***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: Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items The survival of diffuse large B-cell lymphoma patients varies considerably , reflecting the molecular diversity of tumors . In view of the controversy whether cytologic features , immunohistochemical markers or gene expression signatures may capture this molecular diversity , we investigated which features provide prognostic information in a prospect i ve trial in the R-CHOP treatment era . Within the cohort of DLBCLs patients treated in the RICOVER-60 trial of the German High- Grade Lymphoma Study Group ( DSHNHL ) , we tested the prognostic impact of IB morphology in 949 patients . The expression of immunohistochemical markers CD5 , CD10 , BCL2 , BCL6 , human leukocyte antigen (HLA)-DR , interferon regulatory factor-4/multiple myeloma-1 ( IRF4/MUM1 ) , and Ki-67 was assessed in 506 patients .  Expression of the immunohistochemical markers tested was of modest , if any , prognostic relevance . Moreover , the Hans algorithm using the expression patterns of CD10 , BCL6 , and interferon regulatory factor-4/multiple myeloma-1 failed to show prognostic significance in the entire cohort as well as in patient subgroups . IB morphology , however , emerged as a robust , significantly adverse prognostic factor in multivariate analysis , and its diagnosis showed a good reproducibility among expert hematopathologists . We conclude , therefore , that IB morphology in DLBCL is likely to capture some of the adverse molecular alterations that are currently not detectable in a routine diagnostic setting , and that its recognition has significant prognostic power BACKGROUND Dose intensification with a combination of cyclophosphamide , doxorubicin , vincristine , and prednisolone ( CHOP ) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks . We investigated whether this survival benefit from dose intensification persists in the presence of rituximab ( R-CHOP ) in all age groups . METHODS Patients ( aged ≥18 years ) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were r and omly assigned central ly in a one-to-one ratio , using minimisation , to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab ( R-CHOP-14 ) or eight cycles of R-CHOP every 21 days ( R-CHOP-21 ) . R-CHOP-21 was intravenous cyclophosphamide 750 mg/m(2 ) , doxorubicin 50 mg/m(2 ) , vincristine 1·4 mg/m(2 ) ( maximum dose 2 mg ) , and rituximab 375 mg/m(2 ) on day 1 , and oral prednisolone 40 mg/m(2 ) on days 1 - 5 , administered every 21 days for a total of eight cycles . R-CHOP-14 was intravenous cyclophosphamide 750 mg/m(2 ) , doxorubicin 50 mg/m(2 ) , vincristine 2 mg , rituximab 375 mg/m(2 ) on day 1 , and oral prednisolone 100 mg on days 1 - 5 , administered every 14 days for six cycles , followed by two further infusions of rituximab 375 mg/m(2 ) on day 1 every 14 days . The trial was not masked . The primary outcome was overall survival ( OS ) . This study is registered , number IS RCT N 16017947 . FINDINGS 1080 patients were assigned to R-CHOP-21 ( n=540 ) and R-CHOP-14 ( n=540 ) . With a median follow-up of 46 months ( IQR 35 - 57 ) , 2-year OS was 82·7 % ( 79·5 - 85·9 ) in the R-CHOP-14 group and 80·8 % ( 77·5 - 84·2 ) in the R-CHOP-21 ( st and ard ) group ( hazard ratio 0·90 , 95 % CI 0·70 - 1·15 ; p=0·3763 ) . No significant improvement was noted in 2-year progression-free survival  ( R-CHOP-14 75·4 % , 71·8 - 79·1 , and R-CHOP-21 74·8 % , 71·0 - 78·4 ; 0·94 , 0·76 - 1·17 ; p=0·5907 ) . High international prognostic index , poor-prognosis molecular characteristics , and cell of origin were not predictive for benefit from either schedule . Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group ( 318 [ 60 % ] of 534 vs 167 [ 31 % ] of 534 ) , with no prophylactic use of recombinant human granulocyte-colony stimulating factor m and ated in this group , 
    Output:
    
Immunohistochemistry-determined cell-of-origin , and BCL2 and BCL6 translocation status added no additional prognostic value .
Half of the studies on gene expression profiling-determined cell-of-origin and MYC translocation status found that germinal center B-cell – like ( GCB ) and no translocation were associated with better overall survival ( OS ) whereas the remaining studies found no effect of these covariates .