2023
Lenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments anti-tumor activity in melanoma
Tran T, Caulfield J, Zhang L, Schoenfeld D, Djureinovic D, Chiang V, Oria V, Weiss S, Olino K, Jilaveanu L, Kluger H. Lenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments anti-tumor activity in melanoma. JCI Insight 2023, 8: e157347. PMID: 36821392, PMCID: PMC10132152, DOI: 10.1172/jci.insight.157347.Peer-Reviewed Original ResearchConceptsTumor microenvironmentAnti-VEGFCytokine/chemokine signalingCytokine/chemokine profilingBlood-brain barrier modelBlood vesselsLeukocyte transmigrationTumor-associated blood vesselsTumor-associated macrophagesIntratumoral blood vesselsAnti-angiogenesis effectAnti-tumor activityExtracranial diseasePlasmacytoid DCsImmune checkpointsPD-1Melanoma murine modelImmune infiltrationBBB modelChemokine profilingEndothelial stabilizationMurine modelLenvatinibCombined targetingMelanoma model
2021
Incidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis
Sandhu MRS, Chiang VL, Tran T, Yu JB, Weiss S, Goldberg S, Aboian M, Kluger HM, Mahajan A. Incidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis. Journal Of Neuro-Oncology 2021, 154: 197-203. PMID: 34351544, DOI: 10.1007/s11060-021-03813-8.Peer-Reviewed Original ResearchMeSH KeywordsBrain NeoplasmsHumansIncidenceMaleMelanomaPrognosisRetrospective StudiesTesticular NeoplasmsConceptsStage IV melanomaMetastatic brain lesionsStage IIIInitial diagnosisTumor RegistryOverall incidenceBrain lesionsBM incidenceSingle-institute retrospective analysisBM developmentBrain metastases incidenceIncidence of BMInstitution's tumor registryStage III patientsTime of diagnosisMetastatic intracranial lesionsCommon genetic mutationsTumor genetic profileGenetic profileBM occurrenceMedian durationAdvanced melanomaSurveillance regimenIII patientsMedian time
2019
Multi-institutional validation of brain metastasis velocity, a recently defined predictor of outcomes following stereotactic radiosurgery
McTyre ER, Soike MH, Farris M, Ayala-Peacock DN, Hepel JT, Page BR, Shen C, Kleinberg L, Contessa JN, Corso C, Chiang V, Henson-Masters A, Cramer CK, Ruiz J, Pasche B, Watabe K, D'Agostino R, Su J, Laxton AW, Tatter SB, Fiveash JB, Ahluwalia M, Kotecha R, Chao ST, Braunstein SE, Attia A, Chung C, Chan MD. Multi-institutional validation of brain metastasis velocity, a recently defined predictor of outcomes following stereotactic radiosurgery. Radiotherapy And Oncology 2019, 142: 168-174. PMID: 31526671, DOI: 10.1016/j.radonc.2019.08.011.Peer-Reviewed Original ResearchConceptsBrain metastasis velocityDistant brain failureMedian overall survivalOverall survivalBrain metastasesPredictors of OSInitial brain metastasesNew brain metastasesWhole brain radiationKaplan-Meier methodHigh-risk groupPredictors of outcomeProportional hazards methodsMulti-institutional settingMulti-institutional validationMultivariate regression modelingInitial SRSBrain radiationSalvage modalityInitial treatmentBrain failureRecurrence rateValidation cohortBMV groupMelanoma histologyFrequent Use of Local Therapy Underscores Need for Multidisciplinary Care in the Management of Patients With Melanoma Brain Metastases Treated With PD-1 Inhibitors
Qian JM, Yu JB, Mahajan A, Goldberg SB, Kluger HM, Chiang VLS. Frequent Use of Local Therapy Underscores Need for Multidisciplinary Care in the Management of Patients With Melanoma Brain Metastases Treated With PD-1 Inhibitors. International Journal Of Radiation Oncology • Biology • Physics 2019, 105: 1113-1118. PMID: 31479702, DOI: 10.1016/j.ijrobp.2019.08.053.Peer-Reviewed Original ResearchConceptsBrain metastasesLocal therapyNeurologic safetyMelanoma patientsProspective phase 2 trialProgressive brain metastasesSerial brain imagingMelanoma brain metastasesPD-1 inhibitorsPhase 2 trialRapid disease progressionManagement of patientsNeurologic symptomsMultidisciplinary careTrial enrollmentCystic changesClinical trialsDisease progressionPatientsLesion sizeMetastasisMultidisciplinary teamTumor growthTherapyClinical decisionPerilesional edema in brain metastases: potential causes and implications for treatment with immune therapy
Tran TT, Mahajan A, Chiang VL, Goldberg SB, Nguyen DX, Jilaveanu LB, Kluger HM. Perilesional edema in brain metastases: potential causes and implications for treatment with immune therapy. Journal For ImmunoTherapy Of Cancer 2019, 7: 200. PMID: 31362777, PMCID: PMC6668163, DOI: 10.1186/s40425-019-0684-z.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, IntravenousAntibodies, Monoclonal, HumanizedAntigens, CD34Antineoplastic Agents, ImmunologicalBlood-Brain BarrierBrain EdemaBrain NeoplasmsCarcinoma, Non-Small-Cell LungClinical Trials, Phase II as TopicDrug Administration ScheduleHumansLung NeoplasmsMelanomaRetrospective StudiesTight JunctionsTreatment OutcomeTumor Cells, CulturedConceptsMelanoma brain metastasesBrain metastasesPerilesional edemaVessel densityEdema volumeSensitive tumorsBlood-brain barrier model systemNon-small cell lungTight junction resistancePhase II clinical trialSignificant perilesional edemaUntreated brain metastasesBlood-brain barrierPre-clinical modelsDegree of edemaTumor mass effectPotential causesMelanoma brainShort-term cultureExtracranial metastasesImmune therapyMelanoma patientsSignificant morbidityCell lungLarge tumorsReply to A. Shinde et al
Kluger HM, Margolin KA, Davies MA, Long GV, Tawbi HA, Goldberg SB, Chiang VL. Reply to A. Shinde et al. Journal Of Clinical Oncology 2019, 37: jco.18.02463. PMID: 30807233, DOI: 10.1200/jco.18.02463.Peer-Reviewed Original Research
2018
Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial
Kluger HM, Chiang V, Mahajan A, Zito CR, Sznol M, Tran T, Weiss SA, Cohen JV, Yu J, Hegde U, Perrotti E, Anderson G, Ralabate A, Kluger Y, Wei W, Goldberg SB, Jilaveanu LB. Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. Journal Of Clinical Oncology 2018, 37: 52-60. PMID: 30407895, PMCID: PMC6354772, DOI: 10.1200/jco.18.00204.Peer-Reviewed Original ResearchConceptsBrain metastasis responseBrain metastasesMetastasis responseAdverse eventsAnti-programmed cell death-1 (PD-1) agentsDeath ligand 1 (PD-L1) expressionModified Response Evaluation CriteriaPhase II clinical trialActive brain metastasesAsymptomatic brain metastasesCD8 cell densityNeurologic adverse eventsPembrolizumab-treated patientsUse of pembrolizumabMelanoma brain metastasesPrimary end pointLigand 1 expressionPhase II trialResponse Evaluation CriteriaT-cell infiltratesUntreated brain metastasesDeath ligand 1Two-year survivalOverall survival timeResult of progressionBRAF V600 Mutation and BRAF Kinase Inhibitors in Conjunction With Stereotactic Radiosurgery for Intracranial Melanoma Metastases: A Multicenter Retrospective Study
Mastorakos P, Xu Z, Yu J, Hess J, Qian J, Chatrath A, Taylor DG, Kondziolka D, Warnick R, Chiang V, Sheehan J. BRAF V600 Mutation and BRAF Kinase Inhibitors in Conjunction With Stereotactic Radiosurgery for Intracranial Melanoma Metastases: A Multicenter Retrospective Study. Neurosurgery 2018, 84: 868-880. PMID: 29846702, PMCID: PMC6505443, DOI: 10.1093/neuros/nyy203.Peer-Reviewed Original ResearchConceptsMelanoma brain metastasesBrain metastasesBRAF inhibitorsStereotactic radiosurgeryBRAF mutationsIntracerebral hematomaDiagnosis of BMEffects of BRAFiMulticenter retrospective cohort studyIntracranial melanoma metastasesPD-1 inhibitorsMulticenter retrospective studyRetrospective cohort studyKaplan-Meier methodologyPositive prognostic factorBRAF V600 mutationBRAF mutation statusBRAF kinase inhibitorsMultivariate regression analysisWild-type BRAFCohort studyHazard ratioMedian survivalIndependent predictorsPrognostic factors
2017
Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA)
Sperduto PW, Jiang W, Brown PD, Braunstein S, Sneed P, Wattson DA, Shih HA, Bangdiwala A, Shanley R, Lockney NA, Beal K, Lou E, Amatruda T, Sperduto WA, Kirkpatrick JP, Yeh N, Gaspar LE, Molitoris JK, Masucci L, Roberge D, Yu J, Chiang V, Mehta M. Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA). International Journal Of Radiation Oncology • Biology • Physics 2017, 99: 812-816. PMID: 29063850, PMCID: PMC6925529, DOI: 10.1016/j.ijrobp.2017.06.2454.Peer-Reviewed Original ResearchConceptsDiagnosis-Specific Graded Prognostic AssessmentGraded Prognostic AssessmentSignificant prognostic factorsBrain metastasesMelanoma-molGPAPrognostic factorsMelanoma patientsPrognostic assessmentMultiple Cox regressionMedian survival timeRetrospective database analysisLog-rank testHeterogeneous patient populationClinical decision makingTreatment eraHazard ratioMedian survivalMultivariable analysisWorse prognosisCox regressionPatient populationSurvival timePatientsMetastasisCurrent cohortStereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control
An Y, Jiang W, Kim BYS, Qian JM, Tang C, Fang P, Logan J, D'Souza NM, Haydu LE, Wang XA, Hess KR, Kluger H, Glitza IC, Mahajan A, Welsh JW, Lin SH, Yu JB, Davies MA, Hwu P, Sulman EP, Brown PD, Chiang VLS, Li J. Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiotherapy And Oncology 2017, 125: 80-88. PMID: 28916225, DOI: 10.1016/j.radonc.2017.08.009.Peer-Reviewed Original ResearchConceptsIntracranial disease controlNew brain metastasesIntracranial controlStereotactic radiosurgeryBrain metastasesOverall survivalDisease controlLymphocyte countMulti-institutional retrospective analysisYale-New Haven HospitalMD Anderson cohortMelanoma brain metastasesAbsolute lymphocyte countAntitumor immune responseImmune checkpoint blockadeMetastatic melanoma patientsComplete blood countTumor-specific antigensIndependent validation cohortMulti-institutional studyIpilimumab therapyMedian followLast doseCheckpoint blockadeIntracranial recurrenceCumulative Intracranial Tumor Volume Augments the Prognostic Value of Diagnosis-Specific Graded Prognostic Assessment Model for Survival in Patients with Melanoma Cerebral Metastases
Hirshman BR, Wilson BR, Ali MA, Schupper AJ, Proudfoot JA, Goetsch SJ, Carter BS, Sinclair G, Bartek J, Chiang V, Fogarty G, Hong A, Chen CC. Cumulative Intracranial Tumor Volume Augments the Prognostic Value of Diagnosis-Specific Graded Prognostic Assessment Model for Survival in Patients with Melanoma Cerebral Metastases. Neurosurgery 2017, 83: 237-244. PMID: 28973506, DOI: 10.1093/neuros/nyx380.Peer-Reviewed Original ResearchConceptsCumulative intracranial tumor volumeIntracranial tumor volumeMelanoma brain metastasesBrain metastasesPrognostic valueDS-GPATumor volumeStereotactic radiosurgeryIndependent cohortKey prognostic variablesPrognostic assessment modelPrognostic assessment scaleKarnofsky performance statusNet reclassification indexCerebral metastasesPerformance statusMelanoma patientsPrognostic utilityIntracranial metastasesReclassification indexPrognostic accuracyPrognostic scalesPrognostic variablesPatientsMelanoma cohortThe Prognostic Value of BRAF, C-KIT, and NRAS Mutations in Melanoma Patients With Brain Metastases
Sperduto PW, Jiang W, Brown PD, Braunstein S, Sneed P, Wattson DA, Shih HA, Bangdiwala A, Shanley R, Lockney NA, Beal K, Lou E, Amatruda T, Sperduto WA, Kirkpatrick JP, Yeh N, Gaspar LE, Molitoris JK, Masucci L, Roberge D, Yu J, Chiang V, Mehta M. The Prognostic Value of BRAF, C-KIT, and NRAS Mutations in Melanoma Patients With Brain Metastases. International Journal Of Radiation Oncology • Biology • Physics 2017, 98: 1069-1077. PMID: 28721890, PMCID: PMC6925531, DOI: 10.1016/j.ijrobp.2017.03.030.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic AgentsBrain NeoplasmsFemaleGenes, rasHumansImmunotherapyLinear ModelsMaleMelanomaMiddle AgedMolecular Targeted TherapyMutationPrognosisProportional Hazards ModelsProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-kitRetrospective StudiesStatistics, NonparametricTime FactorsConceptsBRAF-negative patientsBRAF-positive patientsBrain metastasesMedian survivalC-kit mutationsMelanoma patientsPrimary diagnosisWhole-brain radiation therapyOverall median survivalMulti-institutional databaseGene mutation statusOverall survivalInitial treatmentMedian timeTreatment patternsClinical parametersBRAF statusPrognostic valueNRAS mutationsRadiation therapyPatientsMutation statusMetastasisC-kitMEK inhibitors
2016
Melanoma central nervous system metastases: current approaches, challenges, and opportunities
Cohen JV, Tawbi H, Margolin KA, Amravadi R, Bosenberg M, Brastianos PK, Chiang VL, de Groot J, Glitza IC, Herlyn M, Holmen SL, Jilaveanu LB, Lassman A, Moschos S, Postow MA, Thomas R, Tsiouris JA, Wen P, White RM, Turnham T, Davies MA, Kluger HM. Melanoma central nervous system metastases: current approaches, challenges, and opportunities. Pigment Cell & Melanoma Research 2016, 29: 627-642. PMID: 27615400, PMCID: PMC5398760, DOI: 10.1111/pcmr.12538.Peer-Reviewed Original ResearchTiming and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery
Qian JM, Yu JB, Kluger HM, Chiang VL. Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer 2016, 122: 3051-3058. PMID: 27285122, PMCID: PMC5030143, DOI: 10.1002/cncr.30138.Peer-Reviewed Original ResearchConceptsMedian percent reductionImmune checkpoint therapyLesional responseStereotactic radiosurgeryCheckpoint therapyLesion volumeAnti-cytotoxic T-lymphocyte-associated protein 4Anti-programmed cell death protein 1T-lymphocyte-associated protein 4Anti-PD-1 therapyGreater median percent reductionsCell death protein 1Administration of immunotherapyWeeks of immunotherapyMelanoma brain metastasesDeath protein 1Type of immunotherapyWilcoxon rank sum testRank sum testNonconcurrent therapyBrain metastasesMelanoma patientsTreatment of cancerSingle institutionPercent reductionPembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial
Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L, Yu J, Hegde U, Speaker S, Madura M, Ralabate A, Rivera A, Rowen E, Gerrish H, Yao X, Chiang V, Kluger HM. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. The Lancet Oncology 2016, 17: 976-983. PMID: 27267608, PMCID: PMC5526047, DOI: 10.1016/s1470-2045(16)30053-5.Peer-Reviewed Original ResearchConceptsProgressive brain metastasesUntreated brain metastasesBrain metastasis responseYale Cancer CenterBrain metastasesPhase 2 trialCell lung cancerAdverse eventsMetastasis responseCancer CenterLung cancerMelanoma cohortGrade 3 colitisGrade 3 fatigueGrade 3 pneumonitisPD-1 axisAcute kidney injuryNeurological adverse eventsPD-1 inhibitorsAcceptable safety profilePD-L1 expressionSystemic immunotherapyKidney injuryPrimary endpointNSCLC cohortMelanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment
Cohen JV, Alomari AK, Vortmeyer AO, Jilaveanu LB, Goldberg SB, Mahajan A, Chiang VL, Kluger HM. Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment. Cancer Immunology Research 2016, 4: 179-182. PMID: 26701266, PMCID: PMC4881844, DOI: 10.1158/2326-6066.cir-15-0160.Peer-Reviewed Original ResearchConceptsCentral nervous systemBrain metastasesActive brain lesionsNew immunomodulating agentsImmune checkpoint inhibitorsRole of immunotherapyPembrolizumab treatmentCheckpoint inhibitorsCNS lesionsReactive astrocytosisImmune suppressionPerilesional edemaInflammatory cellsMicroglial cellsImmunomodulating agentMental statusBrain lesionsHistologic evaluationMost trialsNervous systemCentral enhancementTumor cellsPatientsMetastasisLesions
2015
Clinical trials in melanoma patients with brain metastases
Yushak ML, Chiang VL, Kluger HM. Clinical trials in melanoma patients with brain metastases. Pigment Cell & Melanoma Research 2015, 28: 741-743. PMID: 26205399, PMCID: PMC4834841, DOI: 10.1111/pcmr.12401.Peer-Reviewed Original ResearchCharacterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites
Kluger HM, Zito CR, Barr ML, Baine MK, Chiang VL, Sznol M, Rimm DL, Chen L, Jilaveanu LB. Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites. Clinical Cancer Research 2015, 21: 3052-3060. PMID: 25788491, PMCID: PMC4490112, DOI: 10.1158/1078-0432.ccr-14-3073.Peer-Reviewed Original ResearchConceptsPD-L1 expressionT-cell contentPD-1/PD-L1 inhibitorsHigher T-cell contentT-cell infiltratesPD-L1 inhibitorsAnatomic sitesBrain metastasesMetastatic melanomaTissue microarrayHigh PD-L1 expressionLess PD-L1 expressionLow PD-L1 expressionTumor PD-L1 expressionHigher TIL contentImproved overall survivalT cell infiltrationLess T cellsMetastatic melanoma samplesExtracerebral metastasesCerebral metastasesOverall survivalDermal metastasesImproved survivalPD-L1
2013
Advances in therapy for melanoma brain metastases
Flanigan JC, Jilaveanu LB, Chiang VL, Kluger HM. Advances in therapy for melanoma brain metastases. Clinics In Dermatology 2013, 31: 264-281. PMID: 23608446, DOI: 10.1016/j.clindermatol.2012.08.008.Peer-Reviewed Original Research
2012
Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival.
Knisely JP, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VL. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. Journal Of Neurosurgery 2012, 117: 227-33. PMID: 22702482, PMCID: PMC6098938, DOI: 10.3171/2012.5.jns111929.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntineoplastic AgentsBrain NeoplasmsCombined Modality TherapyCompassionate Use TrialsDisease-Free SurvivalFemaleHumansIpilimumabMaleMelanomaMiddle AgedNeoplasm StagingPrognosisProportional Hazards ModelsRadiosurgeryRetreatmentRetrospective StudiesConceptsMelanoma brain metastasesBrain metastasesPerformance statusMedian survivalDiagnosis-Specific Graded Prognostic Assessment (DS-GPA) scoreInstitutional review board-approved chart reviewSurvival rateGraded Prognostic Assessment scoreBrain metastasis diagnosisPrognostic assessment scoreSurvival of patientsNumber of metastasesDS-GPA scoreRadiation therapy usePrimary disease locationBrain oligometastasesIpilimumab groupIpilimumab useSalvage WBRTChart reviewOverall survivalPatient ageSystemic therapyTherapy useClinical variables