***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: Malignant glioma is a devastating brain tumor with no effective treatment . This r and omised , controlled study involved 36 patients with operable primary or recurrent malignant glioma . Seventeen patients were r and omized to receive AdvHSV-tk gene therapy ( 3 x 10(10 ) pfu ) by local injection into the wound bed after tumor resection , followed by intravenous ganciclovir ( GCV ) , 5 mg/kg twice daily for 14 days . The control group of 19 patients received st and ard care consisting of radical excision followed by radiotherapy in those patients with primary tumors . The primary end-point was survival as defined by death or surgery for recurrence . Secondary end-points were all-cause mortality and tumour progression as determined by MRI . Overall safety and quality of life were also assessed . Findings were also compared with historical controls ( n = 36 ) from the same unit over 2 years preceding the study . AdvHSV-tk treatment produced a clinical ly and statistically significant increase in mean survival from 39.0 + /- 19.7 ( SD ) to 70.6 + /- 52.9 weeks ( P = 0.0095 , log-rank regression vs. r and omized controls ) . The median survival time increased from 37.7 to 62.4 weeks . Six patients had increased anti-adenovirus antibody titers , without adverse effects . The treatment was well tolerated . It is concluded that AdvHSV-tk gene therapy with GCV is a potential new treatment for operable primary or recurrent high- grade glioma The management of patients with glioblastoma remains challenging with an average survival of 32–56 weeks . We report on a clinical trial of patients with recurrent glioblastoma treated with adenovirus/herpex simplex-thymidine kinase/ganciclovir (ADV/HSV-tk/GC).Entry  criteria for this study included : recurrent malignant glioma after surgical resection and conventional radiation therapy . At the time of recurrence , computerized volumetric resection of the tumor was performed and the ADV/HSV-tk complex was injected in the tumor bed . GC was administered 24 h after surgery ( 10 mg/kg/day ) for 7 days . Patients were divided into 3 ADV/HSV-tk dose-escalating cohorts . Adenoviral vector shedding , and local or systemic toxicity did not occur in this study . Magnetic resonance imaging showed lack of increased brain edema in the treated patients . Histological examination of the 5 patients that had repeated surgery after gene therapy treatment showed lack of tissue toxicity . Additionally , PCR for HSV-tk was negative in the brain 3 months after injection . The patients ' Karnofsky score was maintained ≥70 in 8/10 patients ( 80 % ) and 5/9 patients ( 55 % ) 3 and 6 months respectively , after gene therapy . Ten of 11 patients survived ≥52 weeks from diagnosis with an average survival of 112.3 weeks . One patient is still alive 248 weeks from diagnosis . These data show that the ADV/HSV-tk/GC complex at the dose used in this study is safe . Additional dose escalation is currently in progress Between December 1996 and September 1998 , 13 patients with advanced recurrent malignant brain tumors ( 9 with glioblastoma multiforme , 1 with gliosarcoma , and 3 with anaplastic astrocytoma ) were treated with a single intratumoral injection of 2 x 10(9 ) , 2 x 10(10 ) , 2 x 10(11 ) , or 2 x 10(12 ) vector particles ( VP ) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter ( Adv . RSVtk ) , followed by ganciclovir ( GCV ) treatment . The VP to infectious unit ratio was 20:1 . Our primary objective was to determine the safety of this treatment . Injection of Adv . RSVtk in doses < = = 2 x 10(11 ) VP , followed by GCV , was safely tolerated . Patients treated with the highest dose , 2 x 10(12 ) VP , exhibited central nervous system toxicity with confusion , hyponatremia , and seizures . One patient is living and stable 29.2 months after treatment . Two patients survived > 25 months before succumbing to tumor progression . Ten patients died within 10 months of treatment , 9 from tumor progression and 1 with sepsis and endocarditis . Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site , intratumoral foci of coagulative necrosis , and variable infiltration of the residual tumor with macrophages and lymphocytes To determine the safety and evaluate the efficacy of repeated administration of virus-producing cells ( GLI 328 ) containing the herpes simplex virus thymidine-kinase gene followed by ganciclovir treatment in adults with recurrent glioblastoma multiforme , we conducted a phase I/II multi-institutional trial . Eligible patients underwent surgical resection of tumor , followed by injections of vector producing cells ( VPC ) into the brain adjacent to the cavity . An Ommaya reservoir placed after surgery was used to inject a further dose of VPC seven days after surgery , followed seven days later by ganciclovir . Further gene therapy was given at 28-day intervals for up to a total of five cycles . Toxicity and anti-tumor effect were assessed . Of 30 patients who enrolled in the study , 16 experienced serious adverse events possibly related to the experimental therapy . Laboratory testing , including polymerase chain reaction analysis to detect replication-competent retrovirus in peripheral blood lymphocytes and tissues , as well as co-cultivation bioassays , were negative . Before receiving ganciclovir , 37 % of the patients showed evidence of transduced peripheral blood leukocytes , but only 12 % showed a persistence of transduced cells at the end of the first cycle of ganciclovir .  Median survival was 8.4 months . Twenty percent of the patients ( n = 6 ) survived more than 12 months from the date of study entry . This treatment modality is feasible and appears to have some evidence of efficacy . Toxicity may be related in part to the method of gene delivery PURPOSE Despite aggressive therapies , median survival for malignant gliomas is less than 15 months . Patients with unmethylated O(6)-methylguanine-DNA methyltransferase ( MGMT ) fare worse , presumably because of temozolomide resistance . AdV-tk , an adenoviral vector containing the herpes simplex virus thymidine kinase gene , plus prodrug synergizes with surgery and chemoradiotherapy , kills tumor cells , has not shown MGMT dependency , and elicits an antitumor vaccine effect . PATIENTS AND METHODS Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 10(10 ) , 1 × 10(11 ) , or 3 × 10(11 ) vector particles ( vp ) via tumor bed injection at time of surgery followed by 14 days of valacyclovir . Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity . Temozolomide was administered after completing valacyclovir treatment . RESULTS Accrual began December 2005 and was completed in 13 months . Thirteen patients were enrolled and 12 completed therapy , three at dose levels 1 and 2 and six at dose level 3 . There were no dose-limiting or significant added toxicities . One patient withdrew before completing prodrug because of an unrelated surgical complication . Survival at 2 years was 33 % and at 3 years was 25 % . Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain ( FACT-Br ) was stable or improved after treatment . A significant CD3(+ ) T-cell infiltrate was found in four of four tumors analyzed after treatment . Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5 , 8.7 , and 46.4 months . CONCLUSION AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas . Temozolomide did not prevent immune responses . Although not powered for efficacy , the survival and MGMT independence trends are encouraging . A phase II trial is ongoing 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  
    Output:
    
Based on the best available evidence , it appears that adding gene therapy with HSV-tk has some effect in treating HGG patients , especially with respect to MST .
However , neither the pooled analysis of OS , nor the combined analysis of tumor progress indicates any significant advantage to adding gene therapy compared with st and ard treatment alone .