Dimitri G. Trembath, MD, PhD
My research interests are focused on neuropathology, surgical pathology, ophthalmic pathology, and molecular pathology. Currently, my research at UNC currently focuses on two areas: 1) melanoma metastases to the central nervous system (CNS), a collaboration with Dr. Stergios Moschos of the Department of Hematology/Oncology and Dr. Janiel Shields of the Department of Radiation Oncology and 2) assisting in verifying mutations in brain tumors submitted to UNCseq that have possible therapeutic relevance for patients.
Melanoma Metastases to the CNS
Melanoma is the 5th and 6th most frequent cancer amongst men and women respectively (American Cancer Society, 2012 data) and is one of the most frequent tumors to metastasize to the brain (up to 70% in select autopsy series). Despite the short overall survival (4-5 months in most recent series), there is a significant degree of heterogeneity in overall survival which is not well understood. Dr. Moschos has done significant initial work at the University of Pittsburgh identifying histologic features associated with prolonged overall survival; these features include high immune infiltrate and low degree of hemorrhage. Dr. Moschos has also performed whole genome expression profiling of RNA obtained from a subset of melanomas metastatic to the brain and identified a number of Encarta pathways associated with adverse prognosis.
In collaboration with Dr. Moschos, I have identified thirty-six cases of melanoma metastases to brain (MMB) from the pathology files here at UNC. Dr. Moschos and I have done an initial characterization of these tumors, reviewing the H&E stained slides for his previously discovered significant histologic markers, including immune infiltrate and hemorrhage. We have also begun scoring a MMB tissue microarray for different therapeutic targets such as MERTK. We are in the process of comparing the UNC results to those Dr. Moschos obtained in his Pittsburgh cohort. Future directions will include analyzing both the UNC material and the MMB tissue microarray for other targets from Dr. Moschos’s WGEP results, such as tubby and presenillin. For those patients seen at UNC with MMB, we will also be obtaining their original melnoma biopsies/excisions (when available) to compare WGEP between the original tumor and their metastatic disease. Finally, as a neuropathologist I am also particularly interested in the changes in the brain micro-environment that may help/hinder the development of metastases and will be examining differences in gene expression between native CNS cells involved by the tumor (e.g. the endothelial cells of blood vessels encircled by tumor and the nearby reactive astrocytes) and uninvolved native CNS cells.
UNC Sequencing of Brain Tumors
More recently, in collaboration with Dr. David Eberhard of the Department of Pathology and Laboratory Medicine, I have become involved with the efforts of UNCseq to analyze brain tumors for novel mutations that may present possible therapeutic targets. While this project is still in its infancy, at least twenty primary CNS tumors (glial, meningeal, other) have been sequenced by UNCseq with several demonstrating mutations in possible therapeutic targets. Dr. Eberhard and I are verifying these UNCseq findings and will be collaborating with the appropriate clinical groups at UNC in analyzing effects from therapies based on these presence of these mutations.
Miedema J, Solle M, Zanation A, Trembath D. Granular cell tumor of the trigeminal nerve. Clin Neuropathol. 2012 Mar-Apr;31(2):104-7.
Davies JM, Trembath D, Deal AM, Funkhouser WK, Calvo BF, Finnegan T, Weck K, Tepper JE, O’Neil BH. Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy. Radiation Oncology 2011, 6:114
Terry NG, Zhu Y, Rinehart MT, Brown WJ, Gebhart SC, Bright S, Carretta E, Ziefle CG, Panjehpour M, Galanko J, Madanick RD, Dellon ES, Trembath D, Bennett A, Goldblum JR, Overholt BF, Woosley JT, Shaheen NJ, Wax A. Detection of Dysplasia in Barrett's Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements. Gastroenterology 2010 Sep 18.
Trembath, DG. Molecular Testing for Brain Tumors. Advance/Laboratory 2010, Sept 19(9):12-14.
Losh, M, Sullivan, PF, and Trembath, DG. Current Developments in the Genetics of Autism: From Phenome to Genome. J Neuropathol Exp Neurol. 2008 Sep;67(9):829-37.
Trembath, DG, Miller, CR, and Perry, A. Grey Zones in Brain Tumor Classification: Evolving Concepts. Adv Anat Pathol. 2008 Sep;15(5):287-97.
Trembath, DG, Lal, A, Kroll, DJ, Oberlies, NH, Riggins, GJ. Identification of Small Molecules that Selectively Inhibit Glioblastoma Cell Lines Expressing EGFRvIII. Molecular Cancer 2007 Apr 16;6(1):30.
Trembath, DG, Ervin, JF, Broom, L, Szymanski, M, Welsh-Bohmer, K, Piper, C, Hulette, CM. The Distribution of Cerebrovascular Amyloid in Alzheimer’s Disease Varies with APOE Genotype. Acta Neuropathol (Berl). 2007 Jan;113(1):23-31.
Vieira AR, Murray JC, Trembath D, Orioli IM, Castilla EE, Cooper ME, Marazita ML, Lennon-Graham F, Speer M. Studies of reduced folate carrier 1 (RFC1) A80G and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms with neural tube and orofacial cleft defects. Am J Med Genet A. 2005 Jun 1;135(2):220-3.
Trembath DG, Semina EV, Jones DH, Patil SR, Qian Q, Amendt BA, Russo AF, Murray JC. Analysis of two translocation breakpoints and identification of a negative regulatory element in patients with Rieger’s syndrome. Birth Defects Research Part A Clin Mol Teratol. 2004; 70:82-91.
Trembath DG, Dash R, Major NM, Dodd LG. Cytopathology of mesenchymal chondrosarcomas: a report and comparison of four patients. Cancer Cytopathology. 2003; 99:211-6.
Trembath Y, Rosenberg C, Ervin JF, Schmechel DE, Gaskell P, Pericak-Vance M, Vance J, Hulette CM. Lewy body pathology is a frequent co-pathology in familial Alzheimer's disease. Acta Neuropathol (Berl). 2003; 105:484-8.
Trembath DG, Rijhsinghani A. Possible maternal inheritance of a common obstructive urinary tract anomaly. Report of a case of a woman with multiple urinary tract infections and two sons with posterior urethral valves. J Reprod Med. 2002; 47:962-4.
Vieira AR, Trembath D, VanDyke DC, Murray JC, Marker S, Lerner G, Bonner E, Speer M. Studies with His475Tyr glutamate carboxipeptidase II polymorphism and neural tube defects. Am J Med Genet. 2002; 111:218-9.
Van Dyke DC, Ellingrod VL, Berg MJ, Niebyl JR, Sherbondy AL, Trembath DG. Pharmacogenetic screening for susceptibility to fetal malformations in women. Ann Pharmacother. 2000; 34:639-45.
Trembath D, Sherbondy AL, Vandyke DC, Shaw GM, Todoroff K, Lammer EJ, Finnell RH, Marker S, Lerner G, Murray JC. Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population. Teratology. 1999; 59:331-41.