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: OBJECTIVE To evaluate prospect ively renal function in patients with malignant germ-cell tumours ( MGCTs ) > 10 years after retroperitoneal lymph node dissection alone ( RPLND ) , radiotherapy alone ( RAD ) or different schedules of cisplatin-based chemotherapy with or without surgery/radiotherapy ( CHEM ) .  PATIENTS AND METHODS In 85 patients , three groups were identified : RPLND , 14 ; RAD , 18 ; CHEM , 53 , with subdivision of the latter group according to the cumulative cisplatin dose or the additional use of radiotherapy .  Renal function was determined by 131Iodine Hippuran clearance or 99 m DTPA glomerular filtration rate , and was assessed before treatment and four times during 14 years of follow-up . A value of < 70 % of the upper limit of the normal range identified impaired renal function . RESULTS Twenty-five patients displayed long-term impaired renal function , 23 of them from the RAD or CHEM group . In the RAD group , renal function decreased by 8 % , whereas a 14 % reduction of renal function was observed in the CHEM group . In the CHEM group the cumulative dose of cisplatin , and in the RAD group the age at treatment , were associated with impairment of renal function . Combining all patients , age at treatment and the type of treatment were associated with impaired renal function . CONCLUSIONS In 20 - 30 % of the patients with germ-cell tumour , st and ard radiotherapy and chemotherapy strategies are followed by long-term sub clinical impaired renal function . These findings support current intentions to avoid overtreatment with these treatment modalities 4507 Background : Sequential and single high-dose chemotherapy ( HDCT ) can both be curative in patients ( pts ) with relapsed or refractory germ-cell tumors ( GCT ) . The long-term efficacy of either modality is unknown . METHODS Between 11/99 and 11/04 , 211 pts with relapsed or refractory GTC were prospect ively r and omized to treatment with either one cycle of cisplatin 100 mg/m² , etoposide 375 mg/m² and ifosfamide 6 g/m² ( VIP ) plus three cycles of high-dose carboplatin 1,500 mg/m² and etoposide 1,500 mg/m² ( CE , arm A ) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m² , etoposide 1,800 mg/m² and cyclophosphamide 6,400 mg/m² ( CEC , arm B ) followed by stem cell reinfusion ( JCO 2007,25:2778 ) . Five pts were excluded from further analysis due to non-GCT histologies at review . We evaluated long-term progression-free ( PFS ) and overall survival ( OS ) six years after r and omization of the last patient . Survival probabilities were compared using the logrank test . RESULTS Overall , 108 and 103 pts were r and omized to arms A and B respectively . The study was stopped prematurely due to excess treatment-related mortality in am B ( 14 % ) compared to arm A ( 4 % ) ( p=0.01 ) . As of December 2010 , 9/211 ( 4 % ) pts were lost-to-follow at 31 , 32 + , 36 + , 47 + , 47 + , 51 + , 55 , 61 + , 71 + months . Median follow-up was 7.5 years ( range 2.5 to 10.5 years ) . Alive are 94/211 ( 45 % ) and 88/94 pts are progression-free . All but 6 relapsed patients died from progressive disease , 4 pts became disease-free with third-line treatment and two were alive with disease at last follow-up . Five year PFS is 47 % ( 95%CI : 37 - 56 % ) in arm A and 45 % ( 95%CI : 35 - 55 % ) in arm B ( HR=1.16 ( 95%CI : 0.79 - 1.70 , p=0.454 ) . Five year OS is 49 % ( 95%CI : 40 - 59 % ) in arm A and 39 % ( 95%CI : 30 - 49 % ) in arm B ( HR=1.42 ( 95%CI : 0.99 - 2.05 , p=0.057 ) . Relapses more than two years after r and omization occurred in 5/211 ( 2.4 % ) pts . One patient developed secondary acute myeloid leukemia . CONCLUSIONS In this prospect i ve , r and omized trial in pts with relapsed or refractory GCT , sequential HDCT was superior to single HDCT with respect to long-term OS PURPOSE To evaluate the optimal dose of carboplatin as well as the efficacy and tolerability of sequential , dose-intense chemotherapy with paclitaxel and ifosfamide followed by carboplatin and etoposide ( TICE ) plus peripheral-blood stem-cell ( PBSC ) support in patients with germ cell tumors ( GCT ) who are likely to experience treatment failure with conventional-dose salvage treatment . This prospect i ve trial followed a similarly design ed report of TICE , which used a different means of carboplatin dosing . PATIENTS AND METHODS The 48 patients entered onto this trial had progressive GCT and unfavorable prognostic features after chemotherapy . Two cycles of paclitaxel plus ifosfamide were administered with leukapheresis , followed by three cycles of carboplatin plus etoposide with reinfusion of PBSC . RESULTS Twenty-three ( 49 % ) of 47 assessable patients achieved a complete response ( CR ) to chemotherapy . An additional three patients ( 6 % ) achieved a CR to chemotherapy and surgery . The CR rate was 55 % . Six patients experienced relapse , but 24 patients ( 51 % ) are alive and free of disease at a median follow-up time of 40 months . Four patients who experienced relapse or achieved an incomplete response were rendered disease free by salvage surgical resection . When combined with results of the prior trial of similar design , TICE chemotherapy yielded an overall CR of 56 % ( n = 84 ) , with 50 % of patients alive with no evidence of disease . CONCLUSION TICE is an effective and tolerable dose-intense treatment for patients with previously treated metastatic GCT who have a poor predicted outcome to conventional-dose salvage chemotherapy BACKGROUND Bleomycin pulmonary toxicity ( BPT ) has been known since the early clinical trials of bleomycin in the 1960s . Postulated risk factors include cumulative bleomycin dose , reduced glomerular filtration rate ( GFR ) , raised creatinine , older age and supplemental oxygen exposure . PATIENTS AND METHODS From our prospect ively collected testicular cancer research data base , we review ed 835 patients treated at the Royal Marsden NHS Trust ( Sutton , UK ) with bleomycin-containing regimens for germ-cell tumours between January 1982 and December 1999 , to identify those with BPT . RESULTS Fifty-seven ( 6.8 % ) patients had BPT , ranging from X-ray/CT ( computed tomography ) changes to dyspnoea . There were eight deaths ( 1 % of patients treated ) directly attributed to BPT . The median time from the start of bleomycin administration to documented lung toxicity was 4.2 months ( range 1.2 - 8.2 ) . On multivariate analysis , the factors independently predicting for increased risk of BPT were GFR < 80 ml/min [ hazard ratio ( HR ) 3.3 ] , age > 40 years ( HR 2.3 ) , stage IV disease at presentation ( HR 2.6 ) and cumulative dose of bleomycin > 300,000 IU ( HR 3.5 ) . CONCLUSIONS Patients with poor renal function are at high risk of BPT , especially if they are aged > 40 years , have stage IV disease at presentation or receive > 300,000 IU of bleomycin . In such cases alternative drug regimens or dose restriction should be considered BACKGROUND High-dose chemotherapy ( HD-CT ) is able to circumvent platinum resistance of resistant/refractory germ-cell tumors ( GCTs ) , but expectancy of cure remains low . New strategies are needed with new drugs and a sequential approach . MATERIAL S AND METHODS Patients with relapsed poor-prognosis GCTs were scheduled to receive two cycles combining epirubicin and paclitaxel ( Taxol ) followed by three consecutive HD-CT supported by stem cell transplantation [ one course combining cyclophosphamide , 3 g/m(2 ) + thiotepa , 400 mg/m(2 ) , followed by two ICE regimens ( ifosfamide , 10 g/m(2 ) , carboplatin , AUC 20 , etoposide , 1500 mg/m(2 ) ) ] . RESULTS From March 1998 to September 2001 ( median follow-up , 31.8 months ) , 45 patients ( median age , 28 years ) were enrolled in this phase II study . Twenty-two patients received the complete course . Twenty-five patients died from progression and five from toxicity . The overall response rate was 37.7 % , including an 8.9 % complete response rate . The median overall survival was 11.8 months . The 3-year survival and progression-free survival rate was 23.5 % . The ' Beyer ' prognostic score predicted the outcome after HD-CT . CONCLUSION Although our results warrant further studies on HD-CT in relapsed poor prognosis GCTs , patients with a Beyer score > 2 did not benefit from this approach and should not be enrolled in HD-CT trials . Better selection criteria have to be fulfilled in forthcoming studies BACKGROUND The objective of the study was to investigate the activity of sunitinib in a cell line model and subsequently in patients with cisplatin-refractory or multiply relapsed germ cell tumors ( GCT ) . METHODS The effect of sunitinib on cell proliferation in cisplatin-sensitive and cisplatin-refractory GCT cell lines was evaluated after 48-h sunitinib exposure by MTT [ 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ] assay , and IC(50 ) ( concentration that causes 50 % inhibition of growth ) doses were determined . Sunitinib was subsequently administered at a dose of 50 mg/day for 4 weeks followed by a 2-week break to 33 patients using a Simon two-stage design . RESULTS Sunitinib demonstrated comparable dose-dependent growth inhibition in cisplatin-sensitive and cisplatin-resistant cell lines , with IC(50 ) between 3.0 and 3.8 μM. Patient characteristics were as follows : median of 2 ( 1 - 6 ) cisplatin-containing regimens ; high-dose chemotherapy 67 % ; late relapse 33 % ; and cisplatin refractory or absolute cisplatin refractory 54 %  . Toxic effects included fatigue ( 39 % ) , anorexia ( 21 % ) , diarrhea ( 27 % ) , mucositis ( 45 % ) , nausea ( 33 % ) , h and -foot syndrome ( 12 % ) , dyspepsia ( 27 % ) , and skin rash ( 18 % ) . No unexpected side-effects were observed . Thirty -two of 33 patients were assessable for response . Three confirmed partial responses ( PRs ) and one unconfirmed PR were seen for a total response rate of 13 % . Median progression-free survival ( PFS ) was 2 months , with a 6-month PFS rate of 11 % . CONCLUSIONS Sunitinib shows in vitro activity in cisplatin-resistant GCT cell lines . Modest clinical activity in heavily pretreated GCT patients was observed Various staging systems have been proposed for disseminated germ cell neoplasms . The Indiana University staging system was based on clinical and radiographic findings only , whereas the newly created International Germ Cell Cancer Collaborative Group ( IGCCCG ) staging system also utilized serum markers as a prognostic factor . This study up date d the intergroup trial that compared the st and ard therapy of bleomycin , etoposide , and cisplatin ( BEP ) with etoposide , ifosfamide , and cisplatin ( VIP ) in advanced germ cell tumors and reanalyzed the results using the IGCCCG staging system 4508 Background : Up to 50 % of patients ( pts ) with IGCCCG poor prognosis non-seminomatous tumours die yet st and ard chemotherapy has remained bleomycin ( BLM ) , etoposide and cisplatin ( BEP ) for many years . This trial evaluated a new intensive induction chemotherapy regimen , CBOP/BEP , in a r and omized phase II trial also establishing current BEP response rate ( RR ) . METHODS Pts were r and omized to st and ard 4xBEP ( 12 weeks [ wks ] ) or 
    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: OBJECTIVE To evaluate prospect ively renal function in patients with malignant germ-cell tumours ( MGCTs ) > 10 years after retroperitoneal lymph node dissection alone ( RPLND ) , radiotherapy alone ( RAD ) or different schedules of cisplatin-based chemotherapy with or without surgery/radiotherapy ( CHEM ) .  PATIENTS AND METHODS In 85 patients , three groups were identified : RPLND , 14 ; RAD , 18 ; CHEM , 53 , with subdivision of the latter group according to the cumulative cisplatin dose or the additional use of radiotherapy .  Renal function was determined by 131Iodine Hippuran clearance or 99 m DTPA glomerular filtration rate , and was assessed before treatment and four times during 14 years of follow-up . A value of < 70 % of the upper limit of the normal range identified impaired renal function . RESULTS Twenty-five patients displayed long-term impaired renal function , 23 of them from the RAD or CHEM group . In the RAD group , renal function decreased by 8 % , whereas a 14 % reduction of renal function was observed in the CHEM group . In the CHEM group the cumulative dose of cisplatin , and in the RAD group the age at treatment , were associated with impairment of renal function . Combining all patients , age at treatment and the type of treatment were associated with impaired renal function . CONCLUSIONS In 20 - 30 % of the patients with germ-cell tumour , st and ard radiotherapy and chemotherapy strategies are followed by long-term sub clinical impaired renal function . These findings support current intentions to avoid overtreatment with these treatment modalities 4507 Background : Sequential and single high-dose chemotherapy ( HDCT ) can both be curative in patients ( pts ) with relapsed or refractory germ-cell tumors ( GCT ) . The long-term efficacy of either modality is unknown . METHODS Between 11/99 and 11/04 , 211 pts with relapsed or refractory GTC were prospect ively r and omized to treatment with either one cycle of cisplatin 100 mg/m² , etoposide 375 mg/m² and ifosfamide 6 g/m² ( VIP ) plus three cycles of high-dose carboplatin 1,500 mg/m² and etoposide 1,500 mg/m² ( CE , arm A ) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m² , etoposide 1,800 mg/m² and cyclophosphamide 6,400 mg/m² ( CEC , arm B ) followed by stem cell reinfusion ( JCO 2007,25:2778 ) . Five pts were excluded from further analysis due to non-GCT histologies at review . We evaluated long-term progression-free ( PFS ) and overall survival ( OS ) six years after r and omization of the last patient . Survival probabilities were compared using the logrank test . RESULTS Overall , 108 and 103 pts were r and omized to arms A and B respectively . The study was stopped prematurely due to excess treatment-related mortality in am B ( 14 % ) compared to arm A ( 4 % ) ( p=0.01 ) . As of December 2010 , 9/211 ( 4 % ) pts were lost-to-follow at 31 , 32 + , 36 + , 47 + , 47 + , 51 + , 55 , 61 + , 71 + months . Median follow-up was 7.5 years ( range 2.5 to 10.5 years ) . Alive are 94/211 ( 45 % ) and 88/94 pts are progression-free . All but 6 relapsed patients died from progressive disease , 4 pts became disease-free with third-line treatment and two were alive with disease at last follow-up . Five year PFS is 47 % ( 95%CI : 37 - 56 % ) in arm A and 45 % ( 95%CI : 35 - 55 % ) in arm B ( HR=1.16 ( 95%CI : 0.79 - 1.70 , p=0.454 ) . Five year OS is 49 % ( 95%CI : 40 - 59 % ) in arm A and 39 % ( 95%CI : 30 - 49 % ) in arm B ( HR=1.42 ( 95%CI : 0.99 - 2.05 , p=0.057 ) . Relapses more than two years after r and omization occurred in 5/211 ( 2.4 % ) pts . One patient developed secondary acute myeloid leukemia . CONCLUSIONS In this prospect i ve , r and omized trial in pts with relapsed or refractory GCT , sequential HDCT was superior to single HDCT with respect to long-term OS PURPOSE To evaluate the optimal dose of carboplatin as well as the efficacy and tolerability of sequential , dose-intense chemotherapy with paclitaxel and ifosfamide followed by carboplatin and etoposide ( TICE ) plus peripheral-blood stem-cell ( PBSC ) support in patients with germ cell tumors ( GCT ) who are likely to experience treatment failure with conventional-dose salvage treatment . This prospect i ve trial followed a similarly design ed report of TICE , which used a different means of carboplatin dosing . PATIENTS AND METHODS The 48 patients entered onto this trial had progressive GCT and unfavorable prognostic features after chemotherapy . Two cycles of paclitaxel plus ifosfamide were administered with leukapheresis , followed by three cycles of carboplatin plus etoposide with reinfusion of PBSC . RESULTS Twenty-three ( 49 % ) of 47 assessable patients achieved a complete response ( CR ) to chemotherapy . An additional three patients ( 6 % ) achieved a CR to chemotherapy and surgery . The CR rate was 55 % . Six patients experienced relapse , but 24 patients ( 51 % ) are alive and free of disease at a median follow-up time of 40 months . Four patients who experienced relapse or achieved an incomplete response were rendered disease free by salvage surgical resection . When combined with results of the prior trial of similar design , TICE chemotherapy yielded an overall CR of 56 % ( n = 84 ) , with 50 % of patients alive with no evidence of disease . CONCLUSION TICE is an effective and tolerable dose-intense treatment for patients with previously treated metastatic GCT who have a poor predicted outcome to conventional-dose salvage chemotherapy BACKGROUND Bleomycin pulmonary toxicity ( BPT ) has been known since the early clinical trials of bleomycin in the 1960s . Postulated risk factors include cumulative bleomycin dose , reduced glomerular filtration rate ( GFR ) , raised creatinine , older age and supplemental oxygen exposure . PATIENTS AND METHODS From our prospect ively collected testicular cancer research data base , we review ed 835 patients treated at the Royal Marsden NHS Trust ( Sutton , UK ) with bleomycin-containing regimens for germ-cell tumours between January 1982 and December 1999 , to identify those with BPT . RESULTS Fifty-seven ( 6.8 % ) patients had BPT , ranging from X-ray/CT ( computed tomography ) changes to dyspnoea . There were eight deaths ( 1 % of patients treated ) directly attributed to BPT . The median time from the start of bleomycin administration to documented lung toxicity was 4.2 months ( range 1.2 - 8.2 ) . On multivariate analysis , the factors independently predicting for increased risk of BPT were GFR < 80 ml/min [ hazard ratio ( HR ) 3.3 ] , age > 40 years ( HR 2.3 ) , stage IV disease at presentation ( HR 2.6 ) and cumulative dose of bleomycin > 300,000 IU ( HR 3.5 ) . CONCLUSIONS Patients with poor renal function are at high risk of BPT , especially if they are aged > 40 years , have stage IV disease at presentation or receive > 300,000 IU of bleomycin . In such cases alternative drug regimens or dose restriction should be considered BACKGROUND High-dose chemotherapy ( HD-CT ) is able to circumvent platinum resistance of resistant/refractory germ-cell tumors ( GCTs ) , but expectancy of cure remains low . New strategies are needed with new drugs and a sequential approach . MATERIAL S AND METHODS Patients with relapsed poor-prognosis GCTs were scheduled to receive two cycles combining epirubicin and paclitaxel ( Taxol ) followed by three consecutive HD-CT supported by stem cell transplantation [ one course combining cyclophosphamide , 3 g/m(2 ) + thiotepa , 400 mg/m(2 ) , followed by two ICE regimens ( ifosfamide , 10 g/m(2 ) , carboplatin , AUC 20 , etoposide , 1500 mg/m(2 ) ) ] . RESULTS From March 1998 to September 2001 ( median follow-up , 31.8 months ) , 45 patients ( median age , 28 years ) were enrolled in this phase II study . Twenty-two patients received the complete course . Twenty-five patients died from progression and five from toxicity . The overall response rate was 37.7 % , including an 8.9 % complete response rate . The median overall survival was 11.8 months . The 3-year survival and progression-free survival rate was 23.5 % . The ' Beyer ' prognostic score predicted the outcome after HD-CT . CONCLUSION Although our results warrant further studies on HD-CT in relapsed poor prognosis GCTs , patients with a Beyer score > 2 did not benefit from this approach and should not be enrolled in HD-CT trials . Better selection criteria have to be fulfilled in forthcoming studies BACKGROUND The objective of the study was to investigate the activity of sunitinib in a cell line model and subsequently in patients with cisplatin-refractory or multiply relapsed germ cell tumors ( GCT ) . METHODS The effect of sunitinib on cell proliferation in cisplatin-sensitive and cisplatin-refractory GCT cell lines was evaluated after 48-h sunitinib exposure by MTT [ 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ] assay , and IC(50 ) ( concentration that causes 50 % inhibition of growth ) doses were determined . Sunitinib was subsequently administered at a dose of 50 mg/day for 4 weeks followed by a 2-week break to 33 patients using a Simon two-stage design . RESULTS Sunitinib demonstrated comparable dose-dependent growth inhibition in cisplatin-sensitive and cisplatin-resistant cell lines , with IC(50 ) between 3.0 and 3.8 μM. Patient characteristics were as follows : median of 2 ( 1 - 6 ) cisplatin-containing regimens ; high-dose chemotherapy 67 % ; late relapse 33 % ; and cisplatin refractory or absolute cisplatin refractory 54 %  . Toxic effects included fatigue ( 39 % ) , anorexia ( 21 % ) , diarrhea ( 27 % ) , mucositis ( 45 % ) , nausea ( 33 % ) , h and -foot syndrome ( 12 % ) , dyspepsia ( 27 % ) , and skin rash ( 18 % ) . No unexpected side-effects were observed . Thirty -two of 33 patients were assessable for response . Three confirmed partial responses ( PRs ) and one unconfirmed PR were seen for a total response rate of 13 % . Median progression-free survival ( PFS ) was 2 months , with a 6-month PFS rate of 11 % . CONCLUSIONS Sunitinib shows in vitro activity in cisplatin-resistant GCT cell lines . Modest clinical activity in heavily pretreated GCT patients was observed Various staging systems have been proposed for disseminated germ cell neoplasms . The Indiana University staging system was based on clinical and radiographic findings only , whereas the newly created International Germ Cell Cancer Collaborative Group ( IGCCCG ) staging system also utilized serum markers as a prognostic factor . This study up date d the intergroup trial that compared the st and ard therapy of bleomycin , etoposide , and cisplatin ( BEP ) with etoposide , ifosfamide , and cisplatin ( VIP ) in advanced germ cell tumors and reanalyzed the results using the IGCCCG staging system 4508 Background : Up to 50 % of patients ( pts ) with IGCCCG poor prognosis non-seminomatous tumours die yet st and ard chemotherapy has remained bleomycin ( BLM ) , etoposide and cisplatin ( BEP ) for many years . This trial evaluated a new intensive induction chemotherapy regimen , CBOP/BEP , in a r and omized phase II trial also establishing current BEP response rate ( RR ) . METHODS Pts were r and omized to st and ard 4xBEP ( 12 weeks [ wks ] ) or 
    Output:
    