Interdisciplinary management of central nervous system metastasis and neoplastic meningitis: recent developments and future perspectives

Abstract

The incidence of metastatic disease in the central nervous system (CNS) is rising. According to current estimates, up to a third of adult cancer patients will suffer from CNS metastasis. Clinical evidence-based data from prospective randomized trials are rare, however, because CNS metastasis patients were often excluded from clinical trial participation. The management of CNS metastasis patients is therefore rather ill-defined and an interdisciplinary challenge. Recent basic and translational science data have begun contributing to a more profound understanding of the molecular mechanisms leading to invasion of tumor cells into the CNS. This report reviews advances, challenges, and perspectives in this field.

Keywords

Brain tumor / central nervous system metastases / interdisciplinary management

References

[1] Giordana MT,Boghi A.Cerebral metastases as first symptom of cancer: a clinico-pathologic study..J neurooncol2000;50:265-73

[2] Johnson JD.Demographics of brain metastasis. Neurosurgery clinics of North America..Neurosurg Clin N Am1996;7:337-44

[3] Soffietti R,Delattre JY,Graus F,Heimans J,Hoskin P,Krauseneck P,Siegal T.EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force. European journal of neurology..Eur J Neurol2006;13:674-81

[4] Posner JB.Intracranial metastases from systemic cancer. Advances in neurology..Adv Neurol1978;19:579-92

[5] Percy AK.Neoplasms of the central nervous system: epidemiologic considerations..Neurology1970;20:398-9

[6] Fox BD,Patel AJ,Rao G.Epidemiology of metastatic brain tumors..Neurosurg Clin N Am2011;22:1-6

[7] Nayak L,Wen PY.Epidemiology of brain metastases. Current oncology reports..Curr Oncol Rep2012;14:48-54

[8] Margolin K,Hamid O,McDermott D,Wolchok JD,Sznol M,Richards J,Balogh A,Hodi FS.Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial..Lancet Oncol2012;13:459-65

[9] Tsao MN,Wong RK,Rakovitch E,Xu W.Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases..Cochrane Database Syst Rev2012;4:CD003869

[10] Brastianos HC,Brastianos PK.Systemic therapy of brain metastases..Curr Neurol Neurosci Rep2015;15:518

[11] Barnholtz-Sloan JS,Davis FG,Lai P.Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System..J Clin Oncol2004;22:2865-72

[12] Schouten LJ,Huveneers HA.Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma..Cancer2002;94:2698-705

[13] Nieder C,Mehta MP,Geinitz H.Presentation, patterns of care, and survival in patients with brain metastases: what has changed in the last 20 years?.Cancer2011;117:2505-12

[14] Pestalozzi BC.Trastuzumab in CSF..J Clin Oncol2000;18:2349-51

[15] Bria E,Fornier M,Carlini P,Sperduti I,Cognetti F.Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: the dark side of the moon? A meta-analysis of the randomized trials..Breast Cancer Res Treat2008;109:231-9

[16] Chamberlain MC.Neoplastic meningitis..Curr Neurol Neurosci Rep2008;8:249-58

[17] Chamberlain MC.Neoplastic meningitis and metastatic epidural spinal cord compression..Hematol Oncol Clin North Am2012;26:917-31

[18] Winkler F.The brain metastatic niche..J Mol Med2015;93:1213-20

[19] Kienast Y,Fuhrmann M,Goldbrunner R,Winkler F.Real-time imaging reveals the single steps of brain metastasis formation..Nat Med2010;16:116-22

[20] Kodack DP,Yamashita H,Duyverman AM,Farrar CT,Ager E,Goel S,Lussiez A,Mahmood S,Eichler AF,Engelman JA.Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases..Proc Natl Acad Sci U S A2012;109:E3119-27

[21] Fidler IJ,Lin Q,Kim SJ.The brain microenvironment and cancer metastasis..Mol Cells2010;30:93-8

[22] Park ES,Kim SW,Leem SH,Kim SM,Cheong JH,Mills GB,Lee JS.Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis..Proc Natl Acad Sci U S A2011;108:17456-61 PMCID:PMC3198333

[23] Zhang L,Yao J,Zhang Q,Li P,Wang X,Wang H,Cheerathodi M,Palmieri D,Lakhani S,Sahin AA,Steeg PS.Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth..Nature2015;527:100-4 PMCID:PMC4819404

[24] Galon J,Bindea G,Berger A,Lugli A,Hartmann A,Nagtegaal ID,Masucci GV,Tatangelo F,Maio M,Grizzi F,D'Arrigo C,Zavadova E,Ohashi PS,Wouters BG,Nguyen L,Hazama S,Ogino S,Waring P,Torigoe T,Patel PS,Wang Y,Sinicrope FA,Ascierto PA,Fox BA.Towards the introduction of the 'Immunoscore' in the classification of malignant tumours..J Pathol2014;232:199-209 PMCID:PMC4255306

[25] Li W.The molecular profile of microglia under the influence of glioma..Neuro Oncol2012;14:958-78 PMCID:PMC3408253

[26] Bienkowski M.Prognostic role of tumour-infiltrating inflammatory cells in brain tumours: literature review..Curr Opin Neurol2015;28:647-58

[27] Szulzewsky F,Feng X,Markovic D,Holtman IR,Eggen BJ,Hambardzumyan D,Kettenmann H.Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1..PLoS One2015;10:e0116644

[28] Niessner H,Klumpp B,Witte M,Dummer R,Bauer J,Flaherty K,Beck D,Mauch C,Weide B,Schadendorf D,Kulms D,Meier F.Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases..Cancer Med2013;2:76-85 PMCID:PMC3797558

[29] Chen G,Aardalen K,Tetzlaff MT,Kim SB,Ledoux AA,Pereira CG,Lee JS,Aldape KD,Stuart D.Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target..Clin Cancer Res2014;20:5537-46 PMCID:PMC4216765

[30] Saunus JM,Patch AM,Bailey PJ,McCart Reed AE,Wilson PJ,Mariasegaram M,Withers T,Reid LE,Matsika A,Cummings MC,Christ AN,Idrisoglu S,Nourse C,Wani S,Fink JL,Kazakoff S,Newell F,Waddell N,Xu Q,Narayanan V,Teo SH,kConFab,Brandner S,Khanna KK,Grimmond SM,Waddell N.Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance..J Pathol2015;237:363-78

[31] El-Deiry WS,Xiu J,Lim B,Harvey HA,Reddy S.Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites..Cancer Biol Ther2015;16:1726-37 PMCID:PMC4847814

[32] Lin NU,Aoyama H,Barboriak DP,Bendszus M,Camidge DR,Dancey J,Gaspar LE,Hodi FS,Linskey ME,Margolin K,Schiff D,Suh JH,Vogelbaum MA.Response assessment criteria for brain metastases: proposal from the RANO group..Lancet Oncol2015;16:e270-8

[33] Okada H,Huang R,Gilbert MR,Ellingson BM,Pollack IF,Franceschi E,Nayak L,Pope WB,Sampson JH,Reardon DA.Immunotherapy response assessment in neuro-oncology: a report of the RANO working group..Lancet Oncol2015;16:e534-42

[34] Kang TW,Byun HS,Kim K,Lee JI.Morphological and functional MRI, MRS, perfusion and diffusion changes after radiosurgery of brain metastasis..Eur J Radiol2009;72:370-80

[35] Hoefnagels FW,Sanchez E,Knol DL,Vandertop WP.Radiological progression of cerebral metastases after radiosurgery: assessment of perfusion MRI for differentiating between necrosis and recurrence..J Neurol2009;256:878-87 PMCID:PMC2698975

[36] Kruger S,Buck AK,Kley H,Wibmer T,Pauls S.Brain metastasis in lung cancer. Comparison of cerebral MRI and 18F-FDG-PET/CT for diagnosis in the initial staging..Nuklearmedizin2011;50:101-6

[37] Terakawa Y,Iwai Y,Higashiyama S,Ohata K.Diagnostic accuracy of ¹¹C-methionine PET for differentiation of recurrent brain tumors from radiation necrosis after radiotherapy..J Nucl Med2008;49:694-9

[38] Grosu AL,Riedel E,Wiedenmann N,Schwaiger M,Wester HJ.An interindividual comparison of O-(2-[18F]fluoroethyl)-L-tyrosine (FET)- and L-[methyl-11C]methionine (MET)-PET in patients with brain gliomas and metastases..Int J Radiat Oncol Biol Phys2011;81:1049-58

[39] Connell JJ,Cornelissen B,Hamilton A,Anthony DC.Selective permeabilization of the blood-brain barrier at sites of metastasis..J Natl Cancer Inst2013;105:1634-43 PMCID:PMC3818170

[40] Gaspar L,Rotman M,Phillips T,McKenna WG.Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials..Int J Radiat Oncol Biol Phys1997;37:745-51

[41] Sperduto PW,Gaspar LE,Curran W.A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database..Int J Radiat Oncol Biol Phys2008;70:510-4

[42] Sperduto PW,Roberge D,Shanley R,Sneed PK,Weil RJ,Bhatt A,Brown PD,Kirkpatrick J,Fiveash JB,Knisely JP,Lin N.Effect of tumor subtype on survival and the graded prognostic assessment for patients with breast cancer and brain metastases..Int J Radiat Oncol Biol Phys2012;82:2111-7 PMCID:PMC3172400

[43] Sperduto PW,Roberge D,Shanley R,Sneed PK,Weil RJ,Bhatt A,Brown PD,Kirkpatrick J,Fiveash JB,Knisely JP,Lin N.Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases..J Clin Oncol2012;30:419-25 PMCID:PMC3269967

[44] Herrlinger U,Kuker W,Bamberg M,Weller M.Leptomeningeal metastasis: survival and prognostic factors in 155 patients..J Neurol Sci2004;223:167-78

[45] Chamberlain MC,Glantz MJ.Neoplastic meningitis-related prognostic significance of the Karnofsky performance status..Arch Neurol2009;66:74-8

[46] Jaeckle KA.Neoplastic meningitis from systemic malignancies: diagnosis, prognosis and treatment..Semin Oncol2006;33:312-23

[47] Venur VA.Prognostic scores for brain metastasis patients: use in clinical practice and trial design..Chin Clin Oncol2015;4:18

[48] Eigentler TK,Krex D,Mauch C,Bostroem A,Koelbl O,Schadendorf D.Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma..Cancer2011;117:1697-703

[49] Marcus DM,Khan MK,Crocker IR,Melton A,Delman KA,Rizzo M.Prognostic factors for overall survival after radiosurgery for brain metastases from melanoma..Am J Clin Oncol2014;37:580-4

[50] Spanberger T,Dinhof C,Magerle M,Pichler J,Hackl M,Hainfellner JA,Marosi C,Prayer D.Extent of peritumoral brain edema correlates with prognosis, tumoral growth pattern, HIF1a expression and angiogenic activity in patients with single brain metastases..Clin Exp Metastasis2013;30:357-68

[51] Berghoff AS,Ilhan-Mutlu A,Hutterer M,Hackl M,Dieckmann K,Birner P,Preusser M.Preoperative diffusion-weighted imaging of single brain metastases correlates with patient survival times..PLoS One2013;8:e55464

[52] Zakaria R,Radon M,Rudland PR,Jenkinson MD.Diffusion-weighted MRI characteristics of the cerebral metastasis to brain boundary predicts patient outcomes..BMC Med Imaging2014;14:26 PMCID:PMC4126355

[53] Kalkanis SN,Gaspar LE,Asher AL,Ammirati M,Andrews DW,McDermott M,Mikkelsen T,Paleologos NA,Ryken TC.The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline..J Neurooncol2010;96:33-43 PMCID:PMC2808516

[54] Mintz AH,Rathbone MP,Hugenholtz H,Duncan G,Foster G.A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis..Cancer1996;78:1470-6

[55] Lagerwaard FJ,Nowak PJ,Hanssens PE.Identification of prognostic factors in patients with brain metastases: a review of 1292 patients..Int J Radiat Oncol Biol Phys1999;43:795-803

[56] Fife KM,Stevens GN,Moon D,Harman R,Zacest AC,Milton GW,Thompson JF.Determinants of outcome in melanoma patients with cerebral metastases..J Clin Oncol2004;22:1293-300

[57] Ranasinghe MG.Surgical management of brain metastases..Neurosurg Focus2007;22:E2

[58] Eisner W,Bale R,Koppelstatter F,Kolbitsch C.Use of neuronavigation and electrophysiology in surgery of subcortically located lesions in the sensorimotor strip..J Neurol Neurosurg Psychiatry2002;72:378-8 PMCID:PMC1737780

[59] Unsgaard G,Brostrup Muller T,Torp SH,Bang J.Ability of navigated 3D ultrasound to delineate gliomas and metastases--comparison of image interpretations with histopathology..Acta Neurochir (Wien)2005;147:1259-69;discussion 1269

[60] Kamp MA,Felsberg J,Steiger HJ,Sabel M.5-aminolevulinic acid (5-ALA)-induced fluorescence in intracerebral metastases: a retrospective study..Acta Neurochir (Wien)2012;154:223-8;discussion 228

[61] Patchell RA,Walsh JW,Maruyama Y,Markesbery WR,Young B.A Randomized Trial of Surgery in the Treatment of Single Metastases to the Brain..N Engl J Med1990;322:494-500

[62] Vecht CJ,Noordijk EM,Voormolen JH,Tans JT,Metsaars JA,Ronald Brand.Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery?.Ann Neurol1993;33:583-90

[63] Bindal RK,Leavens ME.Surgical treatment of multiple brain metastases..J Neurosurg1993;79:210-6

[64] Stark AM,Buhl R,Mehdorn HM.Surgical treatment for brain metastases: prognostic factors and survival in 177 patients..Neurosurg Rev2005;28:115-9

[65] Paek SH,Sperling MR,Andrews DW.Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques..Neurosurgery2005;56:1021-34;discussion1021-34

[66] Gulati S,Nerland US,Solheim O.The risk of getting worse: surgically acquired deficits, perioperative complications, and functional outcomes after primary resection of glioblastoma..World Neurosurg2011;76:572-9

[67] Kocher M,Abacioglu U,Fauchon F,Fariselli L,Kortmann RD,Ben Hassel M,Valeinis E,Collette S,Mueller RP.Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study..J Clin Oncol2011;29:134-41 PMCID:PMC3058272

[68] Chang EL,Hess KR,Lang FF,Arbuckle RB,Shiu AS,Meyers CA.Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial..Lancet Oncol2009;10:1037-44

[69] Stockham AL,Reddy CA,Kumar A,Barnett GH,Chao ST.Results of a questionnaire regarding practice patterns for the diagnosis and treatment of intracranial radiation necrosis after SRS..J Neurooncol2013;115:469-75

[70] Momose T,Kawabe T,Tanaka Y,Maehara T,Ishii K,Yamamoto M.Clinical benefit of 11C methionine PET imaging as a planning modality for radiosurgery of previously irradiated recurrent brain metastases..Clin Nucl Med2014;39:939-43

[71] Glantz MJ,Chamberlain MC,Recht L,Maria B,Schumann GB,Howell SB.A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors..Clin Cancer Res1999;5:3394-402

[72] Roth P,Weller M.Steroids in neurooncology: actions, indications, side-effects..Curr Opin Neurol2010;23:597-602

[73] Slamon DJ,Wong SG,Ullrich A.Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene..Science1987;235:177-82

[74] Pestalozzi BC,Price KN,Lindtner J,Crivellari D,Murray E,Simoncini E,Gelber RD,Goldhirsch A.Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG)..Ann Oncol2006;17:935-44

[75] Clayton AJ,Jolly S,Burt PA,Wilkinson PM,Magee B,Howell A.Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer..Br J Cancer2004;91:639-43 PMCID:PMC2364775

[76] Pierga JY,Cropet C,Dalenc F,Campone M,Le Rhun E,Leheurteur M,Gutierrez M,Ferrero JM,Bachelot T.Circulating tumor cells and brain metastasis outcome in patients with HER2-positive breast cancer: the LANDSCAPE trial..Ann Oncol2013;24:2999-3004

[77] Verma S,Gianni L,Welslau M,Pegram M,Dieras V,Fang L,Olsen S.Trastuzumab emtansine for HER2-positive advanced breast cancer..N Engl J Med2012;367:1783-91 PMCID:PMC5125250

[78] Krop IE,Blackwell K,Huober J,Miles D,Welslau M.Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA..Ann Oncol2015;26:113-9 PMCID:PMC4679405

[79] Burstein HJ,Dirix LY,Paridaens R,Awada A,Jiao S,Abbas R,Turnbull K,Zacharchuk C.Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer..J Clin Oncol2010;28:1301-7

[80] Leone JP.Breast cancer brain metastases: the last frontier..Exp Hematol Oncol2015;4:33 PMCID:PMC4657380

[81] Wang TJ,Qureshi YH,Nanda T,Rozenblat T,Bruce JN,Lesser J,Stoopler MB,Cheng SK.Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation?.Neuro Oncol2015;17:1022-8

[82] Pao W,Zakowski M,Politi K,Singh B,Rusch V,Mardis E,Wilson R,Varmus H.EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib..Proc Natl Acad Sci U S A2004;101:13306-11 PMCID:PMC516528

[83] Shaw AT,Mino-Kenudson M,Costa DB,Solomon B,Admane S,Settleman J,Mark EJ,Chirieac LR,Lynch TJ.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK..J Clin Oncol2009;27:4247-53 PMCID:PMC2744268

[84] Varella-Garcia M,Su PF,Iafrate AJ,Camidge DR,Haura EB,Khuri FR,Rudin CM,Schiller JH,Johnson BE,Kwiatkowski DJ.J Clin Oncol.2012;30, No 15_suppl:7589

[85] Togashi Y,Masuda S,Fukudo M,Sakamori Y,Kim YH,Mishima M.Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer..Cancer Chemother Pharmacol2012;70:399-405

[86] Lee DH,Lee HG,Lee EK,Kim HK,Lee JS.Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers..Clin Cancer Res2005;11:3032-7

[87] Kim JE,Choi Y,Kim SW,Lee JS.Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis..Lung Cancer2009;65:351-4

[88] Heon S,Lindeman NI,Butaney M,Costa DB,Jackman DM.The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations..Clin Cancer Res2012;18:4406-14 PMCID:PMC3682221

[89] Welsh JW,Amini A,Unger W,Chang JY,McGovern SL,Chen SS,Liao Z,Sulman E,Kim ES.Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer..J Clin Oncol2013;31:895-902 PMCID:PMC3577951

[90] Shaw AT,Nakagawa K,Crino L,De Pas T,Solomon BJ,Wu YL,O'Byrne KJ,Camidge DR,Hirsh V,Iyer S,Polli A,Jänne PA.N Engl J Med.2013;368:2385-94

[91] Solomon BJ,Kim DW,Nakagawa K,Felip E,Paolini J,Iyer S,Wilner KD,Blackhall F.First-line crizotinib versus chemotherapy in ALK-positive lung cancer..N Engl J Med2014;371:2167-77

[92] Soda M,Enomoto M,Yamashita Y,Fujiwara S,Kurashina K,Bando M,Ishikawa Y,Niki T,Sugiyama Y.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer..Nature2007;448:561-6

[93] Costa DB,Pandya SS,Shen Z,Wilner KD.CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib..J Clin Oncol2011;29:e443-5

[94] Costa DB,Ou SH,Riely GJ,Zhou C,Selaru P,Schnell P,Wiltshire R,Crino L.Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases..J Clin Oncol2015;33:1881-8 PMCID:PMC4451171

[95] Falk AT,Otto J,Barrière J.Adenocarcinoma of the lung with miliary brain and pulmonary metastases with echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase translocation treated with crizotinib: a case report..Lung Cancer2012;78:282-4

[96] Flaherty KT,Kim KB,McArthur GA,O'Dwyer PJ,Grippo JF,Chapman PB.Inhibition of mutated, activated BRAF in metastatic melanoma..N Engl J Med2010;363:809-19 PMCID:PMC3724529

[97] Dummer R,Turtschi CP,Michielin O,Veronese L,Felderer L.Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study..Eur J Cancer2014;50:611-21

[98] Kim DW,Mehta UN,Kumar AJ,Kim KB.Prolonged survival of a patient with metastatic leptomeningeal melanoma treated with BRAF inhibition-based therapy: a case report..BMC cancer2015;15:400 PMCID:PMC4440312

[99] Gibney GT,Ayas C,Wu EQ,Reyes C,Yim YM.Treatment patterns and outcomes in BRAF V600E-mutant melanoma patients with brain metastases receiving vemurafenib in the real-world setting..Cancer Med2015;4:1205-13 PMCID:PMC4559032

[100] Long GV,Davies MA,Ascierto PA,Puzanov I,Robert C,Mortier L,Wilhelm T,Switzky J,Martin AM,Goodman V,Kirkwood JM.Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial..Lancet Oncol2012;13:1087-95

[101] Ramanujam S,Long GV.Systemic therapies for melanoma brain metastases: which drug for whom and when?.Chin Clin Oncol2015;4:25

[102] Robert C,Bondarenko I,Weber J,Lebbe C,Testori A,Davidson N,Maio M,Miller WHJr,Lotem M,Ibrahim R,Chen TT,Hoos A.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma..N Engl J Med2011;364:2517-26

[103] Hodi FS,McDermott DF,Sosman JA,Gonzalez R,Schadendorf D,Akerley W,Lutzky J,Vaubel JM,Hogg D,Lebbe C,Quirt I,Wolchok JD,Tian J,Nichol GM,Urba WJ.Improved survival with ipilimumab in patients with metastatic melanoma..N Engl J Med2010;363:711-23 PMCID:PMC3549297

[104] Brown ES,Frol A,Khan DA,Rush AJ,Babcock E.Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy..Biol Psychiatry2004;55:538-45

[105] Brown ES.Effects of glucocorticoids on mood, memory, and the hippocampus. treatment and preventive therapy..Ann N Y Acad Sci2009;1179:41-55

[106] Dijkers EC,Kosterink JG,Jager PL,van Dongen GA,Lub-de Hooge MN.Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer..Clin Pharmacol Ther2010;87:586-92

[107] Gaykema SB,Lub-de Hooge MN,Timmer-Bosscha H,van Dam GM,de Jong JR,de Vries J,de Vries EG.89Zr-bevacizumab PET imaging in primary breast cancer..J Nucl Med2013;54:1014-8

[108] Lipsman N,Schwartz ML,Lozano AM.Intracranial applications of magnetic resonance-guided focused ultrasound..Neurotherapeutics2014;11:593-605 PMCID:PMC4121456

[109] Kobus T.Update on Clinical Magnetic Resonance-Guided Focused Ultrasound Applications..Magn Reson Imaging Clin N Am2015;23:657-67 PMCID:PMC4621790

[110] Werner B.Transcranial focused ultrasound : Neurological applications of magnetic resonance-guided high-intensity focused ultrasound..Radiologe2015;55:976-80,982-3

[111] Ba JL,Nesbit A,Chen M.Current and emerging treatments for brain metastases..Oncology2015;29:250-7