***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 
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    ***EXAMPLES*** 
    Input: A prospect i ve study on 16 patients with advanced ( stage III and IV ) prostate cancer was carried out . TNM stage , general clinical status , serum PSA level , the histological type and Gleason ’s grade of the tumor were registered . Total and rogen blockade or single-drug therapy ( flutamide ) was performed . On average , 4.81 months after the start of therapy rebiopsy , serum PSA determination and general clinical examination were performed . Histologic examination before and after treatment of HE-stained slides , as well as apop-tag reaction to show apoptotic cells , p53 , bcl2 , and Ki-67 immunostaining . Clinical improvement manifested by regression or lack of progression was observed in 10 patients . Increase of the apoptotic index and decrease of the mitotic index was detected in these cases . Serum PSA level decreased in all patients except in 3 fatal cases . The 6 clinical ly nonresponders who died after the second biopsy did not show an increased apoptotic or decreased mitotic index . Ki-67 positivity correlated well with the mitotic activity . Mutant p53 expression was higher in patients in whom anti and rogen therapy was ineffective . The bcl2 expression was a characteristic of the tumors of patients who later died . These results show that the degree of induction of apoptosis in prostate carcinoma by hormonal therapy varies from case to case . A given prostate cancer patient ’s response to therapy may be predicted by following apoptotic and mitotic activity , as well as Ki-67 and p53 expression in repeated biopsies Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer . Although effective surgical and radiation treatments exist for clinical ly localized prostate cancer , metastatic prostate cancer remains essentially incurable . Here we show , through gene expression profiling , that the polycomb group protein enhancer of zeste homolog 2 ( EZH2 ) is overexpressed in hormone-refractory , metastatic prostate cancer . Small interfering RNA ( siRNA ) duplexes targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro . Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes . Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity . Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer ; in addition , clinical ly localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis . Thus , dysregulated expression of EZH2 may be involved in the progression of prostate cancer , as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression BACKGROUND Expression of intrinsic markers of tumour hypoxia and angiogenesis are important predictors of radiotherapeutic , and possibly surgical , outcome in several cancers . Extent of tumour hypoxia in localised prostate cancer is comparable to that in other cancers , but few data exist on the association of extent of tumour hypoxia with treatment outcome . We aim ed to study the predictive value of intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer , both in patients treated with radiotherapy  and in those treated surgically . METHODS We applied a new , needle biopsy tissue microarray ( TMA ) technique to study diagnostic sample s from men with localised , previously untreated prostate cancer treated in two r and omised controlled trials of radiotherapy-dose escalation . Multivariate analysis by Cox proportional hazards was done to assess the association between clinical outcome , in terms of biochemical control , and immunohistochemical staining of hypoxia inducible factor-1 alpha ( HIF-1 alpha ) , vascular endothelial growth factor ( VEGF ) , and osteopontin expression . The analysis was repeated on an independent series of men with localised , previously untreated prostate cancer treated by radical prostatectomy .  The main outcome was time to biochemical ( ie , prostate-specific antigen [ PSA ] ) failure . FINDINGS Between Oct 12 , 1995 , and Feb 5 , 2002 , 308 patients were identified from two prospect i ve , r and omised trials at the Royal Marsden Hospital , London and Sutton , UK , for the radiotherapy cohort and diagnostic biopsies were available for 201 of these patients . Between June 6 , 1995 , and Nov 4 , 2005 , 329 patients were identified from the Aarhus University Hospital , Skejby , Denmark , for the prostatectomy cohort ; of these , 40 patients were excluded because the tumour was too small to sample ( 19 patients ) , because the paraffin block was too thin ( 19 patients ) , or because the blocks were missing ( two patients ) , leaving 289 patients for analysis . For patients treated with radiotherapy , increased staining for VEGF ( p=0.008 ) and HIF-1 alpha ( p=0.02 ) expression , but not increased osteopontin expression ( p=0.978 ) , were significant predictors of a shorter time to biochemical failure on multivariate analysis , independent of clinical tumour stage , Gleason score , serum PSA concentration , and dose of radiotherapy . For patients treated with surgery , increased staining for VEGF ( p<0.0001 ) and HIF-1 alpha ( p<0.0001 ) expression , and increased osteopontin expression ( p=0.0005 ) were each significantly associated with a shorter time to biochemical failure on multivariate analysis , independent of pathological tumour stage , Gleason score , serum PSA concentration , and margin status . INTERPRETATION To our knowledge , this is the largest study of intrinsic markers of hypoxia and angiogenesis in relation to the outcome of radical treatment of localised prostate cancer . Increased expression of VEGF , HIF-1 alpha , and , for patients treated with surgery , osteopontin , identifies patients at high risk of biochemical failure who would be suitable for enrolment into trials of treatment intensification Accurate prognostic parameters in prostate biopsies are needed to better counsel individual patients with prostate cancer . We evaluated the prognostic impact of morphologic and immunohistochemical parameters in preoperative prostate cancer biopsies . A consecutive series of prostate biopsies of 279 men ( 72 % with clinical stage T1c and 23 % with T2 ) who subsequently underwent radical prostatectomy  was prospect ively analysed for Gleason score , number and percentage of positive cores ( NPC , PPC ) , total percentage of biopsy tissue with tumour ( TPT ) , maximum tumour percentage per core ( MTP ) , and expression of Ki67 , Bcl‐2 and p53 . All biopsy features were significantly associated with at least one feature of the radical prostatectomy specimen . pT stage was independently predicted by PSA , seminal vesicle invasion by Ki67 LI , positive margins by PSA and MTP , large tumour diameter by PSA and PPC , and Gleason score by biopsy Gleason score , MTP , and Ki67 LI , respectively . Biopsy Gleason score , NPC ( 1 vs. > 1 ) , TPT ( < 7 vs. ≥7 % ) , and Ki67 LI ( < 10 vs. ≥10 % ) were significant predictors of biochemical recurrence after radical prostatectomy ( p < 0.01 , each ) . KI67 LI was the only independent prognostic factor in case of a low TPT ( < 7 % ) or low Gleason score ( < 7 ) , the hazard ratio being 6.76 and 6.44 , respectively . In summary , preoperative Gleason score , NPC , TPT and Ki67 LI significantly predict the risk of recurrence after radical prostatectomy , and Ki67 is an independent prognosticator in biopsies with low‐volume or low‐ grade prostate cancer . Analysis of Ki67 LI in these biopsies may help to better identify patients with clinical ly insignificant prostate cancer . © 2008 Wiley‐Liss , Purpose : We previously reported that protein kinase A type I ( PKARIα ) overexpression was predictive of outcome in prostate cancer patients treated with radiotherapy ( RT ) ± short-term and rogen deprivation ( STAD ) on Radiation Therapy Oncology Group ( RTOG ) protocol 86 - 10 . Here , we attempt to verify our prior findings and test the hypothesis that the relationship of the length of AD to patient outcome is affected by PKARIα overexpression . Experimental Design : There were 313 cases in the RTOG 92 - 02 study cohort with available tissue and suitable staining by immunohistochemistry . Median follow-up was 10.1 years . The intensity of PKARIα staining intensity was quantified manually and by image analysis . Multivariate analyses were done for overall mortality using Cox proportional hazards models and for local failure , biochemical failure , distant metastasis , and cause-specific mortality using Fine and Gray 's regression models . Results : The expression levels of PKARIα , determined by manual and image analysis , were strongly correlated ( P < 0.0001 ) . In the multivariate analyses , manual-quantified and image analysis –quantified PKARIα staining intensities were independent predictors of distant metastasis ( P < 0.01 ) , local failure ( P < 0.05 ) , and biochemical failure ( P ≤ 0.01 ) . Furthermore , the benefit of long-term AD over STAD was much less when PKARIα expression was high . Conclusions : PKARIα overexpression has been shown in two RTOG trials to be associated with an increased risk of failure after AD + RT . In this series of contemporary high-risk patients , PKARIα overexpression was associated with diminished response to LTAD + RT relative to STAD + RT , suggesting that such patients would be ideal for a PKARIα knockdown strategy . ( Clin Cancer Res 2009;15(17):5478–84 PURPOSE Conventional pathological variables in prostate cancer may not provide optimal prediction of patient outcome . Pathological findings and p53 immunostaining were measured prospect ively in radical prostatectomy specimens to determine the incremental improvement in prediction of patient outcome over clinical findings . MATERIAL S AND METHODS From a previous prospect i ve study of 392 consecutive patients with prostate cancer who did not receive preoperative therapy and were treated with radical prostatectomy 25 had pathological stage pT3aN0M0 , 24 had pT3bN0M0 , 2 had pT2bN1M0 , 7 had pT3aN1M0 and 14 had pT3bN1 prostate cancer . These locally advanced stage cases comprise the current study population and further analysis was done with p53 immunostaining . All prostate specimens were totally embedded , serially sectioned and whole mounted . We examined pathological , clinical and laboratory findings as well as p53 immunostaining . RESULTS Median followup was 5.4 years ( range 0.5 to 6.4 ) . Univariate analysis revealed that pathological stage , 10 % or greater immunostaining for p53 , area and length of extraprostatic cancer extension , and cancer volume ( all p < /=0.03 ) were associated with biochemical ( prostate specific antigen ) or clinical failure . When all variables were considered in stepwise multivariate analysis none attained statistical significance after p53 status entered the model ( p < 0.01 , risk ratio 2.9 for 10 % or greater versus less than 10 % , 95 % confidence interval 1.4 - 6.2 ) . The concordance index analysis for the predictive ability of prostate specific antigen , stage , grade and ploidy ( c = 0.66 ) was inferior to the predictive ability of a statistical model also including p53 status ( c = 0.71 ) . CONCLUSIONS In cases of locally advanced stage cancer p53 immunoreactivity after radical prostatectomy improves outcome prediction . Addition of this variable to those routinely determined may identify a subset of patients who would benefit from more intensive postoperative surveillance and adjuvant therapy OBJECTIVES Locally advanced prostate cancer is frequently treated with radiotherapy and and rogen deprivation because of the greater rate of extracapsular disease and the concern that radical prostatectomy ( RP ) may not be curative in most cases . A case for surgery for locally advanced disease may be made on the basis of a lower rate of local recurrence compared with radiotherapy in our comparative data base , data suggesting a survival advantage with pelvic lymph node dissection in those with positive nodes , and the observation of improved survival in those with metastatic disease treated by RP compared with radiotherapy . We report on the feasibility of RP as a primary treatment modality for locally advanced disease . METHODS A total of 281 consecutive patients treated by RP between January 1998 and June 2004 were review ed . Locally advanced disease was defined as clinical Stage T2b or worse , prostate-specific antigen level greater than 15 ng/mL , and /or a Gleason score of 8 or greater . Data on the pathologic characteristics , operative complications , and follow-up were obtained from a prospect ively maintained institutional review board-approved data base . RESULTS Pathologic examination demonstrated organ-confined disease in 11.7 % , extracapsular extension in 56.9 % , seminal vesicle involvement in 23.1 % , and positive lymph nodes in 8.9 % . The overall complication rate was 9.7 % compared with 6.9 % for all patients undergoing RP . At a mean follow-up of 34 months ( range 1 to 78 ) , 198 ( 70.4 % ) of 281 patients had an undetectable prostate 
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p16 showed potential for treatment stratification between surgery and radiotherapy but needs further validation in independent studies .
Conclusions Despite years of research , very few tissue biomarkers retain predictive value in independent validation across therapy context .
Currently , none have conclusive ability to help treatment selection .