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: PURPOSE TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic setting s. This phase II study ( NCT01144455 ) evaluated gemcitabine plus TH-302 in patients with previously untreated , locally advanced or metastatic pancreatic cancer . PATIENTS AND METHODS Patients were r and omly assigned 1:1:1 to gemcitabine ( 1,000 mg/m(2 ) ) , gemcitabine plus TH-302 240 mg/m(2 ) ( G+T240 ) , or gemcitabine plus TH-302 340 mg/m(2 ) ( G+T340 ) . R and omized crossover after progression on gemcitabine was allowed . The primary end point was progression-free survival ( PFS ) . Secondary end points included overall survival ( OS ) , tumor response , CA 19 - 9 response , and safety . RESULTS Two hundred fourteen patients ( 77 % with metastatic disease ) were enrolled between June 2010 and July 2011 .  PFS was significantly longer with gemcitabine plus TH-302 ( pooled combination arms ) compared with gemcitabine alone ( median PFS , 5.6 v 3.6 months , respectively ; hazard ratio , 0.61 ; 95 % CI , 0.43 to 0.87 ; P = .005 ; median PFS for metastatic disease , 5.1 v 3.4 months , respectively ) . Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months , respectively . Tumor response was 12 % , 17 % , and 26 % in the gemcitabine , G+T240 , and G+T340 arms , respectively ( G+T340 v gemcitabine , P = .04 ) . CA 19 - 9 decrease was greater with G+T340 versus gemcitabine ( -5,398 v -549 U/mL , respectively ; P = .008 ) . Median OS times for gemcitabine , G+T240 , and G+T340 were 6.9 , 8.7 , and 9.2 months , respectively ( P = not significant ) . The most common adverse events ( AEs ) were fatigue , nausea , and peripheral edema ( frequencies similar across arms ) . Skin and mucosal toxicities ( 2 % grade 3 ) and myelosuppression ( 55 % grade 3 or 4 ) were the most common TH-302-related AEs but were not associated with treatment discontinuation . CONCLUSION PFS , tumor response , and CA 19 - 9 response were significantly improved with G+TH-302 . G+T340 is being investigated further in the phase III MAESTRO study ( NCT01746979 ) Two subgroups showing significantly poor survival when treated with single-agent gemcitabine have been identified ; one is defined by an overexpression of ACOX1 in blood , and the other via a pain intensity threshold . Masitinib in combination with gemcitabine appears to have a positive benefit – risk ratio in both subgroups . These findings could influence future trial design in pancreatic cancer BACKGROUND In a phase 1 - 2 trial of albumin-bound paclitaxel ( nab-paclitaxel ) plus gemcitabine , substantial clinical activity was noted in patients with advanced pancreatic cancer . We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer . METHODS We r and omly assigned patients with a Karnofsky performance-status score of 70 or more ( on a scale from 0 to 100 , with higher scores indicating better performance status ) to nab-paclitaxel ( 125 mg per square meter of body-surface area ) followed by gemcitabine  ( 1000 mg per square meter ) on days 1 , 8 , and 15 every 4 weeks or gemcitabine monotherapy ( 1000 mg per square meter ) weekly for 7 of 8 weeks ( cycle 1 ) and then on days 1 , 8 , and 15 every 4 weeks ( cycle 2 and subsequent cycles ) . Patients received the study treatment until disease progression . The primary end point was overall survival ; secondary end points were progression-free survival and overall response rate . RESULTS A total of 861 patients were r and omly assigned to nab-paclitaxel plus gemcitabine ( 431 patients ) or gemcitabine  ( 430 ) . The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group ( hazard ratio for death , 0.72 ; 95 % confidence interval [ CI ] , 0.62 to 0.83 ; P<0.001 ) . The survival rate was 35 % in the nab-paclitaxel-gemcitabine group versus 22 % in the gemcitabine group at 1 year , and 9 % versus 4 % at 2 years . The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group , as compared with 3.7 months in the gemcitabine group ( hazard ratio for disease progression or death , 0.69 ; 95 % CI , 0.58 to 0.82 ; P<0.001 ) ; the response rate according to independent review was 23 % versus 7 % in the two groups ( P<0.001 ) . The most common adverse events of grade 3 or higher were neutropenia ( 38 % in the nab-paclitaxel-gemcitabine group vs. 27 % in the gemcitabine group ) , fatigue ( 17 % vs. 7 % ) , and neuropathy ( 17 % vs. 1 % ) . Febrile neutropenia occurred in 3 % versus 1 % of the patients in the two groups . In the nab-paclitaxel-gemcitabine group , neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days . CONCLUSIONS In patients with metastatic pancreatic adenocarcinoma , nab-paclitaxel plus gemcitabine significantly improved overall survival , progression-free survival , and response rate , but rates of peripheral neuropathy and myelosuppression were increased . ( Funded by Celgene ; Clinical Trials.gov number , NCT00844649 . ) PURPOSE CA 19 - 9 is an important tumor marker in patients with pancreatic adenocarcinoma . A secondary end point of Radiation Therapy Oncology Group trial 9704 was prospect i ve evaluation of the ability of postresectional CA 19 - 9 to predict survival . METHODS CA 19 - 9 expression was analyzed as a dichotomized variable ( < 180 v > or = 180 ) or ( < or = 90 v > 90 ) . Cox proportional hazards models were utilized to identify the impact of CA 19 - 9 expression on overall survival ( OS ) . Actuarial estimates for OS were calculated using Kaplan-Meier methods . RESULTS Three hundred eighty-five patients patients had assessable CA 19 - 9 levels . The majority had a CA 19 - 9 level lower than 180 or < or = 90 ( n = 220 and 200 , respectively ) , while 34 % were Lewis Antigen negative and 33 ( 9 % ) and 53 ( 14 % ) patients had levels higher than 180 and higher than 90 . When CA 19 - 9 was analyzed as a dichotomized variable , there was a significant survival difference favoring patients with CA 19 - 9 lower than 180 ( hazard ratio [ HR ] , 3.53 ; P < .0001 ) . This corresponds to a 72 % reduction in the risk of death for patients with a CA 19 - 9 lower than 180 . This was also true for patients with CA 19 - 9 < or = 90 ( HR , 3.4 ; P < .0001 ) . Multivariate analyses confirmed that CA 19 - 9 , when analyzed as both a continuous and a dichotomized variable , is a highly significant predictor of OS in patients with resected pancreatic cancer . CONCLUSION To our knowledge , this is the first phase III trial to perform prospect i ve analysis of CA 19 - 9 levels in patients treated with adjuvant chemoradiotherapy . It definitively confirms the prognostic importance of postresectional CA 19 - 9 levels after surgery with curative intent in patients with pancreatic cancer Objective : The aim of this study was to evaluate and vali date the proposed 8th edition American Joint Committee on Cancer ( AJCC ) system for T and N staging of pancreatic adenocarcinoma . Summary of Background Data : Investigators have question ed the clinical relevance and reproducibility of previous AJCC staging for pancreatic adenocarcinoma . Methods : Prospect i ve data bases at Memorial Sloan Kettering ( MSK ) , Massachusetts General Hospital ( MGH ) , and Johns Hopkins Hospital ( JHH ) were queried for patients who had undergone resection for pancreatic adenocarcinoma . Patients who underwent a margin-negative ( R0 ) resection , and who had previously undergone pathologic review , were included . Patients were staged according to 7th edition AJCC criteria , as well as the proposed 8th edition system that includes different definitions of tumor size ( T ) and nodal status ( N ) . The data set was r and omly split into training and test sets . Results : Two thous and three hundred eighteen patients were identified who met inclusion criteria . Recursive partitioning on the training set ( n = 1551 ) identified statistically appropriate cutoffs for tumor size ( < 2.2 cm , ≥4.8 cm , ) and nodal status ( no positive nodes , 1 to 3 positive nodes , ≥4 positive nodes ) that supported the proposed 8th edition changes . Median survival in patients staged as T3 , N0 by the 7th edition definitions was different between institutions ( median Center 1 , 24 mo ; Center 2 , 37 mo ; Center 3 , 29 mo ; P = 0.054 ) . This difference was not observed when patients were staged as T3 , N0 by 8th edition criteria . Stage , and stage-specific outcome ( 7th edition ) , on the test set revealed a predominance of patients ( 68 % ) within the IIB subgroup , and a concordance probability estimate ( CPE ) of 0.57 for stage-specific survival . When assessed with 8th edition criteria , no stage subgroup had a majority of patients , and the CPE was 0.58 . Conclusions : The proposed 8th edition changes for T and N classification were statistically valid and may allow a more reproducible system of T staging . This system also stratifies patients more evenly across stages without sacrificing prognostic accuracy 
    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: PURPOSE TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic setting s. This phase II study ( NCT01144455 ) evaluated gemcitabine plus TH-302 in patients with previously untreated , locally advanced or metastatic pancreatic cancer . PATIENTS AND METHODS Patients were r and omly assigned 1:1:1 to gemcitabine ( 1,000 mg/m(2 ) ) , gemcitabine plus TH-302 240 mg/m(2 ) ( G+T240 ) , or gemcitabine plus TH-302 340 mg/m(2 ) ( G+T340 ) . R and omized crossover after progression on gemcitabine was allowed . The primary end point was progression-free survival ( PFS ) . Secondary end points included overall survival ( OS ) , tumor response , CA 19 - 9 response , and safety . RESULTS Two hundred fourteen patients ( 77 % with metastatic disease ) were enrolled between June 2010 and July 2011 .  PFS was significantly longer with gemcitabine plus TH-302 ( pooled combination arms ) compared with gemcitabine alone ( median PFS , 5.6 v 3.6 months , respectively ; hazard ratio , 0.61 ; 95 % CI , 0.43 to 0.87 ; P = .005 ; median PFS for metastatic disease , 5.1 v 3.4 months , respectively ) . Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months , respectively . Tumor response was 12 % , 17 % , and 26 % in the gemcitabine , G+T240 , and G+T340 arms , respectively ( G+T340 v gemcitabine , P = .04 ) . CA 19 - 9 decrease was greater with G+T340 versus gemcitabine ( -5,398 v -549 U/mL , respectively ; P = .008 ) . Median OS times for gemcitabine , G+T240 , and G+T340 were 6.9 , 8.7 , and 9.2 months , respectively ( P = not significant ) . The most common adverse events ( AEs ) were fatigue , nausea , and peripheral edema ( frequencies similar across arms ) . Skin and mucosal toxicities ( 2 % grade 3 ) and myelosuppression ( 55 % grade 3 or 4 ) were the most common TH-302-related AEs but were not associated with treatment discontinuation . CONCLUSION PFS , tumor response , and CA 19 - 9 response were significantly improved with G+TH-302 . G+T340 is being investigated further in the phase III MAESTRO study ( NCT01746979 ) Two subgroups showing significantly poor survival when treated with single-agent gemcitabine have been identified ; one is defined by an overexpression of ACOX1 in blood , and the other via a pain intensity threshold . Masitinib in combination with gemcitabine appears to have a positive benefit – risk ratio in both subgroups . These findings could influence future trial design in pancreatic cancer BACKGROUND In a phase 1 - 2 trial of albumin-bound paclitaxel ( nab-paclitaxel ) plus gemcitabine , substantial clinical activity was noted in patients with advanced pancreatic cancer . We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer . METHODS We r and omly assigned patients with a Karnofsky performance-status score of 70 or more ( on a scale from 0 to 100 , with higher scores indicating better performance status ) to nab-paclitaxel ( 125 mg per square meter of body-surface area ) followed by gemcitabine  ( 1000 mg per square meter ) on days 1 , 8 , and 15 every 4 weeks or gemcitabine monotherapy ( 1000 mg per square meter ) weekly for 7 of 8 weeks ( cycle 1 ) and then on days 1 , 8 , and 15 every 4 weeks ( cycle 2 and subsequent cycles ) . Patients received the study treatment until disease progression . The primary end point was overall survival ; secondary end points were progression-free survival and overall response rate . RESULTS A total of 861 patients were r and omly assigned to nab-paclitaxel plus gemcitabine ( 431 patients ) or gemcitabine  ( 430 ) . The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group ( hazard ratio for death , 0.72 ; 95 % confidence interval [ CI ] , 0.62 to 0.83 ; P<0.001 ) . The survival rate was 35 % in the nab-paclitaxel-gemcitabine group versus 22 % in the gemcitabine group at 1 year , and 9 % versus 4 % at 2 years . The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group , as compared with 3.7 months in the gemcitabine group ( hazard ratio for disease progression or death , 0.69 ; 95 % CI , 0.58 to 0.82 ; P<0.001 ) ; the response rate according to independent review was 23 % versus 7 % in the two groups ( P<0.001 ) . The most common adverse events of grade 3 or higher were neutropenia ( 38 % in the nab-paclitaxel-gemcitabine group vs. 27 % in the gemcitabine group ) , fatigue ( 17 % vs. 7 % ) , and neuropathy ( 17 % vs. 1 % ) . Febrile neutropenia occurred in 3 % versus 1 % of the patients in the two groups . In the nab-paclitaxel-gemcitabine group , neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days . CONCLUSIONS In patients with metastatic pancreatic adenocarcinoma , nab-paclitaxel plus gemcitabine significantly improved overall survival , progression-free survival , and response rate , but rates of peripheral neuropathy and myelosuppression were increased . ( Funded by Celgene ; Clinical Trials.gov number , NCT00844649 . ) PURPOSE CA 19 - 9 is an important tumor marker in patients with pancreatic adenocarcinoma . A secondary end point of Radiation Therapy Oncology Group trial 9704 was prospect i ve evaluation of the ability of postresectional CA 19 - 9 to predict survival . METHODS CA 19 - 9 expression was analyzed as a dichotomized variable ( < 180 v > or = 180 ) or ( < or = 90 v > 90 ) . Cox proportional hazards models were utilized to identify the impact of CA 19 - 9 expression on overall survival ( OS ) . Actuarial estimates for OS were calculated using Kaplan-Meier methods . RESULTS Three hundred eighty-five patients patients had assessable CA 19 - 9 levels . The majority had a CA 19 - 9 level lower than 180 or < or = 90 ( n = 220 and 200 , respectively ) , while 34 % were Lewis Antigen negative and 33 ( 9 % ) and 53 ( 14 % ) patients had levels higher than 180 and higher than 90 . When CA 19 - 9 was analyzed as a dichotomized variable , there was a significant survival difference favoring patients with CA 19 - 9 lower than 180 ( hazard ratio [ HR ] , 3.53 ; P < .0001 ) . This corresponds to a 72 % reduction in the risk of death for patients with a CA 19 - 9 lower than 180 . This was also true for patients with CA 19 - 9 < or = 90 ( HR , 3.4 ; P < .0001 ) . Multivariate analyses confirmed that CA 19 - 9 , when analyzed as both a continuous and a dichotomized variable , is a highly significant predictor of OS in patients with resected pancreatic cancer . CONCLUSION To our knowledge , this is the first phase III trial to perform prospect i ve analysis of CA 19 - 9 levels in patients treated with adjuvant chemoradiotherapy . It definitively confirms the prognostic importance of postresectional CA 19 - 9 levels after surgery with curative intent in patients with pancreatic cancer Objective : The aim of this study was to evaluate and vali date the proposed 8th edition American Joint Committee on Cancer ( AJCC ) system for T and N staging of pancreatic adenocarcinoma . Summary of Background Data : Investigators have question ed the clinical relevance and reproducibility of previous AJCC staging for pancreatic adenocarcinoma . Methods : Prospect i ve data bases at Memorial Sloan Kettering ( MSK ) , Massachusetts General Hospital ( MGH ) , and Johns Hopkins Hospital ( JHH ) were queried for patients who had undergone resection for pancreatic adenocarcinoma . Patients who underwent a margin-negative ( R0 ) resection , and who had previously undergone pathologic review , were included . Patients were staged according to 7th edition AJCC criteria , as well as the proposed 8th edition system that includes different definitions of tumor size ( T ) and nodal status ( N ) . The data set was r and omly split into training and test sets . Results : Two thous and three hundred eighteen patients were identified who met inclusion criteria . Recursive partitioning on the training set ( n = 1551 ) identified statistically appropriate cutoffs for tumor size ( < 2.2 cm , ≥4.8 cm , ) and nodal status ( no positive nodes , 1 to 3 positive nodes , ≥4 positive nodes ) that supported the proposed 8th edition changes . Median survival in patients staged as T3 , N0 by the 7th edition definitions was different between institutions ( median Center 1 , 24 mo ; Center 2 , 37 mo ; Center 3 , 29 mo ; P = 0.054 ) . This difference was not observed when patients were staged as T3 , N0 by 8th edition criteria . Stage , and stage-specific outcome ( 7th edition ) , on the test set revealed a predominance of patients ( 68 % ) within the IIB subgroup , and a concordance probability estimate ( CPE ) of 0.57 for stage-specific survival . When assessed with 8th edition criteria , no stage subgroup had a majority of patients , and the CPE was 0.58 . Conclusions : The proposed 8th edition changes for T and N classification were statistically valid and may allow a more reproducible system of T staging . This system also stratifies patients more evenly across stages without sacrificing prognostic accuracy 
    Output:
    