Citation classics in neuro-oncology: assessment of historical trends and scientific progress

Abstract

Background

Citation classics represent the highest cited works in a field and are often regarded as the most influential literature. Analyzing thematic trends in citation classics across eras enables recognition of important historical advances within a field. We present the first analysis of the citation classics in neuro-oncology.

Methods

The Web of Science database was searched using terms relevant to “neuro-oncology.” Articles with >400 citations were identified and the top 100 cited articles were evaluated.

Results

The top 100 neuro-oncology citation classics consisted of 43 clinical studies (17 retrospective, 10 prospective, 16 randomized trials), 43 laboratory investigations, 8 reviews/meta-analyses, and 6 guidelines/consensus statements. Articles were classified into 4 themes: 13 pertained to tumor classification, 37 to tumor pathogenesis/clinical presentation, 6 to imaging, 44 to therapy (15 chemotherapy, 10 radiotherapy, 5 surgery, 14 new agents). Gliomas were the most common tumor type examined, with 70 articles. There was a significant increase in the number of citation classics in the late 1990s, which was paralleled by an increase in studies examining tumor pathogenesis, chemotherapy, and new agents along with laboratory and randomized studies.

Conclusions

The majority of citation classics in neuro-oncology are related to gliomas and pertain to tumor pathogenesis and treatment. The rise in citation classics in recent years investigating tumor biology, new treatment agents, and chemotherapeutics may reflect increasing scientific interest in nonsurgical treatments for CNS tumors and the need for fundamental investigations into disease processes.

Almost 78000 new cases of CNS tumors are diagnosed every year in the United States, with nearly 17000 lives lost annually to this disease.¹ Despite research efforts and advances in diagnostic and therapeutic strategies, the mortality and morbidity of these tumors remain high.² CNS tumors pose a particular challenge from both a research and a clinical standpoint. The unique features of the blood–brain barrier complicate the delivery of therapeutic agents into the CNS and make it difficult to readily translate findings from other cancer fields.³ Moreover, with over 100 subtypes of CNS tumors, patient enrollment into clinical trials is a challenge, as the incidence of a distinct tumor subtype is relatively low.

While the clinical and scientific interest in better understanding and treating CNS tumors continues to rise, the increasing cost of conducting high-quality research combined with resource scarcity implies that scientific endeavor can benefit from better focusing on the field’s greatest needs. Reflecting on historical trends in neuro-oncology research and examining the literature that has made a significant impact in the field can provide insight into scientific progress over time and identify areas of greatest interest along with those that have been understudied. In the realm of bibliometric research, citation counts are commonly used as a measure of scientific impact. The term “citation classics” has been developed to describe articles with at least 400 citations.⁴ These highly cited works often represent landmarks of the literature that have gained recognition by researchers in the field and laid the groundwork for important clinical and research discoveries.^5,6 Examining citation classics in a field facilitates identification of important literature and provides insight into research trends over time. Here we present the first report of the citation classics in the field of neuro-oncology.

Methods

Search Strategy and Selection Criteria

A search of the Web of Science database was conducted on October 1, 2016 using the following terms: [(brain tumor)OR(brain neoplasm)OR(spine tumor)OR(spine neoplasm)OR(spinal tumor)OR(spinal neoplasm)OR(neuro- oncology)OR(neurooncology)OR(brain cancer)OR(medull oblastoma)OR(glio*)OR(meningioma)OR(cerebellar neoplasm)OR(cerebral neoplasm)]. The Web of Science database, which indexes only ISI journals, was chosen for the search, as it does not include citations from nonscholarly sources, thus avoiding the possibility of inflated citation counts. While databases such as Google Scholar may have a broader scope of indexing, they also include nonscholarly citations, and thus utilization of the Web of Science database produces a more relevant list of highly cited works.

No restrictions were placed on publication date (database coverage included 1900‒present), language, or study type. Records with <400 citations were excluded. Articles were first screened by title for their relevance to neuro-oncology, and remaining articles underwent abstract review. Articles not directly pertaining to neuro-oncology were excluded. Among the final list of studies obtained, the top 100 cited articles were included in the final analysis (Supplementary Fig. S1).

Data Collection

The following parameters were extracted from each article: country, journal, tumor type, citation count. Country of origin was based on the affiliation of the corresponding author. Articles were classified by study design, investigational approach, and topical theme. Article types consisted of clinical papers (retrospective, prospective, or randomized), laboratory investigations, reviews/meta-analyses, and guidelines/consensus statements. In order to assess trends in the literature, articles were classified on the basis of their primary theme. These themes were chosen to represent major areas of neuro-oncology research and encompass important aspects relevant to clinical practice. The themes included: classification, pathogenesis/clinical presentation, imaging, and therapy. Therapy-related articles were subclassified into those primarily pertaining to chemotherapy, radiation, surgery, or newer agents. Newer agents included all other therapies aside from standard chemotherapy, radiation, and surgery, including new drug delivery methods, gene therapy, anti-angiogenic strategies, and target-specific intracellular molecule inhibitors.

Statistics

Correlational analyses between continuous variables were conducted using SigmaStat Software. A P-value < 0.05 was considered significant.

Results

Based on the search strategy, the top 100 neuro-oncology–specific citation classics were obtained (Table 1). The number of times that articles were cited ranged from 565 to 6379 with a median of 815 citations.

Table 1.

Summary of citation classics in neuro-oncology

Rank	Article	No. Times Cited (Overall)	Article Type	Theme
1	Stupp et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996.	6379	Prospective (Randomized)	Therapy– Chemotherapy
2	Louis et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007; 114: 97–109.	4036	Guidelines/ Consensus	Classification
3	Singh et al. Identification of human brain tumour initiating cells. Nature. 2004; 432(7015):396–401.	3991	Laboratory Investigation	Pathogenesis + Clin Pres
4	Singh et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003; 63(18):5821–8.	2976	Laboratory Investigation	Pathogenesis + Clin Pres
5	Bao et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006; 444:756–60.	2672	Laboratory Investigation	Therapy– Radiotherapy
6	Hegi et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005; 352:997–1003.	2580	Prospective (Randomized) a	Therapy– Chemotherapy
7	Parsons et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321:1807–12.	2474	Laboratory Investigation	Classification
8	Chin et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008; 494(7438):506.	2242	Laboratory Investigation	Pathogenesis + Clin Pres
9	Stupp et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–466.	2014	Prospective (Randomized)	Therapy– Chemotherapy
10	Plate et al. Vascular endothelial growth-factor is a potential tumor angiogenesis factor in human gliomas in vivo. Nature. 1992; 359(6398):845–8.	1941	Laboratory Investigation	Pathogenesis + Clin Pres
11	Verhaak et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.	1771	Laboratory Investigation	Classification
12	Yan et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009; 360(8):765–73.	1703	Laboratory Investigation	Pathogenesis + Clin Pres
13	Chan et al. Microrna-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005; 65(14):6029–33.	1636	Laboratory Investigation	Pathogenesis + Clin Pres
14	Patchell et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322:494–500.	1494	Prospective (Randomized)	Therapy–Surgery
15	Wen et al. Malignant gliomas in adults. N Engl J Med. 2008; 359(5):492–507.	1492	Review	Pathogenesis + Clin Pres
16	Macdonald. Response criteria for phase-ii studies of supratentorial malignant glioma. J Clin Oncol. 1990; 8(7):1277–80.	1475	Guidelines/ Consensus	Imaging
17	Culver et al. In vivo gene transfer with retroviral vector producer cells for treatment of experimental brain tumors. Science. 1992;256:1550–1552.	1464	Laboratory Investigation	Therapy–New agents
18	Skog et al. Glioblastoma microvesicles transport rna and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008; (12):1470–6.	1379	Laboratory Investigation	Pathogenesis + Clin Pres
19	Galli et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64(19):7011–21.	1363	Laboratory Investigation	Pathogenesis + Clin Pres
20	Pomeroy et al. Prediction of central nervous system embryonaltumour outcome based on gene expression. Nature. 2002;415:436–442.	1346	Laboratory Investigation	Classification
21	Libermann et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human-brain tumors of glial origin. Nature 1985; 313(5998):144–7.	1281	Laboratory Investigation	Pathogenesis + Clin Pres
22	Phillips et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–173.	1259	Laboratory Investigation	Classification
23	Kleihues et al. The new WHO classification of brain tumors. Brain Pathol. 1993;3:255–268.	1223	Guidelines/ Consensus	Classification
24	Walker et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980;303:1323–1329.	1221	Prospective (Randomized)	Therapy– Radiotherapy
25	Kleihues et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002;61:215–25.	1187	Guidelines/ Consensus	Classification
26	Walker et al. Evaluation of BCNU and/or radiotherapy in treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978;49:333–343.	1184	Prospective (Randomized)	Therapy– Chemotherapy
27	Gaspar et al. Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37(4):745–51.	1182	Retrospective	Therapy– Radiotherapy
28	Esteller et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 2000;343:1350–4.	1171	Prospective	Therapy– Chemotherapy
29	Hemmati et al. Cancerous stem cells can arise from pediatric brain tumors. PNAS. 2003; 100(25):15178–83.	1136	Laboratory Investigation	Pathogenesis + Clin Pres
30	Millauer et al. Glioblastoma growth inhibited in-vivo by a dominant-negative flk-1 mutant. Nature. 1994; 367(6463):576–9.	1085	Laboratory Investigation	Therapy–New agents
31	Calabrese et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007; 11(1):69–82.	1084	Laboratory Investigation	Pathogenesis + Clin Pres
32	Simpson et al. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry. 1957;20:22–39.	1083	Retrospective	Classification
33	Lacroix et al. A multivariate analysis of 416 patients with glioblastomamultiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95:190–8.	1079	Retrospective	Therapy–Surgery
34	Batchelor et al. Azd2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007; 11(1):83–95.	1068	Prospective	Therapy–New agents
35	Lee et al. Tumor stem cells derived from glioblastomas cultured in BFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum- cultured cell lines. Cancer Cell. 2006; 9(5):391–403.	1037	Laboratory Investigation	Pathogenesis + Clin Pres
36	Friedman et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–4740.	1036	Prospective (Randomized)	Therapy–New agents
37	Dang et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009; 462(7274):739–44.	1019	Laboratory Investigation	Pathogenesis + Clin Pres
38	Andrews et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the rtog 9508 randomised trial. Lancet. 2004; 363(9422):1665–72.	1002	Prospective (Randomized)	Therapy– Radiotherapy
39	Stummer et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7:392–401.	998	Prospective (Randomized)	Therapy–Surgery
40	Furnari et al. Malignant astrocyticglioma: genetics, biology, and paths to treatment. Genes Dev. 2007;21:2683–2710.	991	Review	Pathogenesis + Clin Pres
41	Cairncross et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90:1473–1479.	976	Retrospective	Therapy– Chemotherapy
42	Mellinghoff et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005; (19):2012–24.	947	Prospective	Therapy–New agents
43	Liu et al. Analysis of gene expression and chemoresistance of CDI33(+) cancer stem cells in glioblastoma. Mol Cancer. 2006;5.	945	Laboratory Investigation	Therapy– Chemotherapy
44	DeAngelis. Medical progress: brain tumors. N Engl J Med. 2001;344:114–123.	906	Review	Pathogenesis + Clin Pres
45	Young et al. Measurement of clinical and subclinical tumour response using F-18 -fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. Eur J Cancer. 1999;35:1773–1782.	889	Guidelines/ Consensus	Imaging
46	Wen et al. Updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology working group. J Clin Oncol. 2010; 28(11):1963–72.	859	Guidelines/ Consensus	Imaging
47	Pearce et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet. 2012; 380(9840):499–505.	847	Retrospective	Pathogenesis + Clin Pres
48	Kondo et al. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A. 2004;101:781–786.	842	Laboratory Investigation	Pathogenesis + Clin Pres
49	Brem et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet. 1995;345:1008–1012.	822	Prospective (Randomized)	Therapy– Chemotherapy
50	Curran et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst. 1993;85:704–710.	822	Retrospective	Therapy– Radiotherapy
51	Vredenburgh et al. Bevacizumab plus irinotecan in recurrent glioblastomamultiforme. J Clin Oncol. 2007;25:4722–4729.	808	Prospective	Therapy–New agents
52	Noushmehr et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010; 17(5):510–22.	800	Laboratory Investigation	Classification
53	Patchell et al. Postoperative radiotherapy in the treatment of single metastases to the brain—a randomized trial. JAMA. 1998; 280(17):1485–9.	784	Prospective (Randomized)	Therapy– Radiotherapy
54	Aoyama et al. Stereotactic radiosurgery plus whole- brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases—a randomized controlled trial. JAMA. 2006;295:2483–2491.	780	Prospective (Randomized)	Therapy– Radiotherapy
55	Maher et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev. 2001; 15(11):1311–33.	766	Review	Pathogenesis + Clin Pres
56	Aboody et al. Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc Natl Acad Sci U S A. 2000;97:12846–12851.	755	Laboratory Investigation	Therapy–New agents
57	Ciafre et al. Extensive modulation of a set of micrornas in primary glioblastoma. Biochem Biophys Res Commun. 2005;334(4):1351–8.	734	Laboratory Investigation	Pathogenesis + Clin Pres
58	Winkler et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004;6:553–563.	733	Laboratory Investigation	Therapy–New agents
59	Afra et al. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet. 2002;359:1011–1018.	722	Review	Therapy– Chemotherapy
60	Piccirillo et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006;444(7120):761–5.	717	Laboratory Investigation	Therapy–New agents
61	Wong et al. Increased expression of the epidermal growth-factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A. 1987;84(19):6899–903.	711	Laboratory Investigation	Pathogenesis + Clin Pres
62	Kreisl et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–745.	705	Prospective	Therapy–New agents
63	Shih et al. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature. 1981;290(5803):261–4.	702	Laboratory Investigation	Pathogenesis + Clin Pres
64	Daumas-Duport et al. Grading of astrocytomas. A simple and reproducible method. Cancer. 1988;62:2152–2165.	694	Retrospective	Classification
65	Bao et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor Cancer Res. 2006;66(16):7843–8.	693	Laboratory Investigation	Pathogenesis + Clin Pres
66	Ohgaki et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64:6892–6899.	686	Retrospective	Pathogenesis + Clin Pres
67	Patchell et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366:643–648.	686	Prospective (Randomized)	Therapy–Surgery
68	Wasserstrom et al. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer. 1982;49:759–772.	681	Retrospective	Pathogenesis + Clin Pres
69	Fine et al. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer. 1993;71:2585–2597.	677	Review	Therapy– Chemotherapy
70	Sugahara et al. Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas. J Magn Reson Imaging. 1999;9(1):53–60.	676	Prospective	Imaging
71	Beier et al. CD133(+) and CD133(-) glioblastoma- derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007;67(9):4010–5.	666	Laboratory Investigation	Classification
72	Dichiro et al. Glucose-utilization of cerebral gliomas measured by [F-18] fluorodeoxyglucose and positron emission tomography. Neurology. 1982;32(12):1323–9.	660	Prospective	Imaging
73	Nakamizo et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 2005;65(8):3307–18.	660	Laboratory Investigation	Therapy–New agents
74	Ohgaki et al. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170(5):1445–53.	653	Review	Pathogenesis + Clin Pres
75	Hochberg et al. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980;30:907–911.	650	Retrospective	Therapy– Radiotherapy
76	Sidransky et al. Clonal expansion of p53 mutant-cells is associated with brain-tumor progression. Nature. 1992;355(6363):846–7.	648	Laboratory Investigation	Pathogenesis + Clin Pres
77	Lyden et al. ID1 and ID3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature. 1999;401(6754):670–7.	647	Laboratory Investigation	Pathogenesis + Clin Pres
78	Nishikawa et al. A mutant epidermal growth- factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A. 1994;91(16):7727–31.	638	Laboratory Investigation	Pathogenesis + Clin Pres
79	Aronen et al. Cerebral blood-volume maps of gliomas— comparison with tumor grade and histologic-findings. Radiology. 1994;191(1):41–51.	631	Retrospective	Imaging
80	Vredenburgh et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13:1253–1259.	626	Prospective	Therapy–New agents
81	Mirimanoff et al. Meningioma: analysis of recurrence and progression following neurosurgical resection. J Neurosurg. 1985;62:18–24.	624	Retrospective	Therapy–Surgery (outcomes)
82	Ohgaki et al. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005;64(6):479–89.	617	Retrospective	Pathogenesis + Clin Pres
83	Chang et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037–44.	615	Prospective (Randomized)	Therapy– Radiotherapy
84	Yung et al. A phase II study of temozolomide vs procarbazine in patients with glioblastomamultiforme at first relapse. Br J Cancer. 2000;83:588-	602	Prospective (Randomized)	Therapy– Chemotherapy
85	Westphal et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003;5:79–88.	601	Prospective (Randomized)	Therapy– Chemotherapy
86	Seoane et al. Integration of smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell. 2004;117(2):211–23.	598	Laboratory Investigation	Pathogenesis + Clin Pres
87	Markert et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 2000;7:867–874.	592	Prospective	Therapy–New agents
88	Berman et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 2002;297(5586):1559–61.	590	Laboratory Investigation	Therapy–New agents
89	Wong et al. Structural alterations of the epidermal growth-factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. 1987;84(19):6899–903.	589	Laboratory Investigation	Pathogenesis + Clin Pres
90	Fulda et al. Smac agonists sensitize for apo2l/trail- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med. 2002;8(8):808–15.	588	Laboratory Investigation	Therapy– Chemotherapy
91	Kanzawa et al. Role of autophagy in temozolomide- induced cytotoxicity for malignant glioma cells. Cell Death Differ. 2004;11(4):448–57.	588	Laboratory Investigation	Therapy– Chemotherapy
92	Bos et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459(7249):1005–9.	585	Laboratory Investigation	Pathogenesis + Clin Pres
93	Mercer et al. Negative growth-regulation in a glioblastoma tumor-cell line that conditionally expresses human wild-type p53. Proc Natl Acad Sci U S A. 1990;87(16):6166–70.	580	Laboratory Investigation	Pathogenesis + Clin Pres
94	Giese et al. Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol. 2003;21:1624–1636.	578	Review	Pathogenesis + Clin Pres
95	Gilbert et al. Epidural spinal cord compression from metastatic tumor: diagnosis and treatment. Ann Neurol. 1978;3:40–51.	577	Retrospective	Therapy– Radiotherapy
96	Wong et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17:2572–2578.	573	Retrospective	Therapy– Chemotherapy
97	Smith et al. Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol. 2000;18:636–645.	569	Prospective	Classification
98	Clement et al. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol. 2007;17:165–172.	566	Laboratory Investigation	Pathogenesis + Clin Pres
99	Burger et al. Glioblastomamultiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer. 1985;56:1106–1111.	565	Retrospective	Classification
100	Ron et al. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med. 1988;319:1033–1039.	565	Retrospective	Pathogenesis + Clin Pres

^aThe study reanalyzed data from an RCT with inclusion of additional data on MGMT methylation status.

Source

The citation classics were published in 36 different journals (Table 2). Journals were classified into 4 main categories. Forty-three articles were published in general medical/scientific journals, 37 articles in oncology-specific journals, 11 articles in neuroscience-specific journals, and 9 articles in various other journals. There was a significant, but not strong, correlation between journal impact factor and number of citation classics published in a given journal (Pearson coefficient = 0.5759, P = 0.0002). North American institutions produced the majority of the citation classics (71 articles), with the United States leading the list with 68 articles (Table 3). Twenty-five articles were from European centers (Germany, Switzerland, France, UK, Italy).

Table 2.

Journal rankings based on no. citation classics

Journal	Journal Category	# Citation Classics Published	Average # Citations per Paper	IFa
Nature	Gen	13	1452	38.138
N Engl J Med	Gen	10	1846	59.558
J Clin Oncol	Oncol	8	825	20.982
Cancer Cell	Oncol	7	1107	23.214
Cancer Res	Oncol	7	1240	8.556
PNAS	Gen	7	750	9.423
Lancet	Gen	5	816	44.002
Cancer	Oncol	4	654	5.649
J Neurosurg	Neuro	3	962	3.443
Lancet Oncol	Oncol	3	1209	26.509
Science	Gen	3	1509	34.661
Gene Dev	Other	2	879	10.042
J Neuropathol Exp Neurol	Neuro	2	902	3.432
JAMA	Gen	2	782	37.684
J Natl Cancer Inst	Oncol	2	899	11.37
Neurology	Neuro	2	655	8.166
Acta Neuropathol	Neuro	1	4036	11.36
Am J Pathol	Other	1	653	4.206
Ann Neurol	Neuro	1	577	9.638
Biochem Biophys Res Commun	Other	1	734	2.371
Brain Pathol	Neuro	1	1223	5.256
Br J Cancer	Oncol	1	602	5.569
Cell	Gen	1	598	28.71
Cell Death Differ	Other	1	588	8.218
Clin Cancer Res	Oncol	1	626	8.738
Curr Biol	Other	1	566	8.983
Eur J Cancer	Oncol	1	889	6.163
Gene Ther	Other	1	592	3.242
Int J Radiat Oncol Biol Phys	Oncol	1	1182	4.495
J Magn Reson Imaging	Other	1	676	3.25
J Neurol Neurosurg Psych	Neuro	1	1083	6.431
Mol Cancer	Oncol	1	945	5.888
Nat Cell Biol	Gen	1	1379	18.699
Nat Med	Gen	1	588	30.357
Neuro Oncol	Oncol	1	601	7.371
Radiology	Other	1	631	6.798

^aBased on 2015 Impact Factor Ranking.

Oncol = oncology, Neuro = neuroscience, Gen = general medical/science.

Table 3.

Country of origin of citation classics

Rank	Country	# Citation Classics
1	US	68
2	Germany	7
3	Switzerland	6
4	France	5
5	UK	4
6a	Canada	3
6b	Italy	3
6c	Japan	3
7	Israel	1

Study Types

A breakdown of the different study types among the citation classics is provided in Table 4. Forty-three citation classics were clinical studies—specifically, 17 were retrospective analyses, 10 were prospective analyses, and 16 were randomized trials. Of the clinical studies, 7 investigated associations between tumor molecular-genetic markers and patient outcomes. Forty-three citation classics were laboratory investigations, and among these: 8 studies involved molecular-genetic analyses of patient samples that were correlated with clinical outcomes, 19 involved in vivo animal models, and 16 examined tumor-derived samples or cell lines. Eight studies were reviews/meta-analyses and 6 articles were guidelines/consensus statements.

Table 4.

Summary of citation classics based on citation count

Variable	Citation Count
	Total	501–600	601–700	701–800	801–900	901–1000	1001–2000	>2000
Total	100	15	22	11	8	6	29	9
Journal
Nature	13	1	2	2	–	–	5	3
N Engl J Med	10	1	–	–	–	2	5	2
J Clin Oncol	8	3	–	1	2	–	2	–
Cancer Cell	7	–	–	1	1	–	5	–
Cancer Res	7	–	4	–	–	–	2	1
PNAS	7	2	1	2	1	–	1	–
Lancet	5	–	1	1	2	–	1	–
Cancer	4	1	3	–	–	–	–	–
J Neurosurg	3	–	1	–	–	–	2	–
Lancet Oncol	3	–	1	–	–	1	–	1
Science	3	1	–	–	–	–	1	1
Gene Dev	2	–	–	1	–	1	–	–
J Neuropathol Exp Neurol	2	–	1	–	–	–	1	–
JAMA	2	–	–	2	–	–	–	–
J Natl Cancer Inst	2	–	–	–	1	1	–	–
Neurology	2	–	2	–	–	–	–	–
Acta Neuropathol	1	–	–	–	–	–	–	1
J Neurol Neurosurg Psych	1	–	–	–	–	–	1	–
Int J Radiat Oncol Biol Phys	1	–	–	–	–	–	1	–
Brain Pathol	1	–	–	–	–	–	1	–
Nat Cell Biol	1	–	–	–	–	–	1	–
Other	15	6	6	1	1	1	–	–
Study Type
Review/Meta-analysis	8	1	2	2	–	2	1	–
Guidelines/Consensus	6	–	–	–	2	–	3	1
Retrospective	17	4	7	–	2	1	3	–
Prospective	10	2	3	1	1	1	2	–
Randomized	16	–	4	2	1	1	5	3
Laboratory	43	8	6	6	2	1	15	5
Theme
Classification	13	2	2	–	1	–	6	2
Pathogenesis/ClinPres	37	7	8	4	2	2	11	3
Imaging	6	–	3	–	2	–	1	–
Therapy	44	6	9	7	3	4	11	4
Chemotherapy a	15	3	3	1	1	2	2	3
Radiation b	10	1	2	2	1	–	3	1
Surgery	5	–	2	–	–	1	2	–
New Agents	14	2	2	4	1	1	4	–

^aIncludes articles primarily focused on chemotherapy.

^bIncludes articles primarily focused on radiotherapy.

Themes

The citation classics were categorized into 4 major themes, which represent key areas of research in neuro-oncology: (1) classification, (2) pathogenesis and clinical presentation, (3) imaging, and (4) therapy (Table 4).

Classification

Thirteen citation classics pertained to tumor classification systems. Five studies classified tumors primarily based on histological or cellular features and included the original 1993 World Health Organization (WHO) classification along with the 2002 and 2007 updates. Seven studies described genetic or molecular characteristics to further subtype tumors. One study described a grading scale for prediction of recurrence of meningioma based on extent of resection. Histologically based classification systems were generally older than genetic ones, with 4 of the 5 studies published between 1985 and 2002. In contrast, all of the genetic or molecular-based classification systems were published after 2000.

Pathogenesis and clinical presentation

Thirty-seven citation classics focused on tumor pathogenesis or clinical presentation. Six studies reviewed general clinical features and presentation of brain tumors. Among pathogenesis-related articles, there were 2 etiological studies, which demonstrated a link between radiation exposure and brain tumor development. Twenty studies described molecular or genetic features that may predict tumor aggressiveness, malignancy, or treatment response. Among these, 4 studies focused on the role of epidermal growth factor (EGR) receptors; 2 on micro RNAs; 2 on isocitrate dehydrogenase mutations; 2 on p53 mutations; 1 on the role of vascular endothelial growth factor; 1 on inhibitor of DNA binding protein (ID)1/ID3; 1 on the phosphatidylinositol-3 kinase pathway; and 6 on general pathways involved in tumorigenesis. Eight studies examined characteristics of brain cancer stem cells and their role in tumor pathogenesis. One study looked at genetic distinctions between primary and secondary glioblastoma multiforme (GBM).

Imaging

There were 6 citation classics pertaining to imaging of CNS tumors. Four studies examined PET or MRI techniques in order to measure tumor grade and treatment response. The remaining 2 studies included the original and updated consensus statements on malignant glioma response criteria involving radiographic findings.

Therapy

The largest category of citation classics pertained to therapeutic strategies (44 articles). Fifteen articles focused on chemotherapy (published 1978–2009) and among these, 1 examined chemotherapy alone, 5 examined adjuvant chemotherapy in combination with radiotherapy or surgery, 2 described novel methods for the delivery of chemotherapeutic agents, and 7 outlined predictors of chemosensitivity or chemoresistance. Ten studies focused on radiotherapy (published 1978–2009): 6 examined radiotherapy alone, 3 examined adjuvant radiotherapy in combination with surgery or chemotherapy, and 1 outlined predictors of radiosensitivity or radioresistance. Five studies (published 1985–2006) pertained to the surgical treatment of CNS tumors.

Within the category of therapy, 14 articles pertained to new approaches (published 1992–2009). Two articles explored stem cells as drug delivery vehicles, 2 were based on gene therapy, 7 examined anti-angiogenic strategies. Three studies (published 2002–2006) focused on inhibitors targeting specific intracellular molecules or pathways, including EGF receptor kinase and the Hedgehog pathway.

Tumor Types

Gliomas were the most common tumor type examined across the citation classics, with 70 articles accruing a total of 75491 citations (Table 5). Of these, 56 studies specifically focused on malignant/high-grade gliomas (HGGs). Ten studies examined metastases, 2 were specifically about spinal metastases, and 2 studies examined meningiomas.

Table 5.

Tumor types among citation classics

Tumor Type	No. Citation Classics	Total No. Citations
Gliomaa	70	75491
Metastasesb	10	8386
Meningioma	2	1707
Medulloblastoma	1	590
Multiple CNS tumors	12	20318
Included non–CNS tumorsc	5	3868

^aIncludes glioma cell lines used in laboratory investigations along with gliosarcomas.

^bIncludes leptomeningeal metastases.

^cIncludes studies which included non–CNS tumors in their analysis.

Temporal Trends

There was a steep increase in the number of citation classics in the late 1990s, with a decrease in the most recent epoch (2008–2012) (Fig. 1A). This increase largely comprised articles pertaining to tumor pathogenesis along with therapies (Fig. 1B), particularly those focusing on chemotherapy and newer agents (Fig. 1C). There was also an increase in the number of laboratory studies and randomized trials since the late 1990s (Fig. 1D). There was a negative correlation between the average number of citations per year and the number of years since publication for articles; Pearson coefficient = −0.2632, P = 0.007 (Supplementary Fig. S2). Fig. 2 highlights a selection of the citation classics that have had major impact on clinical practice in the field of neuro-oncology over time.

Fig. 1.

Trends in neuro-oncology citation classics over time. (A) Total number of citation classics by epoch. (B) Trends in citation classic themes by epoch. The largest growth in citation classics was seen in articles pertaining to pathogenesis/clinical presentation and therapies. (C) Trends in citation classics focusing on therapies for CNS tumors by epoch. Articles pertaining to chemotherapeutic approaches showed significant growth between 1993 and 2007. Citation classics focusing on new strategies like anti-angiogenic therapies, gene therapy, and specific molecular pathway inhibitors have increased significantly since 1993. (D) Trends in citation classics by study type per epoch. There has been significant growth in the number of laboratory investigations along with randomized trials in the recent epochs.

Fig. 2.

Highlights from the citation classics. Timeline of landmark advances in neuro-oncology research. Abbreviations: RT = radiotherapy; EOR = extent of resection; 5-ALA = 5-aminolevulinic acid; PFS = progression-free survival.

Discussion

In this study, we present the first analysis of the citation classics in neuro-oncology. Through a focused review of the literature we found that the majority of citation classics pertained to gliomas and metastases, with a significant focus on tumor pathogenesis and therapeutic strategies. Moreover, in recent years there has been an increase in citation classics examining fundamental pathways in the tumor disease process, chemotherapeutics, and new pharmacological agents, along with laboratory studies and randomized trials.

Characteristics and Trends in the Citation Classics

As gliomas are among the most common primary brain tumors, it is not surprising that over half of the citation classics examined this tumor type. The aggressive nature of HGGs, in particular GBM, has made treatment difficult, and despite current therapies, prognosis remains poor.² Many citation classics pertaining to gliomas or GBM focused on tumor pathogenesis and new therapeutic strategies, suggesting that there has been significant scientific interest around establishing improved therapies for this tumor. Moreover, clinical trials investigating GBM are facilitated by the fact that clinical endpoints are often reached earlier than tumors that take a more indolent course. Further investigation to elucidate key drivers of the aggressive biology of these tumors and susceptibility to novel targeted therapies will likely be key in improving patient survival.

Only 2 citation classics examined meningiomas despite their accounting for nearly 30% of all brain tumors. As meningiomas are often benign and outcomes of interest such as survival occur on a greater time scale, malignant gliomas have historically received more research funding and scientific attention.⁷ However, a subset of meningiomas exhibit aggressive behavior that poses significant challenges with regard to optimal management and quality of life.⁸ In addition, only 10 studies examined CNS metastases. Similar to malignant gliomas, the prognosis of CNS metastases is often poor and many questions remain regarding optimal treatment, including the role of stereotactic radiosurgery versus whole-brain radiotherapy for multiple intracranial metastases and the use of targeted treatments and chemotherapeutics to cross the blood–brain barrier. Despite this, CNS metastases have received significantly less research attention compared with gliomas, highlighted by disparity in citation classics identified in this study compared with gliomas. Thus, the field may benefit from increased resources and research efforts directed toward better understanding and treating these tumor types.

The wide disparity in citation classics between the United States and other countries is consistent with previous reports examining brain tumor research output across countries and may be attributed to differences in total research output, resource allocation, and funding structures.⁹ Total spending on brain research in 2005 was approximately 4 times higher in the United States than in Europe. A breakdown of funding structures revealed that nearly 39% of brain research in the United States was government funded compared with 16% in Europe.¹⁰ Increased funding and allocation of government resources toward neuro-oncology research may facilitate research output.

There was a significant, but not strong, correlation between journal impact factor and the number of citation classics published in a given journal. Journal type may not necessarily reflect the impact of an individual article, and therefore analyzing citation classics is important to help establish benchmarks for high impact within a field.

Although the majority of citation classics were original research articles, 2 articles were meta-analyses and 6 were literature reviews. Meta-analyses can have a significant impact on clinical and research directions within a field, as they provide high-level evidence, deriving important conclusions from multiple smaller studies that may lack statistical power or have conflicting outcomes. While literature review articles may not contribute original data to the field, we included them in our search, as they can integrate unique findings from many studies which individually may not have accrued a high number of citations, but a synthesis of their findings can produce an important overview of the current state of the field and thus enhance understanding of a topic. In areas where there is limited existing scientific evidence on a topic, review articles may also incorporate important expert opinion that can inform patient management and future research direction.

The dominance of articles related to chemotherapy and “new agents,” especially in recent epochs, may reflect shifts in research interests among the scientific community over time. Historically, both surgery and later radiotherapy received much attention and were established early on as effective therapies for various CNS tumors. While interest may have therefore shifted away from evaluating these methods, there still remain important clinical questions regarding extent of surgical resection and re-resection, optimal radiation protocols for metastases, and ideal timing of radiation for low-grade glioma. In contrast, the survival benefit of chemotherapy for GBM was more recently established² and thus has gained scientific interest in recent epochs, particularly surrounding methods to optimize delivery of chemotherapeutic agents or identify markers that predict chemoresistance or chemosensitivity. Moreover, interest in new agents may have increased in response to the need to develop adjuncts to standard therapies given the poor prognosis of malignant brain tumors.

There was a steep rise in the number of citation classics in the late 1990s, which may be due to a number of factors. The increase in citation classics was paralleled by an increase in the number of laboratory and randomized studies, suggesting that high-quality clinical studies and fundamental investigations into disease processes are seen in a higher regard by the scientific community. Recent studies have emphasized the need for high-quality randomized controlled trials (RCTs) in neuro-oncology and neurosurgery research.^11,12 A similar “90s peak” has been reported in previous analyses of citation classics in other disciplines^13,14 and may be in part a result of older work representing established principles that are no longer cited and newer work having insufficient time to accumulate citations. Moreover, the latter part of the late 90s peak may also reflect improved indexing in online databases which occurred around 2005 as previously reported,^15,16 along with an expansion in the number of investigators conducting research in the field, which may yield increased citation counts among more recent papers. We found that there was a negative correlation between the number of citations per year and the year since publication of an article. This is consistent with previous reports examining citation classics in other fields suggesting that the citation timeline of a scientific article often takes a predictable course. Citations are generally accrued about 2 years after publication, reaching a peak after 3–10 years, then declining in the rate of citations thereafter.^17,18 This trend may also in part explain the decline in the total number of citation classics observed in the most recent epoch, as citation counts for some articles published during this time would be expected to peak in the years following our analysis.

Landmark Advances in Neuro-Oncology

The list of citation classics includes a set of seminal articles which have had major impact on clinical practice in the field of neuro-oncology and can serve as fundamental reading to guide the education of early trainees. Many of the early citation classics in neuro-oncology were dedicated to the histological classification of brain tumors.^19–21 More recently there has been a surge in genetic and molecular-based classification systems, which has been facilitated by advancements in biomedical techniques. This is borne out by landmark changes in the new 2016 WHO guidelines, which include for the first time the use of molecular parameters to define tumors.²² Moreover, seminal work on tumor pathogenesis helped elucidate genetic alterations underlying tumor malignancy states^23,24 and the role of cancer stem cells.^25,26 Refined genetic and molecular classification systems and increased understanding of tumor pathogenesis will help inform the design of future clinical trials with a rational selection of patients for specific experimental protocols, which will hopefully improve the rate of positive trials.

Seminal discoveries pertaining to the treatment of CNS tumors largely paralleled shifts in clinical practice. One of the earliest RCTs, conducted in 1978 by Walker et al, established radiotherapy as a part of the standard of care for patients with malignant gliomas.²⁷ Almost a decade later, Patchell et al conducted the first RCT to show that surgery in combination with radiotherapy is superior to radiotherapy alone for single brain metastases, which revolutionized the field.²⁸ The 1990s witnessed the emergence of genetic-based studies, and in 1998 Cairncross et al demonstrated that anaplastic oligodendrogliomas with loss of chromosome 1p and 19q had increased susceptibility to chemotherapy, thus marking the beginning of the era of “personalized therapies” in neuro-oncology.²⁹ At the same time, chemotherapeutic agents for CNS tumors continued to have an impact in the field. In 2003, Westphal et al demonstrated that local delivery of the chemotherapeutic agent BCNU at the time of surgery for malignant glioma increased survival.³⁰ In 2005, Stupp et al laid the groundwork for the current standard of treatment for GBM showing that temozolomide chemotherapy plus radiotherapy has significant survival benefit for GBM.² In the same year, Hegi et al showed that gene silencing of O⁶-DNA methylguanine-methyltransferase (MGMT) improves response to temozolomide in GBM, further highlighting the need for personalized treatments.²

Although surgical technique has not seen as dramatic an interest as laboratory-based studies, some enhanced surgical techniques have continued to emerge over the last decade. In 2006, Stummer et al conducted the only RCT to date on the use of 5-aminolevulinic acid for fluorescence-guided tumor resection, showing that enhanced resection of HGGs with this agent improves 6-month progression-free survival.³¹ Recent years have also shown the emergence of studies investigating novel targeted therapies, including anti-angiogenic strategies,^32–36 molecular pathway inhibitors,^37,38 and viral vectors³⁹ or stem cells^40,41 for targeted drug delivery.

While the citation classics identified in the present study represent highly influential work in neuro-oncology, our search may not have captured all of the important articles in the field. In particular, recent articles that do not have sufficient time to accumulate citations and older articles where early citations may not be reliably indexed in modern databases would likely not be reflected in this analysis. It is also possible that our search terms may have missed articles relevant to neuro-oncology, although we used broad terms in order to reduce this possibility. Furthermore, setting a citation cutoff too high may miss important articles, yet a cutoff too low can be excessively inclusive. A cutoff of 400 citations has historically been used to define a citation classic,⁴ and analyses across multiple disciplines have commonly utilized this threshold or examined a subset of the highest cited works. In our analysis, we utilized an initial cutoff of 400 citations, then selected the top 100 cited classics among this list in order to provide a comprehensive but practical list of high impact articles in the field of neuro-oncology.

Overall, this study provides an important analysis of the historical trends in the field of neuro-oncology. Our findings suggest that there is currently significant interest among the scientific community in better understanding tumor pathogenesis along with developing nonsurgical therapies for the treatment of CNS tumors with great value placed on high-quality clinical trials and fundamental laboratory investigations. These will likely be areas of continued growth and interest in the emerging future.

Supplementary Material

Supplementary material is available at Neuro-Oncology online.

Funding

None.

Conflict of interest statement. No conflicts declared.