***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 We assessed the prognostic importance of the level of  thymidylate synthase ( TS ) expression in patients with primary rectal cancer and whether , for Dukes ' B and C cancer patients , the benefit of chemotherapy was associated with TS expression . PATIENTS AND METHODS The level of TS expression in the primary rectal cancers of 294 of 801 patients enrolled on protocol R-01 of the National Surgical Adjuvant Breast and Bowel Project ( NSABP ) was immunohistochemically assessed with the monoclonal antibody TS 106 . RESULTS Forty-nine percent of patients whose tumors had low TS levels ( n = 91 ) were disease free at 5 years compared with 27 % of patients with high levels of TS ( n = 203 ; P < .01 ) . Moreover , 60 % of patients with low TS levels were alive after 5 years compared with 40 % of patients with high TS levels ( P < .01 ) . The level of TS protein was significantly associated with Dukes ' stage ( P < .01 ) ; patients with a more advanced Dukes ' stage had a significantly higher level of TS . The level of TS expression remained prognostic for both disease-free survival ( P < .01 ) and survival ( P < .05 ) independent of Dukes ' stage and other pathologic characteristics evaluated . Thirty-eight percent and 54 % of patients with high TS levels ( n = 71 ) were disease free and alive , respectively , after 5 years when treated with chemotherapy , compared with 17 % and 31 % , respectively , of similar patients when treated with surgery alone ( n = 64 ) ( P < .01 ) . No difference was noted in disease-free survival ( P = .46 ) or survival ( P = .43 ) in patients with low TS levels . CONCLUSION The expression of TS is an important independent prognosticator of disease-free survival and survival in patients with rectal cancer .  Adjuvant fluorouracil (5-FU)-based chemotherapy demonstrated significant improvement in disease-free and overall survival for patients with high TS levels . Prospect i ve studies measuring TS levels will be needed to underst and further the role of TS as a prognosticator of survival and chemotherapeutic benefit We performed a clinical study to identify biological markers useful for the treatment of resectable non-small-cell lung cancers ( NSCLCs ) . In all , 173 patients were studied . By immunohistochemistry , we evaluated the Ki-67 proliferation index , tumour vascularity , thymidylate synthase ( TS ) , vascular endothelial growth factor (VEGF)-A , VEGF-C , and E (epithelial)-cadherin . Concerning the survival of NSCLC patients , tumour vascularity ( P<0.01 ) , VEGF-A status ( P=0.03 ) , VEGF-C status ( P=0.03 ) , and E-cadherin status ( P=0.03 ) were significant prognostic factors in patients with stage I NSCLCs . The Ki-67 proliferation index ( P=0.02 ) and TS status ( P<0.01 ) were significant prognostic factors in patients with stage II – III NSCLCs . In patients with stage II – III NSCLCs , furthermore , the survival of UFT ( a combination of tegafur and uracil)-treated patients with TS-negative tumours was significantly better than those of any other patients . Biological markers associated with tumour angiogenesis or metastasis are useful for the detection of aggressive tumours among early-stage NSCLCs . Postoperative chemotherapy might be necessary in such tumours even in stage I. In contrast , tumour proliferation rate and TS status are useful markers for identifying less aggressive tumours in locally advanced NSCLCs . Thymidylate synthase expression is also a useful marker to evaluate responsiveness of UFT-based chemotherapy for these tumours Purpose : This phase II trial of pemetrexed explored potential correlations between treatment outcome ( antitumor activity ) and molecular target expression . Experimental Design : Chemonaïve patients with advanced breast cancer received up to three cycles of pemetrexed 500 mg/m2 ( 10-minute i.v . infusion ) on day 1 of a 21-day cycle , with folic acid and vitamin B12 supplementation . Tumors were surgically removed after the last cycle of pemetrexed as clinical ly indicated . Biopsies were taken at baseline , 24 hours after infusion in cycle 1 , and after cycle 3 . Results : Sixty-one women ( median age , 46 years ; range , 32 - 72 years ) were treated and were evaluable for response .  Objective response rate was 31 % . Simple logistic regression suggested a potential relationship between mRNA expression of thymidylate synthase ( TS ) and pemetrexed response ( P = 0.103 ) . Based on threshold analysis , patients with “ low ” baseline TS ( ≤71 ) were more likely to respond to pemetrexed than patients with “ high ” baseline TS ( > 71 ) . Expression of baseline dihydrofolate reductase and glycinamide ribonucleotide formyl transferase tended to be higher in responders but this association was not significant ( P > 0.311 ) . TS expression increased significantly between baseline and biopsy 2 ( P = 0.004 ) and dropped to near baseline levels at biopsy 3 . Conversely , dihydrofolate reductase and glycinamide ribonucleotide formyl transferase decreased after pemetrexed chemotherapy . Conclusions : Our results suggest a potential association between “ low ” pretreatment TS expression levels and response to pemetrexed chemotherapy . Future trials examining expression levels of other genes important to the folate pathway and /or breast cancer may identify a more robust multigene profile that can better predict response to this novel antifolate The purpose of this study was to define the prognostic value of a group of molecular tumor markers in a well-staged population of patients treated with trimodality therapy for esophageal cancer . The original pretreatment paraffin-embedded endoscopic esophageal tumor biopsy material was obtained from 118 patients treated with concurrent cisplatin + 5-fluorouracil ( 5-FU ) + 45 Gy radiation followed by resection from 1986 until 1997 at the Duke University Comprehensive Cancer Center . Three markers of possible platinum chemotherapy association [ metallothionein ( MT ) , glutathione S-transferase-pi ( GST-pi ) , P-glycoprotein ( P-gp or multidrug resistance ) ] and one marker of possible 5-FU association [ thymidylate synthase ( TS ) ] were measured using immunohistochemistry . The median cancer-free survival was 25.0 months , with a significantly improved survival for the 38 patients who had a complete response ( P < 0.001 ) . High-level expression of GST-pi , P-gp , and TS were associated with a decreased survival . MT was not significant in this population . Multivariate analysis identified high-level expression in two of the platinum markers ( GST-pi and P-gp ) and the 5-FU marker TS as independent predictors of early recurrence and death . In conclusion , this investigation measured three possible markers associated with platinum and one possible marker associated with 5-FU in a cohort of esophageal cancer patients .  Independent prognostic significance was observed , which suggests that it may be possible to predict which patients may benefit most from trimodality therapy . These data need to be reproduced in a prospect i ve investigation Introduction : In retrospective analyses of patients with nonsquamous non – small-cell lung cancer treated with pemetrexed  , low thymidylate synthase ( TS ) expression is associated with better clinical outcomes . This phase II study explored this association prospect ively at the protein and mRNA-expression level . Methods : Treatment-naive patients with nonsquamous non – small-cell lung cancer ( stage IIIB/IV ) had four cycles of first-line chemotherapy with pemetrexed/cisplatin .  Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability .  TS expression ( nucleus/cytoplasm/total ) was assessed in diagnostic tissue sample s by immunohistochemistry ( IHC ; H-scores ) , and quantitative reverse-transcriptase polymerase chain reaction . Cox regression was used to assess the association between H-scores and progression-free/overall survival ( PFS/OS ) distribution estimated by the Kaplan – Meier method . Maximal & khgr;2 analysis identified optimal cutpoints between low TS- and high TS-expression groups , yielding maximal associations with PFS/OS . Results : The study enrolled 70 patients ; of these 43 ( 61.4 % ) started maintenance treatment . In 60 patients with valid H-scores , median ( m ) PFS was 5.5 ( 95 % confidence interval [ CI ] , 3.9–6.9 ) months , mOS was 9.6 ( 95 % CI , 7.3–15.7 ) months . Higher nuclear TS expression was significantly associated with shorter PFS and OS ( primary analysis IHC , PFS : p < 0.0001 ; hazard ratio per 1-unit increase : 1.015 ; 95%CI , 1.008–1.021 ) . At the optimal cutpoint of nuclear H-score ( 70 ) , mPFS in the low TS- versus high TS-expression groups was 7.1 ( 5.7–8.3 ) versus 2.6 ( 1.3–4.1 ) months ( p = 0.0015 ; hazard ratio = 0.28 ; 95%CI , 0.16–0.52 ; n = 40/20 ) . Trends were similar for cytoplasm H-scores , quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints ( OS , response , and disease control ) . Conclusions : The primary endpoint was met ; low TS expression was associated with longer PFS . Further r and omized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts Introduction : This study is to evaluate whether thymidylate synthase ( TS ) or thyroid transcription factor 1 ( TTF1 ) protein expression can predict clinical outcomes for pemetrexed-based chemotherapy in patients with nonsquamous non-small cell lung cancer ( NSCLC ) . Methods : Two hundred eighty-five consecutive patients with nonsquamous NSCLC treated with pemetrexed-based chemotherapy  were immunohistochemically analyzed for the expressions of TS and TTF1 . Results : TS and TTF1 expression were successfully analyzed in 193 and 284 cases , respectively . Tumors with TS-negativity or TTF1-positivity were more frequent in patients who were female , younger , had adenocarcinoma , or had never smoked .  Higher response rates for pemetrexed-based chemotherapy were associated with TS-negativity ( 33.7 % versus 14.1 % , p = 0.002 ) and TTF1-positivity ( 28.1 % versus 9.8 % , p < 0.001 ) . In univariate analysis , progression-free survival for pemetrexed-based chemotherapy was significantly longer in groups with adenocarcinoma ( 2.9 versus 1.4 months , p = 0.001 ) , TS-negativity ( 4.1 versus 2.0 months , p = 0.001 ) , and TTF1-positivity ( 3.8 versus 1.3 months , p < 0.001 ) . In multivariate analysis , TS-negativity ( hazard ratio [ HR ] = 0.70 ; 95 % confidence interval [ CI ] , 0.51–0.97 ) and TTF1-positivity ( HR = 0.51 ; 95 % CI , 0.35–0.73 ) were associated with longer progression-free survival . Patients with TTF1-positive tumors also had significantly longer overall survival times than patients with TTF1-negative tumors ( 25.4 versus 14.2 months , HR = 0.55 ; 95 % CI , 0.39–0.77 ) . Conclusions : Low TS or high TTF1 protein expression was significantly associated with better clinical outcomes in nonsquamous NSCLC patients who were treated with pemetrexed-based chemotherapy . The predictive role of TS or TTF1 expression should be further vali date d in a prospect i ve r and omized study BACKGROUND UFT ( tegafur + uracil ) has been reported to be effective as an adjuvant in postoperative chemotherapy for non-small cell lung cancer ( NSCLC ) in a r and omized prospect i ve study . Thymidylate synthase ( TS ) and dihydropyrimidine dehydrogenase ( DPD ) expression were investigated in resected tumors and the relationship between their expression and clinical factors in NSCLC patients was examined . PATIENTS AND METHODS Fifty-four NSCLC patients had undergone complete surgical resection and lymph node dissection , and had been administered UFT post-surgery .  The TS and DPD expression in the tumor tissues was evaluated by immunohistochemical staining . The relationship between TS and /or DPD expression and clinicopathological factors was examined . RESULTS There were 38 TS-negative and 16 TS-positive cases , and 22 DPD-negative and 32 DPD-positive cases . There was no significant difference between the patients with TS 
    Output:
    
Low TS protein expression is a favorable predictive factor for better OS/PFS in NSCLC patients treated with TS-targeted drugs .