***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 The phosphoinositide 3-kinase (PI3K)/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin ( mTOR ) kinase is an important mediator for its signaling . Our recent in vitro studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3 K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells ( negative feedback loop ) . The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in pre clinical tumor models . Methods Two studies prospect ively enrolled adult patients with advanced pancreatic cancer , Eastern Cooperative Oncology Group performance status 0 - 1 , adequate hematologic , hepatic and renal parameters and measurable disease . In Study A , temsirolimus was administered intravenously at 25 mg weekly . In Study B , everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily . The primary endpoint in both studies was overall survival at 6 months . Secondary endpoints included time to progression , progression-free survival , overall survival , response rate , safety and toxicity . Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR , pAkt/Akt , pErk/Erk , pS6 , p4EBP-1 and PTEN . Results Five patients enrolled in Study A ; Two patients died within a month ( rapid disease progression and hemorrhagic stroke , respectively ) . One patient developed dehydration and another developed asthenia .  Sixteen patients enrolled in Study B. : 12 males , all ECOG PS = 1 . Median cycles = 1 ( range 1 - 2 ) . Grade 4 toxicity : hyponatremia ( n = 1 ) , Grade 3 : diarrhea ( n = 1 ) , cholangitis ( n = 3 ) , hyperglycemia ( n = 1 ) , fatigue ( n = 1 ) . Grade 2 : pneumonia ( n = 2 ) , dehydration ( n = 2 ) , nausea ( n = 2 ) , neutropenia ( n = 1 ) , mucositis ( n = 2 ) & rash ( n = 2 ) . Four patients were hospitalized . Progressive disease occurred in 15 and 1 was non-evaluable . Pretreatment biopsies revealed a higher pAkt/Akt ratio in tumor specimens that in nonmalignant pancreatic tissue . No such trends were noted for the other biomarkers . Conclusions Neither study with mTOR inhibitors demonstrated objective responses or disease stability . The negative feedback loop result ing from mTOR inhibition may account for the disease progression and toxicity noted in these studies . Future strategies should aim for a broader targeting of the PI3 K pathway in pancreatic cancer . Trial Registration Trial registration : Study A : NCT 0075647 . Study B : 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 BACKGROUND Temsirolimus ( CCI-779 ) is a small-molecule inhibitor of the mammalian target of rapamycin ( mTOR ) and represents a rational therapeutic target against glioblastoma multiforme ( GBM ) . METHODS Recurrent GBM patients with < or = 1 chemotherapy regimen for progressive disease were eligible .  Temsirolimus was administered in a 250-mg intravenous dose weekly . RESULTS Sixty-five patients were treated . The incidence of grade 3 or higher nonhematologic toxicity was 51 % , and consisted mostly of hypercholesterolemia ( 11 % ) , hypertriglyceridemia ( 8 % ) , and hyperglycemia ( 8 % ) . Grade 3 hematologic toxicity was observed in 11 % of patients .  Temsirolimus peak concentration ( Cmax ) , and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme-inducing anticonvulsants ( EIACs ) by 73 % , 47 % , and 50 % , respectively , but were still within the therapeutic range of pre clinical models . Twenty patients ( 36 % ) had evidence of improvement in neuroimaging , consisting of decrease in T2 signal abnormality + /- decrease in T1 gadolinium enhancement , on stable or reduced steroid doses . Progression-free survival at 6 months was 7.8 % and median overall survival was 4.4 months . Median time to progression ( TTP ) for all patients was 2.3 months and was significantly longer for responders ( 5.4 months ) versus nonresponders ( 1.9 months ) . Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response ( 71 % v 31 % ; P = .04 ) . Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor sample s ( P = .04 ) . CONCLUSION Temsirolimus is well tolerated in recurrent GBM patients . Despite the effect of EIACs on temsirolimus metabolism , therapeutic levels were achieved . Radiographic improvement was observed in 36 % of temsirolimus-treated patients , and was associated with significantly longer TTP . High levels of phosphorylated p70s6 kinase in baseline tumor sample s appear to predict a patient population more likely to derive benefit from treatment . These findings should be vali date d in other studies of mTOR inhibitors 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 
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These findings suggest a statistically significant increase in the risk of hyperglycemia , hypercholesterolemia ( all grade s and grade 3 and 4 ) , and all grade hypertriglyceridemia associated with mTOR therapy when compared with control .
INTERPRETATION The risk of all grade and grade 3 - 4 , hyperglycemia , hypercholesterolemia , and hypertriglyceridemia , are increase in patients treated with mTOR inhibitors compared with control