AUTONOMIC NERVOUS SYSTEM organization and functions
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%
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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
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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)
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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
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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
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dlm 5 th terakhir setelah pangambilan
- Sedang menjalani sampel
kemoterapi -Merokok (-) & terapi
hormon (-)
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8. 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
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9. Statistik
ROC Logistic regression model
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10. 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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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
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meningkat, sdgkan leptin, IGF-II menurun
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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%
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15
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
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- 362 kontrol sehat 2 misclassified
156 Ca.ovarium 5 misclassified
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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
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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
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tinggi
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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
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training dan test set
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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
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26
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
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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
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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
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
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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
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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
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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
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cytokine production, as well as
promoting cell survival by regulating
apoptosis
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34. OPN is an important anti-apoptotic
factor in many circumstances.
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34
35. Osteopontin is biosynthesized by a
variety of tissue types including
fibroblasts[9] preosteoblasts,
osteoblasts, osteocytes, odontoblasts
,
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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
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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
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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
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roles in the promotion of
cell proliferation and the inhibition of
cell death (apoptosis)
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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.
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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
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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
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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.
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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
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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.
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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
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implicated in insensitivity of cancer
tumors to insulin and IGF1, in
calorie restriction.[3][4]
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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
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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
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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
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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
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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
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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].
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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
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closely associated with the
progression of ovarian cancer, and
OPN may be considered as a
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56. useful molecular target for the
therapeutic development of ovarian
cancer.
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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
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(PI3K)-Akt pathway
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58. Cohort studies: (1) fokusnya adalah
spesifik populasi; (2) dilakukan
secara berkala; (3)
populasi keadaan awal dan diikuti.
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59. 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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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)
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