WashU weekly Neuroscience publications: August 8, 2022

The University of Pennsylvania glioblastoma (UPenn-GBM) cohort: advanced MRI, clinical, genomics, & radiomics
(2022) Scientific Data, 9 (1), art. no. 453, . 

Bakas, S.^a b c , Sako, C.^a b , Akbari, H.^a b , Bilello, M.^b , Sotiras, A.^a b d , Shukla, G.^a b e , Rudie, J.D.^b f , Santamaría, N.F.^b , Kazerooni, A.F.^a b , Pati, S.^a b , Rathore, S.^a b , Mamourian, E.^a b , Ha, S.M.^a b d , Parker, W.^a b , Doshi, J.^a b , Baid, U.^a b c , Bergman, M.^a , Binder, Z.A.^g , Verma, R.^a b , Lustig, R.A.^h , Desai, A.S.ⁱ , Bagley, S.J.ⁱ , Mourelatos, Z.^c , Morrissette, J.^c , Watt, C.D.^c , Brem, S.^g , Wolf, R.L.^b g , Melhem, E.R.^j , Nasrallah, M.L.P.^c , Mohan, S.^b , O’Rourke, D.M.^g , Davatzikos, C.^a b

^a Center for Biomedical Image Computing and Analytics (CBICA), University of Pennsylvania, Philadelphia, PA, United States
^b Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^c Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^d Department of Radiology and Institute for Informatics, Washington University, School of Medicine, St. Louis, MO, United States
^e Department of Radiation Oncology, Christiana Care Health System, Philadelphia, PA, United States
^f Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
^g Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^h Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ⁱ Division of Hematology Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^j Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States

Abstract
Glioblastoma is the most common aggressive adult brain tumor. Numerous studies have reported results from either private institutional data or publicly available datasets. However, current public datasets are limited in terms of: a) number of subjects, b) lack of consistent acquisition protocol, c) data quality, or d) accompanying clinical, demographic, and molecular information. Toward alleviating these limitations, we contribute the “University of Pennsylvania Glioblastoma Imaging, Genomics, and Radiomics” (UPenn-GBM) dataset, which describes the currently largest publicly available comprehensive collection of 630 patients diagnosed with de novo glioblastoma. The UPenn-GBM dataset includes (a) advanced multi-parametric magnetic resonance imaging scans acquired during routine clinical practice, at the University of Pennsylvania Health System, (b) accompanying clinical, demographic, and molecular information, (d) perfusion and diffusion derivative volumes, (e) computationally-derived and manually-revised expert annotations of tumor sub-regions, as well as (f) quantitative imaging (also known as radiomic) features corresponding to each of these regions. This collection describes our contribution towards repeatable, reproducible, and comparative quantitative studies leading to new predictive, prognostic, and diagnostic assessments. © 2022, The Author(s).

Funding details
National Institutes of HealthNIHR01NS042645, U01CA242871, U24CA189523, UL1TR001878
National Cancer InstituteNCI
National Institute of Neurological Disorders and StrokeNINDS
National Center for Advancing Translational SciencesNCATS
University of Pennsylvania
Institute for Translational Medicine and TherapeuticsITMAT

Document Type: Data Paper
Publication Stage: Final
Source: Scopus

Orbitofrontal cortex contributes to the comparison of values underlying economic choices
(2022) Nature Communications, 13 (1), art. no. 4405, . 

Ballesta, S.^a d e , Shi, W.^a f , Padoa-Schioppa, C.^a b c

^a Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
^b Department of Economics, Washington University in St. Louis, St. Louis, MO 63110, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States
^d Laboratoire de Neurosciences Cognitives et Adaptatives (UMR 7364), Strasbourg, France
^e Centre de Primatologie de l’Université de Strasbourg, Niederhausbergen, France
^f Department of Neuroscience, Yale University, New Haven, CT 06510, United States

Abstract
Economic choices between goods entail the computation and comparison of subjective values. Previous studies examined neuronal activity in the orbitofrontal cortex (OFC) of monkeys choosing between different types of juices. Three groups of neurons were identified: offer value cells encoding the value of individual offers, chosen juice cells encoding the identity of the chosen juice, and chosen value cells encoding the value of the chosen offer. The encoded variables capture both the input (offer value) and the output (chosen juice, chosen value) of the decision process, suggesting that values are compared within OFC. Recent work demonstrates that choices are causally linked to the activity of offer value cells. Conversely, the hypothesis that OFC contributes to value comparison has not been confirmed. Here we show that weak electrical stimulation of OFC specifically disrupts value comparison without altering offer values. This result implies that neuronal populations in OFC participate in value comparison. © 2022, The Author(s).

Funding details
National Institutes of HealthNIHR01-DA032758, R01-MH104494

Document Type: Article
Publication Stage: Final
Source: Scopus

Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial
(2022) Journal of Neurology, Neurosurgery and Psychiatry, 93 (8), pp. 871-875. Cited 1 time.

Paganoni, S.^a b , Hendrix, S.^c , Dickson, S.P.^c , Knowlton, N.^c , Berry, J.D.^d , Elliott, M.A.^e , Maiser, S.^f , Karam, C.^g , Caress, J.B.^h , Owegi, M.A.ⁱ , Quick, A.^j , Wymer, J.^k , Goutman, S.A.^l , Heitzman, D.^m , Heiman-Patterson, T.D.ⁿ , Jackson, C.^o , Quinn, C.^g , Rothstein, J.D.^p , Kasarskis, E.J.^q , Katz, J.^r , Jenkins, L.^r , Ladha, S.S.^s , Miller, T.M.^t , Scelsa, S.N.^u , Vu, T.H.^v , Fournier, C.^w , Johnson, K.M.^x , Swenson, A.^y , Goyal, N.^z , Pattee, G.L.^aa , Babu, S.^a , Chase, M.^a , Dagostino, D.^a , Hall, M.^s , Kittle, G.^s , Eydinov, M.^a , Ostrow, J.^a , Pothier, L.^a , Randall, R.^ab ac , Shefner, J.M.^s , Sherman, A.V.^a , Tustison, E.^a , Vigneswaran, P.^a , Yu, H.^a , Cohen, J.^ad , Klee, J.^ad , Tanzi, R.^ae , Gilbert, W.^af , Yeramian, P.^ad , Cudkowicz, M.^a

^a Harvard Medical School, Sean M. Healey and Amg Center for Als, The Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA, United States
^b Department of Pm & R, Spaulding Rehabilitation Hospital, Charlestown, MA, United States
^c Pentara Corporation, Millcreek, UT, United States
^d Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA, United States
^e Swedish Neuroscience Institute, Seattle, WA, United States
^f Department of Neurology, Hennepin Healthcare, Minneapolis, MN, United States
^g Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
^h Department of Neurology, Wake Forest University, School of Medicine, Winston-Salem, NC, United States
ⁱ Department of Neurology, University of Massachusetts Memorial Medical Center, Worcester, MA, United States
^j Department of Neurology, Ohio State University, Columbus, OH, United States
^k Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States
^l Department of Neurology, University of Michigan, Ann Arbor, MI, United States
^m Als Clinic, Texas Neurology, Dallas, TX, United States
ⁿ Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
^o Department of Neurology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
^p Department of Neurology, Johns Hopkins University, Brain Science Institute, Baltimore, MD, United States
^q Department of Neurology, University of Kentucky, Lexington, KY, United States
^r California Pacific Medical Center Research Institute, Forbes Norris MDA/ALS Research and Treatment Center, San Francisco, CA, United States
^s Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
^t Hope Center for Neurological Disorders, Washington University, Saint Louis School of Medicine, Saint Louis, MO, United States
^u Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^v Department of Neurology, University of South Florida, Morsani College of Medicine, Tampa, FL, United States
^w Department of Neurology, Emory University, Atlanta, GA, United States
^x Department of Neurology, Ochsner Health System, New Orleans, LA, United States
^y Department of Neurology, University of Iowa Health Care, Iowa City, IA, United States
^z Department of Neurology, University of California, Irvine School of Medicine, Irvine, CA, United States
^aa Neurology Associates, Lincoln, NE, United States
^ab Worldwide Clinical Trials, Research Triangle Park, NC, United States
^ac Formerly with Gregory W. Fulton Als Center, Barrow Neurological Institute, Phoenix, AZ, United States
^ad Amylyx Pharmaceuticals Inc, Cambridge, MA, United States
^ae Department of Neurology, Genetics and Aging Research Unit, McCance Center for Brain Health, Massachusetts General Hospital, Harvard University, Boston, MA, United States
^af Carl M. Loeb University Professor Emeritus, The Society of Fellows at Harvard, Harvard University, Cambridge, MA, United States

Abstract
Background Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS). Objective Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial. Methods Adults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation. Results Risk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO. Conclusions Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS. Trial registration number NCT03127514; NCT03488524. © 2022 BMJ Publishing Group. All rights reserved.

Author Keywords
ALS;  MOTOR NEURON DISEASE;  NEUROMUSCULAR;  RANDOMISED TRIALS

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDS
National Institute of Environmental Health SciencesNIEHS
Congressionally Directed Medical Research ProgramsCDMRP
ALS AssociationALSA
ALS Hope FoundationALSHF
GlaxoSmithKlineGSK
Muscular Dystrophy AssociationMDA
American Academy of NeurologyAAN
Biogen
Weill Cornell Medical College
American AirlinesAA
Ionis Pharmaceuticals
Acorda Therapeutics
CytokineticsCYTK
Rare Diseases Clinical Research NetworkRDCRN
Amplyx

Document Type: Article
Publication Stage: Final
Source: Scopus

Miswiring of Merkel cell and pruriceptive C fiber drives the itch-scratch cycle
(2022) Science Translational Medicine, 14 (653), p. eabn4819. 

Feng, J.^a b , Zhao, Y.^a , Xie, Z.^a , Zang, K.^a , Sviben, S.^c , Hu, X.^a , Fitzpatrick, J.A.J.^c , Wen, L.^b , Liu, Y.^b , Wang, T.^b , Lawson, K.^d , Liu, Q.^a , Yan, Y.^e , Dong, X.^f g , Han, L.^d , Wu, G.F.^h , Kim, B.S.^a i j , Hu, H.^a

^a Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, MO, Saint Louis 63110, United States
^b Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of ScienceShanghai 201203, China
^c Washington University Center for Cellular Imaging, Washington University School of Medicine, MO, Saint Louis 63110, United States
^d School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, United States
^e Department of Surgery, Washington University School of Medicine, MO, Saint Louis 63110, United States
^f Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^g Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^h Department of Neurology, Washington University School of Medicine, Saint Louis, MO, 63110, USA
ⁱ Division of Dermatology, Department of Medicine, Washington University School of Medicine, MO, Saint Louis 63110, United States
^j Department of Pathology and Immunology, Washington University School of Medicine, MO, Saint Louis 63110, United States

Abstract
Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of mechanoreceptors, it propagates the vicious itch-scratch cycle in chronic itch by further aggravating itch over time. Although well recognized clinically, the peripheral mechanisms underlying the itch-scratch cycle remain poorly understood. Here, we show that mechanical stimulation of the skin results in activation of the Piezo2 channels on Merkel cells that pathologically promotes spontaneous itch in experimental dry skin. Three-dimensional reconstruction and immunoelectron microscopy revealed structural alteration of MRGPRA3+ pruriceptor nerve endings directed toward Merkel cells in the setting of dry skin. Our results uncover a functional miswiring mechanism under pathologic conditions, resulting in touch receptors triggering the firing of pruriceptors in the skin to drive the itch-scratch cycle.

Document Type: Article
Publication Stage: Final
Source: Scopus

Sex-Based Differences in Functional Brain Activity During Working Memory in Survivors of Pediatric Acute Lymphoblastic Leukemia
(2022) JNCI Cancer Spectrum, 6 (2), art. no. pkac026, . 

Gandy, K.^a , Scoggins, M.A.^b , Phillips, N.^a , Van Der Plas, E.^c , Fellah, S.^d , Jacola, L.M.^e , Pui, C.-H.^f g , Hudson, M.M.^a f , Reddick, W.E.^b , Sitaram, R.^b , Krull, K.R.^a e

^a Department of Epidemiology and Cancer Control, St. Jude’s Children’s Research Hospital, Memphis, TN, United States
^b Department of Diagnostic Imaging, St. Jude’s Children’s Research Hospital, Memphis, TN, United States
^c Department of Psychiatry, University of Iowa Hospital and Clinics, Iowa City, IA, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^f Department of Oncology, St. Jude’s Children’s Research Hospital, Memphis, TN, United States
^g Department of Pathology, St. Jude’s Children’s Research Hospital, Memphis, TN, United States

Abstract
Background: Long-term survivors of pediatric acute lymphoblastic leukemia are at elevated risk for neurocognitive deficits and corresponding brain dysfunction. This study examined sex-based differences in functional neuroimaging outcomes in acute lymphoblastic leukemia survivors treated with chemotherapy alone. Methods: Functional magnetic resonance imaging (fMRI) and neurocognitive testing were obtained in 123 survivors (46% male; median [min-max] age = 14.2 years [8.3-26.5 years]; time since diagnosis = 7.7 years [5.1-12.5 years]) treated on the St. Jude Total XV treatment protocol. Participants performed the n-back working memory task in a 3 T scanner. Functional neuroimaging data were processed (realigned, slice time corrected, normalized, smoothed) and analyzed using statistical parametric mapping with contrasts for 1-back and 2-back conditions, which reflect varying degrees of working memory and task load. Group-level fMRI contrasts were stratified by sex and adjusted for age and methotrexate exposure. Statistical tests were 2-sided (P <. 05 statistical significance threshold). Results: Relative to males, female survivors exhibited less activation (ie, reduced blood oxygen dependent-level signals) in the right parietal operculum, supramarginal gyrus and inferior occipital gyrus, and bilateral superior frontal medial gyrus during increased working memory load (family-wise error-corrected P =. 004 to. 008, adjusting for age and methotrexate dose). Female survivors were slower to correctly respond to the 2-back condition than males (P <. 05), though there were no differences in overall accuracy. Performance accuracy was negatively correlated with fMRI activity in female survivors (Pearson’s r = -0.39 to -0.29, P =. 001 to. 02), but not in males. Conclusions: These results suggest the working memory network is more impaired in female survivors than male survivors, which may contribute to ongoing functional deficits. © 2022 The Author(s). Published by Oxford University Press.

Document Type: Article
Publication Stage: Final
Source: Scopus

Combination laser interstitial thermal therapy plus stereotactic radiotherapy increases time to progression for biopsy-proven recurrent brain metastases
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdac086, . 

Grabowski, M.M.^a , Srinivasan, E.S.^b , Vaios, E.J.^c , Sankey, E.W.^b , Otvos, B.^a , Krivosheya, D.^a , Scott, A.^d , Olufawo, M.^d , Ma, J.^e , Fomchenko, E.I.^f , Herndon, J.E.^g , Kim, A.H.^d , Chiang, V.L.^f , Chen, C.C.^e , Leuthardt, E.C.^d , Barnett, G.H.^a h , Kirkpatrick, J.P.^c i , Mohammadi, A.M.^a h , Fecci, P.E.^b i

^a Department of Neurosurgery, Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic and Case Comprehensive Cancer Center, Cleveland, OH, United States
^b Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
^c Department of Radiation Oncology, Duke University Medical Center, Durham, NC, United States
^d Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States
^f Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, United States
^g Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, United States
^h Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States
ⁱ Duke Center for Brain and Spine Metastasis, Durham, NC, United States

Abstract
Background: Improved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases. Methods: A multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by “planned LITT+SRT”versus “LITT alone”versus “repeat SRT alone.”Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Results: Fifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0-30.5), age of 60 years (range: 37-86), Karnofsky Performance Status (KPS) of 80 (range: 60-100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7-19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [P =. 022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression (P =. 004). Conclusions: These data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases. © 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Author Keywords
brain metastasis;  LITT;  progression;  stereotactic radiotherapy;  tumor recurrence

Document Type: Article
Publication Stage: Final
Source: Scopus

Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdac040, . 

De Groot, J.F.^a , Kim, A.H.^b , Prabhu, S.^c , Rao, G.^d , Laxton, A.W.^e , Fecci, P.E.^f , O’Brien, B.J.^g , Sloan, A.^h , Chiang, V.ⁱ , Tatter, S.B.^e , Mohammadi, A.M.^j , Placantonakis, D.G.^k , Strowd, R.E.^l , Chen, C.^m , Hadjipanayis, C.ⁿ , Khasraw, M.^o , Sun, D.^p , Piccioni, D.^q , Sinicrope, K.D.^r , Campian, J.L.^s , Kurz, S.C.^t , Williams, B.^u , Smith, K.^v , Tovar-Spinoza, Z.^w , Leuthardt, E.C.^b

^a Department of Neuro-Oncology, UCSF Weill Institute for Neurosciences, 400 Parnassus Avenue, Suite A808, San Francisco, CA 94143, United States
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
^d Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
^e Department of Neurosurgery, Wake Forest Baptist Health, Winston-Salem, NC, United States
^f Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
^g Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
^h Department of Neurosurgery, University Hospitals – Cleveland Medical Center & Seidman Cancer Center, Cleveland, OH, United States
ⁱ Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
^j Department of Neurosurgery, Cleveland Clinic Lerner College of Medicine at CWRU, Cleveland, OH, United States
^k Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY, United States
^l Department of Neuro-Oncology, Wake Forest Baptist Health, Winston-Salem, NC, United States
^m Department of Neurosurgery, University of Minnesota Medical Center, Minneapolis, MN, United States
ⁿ Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^o Department of Neuro-Oncology, Duke University Medical Center, Durham, NC, United States
^p Department of Neurosurgery, Norton Neuroscience Institute, Louisville, KY, United States
^q Department of Neuro-Oncology, University of California San Diego Health, La JollaCA, United States
^r Department of Neuro-Oncology, Norton Neuroscience Institute, Louisville, KY, United States
^s Department of Neuro-Oncology, Mayo Clinic, Rochester, MN, United States
^t Department of Neuro-Oncology, NYU Langone Perlmutter Cancer Center, New York, NY, United States
^u Department of Neurosurgery, University of Louisville Health, Louisville, KY, United States
^v Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, United States
^w Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, NY, United States

Abstract
Background: Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma. Methods: Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results: A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions: Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT. © 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Author Keywords
high-grade glioma;  IDH wild-type WHO grade 4 glioblastoma;  laser interstitial thermal therapy (LITT);  primary brain tumor;  stereotactic laser ablation (SLA)

Funding details
02392078

Document Type: Article
Publication Stage: Final
Source: Scopus

Phase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance)
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdac041, . 

Galanis, E.^a c e , Anderson, S.K.^f , Twohy, E.^f , Butowski, N.A.^g , Hormigo, A.^h p , Schiff, D.ⁱ , Omuro, A.^j o , Jaeckle, K.A.^k , Kumar, S.^d e , Kaufmann, T.J.^b e , Geyer, S.^f , Kumthekar, P.U.^l , Campian, J.^a m , Giannini, C.^e , Buckner, J.C.^a e , Wen, P.Y.ⁿ

^a Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, United States
^b Department of Pathology, Mayo Clinic, Rochester, MN, United States
^c Mayo Clinic, Rochester, MN, United States
^d Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN, United States
^e Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States
^f Department of Neurology, Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY, United States
^g Department of Neurology, University of Virginia Health System, Charlottesville, VA, United States
^h Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
ⁱ Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
^j Department of Hematology, Mayo Clinic, Rochester, MN, United States
^k Department of Neuroradiology, Mayo Clinic, Rochester, MN, United States
^l Northwestern Medicine, Lou and Jean Malnati Brain Tumor Institute, Chicago, IL, United States
^m Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO, United States
ⁿ Center for Neuro-Oncology, Dana-Farber/Partners Cancer Care, Boston, MA, United States
^o Department of Neurology, Yale School of Medicine, New Haven, CT, United States
^p Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, United States

Abstract
Background: Patients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM. Methods: Phase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients received TRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated. Results: In total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade ≥3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75-1.78, P =. 51). Quality of life scores were similar for both treatment arms. Conclusions: TRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy. © 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Author Keywords
angiogenesis;  bevacizumab;  CD105;  glioblastoma;  TRC105

Funding details
National Institutes of HealthNIHU10CA180821, U10CA180882, UG1CA189823, UG1CA233180, UG1CA233290, UG1CA233339
National Cancer InstituteNCI

Document Type: Article
Publication Stage: Final
Source: Scopus

Pattern of Altered Magnetization Transfer Rate in Alzheimer’s Disease
(2022) Journal of Alzheimer’s Disease, 88 (2), pp. 693-705. 

Duan, W.^a , Sehrawat, P.^a , Zhou, T.D.^b , Becker, J.T.^c d , Lopez, O.L.^d , Gach, H.M.^b , Dai, W.^a

^a Department of Computer Science, State University of New Yorkat Binghamton, Binghamton, NY, United States
^b Departments of Radiation Oncology, Radiology, and Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
^c Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States
^d Department of Psychiatry and Neurology, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Background: Biomarkers for Alzheimer’s disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. Objective: This study aims to quantify the forward magnetization transfer rate (kfor) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal kfor in AD and AD progression. Methods: From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. Results: We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC. Conclusion: Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression. © 2022 – IOS Press. All rights reserved.

Author Keywords
Alzheimer’s disease;  magnetization transfer imaging;  magnetization transfer rate;  mild cognitive impairment

Funding details
National Science FoundationNSFCMMI-2123061
National Institute on AgingNIA
National Heart, Lung, and Blood InstituteNHLBI
National Institute of Neurological Disorders and StrokeNINDSR01AG023629
State University of New YorkSUNY
Washington University in St. LouisWUSTLR01AG066430
University of Pittsburgh

Document Type: Article
Publication Stage: Final
Source: Scopus

Immune deconvolution and temporal mapping identifies stromal targets and developmental intervals for abrogating murine low-grade optic glioma formation
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdab194, . 

De Andrade Costa, A.^a , Chatterjee, J.^a , Cobb, O.^a , Cordell, E.^a , Chao, A.^a , Schaeffer, S.^a , Goldstein, A.^a , Dahiya, S.^b , Gutmann, D.H.^a

^a Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^b Department of Pathology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Brain tumor formation and progression are dictated by cooperative interactions between neoplastic and non-neoplastic cells. This stromal dependence is nicely illustrated by tumors arising in the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where children develop low-grade optic pathway gliomas (OPGs). Using several authenticated Nf1-OPG murine models, we previously demonstrated that murine Nf1-OPG growth is regulated by T cell function and microglia Ccl5 production, such that their inhibition reduces tumor proliferation in vivo. While these interactions are critical for established Nf1-OPG tumor growth, their importance in tumor formation has not been explored. Methods: A combination of bulk and single-cell RNA mouse optic nerve sequencing, immunohistochemistry, T cell assays, and pharmacologic and antibody-mediated inhibition methods were used in these experiments. Results: We show that T cells and microglia are the main non-neoplastic immune cell populations in both murine and human LGGs. Moreover, we demonstrate that CD8+ T cells, the predominant LGG-infiltrating lymphocyte population, are selectively recruited through increased Ccl2 receptor (Ccr4) expression in CD8+, but not CD4+, T cells, in a NF1/RAS-dependent manner. Finally, we identify the times during gliomagenesis when microglia Ccl5 production (3-6 weeks of age) and Ccl2-mediated T cell infiltration (7-10 weeks of age) occur, such that temporally-restricted Ccl2 or Ccl5 inhibition abrogates tumor formation >3.5 months following the cessation of treatment. Conclusions: Collectively, these findings provide proof-of-concept demonstrations that targeting stromal support during early gliomagenesis durably blocks murine LGG formation. © 2021 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Author Keywords
chemokines;  low-grade glioma;  microglia;  T cells;  tumor microenvironment

Funding details
National Institutes of HealthNIH1-R35-NS07211-01

Document Type: Article
Publication Stage: Final
Source: Scopus

Multivariate analysis of associations between clinical sequencing and outcome in glioblastoma
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdac002, . 

Yang, P.H.^a , Tao, Y.^c , Luo, J.^c , Paturu, M.^a , Lu, H.-C.^b , Ramkissoon, S.^e , Heusel, J.W.^b d , Leuthardt, E.C.^a f , Chicoine, M.R.^a f , Dowling, J.L.^a f , Dunn, G.P.^a b f , Duncavage, E.^b , Dahiya, S.^b , Chattherjee, A.R.^g , Kim, A.H.^a d f

^a Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Surgery, Public Health Sciences Division, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^e Foundation Medicine Inc., Cambridge, MA, United States
^f Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave, Box 8057, St. Louis, MO 63110, United States
^g Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Background: Many factors impact survival in patients with glioblastoma, including age, Karnofsky Performance Status, postoperative chemoradiation, IDH1/2 mutation status, MGMT promoter methylation status, and extent of resection. High-throughput next-generation sequencing is a widely available diagnostic tool, but the independent impact of tumors harboring specific mutant genes on survival and the efficacy of extent of resection are not clear. Methods: We utilized a widely available diagnostic platform (FoundationOne CDx) to perform high-throughput next-generation sequencing on 185 patients with newly diagnosed glioblastoma in our tertiary care center. We performed multivariate analysis to control for clinical parameters with known impact on survival to elucidate the independent prognostic value of prevalent mutant genes and the independent impact of gross total resection. Results: When controlling for factors with known prognostic significance including IDH1/2 mutation and after multiple comparisons analysis, CDKN2B and EGFR mutations were associated with reduced overall survival while PTEN mutation was associated with improved overall survival. Gross total resection, compared to other extent of resection, was associated with improved overall survival in patients with tumors harboring mutations in CDKN2A, CDKN2B, EGFR, PTEN, TERT promoter, and TP53. All patients possessed at least one of these 6 mutant genes. Conclusions: This study verifies the independent prognostic value of several mutant genes in glioblastoma. Six commonly found mutant genes were associated with improved survival when gross total resection was achieved. Thus, even when accounting for known predictors of survival and multiple mutant gene comparisons, extent of resection continues to be strongly associated with survival. © 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Author Keywords
DNA;  glioblastoma;  high-throughput nucleotide analysis;  multivariate analysis;  retrospective studies;  sequence analysis

Funding details
National Institutes of HealthNIHR01 NS094670, R01 NS106612

Document Type: Article
Publication Stage: Final
Source: Scopus

Children with supratentorial midline pilocytic astrocytomas exhibit multiple progressions and acquisition of neurologic deficits over time
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdab187, . 

Brossier, N.M.^a , Strahle, J.M.^b , Cler, S.J.^b , Wallendorf, M.^c , Gutmann, D.H.^d

^a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Pilocytic astrocytomas (PAs) are the most common brain tumors of childhood1 and can arise anywhere within the neuroaxis, including the posterior fossa (pf-PA), supratentorial midline (sm-PA; including optic pathway, hypothalamus, thalamus), supratentorial cortex (sc-PA), brainstem (bs-PA), and spinal cord (sp-PA). While tumor location (sm, bs) has been proposed as a prognostic factor associated with poor progression-free survival (PFS),2-4 this effect is abrogated when resection status (gross total resection [GTR], subtotal resection [STR]) is included.2,4 To determine whether tumor location has any value in predicting PA clinical outcome, we evaluated clinical outcomes of children with biopsy-proven PA treated at St. Louis Children’s Hospital between 2003 and 2021 (n = 251). Subjects with a diagnosis of neurofibromatosis type 1 (NF1; n = 13) and those with discrepancies in their pathologic diagnosis (n = 11) or missing pertinent clinical data (n = 36) were excluded, leaving 191 total subjects for analysis. Consistent with prior reports,5 children with sc-PA were typically older at diagnosis than those with pf-PA. There were no differences in PA location incidence by sex,1 but individuals with sm-PA and bs-PA had higher rates of STR (Figure 1A) and reduced PFS (Figure 1B).2,3 Importantly, this difference in PFS was related to resection status, such that longer PFS was observed in sm-JPA and bs-JPA cases in which a GTR was achieved (Figure 1C). © The Author(s) 2021.

Funding details
National Institute of Neurological Disorders and StrokeNINDS1-R35-NS097211-01
National Institute of Child Health and Human DevelopmentNICHDK12
Alex’s Lemonade Stand Foundation for Childhood CancerALSF18-12558
Hyundai Hope On WheelsDR- 2019-672

Document Type: Article
Publication Stage: Final
Source: Scopus