| BackgroundDiffuse large b-cell lymphoma(DLBCL)is the most common subtype of adult aggressive lymphoma with strong heterogeneity in clincopathological features,treatment response and prognosis.Rituximab combined with cyclophosphamide,doxorubicin,vincristine and prednisone(R-CHOP)as the standard treatment regimen significantly improved the prognosis of patients with DLBCL.However,some patients remain to have poor outcome with disease progresses or relapses after standardized treatment.Therefore,it becomes a hot topic to predict prognosis and alter therapeutic regimen early.The International prognostic index(IPI)is a risk-stratified scoring system based on five clinical characteristics of age,ECOG score,Ann Arbor stage,LDH level and the number of extrarenal lesions.However,with increasing insight into molecular mechanisms of DLBCL,the significance of the scoring system based on clinical characteristics has encountered great challenges.18F-FDG PET/CT imaging is anatomical technique for functional metabolism and receptor imaging with the advantages of high sensitivity,high specificity and functional imaging.It is widely used in the staging and efficacy evaluation.Positive PET/CT after end of treatment has been demonstrated to indicate poor survival.But,the prognostic value of interim 18F-FDG PET/CT(iPET/CT)in patients with DLBCL is still controversial,especially to determine the switch to salvage regimen.The development of next-generation sequencing technology plays an important role in the study of the pathogenesis and the discovery of new therapeutic target.Recent studies have found a number of genetic alterations in DLBCL.Some are specific to B-cell lymphomas,others are found in other malignancies.These gene alterations are involved in a wide range of signaling pathway,including B-cell differentiation,B-cell receptor signaling,NF-?B pathway,apoptosis,and epigenetic regulation.We presumed that some specific genetic alterations may be associated with positive iPET/CT,and indicate novel therapeutic approaches.At present,the issue has not been reported.This study retrospectively analyzed the prognostic value of iPET/CT in DLBCL and the genetic characteristics of patients with positive iPET/CT.Part ?:Prognostic Value of Interim 18F-FDG PET/CT in Diffuse Large B-cell LymphomaObjectiveTo investigate the prognostic value of iPET/CT in DLBCL patients.Methods111 patients with newly diagnosed DLBCL were enrolled in the study from April 2015 to September 2019.All of them had complete clinical and pathological data and underwent the assessment of iPET/CT after immunochemotherapy of 3-4 cycles.SPSS sofrware was used to analyze the association of clinicopathological features and survival with positive iPET/CT,retrospectively.Results1.Clinicopathological features:Among 111 patients,52 patients were male and 59 patients were female.The ratio of male to female was 1:1.13.The median age was 55(15 to 89)years.41 patients were classified into the iPET/CT-positive group and 70 patients were classified into the iPET/CT-negative group.There was no significant differences in gender,age,IPI score,LDH level,and extranodal involvement,Ann Arbor staging,cell-of-origin based on Hans classification,Ki-67 index,MYC protein expression,Bcl-2 protein expression and double expression of MYC/Bcl-2 between the two groups.2.Survival analysis:The median time of OS and PFS in positive iPET/CT group were significant lower than negative group.The 2-year OS rate in the iPET/CT negative and positive group was 91.1%and 58.5%(?2=8.849,P=0.003),and the 2-year PFS rate was 77.8%and 28.8%(?2=21.345;P=0.000),with statistically significant differences.3.Univariate analysis showed that gender(?2=4.285,P=0.038),Ki-67 level(?2=5.800,P=0.016),and iPET/CT(?2=8.849,P=0.003)had significant effects on OS.Hans classification(?2=5.994,P=0.014),IPI score(?2=5.692,P=0.017),Ki-67 index(?2=-5.070,P=0.024),double expression of MYC/Bcl-2(?2=4.477,P=0.034),iPET/CT(?2=21.345,P=0.000)had significant effects on PFS.Multivariate analysis showed that male(HR=5.115,95%CI 1.331?19.655,P=0.017),high Ki-67 index(HR= 0.192,95%CI 0.055,0.672,P= 0.01),iPET/CT positive(HR= 6.567,95%CI 1.891?22.799,P= 0.03)were poor independent prognostic factors of OS.High Ki-67 index(HR= 0.430,95%CI 0.240?0.886,P= 0.020),double expression of MYC/Bcl-2(HR= 1.766,95%CI 1.157?2.696,P=0.008),positive iPET/CT(HR=3.588,95%CI 2.032?8.116,P=0.000)had independent relation to poor PFS.ConclusionsInterim 18F-FDG PET/CT Positive was associated with poor prognosis of DLBCL patients.Part ? Genetic Characteristics Related to Positive Interim 18F-FDG PET /CT in Patients with Diffuse Large B-cell LymphomaObjectiveTo explores genetic characteristics related to positive iPET/CT and their association with the efficacy of adjusting salvage regimens in DLBCL patients.MethodsNew-diagnosed patients with DLBCL were enrolled in the study from June 2017 to November 2019.They received the evaluation of iPET/CT after immunochemotherapy of 3-4 cycles and the examination of 93 hot-spot driver genes with next-generation sequencing.SPSS sofrware was used to analyze the association of specific genetic features with positive iPET/CT and the efficacy of adjusting salvage regimens in DLBCL patients.Results1.28 patients were included in this study,including 13 females and 15 males.The male to female ratio was 1.15:1,and the average age was 50.5(21-89)years.2.After the treatment of immunochemotherapy,20 patients with negative iPET/CT continued to complete total 6 cycle of immunochemotherapy and additional 2 cycle of rituximab.8 patients with positive iPET/CT were individed into two groups.One maintained primary regimen and accomplished total 8 cycle of therapy,the other switched to salvage regimen and received total 8 cycle of therapy.At the end of treatment,all of patients with negative iPET/CT kept negative;in patients with positive iPET/CT,5 patients turned negative,and 3 patients remained positive.3.Positive iPET/CT was independently associated with poor prognosis.The median time of PFS in the positive and negative group were 8 and 12 months,one year PFS was 22.5%and 71.4%,and one year OS of was 83.3%and 100%;respectively.The difference between two groups was statistically significant.4.62 gene mutations were detected in these patients.There were 24 genes with high mutation frequency of greater than 10%,including KMT2D,PCLO,CD79B,MYD88,TP53,PIM1,PRDM1,SOCS1,TCF3,ARID1A,ARID1B,B2M,BRAF,ARD11,CCND3,CD58,CREBBP,EP3,ETV6,EZH2,ID3,RELN,STAT3 and TET2.5.KMT2D(50%,4/8),TP53(37.5%,3/8),SOCS1(25%,2/8),PRDM1(25%,2/8),and CD58(25%,2/8)gene mutations have a correlation trend with positive PET/CT.Survival analysis of patinets with positive iPET/CT showed that SOCS1 and CD58 mutation was associated with poor prognosis(P<0.05).ConclusionsThe gene mutation of KMT2D,TP53,SOCS1,PRDM1,and CD58 was associated with positive iPET/CT in DLBCL patients.General conclusion1.Interim 18F-FDG PET/CT Positive was associated with poor prognosis of DLBCL patients.2.The gene mutation of KMT2D,TP53,SOCS1,PRDM1,and CD58 was associated with positive iPET/CT in DLBCL patients. |
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