Neuro-Oncology Practice Neuro-Oncology Practice 2(3), 122 – 126, 2015 doi:10.1093/nop/npv008 Advance Access date 6 May 2015

Complementary therapy and survival in glioblastoma Bhageeradh H. Mulpur, L. Burt Nabors, Reid C. Thompson, Jeffrey J. Olson, Renato V. LaRocca, Zachary Thompson, and Kathleen M. Egan Division of Neuro-Oncology, University of Alabama at Birmingham, Birmingham, Alabama (B.H.M., L.B.N.); Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee (R.C.T.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia (J.J.O.); Norton Cancer Institute, Norton Healthcare, Louisville, Kentucky (R.V.L.); Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (Z.T., K.M.E.) Corresponding Author: L.B. Nabors, MD, Division of Neuro-Oncology. University of Alabama at Birmingham, 1960 6th Ave. S., FOT 1020, Birmingham, AL 35233 ([email protected]).

Background. Complementary therapy (CAM) is common in cancer patients. We undertook this study to assess the association of complementary therapy usage with mortality in glioblastoma (GBM) patients. Methods. The analysis was based on 470 patients. Information on current use of CAM was collected in structured interviews conducted a median of 6 weeks following GBM diagnosis. Proportional hazards regression was used to estimate hazard ratios (HRs) for GBMrelated death according to the use of individual supplements with multivariate adjustment for known prognostic factors including age, KPS, and extent of tumor resection (ESR). Results. Use of CAM agents was common, with 77% of the cohort reporting CAM usage. No mortality association was observed with the use of multivitamins (HR ¼ 0.91; P ¼ .40) or omega-3 fatty acids (HR ¼ 1.07; P ¼ .69). Patients taking vitamin D as an individual supplement (containing higher dosages than in a multivitamin) had reduced mortality when compared with nonusers (age-adjusted HR ¼ 0.68; P ¼ .02). However, the association was diminished after adjustment for KPS and ESR (HR ¼ 0.74; P ¼ .09). Use of herbal supplements was also associated with reduced mortality (HR ¼ 0.58; P ¼ .04). Vitamin E users had a nonsignificantly higher mortality when compared with nonusers (HR ¼ 1.54; P ¼ .09). Conclusions. Use of CAM is common in GBM patients. These exploratory analyses suggest no mortality association with the use of multivitamins or omega-3 fatty acids. Associations observed with vitamins D and E merit further investigation. Keywords: epidemiology, glioblastoma, mortality, supplements, vitamins.

Vitamin and supplement use as complementary or alternate medicinal therapies (CAM) are common in cancer patients. A University of Washington summary of combined epidemiology surveys reported the use of vitamins and supplements to be greater among persons diagnosed with cancer than in the general population. Often, this complementary treatment is initiated after cancer diagnosis. Furthermore, up to 68% of physicians are unaware of supplement use among their patients, potentially leading to negative interactions among the patients’ therapies.1 Glioblastoma multiforme (GBM) is one of the most aggressive and lethal human tumors, with a median survival of only 12– 15 months in patients undergoing current standard of care (SOC) treatment involving surgery, chemotherapy, and radiation therapy.2 Factors associated with patient longevity are not completely

understood, with considerable heterogeneity having been observed in patient survival times. Known prognostic factors including patient age, extent of tumor resection, and KPS may not account for all observed variability in patient prognosis. The aforementioned popularity of complementary therapy has been reported in glioma patients. According to a German study, 40% of patients surveyed with glial tumors ranging from WHO grade II to grade IV reported use of complementary therapies.3 However, the relationship of these agents to outcome in GBM has not been well studied. In the present analysis, we examined the use of complementary therapy and nutritional supplementation in relation to mortality in a series of GBM patients undergoing SOC treatment. Demographic data and overall clinical status were examined according to reported elective use of CAM treatments.

Received 5 December 2014 # The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

122

Mulpur et al.: Complementary therapy in glioblastoma

Methods The study population comprised persons with GBM who participated in an ongoing, clinic-based, case-control study in the United States. Participants were English-speaking persons aged 18 years and older with a recent diagnosis of primary (nonrecurrent) GBM and undergoing treatment at participating medical and oncology centers in the Southeastern United States including Vanderbilt University Medical Center in Nashville, Tennessee; Moffitt Cancer Center & Research Institute in Tampa, Florida; the University of Alabama at Birmingham; Emory University in Atlanta, Georgia; and the Norton Cancer Institute in Louisville, Kentucky. Study protocols were approved by the institutional review committees at each participating center, and all study participants provided written informed consent. A total of 470 GBM patients were included in the analysis. Information on current use and past use (5 years prior to the tumor diagnosis) of nutritional or herbal supplements was collected in a one-time, structured interview conducted with participants a median of 6 weeks following their GBM diagnosis (interquartile range: 2.9–12.4 weeks). Participants were asked if they were currently taking, or had taken up to 5 years before the interview, any type of supplement including multivitamins, individual vitamins, minerals, and any other individual supplement. Responses were categorized by main, active ingredients after consulting manufacturer nutritional/supplement information labels. A total of 373 deaths were documented (all glioma related) 1.3 weeks to 5.3 years following GBM diagnosis (Kaplan-Meier survival 12 and 24 months following diagnosis 66% and 27%, respectively). Proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for glioma-related death according to the use of multivitamins and individual herbal or vitamin supplements with adjustment for age, and in multivariate models with further adjustments for education, KPS, and extent of tumor resections (EORs). Participants were followed from the time of interview to glioma-related death or the censor date in relation to CAM-

related mortality. To examine sensitivity of results to the composition of the referent group for each CAM exposure, we considered associations excluding only nonusers of the specific agent and excluding all CAM users from the referent group.

Results Demographics of Complementary Therapy Users A total of 470 GBM patients treated with SOC were included in the analysis. The median age was 59 years (range: 18 –89 y). The majority of participants were male (58%), with most participants having undergone subtotal resection (68%) of the tumor and having a KPS score of 70 – 90. We considered patient and treatment factors associated with CAM use (Table 1) and classified participants as non-CAM users (N ¼ 106), CAM users at time of interview (N ¼ 364) and, among current CAM users, those reporting CAM usage at time of interview but not 5 years prior to the interview (N ¼ 101) (Table 1). These participants are inferred to have started CAM use after the GBM diagnosis. When compared with non-CAM users, current-only CAM users were younger (57 vs 54 years, respectively) and more likely to be female (33% vs 39%) and to have undergone GTR (30% vs 37%). Current CAM users were also less likely to be current smokers (13% vs 9%) and to have a KPS score under 70 (14% vs 7%). Groups were similar in education, marital status, proportion born outside the United States, and time from symptom onset to diagnosis.

Types of Supplements Used A total of 364 participants (77%) reported using CAM at the time of the study interview. Multivitamin use was the most commonly reported CAM (N ¼ 211 participants [45%]). Other commonly reported CAM agents included vitamin D supplements (13%), omega-3 docosahexaneoic acid (DHA) and eicopentaenoic acid (EPA) supplements (13%), vitamin C (7%), and vitamin E (4%).

Table 1. Demographic and clinical characteristics of glioblastoma patients according to use of vitamin or herbal supplements at study interview Variable

Level

None (N ¼ 106)

Anya (N ¼ 364)

Current Onlyb (N ¼ 101)

Age Sex Education

Median years (range) Female (%) High school or less (%) Some college (%) College degree (%) Graduate degree (%) Presently married (%) Yes (%) Current (%) Past (%) Median months (range) GTR (%) ,70 (%)

57.5 (18– 84) 35 (33.0) 35 (33.0) 31 (29.3) 25 (23.6) 15 (14.2) 85 (80.2) 8 (7.6) 14 (13.2) 35 (33.0) 1.25 (0.3–14.3) 32 (30.2) 15 (14.2)

60.0 (20 –87) 161 (44.2) 111 (30.5) 100 (27.5) 94 (25.8) 59 (16.2) 303 (83.2) 27 (7.4) 26 (7.2) 141 (38.9) 1.32 (0.1 –14.9) 120 (32.9) 36 (9.9)

54.0 (20– 82) 39 (38.6) 36 (35.6) 27 (26.7) 23 (22.8) 15 (14.9) 84 (83.2) 7 (6.9) 9 (8.9) 36 (35.6) 1.35 (0.1– 14.3) 37 (36.6) 7 (6.9)

Marital status Born outside US Cigarette smoking Time from diagnosis Extent of resection KPSc

Abbreviations: GTR, gross total resection; US, United States. Current use of multivitamin or individual nutritional or herbal supplement as reported in study interview. b Excludes participants also using multivitamins or other supplements 5 years before interview. c Restricted to those with known KPS. a

Neuro-Oncology Practice

123

Mulpur et al.: Complementary therapy in glioblastoma

Additionally, a wide variety of supplements outside the traditional categories was reported, including individual antioxidants and herbal supplements (Tables 2 and 3).

Mortality Associations Multivitamin use was unrelated to patient survival time in age-adjusted (HR ¼ 0.90; P ¼ .344) and multivariate (HR ¼ 0.91; P ¼ .398) models. Null findings were also obtained for DHA/EPA, coenzyme Q10, glucosamine, B vitamins, vitamin C, and other miscellaneous antioxidants regardless of the referent group. Extended survival times were observed in participants reporting use of herbal supplements; significant results were obtained with adjustment for age, education, KPS, and EOR (HR ¼ 0.58, P ¼ .039) with a referent group of all non-CAM users. Likewise, Table 2. Antioxidants and miscellaneous health supplements reported by participants with high-grade glioma Antioxidant Supplements

n (#)a Miscellaneous Health Supplements

n (#)a

Acai berry Asparagus root Astragalus Bluegreen algae Chlorophyll Coco capsules Cranberry Essica tea Gingko biloba Ginseng Multicolor antioxidants Mushrooms Oregano supplement Poly mva Raw vegatables Selenium Senna Super green food Tumeric Turbopower energy Turmeric Vitamin C Vitamin E Juice plus Lutein Zinc

2 1 1 1 1 1 2 1 3 1 1 4 1 1 1 2 1 1 1 1 2 33 19 2 1 9

2 1 1 1 1 1 2 3 1 1 1 1 3 1 1 1 6 1 1 7 1 8 1 1 1 1 2 3 1 1 1 1 2 1

a

Aloe Barley Benefiber Borage oil Boric acid Boswellic acid Cinnamon Curcumin Detox daily essential minerals Echinacea Endothelin 3 supreme Fiber Garlic Glycogen algae Healthy trinity Hydrogen peroxide Iron Lecithin Liver cleanse Magnesium Magnesium taurate Melatonin Microhydrin Norwegian kelp Ocean energy Potassium Probiotics Red yeast rice Shark cartilage Triboron Ultimate 10 probiotic Wheat germ oil Wheat grass Whey protein

Participants may have reported more than one supplement.

124

vitamin D was associated with reduced mortality, adjusting only for age (HR ¼ 0.68; P ¼ .019) and adjusting for age plus other covariates (HR ¼ 0.72; P ¼ .043). Results for vitamin D were somewhat attenuated and were no longer significant when the referent was confined to non-CAM users (HR ¼ 0.74; P ¼ .091) in a multivariate model. A suggestion of increased mortality was observed among participants reporting vitamin E supplementation. A significantly increased hazard was found among vitamin E users excluding non-vitamin E users only (HR ¼ 1.63; P ¼ .047), although results were no longer significant (HR ¼ 1.54; P ¼ .094) excluding all CAM users from the referent group. A total of 19 participants reported vitamin E supplement use (Table 3). All results were similar when we excluded from the referent group multivitamin users plus users of the specific CAM only (ie, retaining users of any other CAM) (not shown).

Discussion The prevalence of CAM usage in our GBM patient cohort spanning multiple centers across the southeastern United States supports previously reported findings that CAM usage is popular among GBM patients, with 77% of our cohort reporting regular use of multivitamins or CAM. Furthermore, information regarding supplementation of this nature was obtained from an expansive, structured epidemiological interview that would fall outside the scope of traditional medical history taking. Therefore, the physicians in charge of these patients’ medical care are likely to be unaware of their patients’ CAM usage.4 In the present analysis, patients reporting CAM usage at the time of interview, but denying its usage 5 years prior, were assumed to have initiated CAM usage in a response to the GBM diagnosis. These patients were, on average, younger and less likely to have a poor KPS. Additionally, both new and longstanding CAM users were less likely to be current smokers at the time of the interview despite having similar, if not greater, numbers reporting previous cigarette smoking (Table 2). By virtue of this finding related to smoking cessation, in addition to the aforementioned demographic characteristics of CAM users, we anticipate some degree of “healthy user bias” in both cohorts of patients reporting any CAM use.5 In view of evidence that CAM users had a more favorable prognosis based on clinical factors, we examined associations of CAM with GBM outcome when considering different referent groups encompassing more or less restrictive exclusions. Results for individual CAM were, for the most part, unchanged regardless of the choice of referent group, and provided assurance that findings were not an artifact of healthy user bias. Both individual vitamin D and vitamin D + calcium supplements were considered in the vitamin D category since they both contain increased dosages of vitamin D when compared with a traditional multivitamin. We observed a statistically significant reduced mortality among vitamin D users in age-adjusted and multivariate models depending on the referent group. With multivariate adjustment, results were somewhat attenuated and were no longer statistically significant (Table 3). However, all results were based on limited numbers of vitamin D users (N ¼ 60), and statistical power was limited. Although no wellestablished mechanisms exist, a review of vitamin D-associated literature does indicate some plausible explanations for this

Neuro-Oncology Practice

Mulpur et al.: Complementary therapy in glioblastoma

Table 3. Associations of nutritional and herbal supplements with glioblastoma survival Variable

Exposure/ Referent Group*

Number (%)

Death (%)

Multivitamin

Users Exclude any CAM user Users Exclude users only Exclude any CAM user Users Exclude users only Exclude any CAM user Users Exclude users only Exclude any CAM user Users Exclude users only Exclude any CAM user Users Exclude users only Exclude any CAM user Users Exclude users only Exclude any CAM user Users Exclude users only Exclude any CAM user Users Exclude users only Exclude any CAM user Users Exclude users only Exclude any CAM user

211 (44.89) 192 (47.64) 62 (13.19) 408 (86.81) 192 (75.59) 26 (5.53) 444 (94.47) 192 (88.07) 60 (12.77) 410 (87.23) 192 (76.19) 19 (4.04) 451 (95.96) 192 (91.00) 33 (7.02) 437 (92.98) 192 (85.33) 32 (6.81) 438 (93.19) 192 (85.71) 13 (2.77) 256 (95.17) 192 (93.66) 23 (4.89) 447 (95.11) 192 (89.30) 43 (9.15) 427 (90.85) 192 (81.70)

162 (76.78) 153 (79.69) 51 (82.26) 317 (77.70) 153 (79.69) 17 (65.38) 351 (79.05) 153 (79.69) 42 (70.00) 326 (79.51) 153 (79.69) 18 (94.74) 350 (77.61) 153 (79.69) 25 (75.76) 343 (78.49) 153 (79.69) 20 (62.50) 348 (79.45) 153 (79.69) 10 (76.92) 204 (79.69) 153 (79.69) 16 (69.57) 352 (78.75) 153 (79.69) 31 (72.09) 337 (78.92) 153 (79.69)

DHA/EPA

Herbal Supplements

Vitamin D

Vitamin E

Vitamin C

Other Antioxidants

CoQ10

Glucosamine

B vitamins

Age-adjusted HR (95% CI)

P Value

MV-adjusted HR (95% CI)**

P Value

0.90 (0.72, 1.12)

.3443

0.91 (0.73, 1.14)

.3982

1.09 (0.81, 1.46) 1.01 (0.73, 1.38)

.5741 .9636

1.17 (0.87, 1.57) 1.07 (0.77, 1.47)

.3073 .6897

0.69 (0.42, 1.12) 0.66 (0.40, 1.09)

.1299 .1044

0.62 (0.38, 1.02) 0.58 (0.35, 0.97)

.0599 .0393

0.68 (0.50, 0.94) 0.68 (0.48, 0.95)

.0192 .0244

0.72 (0.52, 0.99) 0.74 (0.52, 1.05)

.0431 .0915

1.45 (0.90, 2.34) 1.29 (0.78, 2.12)

.1258 .3201

1.63 (1.01, 2.65) 1.54 (0.93, 2.56)

.0466 .0940

0.83 (0.55, 1.25) 0.79 (0.51, 1.20)

.3681 .2653

1.02 (0.67, 1.55) 1.09 (0.69, 1.73)

.9175 .6961

0.79 (0.50, 1.24) 0.75 (0.47, 1.19)

.3054 .2247

0.90 (0.57, 1.43) 0.96 (0.59, 1.55)

.6583 .8591

0.91 (0.50, 1.67) 0.85 (0.46, 1.58)

.7724 .6111

1.03 (0.55, 1.91) 0.93 (0.48, 1.81)

.9298 .8388

0.78 (0.47, 1.28) 0.71 (0.42, 1.19)

.3261 .1961

0.93 (0.56, 1.55) 0.91 (0.53, 1.56)

.7756 .7240

0.95 (0.66, 1.37) 0.88 (0.60, 1.30)

.7720 .5160

1.14 (0.78, 1.67) 1.18 (0.79, 1.78)

.4845 .4215

Abbreviations: CAM, complementary and alternative medicine; CI, confidence interval; CoQ10, coenzyme q10; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HR, hazard ratio. *Referent group excludes only users of the specified agent or users of any CAM. **Multivariate HR/CI adjusted for age, education, KPS and EOR.

observed survival benefit. Vitamin D has long been associated with bone metabolism and prevention of osteoporosis,6 but it has recently been credited with playing a significant role in cancer control through diverse mechanisms including signaling macrophages and dendritic cells of the immune system7 and activating the tumor suppressor p53.8 By bolstering the function of the immune system, vitamin D supplementation could potentially increase survival by mitigating some of the immunosuppressive effects of SOC treatment9 or by aiding the immune system in preventing the growth of tumor cells.10 Vitamin D has been reported to improve patient outcomes and to be associated with the occurrence of less aggressive tumors across multiple cancer types11 although, to our knowledge, this is the first report of a survival benefit in GBM. Given the mechanistic support underlying these findings, current results for vitamin D merit further study. A suggestion of increased mortality was observed in the patients taking vitamin E supplements. Although based on a small number of vitamin E users (N ¼ 19), results from the multivariate

Neuro-Oncology Practice

model were marginally significant regardless of the choice of referent group. To our knowledge, there have been no reports demonstrating the increased mortality we observed associated with vitamin E, but the role of antioxidants in nearly all types of cancer is very much a topic of debate and controversy. Vitamin E contains tocopherols, which are known to be potent antioxidants.12 One of the mechanisms by which standard cancer therapy agents (eg, such as radiation)13,14 work is by increasing the oxidative stress on the targeted cells and thereby inducing cell apoptosis. There is a lack of established scientific research in the field,15 but one possible hypothesis is that the antioxidative effects of vitamin E may potentially antagonize the therapeutic effects of radiation therapy by interfering in the oxidative stress-induced killing of cancer cells by radiotherapy agents.16 In the present analysis, vitamin E was the only antioxidant shown to have an increased association with mortality. Other antioxidants, such as vitamin C and other miscellaneous antioxidants as a group, did not show any association with mortality in our SOC-treated cohort of

125

Mulpur et al.: Complementary therapy in glioblastoma

GBM patients. A possible explanation is that vitamin E, in contrast to these other antioxidant compounds, is a lipid-soluble molecule.17 Lipid-soluble molecules are more readily able to diffuse across the blood-brain barrier18 and are therefore more likely to exert their effects on the brain tissues. Further research is warranted to confirm the present results.

Conclusions The use of CAM therapy is common in GBM patients. A wide variety of compounds was reported, ranging from multivitamins, omega-3 fatty acids, vitamin D, and vitamin E to various nontraditional health supplements (Table 2). No mortality associations were observed with multivitamins, omega-3 fatty acids, or nontraditional health supplements considered as a group. The majority of individual health supplements were reported too infrequently to be considered as single agents for associations with survival. These exploratory analyses demonstrate negative mortality associations with vitamin D and herbal supplements and positive associations with vitamin E. In view of these findings, other related clinical outcome results, and mechanistic considerations, these substances merit further investigation to confirm associations with GBM outcome. Additional factors to also consider in future studies are the dosing and the specific individual ingredients of the variety of CAM agents reported. Although participants in this study reported if they were taking CAM at the time of the interview, further information regarding its use during the entirety of their disease course could be informative. In particular, it would be useful to see how CAM usage changed as patients progressed through the disease course and were further removed from their initial surgery and chemoradiation therapies. In addition, information on patient and caregiver expectations for CAM usage and policies for CAM usage during treatment by treatment facilities would be useful to further understand the role of CAM supplementation in GBM patients. Patients and physicians should be encouraged to have an open dialogue regarding nutritional supplementation in addition to their standard cancer therapy.

Funding This project is part of the Southeast Regional Case-Control Study of Adult Glioma funded by a grant from the National Institutes of Health (R01 CA116174). In addition, this research was supported in part by University of Alabama-Birmingham’s Cancer Research Experiences for Students (CaRES) program funded by the National Cancer Institute (5R25CA76023).

Conflict of interest statement. None declared.

References 1.

Velicer CM, Ulrich CM. Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol. 2008;26(4):665 –673.

2.

Krex D, Klink B, Hartmann C, et al. Long-term survival with glioblastoma multiforme. Brain. 2007;130(Pt 10):2596–2606.

3.

Heese O, Schmidt M, Nickel S, et al. Complementary therapy use in patients with glioma: an observational study. Neurology. 2010; 75(24):2229 –2235.

4.

Robinson A, McGrail MR. Disclosure of CAM use to medical practitioners: a review of qualitative and quantitative studies. Complement Ther Med. 2004;12(2 –3):90– 98.

5.

Shrank WH, Patrick AR, Brookhart MA. Healthy user and related biases in observational studies of preventive interventions: a primer for physicians. J Gen Intern Med. 2011;26(5):546– 550.

6.

Lips P, van Schoor NM. The effect of vitamin D on bone and osteoporosis. Best Pract Res Clin Endocrinol Metabol. 2011;25(4): 585–591.

7.

Chun RF, Peercy BE, Orwoll ES, et al. Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol. 2014; 144(Pt A):132–137.

8.

Reichrath J, Reichrath S, Heyne K, Vogt, Roemer K, et al.Tumor suppression in skin and other tissues via cross-talk between vitamin D- and p53-signaling. Front Physiol. 2014;5:166.

9.

Grossman SA, Ye X, Lesser G, et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res. 2011;17(16):5473 – 5480.

10.

Sarkar S, Doring A, Zemp FJ, et al. Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells. Ann Neurosci. 2013;20(4):154.

11.

Li M, Chen P, Li J, et al. Review: the impacts of circulating 25-hydroxyvitamin D levels on cancer patient outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99(7):2327–2336.

12.

Brigelius-Flohe R, Traber MG. Vitamin E: function and metabolism. FASEB J. 1999;13(10):1145–1155.

13. Bairati I, Meyer F, Gelinas M, et al. A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients. J Natl Cancer Inst. 2005;97(7):481 –488. 14. Bairati I, Meyer F, Jobin E, et al. Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients. Int J Cancer. 2006;119(9):2221–2224. 15.

Seifried HE, McDonald SS, Anderson DE, et al. The antioxidant conundrum in cancer. Cancer Res. 2003;63(15):4295–4298.

16.

Lawenda BD, Kelly KM, Ladas EJ, et al. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. 2008;100(11):773 – 783.

17.

Burton GW, Joyce A, Ingold KU. Is vitamin E the only lipid-soluble, chain-breaking antioxidant in human blood plasma and erythrocyte membranes? Arch Biochem and Biophys. 1983;221(1): 281– 290.

Acknowledgments This project has been presented in part at the Society of Neuro-Oncology Conference (SNO 2013) in Washington, DC. Our thanks and acknowledgements go to the entire research support staffs at UAB Division of Neurooncology, H. Lee Moffitt Cancer Center & Research Institute, Vanderbilt University Medical Center, Emory University School of Medicine, and Norton Healthcare. Finally, we would like to express our gratitude to our research patients for their time and cooperation.

126

18. Banks WA. Characteristics of compounds that cross the blood-brain barrier. BMC Neurology. 2009;9(Suppl 1):S3.

Neuro-Oncology Practice