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: BACKGROUND Angiogenesis plays a role in the biology of ovarian cancer . We examined the effect of bevacizumab , the vascular endothelial growth factor inhibitor , on survival in women with this disease . METHODS We r and omly assigned women with ovarian cancer to  carboplatin  ( area under the curve , 5 or 6 ) and paclitaxel ( 175 mg per square meter of body-surface area ) , given every 3 weeks for 6 cycles , or to this regimen plus bevacizumab ( 7.5 mg per kilogram of body weight ) , given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease . Outcome measures included progression-free survival , first analyzed per protocol and then up date d , and interim overall survival . RESULTS A total of 1528 women from 11 countries were r and omly assigned to one of the two treatment regimens . Their median age was 57 years ; 90 % had epithelial ovarian cancer , 69 % had a serous histologic type , 9 % had high-risk early-stage disease , 30 % were at high risk for progression , and 70 % had stage IIIC or IV ovarian cancer .  Progression-free survival ( restricted mean ) at 36 months was 20.3 months with st and ard therapy , as compared with 21.8 months with st and ard therapy plus bevacizumab ( hazard ratio for progression or death with bevacizumab added , 0.81 ; 95 % confidence interval , 0.70 to 0.94 ; P=0.004 by the log-rank test ) . Nonproportional hazards were detected ( i.e. , the treatment effect was not consistent over time on the hazard function scale ) ( P<0.001 ) , with a maximum effect at 12 months , coinciding with the end of planned bevacizumab treatment and diminishing by 24 months . Bevacizumab was associated with more toxic effects ( most often hypertension of grade 2 or higher ) ( 18 % , vs. 2 % with chemotherapy alone ) . In the up date d analyses , progression-free survival ( restricted mean ) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab ( P=0.04 by log-rank test ) ; in patients at high risk for progression , the benefit was greater with bevacizumab than without it , with progression-free survival ( restricted mean ) at 42 months of 14.5 months with st and ard therapy alone and 18.1 months with bevacizumab added , with respective median overall survival of 28.8 and 36.6 months . CONCLUSIONS Bevacizumab improved progression-free survival in women with ovarian cancer . The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression . ( Funded by Roche and others ; ICON7 Controlled-Trials.com number , IS RCT N91273375 . ) Background Intraperitoneal ( i.p . ) epinephrine was shown to increase the accumulation of i.p .  cisplatin in tumours , and thus its antitumour effect in a model of peritoneal carcinomatosis in rats . Methods To determine the tolerance to i.p . epinephrine with cisplatin , 18 patients with recurrent ovarian carcinoma were intraoperatively treated in this phase 1 study . After maximal cytoreductive surgery , the peritoneal cavity was filled twice for 1 h with 30 mg/l of cisplatin and increasing concentrations of epinephrine ( 0 , 1 , 2 , 3 mg/l ) in 3 l of saline solution at 37 ° C . Results No deaths occurred . Three patients were treated at each of the 0 , 1 and 2 mg/l epinephrine levels without adverse events . Two of the three patients who received 3 mg/l epinephrine  experienced cardiac intolerance . Six additional patients received 2 mg/l of epinephrine  without toxicity . A relationship between the serum concentration of  epinephrine  and occurrence of cardiac toxicity was established . A 60 % decrease in serum area under the curve of platinum was calculated in patients receiving i.p . epinephrine compared with i.p . cisplatin alone . Renal toxicity from cisplatin was not increased by epinephrine .  No haematological or neurological toxicity was recorded . The other grade 3–4 adverse events [ thromboembolism ( 5 ) , peritonitis ( 1 ) , abdominal bleeding ( 1 ) , bowel fistula ( 1 ) ] occurred as often as usually reported for this heavy surgical procedure . Conclusion The combination of i.p . epinephrine with cisplatin as intraoperative chemotherapy after optimal cytoreductive surgery is feasible . The recommended concentration for further studies is 2 mg/l for i.p . epinephrine BACKGROUND Despite the progress that has been achieved in the last years , recurrence rates in ovarian cancer patients are still considerably high and the majority of patients ultimately become c and i date s for second-line treatment . Carboplatin reinduction is a broadly adopted regimen in patients with recurrences occurring six months or later after first-line treatment .  Gemcitabine is among the c and i date s as combination partner in second-line regimens . PATIENTS AND METHODS We performed a study with escalating doses of gemcitabine combined with carboplatin in 26 platinum-pretreated patients with recurrent ovarian cancer and a treatment-free interval of 6 + months .  Dose-limiting toxicity ( DLT ) and a maximum tolerable dose ( MTD ) recommendable for further trials was evaluated . RESULTS The DLT was myelosuppression , mainly thrombocytopenia . No dose limiting non-hematological toxicities were observed . The MTD of gemcitabine was 1,000 mg/m2 given on days 1 + 8 of a three-week schedule combined with carboplatin AUC 4 given on day 1 . The majority of evaluable patients showed an objective response ( 62.5 % ) , and median progression-free and overall survival were 10 and 18 + months , respectively . CONCLUSION Gemcitabine-carboplatin given according to the MTD is well tolerated and active against recurrent platinum-sensitive disease . A r and omized trial comparing carboplatin with or without gemcitabine in platinum-sensitive ovarian cancer has already been initiated β-blockers are a class of drugs that are widely used in treating cardiac , respiratory and other ailments . They act by blocking β-adrenergic receptor-mediated signaling . Studies in various cancers have shown that patients taking a β-blocker have higher survival and lower recurrence and metastasis rates . This is supported by several pre clinical and in vitro studies showing that adrenergic activation modulates apoptosis , promotes angiogenesis and other cancer hallmarks , and these effects can be abrogated by β-blockers . These studies provide a rationale for the use of β-blockers as adjuvants with cancer chemotherapy . However , all published studies so far are retrospective and most do not take into account the specific β-blocker used or address which is most likely to benefit cancer patients . The published epidemiological studies are correlative and have not examined the adrenergic receptor status of the tumors . Knowledge of the β-adrenergic receptor status of tumor cells is essential in choosing the best β-blocker for adjuvant therapy . A comprehensive , prospect i ve study is necessary to definitively prove the utility of using β-blockers with chemotherapy and to identify the specific β-blocker most likely to benefit patients with cancer Recent clinical evidence revealed that the use of beta-blockers such as propranolol , prior to diagnosis or concurrently with chemotherapy , could increase relapse-free and overall survival in breast cancer patients . We therefore hypothesized that propranolol may be able to increase the efficacy of chemotherapy either through direct effects on cancer cells or via anti-angiogenic mechanisms . In vitro proliferation assay showed that propranolol ( from 50 - 100 μM ) induces dose-dependent anti-proliferative effects in a panel of 9 human cancer and “ normal ” cell lines . Matrigel assays revealed that propranolol displays potent anti-angiogenic properties at non-toxic concentrations ( < 50 μM ) but exert no vascular-disrupting activity . Combining chemotherapeutic drugs , such as 5-fluorouracil ( 5-FU ) or paclitaxel , with propranolol at the lowest effective concentration result ed in synergistic , additive or antagonistic effects on cell proliferation in vitro depending on the cell type and the dose of chemotherapy used . Interestingly , breast cancer and vascular endothelial cells were among the most responsive to these combinations . Furthermore , Matrigel assays indicated that low concentrations of propranolol ( 10 – 50 μM ) potentiated the anti-angiogenic effects of 5-FU and  paclitaxel  . Using an orthotopic xenograft model of triple-negative breast cancer , based on injection of luciferase-expressing MDA-MB-231 cells in the mammary fat pad of nude mice , we showed that propranolol , when used alone , induced only transient anti-tumor effects , if at all , and did not increase median survival . However , the combination of propranolol with chemotherapy result ed in more profound and sustained anti-tumor effects and significantly increased the survival benefits induced by chemotherapy alone ( + 19 % and + 79 % in median survival for the combination as compared with 5-FU alone and paclitaxel alone , respectively ; p<0.05 ) . Collectively our results show that propranolol can potentiate the anti-angiogenic effects and anti-tumor efficacy of chemotherapy . The current study , together with retrospective clinical data , strongly suggests that the use of propranolol concurrently with chemotherapy may improve the outcome of breast cancer patients , thus providing a strong rationale for the evaluation of this drug combination in prospect i ve clinical studies OBJECTIVE To verify preliminary studies on patients with melanoma exposed to β-blockers  that suggested a reduced risk of disease recurrence and death . PATIENTS AND METHODS Data were obtained from all consecutive patients diagnosed as having melanoma between January 1 , 1993 , and December 31 , 2009 , at the Department of Dermatology of the University of Florence , Azienda Sanitaria di Firenze . Participants were excluded if at baseline they reported a previous diagnosis of cutaneous malignant melanoma or another malignant disease . We also excluded participants with evidence of visceral , lymph nodal , and in-transit metastasis at the time of the diagnosis . RESULTS Of 741 consecutive patients with melanoma , 79 ( 11 % ) were prescribed β-blockers ( for hypertension in most cases ) for 1 or more years ( treated ) and 662 ( 89 % ) were not ( untreated ) . The multivariate Cox model indicated that the treated group had improved overall survival after a median follow-up of 4 years ( P=.005 ) . For each year of β-blocker use , the risk of death was reduced by 38 % . The presence of hypertension , the use of antihypertensive agents for 1 or more years , or the use of other commonly used medicines were not associated with a better outcome for patients with melanoma . CONCLUSION The results confirm and strengthen previous findings that β-blocker use is associated with a reduced risk of melanoma recurrence and death . The results also indicate the strong need for a r and omized clinical trial to conclusively assess whether β-blockers afford protection against melanoma recurrence and death OBJECTIVE Retrospective analyses suggest that the treatment with beta blocker improves survival in patients with breast cancer and melanoma . The aim of this study was to investigate the impact of medication with beta blocker in patients with recurrent ovarian cancer . METHODS Included patients received treatment within two prospect i ve clinical trials : AGO-OVAR 2.4 phase I trial ( carboplatin/gemcitabine ; N=25 , protocol AGO-OVAR 2.4 ) and AGO led intergroup phase III trial ( carboplatin vs carboplatin/gemcitabine ; N=356 , protocol AGO-OVAR 2.5 , EORTC-GCG , NCIC CTG ) . Concurrent medication was documented after every cycle and thorough monitoring was conducted . RESULTS During the studies 38 patients ( 9.97 % ) received a beta blocker as co-medication . Patients treated with beta blockers  were significantly older than patients not treated with beta blockers .  Response rates to chemotherapy were not different between patients treated with beta blockers and those who were not . After a median follow-up of 17 months , 349 ( 91.6 % ) patients had progressive disease and 267 ( 70.1 % ) patients had died . No difference in median progression-free survival ( 7.79 vs 7.62 months ( p=0.95 ) ) and overall survival ( 21.2 vs 17.3 months ( p=0.18 ) ) was recorded for patients treated with and without beta blocker . In multivariate analyses including age , platinum free-interval , study treatment and ECOG performance status beta blocker treatment was not associated with a significant impact on progression-free survival ( HR : 0.92 ; 95 % CI : 0.65 -  
    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: BACKGROUND Angiogenesis plays a role in the biology of ovarian cancer . We examined the effect of bevacizumab , the vascular endothelial growth factor inhibitor , on survival in women with this disease . METHODS We r and omly assigned women with ovarian cancer to  carboplatin  ( area under the curve , 5 or 6 ) and paclitaxel ( 175 mg per square meter of body-surface area ) , given every 3 weeks for 6 cycles , or to this regimen plus bevacizumab ( 7.5 mg per kilogram of body weight ) , given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease . Outcome measures included progression-free survival , first analyzed per protocol and then up date d , and interim overall survival . RESULTS A total of 1528 women from 11 countries were r and omly assigned to one of the two treatment regimens . Their median age was 57 years ; 90 % had epithelial ovarian cancer , 69 % had a serous histologic type , 9 % had high-risk early-stage disease , 30 % were at high risk for progression , and 70 % had stage IIIC or IV ovarian cancer .  Progression-free survival ( restricted mean ) at 36 months was 20.3 months with st and ard therapy , as compared with 21.8 months with st and ard therapy plus bevacizumab ( hazard ratio for progression or death with bevacizumab added , 0.81 ; 95 % confidence interval , 0.70 to 0.94 ; P=0.004 by the log-rank test ) . Nonproportional hazards were detected ( i.e. , the treatment effect was not consistent over time on the hazard function scale ) ( P<0.001 ) , with a maximum effect at 12 months , coinciding with the end of planned bevacizumab treatment and diminishing by 24 months . Bevacizumab was associated with more toxic effects ( most often hypertension of grade 2 or higher ) ( 18 % , vs. 2 % with chemotherapy alone ) . In the up date d analyses , progression-free survival ( restricted mean ) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab ( P=0.04 by log-rank test ) ; in patients at high risk for progression , the benefit was greater with bevacizumab than without it , with progression-free survival ( restricted mean ) at 42 months of 14.5 months with st and ard therapy alone and 18.1 months with bevacizumab added , with respective median overall survival of 28.8 and 36.6 months . CONCLUSIONS Bevacizumab improved progression-free survival in women with ovarian cancer . The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression . ( Funded by Roche and others ; ICON7 Controlled-Trials.com number , IS RCT N91273375 . ) Background Intraperitoneal ( i.p . ) epinephrine was shown to increase the accumulation of i.p .  cisplatin in tumours , and thus its antitumour effect in a model of peritoneal carcinomatosis in rats . Methods To determine the tolerance to i.p . epinephrine with cisplatin , 18 patients with recurrent ovarian carcinoma were intraoperatively treated in this phase 1 study . After maximal cytoreductive surgery , the peritoneal cavity was filled twice for 1 h with 30 mg/l of cisplatin and increasing concentrations of epinephrine ( 0 , 1 , 2 , 3 mg/l ) in 3 l of saline solution at 37 ° C . Results No deaths occurred . Three patients were treated at each of the 0 , 1 and 2 mg/l epinephrine levels without adverse events . Two of the three patients who received 3 mg/l epinephrine  experienced cardiac intolerance . Six additional patients received 2 mg/l of epinephrine  without toxicity . A relationship between the serum concentration of  epinephrine  and occurrence of cardiac toxicity was established . A 60 % decrease in serum area under the curve of platinum was calculated in patients receiving i.p . epinephrine compared with i.p . cisplatin alone . Renal toxicity from cisplatin was not increased by epinephrine .  No haematological or neurological toxicity was recorded . The other grade 3–4 adverse events [ thromboembolism ( 5 ) , peritonitis ( 1 ) , abdominal bleeding ( 1 ) , bowel fistula ( 1 ) ] occurred as often as usually reported for this heavy surgical procedure . Conclusion The combination of i.p . epinephrine with cisplatin as intraoperative chemotherapy after optimal cytoreductive surgery is feasible . The recommended concentration for further studies is 2 mg/l for i.p . epinephrine BACKGROUND Despite the progress that has been achieved in the last years , recurrence rates in ovarian cancer patients are still considerably high and the majority of patients ultimately become c and i date s for second-line treatment . Carboplatin reinduction is a broadly adopted regimen in patients with recurrences occurring six months or later after first-line treatment .  Gemcitabine is among the c and i date s as combination partner in second-line regimens . PATIENTS AND METHODS We performed a study with escalating doses of gemcitabine combined with carboplatin in 26 platinum-pretreated patients with recurrent ovarian cancer and a treatment-free interval of 6 + months .  Dose-limiting toxicity ( DLT ) and a maximum tolerable dose ( MTD ) recommendable for further trials was evaluated . RESULTS The DLT was myelosuppression , mainly thrombocytopenia . No dose limiting non-hematological toxicities were observed . The MTD of gemcitabine was 1,000 mg/m2 given on days 1 + 8 of a three-week schedule combined with carboplatin AUC 4 given on day 1 . The majority of evaluable patients showed an objective response ( 62.5 % ) , and median progression-free and overall survival were 10 and 18 + months , respectively . CONCLUSION Gemcitabine-carboplatin given according to the MTD is well tolerated and active against recurrent platinum-sensitive disease . A r and omized trial comparing carboplatin with or without gemcitabine in platinum-sensitive ovarian cancer has already been initiated β-blockers are a class of drugs that are widely used in treating cardiac , respiratory and other ailments . They act by blocking β-adrenergic receptor-mediated signaling . Studies in various cancers have shown that patients taking a β-blocker have higher survival and lower recurrence and metastasis rates . This is supported by several pre clinical and in vitro studies showing that adrenergic activation modulates apoptosis , promotes angiogenesis and other cancer hallmarks , and these effects can be abrogated by β-blockers . These studies provide a rationale for the use of β-blockers as adjuvants with cancer chemotherapy . However , all published studies so far are retrospective and most do not take into account the specific β-blocker used or address which is most likely to benefit cancer patients . The published epidemiological studies are correlative and have not examined the adrenergic receptor status of the tumors . Knowledge of the β-adrenergic receptor status of tumor cells is essential in choosing the best β-blocker for adjuvant therapy . A comprehensive , prospect i ve study is necessary to definitively prove the utility of using β-blockers with chemotherapy and to identify the specific β-blocker most likely to benefit patients with cancer Recent clinical evidence revealed that the use of beta-blockers such as propranolol , prior to diagnosis or concurrently with chemotherapy , could increase relapse-free and overall survival in breast cancer patients . We therefore hypothesized that propranolol may be able to increase the efficacy of chemotherapy either through direct effects on cancer cells or via anti-angiogenic mechanisms . In vitro proliferation assay showed that propranolol ( from 50 - 100 μM ) induces dose-dependent anti-proliferative effects in a panel of 9 human cancer and “ normal ” cell lines . Matrigel assays revealed that propranolol displays potent anti-angiogenic properties at non-toxic concentrations ( < 50 μM ) but exert no vascular-disrupting activity . Combining chemotherapeutic drugs , such as 5-fluorouracil ( 5-FU ) or paclitaxel , with propranolol at the lowest effective concentration result ed in synergistic , additive or antagonistic effects on cell proliferation in vitro depending on the cell type and the dose of chemotherapy used . Interestingly , breast cancer and vascular endothelial cells were among the most responsive to these combinations . Furthermore , Matrigel assays indicated that low concentrations of propranolol ( 10 – 50 μM ) potentiated the anti-angiogenic effects of 5-FU and  paclitaxel  . Using an orthotopic xenograft model of triple-negative breast cancer , based on injection of luciferase-expressing MDA-MB-231 cells in the mammary fat pad of nude mice , we showed that propranolol , when used alone , induced only transient anti-tumor effects , if at all , and did not increase median survival . However , the combination of propranolol with chemotherapy result ed in more profound and sustained anti-tumor effects and significantly increased the survival benefits induced by chemotherapy alone ( + 19 % and + 79 % in median survival for the combination as compared with 5-FU alone and paclitaxel alone , respectively ; p<0.05 ) . Collectively our results show that propranolol can potentiate the anti-angiogenic effects and anti-tumor efficacy of chemotherapy . The current study , together with retrospective clinical data , strongly suggests that the use of propranolol concurrently with chemotherapy may improve the outcome of breast cancer patients , thus providing a strong rationale for the evaluation of this drug combination in prospect i ve clinical studies OBJECTIVE To verify preliminary studies on patients with melanoma exposed to β-blockers  that suggested a reduced risk of disease recurrence and death . PATIENTS AND METHODS Data were obtained from all consecutive patients diagnosed as having melanoma between January 1 , 1993 , and December 31 , 2009 , at the Department of Dermatology of the University of Florence , Azienda Sanitaria di Firenze . Participants were excluded if at baseline they reported a previous diagnosis of cutaneous malignant melanoma or another malignant disease . We also excluded participants with evidence of visceral , lymph nodal , and in-transit metastasis at the time of the diagnosis . RESULTS Of 741 consecutive patients with melanoma , 79 ( 11 % ) were prescribed β-blockers ( for hypertension in most cases ) for 1 or more years ( treated ) and 662 ( 89 % ) were not ( untreated ) . The multivariate Cox model indicated that the treated group had improved overall survival after a median follow-up of 4 years ( P=.005 ) . For each year of β-blocker use , the risk of death was reduced by 38 % . The presence of hypertension , the use of antihypertensive agents for 1 or more years , or the use of other commonly used medicines were not associated with a better outcome for patients with melanoma . CONCLUSION The results confirm and strengthen previous findings that β-blocker use is associated with a reduced risk of melanoma recurrence and death . The results also indicate the strong need for a r and omized clinical trial to conclusively assess whether β-blockers afford protection against melanoma recurrence and death OBJECTIVE Retrospective analyses suggest that the treatment with beta blocker improves survival in patients with breast cancer and melanoma . The aim of this study was to investigate the impact of medication with beta blocker in patients with recurrent ovarian cancer . METHODS Included patients received treatment within two prospect i ve clinical trials : AGO-OVAR 2.4 phase I trial ( carboplatin/gemcitabine ; N=25 , protocol AGO-OVAR 2.4 ) and AGO led intergroup phase III trial ( carboplatin vs carboplatin/gemcitabine ; N=356 , protocol AGO-OVAR 2.5 , EORTC-GCG , NCIC CTG ) . Concurrent medication was documented after every cycle and thorough monitoring was conducted . RESULTS During the studies 38 patients ( 9.97 % ) received a beta blocker as co-medication . Patients treated with beta blockers  were significantly older than patients not treated with beta blockers .  Response rates to chemotherapy were not different between patients treated with beta blockers and those who were not . After a median follow-up of 17 months , 349 ( 91.6 % ) patients had progressive disease and 267 ( 70.1 % ) patients had died . No difference in median progression-free survival ( 7.79 vs 7.62 months ( p=0.95 ) ) and overall survival ( 21.2 vs 17.3 months ( p=0.18 ) ) was recorded for patients treated with and without beta blocker . In multivariate analyses including age , platinum free-interval , study treatment and ECOG performance status beta blocker treatment was not associated with a significant impact on progression-free survival ( HR : 0.92 ; 95 % CI : 0.65 -  
    Output:
    