(T) exhibited tumorigenic properties as indicated in no significant difference in the formation of mammosphere unit compared to those of CD24-/CD44+(0). After exposure with 1 μM tamoxifen for 21 days, an elevated level of Oct4 and c-Myc expressions were observed; both are known as pluripotency markers and the latter also known as marker of aggresiveness. Parameters for a decreased sensitivity such as ERα66, ERα36 and MRP2 also exhibited an elevated expression after 15 days of exposure, but the decreased expression after 21 days of exposure suggests that there might be another mechanism involved in decreased sensitivity of the breast cancer stem cells toward tamoxifen.

Conclusion: Repeated tamoxifen exposure may decrease the sensitivity of the breast cancer stem cells CD24-/CD44+ through changes in expression of estrogen receptor alpha and efflux transporter MRP2."

"It is pointed out that a cancer stem cell is a type within a tumor that possesses the capacity of self-renewal and can give rise to the heterogeneous lineages of cancer cells, which comprise the tumor. It is emphasized that a unique feature of cancer stem cells is that, although conventional chemotherapy kills most cells in a tumor, cancer stem cells remain intact. Vast applications of the following specific stem cells in disease and tissue injury are discussed: embryonic stem cells, human mesenchymal stem cells, cancer stem cells, arterial stem cells, neural stem cells, cardiac stem cells, dental stem cells, limbal stem cells, and hematopoietic stem cells. Because human embryonic stem cells possess the potential to produce unlimited quantities of any human cell type, considerable focus is placed on their therapeutic potential in this volume. These cells are used in tissue engineering, regenerative medicine, pharmacological and toxicological studies, and fundamental studies of cell differentiation. It is pointed out that the formation of embryoid bodies, which are three-dimensional aggregates of embryonic cells, is the initial step in the differentiation of these cells. Therapeutic implications of signalling pathways in cancer stem cells are pointed out. Targeting self-renewal pathways in cancer stem cells are also included. Application of mesenchymal stem cells for treating ischemic brain injury is explained. Neural stem cells proliferation into the surrounding area of the traumatic brain injury is explained."

"Latar belakang: Karsinoma nasofaring (KNF) merupakan keganasan tersering di regio kepala leher. Terapi utama KNF adalah radiasi karena sifatnya yang radiosensitif, namun rekurensi lokal dan metastasis banyak terjadi. Cancer stem cell (CSC) diduga sebagai salah satu penyebabnya. Octamer binding transcription factor 4 (OCT4) merupakan salah satu penanda sel punca embrionik yang penting dalam progresi keganasan berbagai organ, termasuk nasofaring. Namun peran OCT4 sebagai prediktor respons terapi KNF masih menjadi perdebatan.Metode: Penelitian ini menggunakan metode potong lintang. Sampel berjumlah 41 kasus di Departemen Patologi Anatomik FKUI/RSCM periode Januari 2014 sampai Desember 2016. Dilakukan pulasan imunohistokimia OCT4 dan penilaian terhadap perbedaan rerata proporsi ekspresi positif kuat dan sedang OCT4 pada kelompok respons dan non-respons.Hasil: Terdapat 33 kasus (80,5%) dengan jenis kelamin laki-laki dan 8 kasus (19,5%) dengan jenis kelamin perempuan. Berdasarkan data klinik, 13 kasus (31,7%) berada dalam rentang usia 40-49 tahun, gejala terbanyak ditemukan berupa benjolan leher pada 31 kasus (75,6%) dan 18 kasus (43,9%) berada pada stadium IVA. Ditemukan perbedaan bermakna (p = 0,009) antara rerata proporsi ekspresi OCT4 positif kuat dan sedang kelompok respons (61,29%) dibandingkan kelompok non respons (37%).Kesimpulan: Kesimpulan penelitian ini adalah ditemukan hubungan bermakna antara ekspresi OCT4 dengan respons kemoradiasi KNF tidak berkeratin tidak berdiferensiasi.

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Background: Nasopharyngeal carcinoma (NPC) is the most common head and neck malignancy with high rate of resistance and recurrence. Cancer stem cells (CSC) is considered responsible for cancers relapse and metastasis because of its self-renewal capabilities. Expression of embryonic stem cells marker Octamer binding transcription factor 4 (OCT4) is crucial for progression of various human malignancies, including NPC. But the role of OCT4 as therapy response predictor is controversial.

Method: This study is using cross-sectional method. Sample consist of 41 undifferentiated non keratinizing NPC cases diagnosed in Anatomical Pathology Departement, Faculty of Medicine, Universitas Indonesia-Dr. Cipto Mangunkusumo Hospital from January 2014 until December 2016. OCT4 immunohistochemistry staining was performed then tumour cells with strongly and moderately positive OCT4 staining were counted. Mean difference between both groups is calculated.

Result: There were 33 male cases (80,5%) of 41 and 8 female cases (19,5%). 13 cases (31,7%) were age 40-49 years old. Neck mass was the most common symptom in 31 cases (75,6%) and 18 cases (43,9) were in stadium IVA. Mean difference of strongly and moderately positive OCT4 expression between responsive (61,29%) and non-responsive (37%) to chemoradiation therapy were statically significant (p=0.009)."