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7.1 Simpulan

Penelitian ini mendapatkan kesimpulan bahwa terdapat adanya korelasi positif antara ekspresi Cyclooxygenase-2 dan Microvessel density pada undifferentiated carcinoma nasopharynx.

7.2 Saran

Adanya korelasi Cyclooxygnase-2 dan Microvessel density yang positif pada undifferentiated carcinoma nasopharynx, maka pemberian penghambat COX-2 akan dapat dipertimbangkan pada penderita dengan ekspresi COX-2 positif dan/atau MVD> 4,5.

72 DAFTAR PUSTAKA

Anonim. 2010. Kanker di Indonesia Tahun 2010 Data Histopatologik. Jakarta:

Direktorat Jenderal Pelayanan Medik Departemen Kesehatan RI.

Anonim. 2012. Pengecatan Imunohistokimia p53. Cancer Chemoprevention Research Center fakultas Farmasi UGM.

Anonim. 2009. Primary antibodies. Biocare medical. 4040 pike lane, concord, CA 94520.

Bertagnolli, M., Viner, J.l., Hawk, E.T. 2008.Cyclooxygenase-2 as a Target for Cancer Prevention and Treatment.In : Tavassoli, F.A., Devilee, P (eds).

Molecular Targeting in Oncology. Boston: Humana Press: p. 5093531

Brennan, B. 2006.Nasopharyngeal carcinoma.Orphanet Journal of Rare Diseases, vol 1, no.23.p.1-5

Chan, J.K.C., Pilch, B.Z., Kuo, T.T., Wenig, B.M., Lee, A.W.M.

2005.Nasopharyngeal carcinoma. In: Barnes L, Eveson, J.W, Reichart, P, Sidrasky, D editors. WHO classification of tumours: Pathology and genetics head and neck tumours. Lyon: IARCPress. p. 85-97.

Chang, J.T., Chan, S.H., Lin, C.Y., Lin, T.Y., Wang, H.M., Liao, C.T., Wang, T.H., Lee, L.Y., Cheng, A.J. 2007.Differentially expressed genes in radioresistant nasopharyngeal cancer cells: gp96 and GDF15.Mol. Cancer Ther, 6:2271–

2279.

Cho, WC, 2007. Nasopharyngeal Carcinoma: Molecular Biomarker Discovery and Progres. Molecular Cancer, 6:1.

73

Choi, W.W.L., Lewis, M.M., Lawson, D., Goen, Q.Y., Birdsong, G.G., Cotsonis, G.A. 2005. Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameter and VEGF family gene expression. Mod pathology, 18:143-52.

Chou, J., Lin, Y.C., Kim, J., You, L., Xu, Z., He, B. 2008.Nasopharyngeal carcinoma-review of the molecular mechanisms of tumorigenesis.Head and Neck-DOI, 10:1002.

Choudhary, S., Wang, H.C.R. 2007.Proapoptotic ability of oncogenic H-ras to facilitate apoptosis induced by histone deacetylase inhibitors in human cancer cells.Mol Cancer Ther, 6(3):1099-111.

Desen, W. 2008. Tumor kepala dan leher. In: Desen W, editor. Buku ajar onkologi klinis edisi II. Jakarta: Balai Penerbit Fakultas Kedokteran Universitas Indonesia. p. 263-78.

Divvela, A.K., Challa, S.R., Tagaram, I.S. 2010.Pathogenic Role of Cyclooxygenase32 in Cancer. J H Science, 56:5023516.

El-Gehani, K., Al-Kikhia, L., Mansuri, N., Syrjanen, K., Al-Fituri, O., Elzagheid, A.

2011. Angiogenesis in urinary bladder carcinoma as defined by microvessel density (MVD) after immunohistochemical staining for factor VII and CD31.

Libyan J Med, vol 6, pp. 6016. C.E., Li, J.L. 2010.Identification of biomarkers for predicting nasopharyngeal carcinoma response to radiotherapy by proteomics.Cancer Res, 70: 3450–

3462.

Gallo, O., Franchi, A., Magnelli, L., Sardi, I., Vanacci, A. 2008. Cyclooxygenase-2 Pathway correlates with VEGF expression in head and neck cancer:

implication for tumor angiogenesis and metastasis. Neoplasia. 3(1):53-61.

Garden, A. 2010.The nasopharynx. In: Co, J.D, Ang, K.K, editors. Radiation oncology: rationale, technique, results. Philadelphia: Mosby Elsevier. p. 207-20.

Giordano, A., De-Falco, G., Rubin, E., Rubin, R. 2008.Neoplasia. In: Rubin, R., Strayer, D.S., editors. Rubin’s Pathology Clinicopathologic Foundations Medicine Fifth Edition. Philadelphia: Wolters Kluwer. p. 137-176.

Greenhough, A., Smartt, A.J.M., Moore, A.E., Roberts, H.R., Williams, A.C., Paraskeva, C., Kaidi, A. 2009. The COX-2/PGE2pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Oxford Journal. 30(3): 377-386.

Hasibuan, N.R., Farhat., Haryuna, T.S.H., Yudhistira,a. 2014, Korelasi positif ekspresi cyclooxygenase-2 dengan gambaran microvessel density pada karsinoma nasofaring. ORLI, 44:1.

Howe, L.R. 2007.Cyclooxygenase / Prostaglandin Signaling and Breast Cancer.BC Research, 9:210.

Hsiao, S.H., Lee, M.S., Lin, H.Y., Su, Y.C., Ho, H.C., Hwang, J.H., Lee, C.C., Hung, S.K. 2009. Clinical significance of measuring levels of tumor necrosis factor-alpha and soluble interleukin-2 receptor in nasopharyngeal carcinoma.Acta Otolaryngol. 129, 1519–1523.

Ji, B., Liu, Y., Zhang, P., Wang, Y., Wang, G. 2012. COX-2 Expression and Tumor Angiogenesis in Thyroid Carcinoma Patient among Northeast Chinese Population-Result of Single-Center Study.Int J Med Sci. 9(3): 237-42.

75

Jiang, R., Cabras, G., Sheng, W., Zeng, Y., Ooka, T. 2009. Synergism of BARF1 with ras induced malignant transformation in primary primate epithelial cells and human nasopharyngeal epithelial cells. Neoplasia. 9:964-73.

Klimek, M., Urbański, K., Kojs, Z., Karolewski, K., Pudetek, J., Blecharz, P. 2009.

Role of Cyclooxygenase-2 in Cervical Cancer. Arch Med Sci., 3:303-307.

Korcum, A.F., Özyar, E., Ayhan, A. 2006. Epstein-Barr virus genes and n[-asopharyngeal cancer. Turk J Cancer. 36 (3): 97-107.

Kumar., Abas., Fausto., Aster. 2010. Neoplasm. In: Robbins Cotran Pathologic Basis of Desease. Eight Edition. Kumar Vinay. Philadelphia: Saunders Elsevier. p. 62-70.

Levine, A.J., Hu, W., Feng, Z. 2008. Tumor supressor genes. In: Mendelsohn, J., Howley, P..M, Israel, M.A., Gray, J.W., Thompson, C.B, editors. The moleculaar basis of cancer. 3th ed. Philadelphia: Saunders. p. 31-8.

Lin, D.T., Subbaramaiah, K., Shah, J.P. 2006. Cyclooxygenase-2: a novel molecular target for the prevention and treatment a head and neck cancer. Head neck.

24:792-9.

Lu, H., Ouyang, W., Huang, C. 2006. Inflamation, a Key Event in Cancer Development.Molecular Cancer Research Journal. 4: 221-233.

Machin, D., Cambell, M.J., Tan, S.B., Tan, S.H. 2009.Sample size table for clinical studies.Third edition.A john wiley and sons.UK.

Mantovani, A., Allavena, P., Sica, A., Balkwil, F. 2008. Cancer-related inflammation.Nature, vol. 24, no. 254, pp. 436-44.

Monica, B., Jaye, L., Viner., Ernest, T., Hawk. 2008. Cyclooksigenase-2 as a Target for Cancer Prevention and Treatment. In: Kaufman H.L., Wadler S., Anntman K., Eds. Molecular Targeting In Oncology. Humana Press. p.509-541.

Mozes, S.N., Kupets, R., Rasty, G., Ismiil, N., Covens, A., Khalifa, M.A. 2005.

Cyclooxygenase-2 (COX-2) Immunostaining Does not Correlate withThe Degree of Vulvar Neoplasia. November., (Cited 2006 February. 2).

Available from:

http://www.jogc.com/abstracts/full/200604_Gynaecology_1.pdf. Accessed Pebruari, 10 2014.

Nancy R.T. Epstein Barr Virus in the Pathogenesis of NPC.In: Erles S.R. editor Epstein Barr Virus, 1 st ed. Phyladelphia Pennsylvania 2005:p.71-87.

Nishida, N., Yano, H., Nishida, T., Kamura, T., Kojiro, M. 2006. Angiogenesis in cancer. Vascular Health and Risk Management, vol. 2, no. 3, p. 213-219.

Pang, R.W.C., Poon, R.T.P. 2006.Clinical implications of angiogenesis in cancers.

Vascular Health and Risk Management, vol. 2, no. 2, p. 97-108.

Qu, C., Liang, Z., Huang, J., Zhao, R., Su, C., Wang, S., Wang, X., Zhang, R., Lee, M.H., Yang, H. 2012. MiR-205 determines the radioresistance of human nasopharyngeal carcinoma by directly targeting PTEN. Cell Cycle. 11, 785–

796.

Rao ,V.U.S., Shenoy, A.M., Kanthikeyan, B. 2011. Role of angiogenetic marker to predict neck node metastasis in head and neck.J cancer Res Ther. 6(2): 1412-6.

Ristimaki, A., Sivula, A., Lundin, J., Lundin, M., Salminen, T., Haglun, C., Joensuu, H., Isola, J. 2012.Prognosis Significant of Elevated Cyclooxigenase-2 Expression in Breast Cancer.Cancer Research Journal.62: 632.

Roezin A. 2007. Karsinoma nasofaring. In: Soepardi, Arsyad E, editors. Buku ajar ilmu kesehatan telinga hidung tenggorok kepala dan leher. Jakarta: Fakultas Kedokteran Universitas Indonesia. p. 182-98.

77

Rottey, S., Madani, I., Deron, P., van Belle, S. 2011. Modern treatment for nasopharyngeal carcinoma: Current status and prospects. Curr.Opin.Oncol.

23, 254–258.

Soo R. 2005. Overexpression of Cycloogenase-2 in Nasopharyngeal Carcinoma and Association With Epidermal Growth Factor Receptor Expression Arch Otolaryngol Head Neck Surg. 131;p.147 – 152.

Sonawane, C.S., Jagdale, D.M., Kadam, V.J. 2011. Review Article: Role of Cyclooxygenase-2 in Cancer. International Journal of Research in Pharmacy and Chemistry, 1(3):385-395. MDR1/P3Glycoprotein in Invasive Breast Cancers and their Prognostic Significance. J Breast Cancer, 7: 8623870

Svagzdys, S., Lesauskaite, V., Pavalkis, D., Nedzelskiene, I., Pranys, D., Tamelis, A.

2009. Microvessel density as new prognostic marker after radiotherapy in rectal cancer.Biomed Cancer, 9(95): 1-8.

Tan, E.L., Looi, L.M., Sam, C.K. 2006.Evaluation of plasma Epstein-Barr virus DNA load as a prognostic marker for nasopharyngeal carcinoma. Singapore Med. J. 47, 803–807.

Tan, K.B., Putti, T.C. 2005. Cyclooxygenase-2 expression in nasopharyngeal carcinoma: immunohistochemical finding and potential implication. Journal clinical pathology. 58(5):535-8

Tang, F., Xie, C., Huang, D., Wu, Y., Zeng, M., Yi, L., Wang, Y., Mei, W., Cao, Y., Sun, L. 2011.Novel potential markers of nasopharyngeal carcinoma for diagnosis and therapy.Clin.Biochem. 44, 711–718.

Tao, Q., Anthony, T.C. 2007.Nasopharyngeal carcinoma.Molecular Pathogenesis and Therapeutic Development in Expert review in molecular medicine. Vol 9.

Taweevisit, M., Keelawat, S., Thoner P.S. 2010. Correlation of microvascular density and proliferation index in undifferentiated nasopharyngeal carcinoma.

Asian Biomedicine.vol.4, no.2, pp.315-321.

Tse, L.A., IT-S, Y., OW, KM., Wong, S.L. 2006. Incidence rate trends of histological subtypes of nasopharyngeal carcinoma in Hong Kong. British J Cancer.

95:1269-73.

Uppaluri, R., Dunn, G.P., Lewis, J.S. 2008. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in head and neck cancer. Cancer immunity.8, 16-26.

Widiastuti., Prija, T.K.S., Alsagaf, J.H., Koentjono, W.A. 2011. Ekspresi Protein Cox-2 pada Karsinoma Nasofaring Respon Tinggi dan Respon Rendah Pasca- Radioterapi. JBP, 13(2):105-114.

Wee, J.T., Ha, T.C., Loong, S.L., Qian, C.N. 2010. Is nasopharyngeal cancer really a

“Cantonese cancer”? Chin. J. Cancer. 29, 517–526.

Xie, P., Yue, J.B., Fu, Z., Feng, R., Yu, J.M. 2010. Prognostic value of 18F-FDG PET/CT before and after radiotherapy for locally advanced nasopharyngeal carcinoma. Ann. Oncol. 21, 1078–1082.

Xu, X., Hu, G., Li, S., Xu, F., Li, D., Dai, D., Chen, Y. 2006. Expression of cyclooxygenase-2 in nasopharyngeal carcinoma and its relation to angiogenesis and prognosis.Chinese-German J Clin Oncol. 5(2):104-7.

79

Yang, S., Chen, J., Guo, Y., Lin, H. Zhang, Z., Feng, G., Hao, Y., Cheng, J., Liang, P., Chen, K. 2012.Identification of prognostic biomarkers for response to radiotherapy by DNA microarray in nasopharyngeal carcinoma patients.Int. J.

Oncol. doi:10.3892/ijo.2012.1341.

Zhargi, A., Arfaei, S. 2011. Review Article: Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships. Iran J Pharm Res 10(4):655-683

Zhao, H.C., Qin, R., Chen, X.X., Sheng, X., Wu, J.F., Wang, D.B. 2008. Microvessel density is a prognostic marker of human gastric cancer. World J Gastroenterol. 2006; 12(47): 7598-603.

Zheng, H., Li, L., Hu, D., Deng, X., Cao, Y. 2007. Role of Epstein-Barr virus encoded Latent Membrane Protein 1 in the carcinogenesis of nasopharyngeal carcinoma. Celular & Molecular Immunology. 4(3):185-96.

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80 Lampiran 1. Penilaian ekspresi COX-2 dan CD 31

1. Penilaian ekspresi Cox-2 dibuat berdasarkan analisis persentase sel tumor yang positif dan intensitas pewarnaan. Berdasarkan persentase sel ganas yang menunjukkan overekspresi Cox-2 maka dibagi menjadi 3 skor (0-3) yaitu: 0 (tidak terwarnai), 1 (<10% sel dari seluruh sel ganas terwarnai), 2 (10-50% sel dari seluruh sel ganas terwarnai), 3 (>50% sel dari seluruh sel ganas terwarnai). Berdasarkan intensitas sel-sel ganas yang menunjukkan overeksprei COX-2 maka dibagi menjadi 3 skor (0-3) yaitu: 0 (negatif), 1 (lemah), 2 (sedang), 3 (kuat) (Tan dan Putti, 2005).

Interpretasi ekspresi COX-2 dari sel tumor, sesuai dengan penelitian sebelumnya digunakan skor immunoreaktif, diperoleh dengan mengalikan skor % sel ganas yang mengekspresikan COX-2 dengan skor intensitas. Skor imunoreaktif 4 atau lebih dinilai sebagai ekspresi COX-2 positif, skor imunoreaktif kurang dari 4 dinyatakan sebagai COX-2 negatif (Tan dan Putti, 2005).

2. Untuk penghitungan microvessel density, pulasan CD31 dinilai pada pembesaran lemah (40x) untuk area yang menunjukkan peningkatan pembuluh darah (hot spots).

Pada area hotspot dilihat pada pembesaran kuat 400x dengan mikroskop cahaya binokuler CX-21.Empat lapang pandang pada 1 slide dipilih untuk mewakili area seluas 1 mm2. Intratumoral dan peritumoral microvessel (pembuluh darah dengan diameter ˂ 50µm tanpa lapisan muscular) dihitung jumlah microvessel pada masing-masing empat lapang pandang dengan cara digeser, dan hasilnya digabungkan untuk

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mendapatkan microvessel/mm2 (Taweevisit et al., 2010). Interpretasi MVD rendah dan tinggi ditentukan dengan analisis menggunakan kurva ROC.

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No No CM

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Lampiran 5

Uji Normalitas Data Umur, COX-2, dan CD 31

Cox-2 CD_31 Umur

N 31 31 31

Normal Parametersa Mean 6.03 8.68 49.52

Std. Deviation 2.869 6.720 11.636

Most Extreme Differences Absolute .237 .127 .100

Positive .150 .127 .100

Negative -.237 -.098 -.097

Kolmogorov-Smirnov Z 1.317 .708 .558

Asymp. Sig. (2-tailed) .062 .697 .915

a. Test distribution is Normal.

Lampiran 6

Analisis Deskriptif Jenis Kelamin dan Umur

Jenis_Kelamin

Frequency Percent Valid Percent Cumulative Percent

Valid Laki-laki 26 83.9 83.9 83.9

Correlations

Cox_2 CD_31

Cox-2 Pearson Correlation 1 .868**

Sig. (2-tailed) .000

N 31 31

CD_31 Pearson Correlation .868** 1

Sig. (2-tailed) .000

N 31 31

**. Correlation is significant at the 0.01 level (2-tailed).

Lampiran 8

Kurva ROC Data CD 31

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Area Under the Curve Test Result Variable(s):CD_31

Area Std. Errora Asymptotic Sig.b

Asymptotic 95% Confidence Interval Lower Bound Upper Bound

.914 .056 .054 .804 1.024

The test result variable(s): CD_31 has at least one tie between the positive actual state group and the negative actual state group. Statistics may be biased.

a. Under the nonparametric assumption b. Null hypothesis: true area = 0.5

Coordinates of the Curve Test Result Variable(s):CD_31

Positive if Less Than or Equal Toa Sensitivity 1 - Specificity

-1.00 .000 .000

The test result variable(s): CD_31 has at least one tie between the positive actual state group and the negative actual state group.

a. The smallest cutoff value is the minimum observed test value minus 1, and the largest cutoff value is the maximum observed test value plus 1. All the other cutoff values are the averages of two consecutive ordered observed test values.

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