Faculty Bibliography
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Suprasellar epithelioid hemangioendothelioma: Case report and review of the literature
BACKGROUND: Epithelioid hemangioendothelioma (EHE) is a rare sarcoma of vascular origin, which is clinically and histologically intermediate between benign hemangioma and angiosarcoma. It is most commonly found in the liver, lung, and bone, however, 46 intracranial cases have been reported in the literature, of which this is the fifth reported suprasellar tumor. CASE DESCRIPTION: A 45-year-old woman developed progressive lethargy, somnolence, and memory decline over the course of 6 months. On computed tomography (CT), she was found to have a large hypothalamic mass and underwent subtotal resection via a bifrontal craniotomy. CONCLUSIONS: While primary intracranial EHE is an uncommon presentation of a rare tumor, the suprasellar region does not seem to be an unusual location when it does occur. Prognosis is generally good, and may be better for primary intracranial disease than that for EHE originating elsewhere. Surgery is the first line of therapy, with variable benefit from adjuvant chemotherapy or radiation when total resection is not possible. Chemotherapeutic approaches in current use are directed at preventing endothelial proliferation.
PMCID:5025957
PMID: 27656318
ISSN: 2229-5097
CID: 2254672
Adult Primary Spinal Epidural Extraosseous Ewing's Sarcoma: A Case Report and Review of the Literature
Background. Extraosseous Ewing's sarcoma in the spinal epidural space is a rare malignancy, especially in adults. Case Presentation. A 40-year-old male presented with back pain and urinary hesitancy. MRI revealed a thoracic extradural mass with no osseous involvement. He underwent surgery for gross total resection of the mass, which was diagnosed as Ewing's sarcoma. He was subsequently treated with chemoradiotherapy. He remains disease-free 1 year after surgery. Review of the literature indicated only 45 previously reported cases of spinal epidural extraosseous Ewing's sarcoma in adults. Conclusions. Extraosseous Ewing's sarcoma in the spinal epidural space is a rare clinical entity that should be included in the differential for spinal epidural masses. Its treatment is multidisciplinary but frequently requires surgical intervention due to compressive neurologic symptoms. Gross total resection appears to correlate with improved outcomes.
PMCID:5005550
PMID: 27610254
ISSN: 2090-6668
CID: 2238732
Deformable image registration between pathological images and MR image via an optical macro image
Computed tomography (CT) and magnetic resonance (MR) imaging have been widely used for visualizing the inside of the human body. However, in many cases, pathological diagnosis is conducted through a biopsy or resection of an organ to evaluate the condition of tissues as definitive diagnosis. To provide more advanced information onto CT or MR image, it is necessary to reveal the relationship between tissue information and image signals. We propose a registration scheme for a set of PT images of divided specimens and a 3D-MR image by reference to an optical macro image (OM image) captured by an optical camera. We conducted a fundamental study using a resected human brain after the death of a brain cancer patient. We constructed two kinds of registration processes using the OM image as the base for both registrations to make conversion parameters between the PT and MR images. The aligned PT images had shapes similar to the OM image. On the other hand, the extracted cross-sectional MR image was similar to the OM image. From these resultant conversion parameters, the corresponding region on the PT image could be searched and displayed when an arbitrary pixel on the MR image was selected. The relationship between the PT and MR images of the whole brain can be analyzed using the proposed method. We confirmed that same regions between the PT and MR images could be searched and displayed using resultant information obtained by the proposed method. In terms of the accuracy of proposed method, the TREs were 0.56+/-0.39mm and 0.87+/-0.42mm. We can analyze the relationship between tissue information and MR signals using the proposed method.
PMCID:5097673
PMID: 27613662
ISSN: 1618-0631
CID: 2238882
Pilocytic astrocytoma and glioneuronal tumor with histone H3 K27M mutation [Letter]
PMCID:4983033
PMID: 27519587
ISSN: 2051-5960
CID: 2218812
Methylation profiling of locally advanced rectal cancer (LARC): Exploration of potential predictive markers for neoadjuvant chemoradiation (NACR). [Meeting Abstract]
ISI:000378109600591
ISSN: 1527-7755
CID: 2169652
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2016:113(16):4476-81.DOI: 10.1073/pnas.1525360113
Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival
Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.
PMCID:4843473
PMID: 27044098
ISSN: 1091-6490
CID: 2120752
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2016:113(16):4470-5.DOI: 10.1073/pnas.1525349113
Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages
Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti-Ang-2-neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti-colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells.
PMCID:4843449
PMID: 27044097
ISSN: 1091-6490
CID: 2120762
Development of a 2D Image Reconstruction and Viewing System for Histological Images from Multiple Tissue Blocks: Towards High-Resolution Whole-Organ 3D Histological Images
High-resolution 3D histology image reconstruction of the whole brain organ starts from reconstructing the high-resolution 2D histology images of a brain slice. In this paper, we introduced a method to automatically align the histology images of thin tissue sections cut from the multiple paraffin-embedded tissue blocks of a brain slice. For this method, we employed template matching and incorporated an optimization technique to further improve the accuracy of the 2D reconstructed image. In the template matching, we used the gross image of the brain slice as a reference to the reconstructed 2D histology image of the slice, while in the optimization procedure, we utilized the Jaccard index as the metric of the reconstruction accuracy. The results of our experiment on the initial 3 different whole-brain tissue slices showed that while the method works, it is also constrained by tissue deformations introduced during the tissue processing and slicing. The size of the reconstructed high-resolution 2D histology image of a brain slice is huge, and designing an image viewer that makes particularly efficient use of the computing power of a standard computer used in our laboratories is of interest. We also present the initial implementation of our 2D image viewer system in this paper.
PMID: 27100217
ISSN: 1423-0291
CID: 2113712
A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer
Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.
PMCID:4794335
PMID: 26738797
ISSN: 1946-6242
CID: 2042672
New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs
Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.
PMCID:5139621
PMID: 26919435
ISSN: 1097-4172
CID: 1965622
