***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: BACKGROUND Although Ki-ras and TP53 mutations have probably been the genetic abnormalities most exhaustively implicated and studied in colorectal cancer ( CRC ) progression , their significance in terms of disease relapse and overall survival has not yet clearly been established . PATIENTS AND METHODS A prospect i ve study was carried out on paired tumor and normal colon tissue sample s from a consecutive series of 160 previously-untreated patients , undergoing resective surgery for primary operable sporadic CRC .  Mutations within the TP53 ( exons 5 - 8 ) and Ki-ras ( exon 2 ) genes were detected by PCR-SSCP analyses following sequencing . RESULTS Mutation analyses of exons 5 to 8 of the TP53 gene showed mutations in 43 % ( 68/160 ) of the cases , while mutation analyses of exon 2 of the Ki-ras gene showed mutations in 46 % ( 74/160 ) of the cases . Multivariate analyses showed that clinical outcome were strongly associated with the presence of specific TP53 mutations in L3 domain alone ( only in DFS ) or in combination with specific Ki-ras mutations at codon 13 . CONCLUSION Specific TP53 mutations in L3 domain alone ( only in DFS ) or in combination with specific Ki-ras mutations at codon 13 are associated with a worse prognosis in sporadic CRC BACKGROUND K-ras mutations , one of the earliest events observed in colorectal carcinogenesis , are mostly found in codons 12 and 13 , and less frequently in codon 61 , all three of which are estimated to be critical for the biological activity of the protein . Nevertheless the prognostic significance of such mutations remains controversial . Our purpose was to assess whether any or specific K-ras mutations in primary colorectal cancer had prognostic significance and were linked to clinico-pathological parameters . PATIENTS AND METHODS Paired tumor and normal tissue sample s from a consecutive series of 160 untreated patients ( median of follow up 71 months ) , undergoing resective surgery for primary colorectal carcinoma , were prospect ively studied for K-ras mutations by PCR/single str and conformation polymorphism sequencing . RESULTS Seventy-four of the 160 ( 46 % ) primary colorectal carcinomas presented mutations in K-ras : 54 % in codon 12 , 42 % in codon 13 ( particularly G-->A transition ) and 4 % in both . Codon 12 K-ras mutations were associated with mucinous histotype ( P < 0.01 ) , while codon 13 K-ras mutations were associated with advanced Dukes ' stage ( P < 0.05 ) , lymph-node metastasis ( P < 0.05 ) and high S-phase fraction ( P < 0.05 ) . Multivariate analysis showed that codon 13 K-ras mutations , but not any mutation , were independently related to risk of relapse or death . CONCLUSIONS Our results suggest that codon 12 K-ras mutations may have a role in the mucinous differentiation pathway , while codon 13 mutations have biological relevance in terms of colorectal cancer clinical outcome BACKGROUND Mutations involving the oncogene K-ras in colorectal cancer may be related to tumor aggressiveness . However , the value of K-ras gene determination as a prognostic marker has not been clearly established . PATIENTS AND METHODS The results from 98 patients recruited in a prospect i ve study analyzing the effect of a K-ras mutation as a prognostic factor in colorectal cancer are reported . RESULTS Disease-free ( P = 0.02 ) and overall survival ( P = 0.03 ) were significantly reduced for patients harboring a K-ras mutation . Two specific mutations demonstrated a significantly increased risk of disease recurrence , namely , 12-TGT ( P = 0.04 ) and 13-GAC substitutions ( P = 0.002 ) . Patients with either of these substitutions had a 2-year disease-free survival rate of 37 % compared with that of 67 % for the group of patients harboring any other mutation type or a wild-type status ( P = 0.01 ) . CONCLUSIONS The results herein presented suggest that K-ras acts as a prognostic factor in colorectal cancer and that this effect is probably related to a limited number of defined mutations Between June 1990 and April 1991 , 62 colorectal tumors were assessed in a prospect i ve fashion on the basis of various tumor characteristics . Parameters included K-ras mutation , overexpression of the p53 protein , and proliferating cell nuclear cell antigen , as well as st and ard histopathologic examination . A multivariate analysis showed that K-ras mutation correlated with vascular invasion ( P < 0.01 ) and hematogenous metastasis ( P < 0.01 ) . With regard to survival time , multivariate analyses using the Cox proportional hazard model suggested that status of lymph node metastasis ( P < 0.01 , relative risk [ rr ] = 7.27 ) , TNM stage ( P < 0.05 , rr = 5.37 ) , lymphatic invasion ( P < 0.05 , rr = 4.48 ) , and K-ras mutation ( P < 0.06 , rr = 3.69 ) are the most independent prognostic factors . We compared the prognostic value of the molecular assays and st and ard TNM prognostic factors by multivariate analysis PURPOSE p53 gene and K-ras mutations are among the most common genetic alterations present in colorectal cancer . The prognostic utility of such mutations remains controversial . The purpose of this study was to prospect ively evaluate the prognostic significance of p53 and  K-ras gene mutations in colorectal cancer . PATIENTS AND METHODS One hundred forty patients were analyzed . Tumors belonging to the microsatellite mutator phenotype were excluded ( n = 8) . Mutations at the K-ras and p53 genes were detected and characterized by restriction fragment length polymorphism , single-str and conformation polymorphism , and sequencing , as appropriate . RESULTS p53 mutations were detected in 66 ( 50 % ) and K-ras mutations were detected in 54 ( 41 % ) of the 132 patients . In 26 cases ( 20 % ) , ras and p53 mutations coexisted ; in 38 cases ( 29 % ) , neither mutation was found . Multivariate analysis of the whole population analyzed ( n = 132 ) showed that survival was strongly correlated with the presence of p53 mutations alone or in combination with K-ras mutations ( P = .002 ; log-rank test ) . When only patients undergoing a radical resection were considered ( R0 ; n = 101 ) , p53 mutations were no longer of prognostic significance . CONCLUSION p53 mutations alone or in combination with K-ras mutations are correlated with a worse outcome . However , the routine use of these mutations as prognostic markers in the clinical setting is not recommended Background : Recurrent and metastatic carcinoma of the colorectum remains a major problem . This may be ascribed to the presence of micrometastasis at diagnosis . The purpose of this study was to analyze prospect ively the clinical value of detecting K-ras mutations in the perioperative circulating blood from patients with colorectal carcinoma . Methods : Twenty-four patients whose tumor carried mutations in codon 12 of the K-ras gene were studied for the presence of cancer cells in perioperative blood sample s , in particular , tumor drainage sample s. A detection assay using CD45 immunomagnetic separation plus nested mutant allele specific amplification ( MASA ) was performed . Results : K-ras mutations in CD45 negative cells in tumor drainage blood were detected in 7 ( 29.2 % ) of 24 patients . There was no significant relationship between the presence of a K-ras mutation and clinicopathological features . Four ( 57.1 % ) of the seven patients with a positive K-ras mutation in drainage blood had early recurrent disease . Of the 17 patients with no K-ras mutation , none developed metastatic disease . The recurrence rate of the K-ras mutation positive group was higher than that of the K-ras mutation negative group ( P < .01 ) . There was a significant difference , regarding prognosis , between K-ras mutation positive and negative groups ( P < .01 ) . Conclusions : This preliminary study demonstrates that the detection of circulating cancer cells in the tumor drainage blood by our new assay system may provide a predictor of recurrence and metastasis of colorectal cancer PURPOSE Mutations in the K-ras gene are frequent in human cancer . ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16 . At the clinical level , this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways . PATIENTS AND METHODS We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospect ively collected colorectal carcinomas .  p53 mutations and p14 alternative reading frame methylation status were also assessed . Associations with survival were investigated . RESULTS  K-ras mutations were present in 44 ( 38 % ) of 115 cases , and p16 methylation was present in 42 ( 37 % ) of 113 cases . p53 mutations were detected in 50 % ( 56 of 115 ) and p14 methylation in 29 % ( 32 of 112 ) of cases . K-ras and p16 alterations were independent genetic events . Presence of K-ras or p16 genetic alterations ( analyzed independently ) was associated with shorter survival , although differences were not statistically significant . Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras . Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis . Differences were maintained when cases undergoing radical surgery and without distant metastases were considered . CONCLUSION These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer PURPOSE To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor . PATIENTS AND METHODS Phase II , open-label clinical trial . Patients were required to have EGFr expression demonstrated on formalin-fixed paraffin-embedded tumor tissue by immunohistochemical staining before study participation . Patients were required to have received irinotecan , either alone or in a combination regimen , and to have demonstrated clinical failure on this regimen before study entry . Cetuximab was administered weekly by intravenous infusion . The first dose of 400 mg/m(2 ) was given during the course of 2 hours . Subsequent weekly treatments were given at a dose of 250 mg/m(2 ) during the course of 1 hour . RESULTS Fifty-seven eligible patients were treated . All were assessable for toxicity and response . The most commonly encountered grade 3 to 4 adverse events , regardless of relationship to study drug , were an acne-like skin rash , predominantly on the face and upper torso ( 86 % with any grade ; 18 % with grade 3 ) , and a composite of asthenia , fatigue , malaise , or lethargy ( 56 % with any grade , 9 % with grade 3 ) . Two patients ( 3.5 % ) experienced grade 3 allergic reactions requiring discontinuation of study treatment . A third patient experienced a grade 3 allergic reaction that resolved , and the patient continued on the study . Neither diarrhea nor neutropenia were dose limiting in any of the 57 patients treated . Five patients ( 9 % ; 95 % CI , 3 % to 19 % ) achieved a partial response . Twenty-one additional patients had stable disease or minor responses . The median survival in these previously treated patients with chemotherapy-refractory colorectal cancer is 6.4 months . CONCLUSION Cetuximab on this once-weekly schedule has modest activity and is well-tolerated as a single agent in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor . Further studies of cetuximab will evaluate the use of cetuximab in conjunction with first-line and adjuvant treatments for this disease 
    Output:
    
: Overall K-ras gene mutations seem not to correlate with the prognosis of patients with colorectal cancer .