Han van Krieken Nijmegen The Netherlands

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1 Pathologie vandaag: progressie, differentiatie en transformatie Voorspellen is moeilijk, Vooral als het over de toekomst gaat Han van Krieken Nijmegen The Netherlands PubMed Hits pathology AND prognosis: van Krieken: 76 PubMed hits Pathology AND Predictive: van Krieken: 20

2 Pathologie: diagnostiek CyclinD1 1990: herschikking van de bcl-1 regio in 10/19 gevallen, niet in andere laaggradige B-cell lymfomen 1993: In alle centrocytaire lymfomen: cyclined1 herschikking Centrocytic lymphoma Lymphoma of intermediate differentiation Medeiros LJ, Van Krieken JH, Jaffe ES, Raffeld M. Association of bcl-1 rearrangements with lymphocytic lymphoma of intermediate differentiation. Blood;1990:76:2086 Leiden Pathology Department de Boer CJ, Loyson S, Kluin PM, Kluin-Nelemans HC, Schuuring E, van Krieken JH. Multiple breakpoints within the BCL-1 locus in B-cell lymphoma: rearrangements of the cyclin D1 gene. Cancer Res. 1993;53:4148

3 1995: overexpressie van cycline D1 is een marker voor Mantel Cel Lymfoom 1995: CyclinD1 immunohistochemie is een goede hulp bij de diagnose Mantel Cel Lymfoom Cyclin D1 messenger RNA overexpression as a marker for mantle cell lymphoma de Boer CJ, van Krieken JH, Kluin-Nelemans HC, Kluin PM, Schuuring E Oncogene 1995;10:1833 Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma de Boer CJ, Schuuring E, Dreef E, Peters G, Bartek J, Kluin PM, van Krieken JH Blood. 1995;86: : Double-staining chromogenic in situ hybridization as a useful alternative to split-signal fluorescence in situ van Rijk A, Svenstroup-Poulsen T, Jones M, Cabeçadas J, Cigudosa JC, Leoncini L, Mottok A, Bergman CC, Pouliou E, Dutoit SH, van Krieken HJ. Double-staining chromogenic in situ hybridization as a useful alternative to split-signal fluorescence in situ hybridization in lymphoma diagnostics. Haematologica. 2010;95: Mantle-cell lymphoma: a population-based clinical study Velders GA, Kluin-Nelemans JC, De Boer CJ, Hermans J, Noordijk EM, Schuuring E, Kramer MH,, Kluin PM, Van Krieken JH J Clin Oncol. 1996;14:1269 populatie-gebaseerde non-hodgkin lymfoom (NHL) registratie, 41patienten met mantel cel lymfoom (MCL) MCL: 3.7% of NHLs Mediane leeftijd: 68 jaar; man/vrouw ratio 1.6:1 78% stadium IV bij diagnose Mediane overleving: 31.5 months. proliferatieve index <10%: betere overleving

4 2005: Ki67 is a strong prognostic marker for Mantle Cell Lymphoma 2009: consensus guideline for Ki67 index as prognostic marker in Mantle Cell lymphoma the Ki-67 index a very powerful prognostic biomarker methods to assess the Ki-67 index including stringent counting, digital image analysis, and estimation by eyeballing. counting of 2 x 500 cells is the gold standard estimation by eyeballing and digital image analysis showed a poor concordance with the gold standard counting a reduced number of lymphoma cells (2 x 100 cells) showed high interobserver agreement Tiemann et al, Brit J Hematol 2005; 131:29-38 Ki-67 as a prognostic marker in mantle cell lymphoma-consensus guidelines of the pathology panel of the European MCL Network. Klapper W, Hoster E, Determann O, Oschlies I, van der Laak J,et al. van Krieken JH, Hiddemann W, Dreyling M; for the European MCL Network. J Hematopathol 2009 Pathologie: 130 jaar oud Pathologie: progressie Histochemie Electronen Microscopie Enzym histochemie Immunohistochemie DNA-analyse Expressie profielen Next generation sequencing this will make the classic pathologist, H&E, microscope obsolete..

5 Uitdagingen Logistiek Begrijpen van mechanismen vanziekten Evidence based pathologie Revolutie t.g.v. genetica Logistiek Logistiek Pathologie (lean)

6 NOT RUNNING A HOSPITAL THIS IS A BLOG BY A FORMER CEO OF A LARGE BOSTON HOSPITAL TO SHARE THOUGHTS ABOUT HOSPITALS, MEDICINE, AND HEALTH CARE ISSUES.. check out this almost unheard of phenomenon: A pathologist working in an office with windows! I thought it was a Joint Commission requirement that pathologists be locked in dungeons. (Joke.) This does, however, raise important concerns about productivity and accuracy. After all, if pathologists actually get to see outside scenes and real people, how will they stay focused? (Another joke.) (Oy, I can already imagine the comments I am going to get.) Pathologie nu: differentiatie: begrijpen van mechanismen MSH6 immunohistochemie Pathologie nu: differentiatie: begrijpen van methodologie CD20 immunohistochemie

7 Pathologie nu: differentiatie: begrijpen van methoden CD20 immunohistochemie Pathologie nu: transformatie, moleculaire pathologie Ligand Ligand KRAS testing EGFR dimer A tumor sample is taken and sent to the laboratory the test can use fresh, frozen or paraffinembedded tissue P13K STAT Shc Grb-2 SOS Ras Signal Adapters and Enzymes A pathologist confirms that the tissue is cancerous and selects material A sample of DNA is prepared for the KRAS test. PTEN Akt Raf The polymerase chain reaction (PCR) is used to amplify the DNA and test for KRAS mutation status Transcription Factors mtor FKHR GSK-3 BAD MEK 1/2 MAPK Signal Cascade Jun p27 FOS Myc Cyclin D-1

8 European Society of Pathology Quality Assurance Program for KRAS testing in colorectal cancer Multidisciplinary group was formed at the Multidisciplinary Colorectal Cancer Congres in Berlin (February 2008) A document was discussed at the Inter-continental Congres in Barcelona (May 2008) Manuscript accepted for publication (August 2008): KRAS mutation testing for predicting response to anti- EGFR therapy for colorectal carcinoma: proposal for a European quality assurance program (J.H.J.M. van Krieken et al, Virchows Archive, 2009) Program was started in 2009 with support from Amgen with 13 expert centra Numer of labs Results The Austria Belgium Denmark France Greece UK Spain Sweden Netherlands 3 mistakes mistakes mistake all samples correct Difference between highest and lowest scores TUMOR CONTENT Tumor content Report scores (%) 94,3 94,3 84,0 76,4 67,9 67,9 70,8 71,7 57,5 52,8 50,0 51,9 44,3 37,7 32,1 26,4 26,4 0 Different samples Highest score Lowest score Reference lab regional organizer

9 We moeten het beter doen, en dat kunnen we! De revolutie in genetica: next generation sequening Meer clonogene veranderingen per tumor tumorheterogeniteit Snelle detectie van moleculaire markers Snelle detectie van kiembaanveranderingen Kosten van whole genome sequencing?

10 Klinisch relevante driver mutations in long adenocarcinomen Potentiële problemen bij diagnostiek voor meerdere targets Hoeveelheid beschikbaar materiaal (DNA), vooral bij kleine biopten Doorlooptijden Complexiteit Kosten Next Generation Sequencing! Pao and Hutchinson, Nature Med, 8, 2012 Sanger sequencing 1-5 genes/patiënt Whole genome KRAS: c.173c>t (p.(thr58ile)) Toekomst? PGM: genen/patiënt

11 EGFR: c.2239_2258delinsca (p.(leu747_pro753delinsgln)) Weerstand? Zorg? Angst? Overdonderd? Klagen? Programma tegen klagen: the Dr Phil-Obama approach What did you do about it? Yes, you can Pathologie: progressie, differentiatie, transformatie Progressie Continu verbeteren Differentiatie Deelspecialisatie Nieuwe microscopische technieken Transformatie: elke patholoog moleculair patholoog Netwerken Opleiding Moleculair bioloog in de pathologie AIOS en pathologen