***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 : Oxaliplatin displays a frequent dose-limiting neurotoxicity due to its interference with neuron voltage-gated sodium channels through one of its metabolites , oxalate , a calcium chelator . Different clinical approaches failed in neurotoxicity prevention , except calcium-magnesium infusions . We characterized oxalate outcome following oxaliplatin administration and its interference with cations and amino acids . We then looked for genetic predictive factors of oxaliplatin-induced neurotoxicity . Experimental Design : We first tested patients for cations and oxalate levels and did amino acid chromatograms in urine following oxaliplatin infusion .  In the second stage , before treatment with FOLFOX regimen , we prospect ively looked for variants in genes coding for the enzymes involved ( a ) in the oxalate metabolism , especially glyoxylate aminotransferase ( AGXT ) , and ( b ) in the detoxification glutathione cycle , glutathione S-transferase π , and for genes coding for membrane efflux proteins ( ABCC2 ) . Results : In the first 10 patients  , urinary excretions of oxalate and cations increased significantly within hours following oxaliplatin infusion , accompanied by increased excretions of four amino acids ( glycine , alanine , serine , and taurine ) linked to oxalate metabolism . In a further 135 patients , a minor haplotype of AGXT was found significantly predictive of both acute and chronic neurotoxicity . Neither glutathione S-transferase π nor ABCC2 single nucleotide polymorphisms we looked for were linked to neurotoxicity . Conclusion : These data confirm the involvement of oxalate in oxaliplatin neurotoxicity and support the future use of AGXT genotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity PURPOSE In metastatic colorectal cancer , phase III studies have demonstrated the superiority of fluorouracil ( FU ) with leucovorin ( LV ) in combination with irinotecan or oxaliplatin over FU + LV alone . This phase III study investigated two sequences : folinic acid , FU , and irinotecan ( FOLFIRI ) followed by folinic acid , FU , and oxaliplatin ( FOLFOX6 ; arm A ) , and FOLFOX6 followed by FOLFIRI ( arm B ) . PATIENTS AND METHODS Previously untreated patients with assessable disease were r and omly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2 ) or dl-LV 400 mg/m(2 ) followed by a FU bolus 400 mg/m(2 ) and 46-hour infusion 2,400 to 3,000 mg/m(2 ) every 46 hours every 2 weeks , either with irinotecan 180 mg/m(2 ) or with oxaliplatin 100 mg/m(2 ) as a 2-hour infusion on day 1 . At progression , irinotecan was replaced by oxaliplatin ( arm A ) , or oxaliplatin by irinotecan ( arm B ) . RESULT Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI ( P = .99 ) . Median second progression-free survival ( PFS ) was 14.2 months in arm A versus 10.9 in arm B ( P = .64 ) . In first-line therapy , FOLFIRI achieved 56 % response rate ( RR ) and 8.5 months median PFS , versus FOLFOX6 which achieved 54 % RR and 8.0 months median PFS ( P = .26 ) . Second-line FOLFIRI achieved 4 % RR and 2.5 months median PFS , versus FOLFOX6 which achieved 15 % RR and 4.2 months PFS . In first-line therapy , National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis , nausea/vomiting , and grade 2 alopecia were more frequent with FOLFIRI , and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6 . CONCLUSION Both sequences achieved a prolonged survival and similar efficacy . The toxicity profiles were different PURPOSE Stage II and III adenocarcinoma of the rectum has an overall 5-year survival rate of approximately 50 % , and tumor recurrence remains a major problem despite an improvement in local control through chemotherapy and radiation . The efficacy of chemoradiation therapy may be significantly compromised as a result of interindividual variations in clinical response and host toxicity . Therefore , it is imperative to identify those patients who will benefit from chemoradiation therapy  and those who will develop recurrent disease . In this study , we tested whether a specific pattern of 21 polymorphisms in 18 genes involved in the critical pathways of cancer progression ( i.e. , drug metabolism , tumor microenvironment , cell cycle regulation , and DNA repair ) will predict the risk of tumor recurrence in rectal cancer patients treated with chemoradiation .  PATIENTS AND METHODS A total of 90 patients with Stage II or III rectal cancer treated with chemoradiation  were genotyped using polymerase chain reaction (PCR)-based techniques for 21 polymorphisms . RESULTS A polymorphism in interleukin (IL)-8 was individually associated with risk of recurrence . Classification and regression tree analysis of all polymorphisms and clinical variables developed a risk tree including the following variables : node status , IL-8 , intracellular adhesion molecule-1 , transforming growth factor-beta , and fibroblast growth factor receptor 4 . CONCLUSION Genomic profiling may help to identify patients who are at high risk for developing tumor recurrence , and those who are more likely to benefit from chemoradiation therapy . A larger prospect i ve study is needed to vali date these preliminary data using germline polymorphisms on tumor recurrences in rectal cancer patients treated with chemoradiation In this marker evaluation study , we tested whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways and DNA repair that predict clinical outcome to 5-fluorouracil (5-FU)/oxaliplatin chemotherapy in patients with advanced colorectal cancer could be identified . Functional polymorphisms in DNA-repair genes XPD , ERCC1 , XRCC1 , XPA , and metabolising genes glutathione S-transferase GSTP1 , GSTT1 , GSTM1 , and thymidylate synthase ( TS ) were assessed retrospectively in 106 patients with refractory stage IV disease who received 5-FU/oxaliplatin combination chemotherapy , using a polymerase chain reaction-based RFLP technique .  Favourable genotypes from polymorphisms in XPD-751 , ERCC1 - 118 , GSTP1 - 105 , and TS-3′-untranslated region ( 3′UTR ) that are associated with overall survival were identified . After adjustment for performance status , the relative risks of dying for patients who possessed the unfavourable genotype were : 3.33 for XPD-751 ( P=0.037 ) , 3.25 for GSTP1 - 105 ( P=0.072 ) , 2.05 for ERCC1 - 118 ( P=0.037 ) , and 1.65 for TS-3′UTR ( P=0.091 ) when compared to their respective beneficial genomic variants . Combination analysis with all four polymorphisms revealed that patients possessing ⩾2 favourable genotypes survived a median of 17.4 months ( 95 % confidence interval ( CI ) : 9.4 , 26.5 ) compared to 5.4 months ( 95 % CI : 4.3 , 6.0 ) in patients with no favourable genotype . Patients who carried one favourable genotype demonstrated intermediate survival of 10.2 months ( 95 % CI : 6.8 , 15.3 ; P<0.001 ) . Polymorphisms in the TS-3′UTR and GSTP1 - 105 gene were also associated with time to progression . After adjustment for performance status , patients with an unfavourable TS-3′UTR genotype had a relative risk of disease progression of 1.76 ( P=0.020 ) and those with the unfavourable GSTP1 - 105 genotype showed a relative risk of progression of 2.00 ( P=0.018 ) . The genomic polymorphisms XPD-751 , ERCC1 - 118 , GSTP1 - 105 , and TS-3′UTR may be useful in predicting overall survival and time to progression of colorectal cancer in patients who receive 5-FU/oxaliplatin chemotherapy .  These findings require independent prospect i ve confirmation BACKGROUND The antiepidermal growth factor receptor ( antiEGFR ) monoclonal antibodies cetuximab and panitumumab have good clinical activity in about 10 % of patients with metastatic colorectal cancer that is resistant to chemotherapy . The molecular mechanisms underlying clinical response or resistance to these agents are unknown . METHODS Tumours from 31 patients with metastatic colorectal cancer who had either an objective response ( n=10 ) or stable disease or progressive disease ( n=21 ) after treatment with cetuximab or panitumumab  were screened for genetic changes in EGFR or its immediate intracellular effectors . Specifically , we assessed the EGFR copy number and the mutation profile of the EGFR catalytic domain and of selected exons in KRAS , BRAF , and PIK3CA . RESULTS Eight of nine of patients with objective responses who were assessable by fluorescence in-situ hybridisation ( FISH ) had an increased EGFR copy number . By contrast , one of 21 non-responders assessable by FISH had an increased EGFR copy number ( p<0.0001 for responders vs non-responders , Fisher 's exact test ) . The mutation status of the EGFR catalytic domain and its immediate downstream effectors PIK3CA , KRAS , and BRAF did not correlate with disease response . In colorectal-cancer cell lines , the concentration of cetuximab that completely inhibited proliferation of cells with amplified EGFR copy number did not affect proliferation of cells with unamplified EGFR . INTERPRETATION We propose that the response to antiEGFR treatment has a genetic basis and suggest that patients might be selected for treatment on the basis of EGFR copy number Thymidylate synthase [ TS , ( EC 2.1.1.45 ) ] is the target enzyme in 5-fluorouracil treatment . Recently , the DNA polymorphism of this gene has been found to affect TS protein ( pTS ) expression . However , no prospect i ve studies have been performed to evaluate the influence of this polymorphism on the clinical efficacy of 5-FU-based adjuvant chemotherapy for colorectal cancer ( CRC ) . In this study , we investigated the genotype of TS and immunopathological findings of pTS in 161 colon cancer specimens from patients who were registered in a prospect i ve adjuvant immunochemotherapy clinical trial . The clinical course and prognosis of these patients were checked after the study had been completed . This study comprised 11 ( 6.8 % ) cases of 2R/2R , 40 ( 24.8 % ) of 2R/3R , and 110 ( 68.3 % ) of 3R/3R genotypes . All of the 2R/2R cases were still alive at the time of analysis although this finding was not statistically significant . In this prospect i ve examination on a r and omized controlled trial , the patients with colon cancer of the 2R/2R TS genotype may be good responders to 5-FU-based adjuvant chemotherapy . Furthermore , differences in the proportions of the TS genotypes can account for the interracial differences in the adverse effects of 5-FU-based chemotherapy Purpose : We investigated whether the determination of orotate phosphoribosyltransferase ( OPRT ) and thymidylate synthase ( TYMS ) polymorphisms could predict the toxicity of 5-fluorouracil ( 5-FU ) in colorectal cancer patients . Experimental Design : The determination of OPRT and TYMS genotypes were done in genomic DNA extracted from blood by PCR amplification in 69 patients treated with bolus 5-FU as adjuvant chemotherapy .  Associations between these polymorphisms and toxicity were evaluated retrospectively . Results : The Ala allele in OPRT Gly213Ala polymorphism and the two t and em repeats ( 2R ) in TYMS promoter polymorphism were associated with grade 3 to 4 neutropenia and diarrhea . The multivariate logistic regression models revealed that only TYMS promoter polymorphism had an independent value to predict grade 3 to 4 neutropenia [ odds ratio , 19.2 for patients with the 2R allele compared with patients with homozygous with the three repeat ( 3R ) alleles ] , whereas both OPRT and TYMS promoter polymorphisms were independent predictive factors for grade 3 to 4 diarrhea ( odds ratio , 13.3 for patients with the Ala allele compared with patients in the Gly/Gly genotype and 11.1 for patients with the 2R allele compared with patients in the 3R/3R genotype ) . A significant difference was observed in 
    Output:
    
Overall , evidence indicates associations of the UGT1A1 ( * ) 28 variant genotype with toxicity after irinotecan treatment , mutations in GSTP1 - 105 with improved treatment outcome and the XPD-751 variant genotype with poor treatment outcome after oxaliplatin treatment , and amplification of the EGFR gene with improved treatment outcome after therapy with monoclonal antibodies .