Download PDF
Semin Neurol 2020; 40(03): 315-321
DOI: 10.1055/s-0040-1708867
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Neurocognitive Outcomes in Children with Brain Tumors

Cassie N. Kline
1   Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, California
2   Division of Child Neurology, Department of Neurology, University of California, San Francisco, San Francisco, California
,
Sabine Mueller
1   Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, California
2   Division of Child Neurology, Department of Neurology, University of California, San Francisco, San Francisco, California
3   Division of Neurological Surgery, University of California, San Francisco, San Francisco, California
4   Division of Oncology, University Children's Hospital of Zuerich, Zuerich, Switzerland
› Author Affiliations Funding C.N.K. is supported by grants from the Frank A. Campini Foundation, Cannonball Kids’ Cancer Foundation (A129749), and National Institutes of Health National Center for Advancing Translational Sciences (KL2TR001870). This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Further Information

Publication History

Publication Date:
11 May 2020 (online)

    Permissions and Reprints

Abstract

Brain tumors are the most common solid tumor in childhood, and although survival outcomes continue to improve, survival is frequently offset by devastating late effects from tumor and treatment. The long-term effects of brain tumors and the therapy necessary to treat them range from sensory and neuroendocrine abnormalities to neurocognitive deficits leading to inferior quality of life. The multifactorial neurocognitive injury is one of the most broadly impacting and challenging late effects to predict and subsequently treat. Certain treatment modalities, such as intrathecal methotrexate and radiation, have been shown to be associated with poor neurocognition; however, long-term outcomes remain highly variable. There are efforts underway to investigate how to better predict, identify, and manage such neurocognitive injury in survivors of pediatric brain tumors. Herein, we focus on the current knowledge of neurocognitive outcomes and potential treatment strategies for this high-risk group.

Keywords

pediatric brain tumors - neurocognition - late effects - cranial radiation therapy
 

  • References

  • 1 Ostrom QT, Gittleman H, Fulop J. , et al. CBTRUS Statistical Report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-oncol 2015; 17 (Suppl. 04) iv1-iv62
    PubMedSearch in Google Scholar
  • 2 Ostrom QT, Gittleman H, Liao P. , et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-oncol 2014; 16 (Suppl. 04) iv1-iv63
    PubMedSearch in Google Scholar
  • 3 Bandopadhayay P, Bergthold G, London WB. , et al. Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer 2014; 61 (07) 1173-1179
    CrossrefPubMedSearch in Google Scholar
  • 4 Roddy E, Sear K, Felton E. , et al. Presence of cerebral microbleeds is associated with worse executive function in pediatric brain tumor survivors. Neuro-oncol 2016; 18 (11) 1548-1558
    PubMedSearch in Google Scholar
  • 5 Packer RJ, Gurney JG, Punyko JA. , et al. Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study. J Clin Oncol 2003; 21 (17) 3255-3261
    CrossrefPubMedSearch in Google Scholar
  • 6 Armstrong GT, Liu Q, Yasui Y. , et al. Long-term outcomes among adult survivors of childhood central nervous system malignancies in the Childhood Cancer Survivor Study. J Natl Cancer Inst 2009; 101 (13) 946-958
    CrossrefPubMedSearch in Google Scholar
  • 7 Macartney G, Harrison MB, VanDenKerkhof E, Stacey D, McCarthy P. Quality of life and symptoms in pediatric brain tumor survivors: a systematic review. J Pediatr Oncol Nurs 2014; 31 (02) 65-77
    CrossrefPubMedSearch in Google Scholar
  • 8 Nwachukwu CR, Youland RS, Chioreso C. , et al. Health related quality of life (HRQOL) in long-term survivors of pediatric low grade gliomas (LGGs). J Neurooncol 2015; 121 (03) 599-607
    CrossrefPubMedSearch in Google Scholar
  • 9 Sato I, Higuchi A, Yanagisawa T. , et al. Impact of late effects on health-related quality of life in survivors of pediatric brain tumors: motility disturbance of limb(s), seizure, ocular/visual impairment, endocrine abnormality, and higher brain dysfunction. Cancer Nurs 2014; 37 (06) E1-E14
    PubMedSearch in Google Scholar
  • 10 Fay-McClymont TB, Ploetz DM, Mabbott D. , et al. Long-term neuropsychological follow-up of young children with medulloblastoma treated with sequential high-dose chemotherapy and irradiation sparing approach. J Neurooncol 2017; 133 (01) 119-128
    CrossrefPubMedSearch in Google Scholar
  • 11 Lassaletta A, Bouffet E, Mabbott D, Kulkarni AV. Functional and neuropsychological late outcomes in posterior fossa tumors in children. Childs Nerv Syst 2015; 31 (10) 1877-1890
    CrossrefPubMedSearch in Google Scholar
  • 12 Liu F, Scantlebury N, Tabori U. , et al. White matter compromise predicts poor intellectual outcome in survivors of pediatric low-grade glioma. Neuro-oncol 2015; 17 (04) 604-613
    PubMedSearch in Google Scholar
  • 13 Robinson KE, Kuttesch JF, Champion JE. , et al. A quantitative meta-analysis of neurocognitive sequelae in survivors of pediatric brain tumors. Pediatr Blood Cancer 2010; 55 (03) 525-531
    CrossrefPubMedSearch in Google Scholar
  • 14 Roddy E, Mueller S. Late effects of treatment of pediatric central nervous system tumors. J Child Neurol 2016; 31 (02) 237-254
    CrossrefPubMedSearch in Google Scholar
  • 15 Palmer SL, Armstrong C, Onar-Thomas A. , et al. Processing speed, attention, and working memory after treatment for medulloblastoma: an international, prospective, and longitudinal study. J Clin Oncol 2013; 31 (28) 3494-3500
    CrossrefPubMedSearch in Google Scholar
  • 16 Reeves CB, Palmer SL, Reddick WE. , et al. Attention and memory functioning among pediatric patients with medulloblastoma. J Pediatr Psychol 2006; 31 (03) 272-280
    CrossrefPubMedSearch in Google Scholar
  • 17 Kiehna EN, Mulhern RK, Li C, Xiong X, Merchant TE. Changes in attentional performance of children and young adults with localized primary brain tumors after conformal radiation therapy. J Clin Oncol 2006; 24 (33) 5283-5290
    CrossrefPubMedSearch in Google Scholar
  • 18 Lafay-Cousin L, Fay-McClymont T, Johnston D. , et al. Neurocognitive evaluation of long term survivors of atypical teratoid rhabdoid tumors (ATRT): The Canadian registry experience. Pediatr Blood Cancer 2015; 62 (07) 1265-1269
    CrossrefPubMedSearch in Google Scholar
  • 19 Moxon-Emre I, Bouffet E, Taylor MD. , et al. Impact of craniospinal dose, boost volume, and neurologic complications on intellectual outcome in patients with medulloblastoma. J Clin Oncol 2014; 32 (17) 1760-1768
    CrossrefPubMedSearch in Google Scholar
  • 20 Ellenberg L, Liu Q, Gioia G. , et al. Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology 2009; 23 (06) 705-717
    CrossrefPubMedSearch in Google Scholar
  • 21 Mostow EN, Byrne J, Connelly RR, Mulvihill JJ. Quality of life in long-term survivors of CNS tumors of childhood and adolescence. J Clin Oncol 1991; 9 (04) 592-599
    CrossrefPubMedSearch in Google Scholar
  • 22 Netson KL, Ashford JM, Skinner T. , et al. Executive dysfunction is associated with poorer health-related quality of life in pediatric brain tumor survivors. J Neurooncol 2016; 128 (02) 313-321
    CrossrefPubMedSearch in Google Scholar
  • 23 Noll RB, Patel SK, Embry L. , et al; COG Behavioral Sciences Committee. Children's Oncology Group's 2013 blueprint for research: behavioral science. Pediatr Blood Cancer 2013; 60 (06) 1048-1054
    CrossrefPubMedSearch in Google Scholar
  • 24 Lai J-S, Zelko F, Krull KR. , et al. Parent-reported cognition of children with cancer and its potential clinical usefulness. Qual Life Res 2014; 23 (04) 1049-1058
    CrossrefPubMedSearch in Google Scholar
  • 25 Gershon RC, Cella D, Fox NA, Havlik RJ, Hendrie HC, Wagster MV. Assessment of neurological and behavioural function: the NIH Toolbox. Lancet Neurol 2010; 9 (02) 138-139
    CrossrefPubMedSearch in Google Scholar
  • 26 Mollica CM, Maruff P, Vance A. Development of a statistical approach to classifying treatment response in individual children with ADHD. Hum Psychopharmacol 2004; 19 (07) 445-456
    CrossrefPubMedSearch in Google Scholar
  • 27 Williams J, Thomas PR, Maruff P, Butson M, Wilson PH. Motor, visual and egocentric transformations in children with developmental coordination disorder. Child Care Health Dev 2006; 32 (06) 633-647
    CrossrefPubMedSearch in Google Scholar
  • 28 Diamond A. Executive functions. Annu Rev Psychol 2013; 64: 135-168
    CrossrefPubMedSearch in Google Scholar
  • 29 Hardy KK, Willard VW, Gioia A, Sharkey C, Walsh KS. Attention-mediated neurocognitive profiles in survivors of pediatric brain tumors: comparison to children with neurodevelopmental ADHD. Neuro-oncol 2018; 20 (05) 705-715
    PubMedSearch in Google Scholar
  • 30 Puhr A, Ruud E, Anderson V. , et al. Self-reported executive dysfunction, fatigue, and psychological and emotional symptoms in physically well-functioning long-term survivors of pediatric brain tumor. Dev Neuropsychol 2019; 44 (01) 88-103
    CrossrefPubMedSearch in Google Scholar
  • 31 Nagel BJ, Delis DC, Palmer SL, Reeves C, Gajjar A, Mulhern RK. Early patterns of verbal memory impairment in children treated for medulloblastoma. Neuropsychology 2006; 20 (01) 105-112
    CrossrefPubMedSearch in Google Scholar
  • 32 Ventura LM, Grieco JA, Evans CL. , et al. Executive functioning, academic skills, and quality of life in pediatric patients with brain tumors post-proton radiation therapy. J Neurooncol 2018; 137 (01) 119-126
    CrossrefPubMedSearch in Google Scholar
  • 33 Clark KN, Ashford JM, Pai Panandiker AS. , et al. Cognitive outcomes among survivors of focal low-grade brainstem tumors diagnosed in childhood. J Neurooncol 2016; 129 (02) 311-317
    CrossrefPubMedSearch in Google Scholar
  • 34 Pietilä S, Korpela R, Lenko HL. , et al. Neurological outcome of childhood brain tumor survivors. J Neurooncol 2012; 108 (01) 153-161
    CrossrefPubMedSearch in Google Scholar
  • 35 Reimers TS, Ehrenfels S, Mortensen EL. , et al. Cognitive deficits in long-term survivors of childhood brain tumors: identification of predictive factors. Med Pediatr Oncol 2003; 40 (01) 26-34
    CrossrefPubMedSearch in Google Scholar
  • 36 Chow EJ, Chen Y, Hudson MM. , et al. Prediction of ischemic heart disease and stroke in survivors of childhood cancer. J Clin Oncol 2018; 36 (01) 44-52
    PubMedSearch in Google Scholar
  • 37 Nathan PC, Patel SK, Dilley K. , et al; Children's Oncology Group Long-term Follow-up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer. Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group. Arch Pediatr Adolesc Med 2007; 161 (08) 798-806
    CrossrefPubMedSearch in Google Scholar
  • 38 Chieffo D, Tamburrini G, Frassanito P, Arcangeli V, Caldarelli M, Di Rocco C. Preoperative neurocognitive evaluation as a predictor of brain tumor grading in pediatric patients with supratentorial hemispheric tumors. Childs Nerv Syst 2016; 32 (10) 1931-1937
    CrossrefPubMedSearch in Google Scholar
  • 39 Palmer SL, Gajjar A, Reddick WE. , et al. Predicting intellectual outcome among children treated with 35-40 Gy craniospinal irradiation for medulloblastoma. Neuropsychology 2003; 17 (04) 548-555
    CrossrefPubMedSearch in Google Scholar
  • 40 Anderson FS, Kunin-Batson AS. Neurocognitive late effects of chemotherapy in children: the past 10 years of research on brain structure and function. Pediatr Blood Cancer 2009; 52 (02) 159-164
    CrossrefPubMedSearch in Google Scholar
  • 41 Riva D, Giorgi C, Nichelli F. , et al. Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology 2002; 59 (01) 48-53
    CrossrefPubMedSearch in Google Scholar
  • 42 Montour-Proulx I, Kuehn SM, Keene DL. , et al. Cognitive changes in children treated for acute lymphoblastic leukemia with chemotherapy only according to the Pediatric Oncology Group 9605 protocol. J Child Neurol 2005; 20 (02) 129-133
    CrossrefPubMedSearch in Google Scholar
  • 43 Duffner PK, Armstrong FD, Chen L. , et al. Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group. J Pediatr Hematol Oncol 2014; 36 (01) 8-15
    CrossrefPubMedSearch in Google Scholar
  • 44 Sands SA, Oberg JA, Gardner SL, Whiteley JA, Glade-Bender JL, Finlay JL. Neuropsychological functioning of children treated with intensive chemotherapy followed by myeloablative consolidation chemotherapy and autologous hematopoietic cell rescue for newly diagnosed CNS tumors: an analysis of the Head Start II survivors. Pediatr Blood Cancer 2010; 54 (03) 429-436
    CrossrefPubMedSearch in Google Scholar
  • 45 Dietrich J, Monje M, Wefel J, Meyers C. Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. Oncologist 2008; 13 (12) 1285-1295
    CrossrefPubMedSearch in Google Scholar
  • 46 Dietrich J, Prust M, Kaiser J. Chemotherapy, cognitive impairment and hippocampal toxicity. Neuroscience 2015; 309: 224-232
    CrossrefPubMedSearch in Google Scholar
  • 47 Tringale KR, Nguyen T, Bahrami N. , et al. Identifying early diffusion imaging biomarkers of regional white matter injury as indicators of executive function decline following brain radiotherapy: a prospective clinical trial in primary brain tumor patients. Radiother Oncol 2019; 132: 27-33
    PubMedSearch in Google Scholar
  • 48 Huynh-Le MP, Walker AJ, Burger PC. , et al. Management of pediatric intracranial low-grade gliomas: long-term follow-up after radiation therapy. Childs Nerv Syst 2016; 32 (08) 1425-1430
    CrossrefPubMedSearch in Google Scholar
  • 49 Nordstrom M, Felton E, Sear K. , et al. Large vessel arteriopathy after cranial radiation therapy in pediatric brain tumor survivors. J Child Neurol 2018; 33 (05) 359-366
    CrossrefPubMedSearch in Google Scholar
  • 50 Duffner PK. Risk factors for cognitive decline in children treated for brain tumors. Eur J Paediatr Neurol 2010; 14 (02) 106-115
    CrossrefPubMedSearch in Google Scholar
  • 51 Mulhern RK, Hancock J, Fairclough D, Kun L. Neuropsychological status of children treated for brain tumors: a critical review and integrative analysis. Med Pediatr Oncol 1992; 20 (03) 181-191
    CrossrefPubMedSearch in Google Scholar
  • 52 Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004; 5 (07) 399-408
    CrossrefPubMedSearch in Google Scholar
  • 53 Antonini TN, Ris MD, Grosshans DR. , et al. Attention, processing speed, and executive functioning in pediatric brain tumor survivors treated with proton beam radiation therapy. Radiother Oncol 2017; 124 (01) 89-97
    CrossrefPubMedSearch in Google Scholar
  • 54 Decker AL, Szulc KU, Bouffet E. , et al. Smaller hippocampal subfield volumes predict verbal associative memory in pediatric brain tumor survivors. Hippocampus 2017; 27 (11) 1140-1154
    CrossrefPubMedSearch in Google Scholar
  • 55 Raghubar KP, Lamba M, Cecil KM. , et al. Dose-volume metrics and their relation to memory performance in pediatric brain tumor patients: a preliminary study. Pediatr Blood Cancer 2018; 65 (09) e27245
    CrossrefPubMedSearch in Google Scholar
  • 56 Kahalley LS, Ris MD, Grosshans DR. , et al. Comparing intelligence quotient change after treatment with proton versus photon radiation therapy for pediatric brain tumors. J Clin Oncol 2016; 34 (10) 1043-1049
    CrossrefPubMedSearch in Google Scholar
  • 57 Mueller S, Fullerton HJ, Stratton K. , et al. Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 2013; 86 (04) 649-655
    CrossrefPubMedSearch in Google Scholar
  • 58 Mueller S, Sear K, Hills NK. , et al. Risk of first and recurrent stroke in childhood cancer survivors treated with cranial and cervical radiation therapy. Int J Radiat Oncol Biol Phys 2013; 86 (04) 643-648
    CrossrefPubMedSearch in Google Scholar
  • 59 Howarth RA, Adamson AM, Ashford JM. , et al. Investigating the relationship between COMT polymorphisms and working memory performance among childhood brain tumor survivors. Pediatr Blood Cancer 2014; 61 (01) 40-45
    CrossrefPubMedSearch in Google Scholar
  • 60 Correa DD, Satagopan J, Cheung K. , et al. COMT, BDNF, and DTNBP1 polymorphisms and cognitive functions in patients with brain tumors. Neuro Oncol 2016; 18 (10) 1425-1433
    CrossrefPubMedSearch in Google Scholar
  • 61 Correa DD, Satagopan J, Baser RE. , et al. APOE polymorphisms and cognitive functions in patients with brain tumors. Neurology 2014; 83 (04) 320-327
    CrossrefPubMedSearch in Google Scholar
  • 62 Kline C, Felton E, Byer L. , et al. ApoE4 as a genetic predictor of neurocognitive outcomes in pediatric brain tumor survivors. Neuro-oncol 2018; 20: i167
    PubMedSearch in Google Scholar
  • 63 Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers, Version 5.0. Monrovia, CA: Children’s Oncology Group; 2018. Available at: www.survivorshipguidelines.org . Accessed November 10, 2019
    PubMed
  • 64 Brown PD, Pugh S, Laack NN. , et al; Radiation Therapy Oncology Group (RTOG). Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-oncol 2013; 15 (10) 1429-1437
    PubMedSearch in Google Scholar
  • 65 Benzing V, Eggenberger N, Spitzhüttl J. , et al. The Brainfit study: efficacy of cognitive training and exergaming in pediatric cancer survivors - a randomized controlled trial. BMC Cancer 2018; 18 (01) 18
    CrossrefPubMedSearch in Google Scholar
  • 66 Rodgers SP, Trevino M, Zawaski JA, Gaber MW, Leasure JL. Neurogenesis, exercise, and cognitive late effects of pediatric radiotherapy. Neural Plast 2013; 2013: 698528
    PubMedSearch in Google Scholar
  • 67 Szulc-Lerch KU, Timmons BW, Bouffet E. , et al. Repairing the brain with physical exercise: cortical thickness and brain volume increases in long-term pediatric brain tumor survivors in response to a structured exercise intervention. Neuroimage Clin 2018; 18: 972-985
    CrossrefPubMedSearch in Google Scholar
  • 68 Morris B, Partap S, Yeom K, Gibbs IC, Fisher PG, King AA. Cerebrovascular disease in childhood cancer survivors: a Children's Oncology Group Report. Neurology 2009; 73 (22) 1906-1913
    CrossrefPubMedSearch in Google Scholar
  • 69 Jayakar R, King TZ, Morris R, Na S. Hippocampal volume and auditory attention on a verbal memory task with adult survivors of pediatric brain tumor. Neuropsychology 2015; 29 (02) 303-319
    CrossrefPubMedSearch in Google Scholar
  • 70 Kadan-Lottick NS, Brouwers P, Breiger D. , et al. Comparison of neurocognitive functioning in children previously randomly assigned to intrathecal methotrexate compared with triple intrathecal therapy for the treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 2009; 27 (35) 5986-5992
    CrossrefPubMedSearch in Google Scholar
  • 71 Brinkman TM, Krasin MJ, Liu W. , et al. Long-term neurocognitive functioning and social attainment in adult survivors of pediatric CNS tumors: results from the St Jude Lifetime Cohort Study. J Clin Oncol 2016; 34 (12) 1358-1367
    CrossrefPubMedSearch in Google Scholar
  • 72 Correa DD, DeAngelis LM, Shi W, Thaler HT, Lin M, Abrey LE. Cognitive functions in low-grade gliomas: disease and treatment effects. J Neurooncol 2007; 81 (02) 175-184
    PubMedSearch in Google Scholar
  • 73 Sekeres MJ, Riggs L, Decker A. , et al. Impaired recent, but preserved remote, autobiographical memory in pediatric brain tumor patients. J Neurosci 2018; 38 (38) 8251-8261
    CrossrefPubMedSearch in Google Scholar
  • 74 Zureick AH, Evans CL, Niemierko A. , et al. Left hippocampal dosimetry correlates with visual and verbal memory outcomes in survivors of pediatric brain tumors. Cancer 2018; 124 (10) 2238-2245
    CrossrefPubMedSearch in Google Scholar
  • 75 Olson K, Sands SA. Cognitive training programs for childhood cancer patients and survivors: a critical review and future directions. Child Neuropsychol 2016; 22 (05) 509-536
    CrossrefPubMedSearch in Google Scholar
  • 76 Riggs L, Piscione J, Laughlin S. , et al. Exercise training for neural recovery in a restricted sample of pediatric brain tumor survivors: a controlled clinical trial with crossover of training versus no training. Neuro-oncol 2017; 19 (03) 440-450
    PubMedSearch in Google Scholar
  • 77 Page BR, Shaw EG, Lu L. , et al. Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue. Neuro-oncol 2015; 17 (10) 1393-1401
    PubMedSearch in Google Scholar
  • 78 Castellino SM, Ullrich NJ, Whelen MJ, Lange BJ. Developing interventions for cancer-related cognitive dysfunction in childhood cancer survivors. J Natl Cancer Inst 2014; 106 (08) 106
    PubMedSearch in Google Scholar
  • 79 Netson KL, Conklin HM, Ashford JM, Kahalley LS, Wu S, Xiong X. Parent and teacher ratings of attention during a year-long methylphenidate trial in children treated for cancer. J Pediatr Psychol 2011; 36 (04) 438-450
    CrossrefPubMedSearch in Google Scholar
  • 80 Conklin HM, Reddick WE, Ashford J. , et al. Long-term efficacy of methylphenidate in enhancing attention regulation, social skills, and academic abilities of childhood cancer survivors. J Clin Oncol 2010; 28 (29) 4465-4472
    CrossrefPubMedSearch in Google Scholar