LOGO  1         Journal Reading Divisi Imunologi         Diagnostic Markers for Early         Detection of Ovarium cancer ...
Pendahuluan                       Cancer Ovarium                            Penyebab kematian kanker yg menduduki urutan k...
Tujuan Penelitian                       Mengevaluasi panel biomarker dan                       penggunaan alternatif platf...
Material dan Metode                                       Penelitian ini                       - Prospective cohort study,...
- Diagnosis Ca ovarium ditentukan berdsrkan :                         clinical, surgical, histologic, dan pathologic pd   ...
Kriteria kontrol sehat :                       Kriteria inklusi :          - Umur ≥ 18 th                       - wanita y...
Sampel                            Serum disimpan – 80°C                            Dianalisis dgn ELISA dan Multiplex anal...
Multiplex study design                                                        535 sampel                          Training...
Statistik                       ROC               Logistic regression modelwww.themegallery.com                           ...
Hasil                       Evaluasi ELISA dan multiplex platform                        - membandingkan prolactin, leptin...
www.themegallery.com11                            Tabel 1
Hasil                       Karakteristik six biomarker multiplex platform-                       training set :          ...
www.themegallery.com                            Gbr. 113
www.themegallery.com                            Gbr. 21414
 ROC setiap marker training set  hasilnya                         signifikan dpt membedakan Ca. ovarium dgn             ...
www.themegallery.com                            Gbr. 316
                       Karakteristik six biomarker multiplex platform-                       test set :                  ...
www.themegallery.com                            Gbr. 41818
www.themegallery.com                            Gbr. 51919
www.themegallery.com20                            Tabel. 2
- Berdasarkan stadium :                            36 sampel (stad.I dan II)  4 misclassified                            ...
www.themegallery.com                            Gbr. 62222
 Multiplex six markers sensitivitas-spesifisitas                         lbh baik daripada 4-plex Elisa                  ...
Diskusi                        Pd penelitian ini six biomarker multiplex platform                         dpt membedakan ...
 Anderson, mengusulkan marker diagnosis                         melalui tahapan :                          - penemuan px,...
Kesimpulan                        Tes ini telah memenuhi tahapan yg telah                         diusulkan sebelumnya, s...
www.themegallery.com27                            TERIMA KASIH
 Reasoning that the protein profile in urine may be                         less complex than that in blood, and that pro...
 The proteome is the entire set of proteins                         expressed by a genome, cell, tissue or               ...
Leptin                        is a 16 kDa protein hormone                        plays a key role in regulating energy  ...
Prolactin                        Prolactin (PRL) or Luteotropic                         hormone (LTH) is a peptide hormon...
 Prolactin receptors are present in the                         mamillary glands, ovaries, pituitary                     ...
Osteopontin                        Osteopontin (OPN), also known as                         bone sialoprotein I (BSP-1), ...
 OPN is an important anti-apoptotic                         factor in many circumstances.www.themegallery.com            ...
 Osteopontin is biosynthesized by a                        variety of tissue types including                        fibro...
 Macrophage migration inhibitory                        factor (MIF) is a protein which in                        humans ...
 MIF plays a role in the regulation of                        macrophage function in host defense                        ...
IGF                        The insulin-like growth factors                        (IGFs) are polypeptides with high      ...
 Almost every cell in the human body                        is affected by IGF-1, especially cells                       ...
CA 125                        CA-125 (cancer antigen 125 or                         carbohydrate antigen 125) also       ...
 CA-125 is clinically approved for                        following the response to treatment                        and ...
www.themegallery.com42
 Phosphatidylinositol 3-kinases (PI 3-                        kinases or PI3Ks) are a family of                        en...
High risk Ca ov                        Ovarian cancer is rare in women younger than                        40. Most ovari...
PI3K                        Phosphatidylinositol 3-kinases (PI 3-                        kinases or PI3Ks) are a family o...
 PI3Ks are a family of related                        intracellular signal transducer                        enzymes capa...
www.themegallery.com47
High risk                        Fertility drugs seem to increase the                         risk of the type of ovarian...
Ovarian cancer staging is by the FIGO                        Stage I - limited to one or both ovaries                    ...
International Federation of Gynecologists & Obstetrician                        FIGO Staging, ovarian carcinoma          ...
www.themegallery.com51
 Human leptin is a protein of 167                         amino acids.                        It is manufactured primari...
 Sedangkan faktor resiko tejadinya                        kanker ovarium adalah:                        # Obat kesuburan ...
 Leptin activates the PI3-                        Kinase/AKTsignaling pathway                          pathways have bee...
 In conclusion, the present study has                         demonstrated that acquired                         expressi...
 useful molecular target for the                        therapeutic development of ovarian                        cancer....
 The mechanisms underlying the                        antiapoptotic effect of PRL on ovarian                        carci...
 Cohort studies: (1) fokusnya adalah                         spesifik populasi; (2) dilakukan                         sec...
The immune-complex/                            microsphere is then excited                            by the ****** laser....
www.themegallery.com60
 Gen p53 secara normal menyandi                        protein dengan berat molekul 53 kDa                        yang te...
www.themegallery.com62
www.themegallery.com63
Diagram                       Text                   Text                       Text    Concept        Text               ...
Diagram                       Add Your Text                                                       Add Your Text           ...
Diagram                       Add Your Text                       Add Your Text         Add Your                          ...
Diagram                            Text              Text              Text                       ThemeGallery is    Theme...
Diagram                               Tsssssex1t                                Tsssssex1t                       Te2wwwwxt...
Diagram                                                                Add Your Text                              Text    ...
Diagram                               1                    2                    3                       ThemeGallery is a ...
t                        Tex                     ur                   Yo            ext                        u      rT  ...
Diagram                               ThemeGallery is a Design Digital                       Title   Content & Contents ma...
Block Diagram                       TEXT   TEXT   TEXT     TEXT                       TEXT   TEXT    TEXT     TEXTwww.them...
Table                               Title   Title        Title   Title   Title                       Title    O       O   ...
3-D Pie Chart                                   Text2                                              Text3                  ...
Block Diagram                                     Add Your Text                                     Add Your Textwww.theme...
LOGO       www.themegallery.com                              77
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Jurnal imun 3

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Jurnal imun 3

  1. 1. LOGO 1 Journal Reading Divisi Imunologi Diagnostic Markers for Early Detection of Ovarium cancer Irene Visintin, Ziding Feng, Gary L, David C.Wards et all Clin Cancer Res 2008; 14(4): 1065-1072 Sri Widyaningsih, dr/ Endang Retnowati, dr, MS., SpPK (K) Rabu, 14 Juli 2010 1
  2. 2. Pendahuluan Cancer Ovarium Penyebab kematian kanker yg menduduki urutan ke-5 pd wanita (USA) - Angka kematian yg tinggi disebabkan oleh tes skrining yg krg adekuat pd stad. dini Sensitivitasnya CA 125 pd stad.dini < 60%www.themegallery.com Tes dgn 4 biomarker memberikan sensitivitas 95%, spesifisitas 94% 2
  3. 3. Tujuan Penelitian Mengevaluasi panel biomarker dan penggunaan alternatif platform untuk meningkatkan sensitivitas & spesifisitas Deteksi dini Ca. ovariumwww.themegallery.com 3
  4. 4. Material dan Metode Penelitian ini - Prospective cohort study, Discovery to Cure, in Dept. Obstetrics and Gynecologic,Yale University - Agustus 2002 - November 2006 : - 156 sampel (36 stad I/II, 120 stad III/IV) - wanita yg baru didiagnosis Ca ovarium (25-88 th)www.themegallery.com 4
  5. 5. - Diagnosis Ca ovarium ditentukan berdsrkan : clinical, surgical, histologic, dan pathologic pd Gynecologic Oncology Clinic at the Yale New Haven Hospital - Informed consent untuk semua partisipanwww.themegallery.com 5
  6. 6. Kriteria kontrol sehat : Kriteria inklusi : - Umur ≥ 18 th - wanita yg - Menjalani pemeriksaan baru didiagnosis ginekologi teratur Ca. ovarium -Tidak pernah didiagnosis Ca Kriteria eksklusi -Tdk ada riwayat klg - Punya riwayat Ca. Ca. Ovarium & ovarium bebas penyakit - Didiagnosis Ca lain sedikitnya < 6 blnwww.themegallery.com dlm 5 th terakhir setelah pangambilan - Sedang menjalani sampel kemoterapi -Merokok (-) & terapi hormon (-) 6
  7. 7. Sampel Serum disimpan – 80°C Dianalisis dgn ELISA dan Multiplex analysis Multiplex analysiswww.themegallery.com 1. Leptin, Prolactin, MIF (Macrofage Inhibitory Factor), Osteopontin, CA 125 2. IGF-II (Insulin-like growth factor II) 7
  8. 8. Multiplex study design 535 sampel Training set (294) Test set (224) Kontrol (181) Sampel (113) Kontrol (181) Sampel (43)www.themegallery.com 17 Benign disease 8
  9. 9. Statistik ROC Logistic regression modelwww.themegallery.com 9
  10. 10. Hasil Evaluasi ELISA dan multiplex platform - membandingkan prolactin, leptin, OPN, IGF II pd Elisa & multiplex  sensitivitas (95%) dan spesifisitas (94%) yg samawww.themegallery.com 10
  11. 11. www.themegallery.com11 Tabel 1
  12. 12. Hasil Karakteristik six biomarker multiplex platform- training set : - Meningkatkan sensitivitas dan spesifisitas multiplex assay  + MIF & CA 125 - Pd training set MIF signifikan lbh tinggi pd Ca. ovarium dari pada kontrol sehat - Pd Ca. ovarium prolactin, OPN, CA 125www.themegallery.com meningkat, sdgkan leptin, IGF-II menurun 12
  13. 13. www.themegallery.com Gbr. 113
  14. 14. www.themegallery.com Gbr. 21414
  15. 15.  ROC setiap marker training set  hasilnya signifikan dpt membedakan Ca. ovarium dgn kontrol sehat  Semua model pd training set akurasi klasifikasi >98%  Misclassification model  0,8% - 2,1% Misclassification CA 125 14%www.themegallery.com 15
  16. 16. www.themegallery.com Gbr. 316
  17. 17.  Karakteristik six biomarker multiplex platform- test set : - AUC & ROC dari 4 model lebih baik daripada CA 125 Final model six biomarker pd multiplex platform: - Tdk ada perbedaan model I pd training set, test set, atau kombinasi training dan test set - Final model untuk kombinasi training & test setwww.themegallery.com - 362 kontrol sehat 2 misclassified 156 Ca.ovarium  5 misclassified 17
  18. 18. www.themegallery.com Gbr. 41818
  19. 19. www.themegallery.com Gbr. 51919
  20. 20. www.themegallery.com20 Tabel. 2
  21. 21. - Berdasarkan stadium : 36 sampel (stad.I dan II)  4 misclassified 120 sampel (stad.III dan IV) 1 misclassified  17 sampel benign mass  2 misclassified  Misclassified stad.I dan II:www.themegallery.com granulosa cell carcinoma, undifferentiated carcinoma, papillary serous carcinoma 21
  22. 22. www.themegallery.com Gbr. 62222
  23. 23.  Multiplex six markers sensitivitas-spesifisitas lbh baik daripada 4-plex Elisa  Final model  sensitivitas 95,3% spesifisitas 99,4% PPV = 99,3% NPV = 99,2%  Perlu penelitian multicenter final modelwww.themegallery.com 23
  24. 24. Diskusi  Pd penelitian ini six biomarker multiplex platform dpt membedakan wanita sehat dan Ca. ovarium dgn sensitivitas 95,3%, spesifisitas 99,4%  Lokasi Ca. msh di ovarium pd saat awal diagnosis survival rate selama 10 th (± 90%)  Bila menggunakan salah satu marker sensitivitas & spesifisitas rendah  Kombinasi marker  sensitivitas & spesifisitaswww.themegallery.com tinggi 24
  25. 25.  Anderson, mengusulkan marker diagnosis melalui tahapan : - penemuan px, validasi, implementasi klinik  Multiplex platform memberikan keuntungan untuk penerapan diagnosis  Panel protein dpt mendeteksi dini stad. awal Ca. ovarium  Pd penelitian ini menggunakan different cohortwww.themegallery.com training dan test set 25
  26. 26. Kesimpulan  Tes ini telah memenuhi tahapan yg telah diusulkan sebelumnya, sehingga dpt membatasi untuk skrining hasil positif palsu  Implementasi tes ini untuk deteksi dini Ca. ovariumwww.themegallery.com 26
  27. 27. www.themegallery.com27 TERIMA KASIH
  28. 28.  Reasoning that the protein profile in urine may be less complex than that in blood, and that proteins in urine may be more stable than those in blood, as well as recognizing the convenience that a urinary test would have when compared with a more invasive blood test, Ye et al. (1) assessed the protein/peptide profiles in the urine of women with ovarian cancer.  Proteomic-Based Discovery and Characterization of Glycosylated Eosinophil-Derived Neurotoxin and COOH-Terminal Osteopontin Fragments for Ovarian Cancer in Urinewww.themegallery.com 28
  29. 29.  The proteome is the entire set of proteins expressed by a genome, cell, tissue or organism.  More specifically, it is the set of expressed proteins in a given type of cells or an organism at a given time under defined conditions  Advances in the fields of genomics and proteomics are hoped to provide insights into the molecular complexity of thewww.themegallery.com disease process and thus enable the development of tools to help in treatment as well as in detection and prevention. 29
  30. 30. Leptin  is a 16 kDa protein hormone  plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism  It is manufactured primarily in the adipocytes of white adipose tissue, and the level of circulating leptin is directly proportional to the total amount of fat in the bodywww.themegallery.com  Leptin promotes angiogenesis by increasing vascular endothelial growth factor (VEGF) levels 30
  31. 31. Prolactin  Prolactin (PRL) or Luteotropic hormone (LTH) is a peptide hormone  primarily associated with lactation  Increased serum concentrations of prolactin during pregnancywww.themegallery.com 31
  32. 32.  Prolactin receptors are present in the mamillary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin and areas of the central nervous systemwww.themegallery.com 32
  33. 33. Osteopontin  Osteopontin (OPN), also known as bone sialoprotein I (BSP-1), early T- lymphocyte activation (ETA-1), and secreted phosphoprotein 1  Osteopontin has been implicated as an important factor in bone remodeling  OPN mediates cell activation andwww.themegallery.com cytokine production, as well as promoting cell survival by regulating apoptosis 33
  34. 34.  OPN is an important anti-apoptotic factor in many circumstances.www.themegallery.com 34
  35. 35.  Osteopontin is biosynthesized by a variety of tissue types including fibroblasts[9] preosteoblasts, osteoblasts, osteocytes, odontoblasts ,www.themegallery.com 35
  36. 36.  Macrophage migration inhibitory factor (MIF) is a protein which in humans is encoded by the MIF gene  However, the biological mechanism and significance of MIF remains unknown.  Additionally, some evidence suggests that MIF might be linked towww.themegallery.com a small positive correlation between MIF production and metastatic potential in speculative models of cancer 36
  37. 37.  MIF plays a role in the regulation of macrophage function in host defense through the suppression of anti- inflammatory effects of glucocorticoidswww.themegallery.com 37
  38. 38. IGF  The insulin-like growth factors (IGFs) are polypeptides with high sequence similarity to insulin  IGF-1 is important for both the regulation of normal physiology, as well as a number of pathological states, including cancer  The IGF axis has been shown to playwww.themegallery.com roles in the promotion of cell proliferation and the inhibition of cell death (apoptosis) 38
  39. 39.  Almost every cell in the human body is affected by IGF-1, especially cells in muscle, cartilage, bone, liver, kidney, nerves, skin, and lungs.[ citation needed] In addition to the insulin- like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.www.themegallery.com 39
  40. 40. CA 125  CA-125 (cancer antigen 125 or carbohydrate antigen 125) also known as mucin 16 or MUC16 is a protein that in humans is encoded by the MUC16 gene.[1][2]  CA-125 has found application as a tumor marker or biomarker that may be elevated in the blood of some patients with specific types ofwww.themegallery.com cancers.[4] 40
  41. 41.  CA-125 is clinically approved for following the response to treatment and predicting prognosis after treatment. It is especially useful for detecting the recurrence of ovarian cancerwww.themegallery.com 41
  42. 42. www.themegallery.com42
  43. 43.  Phosphatidylinositol 3-kinases (PI 3- kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.www.themegallery.com 43
  44. 44. High risk Ca ov  Ovarian cancer is rare in women younger than 40. Most ovarian cancers develop after menopause. Half of all ovarian cancers are found in women over the age of 63.  it does seem that obese women (those with a body mass index of at least 30) do have a higher risk of developing ovarian cancer  A woman who has had children has a lowerwww.themegallery.com risk of ovarian cancer than women who have no children 44
  45. 45. PI3K  Phosphatidylinositol 3-kinases (PI 3- kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.www.themegallery.com 45
  46. 46.  PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns).[2] They are also known as phosphatidylinositol-3-kinases. The pathway, with oncogene PIK3CA and tumor suppressor PTEN (gene) iswww.themegallery.com implicated in insensitivity of cancer tumors to insulin and IGF1, in calorie restriction.[3][4] 46
  47. 47. www.themegallery.com47
  48. 48. High risk  Fertility drugs seem to increase the risk of the type of ovarian tumors  Androgens are male hormones  Estrogen therapy and hormone therapy  Family history of ovarian cancer, breast cancer, or colorectal cancer  Talcum powderwww.themegallery.com 48
  49. 49. Ovarian cancer staging is by the FIGO  Stage I - limited to one or both ovaries  Stage II - pelvic extension or implants  Stage III - microscopic peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum  Stage IV - distant metastases to the liver or outside the peritoneal cavitywww.themegallery.com 49
  50. 50. International Federation of Gynecologists & Obstetrician  FIGO Staging, ovarian carcinoma  I Malignancy of one (Ia) or both (Ib) ovaries, without ascites  II Malignancy of one (IIa) or both (IIb) ovaries, with pelvic extension and ascites  III Malignancy involves one/both ovaries, intraperitoneal metastases outside pelvis  IV Involvement of one/both ovaries with metastases and histologically confirmedwww.themegallery.com extension to pleural cavity or liver 50
  51. 51. www.themegallery.com51
  52. 52.  Human leptin is a protein of 167 amino acids.  It is manufactured primarily in the adipocytes of white adipose tissue  and the level of circulating leptin is directly proportional to the total amount of fat in the body  Leptin acts on receptors in thewww.themegallery.com hypothalamus of the brain where it inhibits appetite  52
  53. 53.  Sedangkan faktor resiko tejadinya kanker ovarium adalah: # Obat kesuburan # Pernah menderita kanker payudara # Riwayat keluarga yang menderita kanker payudara dan/atau kanker ovarium # Riwayat keluarga yang menderita kanker kolon, paru-paru, prostat danwww.themegallery.com rahim 53
  54. 54.  Leptin activates the PI3- Kinase/AKTsignaling pathway  pathways have been implicated in playing crucial roles in regulating cell growth, cell proliferation prevention of apoptosis, which altogether attribute tumorigenesis [15].www.themegallery.com 54
  55. 55.  In conclusion, the present study has demonstrated that acquired expression of OPN may enable ovarian cancer cells to thrive under stress conditions by up-regulating the cellular level of HIF-1α protein and activating the PI3-K/Akt survival pathway.  These findings indicate that OPN iswww.themegallery.com closely associated with the progression of ovarian cancer, and OPN may be considered as a 55
  56. 56.  useful molecular target for the therapeutic development of ovarian cancer.www.themegallery.com 56
  57. 57.  The mechanisms underlying the antiapoptotic effect of PRL on ovarian carcinoma cells have not yet been clarified.  Ruffion et al.21 suggested that PRL inhibits apoptosis through stimulation of the phosphatidylinositol-3OH kinasewww.themegallery.com (PI3K)-Akt pathway 57
  58. 58.  Cohort studies: (1) fokusnya adalah spesifik populasi; (2) dilakukan secara berkala; (3)  populasi keadaan awal dan diikuti.www.themegallery.com 58
  59. 59. The immune-complex/ microsphere is then excited by the ****** laser. The bead specific emmission is quantified by the luminex and the bead identified.www.themegallery.com 59
  60. 60. www.themegallery.com60
  61. 61.  Gen p53 secara normal menyandi protein dengan berat molekul 53 kDa yang terlibat dalam kontrol pertumbuhan sel. Terjadinya mutasi pada gen ini dapat menyebabkan pertumbuhan sel menjadi tidak terkontrol (Gondhowiarjo, 2004)www.themegallery.com 61
  62. 62. www.themegallery.com62
  63. 63. www.themegallery.com63
  64. 64. Diagram Text Text Text Concept Text Text Textwww.themegallery.com Add Your Text 64
  65. 65. Diagram Add Your Text Add Your Text Add Your Text Add Your Text Add Your Text Add Your Textwww.themegallery.com Add Your Text Add Your Text 65
  66. 66. Diagram Add Your Text Add Your Text Add Your Titlewww.themegallery.com Add Your Text 66
  67. 67. Diagram Text Text Text ThemeGallery is ThemeGallery is ThemeGallery a Design Digital a Design Digital is a Design Content & Content & Digital Contentwww.themegallery.com Contents mall Contents mall & Contents mall developed by developed by developed by Guild Design Guild Design Guild Design Inc. Inc. Inc. 67
  68. 68. Diagram Tsssssex1t Tsssssex1t Te2wwwwxt Add Yourrrr T4444e3xt Title Tfffe4xtwww.themegallery.com 68
  69. 69. Diagram Add Your Text Text Text Text Title Textwww.themegallery.com Text Text 69
  70. 70. Diagram 1 2 3 ThemeGallery is a ThemeGallery is a ThemeGallery is a Design Digital Design Digital Design Digital Content & Contents Content & Contents Content & Contents mall developed by mall developed by mall developed by Guild Design Inc. Guild Design Inc. Guild Design Inc.www.themegallery.com 70
  71. 71. t Tex ur Yo ext u rT Yo 2004 tDiagram Tex ur Yo T ext ur Yo 2003 71 t Tex ur t Yo Tex ur Yo 2002 Tex t ur t Yo Tex ur Yo 2001 www.themegallery.com
  72. 72. Diagram ThemeGallery is a Design Digital Title Content & Contents mall developed by Guild Design Inc. ThemeGallery is a Design Digital Title Content & Contents mall developed by Guild Design Inc.www.themegallery.com ThemeGallery is a Design Digital Title Content & Contents mall developed by Guild Design Inc. 72
  73. 73. Block Diagram TEXT TEXT TEXT TEXT TEXT TEXT TEXT TEXTwww.themegallery.com 73
  74. 74. Table Title Title Title Title Title Title O O O O O Title O O O O O Title O O O O O Title O O O O O Title O O O O Owww.themegallery.com Title O X O X O 74
  75. 75. 3-D Pie Chart Text2 Text3 Text1 Text4www.themegallery.com Text5 75
  76. 76. Block Diagram Add Your Text Add Your Textwww.themegallery.com concept Concept Concept Concept 76
  77. 77. LOGO www.themegallery.com 77

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