007 kuliah keganasan hematologi 002
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Oleh :SURADI MARYONO Sp.PD -KHOM
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O ER IE&KONSEP BIOLOGIEPIDEMIOLOGI/ INSIDENSI
PATOGENESISDIAGNOSIS :
- GEJALA DAN TANDA KLINIS
- LABORATORIUM : HEMATOLOGI ! SITOKIMIA! SITOGENETIKA. - BMP )BONE MARRO& PUNCTION/ BMA ! BMB )BONE
MARRO& BIOPTIE :SITOMORFOLOGI! IMMUNOPHENOTYPING.
PENATALAKSANAANPROGNOSIS
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INSIDENSI :•LEULKEMIA AKUT DPT TERJADI PD SEMUA UMUR :-ACUTE LYMPHOBLASTIC LEUKEMIA ) ALL ANAK
+ep,l,h h e 0121h-ACUTE MYELOBLASTIC LEUKEMIA ) AML DE&ASA le03h4153 67 h
* LEUKEMIA KRONIS BIASANYA PADA DE&ASA :
- CLL )CHRONIC LYMPHOCYTIC LEUKEMIA JARANGPADA ANAK! PADA ORANG DE&ASA 8 '7 TAHUN
- CML )CHRONIC MYELOBLASTIC LEUKEMIA PADADE&ASA! PUNCAK PD UMUR 67-(7 TAHUN.
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* COMPARISON ACUTE AND CHRONIC LEUKEMIAS:
ACUTE CHRONIC
AGE ALL AGES USUALLY ADULTS
CLINICAL ONSET MENDADAK PERLAHAN
KEMAMPUAN BERTAHAN 9 MO. OR LESS $-9 YEARS
LEUKEMIC CELLS IMMATURE 67; BLASTS MORE MATURE CELL )TTP ADA
MUDAANEMIA BERAT RINGAN
THROMBOCYTOPENIA BERAT RINGAN
&BC COUNT ARIABLE INCREASED
LYMPHADENOPATHY RINGAN SANGAT BESAR
SPLENOMEGALY RINGAN SANGAT BESAR
ARIABLE )MENINGKAT TP TIDAK CUKUO TINGGI
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MENURUT PERJALANAN PENYAKIT :
LEUKEMIA DIKELOMPOKAN $ GRUP UTAMA : - AKUT : - MUNCULNYA MENDADAK - PERJALANANNYA SANGAT AGRESIF. - TERDIRI SEL BERDEFERENSIASI
JELEK DENGAN TIMBUNAN SEL BLAST)SEL MUDA .- KRONIS : - MUNCULNYA PERLAHAN
- KURANG AGRESIF - DIDOMINASI SEL DE&ASA! TDPT
BBRP SEL MUDA )LIMFOBLAST /MIELOBLAST .
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Types of Leukemia * chronic (worse slowly) or acute ( worse quickly): * Chronic leukemia : - Early in the disease, - Abnormal blood cells can still do their work
- May not have any symptoms, - gets worse slowly
* Acute leukemia : - Blood cells are very abnormal. - They cannot carry out their normal work.- Number o abnormal cells increases rapidly . - !orsens "uickly.
#Types leukemia are also grouped by, type o white blood cell that is a ected. - lymphoid cells lymphocytic leukemia . - myeloid cells myeloid leukemia or myelogenous leukemia.
# There are four common types$ - Chronic lymphocytic leukemia (chronic lymphoblastic leukemia, CLL ), - About %,&&& new cases o leukemia each year.
- Most o ten, people diagnosed over age ''. - (t almost never a ects children. - Chronic myeloid leukemia (chronic myelogenous leukemia, CML ).
- Accounts or about ),)&& new cases each year. - (t a ects mainly adults.
- Acute lymphocytic leukemia (acute lymphoblastic leukemia, ALL ). - Accounts about 3,800 new cases each year.- *ommon young children. - - (t also small a ects adults.
- Acute myeloid leukemia (acute myelogenous leukemia A!L). - Accounts or about +&, && new cases each year. - A ects both adults and children. - Hairy cell leukemia is a rare type o chronic leukemia. - Together, these rare leukemias account or about ', && new cases o leukemia each year.
http://www.cancer.gov/dictionary/db_alpha.aspx?expand=chttp://www.cancer.gov/dictionary/db_alpha.aspx?expand=c
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Demographics of Leukemia
Patients (2001 Data) A++/
*/
AM0+/
*M+'/
others+%/
Total 1eported *ases 2 0+,'&&Sources from Leukemia, Lyphoma, Myeloma Facts 2001
CLL=ChronicLymphocytic
ALL=AcuteLymphocytic
C L=Chronic
y!ogenousA L=Acute
y!ogenous
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EPIDEMIOLOGI :Le, e
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PATOGENESIS
Pe5,01h1
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ETIOLOGI: - PENEYEBAB PASTI! BELUM JELAS ADA BBRP FAKTORPREDISPOSISI:
"FAKTOR HOST :
- I 4 4 > pe . He5343 e5 ! e 1431 le, e 5=3l/10 =5
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#$%&C' & *Define acute !eukemiaC!assify !eukemia+n,erstan, the pathogenesis
+n,erstan, the pathophysio!ogyA !e to !ist ,o.n the !a oratory in/estigations re uire, for,iagnosis+n,erstan, the asic management of !eukemia patients
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ACUTE LEUKAEMIA* De 3 e : he e5=>e =,+ >5=,p = 1 43+=54e5+
2h3 h 3+ h151 e53+e4 0 , = 5=lle4 l= 1l 1 41 ,
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SIGNIFICANCE OF ADULT ACUTE
LEUKEMIA:A he3 ,5>eU+,1ll 1 1l 23 h3 2ee + =
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C1,+e+ = 1 , e le, e
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# "e#elop as a result of a $enetic alteration within sin$lecell in the %one marrow
a ). Epidemiological e idence : &. 'ere itary actors - anconi s anaemia
- "own s syn rome - Ata+ia telan$iectasia ,. a iation Chemicals an "ru$s
. /irus relate Leukemias - etro#irus :- 'TL/ & 0 E1/b). Molecular E idence
! "ncogenes : - 2ene that co e for proteins in#ol#e in cell
proliferation or ifferentiation ! #umour $uppressor %enes &
- Chan$es within onco$ene or suppressor $enesare necessary to cause mali$nanttransformation.
- 3nco$ene can %e acti#ate %y : 3 chromosomal translocation
3point mutations 3 inacti#ation* 4n $eneral se#eral $enes ha#e to %e altere to effectneoplastic transformation.
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Patogenesis• Perubahan molekul DNA sel
hemopoetik
• Perubahan gen normal tertentu• Transformasi maligna
• Proliferasi klonal abnormal sel induk/progenitor
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METABOLIC IMBALANCE : - D,e = 43+e1+e =5 5e1
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PATHOPHYSIOLOGY
A , e le, e
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B. I 1+3= = 3 1l =5>1 + - 15 1 =543 > = +,0 pe* H pe5le, = =+3+
- 1,+e 3 5e1+e 3 0l==4 3+ =+3 - P5e43+p=+e = 1 3 =le : 0513 ! l, >! e e+ - I ,43 3=,+ ,+e4 = p1 e4 ell 51 + ,+3= p5e 3p3 1 e h pe5 3+ =+* Le, =+ 1 3 ,e 3 1+ ,l15 + + e< =5
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C. S + e
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"#lasi$kasi %&A'(A!)• & * + tanpa diferensiasi
'D,+imunologik)
• & - + tanpa diferensaisi 'D,.sitokimiadan
imunologik• & + dengan diferensiasi
• & 0 + %eukemia PromielositikAkut
• & 1 + %eukemia &ielomonositik Akut• & 2 + %eukemia &onositik Akut
• & 3 + 4ritroleukemia
• & 5 + %eukemia &egakariositik Akut" #lasi$kasi
%%A
• %- + morfologi sel relatif homogen
bentuksel kecil sitoplasma sedikitnukleoli
kecil/ tidak 6elas
• % + morfologi sel relatif heterogen
sel besar sitoplasma lebih banyak
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4ematopoieticstem cell
Neutrophils
5osinophils
Basophils
Monocytes
6latelets
1ed cells
Myeloidprogenitor
ymphoidprogenitor
B-lymphocytesB-lymphocytes
T-lymphocytes
6lasmacells
naïve
A A
AM AM
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LLA : KlasifkasiImunologik
• Null ALL
• Common ALL• T ALL
•B ALL
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Classifcation oleukemias Acute *hronicMyeloidorigin
ymphoidorigin
Acute Myeloideukemia 7AM 8
7 M+ M%8
Acute ymphoblastic
eukemia 7A 87T *5 ,B *5 ,N9*5 8 7 +, , 08
Chronic !yeloi Leukemia
(C!L)
Chronic Lymphocytic
Leukemia (CLL)
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DIAGNOSIS :
- GEJALA DAN TANDA KLINIS
- LABORATORIUM
- BMP )BONE MARRO& PUNCTION/ BONE
MARRO& ASPIRATION
- BMB )BONE MARRO& BIOPTIE .
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" GEJALA KLINIS:
- LEMAH BADAN! MUDAH CAPAI! - PANAS! - PEDARAHAN
- ORGANOMEGALI
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Tanda khas akibat in$ltrasiorgan+
• Nyeri tulang ' terutama pada anak )• %imfadenopati super$sial
hepatomegalisplenomegali '%%A).
• 8ipertro$ dan in$ltrasi gingi7a kulit'& 1 dan & 2).
• 9indroma meningeal + nyeri kepalamualtumpah penglihatan kabur diplopiaedema papil dan perdarahan retina:sering ditemukan pada %%A+ &1 &2 .
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INFILTRATION OF TISSUES/ORGANS :E l15>e
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LABORATORIUM :
- H0! AE! HCT TURUN ANEMIA- AL MENINGKAT LEUKOSTASIS ! DIDOMINASI SEL MUDA)BLAST MIEOBLAST! LIMFOBLAST
- AT MENURUN TROMBOSITOPENIA- SINDROMA TUMOR LISIS HIPERURISEMIA! GAGAL GINJAL!
ASIDOSIS! HIPOKALSEMIA
- DIC PPT 1PTT. D-DIMER FIBRINOGEN
* GDT ) GAMBARAN DARAH TEPI : - ANEMIA/ BISITOPENIA / PANSITOPENIA
- DIKETEMUKAN SEL ATIPIK SEL GANAS .
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Pemeriksaan %aboratorium• Anemia (no mok om no mosite !
• "itung Leukosit : menu un/no mal/meningkat#ingga $%%.%%%/mm &
• T om'osito enia• )a a# te i : sel 'last (*!+ aue o,s+
omielosit+neut ofl ag anule + sel seu,o elge +e it o'last,alam -umla# 'an ak (M 5 !• umsum tulang : #i e selula + sel 'last (5%0152!.
3a,a LLA as i asi sulit (se a'ut etikulin !. 3a,a M 1 k#as : ansito eni men,a,ak ,anf' osis sumsum tulang. 3eme iksaan aal #emostasis : )IC (M &!• Leukemia otak : L3 tekanan cai an otak
meningkat ,an mengan,ung sel leukemia
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0
• Kimia klinik + peningkatan as.;rat%D8. Tes faal hati dan gin6al dilakukan
sebagai persiapan pemberiansitostatika.• oto 6 + proses lisis tulang '%%A
anak) massa mediastinum' pembesara timus/ kel.limfemediastinum) in$ltrasi paru'infeksi/sel leukemia)
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SITOKIMIA : * ILMU BIOKIMIA : - IDENTIFIKASI - LOKASI - PERANAN SENYA&A KIMIA DALAM TUBUH - PROTEIN! KH! LEMAK! ASAM NUKLEAT
REAKSI EN IMATIS . MISAL: I4e ..E . FOSFATASE ASAM DLM LYSOSOME P0S. )MIK. :
:G,>+. FOSFAT BERASAL DARI SUBTRAT CYTIDINE MONOFOSFAT
P0-FOSFAT P0-SULFAT. )KRISYAL COKLAT KEHITAMAN .
Re1 +3 E 3
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PEMERIKSAAN SITOKIMIA SECARA EN IMATIS:
- MYELO PEROKSIDASE - SUDAN BLACK - ESTERASE :
- SPESIFIK CAE )CHLOR ACETAT ESTERASE- NON SPESIFIK - ANAE ) 1-NAFHTHOL ACETAT ESTERASE- ANBE ) 1-NAFHTHOL BUTIRIC ACID
- PAS ) PERIODIC ACID SCHIFT - MURAMIDASE LYSO YME
- T 4 T ) Te51 +,0 3pe 1.! LNH )L < =
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f LE56E!4A
A!L ! &! ,! ! 7
! 8! 9!
ALL
;ET 3 4L
!3;3
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"asil eme iksaan itokimia (Cal7e t Ma !(8!.
'asil pemeriksaan
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SITO MORFOLOGI
Bone !arrow
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No mal Bone Ma o9)iagnostics 0 C;T<Mo #olog
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MYELOID MATURATION:myeloblast promyelocyte myelocyte metamyelocyte band neutrophil
!AT5 AT43;!AT5 AT43;
Adapted and modi ied rom 9 >a website
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A +. A . A 0.
A . .. .
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A!L
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A!L
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Auer rods in A&%
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Diagnostics <
ImmunophenotypingIdenti$cation of cell surface proteins byreacti7ity with monoclonal antibodies ofknown speci$city=ommon Diagnostic pro$les <AML 0 C) &*+ C)&&*+* C)&4+ * C) 4 *7ecALL 0 C) % * 7e+ T,T*7eT0ALL 0 C)&+ C)1+ T,T *7e
B0ALL 0 C) %+ C) =+ su ace Ig *7eCLL 0 C)5+ C) =+ C)$&+ 9eak su ace Ig *7e
"A IL3>M> IK AAN CI 3A)A AML ( AB M< . )AN
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C;TB L C", ?- ?- ?-!C C"& -
!o& 36!& C"&&% - ?- -
Leu!& C"&8 - ?- ?-
!o, 5C'!& C"&7 - - - -
2lycophurinA
- - - - - -
2=44%?44a C"w7& - - - - - -2= 4% C"w7, - - - - - -
/on4L41 A;". . - - - - - - -
Di g ti 0
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Diagnostics 0a=ommon #aryotype Abnormalities
AML 0 t'>? -) m better prognosis t'-2?-5) m0 better prognosis in7 -3 m1 better prognosis
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&';&0;+'&
&embedakan %&Adengan %%A-.9ebagian besar kasus denan gambaranklinik
morfologi sel 'pengecatan rutin) sudah dapat
membeda
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6. LLA.: - TERUTAMA ANAK- ANAK - UKURAN SEL CENDERUNG HOMOGEN )KECUALI L6 ! LEBIH
KECIL DARI MIELOBLAST! SITOPLASMA SEDIKIT
- NUKLEUS DENGAN KROMATIN AGAK KASAR - BENTUK NUKLEUSNYA RELATIF BULAT LONJONG! NUKLEOLITAK JELAS.
- DALAM SITOPLASMA TIDAK TERDAPAT GRANULAE - SITOPLASMA LEBIH KEBIRUAN
- TIDAK ADA AUER ROD
- TIDAK TERDAPAT PSEUDO PELGER HUET- SERING TERDAPAT LIMPADENOPATIA DAN ORGANOMEGALILMA .:
- TERUTAMA DE&ASA - UKURAN SEL DAN NUKLEUS KURANG HOMOGEN - NUKLEUS DENGAN KROMATIN HALUS
- NUKLEOLI PROMINEN! KADANG " - BENTUK NULKEUS KADANG KURANG BULAT / HEKSAGONAL - SITOPLASMA TIDAK TERDAPAT GRANULAE DAN AUER ROD
- KADANG TERDAPAT SEL PSEUDO PELGER HUET- KADANG TERDAPAT GRANULOSIT LEBIH DE&ASA
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In7estigations
ALL(L m #o'last!
Blast si e +smallC to lasm + 9cantC# omatin + DenseNucleoli
+IndistinctAue 0 o,s + Ne7erpresent
AML (M elo'last !%arge
&oderate(ine %acyProminentPresent in 2*B
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T5e1
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3engelolaan LeukemiaAkut• Terapi suportif terhadap kegagalan ss.tulang.• #emoterapi + berbeda antara %&A dan %%A
baik mengenai regimen maupun lama
pengobatan.
• #emoterapi %&A+ induksi remisi konsolidasiintensi$kasi 'T9T).
• #emoterapi %%A+ induksi remisi konsolidasipencegahan leukemissp.maintenance/intensi$kasi
'T9T)
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A!L :6rotocol remission induction is treatment $- cytosine arabinoside and an anthracycline .- A typical protocol $ # Cytosine ara%inosi e &@@ - ,@@ m$?m, aily
for ays an* "aunoru%icin 7@ - 9@ m$?m, or 4 aru%icin &, - & m$?m , for the first ays.
# 4f after - &@ ays a repeated bone marrow
biopsy shows residual leukemic blasts, theregimen should be repeated .
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A - Treatment
?tabilise - eucostasis , 4aemorrhage, ?epsis6 i meningism
6sychological support4ydration @ allopurinol;rasburicase1B* @ platelet support
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A - ?peci ic treatment(nduction=hase & ays & D ,
aunorubicin @ vincristine days +, ,+'6rednisone days +-
Asparaginase days+%-: mtC (T @ Bone marrow d )8
=hase , starts on day D 7or wbc E0.&8*yclophosphamide days +,+' @ D*ytosine days +-), -++,+'-+ , - '
mp od days +-(ntrathecal MTF days -+,%,+), +
?pecial considerations G thrombophilia, 6*6,ungal in ection
Te a i
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Te a iu o ti • 3emasangan katete 7.sent al ("ickman!+ masuk7ena ca7a su e io melalui salu an 'a9a# kulit
,a,a.Memu,a#kan em'e ian kemote a i+ o,uk
,a a#+ anti'iotika+ nut isi a ente al+engam'ilan sam el ,a a#.
• 3encega#an mual ,an munta# aki'at kemote a i:metoclo ami,e+ 'en o,ia e in+ antagonis
ese to 50"T & selekti(on,ansent on+k t il+na7o'an+,ll!
• Ko eksi anemia: t ans usi e it osit (3 C!
• Perdarahan+ bisa disebabkan oleh trombositopenia/DI=. Transfusi trombosit diberikan bila hitung trom<bosit C *.***/mm 0 atau terdapat perdarahanringan meskipun trombosit masih > *.***/mm 0.!ila ter
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• 3e ,a a#an: 'isa ,ise'a'kan ole#t om'osito enia / )IC. T ans usi t om'osit,i'e ikan 'ila #itung t om0'osit $%.%%%/mm &+atau te ,a at e ,a a#an ingan meski unt om'osit masi# $%.%%%/mm &. Bila te 0,a at )ICe lu t ans usi es# o en 3lasma( 3!.
• Neut o enia me u akan esiko te -a,in a in eksite utama 'ila #itung neut ofl $%%/mm &. 3a,a
en0,e ita Leukemia Akut+ neut ofl 'isa menca ai
% selama $ minggu.• &ikroorganisme penyebab infeksi biasanya berasaldari Eora komensal bakteri gram ' * )staphylococcus /streptococcus gram ' )+Pseudomonas 4
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i us : e es ooste + e es sim leD• Eamu : Can,i,a+ As e gilosis.• 3 oto oa : ToDo lasma gon,ii ('ila
neut o enia 'e langsung lama+ lim o enia+em'e ian anti0 'iotika s ekt um luas!.
PencegahanInfeksi• Isolasi penderita 're7erse barriereisolation)$lter udara.
• 9terilisasi usus +=otrimoksasole Neomycine=olistine Fuinolone Anti 6amur'(lucona oleAmphotericine !).
• #ultur dari urine feses sputum tengorok
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