***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 Background The objective of this study was to evaluate the efficacy and toxicity of infusional 5-fluorouracil ( 5-FU ) , folinic acid and oxaliplatin ( modified FOLFOX-6 ) in patients with advanced gastric cancer ( AGC ) , as first-line palliative combination chemotherapy . We also analyzed the predictive or prognostic value of germline polymorphisms of c and i date genes associated with 5-FU and oxaliplatin . Methods Seventy-three patients were administered a 2 hour infusion of oxaliplatin ( 100 mg/m2 ) and folinic acid ( 100 mg/m2 ) followed by a 46 hour continuous infusion of 5-FU ( 2,400 mg/m2 ) . Genomic DNA from the patients ' peripheral blood mononuclear cells was extracted . Ten polymorphisms within five genes were investigated including TS , GSTP , ERCC , XPD and XRCC . Results The overall response rate ( RR ) was 43.8 % . Median time to progression ( TTP ) and overall survival ( OS ) were 6.0 months and 12.6 months , respectively . Toxicities were generally tolerable and manageable . The RR was significantly higher in patients with a 6-bp deletion homozygote ( -6 bp/-6 bp ) in TS-3'UTR ( 55.0 % vs. 30.3 % in + 6 bp/+6 bp or + 6 bp/-6 bp , p = 0.034 ) , and C/A or A/A in XPD156 ( 52.0 % vs. 26.1 % in C/C , p = 0.038 ) . The -6 bp/-6 bp in TS-3'UTR was significantly associated with a prolonged TTP and OS . In a multivariate analysis , the 6-bp deletion in TS-3'UTR was identified as an independent prognostic marker of TTP ( hazard ratio = 0.561 , p = 0.032 ) . Conclusion Modified FOLFOX-6 chemotherapy appears to be active and well tolerated as first line chemotherapy in AGC patients . The 6-bp deletion in TS-3'UTR might be a c and i date to select patients who are likely to benefit from 5-FU based modified FOLFOX-6 in future large scale trial A Valine residue at position 105 of the GSTP1 protein results in decreased enzyme activity . As nuclear GSTP1 activity decreases irinotecan cytotoxicity , Val-allele carriers may benefit more from irinotecan chemotherapy . Our aim was to investigate the association of GSTP1 genotype with treatment outcome of irinotecan .  Progression-free survival ( PFS ) and toxicity were determined in 267 metastatic colorectal cancer ( MCRC ) patients who were treated with first-line capecitabine ( CAP ) plus irinotecan ( CAPIRI ) , or CAP single agent in a prospect i ve r and omised phase III trial ( CAIRO ) . GSTP1 genotype was determined by Pyrosequencing . Patients receiving CAP showed a PFS of 6.6 ( Ile/Ile ) , 6.0 ( Ile/Val ) and 6.5 months ( Val/Val ) ; compared to 7.0 ( Ile/Ile ) , 8.8 ( Ile/Val ) and 9.2 months ( Val/Val ) with CAPIRI .  Median PFS was 2.7 months longer in Val-allele carriers treated with CAPIRI compared to CAP ( P=0.005 ) . Patients with the Ile/Ile genotype showed similar PFS with CAPIRI and CAP ( 7.0 compared to 6.6 months , P=0.972 ) . Toxicity did not differ significantly among genotypes . GSTP1 codon 105 polymorphism may be predictive for the response to irinotecan-based chemotherapy in patients with MCRC , with the Val-allele being associated with a better outcome . Ile/Ile genotype patients do not appear to benefit from the addition of irinotecan to CAP Objective In Japan , there had been no prospect i ve clinical studies conducted in terms of modified FOLFOX6 + bevacizumab therapy . We performed a post-marketing Phase II multicenter clinical study to examine the efficacy and safety of this regimen as first-line therapy for Japanese patients with advanced/recurrent colorectal cancer . Methods Bevacizumab ( 5 mg/kg ) was administered intravenously , and then oxaliplatin ( 85 mg/m2 ) and levofolinate calcium ( 200 mg/m2 ) were infused intravenously over 2 h. Subsequently , a bolus dose of 5-fluorouracil ( 400 mg/m2 ) was injected , followed by infusion of 5-fluorouracil ( 2400 mg/m2 ) for 46 h. This regimen was repeated every 2 weeks until 24 cycles unless there was disease progression , unacceptable toxicity or patient refusal . The primary end point was the response rate . Results Among the 70 patients enrolled , two patients withdrew the study before treatment , and 68 patients were eligible for analysis of efficacy and safety . The response rate was 51.5 % ( 95 % confidence interval : 39.0–63.8 % ) . The median progression-free survival and median overall survival time were 12.6 months ( 95 % confidence interval : 10.4–14.5 months ) and 28.5 months [ 95 % confidence interval : 23.1 months–(not applicable ) ] , respectively . There were no treatment-related deaths observed . The most common Grade 3 and 4 adverse events included neutropenia in 35.3 % of the patients , peripheral neuropathy in 16.2 % and hypertension in 16.2 % . All adverse events were manageable and tolerable . The exploratory analysis of polymorphisms of three genes , ERCC1 , XPD and GSTP1 , did not show any trends in terms of correlation with the efficacy or safety of modified FOLFOX6 + bevacizumab therapy . Conclusions Modified FOLFOX6 + bevacizumab therapy was manageable and tolerable in Japanese patients , achieving a high response rate We investigated 17 polymorphisms in 11 genes ( TS , MTHFR , ERCC1 , XRCC1 , XRCC3 , XPD , GSTT1 , GSTP1 , GSTM1 , ABCC1 , ABCC2 ) for their association with the toxicity of fluoropyrimidines and oxaliplatin in colorectal cancer patients enrolled in a prospect i ve r and omized trial of adjuvant chemotherapy . The TOSCA Italian adjuvant trial was conducted in high-risk stage II – III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemotherapy .  In the concomitant ancillary pharmacogenetic study , the primary endpoint was the association of polymorphisms with grade 3–4 CTCAE toxicity events ( grade 2–4 for neurotoxicity ) . In 517 analyzed patients , grade ≥ 3 neutropenia and grade ≥ 2 neurotoxicity events occurred in 150 ( 29 % ) and in 132 patients ( 24.8 % ) , respectively . Diarrhea grade ≥ 3 events occurred in 34 ( 6.5 % ) patients . None of the studied polymorphisms showed clinical ly relevant association with toxicity . Hopefully , genome-wide association studies will identify new and more promising genetic variants to be tested in future studies Objectives We aim ed to evaluate the efficacy and safety of combination therapy of Endostar ( recombinant human endostatin ) and S-1 combined with oxaliplatin ( SOX ) in patients with advanced gastric cancer . Methods In this r and omized , controlled trial , 165 late-stage gastric cancer patients were assigned to the experimental arm with Endostar in combination with SOX ( 80 patients ) and the control arm with SOX alone ( 85 patients ) . The end points of this study included progression-free survival , response rate , and disease-control rate . Results There was no statistically significant difference in response rate between the experimental arm and the control arm ( 53.8 % vs 42.4 % , P=0.188 ) . The difference in disease-control rate was also statistically insignificant between the two arms ( 85.0 % vs 72.9 % , P=0.188 ) . Progression-free survival in the experimental arm was significantly higher than that in the control arm ( 15.0 months vs 12.0 months , P=0.0001 ) . Common adverse events included immunosuppression , gastrointestinal distress , and neuropathy . There was no statistical difference in the incidences of adverse events . Conclusion Combination therapy of Endostar and SOX provides therapeutic benefits to advanced gastric cancer patients , with tolerable adverse effects Oxaliplatin and irinotecan have proven effective in the treatment of gastric cancer . We attempted to determine whether single nucleotide polymorphisms in ERCC1 , GST , TS and UGT1A1 predicted overall survival in gastric cancer patients receiving FOLFOX and /or FOLFIRI chemotherapy .  Total genomic DNA was extracted from the whole blood of patients . The PCR-restriction fragment length polymorphism technique was applied in order to detect the known variant sites of ERCC1 , GST , TS and UGT1A1 . The response rate of FOLFOX  ( N=75 ) was 24 % . Grade 3 - 4 neutropenia and neurotoxicity were observed at frequencies of 34.7 and 16 % , respectively . TTP and OS of first-line administration of FOLFOX ( N=35 ) were 3.1 months ( 95 % CI , 0.1 - 6.1 months ) and 13.9 months ( 95 % CI , 12.2 - 15.6 months ) , respectively . Only the GSTM1 positive genotype exhibited a significantly better time to progression ( P=0.023 ) . However , significant genotypic variation of TS , GST and ERCC1 , which was assumed to affect the activity of oxaliplatin , was not observed to affect RR , toxicity and overall survival . The response rate of FOLFIRI ( N=74 ) was 23 % . Grade 3 - 4 neutropenia and diarrhea were observed in 55.4 and 9.5 % of cases , respectively . TTP and OS of first-line administration of FOLFIRI ( N=33 ) was 4.9 months ( 95 % CI , 3.5 - 6.4 months ) and 19.0 months ( 95 % CI , 8.5 - 29.5 months ) . The low expression type ( 2R/2R , 2R/3C and 3C/3C ) of TS was associated with a high incidence of grade > or=3 neutropenia . However , significant genotypic variation of UGT1A1 , which was assumed to affect irinotecan toxicity , was not observed to affect RR , toxicity or survival . In this study , the GSTM1 positive genotype evidence d a significantly better time to progression in cases of advanced gastric cancer being treated with FOLFOX . The low expression type ( 2R/2R , 2R/3C and 3C/3C ) of TS was associated with a high incidence of grade > or=3 neutropenia in cases of advanced gastric cancer treated with FOLFIRI The discovery of pharmacogenomic markers in colorectal cancer ( CRC ) could be setting -specific . FOLFOX4 is employed in the adjuvant and metastatic setting in CRC . This prospect i ve study is aim ed to vali date in the adjuvant setting the pharmacogenomic markers of toxicity reported 
    Output:
    
After pooling all the eligible studies , we identified significant associations of GSTP1 Ile105Val polymorphism with chemotherapy-related tumor response ( G vs. A : OR 1.697 , 95 % CI 1.191–2.418 ; GG vs. AA : OR 2.804 , 95 % CI 1.414–5.560 ; AG vs. AA : OR 1.540 , 95 % CI 1.011–2.347 ; GG vs. AAAG : OR 2.139 , 95 % CI 1.256–3.641 ) , PFS ( GG vs. AA , HR 0.640 , 95 % CI 0.455–0.900 ; AGGG vs. AA : HR 0.718 , 95 % CI 0.562–0.919 ) , and OS ( AG vs. AA : HR 0.857 , 95 % CI 0.746–0.986 ; GG vs. AA : HR 0.679 , 95 % CI 0.523–0.882 ; AGGG vs. AA : HR 0.663 , 95 % CI 0.542–0.812 ) in gastric and colorectal cancers and no significant association was found between the polymorphism with toxicity .
Conclusions GSTP1 Ile105Val polymorphism was associated with tumor response , PFS , and OS in gastric and colorectal cancers after chemotherapy