human
***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: INTRODUCTION Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) adjuvant chemotherapy .  PATIENTS AND METHODS Patients with pT1/T2N0M0 disease whose tumors demonstrated ≥ 10 % nuclear reactivity on central ly performed immunohistochemistry for p53 were offered r and om assignment to three cycles of adjuvant MVAC versus observation ; p53-negative patients were observed . By using a log-rank test with one-sided α = .05 and β = .10 , 190 p53-positive patients were planned to be r and omly assigned to detect an absolute improvement in probability of recurring by 3 years from 0.50 to 0.30 . RESULTS A total of 521 patients were registered , 499 underwent p53 assessment , 272 ( 55 % ) were positive , and 114 ( 42 % ) were r and omly assigned . Accrual was halted on the basis of the data and safety monitoring board review of a futility analysis . Overall 5-year probability of recurring was 0.20 ( 95 % CI , 0.16 to 0.24 ) with no difference on the basis of p53 status . Only 67 % of patients r and omly assigned to MVAC received all three cycles with 12 patients receiving no treatment . There was no difference in recurrence in the r and omly assigned patients ( hazard ratio , 0.78 ; 95 % CI , 0.29 to 2.08 ; P = .62 ) . CONCLUSION Neither the prognostic value of p53 nor the benefit of MVAC chemotherapy in patients with p53-positive tumors was confirmed , but the high patient refusal rate , lower than expected event rate , and failures to receive assigned therapy severely compromised study power BACKGROUND The purpose of the study was to evaluate the benefit of adjuvant chemotherapy ( AC ) versus surgery alone in patients with muscle-invasive bladder cancer ( MIBC ) . PATIENTS AND METHODS One hundred and ninety-four patients with pT2G3 , pT3 - 4 , N0 - 2 transitional cell bladder carcinoma were r and omly allocated to control ( 92 patients ) or to four courses of AC ( 102 patients ) . These latter patients were further r and omly assigned to receive gemcitabine 1000 mg/m(2 ) days 1 , 8 and 15 and cisplatin 70 mg/m(2 ) day 2 or gemcitabine as above plus cisplatin 70 mg/m(2 ) day 15 , every 28 days . RESULTS At a median follow-up of 35 months , the 5-year overall survival ( OS ) was 48.5 % , with no difference between the two arms [ P = 0.24 , hazard ratio ( HR ) 1.29 , 95 % confidence interval ( CI ) 0.84 - 1.99 ] . Mortality hazard was significantly correlated with Nodes ( N ) and Tumor ( T ) stage . The control and AC arms had comparable disease-free survival ( 42.3 % and 37.2 % , respectively ; P = 0.70 , HR 1.08 , 95 % CI 0.73 - 1.59 ) . Only 62 % of patients received the planned cycles . A significant higher incidence of thrombocytopenia was observed in patients receiving cisplatin on day 2 ( P = 0.006 ) . A similar global quality of life was observed in the two arms . CONCLUSION The study was underpowered to demonstrate that AC with cisplatin and gemcitabine improves OS and disease-free survival in patients with MIBC OBJECTIVES In muscle invasive bladder cancer ( MIBC ) , careful clinical staging is essential for patient counseling and decision-making . Bimanual palpation ( BP ) is an integral part and guideline advice of clinical staging . Until now , however , the value of BP has never been studied . With this study , we aim to determine the accuracy of clinical staging through BP . METHODS Detailed clinical data were collected from a population -based series of 1,409 patients with MIBC , diagnosed between 1989 and 2005 , in the region of the Comprehensive Cancer Centre East in The Netherl and s. Selected were all patients who underwent BP ( n = 738 ) . Preoperative  tumor-stage ( cT-stage ) determined through BP was compared with post-cystectomy pT-stage . Contingency tables were made to determine the correlation between cT-stage and pT-stage . RESULTS In 18 of 142 patients in whom BP showed an organ-confined tumor , the tumor was unresectable ( pT4 ) at the time of surgery . Four out of 9 patients who had a suspected T4 tumor on BP but who underwent cystectomy anyway appeared to have operable tumors at cystectomy . In 87 patients ( 57.6 % ) , accurate staging through  BP  was observed . In 17 patients ( 11.3 % ) , clinical overstaging was found , and in 47 patients , ( 31.1 % ) clinical understaging . CONCLUSIONS Frequently , pT-stage after cystectomy does not correlate with preoperative cT-stage based on BP . Discrepancy was observed in 42 % of the patients : in 11 % , clinical overstaging and in 31 % , clinical understaging . Based on these data , some caution is suggested when interpreting the outcome of BP . Prospect i ve data is needed for a more formal evaluation of the staging accuracy of BP PURPOSE We conducted a phase II trial of neoadjuvant paclitaxel , carboplatin and gemcitabine as well as transurethral resection of bladder tumor to evaluate the clinical T0 ( cT0 ) rate with paclitaxel , carboplatin and gemcitabine , and to study cystoscopic surveillance or immediate cystectomy for patients with cT0 status following chemotherapy .  MATERIAL S AND METHODS Patients with T2-T4a chemotherapy and radiation naive urothelial cancer were eligible . T2 + tumor had to be diagnosed by transurethral bladder tumor resection followed by a second transurethral bladder tumor resection to confirm persistent disease within 16 weeks of the first resection . Three cycles of paclitaxel , carboplatin and gemcitabine were administered within 8 weeks of the second transurethral bladder tumor resection . Patients with cT0 status after paclitaxel , carboplatin and gemcitabine therapy could elect immediate cystectomy or cystoscopic surveillance , and those with greater than cT0 status were to undergo immediate cystectomy . RESULTS Of 77 patients 74 were assessable , and cT0 status after paclitaxel , carboplatin and gemcitabine was achieved in 34 of 74 patients ( 46 % ) . Of the 34 patients with cT0 status 10 underwent immediate cystectomy , 6 of whom had persistent cancer . Persistent tumor at transurethral bladder tumor resection was seen in 28 patients ( 38 % ) and 21 underwent cystectomy . Thus , 35 of 74 patients underwent cystectomy . With a median followup of 22 months 2-year overall survival was 59 % ( 95 % CI 45 , 72 ) and among cT0 cases it was 75 % ( 95 % CI 57 , 93 ) . CONCLUSIONS Although neoadjuvant paclitaxel , carboplatin and gemcitabine had a promising 46 % cT0 rate , the study failed to meet the primary objective as there was an unacceptably high rate ( 60 % ) of persistent cancer at cystectomy in patients presumed to have pT0 status . Patients completing neoadjuvant chemotherapy should strongly consider definitive local therapy rather than cystoscopic surveillance regardless of post-chemotherapy cT0 status BACKGROUND Perioperative cisplatin combination chemotherapy is associated with a survival benefit in patients with invasive bladder cancer ( BCa ) . However , in a recent report from the National Cancer Data base ( NCDB ) , only 11.6 % of stage III BCa patients received perioperative chemotherapy , the majority in the adjuvant setting . OBJECTIVE We explore the impact of postoperative complications on the timing of adjuvant chemotherapy . DESIGN , SETTING , AND PARTICIPANTS An independent review board approved the review of 1142 consecutive radical cystectomies ( RC ) , and data from these cases were entered into a prospect i ve complication data base ( 1995 - 2005 ) which was utilized and retrospectively review ed for accuracy at a single , academic , tertiary cancer center . INTERVENTIONS All patients underwent RC/urinary diversion by high-volume , fellowship-trained , urologic oncologists . MEASUREMENTS All complications within 90 d of surgery were defined and grade d using a five- grade modification of the original Clavien system utilized at Memorial Sloan-Kettering Cancer Center and stratified into 11 categories . Grade 2 - 5 complications typically prohibit starting adjuvant chemotherapy . Univariate and multivariable logistic regression were used to evaluate variables associated with complications . RESULTS AND LIMITATIONS Overall , 64 % ( 735 of 1142 patients ) experienced one or more complications , of which 83 % ( 611 of 735 ) were grade 2 - 5 . Furthermore , 57 % of grade 2 - 5 complications ( 347 of 611 ) occurred between discharge and 90 d , 38 % ( 233 of 611 ) within 6 wk , and 19 % ( 114 of 611 ) between 6 wk and 12 wk , the general time frame for adjuvant chemotherapy . Overall , 26 % ( 298 of 1142 patients ) required readmission . Surgical morbidity at a high-volume tertiary cancer center may not reflect the case mix or surgical experience seen in the community setting . CONCLUSION This series demonstrates that 30 % of patients ( 347 of 1142 ) undergoing RC may not have been able to receive adjuvant chemotherapy due to postoperative complications . This information should be taken into consideration when planning multimodal therapy and further supports the use of perioperative chemotherapy in the neoadjuvant setting Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent anti-CTLA-4 antibody .  All clinical trials to date , comprising over 3,000 patients , have been conducted in the metastatic disease setting , which allows for correlation of drug administration with clinical outcome but has limited analyses of intermediate biomarkers to indicate whether the drug has impacted human immune responses within the tumor microenvironment . We conducted a pre-surgical clinical trial in six patients with localized bladder cancer , which allowed for correlation of drug administration with biomarkers in both blood and tumor tissues but did not permit correlation with clinical outcome . We found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator ( ICOS ) . These CD4+ICOShi T cells produced IFN-gamma ( IFNγ ) and could recognize the tumor antigen NY-ESO-1 . Increase in CD4+ICOShi cells led to an increase in the ratio of effector to regulatory T cells . To our knowledge , these are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody , and they may be used to guide dosing and scheduling of this agent to improve clinical responses Conventional development of multivariate gene expression models  ( GEM ) predicting therapeutic response of cancer patients is based on analysis of patients treated with specific regimens , which limits generalization to different or novel drug combinations . We overcome this limitation by developing GEMs based on in vitro drug sensitivities and microarray analyses of the NCI-60 cancer cell line panel . These GEMs were evaluated in blind fashion as predictors of tumor response and /or patient survival in seven independent cohorts of patients with breast ( n = 275 ) , bladder ( n = 59 ) , and ovarian ( n= 143 ) cancer treated with multiagent chemotherapy , of which 233 patients were from prospect ively enrolled clinical trials . In all studies , GEMs effectively stratified tumor response and patient survival independent of established clinical and pathologic tumor variables . In bladder cancer patients treated with neoadjuvant methotrexate , vinblastine , Adriamycin ( doxorubicin ) , and cisplatin , the 3-year overall survival for those with favorable GEM scores was 81 % versus 33 % for those with less favorable scores ( P = 0.002 ) . GEMs for breast cancer patients treated with 5-fluorouracil , Adriamycin ( doxorubicin ) , and cyclophosphamide and ovarian cancer patients treated with platinum-containing regimens also stratified patient survival [ 5-year overall survival 100 % versus 74 % ( P = 0.05 ) and 3-year overall survival 68 % versus 43 % ( P = 0.008 ) , respectively ] . 
    Output:
    
agent
***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: INTRODUCTION Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) adjuvant chemotherapy .  PATIENTS AND METHODS Patients with pT1/T2N0M0 disease whose tumors demonstrated ≥ 10 % nuclear reactivity on central ly performed immunohistochemistry for p53 were offered r and om assignment to three cycles of adjuvant MVAC versus observation ; p53-negative patients were observed . By using a log-rank test with one-sided α = .05 and β = .10 , 190 p53-positive patients were planned to be r and omly assigned to detect an absolute improvement in probability of recurring by 3 years from 0.50 to 0.30 . RESULTS A total of 521 patients were registered , 499 underwent p53 assessment , 272 ( 55 % ) were positive , and 114 ( 42 % ) were r and omly assigned . Accrual was halted on the basis of the data and safety monitoring board review of a futility analysis . Overall 5-year probability of recurring was 0.20 ( 95 % CI , 0.16 to 0.24 ) with no difference on the basis of p53 status . Only 67 % of patients r and omly assigned to MVAC received all three cycles with 12 patients receiving no treatment . There was no difference in recurrence in the r and omly assigned patients ( hazard ratio , 0.78 ; 95 % CI , 0.29 to 2.08 ; P = .62 ) . CONCLUSION Neither the prognostic value of p53 nor the benefit of MVAC chemotherapy in patients with p53-positive tumors was confirmed , but the high patient refusal rate , lower than expected event rate , and failures to receive assigned therapy severely compromised study power BACKGROUND The purpose of the study was to evaluate the benefit of adjuvant chemotherapy ( AC ) versus surgery alone in patients with muscle-invasive bladder cancer ( MIBC ) . PATIENTS AND METHODS One hundred and ninety-four patients with pT2G3 , pT3 - 4 , N0 - 2 transitional cell bladder carcinoma were r and omly allocated to control ( 92 patients ) or to four courses of AC ( 102 patients ) . These latter patients were further r and omly assigned to receive gemcitabine 1000 mg/m(2 ) days 1 , 8 and 15 and cisplatin 70 mg/m(2 ) day 2 or gemcitabine as above plus cisplatin 70 mg/m(2 ) day 15 , every 28 days . RESULTS At a median follow-up of 35 months , the 5-year overall survival ( OS ) was 48.5 % , with no difference between the two arms [ P = 0.24 , hazard ratio ( HR ) 1.29 , 95 % confidence interval ( CI ) 0.84 - 1.99 ] . Mortality hazard was significantly correlated with Nodes ( N ) and Tumor ( T ) stage . The control and AC arms had comparable disease-free survival ( 42.3 % and 37.2 % , respectively ; P = 0.70 , HR 1.08 , 95 % CI 0.73 - 1.59 ) . Only 62 % of patients received the planned cycles . A significant higher incidence of thrombocytopenia was observed in patients receiving cisplatin on day 2 ( P = 0.006 ) . A similar global quality of life was observed in the two arms . CONCLUSION The study was underpowered to demonstrate that AC with cisplatin and gemcitabine improves OS and disease-free survival in patients with MIBC OBJECTIVES In muscle invasive bladder cancer ( MIBC ) , careful clinical staging is essential for patient counseling and decision-making . Bimanual palpation ( BP ) is an integral part and guideline advice of clinical staging . Until now , however , the value of BP has never been studied . With this study , we aim to determine the accuracy of clinical staging through BP . METHODS Detailed clinical data were collected from a population -based series of 1,409 patients with MIBC , diagnosed between 1989 and 2005 , in the region of the Comprehensive Cancer Centre East in The Netherl and s. Selected were all patients who underwent BP ( n = 738 ) . Preoperative  tumor-stage ( cT-stage ) determined through BP was compared with post-cystectomy pT-stage . Contingency tables were made to determine the correlation between cT-stage and pT-stage . RESULTS In 18 of 142 patients in whom BP showed an organ-confined tumor , the tumor was unresectable ( pT4 ) at the time of surgery . Four out of 9 patients who had a suspected T4 tumor on BP but who underwent cystectomy anyway appeared to have operable tumors at cystectomy . In 87 patients ( 57.6 % ) , accurate staging through  BP  was observed . In 17 patients ( 11.3 % ) , clinical overstaging was found , and in 47 patients , ( 31.1 % ) clinical understaging . CONCLUSIONS Frequently , pT-stage after cystectomy does not correlate with preoperative cT-stage based on BP . Discrepancy was observed in 42 % of the patients : in 11 % , clinical overstaging and in 31 % , clinical understaging . Based on these data , some caution is suggested when interpreting the outcome of BP . Prospect i ve data is needed for a more formal evaluation of the staging accuracy of BP PURPOSE We conducted a phase II trial of neoadjuvant paclitaxel , carboplatin and gemcitabine as well as transurethral resection of bladder tumor to evaluate the clinical T0 ( cT0 ) rate with paclitaxel , carboplatin and gemcitabine , and to study cystoscopic surveillance or immediate cystectomy for patients with cT0 status following chemotherapy .  MATERIAL S AND METHODS Patients with T2-T4a chemotherapy and radiation naive urothelial cancer were eligible . T2 + tumor had to be diagnosed by transurethral bladder tumor resection followed by a second transurethral bladder tumor resection to confirm persistent disease within 16 weeks of the first resection . Three cycles of paclitaxel , carboplatin and gemcitabine were administered within 8 weeks of the second transurethral bladder tumor resection . Patients with cT0 status after paclitaxel , carboplatin and gemcitabine therapy could elect immediate cystectomy or cystoscopic surveillance , and those with greater than cT0 status were to undergo immediate cystectomy . RESULTS Of 77 patients 74 were assessable , and cT0 status after paclitaxel , carboplatin and gemcitabine was achieved in 34 of 74 patients ( 46 % ) . Of the 34 patients with cT0 status 10 underwent immediate cystectomy , 6 of whom had persistent cancer . Persistent tumor at transurethral bladder tumor resection was seen in 28 patients ( 38 % ) and 21 underwent cystectomy . Thus , 35 of 74 patients underwent cystectomy . With a median followup of 22 months 2-year overall survival was 59 % ( 95 % CI 45 , 72 ) and among cT0 cases it was 75 % ( 95 % CI 57 , 93 ) . CONCLUSIONS Although neoadjuvant paclitaxel , carboplatin and gemcitabine had a promising 46 % cT0 rate , the study failed to meet the primary objective as there was an unacceptably high rate ( 60 % ) of persistent cancer at cystectomy in patients presumed to have pT0 status . Patients completing neoadjuvant chemotherapy should strongly consider definitive local therapy rather than cystoscopic surveillance regardless of post-chemotherapy cT0 status BACKGROUND Perioperative cisplatin combination chemotherapy is associated with a survival benefit in patients with invasive bladder cancer ( BCa ) . However , in a recent report from the National Cancer Data base ( NCDB ) , only 11.6 % of stage III BCa patients received perioperative chemotherapy , the majority in the adjuvant setting . OBJECTIVE We explore the impact of postoperative complications on the timing of adjuvant chemotherapy . DESIGN , SETTING , AND PARTICIPANTS An independent review board approved the review of 1142 consecutive radical cystectomies ( RC ) , and data from these cases were entered into a prospect i ve complication data base ( 1995 - 2005 ) which was utilized and retrospectively review ed for accuracy at a single , academic , tertiary cancer center . INTERVENTIONS All patients underwent RC/urinary diversion by high-volume , fellowship-trained , urologic oncologists . MEASUREMENTS All complications within 90 d of surgery were defined and grade d using a five- grade modification of the original Clavien system utilized at Memorial Sloan-Kettering Cancer Center and stratified into 11 categories . Grade 2 - 5 complications typically prohibit starting adjuvant chemotherapy . Univariate and multivariable logistic regression were used to evaluate variables associated with complications . RESULTS AND LIMITATIONS Overall , 64 % ( 735 of 1142 patients ) experienced one or more complications , of which 83 % ( 611 of 735 ) were grade 2 - 5 . Furthermore , 57 % of grade 2 - 5 complications ( 347 of 611 ) occurred between discharge and 90 d , 38 % ( 233 of 611 ) within 6 wk , and 19 % ( 114 of 611 ) between 6 wk and 12 wk , the general time frame for adjuvant chemotherapy . Overall , 26 % ( 298 of 1142 patients ) required readmission . Surgical morbidity at a high-volume tertiary cancer center may not reflect the case mix or surgical experience seen in the community setting . CONCLUSION This series demonstrates that 30 % of patients ( 347 of 1142 ) undergoing RC may not have been able to receive adjuvant chemotherapy due to postoperative complications . This information should be taken into consideration when planning multimodal therapy and further supports the use of perioperative chemotherapy in the neoadjuvant setting Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent anti-CTLA-4 antibody .  All clinical trials to date , comprising over 3,000 patients , have been conducted in the metastatic disease setting , which allows for correlation of drug administration with clinical outcome but has limited analyses of intermediate biomarkers to indicate whether the drug has impacted human immune responses within the tumor microenvironment . We conducted a pre-surgical clinical trial in six patients with localized bladder cancer , which allowed for correlation of drug administration with biomarkers in both blood and tumor tissues but did not permit correlation with clinical outcome . We found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator ( ICOS ) . These CD4+ICOShi T cells produced IFN-gamma ( IFNγ ) and could recognize the tumor antigen NY-ESO-1 . Increase in CD4+ICOShi cells led to an increase in the ratio of effector to regulatory T cells . To our knowledge , these are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody , and they may be used to guide dosing and scheduling of this agent to improve clinical responses Conventional development of multivariate gene expression models  ( GEM ) predicting therapeutic response of cancer patients is based on analysis of patients treated with specific regimens , which limits generalization to different or novel drug combinations . We overcome this limitation by developing GEMs based on in vitro drug sensitivities and microarray analyses of the NCI-60 cancer cell line panel . These GEMs were evaluated in blind fashion as predictors of tumor response and /or patient survival in seven independent cohorts of patients with breast ( n = 275 ) , bladder ( n = 59 ) , and ovarian ( n= 143 ) cancer treated with multiagent chemotherapy , of which 233 patients were from prospect ively enrolled clinical trials . In all studies , GEMs effectively stratified tumor response and patient survival independent of established clinical and pathologic tumor variables . In bladder cancer patients treated with neoadjuvant methotrexate , vinblastine , Adriamycin ( doxorubicin ) , and cisplatin , the 3-year overall survival for those with favorable GEM scores was 81 % versus 33 % for those with less favorable scores ( P = 0.002 ) . GEMs for breast cancer patients treated with 5-fluorouracil , Adriamycin ( doxorubicin ) , and cyclophosphamide and ovarian cancer patients treated with platinum-containing regimens also stratified patient survival [ 5-year overall survival 100 % versus 74 % ( P = 0.05 ) and 3-year overall survival 68 % versus 43 % ( P = 0.008 ) , respectively ] . 
    Output:
    