bİyolojİk belİrteÇlerİn prognostİk deĞerİ

BYOLOJK BELRTELERN PROGNOSTK DEERProf. Dr. Abdurrahman ENYTDicle niversitesi Tp FakltesiGs Hast. ADDiyarbakr-TRKYE

MAYIS-2009

EYLL-2009

KASIM- 2009

KASIM 2009

MART-2010

NSAN-2010 (Preop)

Mezotelyomada cerrahi dahil effektif bir tedavi yntemi yoktur. Hastaln erkensaptanmasnn sonucu deitireceine bir bulgu yoktur.Sherpereel A, et al. Curr Opin Pulm Med 2007MMl hastalarda hastaln erken tehis edilmesi durumunda tedaviye daha iyi cevap alnabilecei ynnde bulgular mevcuttur.

Robinson BWS. Lung Cancer 2005

Baas P. Curr Opin Oncol 2003

Bhattacharya K. Mutation Research 2005

GRMezotelyoma fatal bir tmr olup Avrupa lkelerinde insidans gittike artmaktadrAsbest gelien lkelerde yaygn olarak kullanldndan gelecek dekatlarda major sorun oluturmaya devam edecektir.Avrupada insidans 20/milyon/yldr.Trkiyenin Gneydou Anadolu blgesinde yllk insidans 42.9/milyondur.

Senyigit A, et al. Respiration 2000 Sherpereel A, et al. Curr Opin Pulm Med 2007Scherpereel A. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J. 2010

Tanda torakoskopinin rol nedir?

Klinik ve radyolojik olarak mezotelyomadan phelenildii zaman torakoskopi en iyi tan metodudur.

ERS/ATS Task Force. Scherpereel A. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J. 2010

MEZOTELYAL MARKERLERMM insidans Finlandiya poplasyonuna gre asbestozis olgularnda 32 kat ve benign plevral hastalkta 5.5 kat daha yksektir. nceden asbest temasna maruz kalan milyonlarca insanda mezotelyoma gelime riski vardr. Gnmzde bu hastal nceden belirleyebilecek herhangi bir test yoktur. Hastaln gelitii kiilere ait bilgiler ve mezotelyomann lmcl olduuna dair basn bilgileri bir ok asbest iisinde stress oluturur. nceden hastal belirleyebilecek bir marker halk sal zerine byk bir etki oluturacaktr.

Sherpereel A, et al. Curr Opin Pulm Med 2007Pass HI, et al. Semin Thorac Cardiovasc Surg 2009

MEZOTELYAL MARKERLERMezotelyoma iin kullanlacak olan biomarkerin mezotelyomann tm subtiplerini saptayabilmesi, mezotelyomay benign plevral hastalk ve metastatik plevral malignensilerden (zellikle meme ve akcier kanseri) ayrt edebilmesi, tmr arln ve bylece tedaviye cevab belirleyebilmesi ve asbeste maruz kalan olgularda hastal nceden belirleyebilmesi gerekmektedir.Bir ok marker (hyalronik asit, Cyfra 21-1, TPA vs) nerilmesine karn klinik kullanm iin uygun bulunmamlardr. Mezotelyoma iim 3 potansiyel marker mezotelin, megakaryosit potansiye edici faktr ve osteopontindir.

Creaney F. J Thorac Oncol 2008Sherpereel A, et al. Curr Opin Pulm Med 2007

SOLUBL MEZOTELiN VEYA SOLUBL MEZOTELN RELATEDPEPTDLERMezotelin bir hcre yzey glikoproteini olup mezotelyal hcre iin ayrt edici bir markerdir. Mezotelin geni 4 ayr protein retir:megakaryocyte potentiating factor (MPF), mesothelin variant 1, mesothelin variant 2, Soluble mesothelin-related protein (SMRP).Mezotelin normal mezotelyal hcrelerce salnr ancak MM, pankreas ve over kanserlerinde de salnd gibi normal peritonda 49 kat yksek oranda saptanmtr.

Pass HI. Semin Thorac Cardiovasc Surg 2009

SMRPSMRP testi klinik olarak mevcuttur ve serum veya plevrada alld zaman diagnostik bir zgllk ve duyarllk salar.SMRPnin asbeste maruz kalan kiilerde mezotelyoma geliimini tahmin etmedeki rol bu markere kar olan ilgiyi artrmtr.

Sherpereel A, et al. Curr Opin Pulm Med 2007

SMRPBir tan arac olarakHastal izlemde bir ara olarakYksek riskli poplasyonda bir tarama arac olarak

SMRP:Tan arac olaraklk defa maliign mezotelyomal hastalarn serumlarnda SMRPyi Robinson ve ark. almlardr. Bu almada MMl 44 hastann 37sinde (% 84) SMRP konsantrasyonu yksekti.

SMRP ayrca akcier kanserinde (1/30), asbeste maruz kalmayanlarda (0/28) ve asbestli hastalarda (7/40) orannda ykselmiti.

Bu almada SMRPnin malign hastalarda asbeste maruz kalan ve kalmayan salkl bireylerde, farkl akcier ve plevrann benign ve malign durumlara gre ykseldii gsterilmitir.

SMRP seviyeleri tmr yaps ile korele idi. Epitelyal MPMde sarkomatoid MPMye gre SMRP seviyesi daha yksekti.

SMRP seviyesinin ayrca tedaviye cevap alnnca dt ve tmr progresyonu ile artt bildirilmitir.

Aratrmaclar ayrca asbeste maruz kalan bireylerde mezotelyomann erken dnemde saptanmas iin yararl olabileceini bildirmilerdir.

Robinson BWS, et al. Lancet 2003

SMRP:Tan arac olarak1. Salkl olgular, nceden asbeste maruz kalan ve hibir plevral hastal olmayan hastalar ile nceden asbeste maruz kalp benign plevral hastal olanlar MM ile karlatran bir almada SMRP cut-off deeri 0.55 nM/L olarak baz alndnda spesifisite ve sensitivite % 72 olarak saptanmtr.

2. En geni serili Kuzey Amerika SLMP almasnda Ortalama serum SMRP seviyesi akcier kanserine gre daha yksekti. Stage I MM vakalarnda SMRP seviyesi asbeste maruz kalanlara gre yksektiStage II-IV MM vakalarnda serum SMRP seviyeleri stage I MMya gre yksekti.Ayrca SMRP seviyeleri effzyonlara gre daha yksekti.


SMRP:Tan arac olarakMezotelyoma ve dier plevral hastalklara sahip kontrol gruplarndan alnan plevral mayi SMRP seviyeleri 2 geni serili almada deerlendirilmitir.

Dolamdaki SMRPnin plevral mezotelyomadan kaynaklandn ispatlayacak ekilde plevral mayi SMRP seviyeleri, serum SMRP seviyesinden daha yksekti. Plevral mayide SMRP sensitivite ve spesifisiteleri ok merkezli bir Fransz almasnda srasyla % 67 ve % 98, 234 hastalk bir Avustralya kohort almasnda % 67 ve 98 idi.Sherpereel A, et al. Curr Opin Pulm Med 2007

Pass HI, et al. Ann Thorac Surg 2008

Pass HI, et al. Ann Thorac Surg 2008Fig 1. Serum SMRP levels for groups studied. (Adeno adenocarcinoma; LCa lung carcinoma; MPM malignant pleural mesothelioma.)

Pass HI, et al. Ann Thorac Surg 2008Fig 2. Soluble mesothelin-related peptide (SMRP) level for differing malignant pleural mesothelioma (MPM) histologies.

Fig 3. SMRP levels based on the radiographic characteristics of age- and sex-matched normal controls, not exposed to asbestos compared with asbestos exposed controls.Pass HI, et al. Ann Thorac Surg 2008

Pass HI, et al. Ann Thorac Surg 2008Fig 5. SMRP levels for asbestos-exposed individuals and various malignant pleural mesothelioma (MPM) stages.

Pass HI, et al. Ann Thorac Surg 2008Fig 7. Pleural effusion serum SMRP levels for MPM, benign, and other malignancies.

SMRPSchneider, yeni tan konan MPMli hastalar (n:100), relaps gsteren MPMli hastalar (n:29), primer akcier kanseri (n:139) ve benign asbestozisli hastalarn (n:75) serum rneklerinde SMRPnin diagnostik ve prognostik deerini aratrmlardrSchneider J, et al. J Thorac Oncol 2008

Schneider J, et al. J Thorac Oncol 2008

FIGURE 1. SMRP concentrations in serum samples from patients with MPM in relation to tumor stages. There were no significant statistical differences between the individual stages.Schneider J, et al. J Thorac Oncol 2008

FIGURE 3. Box and Whisker plot of SMRP serum concentrations in untreated MPM (MPM/pre) compared with MPM at relapse/progression after an initial therapy (MPM/progressive disease) (p 0.001,two-sided Mann-Whitney U test). Horizontal line indicates the best statistical diagnostic cutoff (1.35 nM) (y axis in logarithmic scale).Schneider J, et al. J Thorac Oncol 2008

Schneider J, et al. J Thorac Oncol 2008THE PROGNOSTIC VALUE OF SMRP

SMRP:Hastalk izlem arac olarakSerum SMRP seviyeleri tmr bymesi ile paraleldir ve tedaviye cevab belirlemede yararl olabilir.Serum SRMP seviyeleri cerrahi evre ile paralellik gsterip rezeksiyon sonucu der ve progresyon ile artar. Bundan dolay serum SMRP seviyeleri cerrahi debulking ilemlerinin etkinliinin iyi bir markeri olabilir.Robinson BWS, et al. Lung Cancer 2005Sherpereel A, et al. Curr Opin Pulm Med 2007

SMRP:RSK GRUBUNDA TARAMA ARACI OLARAKRobinson ve ark. asbet maruziyeti olan 40 olgunun serumlarnda SMRP seviyelerini lmler ve Yedi olguda art saptayp 5 yl iinde bu olgularn nde mezotelyoma ve birinde akcier kanseri saptandn bildirmilerdir.Dier 33 olguda ise 8 yllk takipte mezotelyoma gelimemitir. Ylsek SMRP seviyeleri grlemeyen kk mezotelyoma odaklarnn varln ve dolays ile nceden klinik hastalk durumunu gsterebilir. Robinson BWS, et al. Lancet 2003

SMRPMezotelin biomarkeri mezotelyoma iin iyi bir serum markeridir. Artm bir mezotelin seviyesi malignensiyi ve zellikle mezotelyomay dndrr.Creaney F. J Thorac Oncol 2008

Luo L. Respiratory Medicie 2009

Figure 1 Forest plot of estimates of sensitivity and specificity for mesothelin assays in the diagnosis of malignant mesothelioma. The point estimates of sensitivity and specificity from each study are shown as solid circles. Error bars are 95% confidence intervals.Numbers indicate the reference numbers of studies cited in the reference list.Luo L. Respiratory Medicie 2009

SMRPA META-ANALZ ALIMA Mevcut meta-analiz almasnda yksek spesifisite 0.89 (95% CI 0.88-0.90) saptanmken sensitivite sadece 0.64 (95% CI 0.61-0.68) idi.SMRP MMy saptamada yararl olabilir Luo L., et al. Respiratory Medicie 2009Sonu: Serum SMRP lm mezotelyoma tehisinde nemlidir. SMRP sonular klinik bulgular ve konvansiyonel testlerle beraber yorumlanmaldr.

OSTEOPONTN

Osteopontin pluripotent extraselller hcre adezyon proteinidir ve immn yantta, kemik matrixinin ekillenmesinde ve kanser progresyonunda nemli rol oynar.Yksek OPN seviyeleri tmr invazyonu, progresyonu ve metastazlarnda saptanr.


OSTEOPONTNOsteopontin tberkloz ve birok malignitede (over, kolon, meme, prostat ve akcier kanserleri) salnr.Serum Osteopontin seviyeleri mezotelyomada asbeste maruz kalan salkl kiilerden daha yksektir. Ancak mezotelyomann metastatik plevral karsinom veya asbeste bal benign plevral hastalklardan ayrmnda daha az deerlidir Sherpereel A, et al. Curr Opin Pulm Med 2007

OSTEOPONTNOsteopontin mezotelyoma ve salkl ahslar ayrt etmede nemli ise de tek bana mezotelyoma tasnda kullanlamaz.Ayrca koroner arter hastal, interstisyel pnmoni dahil baz nonmalign, nonplevral efzyon ve dier benign pulmoner hastalklarlarda da serum deeri artar.Creaney F. J Thorac Oncol 2008

OSTEOPONTNMezotelyomada prognostik bir faktr olarak serum osteopontin seviyesinin deeriSerum osteopontin seviyesi survey ile ters orantldr ve yksek seviyeler birok kanserde (meme, prostat, kolon, pankreas zofagus ve akcier kanserleri) kt prognoz ve ileri evre ile ilintilidir. Sherpereel A, et al. Curr Opin Pulm Med 2007

MEGAKARYOCYTE POTENTIATING FACTORMPF baz mezotelyal hcreler ve pankreatik hcrelerce salnr. n vitro olarak megakaryosit koloni formasyonunu stimle eder.Serum MPF seviyeleri MPMli hastalarn % 91inde ykselmiti.MPF seviyeleri peritoneal mezotelyomal hastalarda cerrahi sonras normale dndnden tedaviye cevab takip etmede nemli olabilir.


Biomarker concentrations in serum. Biomarker concentrations were determined at least in duplicate by ELISA and individual patient values are plotted on the graph.A, MPF; B, osteopontin; and C, mesothelin.Creaney J. J Thorac Oncol 2008SMRP, OSTEOPONTIN AND MPF

DER SERUM MARKERLERMMda art gsteren dier markerler:Cytokeratin Fragment 19 (CYFRA 21-1)Cancer Antigen 125 (CA125), Hyaluronic acid.

Roe OD, et al. Lung Cancer 2008

DER SERUM MARKERLER HYALRONK ASTalmalar serum hyalronik asit seviyesinin MMl hastalarda yksek olduunu ve ayn yataki salkl gnlllerde veya nonmezotelyal orjinli malign tmrlerden nemli derecede daha yksek olduunu gsterdi.Asbestozisli hastalarda serum hyaluronan yksek deildi.Dier almalar hastaln klinik seyri esnasnda serum hyaluronat seviyesinin sadece kanserin ileri evresinde arttn, dolays ile hastaln erken dnemde saptanmasnda daha az deere sahip olduunu bildirmilerdir.


DER SERUM MARKERLER HYALRONK ASTHyalronik asit mezotelyomada olas bir diagnostik marker olarak nerilmi ise de yksek serum seviyeleri sadece ileri evre mezotelyomada tanmlanmtr. Ayrca mezotelyomallarn nemli bir ksm HA salmaz. Ancak yksek plevral HA seviyesi (100 g/Lden yksek deerler) MPM tans iin spesifik olarak bildirilmitir.Grigoriu b, et al. Clinical Biochemistry 2009

Grigoriu b, et al. Clinical Biochemistry 2009Results: Using a serum HA cut-off of 100 g/L, 8 patients/33 (24.2%) were positive in the Mets group versus 20/76 (26.3%) in the MPM group and only 1/27 BPLAE patients. The area under ROC curve for serum HA in MPM versus Mets or BPLAE groups was only 0.617 while itwas 0.755 for mesothelin. In pleural fluid, both markers had similar diagnostic valuesIn conclusion, serum mesothelin had a better diagnostic value than serum hyaluronic acid and therefore may be considered as the reference biological marker in MPM diagnosis. In pleural effusion, both markers were equally effective in diagnosing MPM.

VASKLER ENDOTELYAL GROWTH FAKTR (VEGF)VEGF nemli bir angiogenezis reglatr olarak bilinir ve endotelyal hcre proliferasyonu, vaskler permeabilite ve baz inflamatuar lezyonlarn angiogenezisinde kritik bir neme sahiptir.Amati M. Mutation Research. 2008

Yasimatsu A. J Thorac Oncol 2010

FIGURE 3. Survival of MPM subjects according to serumVEGF levels. Estimates of the probability of survival were calculated using the Kaplan-Meier method and compared using the log-rank test.Yasimatsu A. J Thorac Oncol 2010

SONU

SMRP ve Osteopontin halihazrda allan biyolojik markerlerdir.nerilen markerler mezotelyoma tans iin altn standart olarak kabul edilen sitolojik ve histolojik incelemelerin yerini alabilecek derecede yeterli bir zglle sahip deildirler.Hastaln prevalans ve mevcut biomarkerlerin duyarllk ve zgllkleri sebebiyle tarama asbeste maruz kalan tm olgulara uygulandnda yanl pozitif sonular,gerek pozitif olgulardan birka kat daha fazla olduundan biolojik markerler tarama arac olarak kullanlamazlar.SMRPnin MPMde prognostik deeri net deildir ve ilave almalar gerektirir.Mezotelyomaya spesifik yeni markerleri saptamak iin almalar devam etmektedir.

*MMl hastalarda hastaln erken tehis edilmesi durumunda tedaviye daha iyi cevap alnabilecei ynnde bulgular mevcuttur.Mezotelyomada cerrahi dahil effektif bir tedavi yntemi yoktur. Hastaln erken saptanmasnn sonucu deitireceine bir bulgu yoktur. *Bir tan arac olarakHastal monitorize eden bir ara olarakYksek riskli poplasyonda bir tarama arac olarak*lk defa maliign mezotelyomal hastalarn serumlarnda SMRPyi Robinson ve ark. almlardr. Bu almada MMl 44 hastann 37sinde (% 84) SMRP konsantrasyonu yksekti.

SMRP ayrca akcier kanserinde (1/30), asbeste maruz kalmayanlarda (0/28) ve asbestli hastalarda (7/40) orannda ykselmiti. Bu almada SMRPnin malign hastalarda asbeste maruz kalan ve kalmayan salkl bireylerde, eitli akcier ve plevrann benign ve malign durumlara gre ykseldii gsterilmitir.SMRP seviyeleri tmr yaps ile korele idi. Epitelyal MPMde sarkomatoid MPMye gre SMRP seviyesi daha yksekti.SMRP seviyesinin ayrca tedaviye cevap alnnca dt ve tmr progresyonu ile artt bildirilmitir.Aratrmaclar ayrca asbeste maruz kalan bireylerde mezotelyomann erken dnemde saptanmas iin yararl olabileceini bildirmilerdir. ***Serum SMRP levels were different among patients with MPM, lung cancer, andindividuals exposed to asbestos (p 0.0001, Kruskal- Wallis test; Table 2). The mean serum SMRP values for the 90 patients with MPM (5.67 0.82 nM) was significantly higher than those for patients with lung cancer (1.99 0.43 nM, p 0.001 by ANOVA) or from asbestos exposed individuals (0.99 0.10 nM, p 0.001 by*Figure 1 demonstrates the differences in serum SMRP levels between MPM, lung cancer and its various histologies, and the asbestos-exposed cohort. There were no differences between serum SMRP levels for adenocarcinoma (compared with squamous cell carcinoma or small cell carcinoma (p 0.390).*For the MPM cohort, as seen in Figure 2, there were no differences seen in SMRP levels comparing epithelial (n 58, 5.88 0.98 nM) to biphasic (n 29, 5.64 1.61). There was a trend toward a lower SMRP level for sarcomatoid MPM but the small number of pure cases of sarcomatoid prevented any conclusions (n 3, 2.01 1.08).*No differences in SMRP serum levels were noted for asbestos-exposed individualsbased on age, sex, or exposure duration. The level of serum SMRP of 409 normal individuals was significantly lower than the 66 asbestos-exposed individuals (0.39 0.02 vs 0.99 0.09, p 0.001 by ANOVA), but when age and sex were matched between the two groups the difference in serum SMRP was less pronounced but still significant (0.65 0.04 vs 0.89 0.09, p 0.01). There was a trend toward elevation of serum SMRP levels comparing individuals with no plaques and fibrosis to those with evidence of radiographic asbestos changes.*Moreover, as seen in Figure 5, MPM stages greater than stage I had significantly higher SMRP levels (10.61 3.89, p 0.03) than stage I MPMs. Serum SMRP level, however, did not prove to be an independent predictor of survival by the Cox proportional hazards model.**SMRP concentrations were significantly higher in MPM compared with benign asbestosis (p 0.001) or lung cancer (p 0.001). The median values were 1.4 nM, 0.9 nM, and 0.8 nM, respectively. The best statistical cutoff was found to be 1.35 nM resulting in a sensitivity of 53% and a specificity of 82.7%. No significant differences in SMRP levels were found among histologies and stages of MPM. The highest median SMRP levels (4.2 nM) were measured in 29 MPM patients with relapse/progression (75.8% 1.35 nM).

*The highest median SMRP levels (4.2 nM) were measured in 29 MPM patients with relapse/progression (75.8% 1.35 nM).

*The highest median SMRP levels (4.2 nM) were measured in 29 MPM patients with relapse/progression (75.8% 1.35 nM). Univariately, SMRP discriminated significantly (p 0.003) between favorable (n 71, median survival: 17.1 month; 1-year survival: 63.1%) and worse prognosis (n 20, median survival: 8.4 months, 1-year survival: 32%) at 3.5 nM. In multivariate analysis, histology, therapy, and SMRP were shown to be independent prognostic factors in all MPM patients. Nevertheless, subtype driven reanalysis showed only a trend in epithelial MPM.

****In the present meta-analysis, our results indicate that determining concentrations of serum SMRPs produce consistent results with relative high specificity 0.89 (95% CI 0.88e0.90); the summary estimate of sensitivity, however, was only 0.64 (95% CI 0.61e0.68), showing that sensitivity estimates were quite low, andweremore variable than specificity. These datasuggest that SMRP determination might be somehowhelpful in confirming (ruling in) MM. However, these tests maximize specificity at the cost of sensitivity, and this trade-off hassignificant clinical implications. By contrast with the higher specificity, SMRPs had low sensitivity that was not sufficiently low to exclude non-MM when a patients SMRP concentrations are lower than the cut-off values *Mevcut metaanaliz almasnda yksek spesifisite 0.89 (95% CI 0.88-0.90) saptanmken sensitivite yanlzca 0.64 (95% CI 0.61-0.68) idi.SMRP MMy saptamada yararl olabilir Yksek spesifisiteye karn SMRP dk sensitivite hastann SMRP konsantrasyonlar cut-off deerlerinden daha dk olduu zaman non-MMy ekarte etmek iin yeterince dk deildi*****

Its precursor is a 71-kDa protein which is cleaved into a membrane bound 40-kDa C-terminal mesothelin and asoluble 31-kDa N-terminal protein called megakaryocyte potentiating factor (MPF) [9].YAN MPF ASLINDA MEZOTELNN NCL MADDESDR*Serum levels of the three markers were elevated in mesothelioma patients. At a level of specificity of 95% relative to healthy controls and patients with benign asbestos related disease, the sensitivity for mesothelioma was 34% for MPF, 47% for osteopontin and 73% for mesothelin. Osteopontin and MPF were unable to differentiate patients with mesothelioma from patients with other malignancies or those presenting with transudative pleural effusions.

****8OHdG: 8-hydroxy-2-deoxyguanosine

*In summary, we demonstrated that patients with MPM had significantly higher serum levels of VEGF in comparison with a population with a history of asbestos exposure that did not develop MPM, and the patients with advanced stage MPM showed higher levels of VEGF than patients with early stage MPM, suggesting it as a useful serum marker for screening for MPM in symptomless asbestosis-exposed individuals. Moreover, the Kaplan-Meier method revealed a significant correlation between serum VEGF levels and survival, which suggested its usefulness as a marker for estimating prognosis.*

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