2021
An Open Source, Automated Tumor Infiltrating Lymphocyte Algorithm for Prognosis in Triple-Negative Breast Cancer
Bai Y, Cole K, Martinez-Morilla S, Ahmed FS, Zugazagoitia J, Staaf J, Bosch A, Ehinger A, Nimeus E, Hartman J, Acs B, Rimm DL. An Open Source, Automated Tumor Infiltrating Lymphocyte Algorithm for Prognosis in Triple-Negative Breast Cancer. Clinical Cancer Research 2021, 27: clincanres.0325.2021. PMID: 34088723, PMCID: PMC8530841, DOI: 10.1158/1078-0432.ccr-21-0325.Peer-Reviewed Original Research
2020
Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy
Liu Y, Zugazagoitia J, Ahmed FS, Henick BS, Gettinger S, Herbst RS, Schalper KA, Rimm DL. Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy. Clinical Cancer Research 2020, 26: 970-977. PMID: 31615933, PMCID: PMC7024671, DOI: 10.1158/1078-0432.ccr-19-1040.Peer-Reviewed Original ResearchConceptsPD-L1 expressionHigh PD-L1 expressionPD-L1 levelsPD-L1Immune cellsTumor cellsT cellsHigh PD-L1 levelsPredominant immune cell typeNon-small cell lung cancer (NSCLC) casesDifferent immune cell subsetsCell lung cancer casesElevated PD-L1High PD-L1Better overall survivalDeath ligand 1Natural killer cellsImmune cell subsetsMultiple immune cellsCytotoxic T cellsLung cancer casesImmune cell typesCD68 levelsCell typesBlockade therapy
2019
An open source automated tumor infiltrating lymphocyte algorithm for prognosis in melanoma
Acs B, Ahmed FS, Gupta S, Wong P, Gartrell RD, Sarin Pradhan J, Rizk EM, Gould Rothberg BE, Saenger YM, Rimm DL. An open source automated tumor infiltrating lymphocyte algorithm for prognosis in melanoma. Nature Communications 2019, 10: 5440. PMID: 31784511, PMCID: PMC6884485, DOI: 10.1038/s41467-019-13043-2.Peer-Reviewed Original ResearchConceptsOpen sourceOpen source softwareSource softwareTIL scoreTraining setDisease-specific overall survivalHigh TIL scorePoor prognosis cohortsSubset of patientsAlgorithmIndependent prognostic markerBroad adoptionAssessment of tumorOverall survivalFavorable prognosisMelanoma patientsMultivariable analysisValidation cohortIndependent associationPrognostic markerSeparate patientsPrognostic variablesIndependent cohortRetrospective collectionMelanomaDeep Learning Based on Standard H&E Images of Primary Melanoma Tumors Identifies Patients at Risk for Visceral Recurrence and Death
Kulkarni PM, Robinson EJ, Pradhan J, Gartrell-Corrado RD, Rohr BR, Trager MH, Geskin LJ, Kluger HM, Wong PF, Acs B, Rizk EM, Yang C, Mondal M, Moore MR, Osman I, Phelps R, Horst BA, Chen ZS, Ferringer T, Rimm DL, Wang J, Saenger YM. Deep Learning Based on Standard H&E Images of Primary Melanoma Tumors Identifies Patients at Risk for Visceral Recurrence and Death. Clinical Cancer Research 2019, 26: 1126-1134. PMID: 31636101, PMCID: PMC8142811, DOI: 10.1158/1078-0432.ccr-19-1495.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAlgorithmsArea Under CurveBiopsyDeep LearningDisease ProgressionFemaleFollow-Up StudiesHumansImage Processing, Computer-AssistedMaleMelanomaMiddle AgedNeoplasm Recurrence, LocalNeural Networks, ComputerRetrospective StudiesRisk FactorsStaining and LabelingSurvival RateYoung AdultConceptsDeep neural network architectureNeural network architectureDeep learningNetwork architectureComputational modelImage sequencesDigital imagesVote aggregationDisease-specific survivalDSS predictionPractical advancesComputational methodsIHC-based methodsImagesGeisinger Health SystemNovel methodGHS patientsArchitectureLearningKaplan-Meier analysisPrimary melanoma tumorsEarly-stage melanomaClinical trial designModelAdjuvant immunotherapyExpression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non–Small Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell Analysis
Datar I, Sanmamed MF, Wang J, Henick BS, Choi J, Badri T, Dong W, Mani N, Toki M, Mejías L, Lozano MD, Perez-Gracia JL, Velcheti V, Hellmann MD, Gainor JF, McEachern K, Jenkins D, Syrigos K, Politi K, Gettinger S, Rimm DL, Herbst RS, Melero I, Chen L, Schalper KA. Expression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non–Small Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell Analysis. Clinical Cancer Research 2019, 25: 4663-4673. PMID: 31053602, PMCID: PMC7444693, DOI: 10.1158/1078-0432.ccr-18-4142.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, CDBiomarkers, TumorCarcinoma, Non-Small-Cell LungGene Expression Regulation, NeoplasticHepatitis A Virus Cellular Receptor 2HumansLung NeoplasmsLymphocyte ActivationLymphocyte Activation Gene 3 ProteinLymphocytes, Tumor-InfiltratingPrognosisProgrammed Cell Death 1 ReceptorRetrospective StudiesSingle-Cell AnalysisSurvival RateConceptsNon-small cell lung cancerHuman non-small cell lung cancerTumor-infiltrating lymphocytesAdvanced non-small cell lung cancerTim-3PD-1Cell lung cancerLAG-3Lung cancerPD-1 axis blockadeShorter progression-free survivalBaseline samplesTim-3 protein expressionMajor clinicopathologic variablesMultiplexed quantitative immunofluorescencePD-1 expressionProgression-free survivalTim-3 expressionLAG-3 expressionT-cell phenotypeTumor mutational burdenImmune inhibitory receptorsImmune evasion pathwaysTIM-3 proteinMass cytometry analysis
2018
Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations
Toki MI, Mani N, Smithy JW, Liu Y, Altan M, Wasserman B, Tuktamyshov R, Schalper K, Syrigos KN, Rimm DL. Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations. Journal Of Thoracic Oncology 2018, 13: 1884-1896. PMID: 30267840, PMCID: PMC6251746, DOI: 10.1016/j.jtho.2018.09.012.Peer-Reviewed Original ResearchConceptsPD-L1 expressionPD-L1TIL activationHigh PD-L1 levelsDeath ligand 1 (PD-L1) expressionActivation statusKRAS wild-type tumorsKRAS mutantEGFR mutantsHigh PD-L1Multiplexed quantitative immunofluorescenceUnique immune profilePD-L1 levelsLigand 1 expressionDeath-1/EGFR-mutant tumorsImmunotherapy response ratesKRAS mutant tumorsWild-type tumorsHigher CD4NSCLC patientsImmune profileClinical efficacyKRAS WTLymphocyte populations
2014
EGFR expression is associated with decreased benefit from trastuzumab in the NCCTG N9831 (Alliance) trial
Cheng H, Ballman K, Vassilakopoulou M, Dueck AC, Reinholz MM, Tenner K, Gralow J, Hudis C, Davidson NE, Fountzilas G, McCullough AE, Chen B, Psyrri A, Rimm DL, Perez EA. EGFR expression is associated with decreased benefit from trastuzumab in the NCCTG N9831 (Alliance) trial. British Journal Of Cancer 2014, 111: 1065-1071. PMID: 25117817, PMCID: PMC4453859, DOI: 10.1038/bjc.2014.442.Peer-Reviewed Original ResearchConceptsNorth Central Cancer Treatment GroupMetastatic breast cancer cohortEpidermal growth factor receptorBreast cancer cohortHigh EGFR expressionEGFR expressionConcurrent trastuzumabGrowth factor receptorCancer cohortEGFR antibodyNCCTG N9831 trialsAnti-HER2 therapyCancer Treatment GroupDisease-free survivalFactor receptorN9831 trialsSequential trastuzumabAdditive therapyArm AClinical outcomesTreatment optionsWorse outcomesArm CTissue microarrayTreatment groupsCorrelation of Somatic Mutations and Clinical Outcome in Melanoma Patients Treated with Carboplatin, Paclitaxel, and Sorafenib
Wilson MA, Zhao F, Letrero R, D'Andrea K, Rimm DL, Kirkwood JM, Kluger HM, Lee SJ, Schuchter LM, Flaherty KT, Nathanson KL. Correlation of Somatic Mutations and Clinical Outcome in Melanoma Patients Treated with Carboplatin, Paclitaxel, and Sorafenib. Clinical Cancer Research 2014, 20: 3328-3337. PMID: 24714776, PMCID: PMC4058354, DOI: 10.1158/1078-0432.ccr-14-0093.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCarboplatinDouble-Blind MethodFemaleFollow-Up StudiesGenotypeGTP PhosphohydrolasesHumansMaleMelanomaMembrane ProteinsMiddle AgedMutationNeoplasm StagingNiacinamidePaclitaxelPhenylurea CompoundsPrognosisProto-Oncogene Proteins B-rafSkin NeoplasmsSorafenibSurvival RateConceptsProgression-free survivalNRAS-mutant melanomaPlatelet-derived growth factor receptorPerformance statusClinical outcomesNRAS mutationsCox proportional hazards modelVEGF receptorsSomatic mutationsWorse performance statusGood performance statusImproved clinical responseKaplan-Meier methodClinical trial populationsPretreatment tumor samplesSite of diseaseProportional hazards modelEffect of sorafenibBRAF-mutant melanomaFisher's exact testGrowth factor receptorClinical responseOverall survivalClinicopathologic featuresMelanoma patients
2011
Lymph Node Ratio Should Be Considered for Incorporation into Staging for Breast Cancer
Chagpar AB, Camp RL, Rimm DL. Lymph Node Ratio Should Be Considered for Incorporation into Staging for Breast Cancer. Annals Of Surgical Oncology 2011, 18: 3143. PMID: 21847696, DOI: 10.1245/s10434-011-2012-9.Peer-Reviewed Original ResearchConceptsNode-positive breast cancer patientsDifferent OS ratesOverall survivalBreast cancer patientsOS independentClinicopathologic factorsOS ratesCancer patientsBreast cancer staging systemCurrent American Joint CommitteeLymph node ratioAdditional prognostic informationAmerican Joint CommitteeCancer (AJCC) staging systemTraditional clinicopathologic factorsPN statusIntermediate riskNodal statusStaging systemPrognostic informationBreast cancerHigh riskLower riskJoint CommitteeNode ratioEvaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts
Baquero MT, Lostritto K, Gustavson MD, Bassi KA, Appia F, Camp RL, Molinaro AM, Harris LN, Rimm DL. Evaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts. Breast Cancer Research 2011, 13: r85. PMID: 21888627, PMCID: PMC3262195, DOI: 10.1186/bcr2937.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsCohort StudiesCyclophosphamideCytoplasmDocetaxelDoxorubicinEpithelial CellsFemaleFluorouracilHumansKaplan-Meier EstimateMiddle AgedPredictive Value of TestsPrognosisRandomized Controlled Trials as TopicRetrospective StudiesSurvival RateTau ProteinsTaxoidsConceptsOverall survivalBreast cancer cohortTreatment armsPredictive markerCancer cohortPredictive valueResponse rateConventional whole tissue sectionsMAP-tauImproved overall survivalHigh expressionMicrotubule associated protein tauTaxane-based chemotherapyKaplan-Meier analysisLonger median timeUseful predictive markerCox univariate analysisIndependent breast cancer cohortsWhole tissue sectionsFAC chemotherapyLonger TTPMedian timeMeier analysisPrognostic valueClinicopathologic variables
2010
Nuclear Localization of Signal Transducer and Activator of Transcription 3 in Head and Neck Squamous Cell Carcinoma Is Associated with a Better Prognosis
Pectasides E, Egloff AM, Sasaki C, Kountourakis P, Burtness B, Fountzilas G, Dafni U, Zaramboukas T, Rampias T, Rimm D, Grandis J, Psyrri A. Nuclear Localization of Signal Transducer and Activator of Transcription 3 in Head and Neck Squamous Cell Carcinoma Is Associated with a Better Prognosis. Clinical Cancer Research 2010, 16: 2427-2434. PMID: 20371693, PMCID: PMC3030188, DOI: 10.1158/1078-0432.ccr-09-2658.Peer-Reviewed Original ResearchConceptsLonger progression-free survivalNeck squamous cell cancerNeck squamous cell carcinomaProgression-free survivalSquamous cell cancerSquamous cell carcinomaPittsburgh Medical CenterTranscription 3Early Detection Research NetworkCurative intentPrognostic roleSurgical resectionBetter prognosisSignal transducerCell cancerCell carcinomaFavorable outcomeSurvival prognosisClinicopathologic parametersMedical CenterIndependent cohortLower riskTest cohortHNSCCSurvival analysis
2009
Melanoma Prognostic Model Using Tissue Microarrays and Genetic Algorithms
Rothberg BE, Berger AJ, Molinaro AM, Subtil A, Krauthammer MO, Camp RL, Bradley WR, Ariyan S, Kluger HM, Rimm DL. Melanoma Prognostic Model Using Tissue Microarrays and Genetic Algorithms. Journal Of Clinical Oncology 2009, 27: 5772-5780. PMID: 19884546, PMCID: PMC2792999, DOI: 10.1200/jco.2009.22.8239.Peer-Reviewed Original ResearchConceptsHigh-risk groupGrowth factor receptor-bound protein-7 (Grb7) as a prognostic marker and therapeutic target in breast cancer
Nadler Y, González AM, Camp RL, Rimm DL, Kluger HM, Kluger Y. Growth factor receptor-bound protein-7 (Grb7) as a prognostic marker and therapeutic target in breast cancer. Annals Of Oncology 2009, 21: 466-473. PMID: 19717535, PMCID: PMC2826097, DOI: 10.1093/annonc/mdp346.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiomarkers, TumorBlotting, WesternBreast NeoplasmsCarcinoma, Ductal, BreastCarcinoma, LobularFemaleFluorescent Antibody TechniqueFollow-Up StudiesGRB7 Adaptor ProteinHumansImage Processing, Computer-AssistedMiddle AgedPrognosisReceptor, ErbB-2Survival RateTissue Array AnalysisTumor Cells, CulturedYoung AdultConceptsHER2/neuBreast cancerPrognostic markerHER2/neu-positive breast cancerGRB7 expressionHigh HER2/neuNeu-positive breast cancerHER2/neu overexpressionPrimary breast cancerBreast cancer patientsIndependent prognostic markerNode-positive subsetValuable prognostic markerProtein 7Cy5-conjugated antibodiesMultivariable analysisWorse prognosisEntire cohortCancer patientsNeu overexpressionTissue microarrayTherapeutic targetCancerNeuPatients
2008
High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer
Ghosh S, Sullivan CA, Zerkowski MP, Molinaro AM, Rimm DL, Camp RL, Chung GG. High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. Human Pathology 2008, 39: 1835-1843. PMID: 18715621, PMCID: PMC2632946, DOI: 10.1016/j.humpath.2008.06.004.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiomarkers, TumorBreast NeoplasmsCarcinoma, Ductal, BreastCarcinoma, LobularConnecticutFemaleFluorescent Antibody Technique, IndirectHumansImage Processing, Computer-AssistedImmunoenzyme TechniquesKaplan-Meier EstimateMiddle AgedNeuropilin-1Receptors, Vascular Endothelial Growth FactorSurvival RateTissue Array AnalysisVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth Factor Receptor-2Young AdultConceptsVascular endothelial growth factorEndothelial growth factorBreast cancerVEGFR-1Growth factorNeuropilin-1VEGFR-2Kaplan-Meier survival analysisBreast cancer tissue microarrayVascular endothelial growth factor receptorPrimary breast cancerStandard prognostic factorsEndothelial growth factor receptorPrimary breast adenocarcinomaCancer tissue microarrayTumor-specific expressionGrowth factor receptorPrognostic factorsPrognostic significancePrognostic valueWorse outcomesLarge cohortTissue microarraySurvival analysisSignificant association
2007
Melanophages reside in hypermelanotic, aberrantly glycosylated tumor areas and predict improved outcome in primary cutaneous malignant melanoma
Handerson T, Berger A, Harigopol M, Rimm D, Nishigori C, Ueda M, Miyoshi E, Taniguchi N, Pawelek J. Melanophages reside in hypermelanotic, aberrantly glycosylated tumor areas and predict improved outcome in primary cutaneous malignant melanoma. Journal Of Cutaneous Pathology 2007, 34: 679-686. PMID: 17696914, DOI: 10.1111/j.1600-0560.2006.00681.x.Peer-Reviewed Original ResearchConceptsCutaneous malignant melanomaPrimary cutaneous malignant melanomaImproved outcomesMalignant melanomaMelanoma cellsAnti-tumor roleMelanoma tissue microarrayFollow-upWorse outcomesPatient outcomesPoor survivalTissue microarrayBetter outcomesMyeloid cellsImmune systemMelanophagesTumor areaMelanomaCancer cellsMelanoma biologyOutcomesAberrant glycosylationCell typesCellsTumor region
2006
Evaluation of the Prognostic Value of Cellular Inhibitor of Apoptosis Protein in Epithelial Ovarian Cancer Using Automated Quantitative Protein Analysis
Psyrri A, Yu Z, Bamias A, Weinberger PM, Markakis S, Kowalski D, Camp RL, Rimm DL, Dimopoulos MA. Evaluation of the Prognostic Value of Cellular Inhibitor of Apoptosis Protein in Epithelial Ovarian Cancer Using Automated Quantitative Protein Analysis. Cancer Epidemiology Biomarkers & Prevention 2006, 15: 1179-1183. PMID: 16775178, DOI: 10.1158/1055-9965.epi-06-0120.Peer-Reviewed Original ResearchConceptsEpithelial ovarian cancerOvarian cancerPrognostic valuePaclitaxel-based combination chemotherapyOnly significant prognostic factorAdvanced stage ovarian cancerSignificant prognostic factorsOvarian cancer patientsProtein levelsImportant prognostic biomarkerMean followSurgical debulkingCombination chemotherapyOverall survivalPrognostic factorsClinical outcomesMultivariable analysisEntire cohortCancer patientsPrognostic biomarkerPrognostic variablesMembranous expressionApoptosis proteinSurvival rateCellular inhibitorVascular endothelial growth factor, FLT‐1, and FLK‐1 analysis in a pancreatic cancer tissue microarray
Chung GG, Yoon HH, Zerkowski MP, Ghosh S, Thomas L, Harigopal M, Charette LA, Salem RR, Camp RL, Rimm DL, Burtness BA. Vascular endothelial growth factor, FLT‐1, and FLK‐1 analysis in a pancreatic cancer tissue microarray. Cancer 2006, 106: 1677-1684. PMID: 16532435, DOI: 10.1002/cncr.21783.Peer-Reviewed Original ResearchConceptsPancreatic cancer tissue microarrayCancer tissue microarrayTissue microarrayVEGF receptor 1Flt-1Receptor 1Kaplan-Meier survival curvesVascular endothelial growth factor (VEGF) expressionIndependent prognostic factorVascular endothelial growth factorFlk-1Growth factor expressionEndothelial growth factorPrimary antibodyFlt-1 expressionOverall survivalPrognostic factorsWorse survivalAggressive diseaseDisease stagePoor prognosisTumor expressionPancreatic cancerPancreatic adenocarcinomaPrincipal receptor
2005
Subcellular Localization and Protein Levels of Cyclin-Dependent Kinase Inhibitor p27 Independently Predict for Survival in Epithelial Ovarian Cancer
Psyrri A, Bamias A, Yu Z, Weinberger PM, Kassar M, Markakis S, Kowalski D, Efstathiou E, Camp RL, Rimm DL, Dimopoulos MA. Subcellular Localization and Protein Levels of Cyclin-Dependent Kinase Inhibitor p27 Independently Predict for Survival in Epithelial Ovarian Cancer. Clinical Cancer Research 2005, 11: 8384-8390. PMID: 16322299, DOI: 10.1158/1078-0432.ccr-05-1270.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiomarkers, TumorCell DifferentiationCohort StudiesCombined Modality TherapyCyclin-Dependent Kinase Inhibitor p27Cystadenocarcinoma, SerousFemaleHumansMiddle AgedNeoplasm StagingNeoplasms, Glandular and EpithelialOvarian NeoplasmsPrognosisSubcellular FractionsSurvival RateTissue Array AnalysisConceptsNuclear p27 expressionOvarian cancerP27 expression levelsOverall survivalP27 expressionPlatinum-paclitaxel combination chemotherapyAdvanced stage ovarian cancerDisease-free survivalSignificant prognostic factorsStage ovarian cancerEpithelial ovarian cancerValuable prognostic biomarkerExpression levelsP27 protein expressionCyclin-dependent kinase inhibitor p27Mean followSurgical debulkingCombination chemotherapyPrognostic factorsMultivariable analysisPrognostic valueImmunohistochemical assessmentPrognostic biomarkerPrognostic variablesImmunofluorescence-based method
2004
Automated Quantitative Analysis of Tissue Microarrays Reveals an Association between High Bcl-2 Expression and Improved Outcome in Melanoma
Divito KA, Berger AJ, Camp RL, Dolled-Filhart M, Rimm DL, Kluger HM. Automated Quantitative Analysis of Tissue Microarrays Reveals an Association between High Bcl-2 Expression and Improved Outcome in Melanoma. Cancer Research 2004, 64: 8773-8777. PMID: 15574790, DOI: 10.1158/0008-5472.can-04-1387.Peer-Reviewed Original ResearchConceptsBcl-2 expressionHigh Bcl-2 expressionTissue microarrayMetastatic specimensResponse rateSmall cohortProgression-free survivalImproved response ratesLarge patient cohortMelanoma patientsClark levelEntire cohortBreslow depthClinical variablesPatient cohortMetastatic melanomaContinuous index scoreBetter outcomesIndex scoreMelanoma specimensCohortMelanomaBcl-2PatientsOutcomesAutomated Quantitative Analysis of HDM2 Expression in Malignant Melanoma Shows Association with Early-Stage Disease and Improved Outcome
Berger AJ, Camp RL, DiVito KA, Kluger HM, Halaban R, Rimm DL. Automated Quantitative Analysis of HDM2 Expression in Malignant Melanoma Shows Association with Early-Stage Disease and Improved Outcome. Cancer Research 2004, 64: 8767-8772. PMID: 15574789, DOI: 10.1158/0008-5472.can-04-1384.Peer-Reviewed Original ResearchConceptsMurine double minute 2Double minute 2Protein expressionMalignant melanomaMinute 2Early-stage diseaseTissue microarray cohortPotential tissue biomarkersCutaneous malignant melanomaValuable prognostic toolNormal skin samplesSkin cancer deathsMicroarray cohortAdvanced melanomaMetastatic lesionsCancer deathPrimary melanomaImproved outcomesExpression of HDM2Tissue biomarkersPrognostic toolBetter outcomesMelanoma lesionsAggressive natureMelanoma