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,書式設定,書式設定,第,2,第,3,第,4,第,5,書式設定,書式設定,第,2,第,3,第,4,第,5,*,“,The molecular genetic development of hematologic malignancy in Japan,”,Kiyohiko Hatake,M.D.,Ph.D.,Department of Medical Oncology and Hematology,Cancer Institute Hospital,Ariake,Koto,Tokyo,Japan,ASCO-COSA-CSCO-ESMO-JCOG International Symposium,CSCO Annual Meeting 2008,Shanghai,China,Disclosure of COI,Research funding,Chugai/Roche,Kirin,BMS,Kyowa,Yakult,Weyth,Novartis,Pfizer,Taiho,Jansen,Otsuka,Bayer,Employment or leadership position,:none,Stock ownership,Takeda,Astellas,Daiichi-Sankyo,Donation,Pfizer,Kirin,Chugai/Roche,Yakult,Novartis,Jansen,Taiho,Honoraria:,none,Consultant or advisort role:,none,Expert Testimony:none,000000000,Todays talk,Clinical practice of NHL,Registration system for WHO classification of NHL,Standard chemotherapy in NHL and HL,RCHOP in DLBCL,Resistance to rituximab,Live-cell confocal fluorescence microscopy,CDC,ADCC,Relationship CDC and response to rituximab and prognosis,Mutation of CD20 and CDC,Clinical practice of Non-Hodgkins Lymphoma(B-cell lymphoma)in CIH,Old,but an important prognostic marker sIL-2R,and CD5 in RCHOP treatment,DLBCL:treatment result by CHOPRituximab,CHOP n=83:76%,R-CHOP,n=92:97%,P=0.0002 0.05,%:3-year PFS,Days from treatment,Over-all survival rate,87 cases treated by CHOP and 141 cases treated by RCHOP,Were analized in DLBCL.,RCHOP was superior to CHOP in both,RCHOP is superior to CHOP,and sIL-2R is still good marker,For prognosis.,Mechanisms of action of rituximab,proliferation,block,ADCC,CDC,apoptosis,NK,M,PMN,FcR,C1q,C2-C9,CD20,CD20+lymphoma,rituximab,Research methodology,Prediction of response and prognosis,Establishment of clinically applicable bio-imaging,Cancer cells from,the patients,Ultra super speedy,Sensitivity test,Live-cell bio-imaging,Confocal fluoresence,Prediction of response to rituximab by imaging,Response to,rituximab,in lymphoma cells from the patients,Probably,ineffective,Probably,effective,10min,10min,The principle of imaging-based CDC susceptibility assay,Diagnostic details of patients evaluated for CDC susceptibility,Correlation between CDC and clinical response,DLBCL,FL,chemotherapy,with rituximab,chemotherapy,w/o rituximab,P=0.0023,P=0.00067,Reproducible ADCC assay,KHYG-1,LTR,Fcgr3a,(158V),LTR,LTR,Fcgr3a,(158F),LTR,IRES,IRES,ZsGreen,ZsGreen,KHYG-1/mock,-ZsGreen,KHYG-1/158V,-ZsGreen,KHYG-1/158F,-ZsGrreen,NK leukemia cell line,CD3-,CD5-,CD7+,CD16-,CD56+,TCR-,ZsGreen,rituximab,PI,ADCC assay,KHYG-1/mock,KHYG-1/158V,KHYG-1/158F,LDH release assay,Target:Ramos,E/T:1,Co-culture:4hr,51,Cr release assay,Target:Ramos,E/T:1,Co-culture:4hr,Effect of serum on ADCC activity,Serum(-),Serum(+),Rituximab(-),Rituximab(+),Ramos vs KHYG-1/FcRIIIa(158V)in heat-inactivate serum,Effects of IgG on ADCC activity,Daudi vs.KHYG-1/FcRIIIa,Rituximab:0.1g/mL,Co-culture:for 4hr,Daudi vs.KHYG-1/FcRIIIa,Rituximab:0.1g/mL,Co-culture:for 4hr,IgG(12mg/mL),Effect of complement on ADCC activity,Daudi vs.KHYG-1/FcRIIIa,Rituximab:0-100g/mL,Co-culture:for 4hr,serum/heat-inactivated serum:50%(v/v),Summary,Depletion of peripheral B cells,complement,Consumption of C,Serum IgG,CDC,ADCC,C2-C9,rituximab,C1q,NK,M,PMN,CD20,FcR,Mutations of C-terminal region of CD20,molecule predict CD20 expression and,time to progression after rituximab,in non-Hodgkins lymphoma,Yasuhito Terui,Yuji Mishima,Natsuhiko Sugimura,Kiyotsugu Kojima,Takuma Sakurai,Yuko Mishima,Ryoko Kuniyoshi,Akiko Rokudai,Masahiro Yokoyama,Kengo Takeuchi,Chie Watanabe,Shunji Takahashi,Yoshinori Ito,and Kiyohiko Hatake,Department of Medical Oncology and Hematology,Cancer Institute Hospital,Japanese Foundation for Cancer Research;,Division of Clinical Chemotherapy,Cancer Chemotherapy Center,Japanese Foundation for Cancer Research;,Olympus Bio-imaging Laboratory,Cancer Chemotherapy Center,Japanese Foundation for Cancer Research;,Department of Pathology,Cancer Institute Hospital,Japanese Foundation for Cancer Research,Tokyo;,Nutritional Science Laboratory,Morinaga Milk Co.,Kanagawa,Japan.,Terui Y et al.,abstracts in ASH 2006 and ASCO 2007,Methods,Since June 2002 to November 2004,retrospective analysis was performed in CIH(evaluable 50 cases of NHL),2.,We performed flow cytometry(CD20 antigen)in each fresh lymphoma cells from the patients,3.,Mutation analysis of CD20,Structure of,CD20 mutation,CD20 negative DLBCL lymphoma,transformed during R-CHOP treatment,M Raji PT K562,CD20,Flow cytometric analysis,RT-PCR,Sequence analysis,Summary of 50 cases with biopsy after PD,Histopathology,treatment,cases,Biopsy after PD,MALT R 3,1,R-CHOP like 11,R-CHOPRTx 1,R-VP-16 1,1,FL R 1,R-CHOP like 5,2,R-CHOPRTx 1,DLBCL R-CHOP 21 2,RTxR-CHOP 1,1,CLL R 1,1,R-CHOP like 1,SLL R 1,Lymphoplasmacytic R-CHOP like 1,Mantle CHOPRTR,1,1,total,50,9,CD20 mutation site region cases,C-terminal deletion C-terminal cytoplasmic 4,(truncation),2.Extracellular 2nd extracellular 1,TM 4th transmembrane 1,4.Early termination N-terminal cytoplasmic 5,CD20 mutation in 11/50,NHL,CD20 expression in mutated lymphoma cells,
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