untitled h1
14.0 references

1. Cancer Facts and Figures. American Cancer Society, Atlanta, Georgia. 2011.  
2. Aziz NM. Cancer survivorship research: state of knowledge, challenges and opportunities. Acta Oncol.  
2007;46(4):417-32. Review. PMID: 17497308.  
3. Nelson CJ, Nandy N, Roth AJ. Chemotherapy and cognitive deficits: mechanisms, findings, and potential interventions. Palliat Support Care. 2007 Sep;5(3):273-80. Review. PMID: 17969831.  
4. Boykoff N, Moieni M, Subramanian SK. Confronting chemobrain: an in-depth look at survivors' reports of impact on work, social networks, and health care response. J Cancer Surviv. 2009;3(4):223-32. PMCID: PMC2775115.  
5. Vearncombe KJ, Rolfe M, Wright M, Pachana NA, Andrew B, Beadle G. Predictors of cognitive decline after chemotherapy in breast cancer patients. J Int Neuropsychol Soc. 2009;15(6):951-62. PMID: 1970945.  
6. Reid-Arndt SA. Breast cancer and "chemobrain": the consequences of cognitive difficulties following chemotherapy and the potential for recovery. Mo Med. 2009;106(2):127-31. PMID: 19797112.  
7. Jim H & Small B. Cognitive Functioning Following Adjuvant Treatment for Breast Cancer: A Controlled Comparison. Proceedings of the International Cognition and Cancer Task Force in March, 2010.  
8. Jansen C, Miaskowski C, Dodd M, Dowling G, Kramer J. Potential mechanisms for chemotherapy-induced impairments in cognitive function. Oncol Nurs Forum. 2005;32(6):1151-63. Review.  
9. Kumar NB, Allen KA, Riccardi D, Bercu B, Cantor A, Minton S, Balducci L, Jacobsen P. Fatigue, Weight Gain, Lethargy and Amenorrhea in Breast Cancer Patients on Chemotherapy: Is Subclinical Hypothyroidism the Culprit?  
Breast Cancer Research & Treatment. 2004;83:149-59.  
10. O'Shaughnessy JA, Vukelja SJ, Holmes FA, Savin M, Jones M, Royall D, George M, Von Hoff D. Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. Clin Breast Cancer. 2005;5(6):439-46.  
11. Borysov S & Kumar NB. In vitro studies of the potential mechanism of cognitive impairment with taxane-based therapies: Amyloid-β (Aβ) peptide 1-42 accumulation. Unpublished preliminary studies.  
12. Small BJ, Sharp Rawson K, Walsh E, Jim HSL, Hughes TF, Iser L, Andrykowski MA & Jacobsen PB. Catechol-OMethyltransferase (COMT) genotype modulates cancer treatment-related cognitive deficits. Cancer. (In press.)
13. Abushamaa AM, Sporn TA, Folz RJ. Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen. Am J Physiol Lung Cell Mol Physiol. 2002;283(2):L336-45.  
14. Wolinsky FD, Unverzagt FW, Smith DM, Jones R, Stoddard A, Tennstetdt SL. The ACTIVE cognitive training trial and health-related quality of life: Protection that lasts for 5 years Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2006;61:1324-1329.  
15. Rebok GW, Rasmusson DX, Brandt J. Prospects for computerized memory training in normal elderly: Effects of practice on explicit and implicit memory tasks. Applied Cognitive Psychology. 1996;10(3):211-223 16. Rasmusson DX, Rebok GW, Bylsma FW, Brandt J. Effects of three types of memory training in normal elderly.  
Aging, Neuropsychology, and Cognition. 1999;6:56-66.  
17. Labouvie-Veif G, Gonda JN. Cognitive strategy training and intellectual performance in the elderly. J Gerontol.  
1976;31(3):3327-3332.  
18. Kramer AF, Larish JL, Stayer DL. Training for attentional control in dual task settings: A comparison of young and older adults. Journal of Experimental Psychology: Applied. 1995;1(1):50-76.  
19. Schaie KW, Hertzog C, Willis SL, Schulenberg J. Effects of cognitive training on primary mental ability structure.  
Psychol Aging. 1987;2(3):233-242.  
20. Ball KK, Berch DB, Helmers KF, Jobe JB, Leveck MD, Marsiske M, Morris JN, Rebok GW, Smith DM, Tennstedt SL, Unverzagt FW, Willis SL, Advanced Cognitive Training for Independent and Vital Elderly Study Group. Effect of cognitive training interventions with older adults: A randomized controlled trial. Journal of the American Medical Association. 2002;288:2271-2281.  
21. Ball KK, Edwards JD, Ross LA. The impact of speed of processing training on cognitive and everyday functions.  
Journals of Gerontology. Series B, Psychological Sciences and Social Sciences. 2007;62B:19-31. PMID:
16019280.  
22. Edwards JD, Wadley VG, Myers R, Roenker DL, Cissell GM, Ball KK. Transfer of a speed of processing intervention to near and far cognitive functions. Gerontology. 2002;48:329-340.  
23. Edwards JD, Wadley VG, Vance DE, Roenker DL, Ball KK. The impact of speed of processing training on cognitive and everyday performance. Aging & Mental Health. 2005;9:262-271.  
24. Roenker DL, Cissell GM, Ball KK, Wadley VG, Edwards JD. Speed-of-processing and driving simulator training result in improved driving performance. Human Factors. 2003;45(2):218-233.  
26. Wolinsky FD, Unverzagt FW, Smith DM, Jones R, Stoddard A, Tennstetdt SL. The ACTIVE cognitive training trial and health-related quality of life: Protection that lasts for 5 years Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2006;61:1324-1329.  
26. Wolinsky FD, Unverzagt FW, Smith DM, Jones R, Wright E, Tennstetdt SL. The effects of the ACTIVE cognitive training trial on clinically relevant declines in health-related quality of life. Journals of Gerontology. Series A,
Biological Sciences and Medical Sciences. 2006;61B(5):S281-S287.  
27. Shytle RD, Ehrhart J, Tan J, Vila J, Cole M, Sanberg CD, Sanberg PR, Bickford PC. Oxidative stress of neural, hematopoietic, and stem cells: protection by natural compounds. Rejuvenation Res. 2007;10(2):173-8. PMID: 17518694.  
28. Luchsinger JA, Mayeux R. Dietary factors and Alzheimer's disease. The Lancet Neurology. 2004;3:579-587.  
29. Shukitt-Hale B, Lau FC, Joseph JA. Berry Fruit Supplementation and the Aging Brain. Journal of Agricultural and Food Chemistry. 2008;56(3):636-641. PMID: 18211020.  
30. Joseph JA, Denisova N, Fisher D, Bickford P, Prior R, Cao G. Age-related neurodegeneration and oxidative stress:
Putative Nutritional Intervention. Neurologic clinics. 1998;16(3):747-755.  
31. Olanow CW. A radical hypothesis for neurodegeneration. Trends in Neurosciences. 1993;16:439-444. 32. Ramassamy C. Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: A review of their intracellular targets. European Journal of Pharmacology. 2006;545:51-64.  
33. Berger MM. Can oxidative damage be treated nutritionally? Clinical Nutrition. 2004;24:172-183.  
34. Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radical Biology & Medicine.  
1997;23:134-147.  
35. Haddard JJ. Antioxidant and prooxidant mechanisms in the regulation of redox(y)-sensitive transcription factors.  
Cellular Signalling. 2002;14:879-897.  
36. Morris MC, Evans DA, Schneider JA, Tangney CC, Bienias JL, Aggarwal NT. Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease. Journal of Alzheimer's Disease. 2006;9(4):435-443.  
37. Shaik YB, Castellani ML, Perrella A, Conti F, Salini V, Tete S, Madhappan B, Vecchiet J, De Lutiis MA, Caraffa A,
Cerulli G. Role of quercetin (a natural herbal compound) in allergy and inflammation. Journal of Biological Regulators and Homeostatic Agents. 2006;20:47-52.  
38. Ortiz D, Shea TB. Apple juice prevents oxidative stress induced by beta-amyloid in culture. Journal of Alzheimers Disease. 2004;6:27-30.  
39. Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer's disease: The KAME project. American Journal of Medicine. 2006;119:751-759.  
40. Rowland IR, Wiseman H, Sanders TA, Adlercreutz H, Bowey EA. Interindividual variation in metabolism of soy isoflavones and lignans: Influence of habitual diet on equol production by the gut microflora. Nutrition and Cancer. 2000;36:27-32.  
41. Krikorian R, Nash TA, Shidler MD, Shukitt-Hale B, Joseph JA. Concord grape juice supplementation improves memory function in older adults. American Aging Association. Boulder, CO. 2008.  
42. Chan YC, Hosoda K, Tsai CJ, Yamamoto S, Wang MF. Favorable effects of tea on reducing the cognitive deficits and brain morphological changes in senescence-accelerated mice. Journal of Nutrtition Sciences & Vitaminology. 2006;52(4):266-273.  
43. Gallant S, Semyonova M, Yuneva M. Carnosine as a potential anti-senescence drug. Biochemistry. 2000;65(7):866868.  
44. Meydani M. Nutrition interventions in aging and age-associated disease. Annals of the New York Academy of Sciences. 2001;928:226-235.  
45. Willis LM, Shukitt-Hale B, Cheng V, Joseph JA. Dose-dependent effects of walnuts on motor and cognitive function in aged rats. Br J Nutr. 2008;9:1-5. PMID: 18778529.  
46. Siwak CT, Tapp PD, Head E, Zicker SC, Murphey HL, Muggenburg BA, Ikeda-Douglas CJ, Cotman CW, Milgram NW. Chronic antioxidant and mitochondrial cofactor administration improves discrimination learning in aged but not young dogs. Progress in Neuropsychopharmacology & Biological Psychiatry. 2005;29(3):461-469.  
47. Milgram NW, Head E, Zicker SC, Ikeda-Douglas CJ, Murphey H, Muggenburg B, Siwak C, Tapp D, Cotman CW.  
Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiology of Aging. 2005;26(1):77-90.  
48. Joseph JA, Shukitt-Hale B, Denisova NA, Prior RL, Cao G, Martin A, Taglialatela G, Bickford PC. Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signaltransduction and cognitive behavioral deficits. Journal of Neuroscience. 1998;18:8047-8055.  
49. Gemma C, Bickford PC. Interleukin-1beta and caspase-1: players in the regulation of age-related cognitive dysfunction. Review of Neuroscience. 2007;18(2):137-148. PMID: 17593876.  
50. Cartford MC, Gemma C, Bickford PC. Eighteen-month-old Fischer 344 rats fed a spinach-enriched diet show improved delay classical eyeblink conditioning and reduced expression of tumor necrosis factor alpha (TNFalpha) and TNFbeta in the cerebellum. Journal of Neuroscience. 2002;22(14):5813-5816.  
51. Shytle RD, Ehrhart J, Tan J, Vila J, Cole M, Sanberg CD, Sanberg PR, Bickford PC. Oxidative stress of neural, hematopoietic, and stem cells: protection by natural compounds. Rejuvenation Research. 2007;10(2):173-178. PMID: 17518694.  
52. Mazza M, Pomponi M, Janiri L, Bria P, Mazza S. Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: An overview. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2007;31:12-26. PMID: 16938373.  
53. Gadoth N. On fish oil and omega-3 supplementation in children: The role of such supplementation on attention and cognitive dysfunction. Brain Development. 2008;30:309-312. PMID: 18006261.  
54. Barton D, Loprinzi C. Novel approaches to preventing chemotherapy-induced cognitive dysfunction in breast cancer: the art of the possible. Clin Breast Cancer. 2002;Suppl 3:S121-7. Review.  
55. Ferguson RJ, Ahles TA, Saykin AJ, McDonald BC, Furstenberg CT, Cole BF, Mott LA. Cognitive-behavioral management of chemotherapy-related cognitive change. Psychooncology. 2007;16(8):772-7. PMID: 17152119.  
56. Fan HG, Park A, Xu W, Yi QL, Braganza S, Chang J, Couture F, Tannock IF.The influence of erythropoietin on cognitive function in women following chemotherapy for breast cancer. Psychooncology. 2009;18(2):156-61. PMID: 18561284.  
57. Mar Fan HG, Clemons M, Xu W, Chemerynsky I, Breunis H, Braganza S, Tannock IF.A randomised, placebocontrolled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support Care Cancer. 2008;16(6):577-83. PMID: 17972110.  
58. Wald DS, Kasturiratne A, Simmonds M. Effect of folic acid, with or without other B vitamins, on cognitive decline:
meta-analysis of randomized trials. Am J Med. 2010;123(6):522-527.e2. PMID: 20569758.  
59. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. 2008;100(11):773-83.  
PMID: 18505970.  
60. Greenlee H, Gammon MD, Abrahamson PE, Gaudet MM, Terry MB, Hershman DL, Desai M, Teitelbaum SL,
Neugut AI, Jacobson JS. Prevalence and predictors of antioxidant supplement use during breast cancer treatment: the Long Island Breast Cancer Study Project. Cancer. 2009;115(14):3271-82. PMCID:PMC2763503.  
61. Smith PJ, Blumenthal JA. Diet and neurocognition: review of evidence and methodological considerations. Curr Aging Sci. 2010 Feb;3(1):57-66. Review. PMID: 20298171 62. Flirski M, and Sobow T. Biochemical markers and risk factors of Alzheimer's disease. Curr Alzheimer Res.  
2005;2:47-64.  
63. Irizarry MC. Biomarkers of Alzheimer disease in plasma. NeuroRx. 2004;1:226-234.  
64. Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M,
Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007;13:1359-62. PMID: 17934472.  
65. Joseph JA, Shukitt-Hale B, Willis LM. Grape juice, berries, and walnuts affect brain aging and behavior. J Nutr.  
2009;139(9):1813S-7S. PMID: 19640963.  
66. Willis LM, Shukitt-Hale B, Joseph JA.Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain. Genes Nutr. 2009 Aug 29. PMCID:PM2775891.  
67. Kumar NB, Krischer JP, Allen K, Riccardi D, Besterman-Dahan K, Salup R, Kang L, Xu P, Pow-Sang J. A Pilot Randomized, Placebo-Controlled Clinical Trial of Purified Isoflavones in Modulating Steroid Hormones in men diagnosed with Prostate Cancer. Nutr Cancer. 2007;59(2):163-8. PMCID: PMC2435485.  
68. Kumar NB, Krischer JP, Allen K, Riccardi D, Besterman-Dahan K, Salup R, Kang L, Xu P, Pow-Sang J. Safety of purified isoflavones in men with early stage prostate cancer. Nutr Cancer. 2007;59(2):169-75. PMCID: PMC2442460.  
69. Kumar NB, Cantor A, Allen K, Riccardi D, Besterman-Dahan K, Seigne J, Helal M, Salup R, Powsang J. The Specific Role of Isoflavones in Reducing Prostate Cancer Risk. Prostate. 2004;59(2):141-7.  
70. Kumar NB, Allen KA, Cantor A, Riccardi D, Cox CE. The Specific Role of Isoflavones on Estrogen Metabolism in Pre-menopausal Women. Cancer. 2002:94(4):1166-74.  
71. Kumar NB, Besterman-Dahan K, Kang L, Pow-Sang J, Xu P, Allen K, Riccardi D, Krischer JP. Results of a Randomized Clinical Trial of the Action of Several Doses of Lycopene in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy. Clin Med Urol. 2008:1:1-14. http://la-press.com/journal.php?journal_id=75. PMCID:PMC2846655, 72. Kumar NB, Besterman-Dahan K, Kang L, Pow-Sang J, Xu P, Allen K, Riccardi D, Krischer JP. Results of a Randomized Clinical Trial of the Action of Several Doses of Isoflavones in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy. J Soc Integrative Oncology. 2010 Winter;8(1):3-13. PMID:
20205984.  
73. Janle EM, Lila MA, Grannan M, Wood L, Higgins A, Yousef GG, Rogers RB, Kim H, Jackson GS, Ho L, Weaver CM. Pharmacokinetics and tissue distribution of 14C-labeled grape polyphenols in the periphery and the central nervous system following oral administration. J Med Food. 2010;13:926-33. PMID: 206703061.  
74. Milbury PE and Kalt W. Xenobiotic metabolism and berry flavonoid transport across the blood-brain barrier. J
Agric Food Chem. 2010;58:3950-56. PMID: 20128604.  
75. Andres-Lacueva C, Shukitt-Hale B, Galli RL, Jauregui O, Lamuela-Raventos RM, Joseph JA. Anthocyanins in aged lueberry-fed rats are found centrally and may enhance memory. Nutr. Neurosci. 2005; 8:111-20.  
76. Kalt W, Blumberg JB, McDonald JE, Vinqvist-Tymchuk MR, Fillmore SA, Graf BA, O'Leary JM, Milbury PE.  
Identification of anthocyanins in the liver, eye, and brain of blueberry-fed pigs, J. Agric. Food Chem. 2008;56:70512. PMID: 18211026.  
77. Prasain JK, Peng N, Dai Y, Moore R, Arabshahi A, Wilson L, Barnes S, Michael WJ, Kim H, Watts RL. Liquid chromatography tandem mass spectrometry identification of proanthocyanidins in rat plasma after oral administration of grape seed extract. Phytomedicine. 2009;16:233-43. PMID: 19095430.  
78. Lin LC, Wang MN, Tseng TY, Sung JS, Tsai TH. Pharmacokinetics of (-)-epigallocatechin-3-gallate in conscious and freely moving rats and its brain regional distribution. J Agric Food Chem. 2007;55(4):1517-24. PMID:
17256961.  
79. Mandel S, Amit T, Reznichenko L, Weinreb O, Youdim MB. Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. Mol. Nutr. Food Res. 2006;50:229-34.  
39 80. Willis LM, Shukitt-Hale B, Joseph JA. Recent advances in berry supplementation and age-related cognitive decline.  
Curr Opin Clin Nutr Metab Care. 2009;12(1):91-4. PMID: 19057194.  
93. Acosta S, Jernberg J, Sanberg CD, Sanberg PR, Small BJ, Gemma C, Bickford PC. NT-020, a Natural Therapeutic Approach to Optimize Spatial Memory Performance and Increase Neural Progenitor Cell Proliferation and Decrease Inflammation in the Aged Rat. Rejuvenation Res. 2010 Jun 29. Epub ahead of print. PMID: 20586644.  
94. Chan YC, Hosoda K, Tsai CJ, Yamamoto S, Wang MF. Favorable effects of tea on reducing the cognitive deficits and brain morphological changes in senescence-accelerated mice. Journal of Nutrtition Sciences & Vitaminology. 2006;52(4):266-273.  
81. Shukitt-Hale B, Cheng V, Joseph JA. Effects of blackberries on motor and cognitive function in aged rats. Nutr Neurosci. 2009;12(3):135-40. PMID: 19356316.  
82. Willis LM, Shukitt-Hale B, Joseph JA. Modulation of cognition and behavior in aged animals: role for antioxidantand essential fatty acid-rich plant foods. Am J Clin Nutr. 2009;89(5):1602S-1606S. Review. PMID: 19339395.  
83. Joseph JA, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale B. Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging. J Agric Food Chem. 2008;56(22):10544-51. PMID: 18954071.  
84. Kumar NB, Crocker T, Bepler G . Phase II clinical trial of Omega-3 fatty acids in cancer cachexia. Proceeding of the International Society of Preventive Oncology, November 2009.  
85. Mustafa S, Walker A, Bennett G and Peter M. Wigmore5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci. 2008;28:323-30. PMID: 18702703.  
86. Monje ML, Vogel H, Masek M, Ligon KL, Fisher PG, Palmer TD. Impaired Human Hippocampal Neurogenesis after Treatment for Central Nervous System Malignancies. Ann Neurol. 2007;62:515–520. PMID: 17786983.  
87. Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C. Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials. Int J Cancer.  
2008;123(6):1227-39. PMID: 18623084.  
88. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. 2008;100(11):773-83. Review. PMID: 18505970 89. Conklin KA. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness.  
Integr Cancer Ther. 2004;3(4):294-300. Review 90. Whitney KA, Lysaker PH, Steiner AR, Hook JN, Estes DD, Hanna NH. Is "chemobrain" a transient state? A
prospective pilot study among persons with non-small cell lung cancer. J Support Oncol. 2008;6(7):313-21. PMID: 18847074.  
91. Il'yasova D, Mixon G, Wang F, Marcom PK, Marks J, Spasojevich I, Craft N, Arredondo F, DiGiulio R. Markers of oxidative status in a clinical model of oxidative assault: a pilot study in human blood following doxorubicin administration. Biomarkers. 2009;14(5):321-5. PMICD: PMC2716435.  
92. Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radical Biology & Medicine.  
1997;23:134-147.  
95. Gallant S, Semyonova M, Yuneva M. Carnosine as a potential anti-senescence drug. Biochemistry. 2000;65(7):866868.  
96. Gemma C, Vila J, Bachstetter A, and Bickford PC. Oxidative Stress and the Aging Brain: From Theory to Prevention. In Brain Aging: Models, Methods and Mechanisms. Ed. Riddle D. CRC Press. 2007:353374.  
97. Meydani M. Nutrition interventions in aging and age-associated disease. Annals of the New York Academy of Sciences. 2001;928:226-235.  
98. Willis LM, Shukitt-Hale B, Cheng V, Joseph JA. Dose-dependent effects of walnuts on motor and cognitive function in aged rats. Br J Nutr. 2008;9:1-5. PMID: 18778529.  
100. Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N Jr, Ashe KH, Frautschy SA, Cole GM. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model.  
Neuron. 2004;43(5):633-45.  
101. Johnson EJ, Schaefer EJ. Potential role of dietary n-3 fatty acids in the prevention of dementia and macular degeneration. Am J Clin Nutr. 2006;;83 (6 Suppl):1494S-1498S.  
102. Lim WS, Gammack JK, Van Niekerk J, Dangour AD. Omega 3 fatty acid for the prevention of dementia. Cochrane Database Syst Rev. 2006;1:CD005379. Review.  
103. Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005;25(12):3032-40.  
104. Schapira DV, Kumar NB, Lyman GH, Cox CE. Abdominal Obesity and Breast Cancer Risk. Annals of Internal Medicine. 1990;112:182-186. 105. Schapira DV, Kumar NB, Lyman GH. Estimate of Breast Cancer Risk Reduction with Weight Loss Cancer.  
1991;67:2622-2625 106. Godin G, Shephard RJ. A simple method to assess exercise behavior in the community. Can J Appl Sport Sci. 1985 Sep;10(3):141-6. PMID: 4053261.  
107. Jonnalagadda SS, Mitchell DC, Smiciklas-Wright H, Meaker KB, VanHeel N, Karmally W, Ershow A, KrisEtherton PM. Accuracy of energy intake data estimated by a multiple-pass 24-hour recall technique. J Am Diet Assoc. 2000;100:303-311. PMID: 10719403.  
108. Mitchell D, Shacklock F. Computers in nutrition: the Minnesota nutrition database. Nutr Today. 1991;26:52-53.  
109. McBride J. Was it a slab, a slice or a sliver?: high tech innovations take food survey to a new level. Agric Res.  
2001;49:4-7.  
110. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982 . 111. Schroevers MJ, Sanderman R, Sonderen E & Adelita V. The evaluation of the Center for Epidemiologic Studies Depression (CES-D) scale: Depressed and Positive Affect in cancer patients and healthy reference subjects. Quality of Life Research. 2000;9:1015-1029.  
112. Donovan KA, Jacobsen PB, Small BJ, Munster PN & Andrykowski MA. Identifying Clinically Meaningful Fatigue with the Fatigue Symptom Inventory (FSI). J Pain Symptom Manage. 2008;36(5):480–487. PMCID: PMC2590752 113. Diggle PJ, Heagerty P, Liang K-Y, Zeger SL. Analysis of longitudinal data. New York, NY: Oxford University Press. 2002.  
114. Yang H, Jiang Y.Research progress of bioactive constituents, absorption, metabolism, and neuroprotective effects from blueberry. Wei Sheng Yan Jiu. 2010 Jul;39(4):525-8.  
115. Del Rio D, Borges G, Crozier A. Berry flavonoids and phenolics: bioavailability and evidence of protective effects.Br J Nutr. 2010;104(Suppl 3):S67-90.  
116. Spencer JP. The impact of fruit flavonoids on memory and cognition. Br J Nutr. 2010;104(Suppl 3):S40-7. Review.  
117. Zafra-Stone S, Yasmin T, Bagchi M, Chatterjee A, Vinson JA, Bagchi D.Berry anthocyanins as novel antioxidants in human health and disease prevention. Mol Nutr Food Res. 2007;51(6):675-83. Review.  
118. Spencer JP, Vafeiadou K, Williams RJ, Vauzour D. Neuroinflammation: modulation by flavonoids and mechanisms of action. Mol Aspects Med. 2012;33(1):83-97. Epub 2011 Nov 15.  
119. Galli RL, Shukitt-Hale B, Youdim KA, Joseph JA. Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits. Ann N Y Acad Sci. 2002;959:128-32.  
120. Thomasset S, Berry DP, Cai H, West K, Marczylo TH, Marsden D, Brown K, Dennison A, Garcea G, Miller A,
Hemingway D, Steward WP, Gescher AJ. Pilot study of oral anthocyanins for colorectal cancer chemoprevention. Cancer Prev Res (Phila). 2009;2(7):625-33.  
121. Kay CD, Mazza G, Holub BJ, Wang J. Anthocyanin metabolites in human urine and serum.  
Br J Nutr. 2004;91(6):933-42.  
122. de Ruiter MB, Reneman L, Boogerd W, Veltman DJ, van Dam FS, Nederveen AJ, Boven E, & Schagen SB.  
Cerebral hyporesponsiveness and cognitive impairment 1- years after chemotherapy for breast cancer. Human Brain Mapping. 2011;32:1206-19.  
123. McDonald BC, Conroy SK, Ahles TA, West JD, & Saykin AJ. Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study. Breast Cancer Research and Treatment. 2010;123:81928.  
124. Scherling C, Collins B, MacKenzie J, Bielajew C, & Smith A. Pre-chemotherapy differences in visuospatial working memory in breast cancer patients compared to controls: an fMRI study. Frontiers in Human Neuroscience. 2011;5:122.  
125. Talairach J, Tounoux P. Co-planar stereotactic atlas of the human brain: 3-dinsional proportional system: An approach to cerebral imaging. Stuttgart: Thieme. 1988 126. Saykin AJ, McDonald BC, Ahles T, Chesnut LA, Wang PJ, Furstenberg CT, Horrigan SA, & Mamourian AC.  
Altered brain activation following systemic chemotherapy for breast cancer: interim analysis from a perspective fMRI study', in Abstract presented at 34th Annual Meeting of the International Neurophysiological Society, Boston.  
2006.  
127. The Psychological Corporation. Wechsler Test of Adult Reading. San Antonio TX: Harcourt Assessment. 2001.  
128. Bendict R. Brief Visuo-Spatial Memory Test-Revised (BVMT-R). Odessa, FL: Psychological Assessment Resources. 1997.  
129. Brandt J. The Hopkins Verbal Learning Test: development of a new memory test with six equivalent forms. Clin Neuropsychologist. 1991;5:125-42.  
130. Weschler D. WAIS-III administration and scoring manual. San Antonio TX: Psychological Corporation; 1997.  
131. Maj M, D'Elia L, Satz P, Janssen R, Zaudig M, Uchiyama C, Starace F, Galderisi S, Chervinsky A, World Health Organization, Division of Mental Health/Global Programme on AIDS. Evaluation of two new neuropsychological tests designed to minimize cultural bias in the assessment of HIV-1 seropositive persons: A WHO study. Archives of Clinical Neuropsychology. 1993;8:123-35.  
132. Benton A, Hamsher K. Multilingual Aphasia Examination. Iowa City, IA: AJA Associates. 1989.  
133. Meyers J, Meyers KE. Rey Complex Figure Test and Recognition Trial. Lutz, FL: PAR, Inc. 1996.  
134. Weineke MH & Deenst ER. Nueropsychological assessment of cognitive function following chemotherapy for breast cancer. Psycho-oncology. 1995;4: 61-6.  
135. Eriksen BA, Eriksen CW. Effects of noise letters upon identification of a target letter in a non- search task.  
Perception and Psychophysics. 1974; 16:143–9 136. Roche RAP, Garavan H, Foxe JJ, & O'Mara SM. Individual differences discriminate event-related potentials but not performance during response inhibition. Experimental Brain Research. 2005; 160:60-70.  
137. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: The PHQ
primary care study. JAMA. 1999;282:1737-44.  
138. Kroenke K, Spitzer RL, Williams JBW, Lowe B. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: A systematic review. Gen Hosp Psychiary. 2010; 10:345-59.  
139. Thekkumpurath P, Walker J, Butcher I, Hodges L, Kleiboer A, O'Connor M, Wall L, Murray G, Kroenke K, Sharpe M. Screening for major depression in cancer outcomes. Cancer. 2011; 117:218-27.  
140. Hann DM, Jacobsen PB, Azzarello LM, Martin SC, Curran SL, Fields KK, Greenberg H, Lyman G. Measurement of fatigue in cancer patients: Development and validation of the Fatigue Symptom Inventory. Quality of Life Research.  
1998;7:301-10.  
141. Hann DM, Denniston MM, Baker F. Measurement of fatigue in cancer patients: Further validation of the Fatigue Symptom Inventory. Quality of Life Research. 2000;9:847-54.  
142. Chelune CJ, Heaton RK, Leahman RAW. Neuropsychological and personality correlates of patients' complaints of disability. In: Goldstein G, Tarter RE, editors. Advances in Clinical Neuropsychology, Vol. 3. New York: Plenum Press; Plenum Press: 95-126.  
143. Benedict R, Schretlen D, Groninger L, Brandt J. Hopkins Verbal Learning Test Revised: normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychologist. 1998;12:43-55.  
144. Spreen, O. & Straus, E. (1998). A compendium of Neuropsychological Tests: Administration, Norms, and Commentary. NY: Oxford University Press. 2nd Ed.  
145. Deprez S, Amant F, Yigit R, Porke K, Verhoeven J, Van den Stock J, Smeets A, Christiaens MR, Leemans A, Van Hecke W, Vandenberghe J, Vandenbulcke M, Sunaert. S. Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Hum Brain Mapp. 2011 Mar;32(3):480-93. doi: 10.1002/hbm.21033. PubMed PMID: 20725909. 146. Deprez S, Amant F, Smeets A, Peeters R, Leemans A, Van Hecke W, Verhoeven JS, Christiaens MR, Vandenberghe J, Vandenbulcke M, Sunaert S. Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol. 2012 Jan 20;30(3):274-81. doi: 10.1200/JCO.2011.36.8571. Epub 2011 Dec 19. PubMed PMID: 22184379.  
147. Lundervold A. On consciousness, resting state fMRI, and neurodynamics. Nonlinear Biomed Phys. 2010 Jun 3;4 Suppl 1:S9. doi: 10.1186/1753-4631-4-S1-S9. PubMed PMID: 20522270; PubMed Central PMCID: PMC2880806.  
148. van den Heuvel MP, Hulshoff Pol HE. Exploring the brain network: a review on resting-state fMRI functional connectivity. Eur Neuropsychopharmacol. 2010 Aug;20(8):519-34. doi: 10.1016/j.euroneuro.2010.03.008. Epub 2010 May 14. Review.PubMed PMID: 20471808. 149. Ystad M, Hodneland E, Adolfsdottir S, Haász J, Lundervold AJ, Eichele T, Lundervold A. Cortico-striatal connectivity and cognition in normal aging: a combined DTI and resting state fMRI study. Neuroimage. 2011 Mar 1;55(1):24-31. doi: 10.1016/j.neuroimage.2010.11.016. Epub 2010 Nov 10. PubMed PMID: 21073962.  
150. Hodneland E, Ystad M, Haasz J, Munthe-Kaas A, Lundervold A. Automated approaches for analysis of multimodal MRI acquisitions in a study of cognitive aging. Comput Methods Programs Biomed. 2012 Jun;106(3):328-41. doi:
10.1016/j.cmpb.2011.03.010. Epub 2011 Jun 12. PubMed PMID: 21663993. 151. Kesler SR, Kent JS, O'Hara R. Prefrontal cortex and executive function impairments in primary breast cancer. Arch Neurol. 2011 Nov;68(11):1447-53. doi: 10.1001/archneurol.2011.245. PubMed PMID: 22084128; PubMed Central PMCID: PMC3239218. 152. Kesler SR, Wefel JS, Hosseini SM, Cheung M, Watson CL, Hoeft F. Default mode network connectivity distinguishes chemotherapy-treated breast cancer survivors from controls. Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11600-5. doi: 10.1073/pnas.1214551110. Epub 2013 Jun 24. PubMed PMID: 23798392; PubMed Central PMCID: PMC3710809.  
153. Jennifer Bruno, PhD,1 SM Hadi Hosseini, PhD,1 and Shelli Kesler, PhD1,2 Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. Neurobiol Dis. Dec 2012; 48(3): 329–338.  
154. Zuo XN1, Di Martino A, Kelly C, Shehzad ZE, Gee DG, Klein DF, Castellanos FX, Biswal BB, Milham MP.  
The oscillating brain: complex and reliable. Neuroimage. 2010 Jan 15;49(2):1432-45. 155. Reuter-Lorenz PA, Cimprich B. Cognitive function and breast cancer: promise and potential insights from functional brain imaging. Breast Cancer Res Treat. 2013 Jan;137(1):33-43. doi: 10.1007/s10549-012-2266-3.  
156. Patricia A. Ganz, Lorna Kwan, Steven A. Castellon, Amy Oppenheim, Julienne E. Bower, Daniel H. S. Silverman, Steve W. Cole,Michael R. Irwin, Sonia Ancoli-Israel, Thomas R. BelinCognitive Complaints After Breast Cancer Treatments: Examining the Relationship With Neuropsychological Test Performance. J Natl Cancer Inst;2013;105:791–801 157. Pullens MJJ, De Vries J, Roukema JA. Subjective cognitive dysfunction in breast cancer patients: a systematic review. Psycho-Oncology. 2010; 19(11):1127–1138.  
158. Saykin AJ, Wishart HA, Rabin LA, et al. Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI. Neurology.2006; 67(5):834–842.  
159. Ganz PA. Doctor, Will the treatment you are recommending cause chemobrain? J Clin Oncol. 2012; 30(3):229–231.  
160. Robert J. Ferguson, RH, McDonald BC, Rocque MR, Furstenberg CT, Horrigan S, Ahles TA & Saykin AJ. Development of CBT for chemotherapy-related cognitive change: results of a waitlist control trial. Psycho- Oncology, 21: 176–186 (2012).
mcc# 17089
14.0 references

Amendment 11.0; 07 October **2015**
Pilot Trial of COGNUTRIN in Breast Cancer **Survivors**
Principal Investigator:  Nagi Kumar, PhD, RD, **FADA**
mcc# 17089
summary of changes

4.2  Criteria for exclusion Corrected actual creatinine clearance of >60 to <60.  
4.3  Anticipated problems with subject recruitment and retention Increased payment to participants from $25 to $50 for each visit to cover travel expenses.  
Added that participants traveling more than 100 miles from their home to reach the research site will receive an additional $30 for transportation costs.  
Amendment 10.0; 25 February **2015**
Pilot Trial of COGNUTRIN in Breast Cancer Survivors Principal Investigator:  Nagi Kumar, PhD, RD, FADA  
4.2  Criteria for exclusion Added the following:
Subjects with metabolic disorders (a) who are otherwise eligible, (b) treated for hypothyroidism by their primary MD with Synthroid (levothyroxine) and (c) with the approval of the Moffitt treating oncologist will not be excluded from the study.  
Added "(ex. tissue expanders)" as an example of ferromagnetic material that would prohibit MRI
imaging.  
7.7.8  Adverse events monitoring (Appendix VIII)
Added the following:
For each subject, AE's will be collected at the screening, Month 1, Month 2, Month 3/EOT, visits as well as at the 7‐day post‐treatment follow‐up call by the clinical research coordinator. AE's collected at the screening visit will be catalogued as baseline symptoms by the clinical research coordinator and the AE log will be reviewed and signed by either the patient's medical oncologist or PI. AE's collected during Month 1 and 2 visits will be reviewed with the patient by the nurse who drew their blood at CRU and the AE log will be signed by the principal investigator. Finally, at the Month 3 visit, the participant's medical oncologist will review the AE log with the patient and sign‐off on the reported symptoms; if the medical oncologist is unavailable to sign the AE log at this visit, then the PI will review and sign the form. AE's reported at the 7‐day follow‐up call will be reviewed and signed by the PI. The participant's reported symptoms at this time point will be documented on a powerchart telephone note by the clinical research coordinator. Serious adverse events (SAE's) are reported to IRB and FDA. If a participant reports an SAE, the PI will immediately be informed and she will then report it to the IRB and FDA. AE logs will be scanned to patients' medical records by the clinical research coordinator once they are off‐study.  
Amendment 9.0; 22 January 2015 Pilot Trial of COGNUTRIN in Breast Cancer **Survivors**
Principal Investigator:  Nagi Kumar, PhD, RD, **FADA**
Summary of **Changes:** 7.7.9 Assessment of Cognitive Performance (pages 21‐22)
Clarified the procedures in detail for memory testing.  
  
Janelle Perkins, Pharm.D., Chairperson USF Institutional Review Board Re: Summary of Changes IRB\#: Pro0009858 Title: Pilot Trial of COGNUTRIN in Breast Cancer Survivors - MCC \#17089 Attached, you will find a tacked and clean copy of an amendment to the above application. The evaluations during each study visit have been updated to reflect the current standards and evolving methods in the research literature. Modification of faculty in the study is also included based on turnover.  
The following are included with this submission:
A. Tracked copy of the currently approved protocol, reflecting changes below B.  Clean copy of the amended protocol Summary of changes and rationale:
Cover Page: Updated to reflect addition of new staff
.  
Schema: Updated to reflect the following cognitive tests are now conducted at the screening
•
visit instead of baseline:
o HVLT-R
o COWA
Color Trails Part 1 & 2 o Schema: Updated to reflect different versions of cognitive testing forms used at different visits o Schema: Addition of  post intervention phone call 7 +/- 3 days after end of treatment visit
.  
Schema: Updated diet survey distribution during intervention o Table of Contents: Updated to reflect correct protocol page numbering
•
Protocol Section 7:
.  
Updated clinical assessments and procedures to reflect changes mentioned above o removal of concomitant medication collection at weeks 2, 3, 5, 6, 7, 9, 10 & 11 as patient o is not contacted at this time points Section was redone to provide clarity regarding procedures and specific time points o Appendix numbers updated to reflect changes in updated version of appendices o Protocol Section 9.1: Updated blood sample collection to provide clarity regarding where
.  
samples will be kept Thank you,  
  
Senior Member, Population Sciences Division Director, Cancer Chemoprevention, Moffitt Cancer Center Professor, Oncologic Sciences | tel: 8137456885 | fax: 8137457183 | email: nagi.kumar@moffitt.org 12902 Magnolia Drive 1-888-MOFFITT
Tampa, FL 33612-9416 MOFFITT.org
mcc# 17089
july 16 2014

Janelle Perkins, Pharm.D., Chairperson USF Institutional Review Board Re: Summary of Changes IRB\#: Pro00009858 Title: Pilot Trial of COGNUTRIN in Breast Cancer Survivors - MCC \#17089 Attached, you will find a tracked and clean copy of an amendment to the above application. Due to the complicated nature of breast cancer and the treatments associated with this disease, the inclusion criteria has been revised to allow sufficient time for patients to have any necessary surgeries (i.e. breast reconstruction) after completing chemotherapy +/- radiation. Therefore the inclusion criterion has been revised as follows:
Completed neoadjuvant or adjuvant treatment with anthracyclines and/or taxanes + or –Radiation therapy within past 6 months (+/- 7 days) (subjects on concurrent endocrine therapy (TAM, Aromatase inhibitors are also eligible to participate as this is standard of care for this patient population)
Please feel free to contact me if you have any questions regarding these changes. Thank you, Nagi B. Kumar, Ph.D., R.D., FADA Senior Member, Population Sciences Division Director, Cancer Chemoprevention, Moffitt Cancer Center Professor, Oncologic Sciences | tel: 8137456885 | fax: 8137457183 | email: nagi.kumar@moffitt.org  
  
Janelle Perkins, Pharm.D., Chairperson USF Institutional Review Board Re: Summary of Changes IRB\#: Pro0009858 Title: Pilot Trial of COGNUTRIN in Breast Cancer Survivors - MCC \#17089 Attached, you will find a tacked and clean copy of an amendment to the above application.  
Inclusion/exclusion criteria have been modified to include the most current standards and evolving methods.  
Since this clinical trial is a feasibility trial, it is aimed at providing information regarding (Section 2.0 of the protocol):
Available patient population
.  
.  
Likelihood of patients agreeing to participate in the clinical trial
.  
Potential modifications to clinical trial design and eligibility criteria to enhance enrollment We have screened over 90 potentially eligible subjects in the past 30 days and have not identified any subject to be eligible for this clinical trial, although this group of subjects report cognitive impairment. With the constantly evolving changes in treatment options for this subject population as well as the timing of chemotherapy, surgery and radiation therapy along with concurrent endocrine therapy, our team has observed that the criteria of inclusion has to be revised accordingly and has made the following changes in the criteria for inclusion:
.  
. . .  
.  
.  
Schema:  Updated to reflect changes in eligibility criteria Protocol Section 3.0: Screening updated to reflect changes to inclusion criteria Protocol Section 4.0: Screening updated to reflect changes to inclusion criteria Protocol Section 4.1: Inclusion criteria now includes women 30-70 years of age, cases with Stage I-IIIB Breast Cancer, treatment with neoadjuvant or adjuvant anthracyclines or taxanes, treatment completed within the past 60 days Protocol Section 4.2: Exclusion criteria updated to reflect patients with Stage IIIC or IV Protocol Section 7.6.12: Clarification regarding biomarker collection and processing Please feel free to contact me if you have any questions regarding these changes.  
Thank you;  
  
Senior Member, Population Sciences Division Director, Cancer Chemoprevention, Moffitt Cancer Center Professor, Oncologic Sciences | tel | 28137456885 | fax | amp | 7457183 | email: ,
Pilot Trial of COGNUTRIN in Breast Cancer Survivors Principal Investigator: Nagi Kumar, PhD, RD, FADA
Amendment 5.1, 04/08/2014
mcc# 17089
summary of changes

SCHEMA (page 3)
- Revised to correct the questionnaires that will be completed at each visit.  
7 CLINICAL EVALUATIONS AND PROCEDURES (pages 24-26)
- Added window (+/- 7 days) to week 4, week 8, and week 12 visits.  
1 Janelle Perkins, Pharm.D., Chairperson USF Institutional Review Board Re: Summary of Changes IRB\#: Pro00009858 Title: Pilot Trial of COGNUTRIN in Breast Cancer Survivors - MCC \#17089 Enclosed, please find a copy of an amendment to the above application. This modification reflects no substantive changes in procedure. Specific methods as well as inclusion/exclusion criteria have been modified to include the most current standards and evolving methods in the research literature. Modification of faculty in the study is also included based on turnover. The following are included with this submission:
A. Tracked copy of the currently approved protocol, reflecting changes below B. Clean copy of the amended protocol Summary of changes and rationale:
- **Schema & Protocol Section 3.0:** Clarification regarding the inclusion of women on concurrent endocrine therapy; Updated to reflect that all patients will now receive resting-state functional MRI in addition to structural MRI
- **Protocol Section 2.1:** Specific Aim 3 updated to reflect the use of resting-state functional MRI in addition to structural MRI in order to evaluate changes in imaging markers
- **Protocol Sections 4.0 & 4.1:** Clarification regarding the inclusion of women on concurrent endocrine therapy
- **Protocol Section 4.2:** Clarification regarding the parameters for determining the exclusion of women with renal or liver disease
- **Protocol Sections 5.1.2, 5.6 & 6.1.2:** The removal of specific drug bottle descriptions in order to reflect that all study agents are bottled and labeled per investigational drug use regulations
- **Protocol Section 6.5:** Clarification regarding which labs determine abnormal liver function and the adverse event grades that will result in discontinuation of the study agent
- **Protocol Section 7.1:** Updated to reflect that all patients will now receive restingstate functional MRI in addition to structural MRI; Removal of attention tasks during MRI
- **Protocol Section 7.3:** Updated to reflect that all patients will now receive resting state functional MRI in addition to structural MRI
- **Protocol Section 7.6.6:** Removal of additional 5 days of study agent being supplied to patient , agents were bottled based on a 30 day supply
- **Protocol Section 7.6.10:** Functional MRI has been replaced with resting-state functional MRI, therefore working memory tasks to be performed in MRI has been removed from protocol
- Protocol Section: **7.6.15:** Functional MRI methods were replaced with restingstate functional MRI methods
- **Protocol Section 12.5.2:** Secondary endpoint changed to reflect the use of a resting-state functional MRI versus a functional MRI
- **Protocol Section 14.0:** References updated to include those used to support the use of resting-state functional MRI
- **Appendices:** Updated with the Teleform version of questionnaires Please feel free to contact me if you have any questions regarding these changes. Thank you, Nagi B. Kumar, Ph.D., R.D., FADA Senior Member, Population Sciences Division Director, Cancer Chemoprevention, Moffitt Cancer Center Professor, Oncologic Sciences University of South Florida College of Medicine 12902 Magnolia Drive Tampa, FL 33612 | tel: 8137456885 | fax: 8137457183 | email: nagi.kumar@moffitt.org Janelle Perkins, Pharm.D., Chairperson USF Institutional Review Board Re: Summary of Changes IRB\#: Pro00009858 Title: Pilot Trial of COGNUTRIN in Breast Cancer Survivors - MCC \#17089 Enclosed, please find a copy of an amendment to the above application. This modification reflects no substantive changes in procedure. Specific methods as well as inclusion/exclusion criteria have been modified to include the most current standards and evolving methods in the research literature. Modification of faculty in the study is also included based on turnover.  
The following are included with this submission:
A. Tracked copy of the currently approved protocol, reflecting changes below B. Clean copy of the amended protocol Summary of changes and rationale:
- **Schema:** Updated to reflect changes regarding functional MRI (fMRI)
- **Schema:** Updated to reflect removal of weekly phone calls
- **Protocol Section 2.0:** Objective 3 updated to reflect changes regarding fMRI
Rationale for Change: Although fMRI is one of the variables proposed in this clinical trial, there has been several installation issues with regard to the fMRI equipment in association with the MRI equipment current used in structural MRI studies. We anticipate that this will require several months before the equipment can be installed that ensures safety of the MRI. Since funding was received in July of 2013, we have been in the process of identifying MRI equipment where the functional MRI equipment can be added without compromising the safety to the subjects/other patients. We have learned that there will be further delay in the availability of the fMRI. The delay in the availability of the functional MRI has serious implications on (a) bioavailability of the agent we have developed for this clinical trial; (b) cost of reproducing another batch of agent to match the current batch for consistency of components and (c) the funding for this clinical trial. Based on these major concerns, we have amended the proposal to include all other primary and secondary variables that we proposed to monitor in this pilot trial and will perform the functional MRI in the second 10 pairs of subjects (10 from the Treatment arm 10 from the placebo arm).  
- **Protocol Section 7.**1: Removal of weekly phone calls Rational for Change: Subjects will see a Nurse Practitioner (NP) at monthly visits for a limited physical exam assessing any adverse events. Subjects are instructed to contact coordinator, PI or physician should any adverse events occur prior to monthly visit.  
- **Protocol Section 7.3:** Addition of limited physical exam with NP to assess adverse events Please feel free to contact me if you have any questions regarding these changes. Thank you, Nagi B. Kumar, Ph.D., R.D., FADA Senior Member, Population Sciences Division Director, Cancer Chemoprevention, Moffitt Cancer Center Professor, Oncologic Sciences University of South Florida College of Medicine 12902 Magnolia Drive Tampa, FL 33612 | tel: 8137456885 | fax: 8137457183 | email: nagi.kumar@moffitt.org
mcc# 17089
august 21 2013

Janelle Perkins, Pharm.D., Chairperson USF Institutional Review Board Re: Summary of Changes IRB\#: Pro0009858 Title: Pilot Trial of COGNUTRIN in Breast Cancer Survivors - MCC \#17089 Enclosed, please find a copy of an amendment to the above application.  This modification reflects no substantive changes in procedure.  Specific methods as well as inclusion/exclusion criteria have been modified to include the most current standards and evolving methods in the research literature. Modification of faculty in the study is also included based on turnover.  
The following are included with this submission:
A. Tracked copy of the currently approved protocol, reflecting changes below B.   Clean copy of the amended protocol Updated study materials ن Summary of changes and rationale:
Cover Page: Addition of Dr. Hatem Soliman as a co-investigator
.  
Cover Page: Addition of Dr. David Evans as co-investigator (Assistant member)
.  
Cover Page: Deletion of Kate Jan Van Rensberg (Applied Research Scientist)
.  
Schema: Updated to reflect changes made to eligibility criteria
.  
Protocol Section 3.0:  Clarification of study plan summary
.  
Protocol Section 4.0:  Updated to reflect current NCCN guidelines (Version 3.2013),
.  
which state "chemotherapy and endocrine therapy when used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy.  Available data suggest that sequential or concurrent endocrine therapy with radiation therapy is acceptable". Based on these revised guidelines, we have revised the inclusion and exclusion criteria. The rationale for these revisions is to ensure that the current pilot trial includes a homogenous and representative population of patients who are treated using the standard guidelines and who will be potentially benefitted the most with an intervention with COGNUTRIN
Protocol Section 4.1: Inclusion criteria of age updated to be more representative of the
.  
population being studied. Protocol Section 4.1: Allowable treatments updated to allow for endocrine therapy and
.  
radiation therapy as this is standard of care in this population Protocol Section 4.2: Addition of Stage IIIB and IIIC as exclusion criteria
.  
Protocol Section 4.2: Exclusion criteria of advanced diabetes clarified to state insulin
.  
dependent diabetes Protocol Section 4.2: Exclusion criteria updated to include patients with medical history
.  
of concussions as this could skew study results of MRI Brain
.  
.  
. o .  
. .  
.  
Protocol Section 6.2: Administration of Lovaza has been updated to reflect 2,  1 gm capsules will be taken BID for a total of 4 gm daily Protocol Section 6.5(c): Risks due to MRI updated to include section on possible psychological distress posed by MRI's confining environment. Protocol Section 7.6.9:  Removal of the administration of Attention Task and Executive Functioning in MRI and instead using various Working Memory Task  parameters Protocol Section 7.6.12: Collection of biomarkers will now be done in 10ml blood in green top tubes rather than purple top tubes to allow for consistency is sample cllection Protocol Section 7.6.15:  MRI scanner will no longer be completed on Moffitt's 1.5T
scanner, instead they will now be done on University Diagnostic Institute's (UDI) 3T scanner Protocol Section 7.6.15: The addition of Diffusion Tensor Imaging (DTI) to measure changes in white matter tracts across sections Protocol Section 7.6.15: The addition of resting-state fMRI data collection period Protocol Section 12.3: Randomization will now include block randomization to ensure an equal number of subjects in each arm receiving radiation post chemotherapy and concurrent endocrine therapy Please feel free to contact me if you have any questions regarding these changes.  
Thank you,  
  
Nagi B. Kumar, Ph.D., R.D., FADA
Senior Member, Population Sciences Division Director, Cancer Chemoprevention, Moffitt Cancer Center Professor, Oncologic Sciences University of South Florida College of Medicine 12902 Magnolia Drive Tampa, FL 33612 | tel: 8137456885 | fax:  8137457183 | email: nagi.kumar@moffitt.org