Angela Starkweather, Ph.D., ACNP-BC, CNRN Associate Professor Virginia Commonwealth University

1. The Power of Glia:Biomarkers of Glial Activation and Depressive Symptoms in Patients with a Primary Malignant Brain Tumor Angela Starkweather, Ph.D., ACNP-BC, CNRN Associate Professor Virginia Commonwealth University School of Nursing September 14, 2012

2. Primary Malignant Brain Tumors • Each year, 8.2 of every 100,000 people in the United States are diagnosed with a primary malignant brain tumor • 18,500 new cases of primary malignant brain and CNS tumors are expected to be diagnosed in the United States in 2012 (10,620 in males; 7,880 in females)1 • PMBTs represent 2% of all cancers diagnosed in the United States1 • An estimated 13,000 deaths will be attributed to primary malignant brain tumors each year2 • Brain tumors often cause devastating neurologic deficits/ complications and a negative impact on quality of life 1. 2005-2010 data from the Central Brain Tumor Registry of the United States. www.cbtrus.org/factsheet.htm 2. SEER.cancer.gov/CSR/2010_2011

3. Astrocytomas: Median Survival Gliomas are the most commonly diagnosed of both benign and malignant primary brain tumors with astrocytomas representing >35% of primary brain tumors Tumor Type median survival (mos) Low-grade astrocytoma ~60 Anaplasticastrocytoma ~36 Glioblastomamultiforme <18

4. Treatment of Astrocytomas • Dependent on size, growth rate, location, type of symptoms experienced • Craniotomy with intent for complete resection • Ultrasonic aspiration may be used • Polymer wafers may be inserted • Stereotactic radiosurgery • Chemotherapy

5. Depressive Symptoms • Neuro-oncology patients are at particular risk of suffering from depressive symptoms because: • Difficult to recognize or separate situational factors from “major depression” criteria • There is no standard of care for patients with cancer • Pasquini, M. & Biondi, M. (2007). Depression in cancer patients: A critical review. Clinical Practice and Epidemiology in Mental Health, 3, 2. • Raison, C. L., & Miller, A. H. (2003). Depression in cancer: New developments regarding diagnosis and treatment. Biological Psychiatry, 54, 283-294.

6. Symptom experience for patients with a primary brain tumor • Fatigue, drowsiness, and memory problems • Fatigue directly correlated with survival • Fatigue, weakness, drowsiness and mood problems • Distress, fatigue, sleep, sad, irritable • Armstrong, T. S., Mendoza, T., Gring, I., Coco, C., Cohen, M. Z., Eriksen, I., . . . Cleeland, C. (2006). Validation of the M. D. Anderson symptom inventory brain tumor module. Journal of Neuro-Oncology, 80(1), 27-35. • Brown, P. D., Ballman, K. V., Rummans, T. A., Maurer, M. J., Sloan, J. A., Boeve, B.F, … Buckner, J. C. (2006). Prospective study of quality of life in adults with newly diagnosed high grade tumors. Journal of Neuro-Oncology, 76, 283-291. • Fox, S. W., Lyons, D., & Farace, E. (2007, Spring). Symptom clusters in patients with high-grade glioma. Journal of Nursing Scholarship, 39(1), 61-67. • Gleason, J. F., Case, B. A., Rapp, S. R., Ip, E., Naughton, M., & Butler, J. M. (2007). Symptom clusters in patients with newly-diagnosed brain tumors. Supportive Oncology, 427-433.

7. Depressive Symptoms in Cancer • In patients with cancer, depressive symptoms are a strong prognostic indicator of survival. • Gathinji, M., McGirt, M. J., Attenello, F. J., Chaichana, K. L., Than, K., Olivi, A., et al. (2008). Association of preoperative depression and survival after resection of malignant brain astrocytoma. Surgical Neurology, epub Sept 10, 1-7. • Hjerl, K., Andersen, E. W., Keiding, N., Mouridsen, H. T., Mortenson, P. B., & Jorgensen, T. (2003). Depression as a prognostic factor for breast cancer mortality. Psychosomatics, 44, 24-30. • Mainio, A., Tuunanen, S., Hakko, H., Timonen, M., Niemela, A., Koivukangas, J., & Rasanen, P. (2005). Depression in relation to survival among neurosurgical patients with a primary brain tumor: A 5-year follow-up study. Neurosurgery, 56, 1234–1241. • Mainio, A., Hakko, H., Niemela, A., Koivukangas, J., & Rasanen, P. (2005). Depression and functional outcome in patients with brain tumors: A population-based 1-year follow-up study. Journal of Neurosurgery,103, 841–847. • Litofsky, N. S., Farace, E., Anderson, F. Jr, Meyers, C. A., Huang, W., Laws, E. R. Jr, et al. (2004). Depression in patients with high-grade glioma: Results of the Glioma Outcomes Project. Neurosurgery, 54, 358–366. • Nakaya, N., Saito-Nakaya, K., Akizuki, N., Yoshikawa, E., Kobayakawa, M., & Fujimori, M. et al. (2006). Depression and survival in patient with non-small cell lung cancer after curative resection: A preliminary study. Cancer Science, 97, 199-205.

8. Depressive Symptoms • Depressive symptoms may be linked with inflammatory processes in the periphery and central nervous system • Vollmer-Conna, U., Fazou, C., Cameron, B., Li, H., Brennan, C., Luck, L., et al. (2004). Production of pro-inflammatory cytokines correlates with the symptoms of acute sickness behavior in humans. Psychological Medicine, 34, 1289-1297. • Wichers, M., & Maes, M. (2002). The psychoneuroimmuno-pathophysiology of cytokine induced depression in humans. International Journal of Neuropsychopharmacology, 5, 375-388. • Wilson, D. R., & Warise, L. (2008). Cytokines and their role in depression. Perspectives in Psychiatric Care, 44, 285-289.

9. Depressive Symptoms • Astrocytes (as well as lymphocytes, macrophages, and endothelial cells) produce and secrete proinflammatory cytokines resulting in increased glial activation and higher levels of glial fibrillary acidic protein (GFAP) and matrix metalloproteinase-2 (MMP2) and MMP9 • Brommeland, T., Rosengran, L., Fridland, S., Hennig, R., & Isaksen, V. (2007). Serum levels of glialfibrillary acidic protein correlate to tumour volume of high-grade gliomas. ActaNeurologicaScandinavica, 116, 380-384. • Samaras, V., Piperi, C., Korkolopoulou, P., Zisakis, A., Levidou, G., Themistocleous, M., et al. (2007). Application of the ELISPOT method for comparative analysis of interleukin (IL)-6 and IL-10 secretion in peripheral blood of patients with astroglial tumors. Molecular and cellular Biochemistry, 304, 343-351. • Maier, S. F., & Watkins, L. R. (1998). Cytokines for psychologists: Implications of bidirectional immune-to-brain communication for understanding behavior, mood and cognition. Psychological Review, 105, 83-107.

10. Depressive Symptoms in Patients with a Cerebral Astrocytoma • 2-year study to evaluate feasibility of measuring depressive symptoms over the disease trajectory • Patients were assessed for depressive symptoms (CES-D, BDI-II), perceived stress (PSS), and cancer-related symptoms (MDASI-BTM) before and after surgery (pre-op; 3, 6, 9, and 12-months post-resection) • GFAP, MMP2 and MMP9 were measured in tissue samples collected at the time of resection, and in plasma at each time point

11. Sample Description • 23 patients newly diagnosed with a grade IV astrocytoma • Male – 11; Female – 12 • Age range 25-67 years of age • Mean age of 45.7 years • History of depression – 7 (30%)

12. Depressive Symptom Over Time

13. Symptom Profiles Across Time

14. GFAP, MMP2, MMP9 Across Time

15. Relationships between Depressive Symptoms and Biomarkers

16. Relationship between Depressive Symptoms and MDASI Core Symptoms Baseline BDI-II Score was positively associated with MDASI Core Symptoms (F=8.19, p<0.01)

17. Relationship between Depressive Symptoms and MDASI Interference Baseline BDI-II Score was positively associated with MDASI Interference (F=12.2, p<0.002)

18. Conclusions • A clinically significant level of depressive symptoms were very common in this patient population. • Markers of glial activation (GFAP, MMP2 and MMP9) in tumor tissue and plasma were not associated with depressive symptoms. • Baseline depressive symptoms were associated with cancer-related symptoms and symptom interference.