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 —Ghrelin is a novel growth hormone – releasing peptide that also induces vasodilation , inhibits sympathetic nerve activity , and stimulates feeding through growth hormone – independent mechanisms . We investigated the effects of ghrelin on left ventricular ( LV ) function , exercise capacity , and muscle wasting in patients with chronic heart failure ( CHF ) . Methods and Results —Human synthetic ghrelin ( 2 & mgr;g/kg twice a day ) was intravenously administered to 10 patients with CHF for 3 weeks . Echocardiography , cardiopulmonary exercise testing , dual x-ray absorptiometry , and blood sampling were performed before and after ghrelin therapy . A single administration of ghrelin elicited a marked increase in serum GH ( 25-fold ) . Three-week administration of ghrelin result ed in a significant decrease in plasma norepinephrine ( 1132±188 to 655±134 pg/mL ; P<0.001 ) . Ghrelin  increased LV ejection fraction ( 27±2 % to 31±2 % ; P<0.05 ) in association with an increase in LV mass and a decrease in LV end-systolic volume . Treatment with ghrelin  increased peak workload and peak oxygen consumption during exercise  . Ghrelin  improved muscle wasting , as indicated by increases in muscle strength and lean body mass . These parameters remained unchanged in 8 patients with CHF who did not receive ghrelin therapy . Conclusions —These preliminary results suggest that repeated administration of ghrelin improves LV function , exercise capacity , and muscle wasting in patients with CHF BACKGROUND Patients with advanced cancer frequently experience anorexia and cachexia , which are associated with reduced food intake , altered body composition , and decreased functionality . We assessed anamorelin , a novel ghrelin-receptor agonist , on cachexia in patients with advanced non-small-cell lung cancer and cachexia . METHODS ROMANA 1 and ROMANA 2 were r and omised , double-blind , placebo-controlled phase 3 trials done at 93 sites in 19 countries . Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia ( defined as ≥5 % weight loss within 6 months or body-mass index < 20 kg/m(2 ) ) were r and omly assigned 2:1 to anamorelin 100 mg orally once daily or placebo , with a computer-generated r and omisation algorithm stratified by geographical region , cancer treatment status , and weight loss over the previous 6 months . Co- primary efficacy endpoints were the median change in lean body mass and h and grip strength over 12 weeks and were measured in all study participants ( intention-to-treat population ) . Both trials are now completed and are registered with Clinical Trials.gov , numbers NCT01387269 and NCT01387282 . FINDINGS From July 8 , 2011 , to Jan 28 , 2014 , 484 patients were enrolled in ROMANA 1 ( 323 to anamorelin , 161 to placebo ) , and from July 14 , 2011 , to Oct 31 , 2013 , 495 patients were enrolled in ROMANA 2 ( 330 to anamorelin , 165 to placebo ) . Over 12 weeks , lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 ( median increase 0·99 kg [ 95 % CI 0·61 to 1·36 ] vs -0·47 kg [ -1·00 to 0·21 ] , p<0·0001 ) and ROMANA 2 ( 0·65 kg [ 0·38 to 0·91 ] vs -0·98 kg [ -1·49 to -0·41 ] , p<0·0001 ) . We noted no difference in h and grip strength in ROMANA 1 ( -1·10 kg [ -1·69 to -0·40 ] vs -1·58 kg [ -2·99 to -1·14 ] , p=0·15 ) or ROMANA 2 ( -1·49 kg [ -2·06 to -0·58 ] vs -0·95 kg [ -1·56 to 0·04 ] , p=0·65 ) . There were no differences in grade 3 - 4 treatment-related adverse events between study groups ; the most common grade 3 - 4 adverse event was hyperglycaemia , occurring in one ( < 1 % ) of 320 patients given anamorelin in ROMANA 1 and in four ( 1 % ) of 330 patients given anamorelin in ROMANA 2 . INTERPRETATION Anamorelin significantly increased lean body mass , but not h and grip , strength in patients with advanced non-small-cell lung cancer . Considering the unmet medical need for safe and effective treatments for cachexia , anamorelin might be a treatment option for patients with cancer anorexia and cachexia . FUNDING Helsinn Therapeutics Ghrelin , an endogenous lig and for the growth hormone secretagogue receptor , has two major functions : the stimulation of the growth hormone production and the stimulation of food intake . Accumulating evidence also suggests a role of ghrelin in cancer development . We conducted a case-control study on 1359 breast cancer cases and 2389 matched controls , nested within the European Prospect i ve Investigation into Cancer and Nutrition , to examine the association of common genetic variants in the genes coding for ghrelin ( GHRL ) and its receptor ( GHSR ) with anthropometric measures , circulating insulin growth factor I ( IGF-I ) and insulin-like growth factor-binding protein 3 and breast cancer risk .  Pair-wise tagging was used to select the 15 polymorphisms that represent the majority of common genetic variants across the GHRL and GHSR genes . A significant increase in breast cancer risk was observed in carriers of the GHRL rs171407-G allele ( odds ratio : 1.2 ; 95 % confidence interval : 1.0 - 1.4 ; P = 0.02 ) . The GHRL single-nucleotide polymorphism rs375577 was associated with a 5 % increase in IGF-I levels ( P = 0.01 ) . A number of GHRL and GHSR polymorphisms were associated with body mass index ( BMI ) and height ( P between < 0.01 and 0.04 ) . The false-positive report probability ( FPRP ) approach suggests that these results are noteworthy ( FPRP < 0.20 ) . The results presented here add to a growing body of evidence that GHRL variations are associated with BMI . Furthermore , we have observed evidence for association of GHRL polymorphisms with circulating IGF-I levels and with breast cancer risk . These associations , however , might also be due to chance findings and further large studies are needed to confirm our results BACKGROUND Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality . Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity . We assessed the effects of anamorelin on body composition , strength , quality of life , biochemical markers , and safety in patients with cancer anorexia-cachexia . METHODS Data were pooled , a priori , from two completed phase 2 , multicentre , placebo-controlled , double-blind trials in patients with advanced or incurable cancer and weight loss of 5 % or more . Patients were stratified by weight loss severity ( 5 - 15 % , > 15 % ) and r and omly allocated ( 1:1 ) with a computer-generated r and omisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks . Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment .  We assessed safety in all patients who received at least one dose of study drug . The trials are registered with Clinical Trials.gov , numbers NCT00219817 and NCT00267358 . FINDINGS Between June 29 , 2005 , and Oct 26 , 2006 , we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group . 74 patients were eligible for the efficacy analyses . Over 12 weeks , lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1.89 kg ( 95 % CI 0.84 to 2.95 ) compared with a decrease of a least-squares mean of -0.20 kg ( -1.23 to 0.83 ) for 36 patients in the placebo group ( difference 2.09 kg [ 0.94 - 3.25 ] ; p=0.0006 ) . 42 ( 95 % ) of 44 patients treated with anamorelin and 33 ( 87 % ) of 38 patients treated with placebo had adverse events . The most common grade 3 - 4 adverse events ( treatment-related or not ) in the anamorelin group were fatigue , asthenia , atrial fibrillation , and dyspnoea ( two [ 5 % ] each ) ; in the placebo group , such events were pneumonia ( three [ 8 % ] ) and anaemia , thrombocytopenia , abdominal pain , anxiety , and dyspnoea ( two [ 5 % ] each ) . INTERPRETATION Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome . These findings support further investigation in this setting . FUNDING Helsinn Therapeutics ( US ) , Helsinn Healthcare SA Context : In clinical practice , the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown . Objective : The objective of this study was to compare adverse events ( AEs ) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement .  Design and Setting : This was a prospect i ve observational study in the setting of US clinical practice s. Patients and Outcome Measures : AEs were compared between GH-treated ( n = 1988 ) and untreated ( n = 442 ) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate . The st and ardized mortality ratio was calculated using US mortality rates . Results : After a mean follow-up of 2.3 years , there was no significant difference in rates of death , cancer , intracranial tumor growth or recurrence , diabetes , or cardiovascular events in GH-treated compared with untreated patients . The st and ardized mortality ratio was not increased in either group . Unexpected AEs ( GH-treated vs untreated , P ≤ .05 ) included insomnia ( 6.4 % vs 2.7 % ) , dyspnea ( 4.2 % vs 2.0 % ) , anxiety ( 3.4 % vs 0.9 % ) , sleep apnea ( 3.3 % vs 0.9 % ) , and decreased libido ( 2.1 % vs 0.2 % ) . Some of these AEs were related to baseline risk factors ( including obesity and cardiopulmonary disease ) , higher GH dose , or concomitant GH side effects . Conclusions : In GH-deficient adults , there was no evidence for a GH treatment effect on death , cancer , intracranial tumor recurrence , diabetes , or cardiovascular events , although the follow-up period was of insufficient duration to be conclusive for these long-term events . The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement BACKGROUND Infusion of ghrelin to supraphysiologic levels inhibits glucose-stimulated insulin secretion , reduces insulin sensitivity , and worsens glucose tolerance in humans . OBJECTIVE The purpose of this study was to determine the effects of lower doses of ghrelin on insulin secretion and insulin sensitivity in healthy men and women . METHODS Acyl ghrelin ( 0.2 and 0.6 nmol kg(-1 ) h(-1 ) ) or saline was infused for 225 minutes in 16 healthy subjects on 3 separate occasions in r and omized order . An i.v . glucose tolerance test was performed , and the insulin sensitivity index ( SI ) was derived from the minimal model . Insulin secretion was measured as the acute insulin response to glucose ( AIRg ) and the disposition index was computed as AIRg × SI . RESULTS Ghrelin infusions at 0.2 and 0.6 nmol kg(-1 ) h(-1 ) raised steady-state plasma total ghrelin levels 2.2- and 6.1-fold above fasting concentrations . Neither dose of ghrelin altered fasting plasma insulin , glucose , or SI , but both doses reduced insulin secretion compared with the saline control , computed either as AIRg ( 384 ± 75 and 354 ± 65 vs 520 ± 110 pM · min [ mean ± SEM ] , respectively ; P < .01 for both low- and high-dose vs saline ) or disposition index ( 2238 ± 421 and 2067 ± 396 vs 
    Output:
    
agent
The majority of in vivo studies showed a null or inverse association of ghrelin with risk and progression of most cancers , suggesting that ghrelin/ghrelin-receptor agonist treatment may have a favorable safety profile to use for cancer cachexia .
***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 —Ghrelin is a novel growth hormone – releasing peptide that also induces vasodilation , inhibits sympathetic nerve activity , and stimulates feeding through growth hormone – independent mechanisms . We investigated the effects of ghrelin on left ventricular ( LV ) function , exercise capacity , and muscle wasting in patients with chronic heart failure ( CHF ) . Methods and Results —Human synthetic ghrelin ( 2 & mgr;g/kg twice a day ) was intravenously administered to 10 patients with CHF for 3 weeks . Echocardiography , cardiopulmonary exercise testing , dual x-ray absorptiometry , and blood sampling were performed before and after ghrelin therapy . A single administration of ghrelin elicited a marked increase in serum GH ( 25-fold ) . Three-week administration of ghrelin result ed in a significant decrease in plasma norepinephrine ( 1132±188 to 655±134 pg/mL ; P<0.001 ) . Ghrelin  increased LV ejection fraction ( 27±2 % to 31±2 % ; P<0.05 ) in association with an increase in LV mass and a decrease in LV end-systolic volume . Treatment with ghrelin  increased peak workload and peak oxygen consumption during exercise  . Ghrelin  improved muscle wasting , as indicated by increases in muscle strength and lean body mass . These parameters remained unchanged in 8 patients with CHF who did not receive ghrelin therapy . Conclusions —These preliminary results suggest that repeated administration of ghrelin improves LV function , exercise capacity , and muscle wasting in patients with CHF BACKGROUND Patients with advanced cancer frequently experience anorexia and cachexia , which are associated with reduced food intake , altered body composition , and decreased functionality . We assessed anamorelin , a novel ghrelin-receptor agonist , on cachexia in patients with advanced non-small-cell lung cancer and cachexia . METHODS ROMANA 1 and ROMANA 2 were r and omised , double-blind , placebo-controlled phase 3 trials done at 93 sites in 19 countries . Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia ( defined as ≥5 % weight loss within 6 months or body-mass index < 20 kg/m(2 ) ) were r and omly assigned 2:1 to anamorelin 100 mg orally once daily or placebo , with a computer-generated r and omisation algorithm stratified by geographical region , cancer treatment status , and weight loss over the previous 6 months . Co- primary efficacy endpoints were the median change in lean body mass and h and grip strength over 12 weeks and were measured in all study participants ( intention-to-treat population ) . Both trials are now completed and are registered with Clinical Trials.gov , numbers NCT01387269 and NCT01387282 . FINDINGS From July 8 , 2011 , to Jan 28 , 2014 , 484 patients were enrolled in ROMANA 1 ( 323 to anamorelin , 161 to placebo ) , and from July 14 , 2011 , to Oct 31 , 2013 , 495 patients were enrolled in ROMANA 2 ( 330 to anamorelin , 165 to placebo ) . Over 12 weeks , lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 ( median increase 0·99 kg [ 95 % CI 0·61 to 1·36 ] vs -0·47 kg [ -1·00 to 0·21 ] , p<0·0001 ) and ROMANA 2 ( 0·65 kg [ 0·38 to 0·91 ] vs -0·98 kg [ -1·49 to -0·41 ] , p<0·0001 ) . We noted no difference in h and grip strength in ROMANA 1 ( -1·10 kg [ -1·69 to -0·40 ] vs -1·58 kg [ -2·99 to -1·14 ] , p=0·15 ) or ROMANA 2 ( -1·49 kg [ -2·06 to -0·58 ] vs -0·95 kg [ -1·56 to 0·04 ] , p=0·65 ) . There were no differences in grade 3 - 4 treatment-related adverse events between study groups ; the most common grade 3 - 4 adverse event was hyperglycaemia , occurring in one ( < 1 % ) of 320 patients given anamorelin in ROMANA 1 and in four ( 1 % ) of 330 patients given anamorelin in ROMANA 2 . INTERPRETATION Anamorelin significantly increased lean body mass , but not h and grip , strength in patients with advanced non-small-cell lung cancer . Considering the unmet medical need for safe and effective treatments for cachexia , anamorelin might be a treatment option for patients with cancer anorexia and cachexia . FUNDING Helsinn Therapeutics Ghrelin , an endogenous lig and for the growth hormone secretagogue receptor , has two major functions : the stimulation of the growth hormone production and the stimulation of food intake . Accumulating evidence also suggests a role of ghrelin in cancer development . We conducted a case-control study on 1359 breast cancer cases and 2389 matched controls , nested within the European Prospect i ve Investigation into Cancer and Nutrition , to examine the association of common genetic variants in the genes coding for ghrelin ( GHRL ) and its receptor ( GHSR ) with anthropometric measures , circulating insulin growth factor I ( IGF-I ) and insulin-like growth factor-binding protein 3 and breast cancer risk .  Pair-wise tagging was used to select the 15 polymorphisms that represent the majority of common genetic variants across the GHRL and GHSR genes . A significant increase in breast cancer risk was observed in carriers of the GHRL rs171407-G allele ( odds ratio : 1.2 ; 95 % confidence interval : 1.0 - 1.4 ; P = 0.02 ) . The GHRL single-nucleotide polymorphism rs375577 was associated with a 5 % increase in IGF-I levels ( P = 0.01 ) . A number of GHRL and GHSR polymorphisms were associated with body mass index ( BMI ) and height ( P between < 0.01 and 0.04 ) . The false-positive report probability ( FPRP ) approach suggests that these results are noteworthy ( FPRP < 0.20 ) . The results presented here add to a growing body of evidence that GHRL variations are associated with BMI . Furthermore , we have observed evidence for association of GHRL polymorphisms with circulating IGF-I levels and with breast cancer risk . These associations , however , might also be due to chance findings and further large studies are needed to confirm our results BACKGROUND Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality . Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity . We assessed the effects of anamorelin on body composition , strength , quality of life , biochemical markers , and safety in patients with cancer anorexia-cachexia . METHODS Data were pooled , a priori , from two completed phase 2 , multicentre , placebo-controlled , double-blind trials in patients with advanced or incurable cancer and weight loss of 5 % or more . Patients were stratified by weight loss severity ( 5 - 15 % , > 15 % ) and r and omly allocated ( 1:1 ) with a computer-generated r and omisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks . Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment .  We assessed safety in all patients who received at least one dose of study drug . The trials are registered with Clinical Trials.gov , numbers NCT00219817 and NCT00267358 . FINDINGS Between June 29 , 2005 , and Oct 26 , 2006 , we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group . 74 patients were eligible for the efficacy analyses . Over 12 weeks , lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1.89 kg ( 95 % CI 0.84 to 2.95 ) compared with a decrease of a least-squares mean of -0.20 kg ( -1.23 to 0.83 ) for 36 patients in the placebo group ( difference 2.09 kg [ 0.94 - 3.25 ] ; p=0.0006 ) . 42 ( 95 % ) of 44 patients treated with anamorelin and 33 ( 87 % ) of 38 patients treated with placebo had adverse events . The most common grade 3 - 4 adverse events ( treatment-related or not ) in the anamorelin group were fatigue , asthenia , atrial fibrillation , and dyspnoea ( two [ 5 % ] each ) ; in the placebo group , such events were pneumonia ( three [ 8 % ] ) and anaemia , thrombocytopenia , abdominal pain , anxiety , and dyspnoea ( two [ 5 % ] each ) . INTERPRETATION Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome . These findings support further investigation in this setting . FUNDING Helsinn Therapeutics ( US ) , Helsinn Healthcare SA Context : In clinical practice , the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown . Objective : The objective of this study was to compare adverse events ( AEs ) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement .  Design and Setting : This was a prospect i ve observational study in the setting of US clinical practice s. Patients and Outcome Measures : AEs were compared between GH-treated ( n = 1988 ) and untreated ( n = 442 ) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate . The st and ardized mortality ratio was calculated using US mortality rates . Results : After a mean follow-up of 2.3 years , there was no significant difference in rates of death , cancer , intracranial tumor growth or recurrence , diabetes , or cardiovascular events in GH-treated compared with untreated patients . The st and ardized mortality ratio was not increased in either group . Unexpected AEs ( GH-treated vs untreated , P ≤ .05 ) included insomnia ( 6.4 % vs 2.7 % ) , dyspnea ( 4.2 % vs 2.0 % ) , anxiety ( 3.4 % vs 0.9 % ) , sleep apnea ( 3.3 % vs 0.9 % ) , and decreased libido ( 2.1 % vs 0.2 % ) . Some of these AEs were related to baseline risk factors ( including obesity and cardiopulmonary disease ) , higher GH dose , or concomitant GH side effects . Conclusions : In GH-deficient adults , there was no evidence for a GH treatment effect on death , cancer , intracranial tumor recurrence , diabetes , or cardiovascular events , although the follow-up period was of insufficient duration to be conclusive for these long-term events . The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement BACKGROUND Infusion of ghrelin to supraphysiologic levels inhibits glucose-stimulated insulin secretion , reduces insulin sensitivity , and worsens glucose tolerance in humans . OBJECTIVE The purpose of this study was to determine the effects of lower doses of ghrelin on insulin secretion and insulin sensitivity in healthy men and women . METHODS Acyl ghrelin ( 0.2 and 0.6 nmol kg(-1 ) h(-1 ) ) or saline was infused for 225 minutes in 16 healthy subjects on 3 separate occasions in r and omized order . An i.v . glucose tolerance test was performed , and the insulin sensitivity index ( SI ) was derived from the minimal model . Insulin secretion was measured as the acute insulin response to glucose ( AIRg ) and the disposition index was computed as AIRg × SI . RESULTS Ghrelin infusions at 0.2 and 0.6 nmol kg(-1 ) h(-1 ) raised steady-state plasma total ghrelin levels 2.2- and 6.1-fold above fasting concentrations . Neither dose of ghrelin altered fasting plasma insulin , glucose , or SI , but both doses reduced insulin secretion compared with the saline control , computed either as AIRg ( 384 ± 75 and 354 ± 65 vs 520 ± 110 pM · min [ mean ± SEM ] , respectively ; P < .01 for both low- and high-dose vs saline ) or disposition index ( 2238 ± 421 and 2067 ± 396 vs 
    Output:
    