human
***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 The combination of interferon alfa ( IFNalpha ) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines , but it remained unclear whether this combination is more effective than IFNalpha alone in patients with metastatic melanoma . We evaluated safety and efficacy of IFNalpha and isotretinoin compared with IFNalpha alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB . PATIENTS AND METHODS In a prospect i ve , r and omized , double-blind , placebo-controlled trial , 407 melanoma patients in stage IIA ( 301 patients ) and IIB ( 106 patients ) were r and omly assigned to either IFNalpha and isotretinoin ( isotretinoin group ; 206 patients ) or IFNalpha and placebo ( placebo group ; 201 patients ) after excision of the primary tumor . IFNalpha was administered three times a week at a dose of 3 million units subcutaneously for 24 months . Isotretinoin at a dose of 20 mg for patients < or = 73 kg , 30 mg for patients greater than 73 kg , or placebo daily for 24 months . RESULTS A scheduled interim analysis revealed no significant differences in survival rates , with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55 % ( 95 % CI , 46 % to 65 % ) and 67 % ( 95 % CI , 59 % to 75 % ) , respectively , and overall 5-year survival rates of 76 % ( 95 % CI , 67 % to 84 % ) and 81 % ( 95 % CI , 74 % to 88 % ) , respectively . The trial was stopped for futility . CONCLUSION The addition of isotretinoin to an adjuvant treatment of low-dose IFNalpha in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended BACKGROUND We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma . METHODS Patients with a primary cutaneous melanoma were r and omly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred , or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy . RESULTS Among 1269 patients with an intermediate-thickness primary melanoma , the mean ( + /-SE ) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6 % in the biopsy group and 73.1+/-2.1 % in the observation group ( hazard ratio for recurrence[corrected ] , 0.74 ; 95 % confidence interval [ CI ] , 0.59 to 0.93 ; P=0.009 ) . Five-year melanoma-specific survival rates were similar in the two groups ( 87.1+/-1.3 % and 86.6+/-1.6 % , respectively ) . In the biopsy group , the presence of metastases in the sentinel node was the most important prognostic factor ; the 5-year survival rate was 72.3+/-4.6 % among patients with tumor-positive sentinel nodes and 90.2+/-1.3 % among those with tumor-negative sentinel nodes ( hazard ratio for death , 2.48 ; 95 % CI , 1.54 to 3.98 ; P<0.001 ) . The incidence of sentinel-node micrometastases was 16.0 % ( 122 of 764 patients ) , and the rate of nodal relapse in the observation group was 15.6 % ( 78 of 500 patients ) . The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group ( P<0.001 ) , indicating disease progression during observation . Among patients with nodal metastases , the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed ( 72.3+/-4.6 % vs. 52.4+/-5.9 % ; hazard ratio for death , 0.51 ; 95 % CI , 0.32 to 0.81 ; P=0.004 ) . CONCLUSIONS The staging of intermediate-thickness ( 1.2 to 3.5 mm ) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy . ( Clinical Trials.gov number , NCT00275496 [ Clinical Trials.gov ] . ) BACKGROUND Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment . Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability . METHODS 1256 patients with resected stage III melanoma were r and omly assigned to observation ( n=629 ) or pegylated interferon alfa-2b ( n=627 ) 6 mug/kg per week for 8 weeks ( induction ) then 3 mug/kg per week ( maintenance ) for an intended duration of 5 years . R and omisation was stratified for microscopic ( N1 ) versus macroscopic ( N2 ) nodal involvement , number of positive nodes , ulceration and tumour thickness , sex , and centre . R and omisation was done with a minimisation technique . The primary endpoint was recurrence-free survival . Analyses were done by intention to treat . This study is registered with Clinical Trials.gov , number NCT00006249 . FINDINGS All r and omised patients were included in the primary efficacy analysis . 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses . The median length of treatment with pegylated interferon alfa-2b was 12 ( IQR 3.8 - 33.4 ) months . At 3.8 ( 3.2 - 4.2 ) years median follow-up , 328 recurrence events had occurred in the interferon group compared with 368 in the observation group ( hazard ratio 0.82 , 95 % CI 0.71 - 0.96 ; p=0.01 ) ; the 4-year rate of recurrence-free survival was 45.6 % ( SE 2.2 ) in the interferon group and 38.9 % ( 2.2 ) in the observation group . There was no difference in overall survival between the groups . Grade 3 adverse events occurred in 246 ( 40 % ) patients in the interferon group and 60 ( 10 % ) in the observation group ; grade 4 adverse events occurred in 32 ( 5 % ) patients in the interferon group and 14 ( 2 % ) in the observation group . In the interferon group , the most common grade 3 or 4 adverse events were fatigue ( 97 patients , 16 % ) , hepatotoxicity ( 66 , 11 % ) , and depression ( 39 , 6 % ) . Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 ( 31 % ) patients . INTERPRETATION Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant , sustained effect on recurrence-free survival PURPOSE Low-dose ( LD ) interferon ( IFN ) alfa ( LDI ) has demonstrated a consistent disease-free survival benefit for patients with clinical ly lymph node-negative melanoma in clinical trials . However , the optimal duration of treatment is still under discussion , and no previous trial has evaluated this question specifically . A prolongation of LDI from 18 months to 60 months might be of clinical benefit for patients with intermediate or high-risk melanoma . PATIENTS AND METHODS Eight hundred fifty patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness were included in this prospect i ve r and omized , multicenter trial in Germany and Austria . Patients had to be clinical ly lymph node-negative , and sentinel node biopsy ( SLNB ) was performed in a majority of cases . They were r and omly assigned to receive 3 MU IFNalpha2a three times a week subcutaneously for either 18 months ( arm A ) or 60 months ( arm B ) . Results Of 850 r and omly assigned patients , 840 were eligible for evaluation after a median follow-up of 4.3 years . Tumor thickness and other relevant prognostic factors were well balanced between both groups . SLNB was performed in 635 patients ( 75.6 % ) , with a positivity rate of 18.0 % in arm A and 17.5 % in arm B. Neither relapse-free survival ( arm A , 75.6 % v arm B , 72.6 % ; P = .72 ; hazard ratio , 1.05 ; 95 % CI , 0.80 to 1.39 ) nor distant-metastasis-free survival ( 81.9 % v 79.7 % ; P = .56 ; HR , 1.10 ; 95 % CI , 0.80 to 1.52 ) or overall survival ( 85.9 % v 84.9 % ; P = .86 ; HR , 1.03 ; 95 % CI , 0.71 to 1.50 ) showed significant differences . CONCLUSION A prolongation of conventional LDI therapy from 18 to 60 months showed no clinical benefit in patients with intermediate and high-risk primary melanoma 8506 Background : High dose IFNalfa2b , according to the ECOG 1684 schedule , is the only approved adjuvant treatment for stage III melanoma . The risk/benefit profile has limited its use , while efficacy of intravenous ( iv ) phase and optimal duration have not been defined . The IMI Mel . A. trial evaluated the efficacy and safety of a pulsed high dose iv IFNa2b regimen . METHODS Following lymphadenectomy , stage III ( AJCC2002 ) patients ( pts ) , were r and omly assigned to either 4 courses of IFNa2b 20 MU/m2iv 5 d/wk for 4 wks every other month ( IHDI arm ) or the st and ard high dose regimen of a 4 week iv course followed by 10 MU/m2IFNa2b sc 3 times/wk for 11 months ( HDI Arm ) . Overall survival ( OS ) was the primary end point . The sample size of 328 pts and 118 deaths was determined assuming a 55 % 5-y OS for HDI and an increase of 15 % in IHDI ( β=20 % , α=5 % , 2-sided test ) . RESULTS From 1998 to 2010 , 336 pts were r and omized and 330 evaluated for OS : 172 in IHDI , 158 in HDI . Pts were well balanced according to age , sex , PS ( WHO ) , tumor ulceration ( 41 % vs 46 % ) and number of metastatic lymph-nodes ( N1 : 64 % vs 60 % , N2 : 22 % vs 28 % , N3 : 13 % vs 10 % ) . Relapse occurred in 87 ( IHDI : 50.6 % ) vs 80 ( HDI : 50,6 % ) pts with a median relapse free survival ( RFS ) time of 47.9 ( IHDI ) vs 35.6 ( HDI ) months , not statistically different and a 5-y RFS of 45.8 % ( 95%CI : 37.4;53.7 ) in IHDI vs 44.3 % ( 95%CI : 35.7;52.6 ) in HDI arm . 72 pts ( 40.8 % ) died in IHDI arm vs 64 ( 40.7 % ) in HDI arm . The median and 5-y OS were 88.7 months ( 95%CI : 61.2;- ) and 60.1 % ( 95%CI : 53;66.5 ) in IHDI vs 82.6 ( 95%CI : 45.8;- ) and 52.7 % ( 95%CI : 44.9;59.8 ) in HDI arm , and were not significantly different . Discontinuation due to toxicity or refusal was 20 % in IHDI vs 28 % in HDI with 66 % of pts in IHDI completing the treatment vs 49 % in HDI ( p=0.0026 ) . The distribution of all grade s of toxicity was similar in both groups , except for leucopenia , higher in IHDI arm ( 23 % vs 12 % , p=0.0331 ) . CONCLUSIONS Our data show that a shorter but more intensive HDI regimen is more feasible and not more toxic than conventional HDI . No significant differences in efficacy were observed and a meta- analysis of our and DeCog Ma-ADJ-5 trial data could better establish the role of iv HDI BACKGROUND Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemura 
    Output:
    
agent
***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 The combination of interferon alfa ( IFNalpha ) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines , but it remained unclear whether this combination is more effective than IFNalpha alone in patients with metastatic melanoma . We evaluated safety and efficacy of IFNalpha and isotretinoin compared with IFNalpha alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB . PATIENTS AND METHODS In a prospect i ve , r and omized , double-blind , placebo-controlled trial , 407 melanoma patients in stage IIA ( 301 patients ) and IIB ( 106 patients ) were r and omly assigned to either IFNalpha and isotretinoin ( isotretinoin group ; 206 patients ) or IFNalpha and placebo ( placebo group ; 201 patients ) after excision of the primary tumor . IFNalpha was administered three times a week at a dose of 3 million units subcutaneously for 24 months . Isotretinoin at a dose of 20 mg for patients < or = 73 kg , 30 mg for patients greater than 73 kg , or placebo daily for 24 months . RESULTS A scheduled interim analysis revealed no significant differences in survival rates , with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55 % ( 95 % CI , 46 % to 65 % ) and 67 % ( 95 % CI , 59 % to 75 % ) , respectively , and overall 5-year survival rates of 76 % ( 95 % CI , 67 % to 84 % ) and 81 % ( 95 % CI , 74 % to 88 % ) , respectively . The trial was stopped for futility . CONCLUSION The addition of isotretinoin to an adjuvant treatment of low-dose IFNalpha in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended BACKGROUND We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma . METHODS Patients with a primary cutaneous melanoma were r and omly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred , or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy . RESULTS Among 1269 patients with an intermediate-thickness primary melanoma , the mean ( + /-SE ) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6 % in the biopsy group and 73.1+/-2.1 % in the observation group ( hazard ratio for recurrence[corrected ] , 0.74 ; 95 % confidence interval [ CI ] , 0.59 to 0.93 ; P=0.009 ) . Five-year melanoma-specific survival rates were similar in the two groups ( 87.1+/-1.3 % and 86.6+/-1.6 % , respectively ) . In the biopsy group , the presence of metastases in the sentinel node was the most important prognostic factor ; the 5-year survival rate was 72.3+/-4.6 % among patients with tumor-positive sentinel nodes and 90.2+/-1.3 % among those with tumor-negative sentinel nodes ( hazard ratio for death , 2.48 ; 95 % CI , 1.54 to 3.98 ; P<0.001 ) . The incidence of sentinel-node micrometastases was 16.0 % ( 122 of 764 patients ) , and the rate of nodal relapse in the observation group was 15.6 % ( 78 of 500 patients ) . The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group ( P<0.001 ) , indicating disease progression during observation . Among patients with nodal metastases , the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed ( 72.3+/-4.6 % vs. 52.4+/-5.9 % ; hazard ratio for death , 0.51 ; 95 % CI , 0.32 to 0.81 ; P=0.004 ) . CONCLUSIONS The staging of intermediate-thickness ( 1.2 to 3.5 mm ) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy . ( Clinical Trials.gov number , NCT00275496 [ Clinical Trials.gov ] . ) BACKGROUND Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment . Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability . METHODS 1256 patients with resected stage III melanoma were r and omly assigned to observation ( n=629 ) or pegylated interferon alfa-2b ( n=627 ) 6 mug/kg per week for 8 weeks ( induction ) then 3 mug/kg per week ( maintenance ) for an intended duration of 5 years . R and omisation was stratified for microscopic ( N1 ) versus macroscopic ( N2 ) nodal involvement , number of positive nodes , ulceration and tumour thickness , sex , and centre . R and omisation was done with a minimisation technique . The primary endpoint was recurrence-free survival . Analyses were done by intention to treat . This study is registered with Clinical Trials.gov , number NCT00006249 . FINDINGS All r and omised patients were included in the primary efficacy analysis . 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses . The median length of treatment with pegylated interferon alfa-2b was 12 ( IQR 3.8 - 33.4 ) months . At 3.8 ( 3.2 - 4.2 ) years median follow-up , 328 recurrence events had occurred in the interferon group compared with 368 in the observation group ( hazard ratio 0.82 , 95 % CI 0.71 - 0.96 ; p=0.01 ) ; the 4-year rate of recurrence-free survival was 45.6 % ( SE 2.2 ) in the interferon group and 38.9 % ( 2.2 ) in the observation group . There was no difference in overall survival between the groups . Grade 3 adverse events occurred in 246 ( 40 % ) patients in the interferon group and 60 ( 10 % ) in the observation group ; grade 4 adverse events occurred in 32 ( 5 % ) patients in the interferon group and 14 ( 2 % ) in the observation group . In the interferon group , the most common grade 3 or 4 adverse events were fatigue ( 97 patients , 16 % ) , hepatotoxicity ( 66 , 11 % ) , and depression ( 39 , 6 % ) . Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 ( 31 % ) patients . INTERPRETATION Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant , sustained effect on recurrence-free survival PURPOSE Low-dose ( LD ) interferon ( IFN ) alfa ( LDI ) has demonstrated a consistent disease-free survival benefit for patients with clinical ly lymph node-negative melanoma in clinical trials . However , the optimal duration of treatment is still under discussion , and no previous trial has evaluated this question specifically . A prolongation of LDI from 18 months to 60 months might be of clinical benefit for patients with intermediate or high-risk melanoma . PATIENTS AND METHODS Eight hundred fifty patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness were included in this prospect i ve r and omized , multicenter trial in Germany and Austria . Patients had to be clinical ly lymph node-negative , and sentinel node biopsy ( SLNB ) was performed in a majority of cases . They were r and omly assigned to receive 3 MU IFNalpha2a three times a week subcutaneously for either 18 months ( arm A ) or 60 months ( arm B ) . Results Of 850 r and omly assigned patients , 840 were eligible for evaluation after a median follow-up of 4.3 years . Tumor thickness and other relevant prognostic factors were well balanced between both groups . SLNB was performed in 635 patients ( 75.6 % ) , with a positivity rate of 18.0 % in arm A and 17.5 % in arm B. Neither relapse-free survival ( arm A , 75.6 % v arm B , 72.6 % ; P = .72 ; hazard ratio , 1.05 ; 95 % CI , 0.80 to 1.39 ) nor distant-metastasis-free survival ( 81.9 % v 79.7 % ; P = .56 ; HR , 1.10 ; 95 % CI , 0.80 to 1.52 ) or overall survival ( 85.9 % v 84.9 % ; P = .86 ; HR , 1.03 ; 95 % CI , 0.71 to 1.50 ) showed significant differences . CONCLUSION A prolongation of conventional LDI therapy from 18 to 60 months showed no clinical benefit in patients with intermediate and high-risk primary melanoma 8506 Background : High dose IFNalfa2b , according to the ECOG 1684 schedule , is the only approved adjuvant treatment for stage III melanoma . The risk/benefit profile has limited its use , while efficacy of intravenous ( iv ) phase and optimal duration have not been defined . The IMI Mel . A. trial evaluated the efficacy and safety of a pulsed high dose iv IFNa2b regimen . METHODS Following lymphadenectomy , stage III ( AJCC2002 ) patients ( pts ) , were r and omly assigned to either 4 courses of IFNa2b 20 MU/m2iv 5 d/wk for 4 wks every other month ( IHDI arm ) or the st and ard high dose regimen of a 4 week iv course followed by 10 MU/m2IFNa2b sc 3 times/wk for 11 months ( HDI Arm ) . Overall survival ( OS ) was the primary end point . The sample size of 328 pts and 118 deaths was determined assuming a 55 % 5-y OS for HDI and an increase of 15 % in IHDI ( β=20 % , α=5 % , 2-sided test ) . RESULTS From 1998 to 2010 , 336 pts were r and omized and 330 evaluated for OS : 172 in IHDI , 158 in HDI . Pts were well balanced according to age , sex , PS ( WHO ) , tumor ulceration ( 41 % vs 46 % ) and number of metastatic lymph-nodes ( N1 : 64 % vs 60 % , N2 : 22 % vs 28 % , N3 : 13 % vs 10 % ) . Relapse occurred in 87 ( IHDI : 50.6 % ) vs 80 ( HDI : 50,6 % ) pts with a median relapse free survival ( RFS ) time of 47.9 ( IHDI ) vs 35.6 ( HDI ) months , not statistically different and a 5-y RFS of 45.8 % ( 95%CI : 37.4;53.7 ) in IHDI vs 44.3 % ( 95%CI : 35.7;52.6 ) in HDI arm . 72 pts ( 40.8 % ) died in IHDI arm vs 64 ( 40.7 % ) in HDI arm . The median and 5-y OS were 88.7 months ( 95%CI : 61.2;- ) and 60.1 % ( 95%CI : 53;66.5 ) in IHDI vs 82.6 ( 95%CI : 45.8;- ) and 52.7 % ( 95%CI : 44.9;59.8 ) in HDI arm , and were not significantly different . Discontinuation due to toxicity or refusal was 20 % in IHDI vs 28 % in HDI with 66 % of pts in IHDI completing the treatment vs 49 % in HDI ( p=0.0026 ) . The distribution of all grade s of toxicity was similar in both groups , except for leucopenia , higher in IHDI arm ( 23 % vs 12 % , p=0.0331 ) . CONCLUSIONS Our data show that a shorter but more intensive HDI regimen is more feasible and not more toxic than conventional HDI . No significant differences in efficacy were observed and a meta- analysis of our and DeCog Ma-ADJ-5 trial data could better establish the role of iv HDI BACKGROUND Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemura 
    Output:
    