Publications by authors named "Marie-Christine Guiot"

85 Publications

The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Goodman Cancer Research Centre, Faculty of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.

Metastasis to the central nervous system occurs in approximately 20% of patients with advanced solid cancers such as lung cancer, breast cancer, and melanoma. While central nervous system metastases most commonly form in the brain parenchyma, metastatic cancer cells may also reside in the subarachnoid space surrounding the brain and spinal cord to form tumors called leptomeningeal metastases. Leptomeningeal metastasis involves cancer cells that reach the subarachnoid space and proliferate in the cerebrospinal fluid compartment within the leptomeninges, a sequela associated with a myriad of symptoms and poor prognosis. Cancer cells exposed to cerebrospinal fluid in the leptomeninges must contend with a unique microenvironment from those that establish within the brain or other organs. Leptomeningeal lesions provide a formidable clinical challenge due to their often-diffuse infiltration within the subarachnoid space. The molecular mechanisms that promote the establishment of leptomeningeal metastases have begun to be elucidated, demonstrating that it is a biological entity distinct from parenchymal brain metastases and is associated with specific molecular drivers. In this review, we outline the current state of knowledge pertaining to the diagnosis, treatment, and molecular underpinnings of leptomeningeal metastasis.
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http://dx.doi.org/10.3390/cancers13040732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916586PMC
February 2021

Invasive growth associated with Cold-Inducible RNA-Binding Protein expression drives recurrence of surgically resected brain metastases.

Neuro Oncol 2021 Jan 12. Epub 2021 Jan 12.

Division of Experimental Medicine, Montréal, Québec, Canada.

Background: Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival.

Methods: We determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues.

Results: We demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified Cold-Inducible RNA-Binding Protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain.

Conclusions: These data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying post-operative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected brain metastases.
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http://dx.doi.org/10.1093/neuonc/noab002DOI Listing
January 2021

Large-scale mGluR5 network abnormalities linked to epilepsy duration in focal cortical dysplasia.

Neuroimage Clin 2021 29;29:102552. Epub 2020 Dec 29.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada. Electronic address:

To determine the extent of metabotropic glutamate receptor type 5 (mGluR5) network abnormalities associated with focal cortical dysplasia (FCD), we performed graph theoretical analysis of [C]ABP688 PET binding potentials (BP), which allows for quantification of mGluR5 availability. Undirected graphs were constructed for the entire cortex in 17 FCD patients and 33 healthy controls using inter-regional similarity of [C]ABP688 BP. We assessed group differences in network integration between healthy controls and the ipsilateral and contralateral hemispheres of FCD patients. Compared to healthy controls, FCD patients showed reduced network efficiency and reduced small-world connectivity. The mGluR5 network of FCD patients was also less resilient to targeted removal of high centrality nodes, suggesting a less integrated network organization. In highly efficient hub nodes of FCD patients, we observed a significant negative correlation between local efficiency and duration of epilepsy only in the contralateral hemisphere, suggesting that some nodes may be more vulnerable to persistent epileptic activity. Our study provides the first in vivo evidence for a widespread reduction in cortical mGluR5 network integration in FCD patients. In addition, we find that ongoing epileptic activity may alter chemoarchitectural brain organization resulting in reduced efficiency in distant regions that are essential for network integration.
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http://dx.doi.org/10.1016/j.nicl.2020.102552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787952PMC
December 2020

The utility of arterial spin labeling in the presurgical evaluation of poorly defined focal epilepsy in children.

J Neurosurg Pediatr 2020 Dec 25:1-10. Epub 2020 Dec 25.

4Pediatric Neurosurgery.

Objective: The authors sought to assess the utility of arterial spin labeling (ASL) perfusion 3T-MRI for the presurgical evaluation of poorly defined focal epilepsy in pediatric patients.

Methods: Pseudocontinuous ASL perfusion 3T-MRI was performed in 25 consecutive children with poorly defined focal epilepsy. ASL perfusion abnormalities were detected qualitatively by visual inspection and quantitatively by calculating asymmetry index (AI) maps and significant z-score cluster maps based on successfully operated cases. ASL results were prospectively compared to scalp EEG, structural 3T-MRI, FDG-PET, ictal/interictal SPECT, magnetoencephalography (MEG), and intracranial recording results, as well as the final surgically proven epileptogenic zone (EZ) in operated patients who had at least 1 year of good (Engel class I/II) seizure outcome and positive histopathology results.

Results: Qualitative ASL perfusion abnormalities were found in 17/25 cases (68%), specifically in 17/20 MRI-positive cases (85.0%) and in none of the 5 MRI-negative cases. ASL was concordant with localizing scalp EEG findings in 66.7%, structural 3T-MRI in 90%, FDG-PET in 75%, ictal/interictal SPECT in 62.5%, and MEG in 75% of cases, and with intracranial recording results in 40% of cases. Eleven patients underwent surgery; in all 11 cases the EZ was surgically proven by positive histopathology results and the patient having at least 1 year of good seizure outcome. ASL results were concordant with this final surgically proven EZ in 10/11 cases (sensitivity 91%, specificity 50%). All 10 ASL-positive patients who underwent surgery had positive surgical pathology results and good long-term postsurgical seizure outcome at a mean follow-up of 39 months. Retrospective quantitative analysis based on significant z-score clusters found 1 true-positive result that was missed by qualitative analysis and 3 additional false-positive results (sensitivity 100%, specificity 23%).

Conclusions: ASL supports the hypothesis regarding the EZ in poorly defined focal epilepsy cases in children. Due to its convenience and noninvasive nature, the authors recommend that ASL be added routinely to the presurgical MRI evaluation of epilepsy. Future optimized quantitative methods may improve the diagnostic yield of this technique.
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http://dx.doi.org/10.3171/2020.7.PEDS20397DOI Listing
December 2020

Predicting Relapse in Patients With Triple Negative Breast Cancer (TNBC) Using a Deep-Learning Approach.

Front Physiol 2020 23;11:511071. Epub 2020 Sep 23.

Department of Bioengineering, Northeastern University, Boston, MA, United States.

The abundance and/or location of tumor infiltrating lymphocytes (TILs), especially CD8 T cells, in solid tumors can serve as a prognostic indicator in various types of cancer. However, it is often difficult to select an appropriate threshold value in order to stratify patients into well-defined risk groups. It is also important to select appropriate tumor regions to quantify the abundance of TILs. On the other hand, machine-learning approaches can stratify patients in an unbiased and automatic fashion. Based on immunofluorescence (IF) images of CD8 T lymphocytes and cancer cells, we develop a machine-learning approach which can predict the risk of relapse for patients with Triple Negative Breast Cancer (TNBC). Tumor-section images from 9 patients with poor outcome and 15 patients with good outcome were used as a training set. Tumor-section images of 29 patients in an independent cohort were used to test the predictive power of our algorithm. In the test cohort, 6 (out of 29) patients who belong to the poor-outcome group were all correctly identified by our algorithm; for the 23 (out of 29) patients who belong to the good-outcome group, 17 were correctly predicted with some evidence that improvement is possible if other measures, such as the grade of tumors, are factored in. Our approach does not involve arbitrarily defined metrics and can be applied to other types of cancer in which the abundance/location of CD8 T lymphocytes/other types of cells is an indicator of prognosis.
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http://dx.doi.org/10.3389/fphys.2020.511071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538858PMC
September 2020

Author Correction: Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy.

Nat Commun 2020 08 7;11(1):4041. Epub 2020 Aug 7.

Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-17979-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415133PMC
August 2020

Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy.

Nat Commun 2020 07 8;11(1):3406. Epub 2020 Jul 8.

Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada.

Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.
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http://dx.doi.org/10.1038/s41467-020-17186-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343844PMC
July 2020

Elevated V-ATPase Activity Following PTEN Loss Is Required for Enhanced Oncogenic Signaling in Breast Cancer.

Mol Cancer Res 2020 10 25;18(10):1477-1490. Epub 2020 Jun 25.

Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.

PTEN loss-of-function contributes to hyperactivation of the PI3K pathway and to drug resistance in breast cancer. Unchecked PI3K pathway signaling increases activation of the mechanistic target of rapamycin complex 1 (mTORC1), which promotes tumorigenicity. Several studies have suggested that vacuolar (H)-ATPase (V-ATPase) complex activity is regulated by PI3K signaling. In this study, we showed that loss of PTEN elevated V-ATPase activity. Enhanced V-ATPase activity was mediated by increased expression of the ATPase H+ transporting accessory protein 2 (), also known as the prorenin receptor (PRR). PRR is cleaved into a secreted extracellular fragment (sPRR) and an intracellular fragment (M8.9) that remains associated with the V-ATPase complex. Reduced PTEN expression increased V-ATPase complex activity in a PRR-dependent manner. Breast cancer cell lines with reduced PTEN expression demonstrated increased PRR expression. Similarly, PRR expression became elevated upon PTEN deletion in a mouse model of breast cancer. Interestingly, concentration of sPRR was elevated in the plasma of patients with breast cancer and correlated with tumor burden in HER2-enriched cancers. Moreover, PRR was essential for proper HER2 receptor expression, localization, and signaling. PRR knockdown attenuated HER2 signaling and resulted in reduced Akt and ERK 1/2 phosphorylation, and in lower mTORC1 activity. Overall, our study demonstrates a mechanism by which PTEN loss in breast cancer can potentiate multiple signaling pathways through upregulation of the V-ATPase complex. IMPLICATIONS: Our study contributed to the understanding of the role of the V-ATPase complex in breast cancer cell tumorigenesis and provided a potential biomarker in breast cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0088DOI Listing
October 2020

CD44 Promotes PD-L1 Expression and Its Tumor-Intrinsic Function in Breast and Lung Cancers.

Cancer Res 2020 02 13;80(3):444-457. Epub 2019 Nov 13.

Department of Biochemistry, McGill University, Montreal, Quebec, Canada.

The PD-L1 (CD274) immune-checkpoint ligand is often upregulated in cancers to inhibit T cells and elicit immunosuppression. Independent of this activity, PD-L1 has recently been shown to also exert a cancer cell-intrinsic function promoting tumorigenesis. Here, we establish this tumor-intrinsic role of PD-L1 in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Using FACS-assisted shRNA screens, we identified the cell-surface adhesion receptor CD44 as a key positive regulator of PD-L1 expression in these cancers. Mechanistically, CD44 activated transcription in part through its cleaved intracytoplasmic domain (ICD), which bound to a regulatory region of the locus containing a consensus CD44-ICD binding site. Supporting this genetic interaction, CD44 positively correlated with PD-L1 expression at the mRNA and protein levels in primary tumor samples of TNBC and NSCLC patients. These data provide a novel basis for CD44 as a critical therapeutic target to suppress PD-L1 tumor-intrinsic function. SIGNIFICANCE: CD44 is a potential target to suppress PD-L1 function in TNBC. This finding has the potential to open a new area of therapy for TNBC.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1108DOI Listing
February 2020

Feature engineering applied to intraoperative in vivo Raman spectroscopy sheds light on molecular processes in brain cancer: a retrospective study of 65 patients.

Analyst 2019 Nov;144(22):6517-6532

Department of Engineering Physics, Polytechnique Montreal, Montreal, Quebec, Canada.

Raman spectroscopy is a promising tool for neurosurgical guidance and cancer research. Quantitative analysis of the Raman signal from living tissues is, however, limited. Their molecular composition is convoluted and influenced by clinical factors, and access to data is limited. To ensure acceptance of this technology by clinicians and cancer scientists, we need to adapt the analytical methods to more closely model the Raman-generating process. Our objective is to use feature engineering to develop a new representation for spectral data specifically tailored for brain diagnosis that improves interpretability of the Raman signal while retaining enough information to accurately predict tissue content. The method consists of band fitting of Raman bands which consistently appear in the brain Raman literature, and the generation of new features representing the pairwise interaction between bands and the interaction between bands and patient age. Our technique was applied to a dataset of 547 in situ Raman spectra from 65 patients undergoing glioma resection. It showed superior predictive capacities to a principal component analysis dimensionality reduction. After analysis through a Bayesian framework, we were able to identify the oncogenic processes that characterize glioma: increased nucleic acid content, overexpression of type IV collagen and shift in the primary metabolic engine. Our results demonstrate how this mathematical transformation of the Raman signal allows the first biological, statistically robust analysis of in vivo Raman spectra from brain tissue.
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http://dx.doi.org/10.1039/c9an01144gDOI Listing
November 2019

Mechanisms and Antitumor Activity of a Binary EGFR/DNA-Targeting Strategy Overcomes Resistance of Glioblastoma Stem Cells to Temozolomide.

Clin Cancer Res 2019 12 20;25(24):7594-7608. Epub 2019 Sep 20.

Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.

Purpose: Glioblastoma (GBM) is a fatal primary malignant brain tumor. GBM stem cells (GSC) contribute to resistance to the DNA-damaging chemotherapy, temozolomide. The epidermal growth factor receptor (EGFR) displays genomic alterations enabling DNA repair mechanisms in half of GBMs. We aimed to investigate EGFR/DNA combi-targeting in GBM.

Experimental Design: ZR2002 is a "combi-molecule" designed to inflict DNA damage through its chlorethyl moiety and induce irreversible EGFR tyrosine kinase inhibition. We assessed its efficacy in temozolomide-resistant patient-derived GSCs, mesenchymal temozolomide-sensitive and resistant -derived GSC sublines, and U87/EGFR isogenic cell lines stably expressing EGFR/wild-type or variant III (EGFRvIII). We evaluated its antitumor activity in mice harboring orthotopic EGFRvIII or mesenchymal TMZ-resistant GSC tumors.

Results: ZR2002 induced submicromolar antiproliferative effects and inhibited neurosphere formation of all GSCs with marginal effects on normal human astrocytes. ZR2002 inhibited EGF-induced autophosphorylation of EGFR, downstream Erk1/2 phosphorylation, increased DNA strand breaks, and induced activation of wild-type p53; the latter was required for its cytotoxicity through p53-dependent mechanism. ZR2002 induced similar effects on U87/EGFR cell lines and its oral administration significantly increased survival in an orthotopic EGFRvIII mouse model. ZR2002 improved survival of mice harboring intracranial mesenchymal temozolomide-resistant GSC line, decreased EGFR, Erk1/2, and AKT phosphorylation and was detected in tumor brain tissue by MALDI imaging mass spectrometry.

Conclusions: These findings provide the molecular basis of binary EGFR/DNA targeting and uncover the oral bioavailability, blood-brain barrier permeability, and antitumor activity of ZR2002 supporting potential evaluation of this first-in-class drug in recurrent GBM.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0955DOI Listing
December 2019

eIF4A Inhibitors Suppress Cell-Cycle Feedback Response and Acquired Resistance to CDK4/6 Inhibition in Cancer.

Mol Cancer Ther 2019 11 8;18(11):2158-2170. Epub 2019 Aug 8.

Department of Biochemistry, The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.

CDK4/6 inhibitors are FDA-approved drugs for estrogen receptor-positive (ER) breast cancer and are being evaluated to treat other tumor types, including -mutant non-small cell lung cancer (NSCLC). However, their clinical utility is often limited by drug resistance. Here, we sought to better understand the resistant mechanisms and help devise potential strategies to overcome this challenge. We show that treatment with CDK4/6 inhibitors in both ER breast cancer and -mutant NSCLC cells induces feedback upregulation of cyclin D1, CDK4, and cyclin E1, mediating drug resistance. We demonstrate that rocaglates, which preferentially target translation of key cell-cycle regulators, effectively suppress this feedback upregulation induced by CDK4/6 inhibition. Consequently, combination treatment of CDK4/6 inhibitor palbociclib with the eukaryotic initiation factor (eIF) 4A inhibitor, CR-1-31-B, is synergistic in suppressing the growth of these cancer cells and Furthermore, ER breast cancer and -mutant NSCLC cells that acquired resistance to palbociclib after chronic drug exposure are also highly sensitive to this combination treatment strategy. Our findings reveal a novel strategy using eIF4A inhibitors to suppress cell-cycle feedback response and to overcome resistance to CDK4/6 inhibition in cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132330PMC
November 2019

Rheumatoid Meningitis Presenting With Acute Parkinsonism and Protracted Non-convulsive Seizures: An Unusual Case Presentation and Review of Treatment Strategies.

Front Neurol 2019 27;10:163. Epub 2019 Feb 27.

Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada.

Rheumatoid meningitis is a rare complication of rheumatoid arthritis (RA). It is associated with substantial morbidity and mortality. The condition may present in a variety of ways and is therefore diagnostically challenging. Uncertainty still exists regarding the optimal treatment strategy. Herein, we describe the case of a 74-year-old man with a history of well-controlled seropositive RA on low-dose prednisone, hydroxychloroquine, and methotrexate. The patient presented with a several-month history of multiple prolonged episodes of expressive aphasia, right hemiparesis, and encephalopathy. Although no epileptiform activity was recorded on repeated electroencephalography, the symptoms fully resolved following treatment with antiepileptic drugs. He subsequently developed acute asymmetrical parkinsonism of the right hemibody. Magnetic resonance imaging revealed subtle enhancement of the leptomeninges over the left frontoparietal convexity. Cerebrospinal fluid analysis revealed a mild lymphocytic pleocytosis and elevated proteins. Histopathologic analysis of a meningeal biopsy revealed nodular rheumatoid meningitis. The patient was treated with corticosteroids and cyclophosphamide, following which he incompletely recovered. This is the first description of rheumatoid meningitis manifesting with acute parkinsonism and protracted non-convulsive seizures. A summary of cases reported since 2005, including data on pathology, therapy and outcomes, along with a discussion on the efficacy of different treatment strategies are provided.
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http://dx.doi.org/10.3389/fneur.2019.00163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400852PMC
February 2019

Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers.

J Clin Invest 2019 04 18;129(4):1785-1800. Epub 2019 Mar 18.

Goodman Cancer Research Centre and.

Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC, with implications for current therapies including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme B+CD8+ T cells (GzmB+CD8+ T cells), a type 1 IFN signature, and elevated expression of multiple immune inhibitory molecules including indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1), and resulted in good outcomes. An "immune-cold" microenvironment with an absence of tumoral CD8+ T cells was defined by elevated expression of the immunosuppressive marker B7-H4, signatures of fibrotic stroma, and poor outcomes. A distinct poor-outcome immunomodulatory microenvironment, hitherto poorly characterized, exhibited stromal restriction of CD8+ T cells, stromal expression of PD-L1, and enrichment for signatures of cholesterol biosynthesis. Metasignatures defining these TIME subtypes allowed us to stratify TNBCs, predict outcomes, and identify potential therapeutic targets for TNBC.
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http://dx.doi.org/10.1172/JCI96313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436884PMC
April 2019

Infiltration of CD8 T cells into tumor cell clusters in triple-negative breast cancer.

Proc Natl Acad Sci U S A 2019 02 7;116(9):3678-3687. Epub 2019 Feb 7.

Center for Theoretical Biological Physics, Rice University, Houston, TX 77030;

Infiltration of [Formula: see text] T lymphocytes into solid tumors is associated with good prognosis in various types of cancer, including triple-negative breast cancer (TNBC). However, the mechanisms underlying different infiltration levels are largely unknown. Here, we have characterized the spatial profile of [Formula: see text] T cells around tumor cell clusters (tightly connected tumor cells) in the core and margin regions in TNBC patient samples. We found that in some patients, the [Formula: see text] T cell density first decreases when moving in from the boundary of the tumor cell clusters and then rises again when approaching the center. To explain various infiltration profiles, we modeled the dynamics of T cell density via partial differential equations. We spatially modulated the diffusion/chemotactic coefficients of T cells (to mimic physical barriers) or introduced the localized secretion of a diffusing T cell chemorepellent. Combining the spatial-profile analysis and the modeling led to support for the second idea; i.e., there exists a possible chemorepellent inside tumor cell clusters, which prevents [Formula: see text] T cells from infiltrating into tumor cell clusters. This conclusion was consistent with an investigation into the properties of collagen fibers which suggested that variations in desmoplastic elements does not limit infiltration of [Formula: see text] T lymphocytes, as we did not observe significant correlations between the level of T cell infiltration and fiber properties. Our work provides evidence that [Formula: see text] T cells can cross typical fibrotic barriers and thus their infiltration into tumor clusters is governed by other mechanisms possibly involving a local repellent.
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http://dx.doi.org/10.1073/pnas.1817652116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397588PMC
February 2019

CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary.

Nat Commun 2019 02 4;10(1):558. Epub 2019 Feb 4.

Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.

Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.
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http://dx.doi.org/10.1038/s41467-018-06958-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361890PMC
February 2019

SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer.

Nat Commun 2019 02 4;10(1):557. Epub 2019 Feb 4.

Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.

Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.
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http://dx.doi.org/10.1038/s41467-019-08380-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362083PMC
February 2019

Development and first in-human use of a Raman spectroscopy guidance system integrated with a brain biopsy needle.

J Biophotonics 2019 03 28;12(3):e201800396. Epub 2019 Jan 28.

Department of Engineering Physics, Polytechnique Montreal, Montreal, Québec, Canada.

Navigation-guided brain biopsies are the standard of care for diagnosis of several brain pathologies. However, imprecise targeting and tissue heterogeneity often hinder obtaining high-quality tissue samples, resulting in poor diagnostic yield. We report the development and first clinical testing of a navigation-guided fiberoptic Raman probe that allows surgeons to interrogate brain tissue in situ at the tip of the biopsy needle prior to tissue removal. The 900 μm diameter probe can detect high spectral quality Raman signals in both the fingerprint and high wavenumber spectral regions with minimal disruption to the neurosurgical workflow. The probe was tested in three brain tumor patients, and the acquired spectra in both normal brain and tumor tissue demonstrated the expected spectral features, indicating the quality of the data. As a proof-of-concept, we also demonstrate the consistency of the acquired Raman signal with different systems and experimental settings. Additional clinical development is planned to further evaluate the performance of the system and develop a statistical model for real-time tissue classification during the biopsy procedure.
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http://dx.doi.org/10.1002/jbio.201800396DOI Listing
March 2019

In vivo metabotropic glutamate receptor type 5 abnormalities localize the epileptogenic zone in mesial temporal lobe epilepsy.

Ann Neurol 2019 02 20;85(2):218-228. Epub 2019 Jan 20.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Objective: Surgical specimens from patients with mesial temporal lobe epilepsy (MTLE) show abnormalities in tissue concentrations of metabotropic glutamate receptor type 5 (mGluR5). To clarify whether these abnormalities are specific to the epileptogenic zone (EZ), we characterized in vivo whole-brain mGluR5 availability in MTLE patients using positron emission tomography (PET) and [ C]ABP688, a radioligand that binds specifically to the mGluR5 allosteric site.

Methods: Thirty-one unilateral MTLE patients and 30 healthy controls underwent [ C]ABP688 PET. We compared partial volume corrected [ C]ABP688 nondisplaceable binding potentials (BP ) between groups using region-of-interest and whole-brain voxelwise analyses. [ F]Fluorodeoxyglucose (FDG) PET was acquired in 15 patients, for whom we calculated asymmetry indices of [ C]ABP688 BP and [ F]FDG uptake to compare lateralization and localization differences.

Results: [ C]ABP688 BP was focally reduced in the epileptogenic hippocampal head and amygdala (p < 0.001). Patients with hippocampal atrophy showed more extensive abnormalities, including the ipsilateral temporal neocortex (p = 0.006). [ C]ABP688 BP showed interhemispheric differences of higher magnitude and discriminated the epileptogenic structures more accurately when compared to [ F]FDG uptake, which showed more widespread hypometabolism. Among 23 of 25 operated patients with >1 year of follow-up, 13 were seizure-free (Engel Ia) and showed significantly lower [ C]ABP688 BP in the ipsilateral entorhinal cortex.

Interpretation: [ C]ABP688 PET provides a focal biomarker for the EZ in MTLE with higher spatial accuracy compared to [ F]FDG PET. Focally reduced mGluR5 availability in the EZ might reflect receptor internalization or conformational changes in response to excessive extracellular glutamate, supporting a potential role for mGluR5 as therapeutic target in human MTLE. Ann Neurol 2019; 1-11 ANN NEUROL 2019;85:218-228.
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http://dx.doi.org/10.1002/ana.25404DOI Listing
February 2019

Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant Melanomas.

Clin Cancer Res 2018 12 14;24(24):6483-6494. Epub 2018 Jun 14.

Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Purpose: Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi.

Experimental Design: Tumors from patients with BRAF wild-type (WT), V600E (class I), and L597S (class II) metastatic melanoma were used to generate patient-derived xenografts (PDX). We assembled a panel of melanoma cell lines with class IIa (activation segment) or IIb (p-loop) mutations and compared these with WT or V600E/K BRAF mutant cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib, and LY3009120), MEKi (cobimetinib, trametinib, and binimetinib), or the combination. We identified 2 patients with BRAF L597S metastatic melanoma who were treated with dMAPKi.

Results: BRAFi impaired MAPK signaling and cell growth in class I and II BRAF mutant cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor regression in two melanoma PDXs with class II BRAF mutations and prolonged survival of mice with class II BRAF mutant melanoma brain metastases. Two patients with BRAF L597S mutant melanoma clinically responded to dMAPKi.

Conclusions: Class II BRAF mutant melanoma is growth inhibited by dMAPKi. Responses to dMAPKi have been observed in 2 patients with class II BRAF mutant melanoma. These data provide rationale for clinical investigation of dMAPKi in patients with class II BRAF mutant metastatic melanoma..
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3384DOI Listing
December 2018

KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer.

Cell Rep 2018 03;22(12):3191-3205

Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, Canada; Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada. Electronic address:

Triple-negative breast cancers (TNBCs) display a complex spectrum of mutations and chromosomal aberrations. Chromosome 5q (5q) loss is detected in up to 70% of TNBCs, but little is known regarding the genetic drivers associated with this event. Here, we show somatic deletion of a region syntenic with human 5q33.2-35.3 in a mouse model of TNBC. Mechanistically, we identify KIBRA as a major factor contributing to the effects of 5q loss on tumor growth and metastatic progression. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro. KIBRA functions co-operatively with the protein tyrosine phosphatase PTPN14 to trigger mechanotransduction-regulated signals that inhibit the nuclear localization of oncogenic transcriptional co-activators YAP/TAZ. Our results argue that the selective advantage produced by 5q loss involves reduced dosage of KIBRA, promoting oncogenic functioning of YAP/TAZ in TNBC.
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http://dx.doi.org/10.1016/j.celrep.2018.02.095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873529PMC
March 2018

A new method using Raman spectroscopy for in vivo targeted brain cancer tissue biopsy.

Sci Rep 2018 01 29;8(1):1792. Epub 2018 Jan 29.

Dept. of Engineering Physics, Polytechnique Montreal, CP 6079, Succ. Centre-Ville, Montreal, QC, H3C 3A7, Canada.

Modern cancer diagnosis requires histological, molecular, and genomic tumor analyses. Tumor sampling is often achieved using a targeted needle biopsy approach. Targeting errors and cancer heterogeneity causing inaccurate sampling are important limitations of this blind technique leading to non-diagnostic or poor quality samples, and the need for repeated biopsies pose elevated patient risk. An optical technology that can analyze the molecular nature of the tissue prior to harvesting could improve cancer targeting and mitigate patient risk. Here we report on the design, development, and validation of an in situ intraoperative, label-free, cancer detection system based on high wavenumber Raman spectroscopy. This optical detection device was engineered into a commercially available biopsy system allowing tumor analysis prior to tissue harvesting without disrupting workflow. Using a dual validation approach we show that high wavenumber Raman spectroscopy can detect human dense cancer with >60% cancer cells in situ during surgery with a sensitivity and specificity of 80% and 90%, respectively. We also demonstrate for the first time the use of this system in a swine brain biopsy model. These studies set the stage for the clinical translation of this optical molecular imaging method for high yield and safe targeted biopsy.
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http://dx.doi.org/10.1038/s41598-018-20233-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788981PMC
January 2018

Prognostic factors for progression in atypical meningioma.

J Neurosurg 2018 11;129(5):1240-1248

5Neuropathology, Cedars Cancer Centre, McGill University Health Centre, Montreal, Quebec, Canada.

In patients with postoperative residual atypical meningiomas, by using volumetric instead of linear measurements in follow-up imaging studies, the authors detected disease progression earlier. By using this approach, treatment for recurrent disease can be instituted promptly with potentially better tumor control and less toxicity due to smaller volume of residual disease.
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http://dx.doi.org/10.3171/2017.6.JNS17120DOI Listing
November 2018

Cavernous sinus syndrome associated with metastatic colorectal cancer and perineural spread along the trigeminal nerve.

Am J Ophthalmol Case Rep 2017 Jun 14;6:67-70. Epub 2017 Mar 14.

McGill University Health Centre, 1001 Boulevard Décarie, Montreal, Quebec, Canada.

Purpose: We report the case of a patient with cavernous sinus syndrome associated with biopsy-confirmed metastasis from colorectal cancer.

Observations: A patient known for laryngeal carcinoma and metastatic colorectal carcinoma presented with symptoms of left trigeminal neuralgia and progressive, near-complete ophthalmoplegia. Magnetic resonance imaging (MRI) revealed a mass in the left cavernous sinus, extending into Meckel's cave with perineural spread along the mandibular branch of the left trigeminal nerve. A transsphenoidal biopsy was performed and demonstrated metastatic colon adenocarcinoma. We review the existing literature on colorectal cancer associated cavernous sinus syndrome.

Conclusions And Importance: Cavernous sinus metastasis from colorectal cancer is exceedingly rare. We report the second case of this entity with histopathologic confirmation, and the first case with concurrent perineural spread involving the trigeminal nerve. Cavernous sinus metastasis may represent a poor prognostic factor in colorectal cancer.
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http://dx.doi.org/10.1016/j.ajoc.2016.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722136PMC
June 2017

Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy.

Oncotarget 2017 Sep 12;8(44):77846-77859. Epub 2017 Sep 12.

Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre, and Department Biochemistry, McGill University, Montreal, QC, Canada.

Tumor cells are particularly dependent on NAD due to higher rates of metabolism, DNA synthesis and repair. Nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) inhibit NAD biosynthesis and represent promising new anti-cancer agents. However, clinical efficacy has been limited by toxicities demonstrating the need for drug combinations to broaden the therapeutic index. One potential combination involves niacin/NAMPTi co-administration. Niacin can rescue NAD biosynthesis through a parallel pathway that depends on nicotinic acid phosphoribosyltransferase (NAPRT) expression. Most normal tissues express NAPRT while a significant proportion of malignant cells do not, providing a possible selection marker for patients to achieve NAMPTi efficacy while minimizing toxicities. Here we identify and validate a novel highly NAPRT-specific monoclonal antibody (3C6D2) that detects functional NAPRT in paraffin embedded tissue sections by immunohistochemistry (IHC). NAPRT detection by 3C6D2 coincides with the ability of niacin to rescue cells from NAMPTi induced cytotoxicity in cell lines and animal xenograft models. 3C6D2 binds to an epitope that is unique to NAPRT among phosphoribosyltransferases. In a series of primary tumor samples from lung and brain cancer patients, we demonstrate that >70 % of human small cell lung carcinomas, glioblastomas and oligodendrogliomas lack NAPRT identifying them as potentially suitable indications for the NAMPT/niacin combination.
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http://dx.doi.org/10.18632/oncotarget.20840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652819PMC
September 2017

A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer.

Cell Rep 2017 Oct;21(5):1140-1149

Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1A4, Canada; Center of Innovation in Personalized Medicine, Cancer and Mutagen Unit, King Fahd Center for Medical Research, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:

Therapies targeting epidermal growth factor receptor (EGFR) have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR. Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster. Sorted EGFR subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFR cells gave rise to EGFR and EGFR cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFR subpopulations were identified in independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity. This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention.
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http://dx.doi.org/10.1016/j.celrep.2017.10.015DOI Listing
October 2017

CUX1 stimulates APE1 enzymatic activity and increases the resistance of glioblastoma cells to the mono-alkylating agent temozolomide.

Neuro Oncol 2018 03;20(4):484-493

Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.

Background: Cut Like homeobox 1 (CUX1), which encodes an auxiliary factor in base excision repair, resides on 7q22.1, the most frequently and highly amplified chromosomal region in glioblastomas. The resistance of glioblastoma cells to the mono-alkylating agent temozolomide is determined to some extent by the activity of apurinic/apyrimidinic endonuclease 1 (APE1).

Methods: To monitor the effect of CUX1 and its CUT domains on APE1 activity, DNA repair assays were performed with purified proteins and cell extracts. CUX1 protein expression was analyzed by immunohistochemistry using a tumor microarray of 150 glioblastoma samples. The effect of CUX1 knockdown and overexpression on the resistance of glioblastoma cell lines to temozolomide was investigated.

Results: We show that CUT domains stimulate APE1 activity. In agreement with these findings, CUX1 knockdown causes an increase in the number of abasic sites in genomic DNA and a decrease in APE1 activity as measured in cell extracts. Conversely, ectopic CUX1 expression increases APE1 activity and lowers the number of abasic sites. Having established that CUX1 is expressed at high levels in most glioblastomas, we next show that the resistance of glioblastoma cells to temozolomide and to a combined treatment of temozolomide and ionizing radiation is reduced following CUX1 knockdown, but increased by overexpression of CUX1 or a short protein containing only 2 CUT domains, which is active in DNA repair but devoid of transcriptional activity.

Conclusion: These findings indicate that CUX1 expression level impacts on the response of glioblastoma cells to treatment and identifies the CUT domains as potential therapeutic targets.
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http://dx.doi.org/10.1093/neuonc/nox178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909652PMC
March 2018

Highly Accurate Detection of Cancer with Intraoperative, Label-Free, Multimodal Optical Spectroscopy.

Cancer Res 2017 07 28;77(14):3942-3950. Epub 2017 Jun 28.

Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

Effectiveness of surgery as a cancer treatment is reduced when all cancer cells are not detected during surgery, leading to recurrences that negatively impact survival. To maximize cancer cell detection during cancer surgery, we designed an intraoperative, label-free, optical cancer detection system that combines intrinsic fluorescence spectroscopy, diffuse reflectance spectroscopy, and Raman spectroscopy. Using this multimodal optical cancer detection system, we found that brain, lung, colon, and skin cancers could be detected during surgery with an accuracy, sensitivity, and specificity of 97%, 100%, and 93%, respectively. This highly sensitive optical molecular imaging approach can profoundly impact a wide range of surgical and noninvasive interventional oncology procedures by improving cancer detection capabilities, thereby reducing cancer burden and improving survival and quality of life. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0668DOI Listing
July 2017

Monoamine oxidase B inhibitor, selegiline, reduces F-THK5351 uptake in the human brain.

Alzheimers Res Ther 2017 Mar 31;9(1):25. Epub 2017 Mar 31.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.

Background: F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on F-THK5351 brain uptake using PET and autoradiography.

Methods: Eight participants (five mild cognitive impairment, two Alzheimer's disease, and one progressive supranuclear palsy) had baseline F-AZD4694 and F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third F-THK5351 scan 9-28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region. F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline.

Results: At baseline, F-THK5351 SUVs were highest in the basal ganglia (0.64 ± 0.11) and thalamus (0.62 ± 0.14). In the post-selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9-28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on F-THK5351 uptake.

Conclusions: These results indicate that the interpretation of F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain. In addition, the heterogeneous MAO-B availability across the cortex may limit the interpretation of F-THK5351 scans using reference region methods.
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http://dx.doi.org/10.1186/s13195-017-0253-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374697PMC
March 2017

Raman spectroscopy detects distant invasive brain cancer cells centimeters beyond MRI capability in humans.

Biomed Opt Express 2016 Dec 16;7(12):5129-5137. Epub 2016 Nov 16.

Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, 3801 University St., Montreal, QC, H3A 2B4, Canada; These authors contributed equally to this work;

Surgical treatment of brain cancer is limited by the inability of current imaging capabilities such as magnetic resonance imaging (MRI) to detect the entirety of this locally invasive cancer. This results in residual cancer cells remaining following surgery, leading to recurrence and death. We demonstrate that intraoperative Raman spectroscopy can detect invasive cancer cells centimeters beyond pathological T1-contrast-enhanced and T2-weighted MRI signals. This intraoperative optical guide can be used to detect invasive cancer cells and minimize post-surgical cancer burden. The detection of distant invasive cancer cells beyond MRI signal has the potential to increase the effectiveness of surgery and directly lengthen patient survival.
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http://dx.doi.org/10.1364/BOE.7.005129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175557PMC
December 2016