***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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    Input: Locally advanced rectal cancer is currently treated with pre-operative radiochemotherapy ( p RCT ) , but the response is not uniform . Identification of patients with higher likelihood of responding to p RCT is clinical ly relevant , as patients with resistant tumors could be spared exposure to radiation or DNA-damaging drugs that are associated with adverse side effects . To highlight predictive biomarkers of response to p RCT , a systematic search of PubMed was conducted with a combination of the following terms : “ rectal ” , “ predictive ” , “ radiochemotherapy ” , “ neoadjuvant ” , “ response ” and “ biomarkers ” . Genetic polymorphisms in epithelial growth factor receptor ( EGFR ) and thymidylate synthase ( TS ) genes , the expression of several markers , such as EGFR , bcl-2/bax and cyclooxygenase (COX)-2 , and circulating biomarkers , such as serum carcinoembryonic antigen ( CEA ) level , are promising as predictor markers , but need to be further evaluated . The majority of the studies did not support the predictive value of p53 , while the values of Ki-67 , TS and p21 is still controversial . Gene expression profiles of thous and s of genes using microarrays , microRNA studies and the search for new circulating molecules , such as human telomerase reverse transcriptase mRNA and cell-free DNA , are providing interesting results that might lead to the identification of new useful biomarkers . Evaluation of biomarkers in larger , prospect i ve trials are required to guide therapeutic strategies Objective : To prospect ively describe patient-reported outcomes ( PROs ) after preoperative chemoradiotherapy ( pCRT ) for rectal cancer . Background : Little evidence is available on PROs after pCRT for rectal cancer . Patients and Methods : Patients with rectal cancer , c and i date s to receive pCRT , were enrolled in a multicenter prospect i ve observational trial . Health-related quality of life was assessed using the European Organisation for Research and Treatment of Cancer ( EORTC ) QLQ-C30 and its colorectal cancer module ( QLQ-CR38 ) , and fecal incontinence and bowel function were evaluated using the fecal incontinence score question naire and a set of ad hoc questions . Question naires were filled out before CRT ( t0 ) , 2 to 3 weeks after completion of CRT ( t1 ) , and at 6 ( t2 ) and 12 months ( t3 ) after surgery . Primary analysis of selected scales included : global quality of life , physical functioning , social functioning , fatigue , body image , future prospect i ve , and gender-related sexual problems . Results : Of 149 eligible patients , question naires were completed in 100 % , 95 % , 88 % and 77 % of cases at t0 , t1 , t2 , and t3 , respectively . At t3 , 78 % of patients reported stool fractionation and 72 % sensation of incomplete defecation . Only 14 % of patients had optimal continence . Physical/social functioning , fatigue , and body image showed a decrease just after pCRT and returned to baseline levels at 1 year after treatment . Global quality of life was stable over time . Male sexual problems were greatly impaired throughout the study period ( P < 0.001 ) with major clinical ly meaningful changes between baseline and 1 year after treatment . Conclusions : These findings add to the body of evidence available regarding pCRT and help clinicians to make more informed treatment decisions AIMS The identification of predictive markers of response to chemoradiotherapy treatment remains a promising approach for patient management in order to obtain the best response with minor side effects . Initially , we investigated whether the analysis of several markers previously studied and others not yet evaluated could predict response to 5-fluorouracil- and capecitabine-based neoadjuvant treatment in locally advanced rectal cancer . METHODS & MATERIAL S We studied germline and tumoral sample s of 65 stage II/III rectal patients . A panel of pharmacogenetic markers was genotyped in paired peripheral blood sample s and rectal cancer tumors . RESULTS Our results seem to confirm the previously described association of thymidylate synthase and the prediction of chemoradiotherapy response in rectal cancer . However , it failed to confirm the clinical utility proposed for XRCC1 , ERCC1 , ERCC2 , MTHFR and EGFR polymorphisms in blood/germline sample s. Subsequently , with the aim of improving prediction of individual response and assessing the role of studied polymorphisms in response to treatment , we determined if changes in tumor response to these markers could predict clinical outcome . We found a high degree of changes between germline and tumor sample s , mainly somatic mutations without microsatellite instability , and a minor frequency of loss-of-heterozygosity events . In tumoral sample s , XRCC1 appeared to be significantly associated ( p = 0.006 ) with downstaging of the tumor ( odds ratio : 7.93 ; 95 % CI : 1.03 - 60.83 ) , but the increasing of TYMS low-expression alleles contradict the previous results observed in germline sample s. CONCLUSION The detection of somatic mutations in rectal cancer tumors led us to re-evaluate the utility of the tests performed in blood sample s for these polymorphisms in rectal cancer . Furthermore , studies aim ed at assessing the influence of pharmacogenetic markers in treatment response performed in blood sample s should take into account the particular pattern of hypermutability present in each tumor type . We hypothesize that different patterns of hypermutability present in each tumor type would be related to the different results in association studies related to response to the treatment PURPOSE We compared the combined radiation therapy ( RT ) plus chemotherapy segments of two separate parallel phase I trials to determine if combined pelvic RT , fluorouracil ( 5-FU ) , and high-dose leucovorin ( LV ) had less acute toxicity when delivered preoperatively versus postoperatively in patients with rectal cancer . PATIENTS AND METHODS Patients with unresectable disease received preoperative RT plus LV and 5-FU followed by surgery and postoperative LV and 5-FU .  Patients with resectable disease received identical doses , techniques , and schedules of RT and LV and 5-FU except all therapy was delivered postoperatively . On day 1 , patients received LV and 5-FU times one cycle . RT began on day 8 . A second cycle of LV and 5-FU was given concurrently with the fourth week of RT . RESULTS Although more patients ( 75 % v 32 % ; P = .02 ) received the higher dose level of 5-FU ( 250 mg/m2 ) , significantly fewer experienced acute grade 3 to 4 toxicity with preoperative versus postoperative therapy ( 13 % v 48 % ; P = .045 ) . There was no grade 3 to 4 myelosuppression in either group . The two grade 3 toxicities in the preoperative group were gastrointestinal . The grade 3 toxicities in the postoperative group included seven gastrointestinal and two genitourinary ; four patients had a grade 4 toxicity . CONCLUSION Given the high incidence of grade 3 to 4 toxicity also reported in the postoperative combined modality adjuvant r and omized trials , future adjuvant trials should explore the preoperative approach The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma ( cT3 - 4 cN0 - 1 cM0 ) after multimodal treatment ( radiochemotherapy±surgical resection )  , and the presence of genetic polymorphisms in genes involved in folate metabolism . In total , 68 patients who took part in a prospect i ve multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy , optionally followed by surgery . DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes ( MTHFR C677 T , MTR A2756 G , TS t and em repeat polymorphism ) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy . The genotypes were correlated with tumour response to polychemotherapy , radiochemotherapy and with overall survival . Tumours with the MTR wild-type genotype ( 2756AA ) showed a median survival time of 16 months , whereas tumours with an MTR variant genotype ( 2756AG/2756GG ) showed a median survival time of 42 months ( P=0.0463 ) . No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene . Among tumours treated with radiochemotherapy and subsequent resection , MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype ( P=0.0442 ) . In contrast , no significant relationship between clinical ly determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed . In conclusion , pretherapeutic determination of the MTR A2756 G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas . Determination of MTHFR C677 T and TS t and em repeat polymorphism has no predictive value Objective The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase ( MTHFR ) C677 T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter , namely the variable number t and em repeat polymorphism ( TS VNTR ) and the intrarepeat G to C single nucleotide polymorphism ( TS SNP ) , are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy . Basic methods Blood sample s from 125 patients with primary adenocarcinoma of the mid – low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy ( median dose 48.4 Gy ) , 125 patients ( women n=45 , men n=80 ; median age 60 years , range 31–79 years ) were genotyped . Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria . On the basis of the pathologic response , patients were classified as responders ( TRG 1–2 , n=48 ) and non-responders ( TRG 3–5 , n=74 ) . Three patients were excluded because of insufficient data . Main results Among the polymorphic variants examined , the MTHFR 677T-1298A haplotype was , upon univariate analysis , the only variable found associated with tumor regression ( P=0.004 ) . Moreover , at multivariate analysis , the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression . Patients not carrying the MTHFR 677T-1298A haplotype ( odds ratio 0.29 , 95 % confidence interval 0.13–0.64 , P=0.002 ) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype . Conclusions Unlike TS VNTR and SNP polymorphisms , MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients su bmi tted to preoperative Objective : To identify a biomarker profile associated with tumor response to chemoradiation ( CRT ) in locally advanced rectal cancer . Background : Rectal cancer response to neoadjuvant CRT is variable . Whereas some patients have a minimal response , others achieve a pathologic complete response ( pCR ) and have no viable cancer cells in their surgical specimens . Identifying biomarkers of response will help select patients more likely to benefit from CRT . Methods : This study includes 132 patients with locally advanced rectal cancer treated with neoadjuvant CRT followed by surgery . Tumor DNA from pretreatment tumor biopsies and control DNA from paired normal surgical specimens was screened for mutations and polymorphisms in 23 genes . Genetic biomarkers were correlated with tumor response to CRT ( pCR vs non-pCR ) , and the association of single or combined biomarkers with tumor response was determined . Results : Thirty-three of 132 ( 25 % ) patients achieved a pCR and 99 ( 75 % ) patients had non-pCR . Three individual markers were associated with non-pCR ; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutation ( P = 0.0145 ) , cyclin D1 G870A ( AA ) polymorphism ( P = 0.0138 ) , and methylenetetrahydrofolate reductase ( NAD(P)H ) C677 T ( TT ) polymorphism ( P = 0.0120 ) . Analysis of biomarker combinations revealed that none of the 27 patients with both tumor protein p53 ( p53 ) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations had a pCR . Further , in patients with both p53 and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations or the cyclin D1 G870A ( AA ) polymorphism or the methylenetetrahydrofolate reductase ( NAD(P)H ) C677 T ( TT ) polymorphism ( n = 52 ) the association with non-pCR was further strengthened ; 51 of 52 ( 98 % ) of patients were non-pCR . These biomarker combinations had a validity of more than 70 % and a positive predictive value of 97 % to 10 
    Output:
    
Conclusions MTHFR C677 T might be correlated with the tumor response to p RCT .