title: The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases.
abstract: BACKGROUND
  Oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway plays a critical role in cell proliferation and growth. Phosphorylated AKT (p-AKT) has been reported to be abnormally overexpressed and to have poor prognostic impact in solid tumors.
  
  
  METHODS
  To define the clinical implications of p-AKT expression in diffuse large B-cell lymphoma (DLBCL), we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression and investigated the impact of p-AKT expression on clinical outcomes. We assessed 262 patients with DLBCL. Based on a cutoff value of the upper limit of the third quartile of AUs, 56 patients were classified as high p-AKT and the remaining 206 patients were classified as low p-AKT.
  
  
  RESULTS
  The high p-AKT group was closely associated with more advanced stage (stage III-IV, P = 0.02), two or more extranodal involvement (P = 0.03), lactic dehydrogenase elevation (P = 0.03), higher International Prognostic Index risk groups (high intermediate/high, P = 0.02), and the presence of B-symptoms (P = 0.01). The high p-AKT group showed substantially worse overall survival (OS) (median OS, 115.0 months versus not reached, P = 0.004) and progression-free survival (PFS) (median PFS, 25.5 versus 105.8 months, P = 0.019) compared with the low p-AKT group. Multivariate analysis revealed that high p-AKT expression retained its significant poor prognostic impact for OS (hazard ratio 1.7; 95% confidence interval, 1.0-2.7; P = 0.031). The subgroup with high p-AKT expression and concurrent Epstein-Barr virus positivity showed worst prognosis with the median OS and PFS of 15.2 and 7.4 months.
  
  
  CONCLUSIONS
  DLBCL patients with high p-AKT expression showed distinct clinical features and followed a more rapidly deteriorating clinical course with worse OS and PFS. Thus, a more effective treatment option should be developed for this subset of DLBCL patients, and targeting PI3K/AKT pathway may be a promising therapeutic strategy.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine and.
authors.forename: J Y
authors.initials: JY
authors.lastname: Hong
authors.forename: M E
authors.initials: ME
authors.lastname: Hong
authors.forename: M K
authors.initials: MK
authors.lastname: Choi
authors.forename: Y S
authors.initials: YS
authors.lastname: Kim
authors.forename: W
authors.initials: W
authors.lastname: Chang
authors.forename: C H
authors.initials: CH
authors.lastname: Maeng
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.forename: S J
authors.initials: SJ
authors.lastname: Lee
authors.forename: I-G
authors.initials: IG
authors.lastname: Do
authors.forename: J-S
authors.initials: JS
authors.lastname: Jo
authors.forename: S H
authors.initials: SH
authors.lastname: Jung
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.forename: Y H
authors.initials: YH
authors.lastname: Ko
authors.forename: W S
authors.initials: WS
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality / Q000628:therapy; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000821:virology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D051057:Proto-Oncogene Proteins c-akt
keywords: PI3K/AKT pathway; diffuse large b-cell lymphoma; p-AKT