2022
PRESTO 2: An International Survey to Evaluate Patients’ Injection Experiences with the Latest Devices/Formulations of Long-Acting Somatostatin Analog Therapies for Neuroendocrine Tumors or Acromegaly
O’Toole D, Kunz P, Webb S, Goldstein G, Khawaja S, McDonnell M, Boiziau S, Gueguen D, Houchard A, Ribeiro-Oliveira A, Prebtani A. PRESTO 2: An International Survey to Evaluate Patients’ Injection Experiences with the Latest Devices/Formulations of Long-Acting Somatostatin Analog Therapies for Neuroendocrine Tumors or Acromegaly. Advances In Therapy 2022, 40: 671-690. PMID: 36502449, PMCID: PMC9741754, DOI: 10.1007/s12325-022-02360-6.Peer-Reviewed Original ResearchConceptsInjection site painNeuroendocrine tumorsInjection experienceRecent injectionLanreotide autogel/depotMultivariate logistic regression modelOdds of painSomatostatin analogue therapyProportion of patientsInjection site reactionsLogistic regression modelsSSA useAnalogue therapySecondary endpointsDisease subgroupsPainPatientsAcromegalyInjection modalitiesMonthsInjectionTumors
2021
177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial
Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP, investigators N. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. The Lancet Oncology 2021, 22: 1752-1763. PMID: 34793718, DOI: 10.1016/s1470-2045(21)00572-6.Peer-Reviewed Original ResearchConceptsMedian overall survivalMidgut neuroendocrine tumorsTreatment-related serious adverse eventsLong-term safety resultsFinal overall survivalPrespecified final analysisPhase 3 trialProgression-free survivalSerious adverse eventsOverall survivalLu-DOTATATE treatmentAdverse eventsNeuroendocrine tumorsLu-DOTATATESecondary endpointsLast patientMyelodysplastic syndromeSafety resultsInteractive web-based response systemControl groupAdvanced midgut neuroendocrine tumorsFinal overall survival analysisWeb-based response systemFinal analysisNETTER-1 trialTemozolomide in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Retrospective Review
Chan DL, Bergsland EK, Chan JA, Gadgil R, Halfdanarson TR, Hornbacker K, Kelly V, Kunz PL, McGarrah PW, Raj NP, Reidy DL, Thawer A, Whitman J, Wu L, Becker C, Singh S. Temozolomide in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Retrospective Review. The Oncologist 2021, 26: 950-955. PMID: 34342086, PMCID: PMC8571741, DOI: 10.1002/onco.13923.Peer-Reviewed Original ResearchConceptsG3 neuroendocrine neoplasmsFirst-line settingPercent of patientsMulticenter retrospective reviewTreatment failureGastroenteropancreatic neuroendocrine neoplasmsNeuroendocrine neoplasmsRetrospective reviewOptimal treatmentResponse rateGastrointestinal neuroendocrine neoplasmsLocal pathology reportsDiscontinuation of therapyMedian TTFFirst-line treatmentOverall response rateConfirmatory prospective studiesViable treatment optionPancreatic neuroendocrine neoplasmsRadiologic responseTemozolomide regimenPrimary endpointAdverse eventsMedian durationRadiographic responseRapid Progression After 177Lu-DOTATATE in Patients With Neuroendocrine Tumors
Assi HA, Hornbacker K, Shaheen S, Wittenberg T, Silberman R, Kunz PL. Rapid Progression After 177Lu-DOTATATE in Patients With Neuroendocrine Tumors. Pancreas 2021, 50: 890-894. PMID: 34398071, DOI: 10.1097/mpa.0000000000001841.Peer-Reviewed Original ResearchConceptsPeptide receptor radionuclide therapyProgressive diseaseNeuroendocrine tumorsBiopsy-proven neuroendocrine tumorHigher disease control rateMedian progression-free survivalShorter progression-free intervalStanford Cancer CenterDisease control rateMetastatic neuroendocrine tumorsMonths of therapyProgression-free survivalProgression-free intervalReceptor radionuclide therapyBetter patient selectionLarge patient cohortHigh-grade componentHigher disease gradeLow-grade componentRepeat biopsyMedian timePatient selectionInitial pathologyPredictive factorsCancer CenterAnalysis of Survival Among Adults With Early-Onset Colorectal Cancer in the National Cancer Database
Cheng E, Blackburn HN, Ng K, Spiegelman D, Irwin ML, Ma X, Gross CP, Tabung FK, Giovannucci EL, Kunz PL, Llor X, Billingsley K, Meyerhardt JA, Ahuja N, Fuchs CS. Analysis of Survival Among Adults With Early-Onset Colorectal Cancer in the National Cancer Database. JAMA Network Open 2021, 4: e2112539. PMID: 34132794, PMCID: PMC8209612, DOI: 10.1001/jamanetworkopen.2021.12539.Peer-Reviewed Original ResearchConceptsEarly-onset colorectal cancerOnset colorectal cancerNational Cancer DatabaseColorectal cancerAge 51Overall survivalCancer DatabaseIncidence of CRCCox proportional hazards regressionPrimary colorectal cancerKaplan-Meier analysisProportional hazards regressionAge 50 yearsAge 25 yearsAnalysis of survivalCohort studySurvival benefitHazards regressionUnadjusted analysesCancer incidenceMAIN OUTCOMEAge 35Survival advantageLower riskStage I
2020
PAM staining intensity of primary neuroendocrine neoplasms is a potential prognostic biomarker
Horton TM, Sundaram V, Lee CH, Hornbacker K, Van Vleck A, Benjamin KN, Zemek A, Longacre TA, Kunz PL, Annes JP. PAM staining intensity of primary neuroendocrine neoplasms is a potential prognostic biomarker. Scientific Reports 2020, 10: 10943. PMID: 32616904, PMCID: PMC7331689, DOI: 10.1038/s41598-020-68071-6.Peer-Reviewed Original ResearchConceptsPrimary neuroendocrine neoplasmsNeuroendocrine neoplasmsPAM immunoreactivityPAM stainingStage-independent predictorUnpredictable clinical behaviorRisk of deathIndividual patient prognosisRare epithelial tumorsHigh-grade tumorsPotential prognostic biomarkerMedian timeSmall bowelAvailable biomarkersTumor sizeDisease stageClinical associationsGrade tumorsClinical behaviorPatient prognosisPrognostic biomarkerEpithelial tumorsTherapy selectionSurvival implicationsPatientsTime to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome
Dillon JS, Kulke MH, Hörsch D, Anthony LB, Warner RRP, Bergsland E, Welin S, O’Dorisio T, Kunz PL, McKee C, Lapuerta P, Banks P, Pavel M. Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome. Journal Of Gastrointestinal Cancer 2020, 52: 212-221. PMID: 32146619, PMCID: PMC7714089, DOI: 10.1007/s12029-020-00375-2.Peer-Reviewed Original ResearchConceptsCarcinoid syndrome diarrheaBM frequencyPhase III studyTelotristat ethylBowel movementsCarcinoid syndromeIII studySomatostatin analoguesDouble-blind treatment periodBowel movement frequencyMajority of patientsLog-rank testCox regression modelTime of onsetPlacebo TIDHazard ratioPrespecified analysisMedian timeSustained responseTreatment periodSustained reductionPatientsConsecutive weeksTELESTARSurvival analysis methods
2019
Prognostic value of somatostatin receptor expressing tumor volume calculated from 68Ga-DOTATATE PET/CT in patients with well-differentiated neuroendocrine tumors
Toriihara A, Baratto L, Nobashi T, Park S, Hatami N, Davidzon G, Kunz PL, Iagaru A. Prognostic value of somatostatin receptor expressing tumor volume calculated from 68Ga-DOTATATE PET/CT in patients with well-differentiated neuroendocrine tumors. European Journal Of Nuclear Medicine And Molecular Imaging 2019, 46: 2244-2251. PMID: 31350603, DOI: 10.1007/s00259-019-04455-9.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overDisease ProgressionDisease-Free SurvivalFemaleHumansImage Processing, Computer-AssistedKaplan-Meier EstimateLiver NeoplasmsMaleMiddle AgedMultivariate AnalysisNeoplasm MetastasisNeuroendocrine TumorsOrganometallic CompoundsPositron Emission Tomography Computed TomographyPrognosisProgression-Free SurvivalProportional Hazards ModelsProspective StudiesReceptors, SomatostatinRetrospective StudiesConceptsProgression-free survivalProportional hazards modelPET/CTPrognostic valueTumor volumeNeuroendocrine tumorsTumor gradeSomatostatin receptorsKaplan-Meier survival analysisCox proportional hazards modelPositron emission tomography/Volume of interestMaximum standardized uptake valueMethodsNinety-two patientsWHO tumor gradeLog-rank testSomatostatin receptor expressionEmission tomography/Standardized uptake valueSignificant differencesVolumetric parametersPrimary endpointIndependent predictorsResultsUnivariate analysisTomography/
2018
Organoid Modeling of the Tumor Immune Microenvironment
Neal JT, Li X, Zhu J, Giangarra V, Grzeskowiak CL, Ju J, Liu IH, Chiou SH, Salahudeen AA, Smith AR, Deutsch BC, Liao L, Zemek AJ, Zhao F, Karlsson K, Schultz LM, Metzner TJ, Nadauld LD, Tseng YY, Alkhairy S, Oh C, Keskula P, Mendoza-Villanueva D, De La Vega FM, Kunz PL, Liao JC, Leppert JT, Sunwoo JB, Sabatti C, Boehm JS, Hahn WC, Zheng GXY, Davis MM, Kuo CJ. Organoid Modeling of the Tumor Immune Microenvironment. Cell 2018, 175: 1972-1988.e16. PMID: 30550791, PMCID: PMC6656687, DOI: 10.1016/j.cell.2018.11.021.Peer-Reviewed Original ResearchConceptsTumor-infiltrating lymphocytesPatient-derived organoidsImmune checkpoint blockadePrimary tumor epitheliumTumor epitheliumTumor microenvironmentAntigen-specific tumor-infiltrating lymphocytesTumor immune microenvironmentAir-liquid interface methodSyngeneic immunocompetent hostsImmune stromaCheckpoint blockadeImmunocompetent hostsImmune microenvironmentNeoplastic epitheliumImmune cellsTumor TTumor cytotoxicityMouse tumorsHuman biopsiesImmune repertoireCancer culturesEpitheliumThree-dimensional organoidsOrganoid modelingSurgical and molecular characterization of primary and metastatic disease in a neuroendocrine tumor arising in a tailgut cyst
Erdrich J, Schaberg KB, Khodadoust MS, Zhou L, Shelton AA, Visser BC, Ford JM, Alizadeh AA, Quake SR, Kunz PL, Beausang JF. Surgical and molecular characterization of primary and metastatic disease in a neuroendocrine tumor arising in a tailgut cyst. Molecular Case Studies 2018, 4: a003004. PMID: 30087100, PMCID: PMC6169824, DOI: 10.1101/mcs.a003004.Peer-Reviewed Original ResearchConceptsGene expression profilesTranscriptomic analysisExpression profilesGenomic characteristicsMolecular characterizationPutative cellSomatic mutationsL cellsGenomic profilingGastrointestinal cellsCellsUnknown significanceNeuroendocrine tumorsFrameshiftMutationsTailgut cystEnteroendocrine L cellsProfilingOriginGenomic testingPotential therapeutic optionRare neuroendocrine tumorsLong-Term Survivors of Pancreatic Cancer
Kardosh A, Lichtensztajn DY, Gubens MA, Kunz PL, Fisher GA, Clarke CA. Long-Term Survivors of Pancreatic Cancer. Pancreas 2018, 47: 958-966. PMID: 30074526, PMCID: PMC6095724, DOI: 10.1097/mpa.0000000000001133.Peer-Reviewed Original ResearchConceptsLong-term survivalPancreatic cancerPancreatic adenocarcinomaCalifornia Cancer RegistryLong-term survivorsPancreatic cancer mortalityAsian/Pacific IslandersNational Cancer InstituteNon-Hispanic whitesAdjuvant chemotherapyUnresectable patientsBaseline characteristicsSurgical resectionTerm survivorsCancer RegistryPoor prognosisSurgical interventionCancer CenterCancer mortalityDegree of differentiationCancer InstituteSurvival rateYounger ageLogistic regressionPatientsChanges in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome
Weickert MO, Kaltsas G, Hörsch D, Lapuerta P, Pavel M, Valle JW, Caplin ME, Bergsland E, Kunz PL, Anthony LB, Grande E, Öberg K, Welin S, Lombard-Bohas C, Ramage JK, Kittur A, Yang QM, Kulke MH. Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome. Clinical Therapeutics 2018, 40: 952-962.e2. PMID: 29724499, DOI: 10.1016/j.clinthera.2018.04.006.Peer-Reviewed Original ResearchConceptsMetastatic neuroendocrine tumorsTelotristat ethylCarcinoid syndromePlacebo TIDWeek 12Neuroendocrine tumorsMetabolic parametersNutritional statusDouble-blind treatment periodWeight gainWeight lossUncontrolled carcinoid syndromeSomatostatin analogue therapyBowel movement frequencyStatistical analysis planOverall nutritional statusAnalogue therapyDiarrhea severityTreatment periodPatientsSyndromeWeight changeAnalysis planMovement frequencyTumorsTelotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial
Pavel M, Gross DJ, Benavent M, Perros P, Srirajaskanthan R, Warner RRP, Kulke MH, Anthony LB, Kunz PL, Hörsch D, Weickert MO, Lapuerta P, Jiang W, Kassler-Taub K, Wason S, Fleming R, Fleming D, Garcia-Carbonero R. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial. Endocrine Related Cancer 2018, 25: 309-322. PMID: 29330194, PMCID: PMC5811631, DOI: 10.1530/erc-17-0455.Peer-Reviewed Original ResearchConceptsTreatment-emergent adverse eventsOpen-label extensionCarcinoid syndromeTelotristat ethylSomatostatin analoguesWeek 12Rates of TEAEsDouble-blind treatment periodPhase 3 trialTryptophan hydroxylase inhibitorMedian treatment differencesCS diarrheaBowel movementsEfficacy endpointAdverse eventsPrimary safetyTreatment periodHydroxylase inhibitorPatientsSerious eventsPercent changeTreatment differencesPlaceboEfficacySignificant reduction
2017
Carcinoid Syndrome Complicating a Pancreatic Neuroendocrine Tumor
Gerson JN, Witteles RM, Chang DT, Beygui RE, Iagaru AH, Kunz PL. Carcinoid Syndrome Complicating a Pancreatic Neuroendocrine Tumor. Pancreas 2017, 46: 1381-1385. PMID: 29040196, DOI: 10.1097/mpa.0000000000000932.Peer-Reviewed Original ResearchConceptsPancreatic neuroendocrine tumorsNeuroendocrine tumorsCarcinoid syndromeRight upper quadrant abdominal painUpper quadrant abdominal painMetastatic pancreatic neuroendocrine tumorsRight-sided heart diseaseQuadrant abdominal painPulmonic valve replacementAbdominal painSystemic chemotherapyTreatable complicationHormone excessSerum serotoninValve replacementHeart diseaseHeterogeneous groupSyndromeElevated levelsTumorsDiseaseImportant entityDyspneaEmesisPainUnderstanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-controlled Study of Telotristat Ethyl
Anthony L, Ervin C, Lapuerta P, Kulke MH, Kunz P, Bergsland E, Hörsch D, Metz DC, Pasieka J, Pavlakis N, Pavel M, Caplin M, Öberg K, Ramage J, Evans E, Yang QM, Jackson S, Arnold K, Law L, DiBenedetti DB. Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-controlled Study of Telotristat Ethyl. Clinical Therapeutics 2017, 39: 2158-2168. PMID: 29074312, DOI: 10.1016/j.clinthera.2017.09.013.Peer-Reviewed Original ResearchConceptsTelotristat ethylBM frequencyCarcinoid syndromeBowel movementsPatient experienceDouble-blind treatment periodCarcinoid syndrome symptomsPrimary end pointSomatostatin analogue therapyPhase III studyClinical trial experienceTryptophan hydroxylase inhibitorEligible patientsStudy drugAnalogue therapyIII studyPatient interviewsResponder analysisTreatment periodPatient reportsSyndrome symptomsTreatment responsePrespecified criteriaHydroxylase inhibitorPatientsPhase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. New England Journal Of Medicine 2017, 376: 125-135. PMID: 28076709, PMCID: PMC5895095, DOI: 10.1056/nejmoa1607427.Peer-Reviewed Original ResearchConceptsMidgut neuroendocrine tumorsProgression-free survivalAdvanced midgut neuroendocrine tumorsOverall survivalNeuroendocrine tumorsControl groupInterim analysisResponse rateLu-DOTATATEHigh-dose octreotide LARLonger progression-free survivalEnd pointMetastatic midgut neuroendocrine tumorsFinal analysisData cutoff dateObjective response rateOverall survival benefitPrimary end pointSecondary end pointsSomatostatin analogue therapyPhase 3 trialSide effect profileRenal toxic effectsHigh response rateOctreotide LAR
2016
Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome
Kulke MH, Hörsch D, Caplin ME, Anthony LB, Bergsland E, Öberg K, Welin S, Warner RR, Lombard-Bohas C, Kunz PL, Grande E, Valle JW, Fleming D, Lapuerta P, Banks P, Jackson S, Zambrowicz B, Sands AT, Pavel M. Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome. Journal Of Clinical Oncology 2016, 35: 14-23. PMID: 27918724, DOI: 10.1200/jco.2016.69.2780.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntineoplastic Agents, HormonalDefecationDiarrheaDouble-Blind MethodFemaleGamma-GlutamyltransferaseGastrointestinal AgentsHumansHydroxyindoleacetic AcidMaleMalignant Carcinoid SyndromeMiddle AgedNauseaOctreotidePeptides, CyclicPhenylalaninePyrimidinesSomatostatinTryptophan HydroxylaseConceptsDouble-blind treatment periodOpen-label extensionTelotristat ethylTryptophan hydroxylase inhibitorBM frequencyCarcinoid syndromeWeek 12Treatment periodHydroxylase inhibitorPlacebo-controlled phase III studyPrimary end pointSomatostatin analogue therapyBowel movement frequencyNew safety signalsPhase III studyGamma-glutamyl transferaseAsymptomatic increaseMild nauseaAnalogue therapyIII studyMethods PatientsSomatostatin analoguesSafety signalsPlaceboPatientsNeuroendocrine tumors of the pancreas: Degree of cystic component predicts prognosis
Cloyd JM, Kopecky KE, Norton JA, Kunz PL, Fisher GA, Visser BC, Dua MM, Park WG, Poultsides GA. Neuroendocrine tumors of the pancreas: Degree of cystic component predicts prognosis. Surgery 2016, 160: 708-713. PMID: 27216830, DOI: 10.1016/j.surg.2016.04.005.Peer-Reviewed Original ResearchConceptsCystic pancreatic neuroendocrine tumorsPancreatic neuroendocrine tumorsRecurrence-free survivalNeuroendocrine tumorsCystic tumorCystic componentSolid tumorsTumor sizeSingle academic medical centerMost pancreatic neuroendocrine tumorsFavorable clinicopathologic featuresSynchronous liver metastasesLymph node positivityLymph node metastasisTotal tumor sizeHigh gradeCross-sectional imagingAcademic medical centerSynchronous liverImmediate resectionLiver metastasesMetastatic diseaseNode positivityOperative resectionClinicopathologic characteristicsA Multi-institutional Analysis of Duodenal Neuroendocrine Tumors: Tumor Biology Rather than Extent of Resection Dictates Prognosis
Margonis GA, Samaha M, Kim Y, Postlewait LM, Kunz P, Maithel S, Tran T, Berger N, Gamblin TC, Mullen MG, Bauer TW, Pawlik TM. A Multi-institutional Analysis of Duodenal Neuroendocrine Tumors: Tumor Biology Rather than Extent of Resection Dictates Prognosis. Journal Of Gastrointestinal Surgery 2016, 20: 1098-1105. PMID: 27008594, DOI: 10.1007/s11605-016-3135-x.Peer-Reviewed Original ResearchConceptsDuodenal neuroendocrine tumorsLocal surgical resectionNeuroendocrine tumorsAdvanced tumor gradeEndoscopic resectionLymph nodesTumor gradeProcedure typeTumor biologyLonger hospital stayOutcomes of patientsSevere postoperative complicationsMetastatic lymph nodesLymph node metastasisMulti-institutional analysisMulti-institutional databaseWorse RFSHospital stayPerioperative complicationsPostoperative complicationsSurgical resectionClinicopathologic characteristicsNode metastasisMedian lengthPD patients
2015
Phase II pilot study of single-agent etirinotecan pegol (NKTR-102) in bevacizumab-resistant high grade glioma
Nagpal S, Recht CK, Bertrand S, Thomas RP, Ajlan A, Pena J, Gershon M, Coffey G, Kunz PL, Li G, Recht LD. Phase II pilot study of single-agent etirinotecan pegol (NKTR-102) in bevacizumab-resistant high grade glioma. Journal Of Neuro-Oncology 2015, 123: 277-282. PMID: 25935109, PMCID: PMC4452613, DOI: 10.1007/s11060-015-1795-0.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAngiogenesis InhibitorsAntineoplastic AgentsBevacizumabBrain NeoplasmsDrug Resistance, NeoplasmFemaleFollow-Up StudiesGliomaHeterocyclic Compounds, 4 or More RingsHumansMaleMiddle AgedNeoplasm GradingNeoplasm Recurrence, LocalPilot ProjectsPolyethylene GlycolsPrognosisProspective StudiesSurvival RateYoung AdultConceptsHigh-grade gliomasEtirinotecan pegolOverall survivalRANO criteriaPhase II pilot studyGrade 3 toxicityMedian overall survivalOpen-label trialFurther clinical investigationMedian KPSChemotherapy cyclesHematologic toxicityPrimary endpointSecondary endpointsPartial responseMedian agePatient agePoor prognosisHGG patientsTumor exposureClinical dataAnaplastic astrocytomaBevacizumabClinical investigationGrade gliomas