***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: To investigate the role of gefitinib in patients with high- grade gliomas ( HGGs ) , a phase II trial ( 1839IL/0116 ) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy . Adult patients with histologically confirmed recurrent HGGs following surgery , radiotherapy and first-line chemotherapy , were considered eligible . Patients were treated with gefitinib ( 250 mgday−1 ) continuously until disease progression . The primary end point was progression-free survival at 6 months progression-free survival at 6 months ( PFS-6 ) . Tissue biomarkers ( epidermal growth factor receptor ( EGFR ) gene status and expression , phosphorylated Akt ( p-Akt ) expression ) were assessed . Twenty-eight patients ( median age , 55 years ; median ECOG performance status , 1 ) were enrolled ; all were evaluable for drug activity and safety . Sixteen patients had glioblastoma , three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma . Five patients ( 17.9 % , 95 % CI 6.1–36.9 % ) showed disease stabilisation . The overall median time to progression was 8.4 ( range 2–104 + ) weeks and PFS-6 was 14.3 % ( 95 % CI 4.0–32.7 % ) . The median overall survival was 24.6 weeks ( range 4–104 + ) . No grade 3–4 gefitinib-related toxicity was found . Gefitinib showed limited activity in patients affected by HGGs . Epidermal growth factor receptor expression or gene status , and p-Akt expression do not seem to predict activity of this drug BACKGROUND The epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor erlotinib ( also known as Tarceva or OSI-774 ) has shown promising response rates in malignant gliomas . We investigated the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylating agent temozolomide . METHODS Expression of EGFR and lig and -independent EGFRvIII mutant proteins and of phosphorylated protein kinase B (PKB)/Akt in specimens from glioma patients were assessed by immunohistochemistry . EGFR gene amplification was evaluated by fluorescence in situ hybridization . Mutations in PTEN and EGFR were assessed by polymerase chain reaction amplification and sequencing . Response was evaluated by sequential magnetic resonance imaging every 2 months . The Cochran-Mantel-Haenzel test was used to assess associations between biomarker status and response . All statistical tests were two-sided . RESULTS Of 41 glioma patients , eight responded to treatment . Response to erlotinib was associated with EGFR expression ( P = .07 ) and EGFR amplification ( P = .08 ) . These associations were stronger and statistically significant among the 29 patients initially diagnosed with glioblastoma multiforme ( P = .03 and P = .02 , respectively ) . Among six responders with sufficient tumor tissue , none had EGFRvIII mutations . None of the 22 tumors with high levels of phosphorylated PKB/Akt responded to erlotinib treatment , whereas eight of the 18 tumors with low levels of phosphorylated PKB/Akt responded to erlotinib treatment ( P < .001 ) . The level of phosphorylated PKB/Akt was also associated with time to progression ( P < .001 ) . CONCLUSIONS Among glioma patients , those with glioblastoma multiforme tumors who have high levels of EGFR expression and low levels of phosphorylated PKB/Akt had better response to erlotinib treatment than those with low levels of EGFR expression and high levels of phosphorylated PKB/Akt BACKGROUND Recurrent glioblastoma multiforme ( GBM ) is resistant to most therapeutic endeavors , with low response rates and survival rarely exceeding six months . There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life . PATIENTS AND METHODS We report an open-label , uncontrolled , multicenter phase II trial of temozolomide in 138 patients ( intent-to-treat [ ITT ] population ) with glioblastoma multiforme at first relapse and a Karnofsky performance status ( KPS ) > or = 70 . One hundred twenty-eight patients were histologically confirmed with GBM or gliosarcoma ( GS ) by independent central review . Chemotherapy-naïve patients were treated with temozolomide 200 mg/m2/day orally for the first five days of a 28-day cycle . Patients previously treated with nitrosourea-containing adjuvant chemotherapy  received 150 mg/m2/day for the first five days of a 28-day cycle . In the absence of grade 3 or 4 toxicity , patients on the 150 mg/m2 dose schedule were eligible for a 200 mg/m2 dose on the next cycle . RESULTS The primary endpoint was six-month progression-free survival assessed with strict radiological and clinical criteria . Secondary endpoints included radiological response and Health-related Quality of Life ( HQL ) . Progression-free survival at six months was 18 % ( 95 % confidence interval ( CI ) : 11%-26 % ) for the eligible-histology population . Median progression-free survival and median overall survival were 2.1 months and 5.4 months , respectively . The six-month survival rate was 46 % . The objective response rate ( complete response and partial response ) determined by independent central review of gadolinium-enhanced magnetic resonance imaging ( MRI ) scans was 8 % for both the ITT and eligible-histology population s , with an additional 43 % and 45 % of patients , respectively , having stable disease ( SD ) . Objective ly assessed response and maintenance of a progression-free status were both associated with HQL benefits ( characterized by improvements over baseline in HQL domains ) . Temozolomide had an acceptable safety profile , with only 9 % of therapy cycles requiring a dose reduction due to thrombocytopenia . There was no evidence of cumulative hematologic toxicity . CONCLUSIONS Temozolomide demonstrated modest clinical efficacy , with an acceptable safety profile and measurable improvement in quality of life in patients with recurrent GBM . The use of this drug should be explored further in an adjuvant setting and in combination with other agents Reports suggest reasonable efficacy and minimal myelosuppression from combination imatinib and hydroxyurea for recurrent malignant glioma . We retrospectively review ed 16 patients treated with this regimen who were evaluable for toxicity ; 14 were also evaluable for response . The incidence of grade 3–4 hematologic toxicity was 25 % . The best radiographic response , by Macdonald criteria , was partial response ( PR ) in three patients ( 21 % ) , stable disease ( SD ) in four ( 29 % ) , and progressive disease ( PD ) in seven ( 50 % ) . One patient with a PR developed therapy-limiting hematologic toxicity on day 19 of treatment , progressing to grade 4 on day 64 , and persisting until death on day 127 despite discontinuing both drugs . Another patient with PR and two of four patients with SD also developed grade 3 hematologic toxicity . All patients with grade 3–4 hematologic toxicity had disease control ( PR or SD ) as best radiographic response , whereas none with PD suffered grade 3–4 hematologic toxicity .  Combining imatinib with hydroxyurea is effective in some patients with malignant glioma . However , myelosuppression can persist for months after discontinuing the regimen , precluding further chemotherapy . Disease control may also correlate with hematologic toxicity ( p = 0.08 ) , suggesting that glioma and marrow stem cells may share a common sensitivity to this chemotherapy regimen Using MRI techniques , we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset , is prolonged but reversible , and has the significant clinical benefit of alleviating edema . Reversal of normalization began by 28 days , though some features persisted for as long as four months . Basic FGF , SDF1alpha , and viable circulating endothelial cells ( CECs ) increased when tumors escaped treatment , and circulating progenitor cells ( CPCs ) increased when tumors progressed after drug interruption . Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor PURPOSE We performed a phase II study to evaluate the combination of imatinib mesylate , an adenosine triphosphate mimetic , tyrosine kinase inhibitor , plus hydroxyurea , a ribonucleotide reductase inhibitor , in patients with recurrent glioblastoma multiforme ( GBM ) . PATIENTS AND METHODS Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea ( 500 mg twice a day ) orally on a continuous , daily schedule . The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs ( EIAEDs ) and 400 mg once a day for those not on EIAEDs . Assessment s were performed every 28 days . The primary end point was 6-month progression-free survival ( PFS ) . RESULTS Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy .  With a median follow-up of 58 weeks , 27 % of patients were progression-free at 6 months , and the median PFS was 14.4 weeks . Three patients ( 9 % ) achieved radiographic response , and 14 ( 42 % ) achieved stable disease . Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS . The most common toxicities included grade 3 neutropenia ( 16 % ) , thrombocytopenia ( 6 % ) , and edema ( 6 % ) . There were no grade 4 or 5 events . Concurrent EIAED use lowered imatinib mesylate exposure . Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients , suggesting an effect of hydroxyurea . CONCLUSION Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM Background There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation , measure anti-tumor activity , and enrich the clinical trial population for patients who are more likely to benefit . Small , molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population . Methods and Findings Based on pre clinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 ( PTEN ) loss sensitizes tumors to the inhibition of mammalian target of rapamycin ( mTOR ) , we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma , whose tumors lacked expression of the tumor suppressor PTEN . We aim ed to assess the safety profile of daily rapamycin in patients with glioma , define the dose of rapamycin required for mTOR inhibition in tumor tissue , and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma . Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients , the magnitude of mTOR inhibition in tumor cells ( measured by reduced ribosomal S6 protein phosphorylation ) varied substantially . Tumor cell proliferation ( measured by Ki-67 staining ) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition ( p = 0.0047 , Fisher exact test ) but not the intratumoral rapamycin concentration . Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo , indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic . Rapamycin treatment led to Akt activation in seven patients , presumably due to loss of negative feedback , and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy ( p < 0.05 , Logrank test ) . Conclusions Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3 K pathway inhibitors . The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development . Trial registration : http://www . Clinical Trials.gov ( # NCT00047073 ) 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 
    Output:
    
The main findings were that ( i ) efficacy of small-molecule  kinase inhibitors in clinical studies with glioblastoma patients does not yet warrant a change in st and ard clinical practice and ( ii ) 6 main kinase targets for inhibitors have been evaluated in these studies : EGFR , mTOR , KDR , FLT1 , PKCbeta , and PDGFR