***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: PURPOSE The International Prognostic Index ( IPI ) is widely used for risk stratification of patients with aggressive B-cell lymphoma . The introduction of rituximab has markedly improved outcome , and R-CHOP ( rituximab + cyclophosphamide , doxorubicin , vincristine , prednisone ) has become the st and ard treatment for CD20(+ ) diffuse large B-cell lymphoma . To investigate whether the IPI has maintained its power for risk stratification when rituximab is combined with CHOP , we analyzed the prognostic relevance of IPI in three prospect i ve clinical trials . PATIENTS AND METHODS In total , 1,062 patients treated with rituximab were included ( MabThera International Trial [ MInT ] , 380 patients ; dose-escalated regimen of cyclophosphamide , doxorubicin , vincristine , etoposide , and prednisone ( MegaCHOEP ) trial , 72 patients ; CHOP + rituximab for patients older than age 60 years [ RICOVER-60 ] trial , 610 patients ) . A multivariate proportional hazards modeling was performed for single IPI factors under rituximab on event-free , progression-free , and overall survival . RESULTS IPI score was significant for all three end points . Rituximab significantly improved treatment outcome within each IPI group result ing in a quenching of the Kaplan-Meier estimators . However , IPI was a significant prognostic factor in all three end points and the ordering of the IPI groups remained valid . The relative risk estimates of single IPI factors and their order in patients treated with R-CHOP were similar to those found with CHOP . CONCLUSION The effects of rituximab were superimposed on the effects of CHOP with no interactions between chemotherapy and antibody therapy . These results demonstrate that the IPI is still valid in the R-CHOP era BACKGROUND The introduction of rituximab ( R ) to conventional CHOP chemotherapy for newly diagnosed diffuse large B-cell lymphoma ( DLBCL ) led to an unequivocal improvement in survival , establishing RCHOP as the st and ard of care . Still , nearly 40 % of DLBCL patients will eventually die of relapsed disease . Efforts to improve outcomes by addition of new biologic agents ( X ) to the RCHOP backbone are underway . In this era of R(X)CHOP , it is imperative to develop prognostic and predictive markers , not only to identify patients who will suffer a particularly aggressive course , but also to accurately select patients for clinical trials from which they will most benefit . DESIGN The following review was undertaken to describe prognostic factors in DLBCL , with emphasis on markers that are accurate , relatively available , and clinical ly applicable in 2014 . RESULTS The International Prognostic Index retains its validity in the era of RCHOP , although with limited ability to predict those with < 50 % chance of long-term survival . Gene expression profiling has provided novel insights into the biology of DLBCL and led to the development of immunohistochemistry ( IHC ) algorithms that are in routine practice . Identification of a ' double-hit ' ( DH ) lymphoma by fluorescent in situ hybridization with aberrations involving MYC and /or BCL2 and BCL6 genes has important implication s due to its extremely dismal prognosis with RCHOP . Other markers such as the absolute lymphocyte count ( ALC ) , serum immunoglobulin free light chains , vitamin D levels , serum cytokines/chemokines , and imaging with positron emission tomography ( PET ) have all shown promise as future predictive/prognostic tests . CONCLUSIONS The future for new treatment options in DLBCL is promising with current clinical trials testing novel targeted agents such as bortezomib , lenalidomide , and ibrutinib as the ' X ' in R(X)CHOP . Predictive factors are required to select and r and omize patients appropriately for these trials . We envision the day when ' X ' will be chosen based on the biological characteristics of the tumor Double hit lymphoma ( DHL ) and double protein‐expressing ( MYC , BCL2 ) lymphomas ( DPL ) fare poorly with R‐CHOP ( rituximab + cyclophosphamide , doxorubicin , vincristine , prednisolone ) ; consolidative autologous stem cell transplant ( ASCT ) may improve outcomes . S9704 , a phase III r and omized study of CHOP + /−R with or without ASCT enabled evaluation of intensive consolidation . Immunohistochemistry ( IHC ) identified 27 of 198 patients ( 13·6 % ) with MYC overexpression ; 20 ( 74 % ) harboured concurrent BCL2 overexpression . Four had DHL and 16 had DPL only . With median 127 months follow‐up , there is a trend favouring outcomes after ASCT in DPL and MYC protein overexpressing patients , whereas all DHL patients have died irrespective of ASCT MYC rearrangements occur in 5 % to 10 % of diffuse large B-cell lymphomas ( DLBCL ) and confer an increased risk to cyclophosphamide , hydroxydaunorubicin , oncovin , and prednisone ( CHOP ) and rituximab (R)-CHOP treated patients . We investigated the prognostic relevance of MYC- , BCL2- and BCL6-rearrangements and protein expression in a prospect i ve r and omized trial . Paraffin-embedded tumor sample s from 442 de novo DLBCL treated within the RICOVER study of the German High- Grade Non-Hodgkin Lymphoma Study Group ( DSHNHL ) were investigated using immunohistochemistry and fluorescence in situ hybridization ( FISH ) to detect protein expression and breaks of MYC , BCL2 , and BCL6 . Rearrangements of MYC , BCL2 , and BCL6 were detected in 8.8 % , 13.5 % , and 28.7 % , respectively . Protein overexpression of MYC ( > 40 % ) was encountered in 31.8 % of tumors ; 79.6 % and 82.8 % of tumors expressed BCL2 and BCL6 , respectively . MYC translocations , MYChigh , BCL2high , and BCL6low protein expressions were associated with inferior survival . In multivariate Cox regression modeling , protein expression patterns of MYC , BCL2 and BCL6 , and MYC rearrangements were predictive of outcome and provided prognostic information independent of the International Prognostic Index ( IPI ) for overall survival and event-free survival . A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15 % of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP . Registered at http://www.cancer.gov/ clinical trials : RICOVER trial of the DSHNHL is NCT 00052936 In large B-cell lymphoma ( LBCL ) MYC- and MYC/BCL2 double-hit ( DH ) translocations have been associated with inferior survival . We hypothesised that the negative prognostic impact of MYC translocation was determined by an immunoglobulin MYC translocation partner gene ( IG-MYC ) , as opposed to a non-immunoglobulin partner gene ( nonIG-MYC ) . In a prospect i ve , unselected cohort of 237 LBCL patients MYC and BCL2 translocations were identified by fluorescent in situ hybridisation ( FISH ) with split probes . MYC translocation partner gene was identified by IGH/MYC fusion probes and /or kappa/lambda split probes . Clinical data were collected from patient files . MYC translocation was identified in 28/225 patients .  IG-MYC translocation partner gene was identified in 12/24 patients .  DH translocation was identified in 23/228 patients .  IG-MYC translocation partner gene was identified in 9/19 DH patients . Neither MYC-nor DH translocation showed correlation with survival . However , MYC translocation with IG-MYC translocation partner gene was associated with worse OS compared with both MYC translocation with nonIG-MYC translocation partner gene ( P = 0.02 ) as well as absence of MYC translocation ( P = 0.03 ) . In patients with DH a similar , however , stronger correlation was seen ( P = 0.003 and P = 0.0004 respectively ) . MYC - or DH translocation with nonIG-MYC translocation partner gene was not associated with worse overall survival ( P = 0.2 and P = 0.3 respectively ) . Most patients received Rituximab ( 86 % ) and CHOP/CHOP-like chemotherapy regimes ( 81 % ) . We suggest that prognostic stratification of LBCL patients by MYC and /or DH translocations should include identification of MYC translocation partner gene because approximately half of the cases harbour nonIG-MYC translocation partner genes with no or minor influence on survival 
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The current analysis indicated that MYC and /or BCL2 protein overexpression , and particularly co-overexpression was related to short overall survival  in R-CHOP treated DLBCL patients , showing that application of the two new biomarkers can help to better stratify DLBCL patients and guide targeted treatment