***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 : Loss of PTEN , which is common in glioblastoma multiforme ( GBM ) , results in activation of the mammalian target of rapapmycin ( mTOR ) , thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression . CCI-779 is an inhibitor of mTOR . The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug . Experimental Design : CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs ( EIAEDs ) . Patients not on EIAEDs were initially treated at 250 mg ; however , the dose was reduced to 170 mg because of intolerable side effects . Treatment was continued until unacceptable toxicity , tumor progression , or patient withdrawal . The primary endpoint was 6-month progression-free survival . Results : Forty-three patients were enrolled ; 29 were not on EIAEDs . The expected toxicity profile of increased lipids , lymphopenia , and stomatitis was seen . There were no grade IV hematological toxicities and no toxic deaths . One patient was progression free at 6 months . Of the patients assessable for response , there were 2 partial responses and 20 with stabilization of disease . The median time to progression was 9 weeks . Conclusions : CCI-779 was well tolerated at this dose schedule ; however , there was no evidence of efficacy in patients with recurrent GBM . Despite initial disease stabilization in approximately 50 % of patients , the durability of response was short . Because of the low toxicity profile , CCI-779 may merit exploration in combination with other modalities St and ard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity . A phase II study was design ed to evaluate the efficacy , safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma ( NEC ) . Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of  25 mg of temsirolimus . Patients were evaluated for tumour response , time to progression ( TTP ) , overall survival ( OS ) and adverse events ( AE ) .  Twenty-two archival specimens , as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers . The intent-to-treat response rate was 5.6 % ( 95 % CI 0.6–18.7 % ) , median TTP 6 months and 1-year OS rate 71.5 % . The most frequent drug-related AE of all grade s as percentage of patients were : fatigue ( 78 % ) , hyperglycaemia ( 69 % ) and rash/desquamation ( 64 % ) . Temsirolimus effectively inhibited the phosphorylation of S6 ( P=0.02 ) . Higher baseline levels of pmTOR ( phosphorylated mammalian target of rapamycin ) ( P=0.01 ) predicted for a better response . Increases in pAKT ( P=0.041 ) and decreases in pmTOR ( P=0.048 ) after treatment were associated with an increased TTP .  Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC . Pharmacodynamic analysis revealed effective mTOR pathway downregulation Hypothesis : To study the progression-free survival ( PFS ) and toxicity with 25- or 250-mg doses of temsirolimus ( CCI-779 ) after induction chemotherapy in patients with extensive small-cell lung cancer . Methods : Patients with either stable or responding disease to four to six cycles of cisplatin or carboplatin plus etoposide or irinotecan  were r and omized between 4 and 8 weeks after completion of induction therapy to receive either 25 or 250 mg of temsirolimus intravenously every week until disease progression . Results : Eighty-seven patients entered between January 2002 and December 2003 , of whom 85 were eligible : 44 received 25 mg ( arm A ) , and 41 received 250 mg ( arm B ) . The overall median follow-up time for all eligible patients was 34.6 months . Median age was 59 years ( range , 39–80 ) ; 42 ( 49.4 % ) were male and 43 ( 50.6 % ) female ; 12.9 % had brain metastases . The overall median and 1-year PFS were 2.2 months ( 95 % confidence interval [ CI ] : 1.8 , 2.9 ) and 4.7 % ( 95 % CI : 0.2 % , 9.2 % ) , respectively . The median PFS ( 95 % CI ) for arm A was 1.9 months ( 1.6 , 2.3 ) ; for arm B , it was 2.5 months ( 1.9 , 3.4 ; p = 0.24 ) . The median overall survival from r and omization was 8 months ( 95 % CI : 6.5 , 9.5 ) . Among the 86 patients with reported  toxicities , 36 ( 42 % ) had grade 3 toxicities , the most common of which were thrombocytopenia , hypophosphatemia , and fatigue , and an additional 12 ( 14 % ) had grade 4 toxicities , the most common of which was neutropenia . No patients experienced lethal toxicities . Conclusion : Temsirolimus ( CCI 779 ) , given at 25 or 250 mg weekly , seemed not to increase the PFS in this patient population PURPOSE Cross-talk between the estrogen receptor ( ER ) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin ( mTOR ) pathways is a mechanism of resistance to endocrine therapy , and blockade of both pathways enhances antitumor activity in pre clinical models . This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor , everolimus ( RAD001 ) . PATIENTS AND METHODS Two hundred seventy postmenopausal women with operable ER-positive breast cancer were r and omly assigned to receive 4 months of neoadjuvant treatment with letrozole ( 2.5 mg/day ) and either everolimus ( 10 mg/day ) or placebo . The primary end point was clinical response by palpation . M and atory biopsies were obtained at baseline and after 2 weeks of treatment ( ie , day 15 ) . Sample s were assessed for PI3 K mutation status ( PIK3CA ) and for pharmacodynamic changes of Ki67 , phospho-S6 , cyclin D1 , and progesterone receptor ( PgR ) by immunohistochemistry . RESULTS Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone ( ie , placebo ; 68.1 % v 59.1 % ) , which was statistically significant at the preplanned , one-sided , alpha = 0.1 level ( P = .062 ) . Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms , and dramatic downregulation of phospho-S6 occurred only in the everolimus arm . An antiproliferative response , as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15 , occurred in 52 ( 57 % ) of 91 patients in the everolimus arm and in 25 ( 30 % ) of 82 patients in the placebo arm ( P < .01 ) . The safety profile was consistent with historical results of everolimus monotherapy ; grade s 3 to 4 adverse events occurred in 22.6 % of patients who received everolimus and in 3.8 % of patients who received placebo . CONCLUSION Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer BACKGROUND Everolimus ( RAD001 ) is an orally administered inhibitor of the mammalian target of rapamycin ( mTOR ) , a therapeutic target for metastatic renal cell carcinoma . We did a phase III , r and omised , double-blind , placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy . METHODS Patients with metastatic renal cell carcinoma which had progressed on sunitinib , sorafenib , or both , were r and omly assigned in a two to one ratio to receive everolimus 10 mg once daily ( n=272 )  or placebo  ( n=138 ) , in conjunction with best supportive care . R and omisation was done central ly via an interactive voice response system using a vali date d computer system , and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy , with a permuted block size of six . The primary endpoint was progression-free survival , assessed via a blinded , independent central review . The study was design ed to be terminated after 290 events of progression . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00410124 . FINDINGS All r and omised patients were included in efficacy analyses . The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed ( 101 [ 37 % ] events in the everolimus group , 90 [ 65 % ] in the placebo group ; hazard ratio 0.30 , 95 % CI 0.22 - 0.40 , p<0.0001 ; median progression-free survival 4.0 [ 95 % CI 3.7 - 5.5 ] vs 1.9 [ 1.8 - 1.9 ] months ) . Stomatitis ( 107 [ 40 % ] patients in the everolimus group vs 11 [ 8 % ] in the placebo group ) , rash ( 66 [ 25 % ] vs six [ 4 % ] ) , and fatigue ( 53 [ 20 % ] vs 22 [ 16 % ] ) were the most commonly reported adverse events , but were mostly mild or moderate in severity . Pneumonitis ( any grade ) was detected in 22 ( 8 % ) patients in the everolimus group , of whom eight had pneumonitis of grade 3 severity . INTERPRETATION Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies BACKGROUND Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability .  Temsirolimus , a specific inhibitor of the mammalian target of rapamycin kinase , may benefit patients with this disease . METHODS In this multicenter , phase 3 trial , we r and omly assigned 626 patients with previously untreated , poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly , 3 million U of interferon alfa ( with an increase to 18 million U ) subcutaneously three times weekly , or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly . The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group . RESULTS Patients who received temsirolimus alone had longer overall survival ( hazard ratio for death , 0.73 ; 95 % confidence interval [ CI ] , 0.58 to 0.92 ; P=0.008 ) and progression-free survival ( P<0.001 ) than did patients who received interferon alone . Overall survival in the combination-therapy group did not differ significantly from that in the interferon group ( hazard ratio , 0.96 ; 95 % CI , 0.76 to 1.20 ; P=0.70 ) . Median overall survival times in the interferon group , the temsirolimus group , and the combination-therapy group were 7.3 , 10.9 , and 8.4 months , respectively . Rash , peripheral edema , hyperglycemia , and hyperlipidemia were more common in the temsirolimus group , whereas asthenia was more common in the interferon group . There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group ( P=0.02 ) . CONCLUSIONS As compared with interferon alfa , temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis . The addition of temsirolimus to interferon did not improve survival . ( Clinical Trials.gov number , NCT00065468 [ Clinical Trials.gov ] . ) The primary goal of this trial was to evaluate the confirmed response rate of temsirolimus ( CCI‐779 ) , a mammalian target of rapamycin in patients with advanced soft tissue sarcomas ( STS ) PURPOSE To evaluate the efficacy , safety , and pharmacokinetics of multiple 
    Output:
    
The use of mTOR inhibitors is associated with a significant increase in the risk of developing all- grade and high- grade anemia and thrombocytopenia compared with placebo/control arms