***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 
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    Input: The cancer stem cell ( CSC ) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties . Although the existence of CSCs in human leukaemia is established , little evidence exists for CSCs in solid tumours , except for breast cancer . Recently , we prospect ively isolated a CD133 + cell sub population from human brain tumours that exhibited stem cell properties in vitro . However , the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour . Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo . Only the CD133 + brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID ( non-obese diabetic , severe combined immunodeficient ) mouse brains . Injection of as few as 100 CD133 + cells produced a tumour that could be serially transplanted and was a phenocopy of the patient 's original tumour , whereas injection of 105 CD133- cells engrafted but did not cause a tumour . Thus , the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis , giving strong support for the CSC hypothesis as the basis for many solid tumours , and establishes a previously unidentified cellular target for more effective cancer therapies PURPOSE Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas . Consequently , we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector ( Ad-p53 , INGN 201 ) . MATERIAL S AND METHODS To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53 , patients underwent a two-stage approach . In stage 1 , Ad-p53 was stereotactically injected intratumorally via an implanted catheter . In stage 2 , the tumor-catheter was resected en bloc , and the postresection cavity was treated with Ad-p53 . This protocol provided intact Ad-p53-treated biologic specimens that could be analyzed for molecular end points , and because the resection cavity itself was injected with Ad-p53 , patients could be observed for clinical toxicity . RESULTS Of fifteen patients enrolled , twelve underwent both treatment stages . In all patients , exogenous p53 protein was detected within the nuclei of astrocytic tumor cells . Exogenous p53 transactivated p21CIP/WAF and induced apoptosis . However , transfected cells resided on average within 5 mm of the injection site . Clinical toxicity was minimal and a maximum-tolerated dose was not reached . Although anti-adenovirus type 5 ( Ad5 ) titers increased in most patients , there was no evidence of systemic viral dissemination . CONCLUSION Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein . However , at the dose and schedule evaluated , transduced cells were only found within a short distance of the injection site . Although toxicity was minimal , widespread distribution of this agent remains a significant goal Abstract Object : In mouse models of prostate and breast cancer therapeutic effects are enhanced when adenoviral HSV TK gene therapy is combined with ionizing radiation . In the present study , we adopted this approach for the treatment of human glioblastoma xenografts in an athymic mouse model and assessed treatment results as well as toxic side effects . Methods : About 72 nude mice received intracerebral inoculations of 2 × 105 U87ΔEGFR cells . On day 7 after tumor implantation the study population was r and omized into six treatment arms : ( 1 ) intratumoral buffer inoculation on day 7 , ( 2 ) intratumoral adenoviral vector injection ( 2 × 109 vp ) on day 7 , ( 3 ) single dose radiation ( 2.1 Gy ) on day 9 , ( 4 ) adenoviral injection + radiation , ( 5 ) adenoviral injection + ganciclovir ( GCV ) ( 20 ug/g twice daily from day 8 to 17 ) , ( 6 ) adenoviral injection + GCV + radiation . On day 21 half of the animals were sacrificed for histological evaluation of the brain tumors , the other half was assessed for survival . Results : This study showed significantly prolonged median survival time of 5 days for the GCV treated groups . The addition of radiation decreased the frequency of neurological symptoms and delayed the onset of deficits without altering the expression of thymidine kinase in the tumor cells . Conclusions : We conclude that adenoviral HSV TK gene therapy in combination with adjuvant radiotherapy does not generate increased toxic side effects in glioblastoma treatment . The prolonged survival time of animals receiving gene therapy and the reduced occurrence of neurological symptoms in irradiated mice constitute promising features of the combined treatment Herpes simplex virus thymidine kinase ( HSV tk ) gene therapy combined with ganciclovir ( GCV ) medication is a potential new method for the treatment of malignant glioma . We have used both retrovirus-packaging cells ( PA317/tk ) and adenoviruses ( Adv/tk ) for gene therapy for malignant glioma . Retrovirus-packaging cells were used for eight tumors in seven patients and adenoviruses were used for seven tumors in seven patients . As a control group , seven tumors in seven patients were transduced with lacZ marker gene 4 - 5 days before tumor resection . Safety and efficacy of the gene therapy were studied with clinical evaluation , blood and urine sample s , MRI follow-up , and survival of the patients . Four patients with adenovirus injections had a significant increase in anti-adenovirus antibodies and two of them had a short-term fever reaction . Frequency of epileptic seizures increased in two patients . No other adverse events possibly related to gene therapy were detected . In the retrovirus group , all treated gliomas showed progression by MRI at the 3-month time point , whereas three of the seven patients treated with Adv/tk remained stable ( p < 0.05 ) . Mean survival times for retrovirus , adenovirus , and control groups were 7.4 , 15.0 , and 8 . 3 months , respectively . The difference in the survival times between the adenovirus and retrovirus groups was significant ( p < 0.012 ) . It is concluded that HSV tk gene therapy is safe and well tolerated . On the basis of these results further trials are justified , especially with adenovirus vectors Intratumoral implantation of murine cells modified to produce retroviral vectors containing the herpes simplex virus-thymidine kinase ( HSV-TK ) gene induces regression of experimental brain tumors in rodents after ganciclovir ( GCV ) administration . We evaluated this approach in 15 patients with progressive growth of recurrent malignant brain tumors . Antitumor activity was detected in five of the smaller tumors ( 1.4 ± 0.5 ml ) . In situ hybridization for HSV-TK demonstrated survival of vector-producing cells ( VPCs ) at 7 days but indicated limited gene transfer to tumors , suggesting that indirect , “ byst and er , ” mechanisms provide local antitumor activity in human tumors . However , the response of only very small tumors in which a high density of vector-producing cells had been placed suggests that techniques to improve delivery and distribution of the therapeutic gene will need to be developed if clinical utility is to be achieved with this approach Previous uncontrolled clinical trials have shown the in vivo retrovirus (RV)-mediated transduction of glioblastoma cells with the herpes simplex virus thymidine kinase ( HSV-tk ) gene and subsequent systemic treatment with ganciclovir to be feasible and well tolerated . However , because of continued tumor progression in most patients , the antitumor effect could not be determined using historical controls . Here , we describe a phase III , multicenter , r and omized , open-label , parallel-group , controlled trial of the technique in the treatment of 248 patients with newly diagnosed , previously untreated glioblastoma multiforme ( GBM ) . Patients received , in equal numbers , either st and ard therapy ( surgical resection and radiotherapy ) or st and ard therapy plus adjuvant gene therapy during surgery . Progression-free median survival in the gene therapy group was 180 days compared with 183 days in control subjects . Median survival was 365 versus 354 days , and 12-month survival rates were 50 versus 55 % in the gene therapy and control groups , respectively . These differences were not significant . Therefore , the adjuvant treatment improved neither time to tumor progression nor overall survival time , although the feasibility and good biosafety profile of this gene therapy strategy were further supported . The failure of this specific protocol may be due mainly to the presumably poor rate of delivery of the HSV-tk gene to tumor cells . In addition , the current mode of manual injection of vector-producing cells with a nonmigratory fibroblast phenotype limits the distribution of these cells and the released replication-deficient RV vectors to the immediate vicinity of the needle track . Further evaluation of the RV-mediated gene therapy strategy must incorporate refinements such as improved delivery of vectors and transgenes to the tumor cells , noninvasive in vivo assessment of transduction rates , and improved delivery of the prodrug across the blood-brain and blood-tumor barrier to the transduced tumor cells A material of 108 patients with glioblastoma is presented . The series was r and omized in two groups : cases only operated upon and cases with postoperative irradiation in addition . Patients dead within 2 months after operation were excluded in estimating the real value of the postoperative irradiation . The irradiated cases had a 6-month survival rate of 64 per cent and a one-year survival rate of 19 per cent ; the non-irradiated cases a 6-month survival rate of 28 per cent and a one-year survival rate of 0 per cent BACKGROUND Glioblastoma , the most common primary brain tumor in adults , is usually rapidly fatal . The current st and ard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible , followed by adjuvant radiotherapy . In this trial we compared radiotherapy alone with radiotherapy plus temozolomide , given concomitantly with and after radiotherapy , in terms of efficacy and safety . METHODS Patients with newly diagnosed , histologically confirmed glioblastoma were r and omly assigned to receive radiotherapy alone ( fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks , for a total of 60 Gy ) or radiotherapy plus continuous daily temozolomide ( 75 mg per square meter of body-surface area per day , 7 days per week from the first to the last day of radiotherapy ) , followed by six cycles of adjuvant temozolomide ( 150 to 200 mg per square meter for 5 days during each 28-day cycle ) . The primary end point was overall survival . RESULTS A total of 573 patients from 85 centers underwent r and omization . The median age was 56 years , and 84 percent of patients had undergone debulking surgery . At a median follow-up of 28 months , the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone . The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 ( 95 percent confidence interval , 0.52 to 0.75 ; P<0.001 by the log-rank test ) . The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone . Concomitant treatment with radiotherapy plus temozolomide result ed in grade 3 or 4 hematologic toxic effects in 7 percent of patients . CONCLUSIONS The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma result ed in a clinical ly meaningful and statistically significant survival benefit with minimal additional toxicity The relationship between increasing survival and increasing doses of radiotherapy has been examined in 621 patients who were entered into three successive Brain Tumor Study Group protocol s between 1966 and 1975 . These patients were operated upon and had histologically proven malignant gliomas . The median survival of patients who received no radiotherapy was 18.0 weeks ; for those who had ⪯4500 rad , it was 13.5 weeks ( p = .346 ) ; those who received 5000 rad had a median survival of 28 weeks ( p < .001 ) , 5500 rad - 36.0 weeks ( p < .001 ) , and 6000 rad - 42.0 weeks ( p < .001 ) . The specific relationship between 5000 and 6000 rad indicates a 1.3 times increase in median life span associated with the higher dose ( p = .004 ) . A detailed analysis of specific factors which might have significantly biased results indicated that patients who received less than 4500 rad were not comparable to other groups of patients because they had a poorer initial performance status and a greater number died before completion of radiotherapy . Factors of importance including parameters of radiotherapy , pathology distribution , the influence of corticosteroids , and the effect of age , sex , and initial performance status were all comparable within the various other subgroups . No other treatment characteristics or selective factors which might have a direct effect on survival were identified . It was concluded that radiotherapy had a significant influence on the survival of patients with malignant glioma and that a clear-cut dose-effect relationship exists This study has investigated the effects of herpes simplex 
    Output:
    
CONCLUSION As the dysregulation of key molecular pathways is characteristic of gliomas , gene therapy remains a promising treatment for glioma .