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         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
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%
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                       Tes dgn 4 biomarker memberikan sensitivitas 95%, spesifisitas 94%



                                                         2
Tujuan Penelitian




                       Mengevaluasi panel biomarker dan
                       penggunaan alternatif platform untuk
                       meningkatkan sensitivitas & spesifisitas



                       Deteksi dini Ca. ovarium
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                                           3
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)
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                                               4
- Diagnosis Ca ovarium ditentukan berdsrkan :
                         clinical, surgical, histologic, dan pathologic pd
                         Gynecologic Oncology Clinic at the Yale New
                          Haven Hospital
                       - Informed consent untuk semua partisipan
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                                                5
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 bln
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                         dlm 5 th terakhir          setelah pangambilan
                       - Sedang menjalani           sampel
                         kemoterapi                -Merokok (-) & terapi
                                                     hormon (-)

                                               6
Sampel
                            Serum disimpan – 80°C



                            Dianalisis dgn ELISA dan Multiplex analysis



                            Multiplex analysis
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                            1. Leptin, Prolactin, MIF (Macrofage Inhibitory
                                Factor), Osteopontin, CA 125
                            2. IGF-II (Insulin-like growth factor II)

                                                 7
Multiplex study design
                                                        535 sampel



                          Training set (294)                                  Test set (224)




                       Kontrol (181)     Sampel (113)                Kontrol (181)      Sampel (43)
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                                                         17 Benign
                                                          disease




                                                             8
Statistik
                       ROC               Logistic regression model
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                                    9
Hasil
                       Evaluasi ELISA dan multiplex platform
                        - membandingkan prolactin, leptin, OPN, IGF II
                          pd Elisa & multiplex  sensitivitas (95%) dan
                          spesifisitas (94%) yg sama
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                                               10
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11
                            Tabel 1
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 125
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                          meningkat, sdgkan leptin, IGF-II menurun



                                                12
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                            Gbr. 1




13
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                            Gbr. 2




14
14
 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%
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                                                15
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                            Gbr. 3




16

                       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 set
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                         - 362 kontrol sehat 2 misclassified
                           156 Ca.ovarium  5 misclassified

                                                17
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                            Gbr. 4




18
18
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                            Gbr. 5




19
19
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20
                            Tabel. 2
- 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:
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                         granulosa cell carcinoma, undifferentiated
                         carcinoma, papillary serous carcinoma


                                                21
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                            Gbr. 6




22
22
 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 model
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                                                 23
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 & spesifisitas
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                         tinggi



                                                 24
 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 cohort
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                         training dan test set


                                               25
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. ovarium
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                                              26
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27
                            TERIMA KASIH
 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 Urine
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                                                  28
 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 the
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                         disease process and thus enable the
                         development of tools to help in treatment
                         as well as in detection and prevention.

                                               29
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 body
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                        Leptin promotes angiogenesis by
                         increasing
                         vascular endothelial growth factor
                         (VEGF) levels       30
Prolactin

                        Prolactin (PRL) or Luteotropic
                         hormone (LTH) is a peptide hormone
                        primarily associated with lactation
                        Increased serum concentrations of
                         prolactin during pregnancy
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                                          31
 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
                         system
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                                           32
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 and
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                         cytokine production, as well as
                         promoting cell survival by regulating
                         apoptosis

                                           33
 OPN is an important anti-apoptotic
                         factor in many circumstances.
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                                          34
 Osteopontin is biosynthesized by a
                        variety of tissue types including
                        fibroblasts[9] preosteoblasts,
                        osteoblasts, osteocytes, odontoblasts
                        ,
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                                          35
 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 to
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                        a small positive correlation between
                        MIF production and metastatic
                        potential in speculative models of
                        cancer
                                          36
 MIF plays a role in the regulation of
                        macrophage function in host defense
                        through the suppression of anti-
                        inflammatory effects of
                        glucocorticoids
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                                           37
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 play
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                        roles in the promotion of
                        cell proliferation and the inhibition of
                        cell death (apoptosis)

                                           38
 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.
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                                              39
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 of
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                         cancers.[4]


                                          40
 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
                        cancer
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                                           41
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42
 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.
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                                            43
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 lower
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                        risk of ovarian cancer than women who have no
                        children


                                              44
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.
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                                            45
 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) is
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                        implicated in insensitivity of cancer
                        tumors to insulin and IGF1, in
                        calorie restriction.[3][4]
                                          46
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47
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 powder
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                                           48
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 cavity
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                                                  49
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 confirmed
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                         extension to pleural cavity or liver




                                                   50
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51
 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 the
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                         hypothalamus of the brain where it
                         inhibits appetite
                       
                                            52
 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 dan
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                        rahim


                                         53
 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].
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                                                 54
 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 is
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                         closely associated with the
                         progression of ovarian cancer, and
                         OPN may be considered as a
                                          55
 useful molecular target for the
                        therapeutic development of ovarian
                        cancer.
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                                         56
 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 kinase
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                        (PI3K)-Akt pathway



                                          57
 Cohort studies: (1) fokusnya adalah
                         spesifik populasi; (2) dilakukan
                         secara berkala; (3)
                        populasi keadaan awal dan diikuti.
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                                          58
The immune-complex/
                            microsphere is then excited
                            by the ****** laser. The bead
                            specific emmission is
                            quantified by the luminex
                            and the bead identified.
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                       59
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60
 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)
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                                         61
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LOGO




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                              77

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Jurnal imun 3

  • 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. 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. Tujuan Penelitian Mengevaluasi panel biomarker dan penggunaan alternatif platform untuk meningkatkan sensitivitas & spesifisitas Deteksi dini Ca. ovarium www.themegallery.com 3
  • 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. - Diagnosis Ca ovarium ditentukan berdsrkan : clinical, surgical, histologic, dan pathologic pd Gynecologic Oncology Clinic at the Yale New Haven Hospital - Informed consent untuk semua partisipan www.themegallery.com 5
  • 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 bln www.themegallery.com dlm 5 th terakhir setelah pangambilan - Sedang menjalani sampel kemoterapi -Merokok (-) & terapi hormon (-) 6
  • 7. Sampel Serum disimpan – 80°C Dianalisis dgn ELISA dan Multiplex analysis Multiplex analysis www.themegallery.com 1. Leptin, Prolactin, MIF (Macrofage Inhibitory Factor), Osteopontin, CA 125 2. IGF-II (Insulin-like growth factor II) 7
  • 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. Statistik ROC Logistic regression model www.themegallery.com 9
  • 10. Hasil Evaluasi ELISA dan multiplex platform - membandingkan prolactin, leptin, OPN, IGF II pd Elisa & multiplex  sensitivitas (95%) dan spesifisitas (94%) yg sama www.themegallery.com 10
  • 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 125 www.themegallery.com meningkat, sdgkan leptin, IGF-II menurun 12
  • 13. www.themegallery.com Gbr. 1 13
  • 14. www.themegallery.com Gbr. 2 14 14
  • 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. www.themegallery.com Gbr. 3 16
  • 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 set www.themegallery.com - 362 kontrol sehat 2 misclassified 156 Ca.ovarium  5 misclassified 17
  • 18. www.themegallery.com Gbr. 4 18 18
  • 19. www.themegallery.com Gbr. 5 19 19
  • 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. www.themegallery.com Gbr. 6 22 22
  • 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 model www.themegallery.com 23
  • 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 & spesifisitas www.themegallery.com tinggi 24
  • 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 cohort www.themegallery.com training dan test set 25
  • 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. ovarium www.themegallery.com 26
  • 27. www.themegallery.com 27 TERIMA KASIH
  • 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 Urine www.themegallery.com 28
  • 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 the www.themegallery.com disease process and thus enable the development of tools to help in treatment as well as in detection and prevention. 29
  • 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 body www.themegallery.com  Leptin promotes angiogenesis by increasing vascular endothelial growth factor (VEGF) levels 30
  • 31. Prolactin  Prolactin (PRL) or Luteotropic hormone (LTH) is a peptide hormone  primarily associated with lactation  Increased serum concentrations of prolactin during pregnancy www.themegallery.com 31
  • 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 system www.themegallery.com 32
  • 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 and www.themegallery.com cytokine production, as well as promoting cell survival by regulating apoptosis 33
  • 34.  OPN is an important anti-apoptotic factor in many circumstances. www.themegallery.com 34
  • 35.  Osteopontin is biosynthesized by a variety of tissue types including fibroblasts[9] preosteoblasts, osteoblasts, osteocytes, odontoblasts , www.themegallery.com 35
  • 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 to www.themegallery.com a small positive correlation between MIF production and metastatic potential in speculative models of cancer 36
  • 37.  MIF plays a role in the regulation of macrophage function in host defense through the suppression of anti- inflammatory effects of glucocorticoids www.themegallery.com 37
  • 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 play www.themegallery.com roles in the promotion of cell proliferation and the inhibition of cell death (apoptosis) 38
  • 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. 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 of www.themegallery.com cancers.[4] 40
  • 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 cancer www.themegallery.com 41
  • 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. 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 lower www.themegallery.com risk of ovarian cancer than women who have no children 44
  • 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.  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) is www.themegallery.com implicated in insensitivity of cancer tumors to insulin and IGF1, in calorie restriction.[3][4] 46
  • 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 powder www.themegallery.com 48
  • 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 cavity www.themegallery.com 49
  • 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 confirmed www.themegallery.com extension to pleural cavity or liver 50
  • 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 the www.themegallery.com hypothalamus of the brain where it inhibits appetite  52
  • 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 dan www.themegallery.com rahim 53
  • 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.  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 is www.themegallery.com closely associated with the progression of ovarian cancer, and OPN may be considered as a 55
  • 56.  useful molecular target for the therapeutic development of ovarian cancer. www.themegallery.com 56
  • 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 kinase www.themegallery.com (PI3K)-Akt pathway 57
  • 58.  Cohort studies: (1) fokusnya adalah spesifik populasi; (2) dilakukan secara berkala; (3)  populasi keadaan awal dan diikuti. www.themegallery.com 58
  • 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
  • 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
  • 64. Diagram Text Text Text Concept Text Text Text www.themegallery.com Add Your Text 64
  • 65. Diagram Add Your Text Add Your Text Add Your Text Add Your Text Add Your Text Add Your Text www.themegallery.com Add Your Text Add Your Text 65
  • 66. Diagram Add Your Text Add Your Text Add Your Title www.themegallery.com Add Your Text 66
  • 67. Diagram Text Text Text ThemeGallery is ThemeGallery is ThemeGallery a Design Digital a Design Digital is a Design Content & Content & Digital Content www.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. Diagram Tsssssex1t Tsssssex1t Te2wwwwxt Add Yourrrr T4444e3xt Title Tfffe4xt www.themegallery.com 68
  • 69. Diagram Add Your Text Text Text Text Title Text www.themegallery.com Text Text 69
  • 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. t Tex ur Yo ext u rT Yo 2004 t Diagram 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. 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. Block Diagram TEXT TEXT TEXT TEXT TEXT TEXT TEXT TEXT www.themegallery.com 73
  • 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 O www.themegallery.com Title O X O X O 74
  • 75. 3-D Pie Chart Text2 Text3 Text1 Text4 www.themegallery.com Text5 75
  • 76. Block Diagram Add Your Text Add Your Text www.themegallery.com concept Concept Concept Concept 76
  • 77. LOGO www.themegallery.com 77