Advertisement

Journal of Neuro-Oncology

, Volume 93, Issue 1, pp 61–77 | Cite as

Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma

  • Scott R. Plotkin
  • Chris Halpin
  • Jaishri O. Blakeley
  • William H. SlatteryIII
  • D. Bradley Welling
  • Susan M. Chang
  • Jay S. Loeffler
  • Gordon J. Harris
  • A. Gregory Sorensen
  • Michael J. McKenna
  • Fred G. BarkerII
Topic Review

Abstract

Neurofibromatosis type 2 (NF2) is a tumor suppressor gene syndrome characterized by multiple schwannomas, especially vestibular schwannomas (VS), and meningiomas. Anticancer drug trials are now being explored, but there are no standardized endpoints in NF2. We review the challenges of NF2 clinical trials and suggest possible response criteria for use in initial phase II studies. We suggest two main response criteria in such trials. Objective radiographic response is defined as a durable 20% or greater reduction in VS volume based on post-contrast T1-weighted MRI images collected with 3 mm or finer cuts through the internal auditory canal. Hearing response is defined as a statistically significant improvement in word recognition scores using 50-word recorded lists in audiology. A possible composite endpoint incorporating both radiographic response and hearing response is outlined. We emphasize pitfalls in response assessment and suggest guidelines to minimize misinterpretations of response. We also identify research goals in NF2 to facilitate future trial conduct, such as identifying the expectations for time to tumor progression and time to measurable hearing loss in untreated NF2-related VS, and the relation of both endpoints to patient prognostic factors (such as age, baseline tumor volume, and measures of disease severity). These data would facilitate future use of endpoints based on stability of tumor size and hearing, which might be more appropriate for testing certain drugs. We encourage adoption of standardized endpoints early in the development of phase II trials for this population to facilitate comparison of results across trials of different agents.

Keywords

Vestibular schwannoma Acoustic neuroma Neurofibromatosis type 2 Trial design Phase II trial 

References

  1. 1.
    Central Brain Tumor Registry of the United States (2008) Statistical Report: primary brain tumors in the United States, 2000–2004. CBTRUS, Hinsdale, ILGoogle Scholar
  2. 2.
    Regis J, Roche P-H (eds) (2008) Modern management of acoustic neuroma. Karger, BaselGoogle Scholar
  3. 3.
    Evans DG, Moran A, King A, Saeed S, Gurusinghe N, Ramsden R (2005) Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol Neurotol 26:93–97. doi: 10.1097/00129492-200501000-00016 PubMedGoogle Scholar
  4. 4.
    Evans DG, Huson SM, Donnai D, Neary W, Blair V, Teare D, Newton V, Strachan T, Ramsden R, Harris R (1992) A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet 29:841–846. doi: 10.1136/jmg.29.12.841 PubMedGoogle Scholar
  5. 5.
    Barker FG II, Carter BS, Ojemann RG, Jyung RW, Poe DS, McKenna MJ (2003) Surgical excision of acoustic neuroma: patient outcome and provider caseload. Laryngoscope 113:1332–1343. doi: 10.1097/00005537-200308000-00013 PubMedGoogle Scholar
  6. 6.
    Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, Harris R (1992) A clinical study of type 2 neurofibromatosis. Q J Med 84:603–618PubMedGoogle Scholar
  7. 7.
    Otsuka G, Saito K, Nagatani T, Yoshida J (2003) Age at symptom onset and long-term survival in patients with neurofibromatosis Type 2. J Neurosurg 99:480–483PubMedGoogle Scholar
  8. 8.
    Baser ME, Friedman JM, Aeschliman D, Joe H, Wallace AJ, Ramsden RT, Evans DG (2002) Predictors of the risk of mortality in neurofibromatosis 2. Am J Hum Genet 71:715–723. doi: 10.1086/342716 PubMedGoogle Scholar
  9. 9.
    Samii M, Matthies C, Tatagiba M (1997) Management of vestibular schwannomas (acoustic neuromas): auditory and facial nerve function after resection of 120 vestibular schwannomas in patients with neurofibromatosis 2. Neurosurgery 40:696–705. doi: 10.1097/00006123-199704000-00007 discussion 705-696PubMedGoogle Scholar
  10. 10.
    Mathieu D, Kondziolka D, Flickinger JC, Niranjan A, Williamson R, Martin JJ, Lunsford LD (2007) Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, complications, and hearing preservation rates. Neurosurgery 60:460–468 discussion 468–470PubMedGoogle Scholar
  11. 11.
    Rowe J, Radatz M, Kemeny A (2008) Radiosurgery for type II neurofibromatosis. Prog Neurol Surg 21:176–182. doi: 10.1159/000156907 PubMedGoogle Scholar
  12. 12.
    Phi JH, Kim DG, Chung HT, Lee J, Paek SH, Jung HW (2009) Radiosurgical treatment of vestibular schwannomas in patients with neurofibromatosis type 2: tumor control and hearing preservation. Cancer 115:390–398. doi: 10.1002/cncr.24036 PubMedGoogle Scholar
  13. 13.
    Sobel RA (1993) Vestibular (acoustic) schwannomas: histologic features in neurofibromatosis 2 and in unilateral cases. J Neuropathol Exp Neurol 52:106–113. doi: 10.1097/00005072-199303000-00002 PubMedGoogle Scholar
  14. 14.
    Wechsler J, Lantieri L, Zeller J, Voisin MC, Martin-Garcia N, Wolkenstein P (2003) Aberrant axon neurofilaments in schwannomas associated with phacomatoses. Virchows Arch 443:768–773. doi: 10.1007/s00428-003-0895-y PubMedGoogle Scholar
  15. 15.
    Hamada Y, Iwaki T, Fukui M, Tateishi J (1997) A comparative study of embedded nerve tissue in six NF2-associated schwannomas and 17 nonassociated NF2 schwannomas. Surg Neurol 48:395–400. doi: 10.1016/S0090-3019(96)00487-9 PubMedGoogle Scholar
  16. 16.
    Jaaskelainen J, Paetau A, Pyykko I, Blomstedt G, Palva T, Troupp H (1994) Interface between the facial nerve and large acoustic neurinomas. Immunohistochemical study of the cleavage plane in NF2 and non-NF2 cases. J Neurosurg 80:541–547PubMedGoogle Scholar
  17. 17.
    Sakamoto T, Shirato H, Takeichi N, Aoyama H, Fukuda S, Miyasaka K (2001) Annual rate of hearing loss falls after fractionated stereotactic irradiation for vestibular schwannoma. Radiother Oncol 60:45–48. doi: 10.1016/S0167-8140(01)00375-9 PubMedGoogle Scholar
  18. 18.
    Combs SE, Volk S, Schulz-Ertner D, Huber PE, Thilmann C, Debus J (2005) Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): long-term results in 106 patients treated in a single institution. Int J Radiat Oncol Biol Phys 63:75–81. doi: 10.1016/j.ijrobp.2005.01.055 PubMedGoogle Scholar
  19. 19.
    Ju DT, Lin JW, Lin MS, Lee LM, Tseng HM, Wei CP, Yen CH, Hung CC, Hung KS, Lin CM, Lin TJ, Chiu WT, Tsai JT (2008) Hypofractionated CyberKnife stereotactic radiosurgery for acoustic neuromas with and without association to neurofibromatosis Type 2. Acta Neurochir Suppl (Wien) 101:169–173. doi: 10.1007/978-3-211-78205-7_29 Google Scholar
  20. 20.
    Chang SM, Lamborn KR, Kuhn JG, Yung WK, Gilbert MR, Wen PY, Fine HA, Mehta MP, DeAngelis LM, Lieberman FS, Cloughesy TF, Robins HI, Abrey LE, Prados MD (2008) Neurooncology clinical trial design for targeted therapies: lessons learned from the North American Brain Tumor Consortium. Neuro-Oncology 10:631–642. doi: 10.1215/15228517-2008-021 PubMedGoogle Scholar
  21. 21.
    Welling DB, Packer MD, Chang LS (2007) Molecular studies of vestibular schwannomas: a review. Curr Opin Otolaryngol Head Neck Surg 15:341–346. doi: 10.1097/MOO.0b013e3282b97310 PubMedGoogle Scholar
  22. 22.
    Neff BA, Welling DB, Akhmametyeva E, Chang LS (2006) The molecular biology of vestibular schwannomas: dissecting the pathogenic process at the molecular level. Otol Neurotol 27:197–208. doi: 10.1097/01.mao.0000180484.24242.54 PubMedGoogle Scholar
  23. 23.
    Caye-Thomasen P, Werther K, Nalla A, Bog-Hansen TC, Nielsen HJ, Stangerup SE, Thomsen J (2005) VEGF and VEGF receptor-1 concentration in vestibular schwannoma homogenates correlates to tumor growth rate. Otol Neurotol 26:98–101. doi: 10.1097/00129492-200501000-00017 PubMedGoogle Scholar
  24. 24.
    Scoles DR (2008) The merlin interacting proteins reveal multiple targets for NF2 therapy. Biochim Biophys Acta 1785:32–54PubMedGoogle Scholar
  25. 25.
    Hanemann CO (2008) Magic but treatable? Tumours due to loss of merlin. Brain 131:606–615. doi: 10.1093/brain/awm249 PubMedGoogle Scholar
  26. 26.
    Doherty JK, Ongkeko W, Crawley B, Andalibi A, Ryan AF (2008) ErbB and Nrg: potential molecular targets for vestibular schwannoma pharmacotherapy. Otol Neurotol 29:50–57PubMedGoogle Scholar
  27. 27.
    Plotkin SR, Halpin CF, McKenna MJ, Batchelor TT, Loeffler JS, Barker FG (2008) Treatment of progressive NF2-related vestibular schwannoma with erlotinib. J Clin Oncol 26(15 Suppl 1):100s, (Abstract 2045)Google Scholar
  28. 28.
    Plotkin SR, Singh MA, O’Donnell CC, Harris GJ, McClatchey AI, Halpin C (2008) Audiologic and radiographic response of NF2-related vestibular schwannoma to erlotinib therapy. Nat Clin Pract Oncol 5:487–491. doi: 10.1038/ncponc1157 PubMedGoogle Scholar
  29. 29.
    Plotkin SR, Halpin C, Stemmer-Rachamimoff A, Barker F, Sorensen G, Jain R, Di Tomaso E (2008) Activity of bevacizumab against NF2-related vestibular schwannomas. Neuro-Oncology 10:796. [Abstract ET-51]Google Scholar
  30. 30.
    Freidlin B, Simon R (2005) Evaluation of randomized discontinuation design. J Clin Oncol 23:5094–5098. doi: 10.1200/JCO.2005.02.520 PubMedGoogle Scholar
  31. 31.
    Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA (2005) Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol 23:7199–7206. doi: 10.1200/JCO.2005.01.149 PubMedGoogle Scholar
  32. 32.
    Jones B, Kenward MG (2003) Design and analysis of cross-over trials, 2nd edn. Chapman & Hall, Boca Raton, FLGoogle Scholar
  33. 33.
    Stadler WM (2007) The randomized discontinuation trial: a phase II design to assess growth-inhibitory agents. Mol Cancer Ther 6:1180–1185. doi: 10.1158/1535-7163.MCT-06-0249 PubMedGoogle Scholar
  34. 34.
    Koutras AK, Mastronikolis NS, Evans TR, Papadeas ES, Makatsoris T, Kalofonos HP (2008) Irreversible ototoxicity associated with the use of erlotinib in a patient with pancreatic cancer. Acta Oncol 47:1171–1173. doi: 10.1080/02841860802213328 PubMedGoogle Scholar
  35. 35.
    Nayfield SG, Gorin MB (1996) Tamoxifen-associated eye disease. A review. J Clin Oncol 14:1018–1026PubMedGoogle Scholar
  36. 36.
    Vickers AJ, Ballen V, Scher HI (2007) Setting the bar in phase II trials: the use of historical data for determining “go/no go” decision for definitive phase III testing. Clin Cancer Res 13:972–976. doi: 10.1158/1078-0432.CCR-06-0909 PubMedGoogle Scholar
  37. 37.
    Buyse M, Thirion P, Carlson RW, Burzykowski T, Molenberghs G, Piedbois P (2000) Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet 356:373–378. doi: 10.1016/S0140-6736(00)02528-9 PubMedGoogle Scholar
  38. 38.
    Paesmans M, Sculier JP, Libert P, Bureau G, Dabouis G, Thiriaux J, Michel J, Van Cutsem O, Sergysels R, Mommen P, Klastersky J (1997) Response to chemotherapy has predictive value for further survival of patients with advanced non-small cell lung cancer: 10 years experience of the European Lung Cancer Working Party. Eur J Cancer 33:2326–2332. doi: 10.1016/S0959-8049(97)00325-0 PubMedGoogle Scholar
  39. 39.
    Burzykowski T, Buyse M, Piccart-Gebhart MJ, Sledge G, Carmichael J, Luck HJ, Mackey JR, Nabholtz JM, Paridaens R, Biganzoli L, Jassem J, Bontenbal M, Bonneterre J, Chan S, Basaran GA, Therasse P (2008) Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol 26:1987–1992. doi: 10.1200/JCO.2007.10.8407 PubMedGoogle Scholar
  40. 40.
    Johnson KR, Ringland C, Stokes BJ, Anthony DM, Freemantle N, Irs A, Hill SR, Ward RL (2006) Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet Oncol 7:741–746. doi: 10.1016/S1470-2045(06)70800-2 PubMedGoogle Scholar
  41. 41.
    Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9:453–461. doi: 10.1016/S1470-2045(08)70125-6 PubMedGoogle Scholar
  42. 42.
    de Wit MC, de Bruin HG, Eijkenboom W, Sillevis Smitt PA, van den Bent MJ (2004) Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 63:535–537PubMedGoogle Scholar
  43. 43.
    Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD (2008) Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro-Oncology 10:162–170. doi: 10.1215/15228517-2007-062 PubMedGoogle Scholar
  44. 44.
    Levin VA, Ictech S, Hess KR (2007) Impact of phase II trials with progression-free survival as end-points on survival-based phase III studies in patients with anaplastic gliomas. BMC Cancer 7:106. doi: 10.1186/1471-2407-7-106 PubMedGoogle Scholar
  45. 45.
    Ballman KV, Buckner JC, Brown PD, Giannini C, Flynn PJ, LaPlant BR, Jaeckle KA (2007) The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro-Oncology 9:29–38. doi: 10.1215/15228517-2006-025 PubMedGoogle Scholar
  46. 46.
    Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Benjamin RS (2007) Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 25:1753–1759. doi: 10.1200/JCO.2006.07.3049 PubMedGoogle Scholar
  47. 47.
    Benjamin RS, Choi H, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Charnsangavej C (2007) We should desist using RECIST, at least in GIST. J Clin Oncol 25:1760–1764. doi: 10.1200/JCO.2006.07.3411 PubMedGoogle Scholar
  48. 48.
    Schuetze SM, Rubin BP, Vernon C, Hawkins DS, Bruckner JD, Conrad EU III, Eary JF (2005) Use of positron emission tomography in localized extremity soft tissue sarcoma treated with neoadjuvant chemotherapy. Cancer 103:339–348. doi: 10.1002/cncr.20769 PubMedGoogle Scholar
  49. 49.
    Gerstner ER, Sorensen AG, Jain RK, Batchelor TT (2008) Advances in neuroimaging techniques for the evaluation of tumor growth, vascular permeability, and angiogenesis in gliomas. Curr Opin Neurol 21:728–735. doi: 10.1097/WCO.0b013e328318402a PubMedGoogle Scholar
  50. 50.
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95. doi: 10.1016/j.ccr.2006.11.021 PubMedGoogle Scholar
  51. 51.
    Sorensen AG, Batchelor TT, Wen PY, Zhang WT, Jain RK (2008) Response criteria for glioma. Nat Clin Pract Oncol 5:634–644. doi: 10.1038/ncponc1204 PubMedGoogle Scholar
  52. 52.
    Abaza MM, Makariou E, Armstrong M, Lalwani AK (1996) Growth rate characteristics of acoustic neuromas associated with neurofibromatosis type 2. Laryngoscope 106:694–699. doi: 10.1097/00005537-199606000-00007 PubMedGoogle Scholar
  53. 53.
    Masuda A, Fisher LM, Oppenheimer ML, Iqbal Z, Slattery WH (2004) Hearing changes after diagnosis in neurofibromatosis type 2. Otol Neurotol 25:150–154. doi: 10.1097/00129492-200403000-00012 PubMedGoogle Scholar
  54. 54.
    Hajioff D, Raut VV, Walsh RM, Bath AP, Bance ML, Guha A, Tator CH, Rutka JA (2008) Conservative management of vestibular schwannomas: third review of a 10-year prospective study. Clin Otolaryngol 33:255–259. doi: 10.1111/j.1749-4486.2008.01705.x PubMedGoogle Scholar
  55. 55.
    Massick DD, Welling DB, Dodson EE, Scholfield M, Nagaraja HN, Schmalbrock P, Chakeres DW (2000) Tumor growth and audiometric change in vestibular schwannomas managed conservatively. Laryngoscope 110:1843–1849. doi: 10.1097/00005537-200011000-00015 PubMedGoogle Scholar
  56. 56.
    Walsh RM, Bath AP, Bance ML, Keller A, Rutka JA (2000) Consequences to hearing during the conservative management of vestibular schwannomas. Laryngoscope 110:250–255. doi: 10.1097/00005537-200002010-00012 PubMedGoogle Scholar
  57. 57.
    Tschudi DC, Linder TE, Fisch U (2000) Conservative management of unilateral acoustic neuromas. Am J Otol 21:722–728PubMedGoogle Scholar
  58. 58.
    Sampath P, Holliday MJ, Brem H, Niparko JK, Long DM (1997) Facial nerve injury in acoustic neuroma (vestibular schwannoma) surgery: etiology and prevention. J Neurosurg 87:60–66PubMedGoogle Scholar
  59. 59.
    Mautner VF, Baser ME, Thakkar SD, Feigen UM, Friedman JM, Kluwe L (2002) Vestibular schwannoma growth in patients with neurofibromatosis Type 2: a longitudinal study. J Neurosurg 96:223–228PubMedGoogle Scholar
  60. 60.
    Slattery WH III, Fisher LM, Iqbal Z, Oppenhiemer M (2004) Vestibular schwannoma growth rates in neurofibromatosis type 2 natural history consortium subjects. Otol Neurotol 25:811–817. doi: 10.1097/00129492-200409000-00027 PubMedGoogle Scholar
  61. 61.
    Linskey ME, Lunsford LD, Flickinger JC (1992) Tumor control after stereotactic radiosurgery in neurofibromatosis patients with bilateral acoustic tumors. Neurosurgery 31:829–838. doi: 10.1097/00006123-199211000-00002 discussion 838–829PubMedGoogle Scholar
  62. 62.
    Baser ME, Makariou EV, Parry DM (2002) Predictors of vestibular schwannoma growth in patients with neurofibromatosis Type 2. J Neurosurg 96:217–222PubMedGoogle Scholar
  63. 63.
    Kida Y, Kobayashi T, Tanaka T, Mori Y (2000) Radiosurgery for bilateral neurinomas associated with neurofibromatosis type 2. Surg Neurol 53:383–389. doi: 10.1016/S0090-3019(00)00174-9 discussion 389–390PubMedGoogle Scholar
  64. 64.
    Baser ME, Mautner VF, Parry DM, Evans DG (2005) Methodological issues in longitudinal studies: vestibular schwannoma growth rates in neurofibromatosis 2. J Med Genet 42:903–906. doi: 10.1136/jmg.2005.031302 PubMedGoogle Scholar
  65. 65.
    Rowe JG, Radatz MW, Walton L, Soanes T, Rodgers J, Kemeny AA (2003) Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry 74:1288–1293. doi: 10.1136/jnnp.74.9.1288 PubMedGoogle Scholar
  66. 66.
    Bederson JB, von Ammon K, Wichmann WW, Yasargil MG (1991) Conservative treatment of patients with acoustic tumors. Neurosurgery 28:646–651. doi: 10.1097/00006123-199105000-00002 PubMedGoogle Scholar
  67. 67.
    Battaglia A, Mastrodimos B, Cueva R (2006) Comparison of growth patterns of acoustic neuromas with and without radiosurgery. Otol Neurotol 27:705–712. doi: 10.1097/01.mao.0000226302.59198.87 PubMedGoogle Scholar
  68. 68.
    Yoshimoto Y (2005) Systematic review of the natural history of vestibular schwannoma. J Neurosurg 103:59–63PubMedGoogle Scholar
  69. 69.
    Smouha EE, Yoo M, Mohr K, Davis RP (2005) Conservative management of acoustic neuroma: a meta-analysis and proposed treatment algorithm. Laryngoscope 115:450–454. doi: 10.1097/00005537-200503000-00011 PubMedGoogle Scholar
  70. 70.
    Meiteles LZ, Liu JK, Couldwell WT (2002) Hearing restoration after resection of an intracanalicular vestibular schwannoma: a role for emergency surgery? Case report and review of the literature. J Neurosurg 96:796–800PubMedCrossRefGoogle Scholar
  71. 71.
    Niranjan A, Lunsford LD, Flickinger JC, Maitz A, Kondziolka D (1999) Can hearing improve after acoustic tumor radiosurgery? Neurosurg Clin N Am 10:305–315PubMedGoogle Scholar
  72. 72.
    Stidham KR, Roberson JB Jr (2001) Hearing improvement after middle fossa resection of vestibular schwannoma. Otol Neurotol 22:917–921. doi: 10.1097/00129492-200111000-00035 PubMedGoogle Scholar
  73. 73.
    Inoue Y, Ogawa K, Kanzaki J (2003) Hearing improvement after tumor removal in a vestibular schwannoma patient with severe hearing loss. Eur Arch Otorhinolaryngol 260:487–489. doi: 10.1007/s00405-003-0583-1 PubMedGoogle Scholar
  74. 74.
    Fischer G, Costantini JL, Mercier P (1980) Improvement of hearing after microsurgical removal of acoustic neurinoma. Neurosurgery 7:154–159. doi: 10.1097/00006123-198008000-00008 PubMedGoogle Scholar
  75. 75.
    Shelton C, House WF (1990) Hearing improvement after acoustic tumor removal. Otolaryngol Head Neck Surg 103:963–965PubMedGoogle Scholar
  76. 76.
    Telian SA, Kemink JL, Kileny P (1988) Hearing recovery following suboccipital excision of acoustic neuroma. Arch Otolaryngol Head Neck Surg 114:85–87PubMedGoogle Scholar
  77. 77.
    Gray R, Manola J, Saxman S, Wright J, Dutcher J, Atkins M, Carducci M, See W, Sweeney C, Liu G, Stein M, Dreicer R, Wilding G, DiPaola RS (2006) Phase II clinical trial design: methods in translational research from the Genitourinary Committee at the Eastern Cooperative Oncology Group. Clin Cancer Res 12:1966–1969. doi: 10.1158/1078-0432.CCR-05-1136 PubMedGoogle Scholar
  78. 78.
    Charabi S, Thomsen J, Mantoni M, Charabi B, Jorgensen B, Borgesen SE, Gyldensted C, Tos M (1995) Acoustic neuroma (vestibular schwannoma): growth and surgical and nonsurgical consequences of the wait-and-see policy. Otolaryngol Head Neck Surg 113:5–14. doi: 10.1016/S0194-5998(95)70138-9 PubMedGoogle Scholar
  79. 79.
    Luetje CM (2000) Spontaneous involution of acoustic tumors. Am J Otol 21:393–398. doi: 10.1016/S0196-0709(00)80050-2 PubMedGoogle Scholar
  80. 80.
    Yasumoto Y, Ito M (2006) Spontaneous regression of a growing vestibular schwannoma. Neurol Med Chir (Tokyo) 46:601–604. doi: 10.2176/nmc.46.601 Google Scholar
  81. 81.
    Redleaf MI, McCabe BF (1993) Disappearing recurrent acoustic neuroma in an elderly woman. Ann Otol Rhinol Laryngol 102:518–520PubMedGoogle Scholar
  82. 82.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216. doi: 10.1093/jnci/92.3.205 PubMedGoogle Scholar
  83. 83.
    Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214. doi: 10.1002/1097-0142(19810101)47:1<207::AID-CNCR2820470134>3.0.CO;2-6 PubMedGoogle Scholar
  84. 84.
    Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  85. 85.
    Shah GD, Kesari S, Xu R, Batchelor TT, O’Neill AM, Hochberg FH, Levy B, Bradshaw J, Wen PY (2006) Comparison of linear and volumetric criteria in assessing tumor response in adult high-grade gliomas. Neuro-Oncology 8:38–46. doi: 10.1215/S1522851705000529 PubMedGoogle Scholar
  86. 86.
    Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J (2006) The natural history of vestibular schwannoma. Otol Neurotol 27:547–552. doi: 10.1097/00129492-200606000-00018 PubMedGoogle Scholar
  87. 87.
    Marshall AH, Owen VM, Nikolopoulos TP, O’Donoghue GM (2005) Acoustic schwannomas: awareness of radiologic error will reduce unnecessary treatment. Otol Neurotol 26:512–515. doi: 10.1097/01.mao.0000169782.69341.6d PubMedGoogle Scholar
  88. 88.
    Walsh RM, Bath AP, Bance ML, Keller A, Tator CH, Rutka JA (2000) The natural history of untreated vestibular schwannomas. Is there a role for conservative management? Rev Laryngol Otol Rhinol (Bord) 121:21–26Google Scholar
  89. 89.
    Harris GJ, Plotkin SR, Maccollin M, Bhat S, Urban T, Lev MH, Slattery WH (2008) Three-dimensional volumetrics for tracking vestibular schwannoma growth in neurofibromatosis type II. Neurosurgery 62:1314–1319. doi: 10.1227/01.neu.0000316266.97714.da discussion 1319–1320PubMedGoogle Scholar
  90. 90.
    Committee on Hearing and Equilibrium (1995) guidelines for the evaluation of hearing preservation in acoustic neuroma (vestibular schwannoma). American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc. Otolaryngol Head Neck Surg 113:179–180. doi: 10.1016/S0194-5998(95)70101-X
  91. 91.
    Roche PH, Robitail S, Regis J (2007) Two- and three dimensional measures of vestibular schwannomas and posterior fossa—implications for the treatment. Acta Neurochir (Wien) 149:267–273. doi: 10.1007/s00701-006-1093-x discussion 273Google Scholar
  92. 92.
    Slattery WH, Lev MH, Fisher LM, Connell SS, Iqbal Z, Go JL (2005) MRI evaluation of neurofibromatosis 2 patients: a standardized approach for accuracy in interpretation. Otol Neurotol 26:733–740. doi: 10.1097/01.mao.0000169048.15889.80 PubMedGoogle Scholar
  93. 93.
    Snell JW, Sheehan J, Stroila M, Steiner L (2006) Assessment of imaging studies used with radiosurgery: a volumetric algorithm and an estimation of its error. Technical note. J Neurosurg 104:157–162. doi: 10.3171/jns.2006.104.1.157 PubMedGoogle Scholar
  94. 94.
    Henson JW, Ulmer S, Harris GJ (2008) Brain tumor imaging in clinical trials. AJNR Am J Neuroradiol 29:419–424. doi: 10.3174/ajnr.A0963 PubMedGoogle Scholar
  95. 95.
    Babovic-Vuksanovic D, Ballman K, Michels V, McGrann P, Lindor N, King B, Camp J, Micic V, Babovic N, Carrero X, Spinner R, O’Neill B (2006) Phase II trial of pirfenidone in adults with neurofibromatosis type 1. Neurology 67:1860–1862. doi: 10.1212/01.wnl.0000243231.12248.67 PubMedGoogle Scholar
  96. 96.
    Babovic-Vuksanovic D, Widemann BC, Dombi E, Gillespie A, Wolters PL, Toledo-Tamula MA, O’Neill BP, Fox E, MacDonald T, Beck H, Packer RJ (2007) Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas. Pediatr Neurol 36:293–300. doi: 10.1016/j.pediatrneurol.2007.01.009 PubMedGoogle Scholar
  97. 97.
    Barlow JH, Turner AP, Hammond CL, Gailey L (2007) Living with late deafness: insight from between worlds. Int J Audiol 46:442–448. doi: 10.1080/14992020701355108 PubMedGoogle Scholar
  98. 98.
    Petrou S, McCann D, Law CM, Watkin PM, Worsfold S, Kennedy CR (2007) Health status and health-related quality of life preference-based outcomes of children who are aged 7 to 9 years and have bilateral permanent childhood hearing impairment. Pediatrics 120:1044–1052. doi: 10.1542/peds.2007-0159 PubMedGoogle Scholar
  99. 99.
    Chia EM, Wang JJ, Rochtchina E, Cumming RR, Newall P, Mitchell P (2007) Hearing impairment and health-related quality of life: the Blue Mountains Hearing Study. Ear Hear 28:187–195. doi: 10.1097/AUD.0b013e31803126b6 PubMedGoogle Scholar
  100. 100.
    Dalton DS, Cruickshanks KJ, Klein BE, Klein R, Wiley TL, Nondahl DM (2003) The impact of hearing loss on quality of life in older adults. Gerontologist 43:661–668PubMedGoogle Scholar
  101. 101.
    Mulrow CD, Aguilar C, Endicott JE, Velez R, Tuley MR, Charlip WS, Hill JA (1990) Association between hearing impairment and the quality of life of elderly individuals. J Am Geriatr Soc 38:45–50PubMedGoogle Scholar
  102. 102.
    Ringdahl A, Grimby A (2000) Severe-profound hearing impairment and health-related quality of life among post-lingual deafened Swedish adults. Scand Audiol 29:266–275. doi: 10.1080/010503900750022907 PubMedGoogle Scholar
  103. 103.
    Vermeire K, Brokx JP, Wuyts FL, Cochet E, Hofkens A, Van de Heyning PH (2005) Quality-of-life benefit from cochlear implantation in the elderly. Otol Neurotol 26:188–195. doi: 10.1097/00129492-200503000-00010 PubMedGoogle Scholar
  104. 104.
    Lassaletta L, Castro A, Bastarrica M, de Sarria MJ, Gavilan J (2006) Quality of life in postlingually deaf patients following cochlear implantation. Eur Arch Otorhinolaryngol 263:267–270. doi: 10.1007/s00405-005-0987-1 PubMedGoogle Scholar
  105. 105.
    Shin YJ, Fraysse B, Deguine O, Vales O, Laborde ML, Bouccara D, Sterkers O, Uziel A (2000) Benefits of cochlear implantation in elderly patients. Otolaryngol Head Neck Surg 122:602–606. doi: 10.1016/S0194-5998(00)70112-4 PubMedGoogle Scholar
  106. 106.
    Metselaar M, Maat B, Krijnen P, Verschuure H, Dreschler WA, Feenstra L (2009) Self-reported disability and handicap after hearing-aid fitting and benefit of hearing aids: comparison of fitting procedures, degree of hearing loss, experience with hearing aids and uni- and bilateral fittings. Eur Arch Otorhinolaryngol. doi:  10.1007/s00405-008-0847-x
  107. 107.
    Klop WM, Boermans PP, Ferrier MB, van den Hout WB, Stiggelbout AM, Frijns JH (2008) Clinical relevance of quality of life outcome in cochlear implantation in postlingually deafened adults. Otol Neurotol 29:615–621PubMedGoogle Scholar
  108. 108.
    Chisolm TH, Johnson CE, Danhauer JL, Portz LJ, Abrams HB, Lesner S, McCarthy PA, Newman CW (2007) A systematic review of health-related quality of life and hearing aids: final report of the American Academy of Audiology Task Force On the Health-Related Quality of Life Benefits of Amplification in Adults. J Am Acad Audiol 18:151–183. doi: 10.3766/jaaa.18.2.7 PubMedGoogle Scholar
  109. 109.
    Morzaria S, Westerberg BD, Anzarut A (2003) Quality of life following ear surgery measured by the 36-item Short Form Health Survey and the Glasgow Benefit Inventory. J Otolaryngol 32:323–327. doi: 10.2310/7070.2003.11435 PubMedGoogle Scholar
  110. 110.
    Joore MA, Brunenberg DE, Chenault MN, Anteunis LJ (2003) Societal effects of hearing aid fitting among the moderately hearing impaired. Int J Audiol 42:152–160PubMedGoogle Scholar
  111. 111.
    Uyama K, Takahashi M, Saito A, Okada Y, Tomizawa I, Kanzaki J (1991) Questionnaire evaluation of balance in the performance of everyday activities after acoustic neuroma surgery. Acta Otolaryngol Suppl 487:91–98. doi: 10.3109/00016489109130452 PubMedGoogle Scholar
  112. 112.
    Myrseth E, Moller P, Wentzel-Larsen T, Goplen F, Lund-Johansen M (2006) Untreated vestibular schwannomas: vertigo is a powerful predictor for health-related quality of life. Neurosurgery 59:67–76. doi: 10.1227/01.NEU.0000219838.80931.6B discussion 67–76PubMedGoogle Scholar
  113. 113.
    McCombe A, Baguley D, Coles R, McKenna L, McKinney C, Windle-Taylor P (2001) Guidelines for the grading of tinnitus severity: the results of a working group commissioned by the British Association of Otolaryngologists, Head and Neck Surgeons, 1999. Clin Otolaryngol Allied Sci 26:388–393. doi: 10.1046/j.1365-2273.2001.00490.x PubMedGoogle Scholar
  114. 114.
    Andersson G, Ekvall L, Kinnefors A, Nyberg G, Rask-Andersen H (1997) Evaluation of quality of life and symptoms after translabyrinthine acoustic neuroma surgery. Am J Otol 18:421–426PubMedGoogle Scholar
  115. 115.
    Rigby PL, Shah SB, Jackler RK, Chung JH, Cooke DD (1997) Acoustic neuroma surgery: outcome analysis of patient-perceived disability. Am J Otol 18:427–435PubMedGoogle Scholar
  116. 116.
    House JW, Brackmann DE (1985) Facial nerve grading system. Otolaryngol Head Neck Surg 93:146–147PubMedGoogle Scholar
  117. 117.
    Lassaletta L, Alfonso C, Del Rio L, Roda JM, Gavilan J (2006) Impact of facial dysfunction on quality of life after vestibular schwannoma surgery. Ann Otol Rhinol Laryngol 115:694–698PubMedGoogle Scholar
  118. 118.
    Ryzenman JM, Pensak ML, Tew JM Jr (2004) Patient perception of comorbid conditions after acoustic neuroma management: survey results from the acoustic neuroma association. Laryngoscope 114:814–820. doi: 10.1097/00005537-200405000-00005 PubMedGoogle Scholar
  119. 119.
    Tufarelli D, Meli A, Alesii A, De Angelis E, Badaracco C, Falcioni M, Sanna M (2006) Quality of life after acoustic neuroma surgery. Otol Neurotol 27:403–409. doi: 10.1097/00129492-200604000-00018 PubMedGoogle Scholar
  120. 120.
    Fisher LM, Doherty JK, Lev MH, Slattery WH III (2007) Distribution of nonvestibular cranial nerve schwannomas in neurofibromatosis 2. Otol Neurotol 28:1083–1090PubMedGoogle Scholar
  121. 121.
    Gardner G, Robertson JH (1988) Hearing preservation in unilateral acoustic neuroma surgery. Ann Otol Rhinol Laryngol 97:55–66PubMedGoogle Scholar
  122. 122.
    Robinson K, Gatehouse S, Browning GG (1996) Measuring patient benefit from otorhinolaryngological surgery and therapy. Ann Otol Rhinol Laryngol 105:415–422PubMedGoogle Scholar
  123. 123.
    Hawthorne G, Hogan A (2002) Measuring disability-specific patient benefit in cochlear implant programs: developing a short form of the Glasgow Health Status Inventory, the Hearing Participation Scale. Int J Audiol 41:535–544PubMedCrossRefGoogle Scholar
  124. 124.
    Stewart MG (2001) Outcomes and patient-based hearing status in conductive hearing loss. Laryngoscope 111:1–21. doi: 10.1097/00005537-200111001-00001 PubMedGoogle Scholar
  125. 125.
    Zhao F, Bai Z, Stephens D (2008) The relationship between changes in self-rated quality of life after cochlear implantation and changes in individual complaints. Clin Otolaryngol 33:427–434. doi: 10.1111/j.1749-4486.2008.01773.x PubMedGoogle Scholar
  126. 126.
    Mahmud MR, Khan AM, Nadol JB Jr (2003) Histopathology of the inner ear in unoperated acoustic neuroma. Ann Otol Rhinol Laryngol 112:979–986PubMedGoogle Scholar
  127. 127.
    Caye-Thomasen P, Dethloff T, Hansen S, Stangerup SE, Thomsen J (2007) Hearing in patients with intracanalicular vestibular schwannomas. Audiol Neurootol 12:1–12. doi: 10.1159/000096152 PubMedGoogle Scholar
  128. 128.
    Wei BP, Mubiru S, O’Leary S (2006) Steroids for idiopathic sudden sensorineural hearing loss. Cochrane Database Syst Rev: CD003998Google Scholar
  129. 129.
    Pollock BE (2006) Management of vestibular schwannomas that enlarge after stereotactic radiosurgery: treatment recommendations based on a 15 year experience. Neurosurgery 58:241–248. doi: 10.1227/01.NEU.0000194833.66593.8B discussion 241–248PubMedGoogle Scholar
  130. 130.
    Hasegawa T, Kida Y, Yoshimoto M, Koike J, Goto K (2006) Evaluation of tumor expansion after stereotactic radiosurgery in patients harboring vestibular schwannomas. Neurosurgery 58:1119–1128. doi: 10.1227/01.NEU.0000215947.35646.DD discussion 1119–1128PubMedGoogle Scholar
  131. 131.
    Delsanti C, Tamura M, Galanaud D, Regis J (2004) Changing radiological results, pitfalls and criteria of failure. Neurochirurgie 50:312–319PubMedGoogle Scholar
  132. 132.
    Nakamura H, Jokura H, Takahashi K, Boku N, Akabane A, Yoshimoto T (2000) Serial follow-up MR imaging after gamma knife radiosurgery for vestibular schwannoma. AJNR Am J Neuroradiol 21:1540–1546PubMedGoogle Scholar
  133. 133.
    Yang SY, Kim DG, Chung HT, Park SH, Paek SH, Jung HW (2008) Evaluation of tumour response after gamma knife radiosurgery for residual vestibular schwannomas based on MRI morphological features. J Neurol Neurosurg Psychiatry 79:431–436. doi: 10.1136/jnnp.2007.119602 PubMedGoogle Scholar
  134. 134.
    Kondziolka D, Lunsford LD, McLaughlin MR, Flickinger JC (1998) Long-term outcomes after radiosurgery for acoustic neuromas. N Engl J Med 339:1426–1433. doi: 10.1056/NEJM199811123392003 PubMedGoogle Scholar
  135. 135.
    Meijer OW, Weijmans EJ, Knol DL, Slotman BJ, Barkhof F, Vandertop WP, Castelijns JA (2008) Tumor-volume changes after radiosurgery for vestibular schwannoma: implications for follow-up MR imaging protocol. AJNR Am J Neuroradiol 29:906–910. doi: 10.3174/ajnr.A0969 PubMedGoogle Scholar
  136. 136.
    Brors D, Schafers M, Bodmer D, Draf W, Kahle G, Schick B (2003) Postoperative magnetic resonance imaging findings after transtemporal and translabyrinthine vestibular schwannoma resection. Laryngoscope 113:420–426. doi: 10.1097/00005537-200303000-00006 PubMedGoogle Scholar
  137. 137.
    Weissman JL, Hirsch BE, Fukui MB, Rudy TE (1997) The evolving MR appearance of structures in the internal auditory canal after removal of an acoustic neuroma. AJNR Am J Neuroradiol 18:313–323PubMedGoogle Scholar
  138. 138.
    Smith M, Castillo M, Campbell J, Pillsbury H, Walters T (1995) Baseline and follow-up MRI of the internal auditory canal after suboccipital resection of acoustic schwannoma: appearances and clinical correlations. Neuroradiology 37:317–320. doi: 10.1007/BF00588345 PubMedGoogle Scholar
  139. 139.
    Bennett ML, Jackson CG, Kaufmann R, Warren F (2008) Postoperative imaging of vestibular schwannomas. Otolaryngol Head Neck Surg 138:667–671. doi: 10.1016/j.otohns.2008.01.012 PubMedGoogle Scholar
  140. 140.
    Umezu H, Seki Y (1999) Postoperative magnetic resonance imaging after acoustic neuroma surgery: influence of packing materials in the drilled internal auditory canal on assessment of residual tumor. Neurol Med Chir (Tokyo) 39:141–147. doi: 10.2176/nmc.39.141 discussion 147–149Google Scholar
  141. 141.
    Hirsh IJ, Davis H, Silverman SR, Reynolds EG, Eldert E, Benson RW (1952) Development of materials for speech audiometry. J Speech Hear Disord 17:321–337PubMedGoogle Scholar
  142. 142.
    Tillman T, Carhart R (1966) An expanded test for speech discrimination utilizing CNC monosyllabic words. Northwestern University Auditory test #6; Technical Report SAM-TR-66-55. USAF School of Aerospace Medicine, Brooks Air Force Base, TXGoogle Scholar
  143. 143.
    Causey GD, Hood LJ, Hermanson CL, Bowling LS (1984) The Maryland CNC Test: normative studies. Audiology 23:552–568. doi: 10.3109/00206098409081538 PubMedGoogle Scholar
  144. 144.
    De Cardenas M, Marrero V (1994) Cuaderno de logoaudiometria. Universidad Nacional de Educacion a Distancia, MadridGoogle Scholar
  145. 145.
    Halpin C (2008) Measuring audiometric outcomes. In: Shin J, Hartnick G, Randolph G (eds) Evidence based otolaryngology. Springer, New York, pp 227–238Google Scholar
  146. 146.
    Monsell EM (1995) New and revised reporting guidelines from the Committee on Hearing and Equilibrium. American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc. Otolaryngol Head Neck Surg 113:176–178. doi: 10.1016/S0194-5998(95)70100-1 PubMedGoogle Scholar
  147. 147.
    Thornton AR, Raffin MJ (1978) Speech-discrimination scores modeled as a binomial variable. J Speech Hear Res 21:507–518PubMedGoogle Scholar
  148. 148.
    Halpin C, Rauch SD (2006) Using audiometric thresholds and word recognition in a treatment study. Otol Neurotol 27:110–116. doi: 10.1097/00129492-200601000-00020 PubMedGoogle Scholar
  149. 149.
    Aronzon A, Ruckenstein MJ, Bigelow DC (2003) The efficacy of corticosteroids in restoring hearing in patients undergoing conservative management of acoustic neuromas. Otol Neurotol 24:465–468. doi: 10.1097/00129492-200305000-00018 PubMedGoogle Scholar
  150. 150.
    Nageris BI, Popovtzer A (2003) Acoustic neuroma in patients with completely resolved sudden hearing loss. Ann Otol Rhinol Laryngol 112:395–397PubMedGoogle Scholar
  151. 151.
    Gaffney RJ, McShane DP (1996) Bilateral acoustic neurofibromatosis camouflaged by corticosteroid treatment of sudden sensorineural hearing loss. Ir J Med Sci 165:151–152. doi: 10.1007/BF02940237 PubMedGoogle Scholar
  152. 152.
    Riccardi VM (1987) Mast-cell stabilization to decrease neurofibroma growth. Preliminary experience with ketotifen. Arch Dermatol 123:1011–1016. doi: 10.1001/archderm.123.8.1011 PubMedGoogle Scholar
  153. 153.
    Jahrsdoerfer RA, Benjamin RS (1988) Chemotherapy of bilateral acoustic neuromas. Otolaryngol Head Neck Surg 98:273–282PubMedGoogle Scholar
  154. 154.
    El-Maraghi RH, Eisenhauer EA (2008) Review of phase II trial designs used in studies of molecular targeted agents: outcomes and predictors of success in phase III. J Clin Oncol 26:1346–1354. doi: 10.1200/JCO.2007.13.5913 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Scott R. Plotkin
    • 1
  • Chris Halpin
    • 2
  • Jaishri O. Blakeley
    • 3
  • William H. SlatteryIII
    • 4
  • D. Bradley Welling
    • 5
  • Susan M. Chang
    • 6
  • Jay S. Loeffler
    • 7
  • Gordon J. Harris
    • 8
  • A. Gregory Sorensen
    • 8
  • Michael J. McKenna
    • 9
  • Fred G. BarkerII
    • 10
  1. 1.Department of Neurology and Cancer CenterMassachusetts General HospitalBostonUSA
  2. 2.Audiology DepartmentMassachusetts Eye and Ear InfirmaryBostonUSA
  3. 3.Department of NeurologyJohns Hopkins Medical InstituteBaltimoreUSA
  4. 4.Department of OtolaryngologyHouse Ear InstituteLos AngelesUSA
  5. 5.Department of OtolaryngologyOhio State UniversityColumbusUSA
  6. 6.Department of Neurological SurgeryUniversity of CaliforniaSan FranciscoUSA
  7. 7.Department of Radiation OncologyMassachusetts General HospitalBostonUSA
  8. 8.Department of RadiologyMassachusetts General HospitalBostonUSA
  9. 9.Department of OtolaryngologyMassachusetts Eye and Ear InfirmaryBostonUSA
  10. 10.Neurosurgical Service, Pappas Center for Neuro-Oncology, Yawkey 9EMassachusetts General HospitalBostonUSA

Personalised recommendations