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2. “De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade

Author

Hadad, Sara, Gupta, Rohit, Oberheim Bush, Nancy Ann, Taylor, Jennie W, Villanueva-Meyer, Javier E, Young, Jacob S, Wu, Jasper, Ravindranathan, Ajay, Zhang, Yalan, Warrier, Gayathri, McCoy, Lucie, Shai, Anny, Pekmezci, Melike, Perry, Arie, Bollen, Andrew W, Phillips, Joanna J, Braunstein, Steve E, Raleigh, David R, Theodosopoulos, Philip, Aghi, Manish K, Chang, Edward F, Hervey-Jumper, Shawn L, Costello, Joseph F, de Groot, John, Butowski, Nicholas A, Clarke, Jennifer L, Chang, Susan M, Berger, Mitchel S, Molinaro, Annette M, and Solomon, David A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Brain Cancer, Cancer, Precision Medicine, Brain Disorders, Genetics, Human Genome, Clinical Research, Cancer Genomics, Neurosciences, Immunotherapy, Orphan Drug, Rare Diseases, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Humans, Child, Middle Aged, Aged, Glioblastoma, Immune Checkpoint Inhibitors, Homozygote, Prospective Studies, Brain Neoplasms, Sequence Deletion, Mutation, Isocitrate Dehydrogenase, Giant cell glioblastoma, Hypermutation, Ultrahypermutation, Mismatch repair deficiency, POLE, Lynch syndrome, Immune checkpoint blockade, Molecular neuropathology, Molecular neuro-oncology, Neurology & Neurosurgery
Abstract

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p

Published
2024

3. Automatic Brain Tissue and Lesion Segmentation and Multi-Parametric Mapping of Contrast-Enhancing Gliomas without the Injection of Contrast Agents: A Preliminary Study.

Author

Liu, Jing, Jakary, Angela, Butowski, Nicholas, Clarke, Jennifer, Xu, Duan, Lupo, Janine, Oberheim Bush, Nancy, Saloner, David, Chang, Susan, Taylor, Jennie, and Villanueva-Meyer, Javier

Subjects
automatic lesion detection, gliomas, macromolecular proton fraction, multi-contrast, multi-parametric mapping, two-compartment model
Abstract

This study aimed to develop a rapid, 1 mm3 isotropic resolution, whole-brain MRI technique for automatic lesion segmentation and multi-parametric mapping without using contrast by continuously applying balanced steady-state free precession with inversion pulses throughout incomplete inversion recovery in a single 6 min scan. Modified k-means clustering was performed for automatic brain tissue and lesion segmentation using distinct signal evolutions that contained mixed T1/T2/magnetization transfer properties. Multi-compartment modeling was used to derive quantitative multi-parametric maps for tissue characterization. Fourteen patients with contrast-enhancing gliomas were scanned with this sequence prior to the injection of a contrast agent, and their segmented lesions were compared to conventionally defined manual segmentations of T2-hyperintense and contrast-enhancing lesions. Simultaneous T1, T2, and macromolecular proton fraction maps were generated and compared to conventional 2D T1 and T2 mapping and myelination water fraction mapping acquired with MAGiC. The lesion volumes defined with the new method were comparable to the manual segmentations (r = 0.70, p < 0.01; t-test p > 0.05). The T1, T2, and macromolecular proton fraction mapping values of the whole brain were comparable to the reference values and could distinguish different brain tissues and lesion types (p < 0.05), including infiltrating tumor regions within the T2-lesion. Highly efficient, whole-brain, multi-contrast imaging facilitated automatic lesion segmentation and quantitative multi-parametric mapping without contrast, highlighting its potential value in the clinic when gadolinium is contraindicated.

Published
2024

4. Advanced Hyperpolarized 13C Metabolic Imaging Protocol for Patients with Gliomas: A Comprehensive Multimodal MRI Approach

Author

Autry, Adam W, Vaziri, Sana, Gordon, Jeremy W, Chen, Hsin-Yu, Kim, Yaewon, Dang, Duy, LaFontaine, Marisa, Noeske, Ralph, Bok, Robert, Villanueva-Meyer, Javier E, Clarke, Jennifer L, Bush, Nancy Ann Oberheim, Chang, Susan M, Xu, Duan, Lupo, Janine M, Larson, Peder EZ, Vigneron, Daniel B, and Li, Yan

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Biomedical Imaging, Bioengineering, Neurosciences, Brain Disorders, Rare Diseases, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, hyperpolarized carbon-13, atlas-based prescription, glioma, serial imaging, metabolism, kinetics, Warburg, Oncology and Carcinogenesis, Oncology and carcinogenesis
Abstract

This study aimed to implement a multimodal 1H/HP-13C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-13C metabolic data. A total of 100 1H/HP [1-13C]-pyruvate MR examinations (104 HP-13C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient. Serial atlas-based HP-13C MRI demonstrated consistency in volumetric coverage measured by inter-exam dice coefficients (0.977 ± 0.008, mean ± SD; four patients/11 exams). The atlas-derived prescription provided significantly improved data quality compared to manually prescribed acquisitions (n = 26/78; p = 0.04). The water-based method for referencing [1-13C]-pyruvate center frequency significantly reduced off-resonance excitation relative to the coil-embedded [13C]-urea phantom (4.1 ± 3.7 Hz vs. 9.9 ± 10.7 Hz; p = 0.0007). Significantly improved capture of tracer inflow was achieved with the 2-s versus 5-s HP-13C MRI acquisition delay (p = 0.007). This study demonstrated the implementation of a comprehensive multimodal 1H/HP-13C MR protocol emphasizing the monitoring of steady-state/dynamic metabolism in patients with glioma.

Published
2024

8. Data sharing and ontology use among agricultural genetics, genomics, and breeding databases and resources of the AgBioData Consortium

Author

Clarke, Jennifer L., Cooper, Laurel D., Poelchau, Monica F., Berardini, Tanya Z., Elser, Justin, Farmer, Andrew D., Ficklin, Stephen, Kumari, Sunita, Laporte, Marie-Angélique, Nelson, Rex T., Sadohara, Rie, Selby, Peter, Thessen, Anne E., Whitehead, Brandon, and Sen, Taner Z.

Subjects
Computer Science - Databases
Abstract

Over the last several decades, there has been rapid growth in the number and scope of agricultural genetics, genomics and breeding (GGB) databases and resources. The AgBioData Consortium (https://www.agbiodata.org/) currently represents 44 databases and resources covering model or crop plant and animal GGB data, ontologies, pathways, genetic variation and breeding platforms (referred to as 'databases' throughout). One of the goals of the Consortium is to facilitate FAIR (Findable, Accessible, Interoperable, and Reusable) data management and the integration of datasets which requires data sharing, along with structured vocabularies and/or ontologies. Two AgBioData working groups, focused on Data Sharing and Ontologies, conducted a survey to assess the status and future needs of the members in those areas. A total of 33 researchers responded to the survey, representing 37 databases. Results suggest that data sharing practices by AgBioData databases are in a healthy state, but it is not clear whether this is true for all metadata and data types across all databases; and that ontology use has not substantially changed since a similar survey was conducted in 2017. We recommend 1) providing training for database personnel in specific data sharing techniques, as well as in ontology use; 2) further study on what metadata is shared, and how well it is shared among databases; 3) promoting an understanding of data sharing and ontologies in the stakeholder community; 4) improving data sharing and ontologies for specific phenotypic data types and formats; and 5) lowering specific barriers to data sharing and ontology use, by identifying sustainability solutions, and the identification, promotion, or development of data standards. Combined, these improvements are likely to help AgBioData databases increase development efforts towards improved ontology use, and data sharing via programmatic means., Comment: 17 pages, 8 figures

Published
2023

9. Data sharing and ontology use among agricultural genetics, genomics, and breeding databases and resources of the Agbiodata Consortium

Author

Clarke, Jennifer L, Cooper, Laurel D, Poelchau, Monica F, Berardini, Tanya Z, Elser, Justin, Farmer, Andrew D, Ficklin, Stephen, Kumari, Sunita, Laporte, Marie-Angélique, Nelson, Rex T, Sadohara, Rie, Selby, Peter, Thessen, Anne E, Whitehead, Brandon, and Sen, Taner Z

Subjects
Biological Sciences, Genetics, Networking and Information Technology R&D (NITRD), Data Format, Library and Information Studies, Bioinformatics and computational biology, Data management and data science
Abstract

Over the last couple of decades, there has been a rapid growth in the number and scope of agricultural genetics, genomics and breeding databases and resources. The AgBioData Consortium (https://www.agbiodata.org/) currently represents 44 databases and resources (https://www.agbiodata.org/databases) covering model or crop plant and animal GGB data, ontologies, pathways, genetic variation and breeding platforms (referred to as 'databases' throughout). One of the goals of the Consortium is to facilitate FAIR (Findable, Accessible, Interoperable, and Reusable) data management and the integration of datasets which requires data sharing, along with structured vocabularies and/or ontologies. Two AgBioData working groups, focused on Data Sharing and Ontologies, respectively, conducted a Consortium-wide survey to assess the current status and future needs of the members in those areas. A total of 33 researchers responded to the survey, representing 37 databases. Results suggest that data-sharing practices by AgBioData databases are in a fairly healthy state, but it is not clear whether this is true for all metadata and data types across all databases; and that, ontology use has not substantially changed since a similar survey was conducted in 2017. Based on our evaluation of the survey results, we recommend (i) providing training for database personnel in a specific data-sharing techniques, as well as in ontology use; (ii) further study on what metadata is shared, and how well it is shared among databases; (iii) promoting an understanding of data sharing and ontologies in the stakeholder community; (iv) improving data sharing and ontologies for specific phenotypic data types and formats; and (v) lowering specific barriers to data sharing and ontology use, by identifying sustainability solutions, and the identification, promotion, or development of data standards. Combined, these improvements are likely to help AgBioData databases increase development efforts towards improved ontology use, and data sharing via programmatic means. Database URL  https://www.agbiodata.org/databases.

Published
2023

10. Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma.

Author

Raymond, Catalina, Yao, Jingwen, Wen, Patrick, Ahluwalia, Manmeet, Piotrowski, Anna, Desai, Arati, Lieberman, Frank, Desideri, Serena, Nabors, L, Ye, Xiaobu, Grossman, Stuart, Strowd, Roy, Clarke, Jennifer, and Ellingson, Benjamin

Subjects
Amine imaging, Glioblastoma, Hypoxia, Hypoxia-inducible factor, Adult, Humans, Middle Aged, Brain Neoplasms, Glioblastoma, Hypoxia, Neoplasm Recurrence, Local, Vascular Endothelial Growth Factor A, Aged
Abstract

INTRODUCTION: Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM. METHODS: A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 Cmin), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR. RESULTS: Of the 24 enrolled patients, median age was 62.1 (38.7-76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6-2.5) and OS was 7.7 months (95% CI 4.9-12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R2 = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. CONCLUSIONS: PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.

Published
2023

11. Current challenges and future of agricultural genomes to phenomes in the USA

Author

Tuggle, Christopher K., Clarke, Jennifer L., Murdoch, Brenda M., Lyons, Eric, Scott, Nicole M., Beneš, Bedrich, Campbell, Jacqueline D., Chung, Henri, Daigle, Courtney L., Das Choudhury, Sruti, Dekkers, Jack C. M., Dórea, Joao R. R., Ertl, David S., Feldman, Max, Fragomeni, Breno O., Fulton, Janet E., Guadagno, Carmela R., Hagen, Darren E., Hess, Andrew S., Kramer, Luke M., Lawrence-Dill, Carolyn J., Lipka, Alexander E., Lübberstedt, Thomas, McCarthy, Fiona M., McKay, Stephanie D., Murray, Seth C., Riggs, Penny K., Rowan, Troy N., Sheehan, Moira J., Steibel, Juan P., Thompson, Addie M., Thornton, Kara J., Van Tassell, Curtis P., and Schnable, Patrick S.

Published
2024
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14. Interactive Effects of Molecular, Therapeutic, and Patient Factors on Outcome of Diffuse Low-Grade Glioma

Author

Hervey-Jumper, Shawn L, Zhang, Yalan, Phillips, Joanna J, Morshed, Ramin A, Young, Jacob S, McCoy, Lucie, Lafontaine, Marisa, Luks, Tracy, Ammanuel, Simon, Kakaizada, Sofia, Egladyous, Andrew, Gogos, Andrew, Villanueva-Meyer, Javier, Shai, Anny, Warrier, Gayathri, Rice, Terri, Crane, Jason, Wrensch, Margaret, Wiencke, John K, Daras, Mariza, Bush, Nancy Ann Oberheim, Taylor, Jennie W, Butowski, Nicholas, Clarke, Jennifer, Chang, Susan, Chang, Edward, Aghi, Manish, Theodosopoulos, Philip, McDermott, Michael, Jakola, Asgeir S, Kavouridis, Vasileios K, Nawabi, Noah, Solheim, Ole, Smith, Timothy, Berger, Mitchel S, and Molinaro, Annette M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Patient Safety, Neurosciences, Orphan Drug, Cancer, Brain Cancer, Brain Disorders, Clinical Research, Rare Diseases, Precision Medicine, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Humans, Oligodendroglioma, Retrospective Studies, Brain Neoplasms, Neurosurgical Procedures, Glioma, Astrocytoma, Treatment Outcome, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposeIn patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with different levels of EOR is not feasible.MethodsIn a 20-year retrospective cohort of 392 patients with IDH-mutant grade 2 glioma, we analyzed the combined effects of volumetric EOR and molecular and clinical factors on overall survival (OS) and progression-free survival by recursive partitioning analysis. The OS results were validated in two external cohorts (n = 365). Propensity score analysis of the combined cohorts (n = 757) was used to mimic a randomized clinical trial with varying levels of EOR.ResultsRecursive partitioning analysis identified three survival risk groups. Median OS was shortest in two subsets of patients with astrocytoma: those with postoperative tumor volume (TV) > 4.6 mL and those with preoperative TV > 43.1 mL and postoperative TV ≤ 4.6 mL. Intermediate OS was seen in patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL in addition to oligodendroglioma patients with either preoperative TV > 43.1 mL and residual TV ≤ 4.6 mL or postoperative residual volume > 4.6 mL. Longest OS was seen in astrocytoma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL who received no chemotherapy and oligodendroglioma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL. EOR ≥ 75% improved survival outcomes, as shown by propensity score analysis.ConclusionAcross both subtypes of LGG, EOR beginning at 75% improves OS while beginning at 80% improves progression-free survival. Nonetheless, maximal resection with preservation of neurological function remains the treatment goal. Our findings have implications for surgical strategies for LGGs, particularly oligodendroglioma.

Published
2023

16. Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial

Author

Mellinghoff, Ingo K, Lu, Min, Wen, Patrick Y, Taylor, Jennie W, Maher, Elizabeth A, Arrillaga-Romany, Isabel, Peters, Katherine B, Ellingson, Benjamin M, Rosenblum, Marc K, Chun, Saewon, Le, Kha, Tassinari, Ania, Choe, Sung, Toubouti, Youssef, Schoenfeld, Steven, Pandya, Shuchi S, Hassan, Islam, Steelman, Lori, Clarke, Jennifer L, and Cloughesy, Timothy F

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Trials and Supportive Activities, Brain Cancer, Orphan Drug, Rare Diseases, Clinical Research, Genetics, Cancer, Brain Disorders, Neurosciences, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Humans, Pyridines, Isocitrate Dehydrogenase, Glioma, Mutation, Pharmaceutical Preparations, Brain Neoplasms, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.

Published
2023

17. Quantitative analysis of MGMT promoter methylation in glioblastoma suggests nonlinear prognostic effect.

Author

Gibson, David, Ravi, Akshay, Rodriguez, Eduardo, Chang, Susan, Oberheim Bush, Nancy, Taylor, Jennie, Butowski, Nicholas, Solomon, David, Scheffler, Aaron, Witte, John, Lambing, Hannah, Berger, Mitchel, Clarke, Jennifer, Chehab, Farid, and Okada, Hideho

Subjects
CpG, MGMT, bisulfite sequencing, glioblastoma, methylation
Abstract

BACKGROUND: Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative methods of measuring promoter methylation, providing clearer insight into its functional relationship with survival. METHODS: A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point, MGMT promoter methylation index. GBMs of 240 newly diagnosed patients were sequenced and risk for mortality was assessed. Nonlinearities were captured by fitting splines to Cox proportional hazard models and plotting smoothed residuals. Covariates included age, Karnofsky performance status, IDH1 mutation, and extent of resection. RESULTS: Median follow-up time and progression-free survival were 16 and 9 months, respectively. A total of 176 subjects experienced death. A one-unit increase in promoter CpG methylation resulted in a 4% reduction in hazard (95% CI 0.93-0.99, P

Published
2023

18. Multi-parametric hyperpolarized 13C/1H imaging reveals Warburg-related metabolic dysfunction and associated regional heterogeneity in high-grade human gliomas

Author

Autry, Adam W, Vaziri, Sana, LaFontaine, Marisa, Gordon, Jeremy W, Chen, Hsin-Yu, Kim, Yaewon, Villanueva-Meyer, Javier E, Molinaro, Annette, Clarke, Jennifer L, Bush, Nancy Ann Oberheim, Xu, Duan, Lupo, Janine M, Larson, Peder EZ, Vigneron, Daniel B, Chang, Susan M, and Li, Yan

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Cancer, Neurosciences, Bioengineering, Cancer, Biomedical Imaging, Orphan Drug, Rare Diseases, Brain Disorders, 4.4 Population screening, Humans, Bicarbonates, Glioma, Lactic Acid, Glioblastoma, Pyruvic Acid, GBM, Hyperpolarized carbon-13, Metabolism, Treatment effects, IDH, Biological psychology, Clinical and health psychology
Abstract

BackgroundDynamic hyperpolarized (HP)-13C MRI has enabled real-time, non-invasive assessment of Warburg-related metabolic dysregulation in glioma using a [1-13C]pyruvate tracer that undergoes conversion to [1-13C]lactate and [13C]bicarbonate. Using a multi-parametric 1H/HP-13C imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor.MethodsMulti-parametric 1H/HP-13C MRI data were acquired from fifteen patients with progressive/treatment-naïve glioblastoma [prog/TN GBM, IDH-wildtype (n = 11)], progressive astrocytoma, IDH-mutant, grade 4 (G4AIDH+, n = 2) and GBM manifesting treatment effects (n = 2). Voxel-wise regional analysis of the cohort with prog/TN GBM assessed imaging heterogeneity across contrast-enhancing/non-enhancing lesions (CEL/NEL) and normal-appearing white matter (NAWM) using a mixed effects model. To enable cross-nucleus parameter association, normalized perfusion, diffusion, and dynamic/steady-state (HP-13C/spectroscopic) metabolic data were collectively examined at the 13C resolution. Prog/TN GBM were similarly compared against progressive G4AIDH+ and treatment effects.ResultsRegional analysis of Prog/TN GBM metabolism revealed statistically significant heterogeneity in 1H choline-to-N-acetylaspartate index (CNI)max, [1-13C]lactate, modified [1-13C]lactate-to-[1-13C]pyruvate ratio (CELval > NELval > NAWMval); [1-13C]lactate-to-[13C]bicarbonate ratio (CELval > NELval/NAWMval); and 1H-lactate (CELval/NELval > NAWMundetected). Significant associations were found between normalized perfusion (cerebral blood volume, nCBV; peak height, nPH) and levels of [1-13C]pyruvate and [1-13C]lactate, as well as between CNImax and levels of [1-13C]pyruvate, [1-13C]lactate and modified ratio. GBM, by comparison to G4AIDH+, displayed lower perfusion %-recovery and modeled rate constants for [1-13C]pyruvate-to-[1-13C]lactate conversion (kPL), and higher 1H-lactate and [1-13C]pyruvate levels, while having higher nCBV, %-recovery, kPL, [1-13C]pyruvate-to-[1-13C]lactate and modified ratios relative to treatment effects.ConclusionsGBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-13C/1H imaging techniques.

Published
2023

21. Evaluation of cross-platform compatibility of a DNA methylation-based glucocorticoid response biomarker

Author

Tang, Emily, Wiencke, John K, Warrier, Gayathri, Hansen, Helen, McCoy, Lucie, Rice, Terri, Bracci, Paige M, Wrensch, Margaret, Taylor, Jennie W, Clarke, Jennifer L, Koestler, Devin C, Salas, Lucas A, Christensen, Brock C, Kelsey, Karl T, and Molinaro, Annette M

Subjects
Biological Sciences, Genetics, Clinical Research, Brain Disorders, Human Genome, Adult, Infant, Newborn, Humans, CpG Islands, DNA Methylation, Glucocorticoids, Oligonucleotide Array Sequence Analysis, Genetic Markers, Dexamethasone, DNA methylation, Whole blood, Cord blood, Glucocorticoid, Algorithmic biomarker, 450K versus 850K, Clinical Sciences, Paediatrics and Reproductive Medicine
Abstract

BackgroundIdentifying blood-based DNA methylation patterns is a minimally invasive way to detect biomarkers in predicting age, characteristics of certain diseases and conditions, as well as responses to immunotherapies. As microarray platforms continue to evolve and increase the scope of CpGs measured, new discoveries based on the most recent platform version and how they compare to available data from the previous versions of the platform are unknown. The neutrophil dexamethasone methylation index (NDMI 850) is a blood-based DNA methylation biomarker built on the Illumina MethylationEPIC (850K) array that measures epigenetic responses to dexamethasone (DEX), a synthetic glucocorticoid often administered for inflammation. Here, we compare the NDMI 850 to one we built using data from the Illumina Methylation 450K (NDMI 450).ResultsThe NDMI 450 consisted of 22 loci, 15 of which were present on the NDMI 850. In adult whole blood samples, the linear composite scores from NDMI 450 and NDMI 850 were highly correlated and had equivalent predictive accuracy for detecting DEX exposure among adult glioma patients and non-glioma adult controls. However, the NDMI 450 scores of newborn cord blood were significantly lower than NDMI 850 in samples measured with both assays.ConclusionsWe developed an algorithm that reproduces the DNA methylation glucocorticoid response score using 450K data, increasing the accessibility for researchers to assess this biomarker in archived or publicly available datasets that use the 450K version of the Illumina BeadChip array. However, the NDMI850 and NDMI450 do not give similar results in cord blood, and due to data availability limitations, results from sample types of newborn cord blood should be interpreted with care.

Published
2022

22. Prospective genomically guided identification of “early/evolving” and “undersampled” IDH-wildtype glioblastoma leads to improved clinical outcomes

Author

Zhang, Yalan, Lucas, Calixto-Hope G, Young, Jacob S, Morshed, Ramin A, McCoy, Lucie, Bush, Nancy Ann Oberheim, Taylor, Jennie W, Daras, Mariza, Butowski, Nicholas A, Villanueva-Meyer, Javier E, Cha, Soonmee, Wrensch, Margaret, Wiencke, John K, Lee, Julieann C, Pekmezci, Melike, Phillips, Joanna J, Perry, Arie, Bollen, Andrew W, Aghi, Manish K, Theodosopoulos, Philip, Chang, Edward F, Hervey-Jumper, Shawn L, Berger, Mitchel S, Clarke, Jennifer L, Chang, Susan M, Molinaro, Annette M, and Solomon, David A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Cancer, Biotechnology, Brain Disorders, Neurosciences, Clinical Research, Human Genome, Brain Cancer, Genetics, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Adult, Astrocytoma, Brain Neoplasms, Glioblastoma, Glioma, Humans, Isocitrate Dehydrogenase, Mutation, Prospective Studies, genomic profiling, glioblastoma, molecular diagnostics, molecular neuro-oncology, precision medicine, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundGenomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic and/or epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma.MethodsClinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of "diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV" per cIMPACT-NOW criteria.ResultsWe identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term "early/evolving" and "undersampled" glioblastoma, IDH-wildtype. We found that prospective genomically guided identification of early/evolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone.ConclusionsThese results support routine use of genomic and/or epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.

Published
2022

23. Predictive Criteria for Prior Selection Using Shrinkage in Linear Models

Author

Dustin, Dean, Clarke, Bertrand, and Clarke, Jennifer

Subjects
Statistics - Methodology
Abstract

Choosing a shrinkage method can be done by selecting a penalty from a list of pre-specified penalties or by constructing a penalty based on the data. If a list of penalties for a class of linear models is given, we provide comparisons based on sample size and number of non-zero parameters under a predictive stability criterion based on data perturbation. These comparisons provide recommendations for penalty selection in a variety of settings. If the preference is to construct a penalty customized for a given problem, then we propose a technique based on genetic algorithms, again using a predictive criterion. We find that, in general, a custom penalty never performs worse than any commonly used penalties but that there are cases the custom penalty reduces to a recognizable penalty. Since penalty selection is mathematically equivalent to prior selection, our method also constructs priors. The techniques and recommendations we offer are intended for finite sample cases. In this context, we argue that predictive stability under perturbation is one of the few relevant properties that can be invoked when the true model is not known. Nevertheless, we study variable inclusion in simulations and, as part of our shrinkage selection strategy, we include oracle property considerations. In particular, we see that the oracle property typically holds for penalties that satisfy basic regularity conditions and therefore is not restrictive enough to play a direct role in penalty selection. In addition, our real data example also includes considerations merging from model mis-specification.

Published
2022

24. PI3K/AKT/mTOR signaling pathway activity in IDH-mutant diffuse glioma and clinical implications

Author

Mohamed, Esraa, Kumar, Anupam, Zhang, Yalan, Wang, Albert S, Chen, Katharine, Lim, Yunita, Shai, Anny, Taylor, Jennie W, Clarke, Jennifer, Hilz, Stephanie, Berger, Mitchel S, Solomon, David A, Costello, Joseph F, Molinaro, Annette M, and Phillips, Joanna J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Brain Disorders, Neurosciences, Cancer, Rare Diseases, Minority Health, Human Genome, Brain Cancer, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Brain Neoplasms, Female, Glioma, Humans, Isocitrate Dehydrogenase, Male, Mutation, Phosphatidylinositol 3-Kinases, Proteomics, Proto-Oncogene Proteins c-akt, Retrospective Studies, Signal Transduction, TOR Serine-Threonine Kinases, biomarker, glioma, outcome, PI3K, AKT, mTOR, quantitative immunoprofiling, PI3K/AKT/mTOR, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundIDH-mutant diffuse gliomas are heterogeneous, and improved methods for optimal patient therapeutic stratification are needed. PI3K/AKT/mTOR signaling activity can drive disease progression and potential therapeutic inhibitors of the pathway are available. Yet, the prevalence of PI3K/AKT/mTOR signaling pathway activity in IDH-mutant glioma is unclear and few robust strategies to assess activity in clinical samples exist.MethodsPI3K/AKT/mTOR signaling pathway activity was evaluated in a retrospective cohort of 132 IDH-mutant diffuse glioma (91 astrocytoma and 41 oligodendroglioma, 1p/19q-codeleted) through quantitative multiplex immunoprofiling using phospho-specific antibodies for PI3K/AKT/mTOR pathway members, PRAS40, RPS6, and 4EBP1, and tumor-specific anti-IDH1 R132H. Expression levels were correlated with genomic evaluation of pathway intrinsic genes and univariate and multivariate Cox proportional hazard regression models were used to evaluate the relationship with outcome.ResultsTumor-specific expression of p-PRAS40, p-RPS6, and p-4EBP1 was common in IDH-mutant diffuse glioma and increased with CNS WHO grade from 2 to 3. Genomic analysis predicted pathway activity in 21.7% (13/60) while protein evaluation identified active PI3K/AKT/mTOR signaling in 56.6% (34/60). Comparison of expression in male versus female patients suggested sexual dimorphism. Of particular interest, when adjusting for clinical prognostic factors, the level of phosphorylation of RPS6 was strongly associated with PFS (P

Published
2022

25. Circulating Immune Cell and Outcome Analysis from the Phase 2 Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent GlioblastomaPD-L1 blockade with durvalumab for glioblastoma

Author

Nayak, Lakshmi, Standifer, Nathan, Dietrich, Jorg, Clarke, Jennifer L, Dunn, Gavin P, Lim, Michael, Cloughesy, Timothy, Gan, Hui K, Flagg, Elizabeth, George, Elizabeth, Gaffey, Sarah, Hayden, Julia, Holcroft, Christina, Wen, Patrick Y, Macri, Mary, Park, Andrew J, Ricciardi, Toni, Ryan, Aileen, Schwarzenberger, Paul, Venhaus, Ralph, de los Reyes, Melissa, Durham, Nicholas M, Creasy, Todd, Huang, Raymond Y, Kaley, Thomas, and Reardon, David A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Brain Disorders, Brain Cancer, Clinical Research, Rare Diseases, Cancer, Antibodies, Monoclonal, B7-H1 Antigen, Bevacizumab, Biomarkers, Tumor, Dexamethasone, Glioblastoma, Humans, Ki-67 Antigen, Neoplasm Recurrence, Local, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposePD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers.Patients and methodsMGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS).ResultsNo cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome.ConclusionsPatients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.

Published
2022

26. Characteristics and outcomes of COVID-19 patients admitted to hospital with and without respiratory symptoms

Author

Moharam, S.A., Abdalasalam, Sabriya, Abdalhadi, Alaa Abdalfattah, Abdalla, Naana Reyam, Abdalla, Walaa, Abdalrheem, Almthani Hamza, Abdalsalam, Ashraf, Abdeewi, Saedah, Abdelgaum, Esraa Hassan, Abdelhalim, Mohamed, Abdelkabir, Mohammed, Abdelrahman, Israa, Abdukahil, Sheryl Ann, Abdulbaqi, Lamees Adil, Abdulhamid, Salaheddin, Abdulhamid, Widyan, Abdulkadir, Nurul Najmee, Abdulwahed, Eman, Abdunabi, Rawad, Abe, Ryuzo, Abel, Laurent, Abodina, Ahmed Mohammed, Abrous, Amal, Absil, Lara, Jabal, Kamal Abu, Salah, Nashat Abu, Abusalama, Abdurraouf, Abuzaid, Tareg Abdallah, Acharya, Subhash, Acker, Andrew, Adam, Elisabeth, Adem, Safia, Ademnou, Manuella, Adewhajah, Francisca, Adrião, Diana, Afum-Adjei Awuah, Anthony, Agbogbatey, Melvin, Al Ageel, Saleh, Ahmed, Aya Mustafa, Ahmed, Musaab Mohammed, Ahmed, Shakeel, Alaraji, Zainab Ahmed, Elhefnawy Enan, Abdulrahman Ahmed, Ahmed Khalil, Reham Abdelhamid, Ahmed Mohamed Abdelaziz, Ali Mostafa, Ainscough, Kate, Airlangga, Eka, Aisa, Tharwat, Aisha, Ali, Aisha, Bugila, Hssain, Ali Ait, Tamlihat, Younes Ait, Akimoto, Takako, Akmal, Ernita, Akwani, Chika, Al Qasim, Eman, Alajeeli, Ahmed, Alali, Ahmed, Alalqam, Razi, Alameen, Aliya Mohammed, Al-Aquily, Mohammed, Alaraji, Zinah A., Albakry, Khalid, Albatni, Safa, Alberti, Angela, Aldabbourosama, Osama, Al-dabbous, Tala, Aldhalia, Amer, Aldoukali, Abdulkarim, Alegesan, Senthilkumar, Alessi, Marta, Alex, Beatrice, Alexandre, Kévin, Al-Fares, Abdulrahman, Alflite, Asil, Alfoudri, Huda, Alhadad, Qamrah, Alhaddad, Hoda Salem, Mohamed Abdalla Alhasan, Maali Khalid, Alhouri, Ahmad Nabil, Alhouri, Hasan, Ali, Adam, Ali, Imran, TagElser Mohammed Ali, Maha, Abbas, Syed Ali, Abdelghafar, Yomna Ali, Sheikh, Naseem Ali, Alidjnou, Kazali Enagnon, Aljadi, Mahmoud, Aljamal, Sarah, Alkahlout, Mohammed, Alkaseek, Akram, Alkhafajee, Qabas, Allavena, Clotilde, Allou, Nathalie, Almasri, Lana, Almjersah, Abdulrahman, Alqandouz, Raja Ahmed, Alrfaea, Walaa, Alrifaee, Moayad, Alsaadi, Rawan, Al-Saba'a, Yousef, Alshareea, Entisar, Alshenawy, Eslam, Altaf, Aneela, Alves, João Melo, Alves, João, Alves, Rita, Cabrita, Joana Alves, Amaral, Maria, Amer, Amro Essam, Amira, Nur, Adusei, Amos Amoako, Amuasi, John, Andini, Roberto, Andrejak, Claire, Angheben, Andrea, Angoulvant, François, Ankrah, Sophia, Ansart, Séverine, Anthonidass, Sivanesen, Antonelli, Massimo, Antunes de Brito, Carlos Alexandre, Apriyana, Ardiyan, Arabi, Yaseen, Aragao, Irene, Arancibia, Francisco, Araujo, Carolline, Arcadipane, Antonio, Archambault, Patrick, Arenz, Lukas, Arlet, Jean-Benoît, Arnold-Day, Christel, Arora, Lovkesh, Arora, Rakesh, Artaud-Macari, Elise, Aryal, Diptesh, Asensio, Angel, Ashley, Elizabeth A., Ashraf, Muhammad, Ashraf, Muhammad Sheharyar, Ben Ashur, Abir, Asiedu-Bekoe, Franklin, Asif, Namra, Asim, Mohammad, Assi, Grace, Assie, Jean Baptiste, Asyraf, Amirul, Atangana, Fouda, Atia, Ahmed, Atif, Minahel, Abdelrhman Abdallahrs, Asia Atif, Atique, Anika, Atlowly, Moad, Attanyake, AM Udara Lakshan, Auchabie, Johann, Aumaitre, Hugues, Auvet, Adrien, Ali Mohammed, Abdelmalek Awad, Axelsen, Eyvind W., Ayad, Ared, Hassan Helmi, Ahmed Ayman, Azemar, Laurène, Azizeldin, Mohammed, Azoulay, Cecile, Babatunde, Hakeem, Bach, Benjamin, Bachelet, Delphine, Badr, Claudine, Bævre-Jensen, Roar, Baig, Nadia, Baillie, John Kenneth, Baird, J Kevin, Bak, Erica, Bakakos, Agamemnon, Bakar, Nazreen Abu, Bakeer, Hibah Bileid, Bakri, Ashraf, Bal, Andriy, Balakrishnan, Mohanaprasanth, Bandoh, Irene, Bani-Sadr, Firouzé, Barbalho, Renata, Barbosa, Nicholas Yuri, Barclay, Wendy S., Barnett, Saef Umar, Barnikel, Michaela, Barrasa, Helena, Barrigoto, Cleide, Bartoli, Marie, Baruch, Joaquín, Basmaci, Romain, Basri, Muhammad Fadhli Hassin, Batool, AbdAlkarim, Battaglini, Denise, Bauer, Jules, Bautista Rincon, Diego Fernando, Dow, Denisse Bazan, Beane, Abigail, Bedossa, Alexandra, Bee, Ker Hong, Begum, Husna, Behilill, Sylvie, Beishuizen, Albertus, Beljantsev, Aleksandr, Bellemare, David, Beltrame, Anna, Beltrão, Beatriz Amorim, Beluze, Marine, Benech, Nicolas, Benjiman, Lionel Eric, Bennett, Suzanne, Bento, Luís, Berdal, Jan-Erik, Berdeweel, Lamis, Bergeaud, Delphine, Bergin, Hazel, Bertoli, Giulia, Bertolino, Lorenzo, Bessis, Simon, Bevilcaqua, Sybille, Bezulier, Karine, Bhatt, Amar, Bhavsar, Krishna, Bianchi, Isabella, Bianco, Claudia, Bichoka, Sandra, Bidin, Farah Nadiah, Humaid, Felwa Bin, Bin Kamarudin, Mohd Nazlin, Binnawara, Muhannud, Bisoffi, Zeno, Biston, Patrick, Bitker, Laurent, Bittaye, Mustapha, Bitton, Jonathan, Blanco-Schweizer, Pablo, Blier, Catherine, Bloos, Frank, Blot, Mathieu, Boccia, Filomena, Bodenes, Laetitia, Bogaert, Debby, Boivin, Anne-Hélène, Bolanga, Ariel, Bolaños, Isabela, Bolze, Pierre-Adrien, Bompart, François, Bonifasius, Aurelius, Bonney, Joe, Borges, Diogo, Borie, Raphaël, Bosse, Hans Martin, Botelho-Nevers, Elisabeth, Bouadma, Lila, Bouchaud, Olivier, Bouchez, Sabelline, Bouhour, Damien, Bouiller, Kévin, Bouillet, Laurence, Bouisse, Camile, Bountthasavong, Latsaniphone, Boureau, Anne-Sophie, Bourke, John, Bouscambert, Maude, Bousquet, Aurore, Boyer-Besseyre, Marielle, Boylan, Maria, Bozza, Fernando Augusto, Braconnier, Axelle, Braga, Cynthia, Brandenburger, Timo, Monteiro, Filipa Brás, Brazzi, Luca, Breen, Dorothy, Breen, Patrick, Brewster, David, Brickell, Kathy, Broadley, Tessa, Brotherton, Helen, Browne, Alex, Brozzi, Nicolas, Brunvoll, Sonja Hjellegjerde, Brusse-Keizer, Marjolein, Bryda, Petra, Buchtele, Nina, Bugaeva, Polina, Buisson, Marielle, Buonsenso, Danilo, Burhan, Erlina, Buri, Donald, Burrell, Aidan, Bustos, Ingrid G., Butnaru, Denis, Cabie, André, Cabral, Susana, Cabrita, Joana, Caceres, Eder, Cadoz, Cyril, Garcês, Rui Caetano, Calligy, Kate, Calvache, Jose Andres, Camões, João, Campana, Valentine, Campbell, Paul, Campisi, Josie, Canepa, Cecilia, Cantero, Mireia, Caoili, Janice, Caraux-Paz, Pauline, Cárcel, Sheila, Cardoso, Filipa, Cardoso, Filipe, Cardoso, Nelson, Cardoso, Sofia, Carelli, Simone, Carlier, Nicolas, Carmoi, Thierry, Carney, Gayle, Carqueja, Inês, Carret, Marie-Christine, Carrier, François Martin, Carroll, Ida, Carson, Gail, Casanova, Maire-Laure, Cascão, Mariana, Casey, Siobhan, Casimiro, José, Cassandra, Bailey, Castañeda, Silvia, Castanheira, Nidyanara, Castor-Alexandre, Guylaine, Castro, Ivo, Catarino, Ana, Catherine, François-Xavier, Cattaneo, Paolo, Cavalin, Roberta, Cavalli, Giulio Giovanni, Cavayas, Alexandros, Ceccato, Adrian, Ceesay, Masaneh, Cerkovnik, Shelby, Cervantes-Gonzalez, Minerva, Cevik, Muge, Chair, Anissa, Chakveatze, Catherine, Chan, Adrienne, Chand, Meera, Chapplain, Jean-Marc, Charpentier, Charlotte, Chas, Julie, Chaudry, Muhammad Mobin, Chávez Iñiguez, Jonathan Samuel, Chen, Anjellica, Chen, Yih-Sharng, Chenard, Léo, Cheng, Matthew Pellan, Cheret, Antoine, Chiarabini, Thibault, Chica, Julian, Chidambaram, Suresh Kumar, Tho, Leong Chin, Chirouze, Catherine, Chiumello, Davide, Cho, Sung-Min, Cholley, Bernard, Chommanam, Danoy, Chopin, Marie-Charlotte, Chow, Yock Ping, Chow, Ting Soo, Christy, Nathaniel, Chua, Hiu Jian, Chua, Jonathan, Cidade, Jose Pedro, Cisneros Herreros, José Miguel, Citarella, Barbara Wanjiru, Ciullo, Anna, Clarke, Jennifer, Claure-Del Granado, Rolando, Clohisey, Sara, Codan, Cassidy, Cody, Caitriona, Coles, Jennifer, Coles, Megan, Colin, Gwenhaël, Collins, Michael, Combs, Pamela, Connolly, Jennifer, Connor, Marie, Conrad, Anne, Conway, Elaine, Cooke, Graham S., Cordel, Hugues, Corley, Amanda, Cornelis, Sabine, Cornet, Alexander Daniel, Corpuz, Arianne Joy, Cortegiani, Andrea, Corvaisier, Grégory, Couffignal, Camille, Couffin-Cadiergues, Sandrine, Courtois, Roxane, Cousse, Stéphanie, Cowan, Juthaporn, Cregan, Rachel, Crowl, Gloria, Crump, Jonathan, Cruz, Claudina, Csete, Marc, Cullen, Ailbhe, Cummings, Matthew, Curley, Gerard, Curlier, Elodie, Curran, Colleen, Custodio, Paula, da Silva Filipe, Ana, Da Silveira, Charlene, Dabaliz, Al-Awwab, Dagens, Andrew, Dahl, John Arne, Dahly, Darren, D'Alessandro, Umberto, Daley, Peter, Dalloul, Zaina, Dalton, Heidi, Dalton, Jo, Daly, Seamus, Damas, Juliana, Dame, Joycelyn, Damien, Cammandji, Daneman, Nick, Dantas, Jorge, D'Aragon, Frédérick, de Loughry, Gillian, de Mendoza, Diego, De Montmollin, Etienne, França, Rafael Freitas de Oliveira, Isabel de Pinho Oliveira, Ana, De Rosa, Rosanna, De Rose, Cristina, de Silva, Thushan, de Vries, Peter, Deacon, Jillian, Dean, David, Debard, Alexa, DeBenedictis, Bianca, Debray, Marie-Pierre, DeCastro, Nathalie, Dechert, William, Decours, Romain, Defous, Eve, Delacroix, Isabelle, Delamou, Alexandre, Delaveuve, Eric, Delavigne, Karen, Delfos, Nathalie M., Deligiannis, Ionna, Dell'Amore, Andrea, Delmas, Christelle, Delobel, Pierre, Delsing, Corine, Demonchy, Elisa, Denis, Emmanuelle, Deplanque, Dominique, Depuydt, Pieter, Descamps, Diane, Desvallées, Mathilde, Dewayanti, Santi, Dhangar, Pathik, Diallo, Alpha, Diallo, Souleymane Taran, Diamantis, Sylvain, Dias, André, Da Silva, Fernanda Dias, Diaz, Rodrigo, Diaz, Juan Jose, Diaz, Priscila, Dibba, Bakary K., Didier, Kévin, Diehl, Jean-Luc, Dieperink, Wim, Dimet, Jérôme, Dinot, Vincent, Diop, Fara, Diouf, Alphonsine, Dishon, Yael, Djadda, Cedric, Djossou, Félix, Docherty, Annemarie B., Doherty, Helen, Dondorp, Arjen M., Donnelly, Christl A., Donohue, Yoann, Donohue, Sean, Doran, Peter, Dorival, Céline, D'Ortenzio, Eric, Doshi, Yash, Douangdala, Phouvieng, Douglas, James Joshua, Douma, Renee, Dournon, Nathalie, Downey, Joanne, Downing, Mark, Drake, Thomas, Driscoll, Aoife, Duah, Ibrahim Kwaku, Fonseca, Claudio Duarte, Dubee, Vincent, Dubos, François, Dubot-Pérès, Audrey, Ducancelle, Alexandre, Duculan, Toni, Dudman, Susanne, Duggal, Abhijit, Dunand, Paul, Dunning, Jake, Duplaix, Mathilde, Durante-Mangoni, Emanuele, Durham, Lucian, III, Dussol, Bertrand, Duthoit, Juliette, Duval, Xavier, Dyrhol-Riise, Anne Margarita, Ean, Sim Choon, Ebo, Ada, Echeverria-Villalobos, Marco, Edelstein, Michael, Egan, Siobhan, Eggesbø, Linn Margrete, Ehzaz, Khadeja, Eira, Carla, El Sanharawi, Mohammed, El Sayed, Marwan, Elabid, Mohammed, Elagili, Mohamed Bashir, Elapavaluru, Subbarao, Elbahnasawy, Mohammad, Elboshra, Sohail, Elharrar, Brigitte, Ellerbroek, Jacobien, Ellingjord-Dale, Merete, ELMagrahi, Hamida, Elmubark, Mohammad Muatasm, Elotmani, Loubna, Eloundou, Lauren, Eloy, Philippine, Elshaikhy, Basma, Elshazly, Tarek, Elsokni, Wafa, Eltayeb, Aml Ahmed, Elyazar, Iqbal, Emad, Zarief Kamel, Embarek, Hussein, Enderle, Isabelle, Endo, Tomoyuki, Eneli, Gervais, Eng, Chan Chee, Engelmann, Ilka, Enouf, Vincent, Epaulard, Olivier, Esaadi, Haneen, Esperatti, Mariano, Esperou, Hélène, Santo, Catarina Espírito, Esposito-Farese, Marina, Essaka, Rachel, Essuman, Lorinda, Estevão, João, Etienne, Manuel, Everding, Anna Greti, Evers, Mirjam, Fabre, Isabelle, Fabre, Marc, Fadera, Ismaila, Abdalla Fadlalla, Asgad Osman, Faheem, Amna, Fahy, Arabella, Fairfield, Cameron J., Fakar, Zul, Fareed, Komal, Faria, Pedro, Farooq, Ahmed, Fateena, Hanan, Fathi, Mohamed, Fatima, Salem, Fatoni, Arie Zainul, Faure, Karine, Favory, Raphaël, Fayed, Mohamed, Feely, Niamh, Fernandes, Jorge, Fernandes, Marília Andreia, Fernandes, Susana, Ferrand, François-Xavier, Devouge, Eglantine Ferrand, Ferrão, Joana, Ferraz, Mário, Ferreira, Benigno, Ferreira, Isabel, Ferreira, Bernardo, Ferreira, Sílvia, Ferriere, Nicolas, Ficko, Céline, Figueiredo-Mello, Claudia, Finlayson, William, Flament, Thomas, Fletcher, Tom, Florence, Aline-Marie, Florio, Letizia Lucia, Flynn, Brigid, Flynn, Deirdre, Foley, Jean, Fomin, Victor, Fonseca, Tatiana, Fontela, Patricia, Forrest, Karen, Forsyth, Simon, Foster, Denise, Foti, Giuseppe, Fotso, Berline, Fourn, Erwan, Fowler, Robert A., Fraher, Marianne, Franch-Llasat, Diego, Fraser, Christophe, Fraser, John F., Freire, Marcela Vieira, Ribeiro, Ana Freitas, French, Craig, Friedrich, Caren, Fritz, Ricardo, Fry, Stéphanie, Fuentes, Nora, Fukuda, Masahiro, Argin, G., Gaborieau, Valérie, Gaci, Rostane, Gagliardi, Massimo, Gagnard, Jean-Charles, Gagneux-Brunon, Amandine, Gai, Abdou, Gaião, Sérgio, Skeie, Linda Gail, Galal Mohamed Ramadan, Adham Mohamed, Gallagher, Phil, Gamble, Carrol, Gani, Yasmin, Garan, Arthur, Garcia, Rebekha, Garcia-Diaz, Julia, Garcia-Gallo, Esteban, Garimella, Navya, Garot, Denis, Garrait, Valérie, Gauli, Basanta, Gavrylov, Anatoliy, Gaymard, Alexandre, Gebauer, Johannes, Geraud, Eva, Morlaes, Louis Gerbaud, Germano, Nuno, Ghemmeid, Malak, Ghisulal, Praveen Kumar, Ghosn, Jade, Giani, Marco, Gigante, Tristan, Gilroy, Elaine, Giordano, Guillermo, Girvan, Michelle, Gissot, Valérie, Giwangkancana, Gezy, Glikman, Daniel, Glybochko, Petr, Gnall, Eric, Goco, Geraldine, Goehringer, François, Goepel, Siri, Goffard, Jean-Christophe, Goh, Jin Yi, Golács, Brigitta, Golob, Jonathan, Gomez, Kyle, Gómez-Junyent, Joan, Gominet, Marie, Gonzalez, Alicia, Gordon, Patricia, Gorenne, Isabelle, Goubert, Laure, Goujard, Cécile, Goulenok, Tiphaine, Grable, Margarite, Graf, Jeronimo, Grandin, Edward Wilson, Granier, Pascal, Grasselli, Giacomo, Grazioli, Lorenzo, Green, Christopher A., Greene, Courtney, Greenhalf, William, Greffe, Segolène, Grieco, Domenico Luca, Griffee, Matthew, Griffiths, Fiona, Grigoras, Ioana, Groenendijk, Albert, Grovogui, Fassou Mathias, Gruner, Heidi, Gu, Yusing, Guedj, Jérémie, Guego, Martin, Guerguerian, Anne-Marie, Guerreiro, Daniela, Guery, Romain, Guillaumot, Anne, Guilleminault, Laurent, Guimarães de Castro, Maisa, Guimard, Thomas, Haalboom, Marieke, Haber, Daniel, Hachemi, Ali, Haddud, Abdurrahman, Hadri, Nadir, Hafez, Wael, Haidri, Fakhir Raza, Rida Hajij, Fatima Mhd, Hakak, Sheeba, Hall, Adam, Hall, Matthew, Halpin, Sophie, Hamdan, Shaher, Hamdi, Abdelhafeez, Hameed, Jawad, Hamer, Ansley, Hamers, Raph L., Hamidfar, Rebecca, Hammarström, Bato, Hammond, Naomi, Hammond, Terese, Han, Lim Yuen, Hanan, Matly, Haniffa, Rashan, Hao, Kok Wei, Hardwick, Hayley, Harrison, Ewen M., Harrison, Janet, Ekow Harrison, Samuel Bernard, Hartman, Alan, Hasan, Sulieman, Nabil Hasan, Mohammad Ali, Hasan, Mohd Shahnaz, Hashmi, Junaid, Hashmi, Madiha, Hassan, Amoni, Hassanin, Ebtisam, Hayat, Muhammad, Hayes, Ailbhe, Hays, Leanne, Heerman, Jan, Heggelund, Lars, Helmi, Ahmed, Hendry, Ross, Hennessy, Martina, Henriquez-Trujillo, Aquiles Rodrigo, Hentzien, Maxime, Hernandez, Diana, Hershey, Andrew, Hesstvedt, Liv, Hidayah, Astarini, Higgins, Eibhlin, Higgins, Rupert, Hinton, Samuel, Hiraiwa, Hiroaki, Hirkani, Haider, Hitoto, Hikombo, Ho, Antonia, Ho, Yi Bin, Hoctin, Alexandre, Hoffmann, Isabelle, Hoh, Wei Han, Hoiting, Oscar, Holt, Rebecca, Holter, Jan Cato, Horby, Peter, Horcajada, Juan Pablo, Houas, Ikram, Houderi, Mabrouka, Hough, Catherine L., Houltham, Stuart, Ming-Yang Hsu, Jimmy, Hulot, Jean-Sébastien, Hurd, Abby, Hussain, Iqbal, Hussein, Aliae Mohamed, Hussein, Mahmood, Ibrahim, Fatima, Ibran, Bashir, Ijaz, Samreen, Ikram, M. Arfan, Illana, Carlos Cañada, Imbert, Patrick, Ansari, Muhammad Imran, Sikander, Rana Imran, Inácio, Hugo, Dominguez, Carmen Infante, Ing, Yun Sii, Ippolito, Mariachiara, Irawany, Vera, Isgett, Sarah, Isidoro, Tiago, Ismail, Nadiah, Isnard, Margaux, Istre, Mette Stausland, Itai, Junji, Ivulich, Daniel, Jaafar, Danielle, Jaafoura, Salma, Jaber, Hamza, Jabot, Julien, Jackson, Clare, Jagne, Abubacarr, Jaureguiberry, Stéphane, Jaworsky, Denise, Jego, Florence, Jelani, Anilawati Mat, Jenum, Synne, Jimbo-Sotomayor, Ruth, Joe, Ong Yiaw, Jorge García, Ruth Noemí, Jørgensen, Silje Bakken, Joseph, Cédric, Joseph, Mark, Joshi, Swosti, Jourdain, Mercé, Jouvet, Philippe, Jung, Anna, Jung, Hanna, Juzar, Dafsah, Kafif, Ouifiya, Kaguelidou, Florentia, Kaisbain, Neerusha, Kaleesvran, Thavamany, Kali, Sabina, Kalleberg, Karl Trygve, Kalomoiri, Smaragdi, Ayadi Kamaluddin, Muhammad Aisar, Kamano, Armand Saloun, Che Kamaruddin, Zul Amali, Kamarudin, Nadiah, Kamineni, Kavita, Kandamby, Darshana Hewa, Kang, Kong Yeow, Kanwal, Darakhshan, Kanyawati, Dyah, Karghul, Mohamed, Karpayah, Pratap, Karsies, Todd, Kartsonaki, Christiana, Kasugai, Daisuke, Katz, Kevin, Kay, Christy, Kayyali, Lamees, Keating, Seán, Kedia, Pulak, Kelly, Andrea, Kelly, Aoife, Kelly, Claire, Kelly, Niamh, Kelly, Sadie, Kelly, Yvelynne, Kelsey, Maeve, Kennon, Kalynn, Keomany, Sommay, Kernan, Maeve, Kerroumi, Younes, Keshav, Sharma, Khail, Shams, Khaled, Sarah, Khalid, Imrana, Khalil, Antoine, Khan, Irfan, Khan, Quratul Ain, Khanal, Sushil, Khatak, Abid, Kherajani, Krish, Kho, Michelle E., Khoo, Denisa, Khoo, Ryan, Khoo, Saye, Khoso, Muhammad Nasir, Khuwaja, Amin, Kiat, Khor How, Kida, Yuri, Kiiza, Peter, Granerud, Beathe Kiland, Kildal, Anders Benjamin, Kim, Jae Burm, Kimmoun, Antoine, Kindgen-Milles, Detlef, Kitamura, Nobuya, Kjetland Kjetland, Eyrun Floerecke, Klenerman, Paul, Klont, Rob, Bekken, Gry Kloumann, Knight, Stephen R., Kobbe, Robin, Forson, Paa Kobina, Kodippily, Chamira, Vasconcelos, Malte Kohns, Koirala, 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Eoin, Wham, Murray, Whelan, Bryan, White, Nicole, Wicky, Paul Henri, Wiedemann, Aurélie, Wijaya, Surya Otto, Wille, Keith, Willems, Sue, Williams, Bailey, Williams, Patricia J., Williams, Virginie, Wils, Evert-Jan, Wittman, Jessica, Wong, Calvin, Wong, Xin Ci, Wong, Yew Sing, Wong, Teck Fung, Wright, Natalie, Xian, Lim Saio, Xynogalas, Ioannis, Binti Mohd Yakop, Siti Rohani, Yamazaki, Masaki, Yarad, Elizabeth, Yazdanpanah, Yazdan, Hing, Nicholas Yee Liang, Mahmoud Abdelaal, Abdelrahman Yehia, Yelnik, Cécile, Yeoh, Chian Hui, Yerkovich, Stephanie, Yiaye, Touxiong, Yokoyama, Toshiki, Yonis, Hodane, Yousif, Obada, Yuliarto, Saptadi, Zaaqoq, Akram, Zabbe, Marion, Zabert, Gustavo E., Zacharowski, Kai, Zahid, Masliza, Zahran, Maram, Binti Zaidan, Nor Zaila, Zambon, Maria, Zambrano, Miguel, Zanella, Alberto, Zaynah, Nurul, Zayyad, Hiba, Zoufaly, Alexander, Zucman, David, Ibáñez-Prada, Elsa D., Gonçalves, Bronner P., Baruch, Joaquin, Escher, Martina, Philippy, Fred, Kutsogiannis, Demetrios James, Vaillant, Michel, and Olliaro, Piero

Published
2024
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28. Interactions of Age and Blood Immune Factors and Noninvasive Prediction of Glioma Survival

Author

Molinaro, Annette M, Wiencke, John K, Warrier, Gayathri, Koestler, Devin C, Chunduru, Pranathi, Lee, Ji Yoon, Hansen, Helen M, Lee, Sean, Anguiano, Joaquin, Rice, Terri, Bracci, Paige M, McCoy, Lucie, Salas, Lucas A, Christensen, Brock C, Wrensch, Margaret, Kelsey, Karl T, Taylor, Jennie W, and Clarke, Jennifer L

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Brain Cancer, Brain Disorders, Neurosciences, Cancer, Genetics, Rare Diseases, Good Health and Well Being, Adult, Brain Neoplasms, Child, Preschool, Glioma, Humans, Immunologic Factors, Isocitrate Dehydrogenase, Mutation, Prognosis, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundTumor-based classification of human glioma portends patient prognosis, but considerable unexplained survival variability remains. Host factors (eg, age) also strongly influence survival times, partly reflecting a compromised immune system. How blood epigenetic measures of immune characteristics and age augment molecular classifications in glioma survival has not been investigated. We assess the prognostic impact of immune cell fractions and epigenetic age in archived blood across glioma molecular subtypes for the first time.MethodsWe evaluated immune cell fractions and epigenetic age in archived blood from the University of California San Francisco Adult Glioma Study, which included a training set of 197 patients with IDH-wild type, 1p19q intact, TERT wild type (IDH/1p19q/TERT-WT) glioma, an evaluation set of 350 patients with other subtypes of glioma, and 454 patients without glioma.ResultsIDH/1p19q/TERT-WT patients had lower lymphocyte fractions (CD4+ T, CD8+ T, natural killer, and B cells) and higher neutrophil fractions than people without glioma. Recursive partitioning analysis delineated 4 statistically significantly different survival groups for patients with IDH/1p19q/TERT-WT based on an interaction between chronological age and 2 blood immune factors, CD4+ T cells, and neutrophils. Median overall survival ranged from 0.76 years (95% confidence interval = 0.55-0.99) for the worst survival group (n = 28) to 9.72 years (95% confidence interval = 6.18 to not available) for the best (n = 33). The recursive partitioning analysis also statistically significantly delineated 4 risk groups in patients with other glioma subtypes.ConclusionsThe delineation of different survival groups in the training and evaluation sets based on an interaction between chronological age and blood immune characteristics suggests that common host immune factors among different glioma types may affect survival. The ability of DNA methylation-based markers of immune status to capture diverse, clinically relevant information may facilitate noninvasive, personalized patient evaluation in the neuro-oncology clinic.

Published
2022

29. Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T-cell response in low-grade gliomas

Author

Ogino, Hirokazu, Taylor, Jennie W, Nejo, Takahide, Gibson, David, Watchmaker, Payal B, Okada, Kaori, Saijo, Atsuro, Tedesco, Meghan R, Shai, Anny, Wong, Cynthia M, Rabbitt, Jane E, Olin, Michael R, Moertel, Christopher L, Nishioka, Yasuhiko, Salazar, Andres M, Molinaro, Annette M, Phillips, Joanna J, Butowski, Nicholas A, Clarke, Jennifer L, Bush, Nancy Ann Oberheim, Hervey-Jumper, Shawn L, Theodosopoulos, Philip, Chang, Susan M, Berger, Mitchel S, and Okada, Hideho

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Prevention, Vaccine Related, Cancer, Clinical Trials and Supportive Activities, Orphan Drug, Brain Cancer, Neurosciences, Immunization, Brain Disorders, Biotechnology, Rare Diseases, Evaluation of treatments and therapeutic interventions, Prevention of disease and conditions, and promotion of well-being, 3.4 Vaccines, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Adult, Aged, CD8-Positive T-Lymphocytes, Cancer Vaccines, Carboxymethylcellulose Sodium, Female, Glioma, Humans, Male, Middle Aged, Neoadjuvant Therapy, Poly I-C, Polylysine, Tumor Microenvironment, Vaccination, Brain cancer, Cancer immunotherapy, Oncology, T cells, Vaccines, Medical and Health Sciences, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BACKGROUNDLong-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODSWe conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor.RESULTSA total of 17 eligible patients were enrolled - 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident-like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination.CONCLUSIONThe regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT02549833.FUNDINGNIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.

Published
2022

30. Association of Neurological Impairment on the Relative Benefit of Maximal Extent of Resection in Chemoradiation-Treated Newly Diagnosed Isocitrate Dehydrogenase Wild-Type Glioblastoma

Author

Aabedi, Alexander A, Young, Jacob S, Zhang, Yalan, Ammanuel, Simon, Morshed, Ramin A, Ore, Cecilia Dalle, Brown, Desmond, Phillips, Joanna J, Bush, Nancy Ann Oberheim, Taylor, Jennie W, Butowski, Nicholas, Clarke, Jennifer, Chang, Susan M, Aghi, Manish, Molinaro, Annette M, Berger, Mitchel S, and Hervey-Jumper, Shawn L

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Brain Cancer, Neurosciences, Rare Diseases, Brain Disorders, Cancer, Brain Neoplasms, Chemoradiotherapy, Glioblastoma, Humans, Isocitrate Dehydrogenase, Prognosis, Retrospective Studies, Glioma, Cognition, Neurological impairments, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundIncreases in the extent of resection of both contrast-enhanced (CE) and non-contrast-enhanced (NCE) tissue are associated with substantial survival benefits in patients with isocitrate dehydrogenase wild-type glioblastoma. The fact, however, remains that these lesions exist within the framework of complex neural circuitry subserving cognition, movement, and behavior, all of which affect the ultimate survival outcome. The prognostic significance of the interplay between CE and NCE cytoreduction and neurological morbidity is poorly understood.ObjectiveTo identify a clinically homogenous population of 228 patients with newly diagnosed isocitrate dehydrogenase wild-type glioblastoma, all of whom underwent maximal safe resection of CE and NCE tissue and adjuvant chemoradiation. We then set out to delineate the competing interactions between resection of CE and NCE tissue and postoperative neurological impairment with respect to overall survival.MethodsNonparametric multivariate models of survival were generated via recursive partitioning to provide a clinically intuitive framework for the prognostication and surgical management of such patients.ResultsWe demonstrated that the presence of a new postoperative neurological impairment was the key factor in predicting survival outcomes across the entire cohort. Patients older than 60 yr who suffered from at least one new impairment had the worst survival outcome regardless of extent of resection (median of 11.6 mo), whereas those who did not develop a new impairment had the best outcome (median of 28.4 mo) so long as all CE tissue was resected.ConclusionOur data provide novel evidence for management strategies that prioritize safe and complete resection of CE tissue.

Published
2022

31. Combining radiomics and deep convolutional neural network features from preoperative MRI for predicting clinically relevant genetic biomarkers in glioblastoma

Author

Calabrese, Evan, Rudie, Jeffrey D, Rauschecker, Andreas M, Villanueva-Meyer, Javier E, Clarke, Jennifer L, Solomon, David A, and Cha, Soonmee

Subjects
Brain Disorders, Brain Cancer, Rare Diseases, Neurosciences, Cancer, Genetics, Good Health and Well Being, artificial intelligence, deep learning, glioblastoma, radiogenomics, radiomics
Abstract

BackgroundGlioblastoma is the most common primary brain malignancy, yet treatment options are limited, and prognosis remains guarded. Individualized tumor genetic assessment has become important for accurate prognosis and for guiding emerging targeted therapies. However, challenges remain for widespread tumor genetic testing due to costs and the need for tissue sampling. The aim of this study is to evaluate a novel artificial intelligence method for predicting clinically relevant genetic biomarkers from preoperative brain MRI in patients with glioblastoma.MethodsWe retrospectively analyzed preoperative MRI data from 400 patients with glioblastoma, IDH-wildtype or WHO grade 4 astrocytoma, IDH mutant who underwent resection and genetic testing. Nine genetic biomarkers were assessed: hotspot mutations of IDH1 or TERT promoter, pathogenic mutations of TP53, PTEN, ATRX, or CDKN2A/B, MGMT promoter methylation, EGFR amplification, and combined aneuploidy of chromosomes 7 and 10. Models were developed to predict biomarker status from MRI data using radiomics features, convolutional neural network (CNN) features, and a combination of both.ResultsCombined model performance was good for IDH1 and TERT promoter hotspot mutations, pathogenic mutations of ATRX and CDKN2A/B, and combined aneuploidy of chromosomes 7 and 10, with receiver operating characteristic area under the curve (ROC AUC) >0.85 and was fair for all other tested biomarkers with ROC AUC >0.7. Combined model performance was statistically superior to individual radiomics and CNN feature models for prediction chromosome 7 and 10 aneuploidy, MGMT promoter methylation, and PTEN mutation.ConclusionsCombining radiomics and CNN features from preoperative MRI yields improved noninvasive genetic biomarker prediction performance in patients with WHO grade 4 diffuse astrocytic gliomas.

Published
2022

32. DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival

Author

Wiencke, JK, Molinaro, Annette M, Warrier, Gayathri, Rice, Terri, Clarke, Jennifer, Taylor, Jennie W, Wrensch, Margaret, Hansen, Helen, McCoy, Lucie, Tang, Emily, Tamaki, Stan J, Tamaki, Courtney M, Nissen, Emily, Bracci, Paige, Salas, Lucas A, Koestler, Devin C, Christensen, Brock C, Zhang, Ze, and Kelsey, Karl T

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Rare Diseases, Brain Disorders, Clinical Research, Genetics, Precision Medicine, Cancer, Brain Cancer, Neurosciences, 2.1 Biological and endogenous factors, Inflammatory and immune system, Biomarkers, DNA Methylation, Dexamethasone, Glioma, Glucocorticoids, Humans, Maleimides, Prednisone
Abstract

Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response.

Published
2022

33. Assessment of higher-order singular value decomposition denoising methods on dynamic hyperpolarized [1-13C]pyruvate MRI data from patients with glioma

Author

Vaziri, Sana, Autry, Adam W, Lafontaine, Marisa, Kim, Yaewon, Gordon, Jeremy W, Chen, Hsin-Yu, Hu, Jasmine Y, Lupo, Janine M, Chang, Susan M, Clarke, Jennifer L, Villanueva-Meyer, Javier E, Bush, Nancy Ann Oberheim, Xu, Duan, Larson, Peder EZ, Vigneron, Daniel B, and Li, Yan

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Biomedical Imaging, Brain Disorders, Neurosciences, Bioengineering, Cancer, Rare Diseases, Brain Cancer, Humans, Pyruvic Acid, Bicarbonates, Glioma, Magnetic Resonance Imaging, Lactic Acid, Hyperpolarized, Carbon-13, Denoising, Signal-to-noise ratio, Higher-order singular value decomposition, Biological psychology, Clinical and health psychology
Abstract

BackgroundReal-time metabolic conversion of intravenously-injected hyperpolarized [1-13C]pyruvate to [1-13C]lactate and [13C]bicarbonate in the brain can be measured using dynamic hyperpolarized carbon-13 (HP-13C) MRI. However, voxel-wise evaluation of metabolism in patients with glioma is challenged by the limited signal-to-noise ratio (SNR) of downstream 13C metabolites, especially within lesions. The purpose of this study was to evaluate the ability of higher-order singular value decomposition (HOSVD) denoising methods to enhance dynamic HP [1-13C]pyruvate MRI data acquired from patients with glioma.MethodsDynamic HP-13C MRI were acquired from 14 patients with glioma. The effects of two HOSVD denoising techniques, tensor rank truncation-image enhancement (TRI) and global-local HOSVD (GL-HOSVD), on the SNR and kinetic modeling were analyzed in [1-13C]lactate data with simulated noise that matched the levels of [13C]bicarbonate signals. Both methods were then evaluated in patient data based on their ability to improve [1-13C]pyruvate, [1-13C]lactate and [13C]bicarbonate SNR. The effects of denoising on voxel-wise kinetic modeling of kPL and kPB was also evaluated. The number of voxels with reliable kinetic modeling of pyruvate-to-lactate (kPL) and pyruvate-to-bicarbonate (kPB) conversion rates within regions of interest (ROIs) before and after denoising was then compared.ResultsBoth denoising methods improved metabolite SNR and regional signal coverage. In patient data, the average increase in peak dynamic metabolite SNR was 2-fold using TRI and 4-5 folds using GL-HOSVD denoising compared to acquired data. Denoising reduced kPL modeling errors from a native average of 23% to 16% (TRI) and 15% (GL-HOSVD); and kPB error from 42% to 34% (TRI) and 37% (GL-HOSVD) (values were averaged voxelwise over all datasets). In contrast-enhancing lesions, the average number of voxels demonstrating within-tolerance kPL modeling error relative to the total voxels increased from 48% in the original data to 84% (TRI) and 90% (GL-HOSVD), while the number of voxels showing within-tolerance kPB modeling error increased from 0% to 15% (TRI) and 8% (GL-HOSVD).ConclusionPost-processing denoising methods significantly improved the SNR of dynamic HP-13C imaging data, resulting in a greater number of voxels satisfying minimum SNR criteria and maximum kinetic modeling errors in tumor lesions. This enhancement can aid in the voxel-wise analysis of HP-13C data and thereby improve monitoring of metabolic changes in patients with glioma following treatment.

Published
2022

34. Author Correction: Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial

Author

Mellinghoff, Ingo K., Lu, Min, Wen, Patrick Y., Taylor, Jennie W., Maher, Elizabeth A., Arrillaga-Romany, Isabel, Peters, Katherine B., Ellingson, Benjamin M., Rosenblum, Marc K., Chun, Saewon, Le, Kha, Tassinari, Ania, Choe, Sung, Toubouti, Youssef, Schoenfeld, Steven, Pandya, Shuchi S., Hassan, Islam, Steelman, Lori, Clarke, Jennifer L., and Cloughesy, Timothy F.

Published
2024
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35. Diffuse hemispheric glioma, H3 G34-mutant: Genomic landscape of a new tumor entity and prospects for targeted therapy

Author

Lucas, Calixto-Hope G, Mueller, Sabine, Reddy, Alyssa, Taylor, Jennie W, Bush, Nancy Ann Oberheim, Clarke, Jennifer L, Chang, Susan M, Gupta, Nalin, Berger, Mitchel S, Perry, Arie, Phillips, Joanna J, and Solomon, David A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Neoplasms, Genomics, Glioma, Histones, Humans, Mutation, Neurosciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Published
2021

36. Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas

Author

Yu, Yao, Villanueva-Meyer, Javier, Grimmer, Matthew R, Hilz, Stephanie, Solomon, David A, Choi, Serah, Wahl, Michael, Mazor, Tali, Hong, Chibo, Shai, Anny, Phillips, Joanna J, Wainer, Bruce H, McDermott, Michael, Haas-Kogan, Daphne, Taylor, Jennie W, Butowski, Nicholas, Clarke, Jennifer L, Berger, Mitchel S, Molinaro, Annette M, Chang, Susan M, Costello, Joseph F, and Bush, Nancy Ann Oberheim

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Brain Disorders, Neurosciences, Brain Cancer, Cancer, Rare Diseases, Orphan Drug, Clinical Research, Brain, Brain Neoplasms, Glioma, Humans, Mutation, Neoplasm Recurrence, Local, Temozolomide, hypermutation, IDH-mutant, low-grade glioma, temozolomide, tumor mutational burden, IDH-mutant, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundChemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications.MethodsWe sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes.ResultsHypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM.ConclusionsTMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.

Published
2021

37. BIOM-07. QUANTITATIVE MGMT PROMOTER METHYLATION INDEX INDICATES A NON-LINEAR PROGNOSTIC EFFECT IN GLIOBLASTOMA, SUGGESTING THAT USE OF OPTIMAL CUTOFF POINTS MAY BE CLINICALLY DISADVANTAGEOUS

Author

Gibson, David, Ravi, Akshay, Almaraz, Eduardo Rodriguez, Chang, Susan, Oberheim-Bush, Nancy Ann, Taylor, Jennie, Clarke, Jennifer, Solomon, David, Scheffler, Aaron, Witte, John, Lambing, Hannah, Berger, Mitchel, Okada, Hideho, Chehab, Farid, and Butowski, Nicholas

Subjects
Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Abstract BACKGROUND Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative approaches that measure methylation, providing clearer insights into methylation’s functional relationship with survival. METHODS A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point MGMT promoter methylation index derived from the number of methylated CpG sites. Retrospective review of 240 newly diagnosed GBM patients was performed in order to discern how risk for mortality transforms as promoter methylation increases. Non-linearities were captured by fitting splines to Cox proportional hazard models, plotting smoothed residuals, and creating survival plots. Covariates included age, KPS, IDH1 mutation, and extent of resection. RESULTS Median follow-up time and progression free survival were 16 and 9 months, respectively. 176 subjects experienced death. A one-unit increase in CpG methylation on a scale of 1-17 resulted in a 4% reduction in hazard (95% CI 0.93–0.99, P< 0.005). Moreover, GBM patients with low-levels of methylation (1-6 CpG sites) fared markedly worse (HR=1.62, 95% CI 1.03-2.54, P< 0.036) than individuals who were unmethylated (reference group). Subjects with medium-levels of methylation (7-12 CpG sites) had the greatest reduction in hazard (HR=0.48, 95% CI 0.29-0.80, P< 0.004), followed by individuals in the highest methylation tertile (HR=0.62, 95% CI 0.40-0.97, P< 0.035). CONCLUSION This novel approach offers greater bisulfite conversion efficiency when compared to alternative methods, reducing the likelihood of false positives. Analysis of the resulting methylation index scores demonstrates a non-linear relationship between MGMT methylation and survival, suggesting conformation of the marker’s protective effect. These findings challenge the current understanding of MGMT’s functional form and underline why implementing an “optimal cutoff point” may be disadvantageous.

Published
2021

38. CTIM-24. RANDOMIZED TRIAL OF NEOADJUVANT VACCINATION WITH TUMOR-CELL LYSATE INDUCES T CELL RESPONSE IN LOW-GRADE GLIOMAS

Author

Taylor, Jennie, Ogino, Hirokazu, Nejo, Takahide, Gibson, David, Watchmaker, Payal, Okada, Kaori, Saijo, Atsuro, Tedesco, Meghan, Shai, Anny, Wong, Cynthia, Rabbitt, Jane, Olin, Michael, Moertel, Christopher, Nishioka, Yasuhiko, Salazar, Andres, Molinaro, Annette, Phillips, Joanna, Butowski, Nicholas, Clarke, Jennifer, Oberheim-Bush, Nancy Ann, Hervey-Jumper, Shawn, Theodosopoulos, Philip, Chang, Susan, Berger, Mitchel, and Okada, Hideho

Subjects
Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Abstract BACKGROUND The prognosis of WHO grade II low-grade gliomas (LGG) is varied with potential for long survival.Given their relatively intact immune system and slow growth rate, vaccines are an attractive treatment strategy for LGG in an attempt to defer more toxic treatments. The goals of this pilot study were to evaluate safety and immunological effects of vaccination with GBM6-AD, an allogeneic glioblastoma stem cell line lysate, with poly-ICLC in LGG. METHODS Eligible patients were ≥ 18 years old, ≥ 70 KPS, with recurrent LGG or imaging consistent with LGG, and amenable to resection. Patients were randomized to vaccine prior to surgery (Arm 1) or not (Arm 2) and all received adjuvant vaccine. Co-primary outcomes were safety and immune response in the tumor, with exploratory outcomes of survival and immunologic effects in peripheral blood. RESULTS A total of 17 eligible patients were evaluable – nine into Arm 1 and eight into Arm 2. Median age was 33 years, with median time from initial diagnosis of 4.7 years (0 – 20). Two patients (11.8%) previously received radiotherapy and seven (41.2%) prior systemic therapy. No dose limiting toxicities or grade 3 AEs were observed. Neoadjuvant vaccination induced up regulation of type-1 cytokines and chemokines in peripheral blood, and CD8+ T cell clones that reacted to the vaccine were also detected in the tumor. Median follow-up time from first post-operative vaccine was 20.8 months with median PFS of 11.0 months and time to change in therapy of 23.7 months. Of the six patients to receive additional treatment, three had second surgery only one confirming malignant progression to anaplastic oligodendroglioma. CONCLUSION Treatment was well-tolerated with no regimen-limiting toxicity. GBM6-AD plus poly-ICLC induced effector CD8+ T cell response in peripheral blood and enables some vaccine-reactive CD8+ T cells to migrate into the TME. Further investigation is warranted.

Published
2021

39. QOLP-32. EFFECT OF CANNABIS USE ON QUALITY OF LIFE AMONG GLIOMA PATIENTS: A LONGITUDINAL PERSPECTIVE

Author

Almaraz, Eduardo Rodriguez, Chang, Susan, Oberheim-Bush, Nancy Ann, Clarke, Jennifer, Taylor, Jennie, Schulte, Jessica, Daras, Mariza, Busby, Laura, Gibson, David, and Butowski, Nicholas

Subjects
Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Abstract BACKGROUND Gliomas are devastating primary tumors of the central nervous system that often present with difficult to manage symptoms in addition to the antineoplastic tumor itself. Due to recent increase in popularity and societal acceptance of cannabis products, their use by glioma patients has increased. METHODS We conducted a single center, prospective study: patients with glioma answered a locally validated survey to inquire about their cannabis use at baseline and every three months. Quality of Life was measured using the EORTC QLQ-C30, its complementary module BN-20 and the EQ-5D-5L instrument. Eligible participants were classified as cannabis users or non-users. We performed linear regression clustered by subjects to see differences by user group and trends overtime. RESULTS To date, 89 patients agreed to participate, enrolled, and answered the baseline questionnaires, and 64 have answered the 3 month follow up survey. The mean age was 49.7(SD 13.74), 55 were male, 55 were cannabis users at baseline (61.8%) and 34 at 3 months (53.13%). Patients who were cannabis users scored 11.73 lower points at baseline when compared to non-users (79.65 [SD 18.93] vs 67.92 [SD 19.22]) in the QLQ-C30 instrument. Similarly, cannabis users recorded 9.624 lower points at 3 months compared to non-users (70.1 [SD 21.33] vs 79.72 [SD13.95]). The difference-in-difference estimator was 2.108 (p< 0.7). CONCLUSION Although we observed cannabis users scoring lower QoL measurements (p< 0.05) at baseline and 3 months, we observed a slight improvement in QoL of cannabis users while observing no change or decline (in some measures) among non-users. Our findings provide insight to the impact that cannabis has in QoL over time. While not conclusive, these preliminary results need to be studied on a longer-term basis with a larger sample size in order to detect trends on quality of life among patients with different tumor types.

Published
2021

40. BIOM-43. CROSS-PLATFORM ROBUSTNESS IN THE GLUCOCORTICOID RESPONSE PHARMACODYNAMIC BIOMARKER

Author

Tang, Emily, Wiencke, John, Warrier, Gayathri, Hansen, Helen, McCoy, Lucie, Rice, Terri, Bracci, Paige, Wrensch, Margaret, Taylor, Jennie, Clarke, Jennifer, Koestler, Devin, Salas, Lucas, Christensen, Brock, Kelsey, Karl, and Molinaro, Annette

Subjects
Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Abstract The neutrophil dexamethasone methylation index (NDMI) is an algorithm-based biomarker to assess individuals’ exposures to dexamethasone, a synthetic glucocorticoid commonly administered for inflammation. Cortisol is the main endogenous glucocorticoid that controls vital processes including the immune response and lipid and carbohydrate metabolism. Variations in the NDMI score reflect individuals’ sensitivities of exposures to both exogenous and endogenous glucocorticoids, and this biomarker was trained using elastic net regression on Illumina’s most recent DNA methylation beadarray, the EPIC array, which contains 850,000 cytosine-guanine (CpG) sites. While technology for microarray research continues to advance over time, researchers are capable of conducting more comprehensive epigenome-wide association studies (EWAS). However, many studies are still run and archived using Illumina’s historical 450K platform with approximately 450,000 CpGs, and there are fewer published databases using the 850K EPIC array. To evaluate the cross-platform bioinformatic comparability, we performed elastic net regression modeling using predictors available in the 450K to train the NDMI. Among the 135 pre-surgery glioma cases from the UCSF Immune Profiles Study (IPS), NDMI scores between the 450K and 850K model were strongly correlated (r = 0.99, p < 0.0001). In the 311 controls from the UCSF Adult Glioma Study (AGS), similar correlations were observed (r = 0.96, p < 0.0001). We observe that NDMI remains a robust tool using historical 450K data and conclude that this algorithmic tool is capable of detecting the variations in individuals’ responses to dexamethasone.

Published
2021

41. NIMG-21. VARIABLE RESOLUTION HYPERPOLARIZED [2-13C]PYRUVATE MRI IN HEALTHY VOLUNTEERS AND PATIENTS WITH IDH-MUTANT GLIOMA

Author

Vaziri, Sana, Kim, Yaewon, Autry, Adam, Chen, Hsin-Yu, Gordon, Jeremy, LaFontaine, Marisa, Hu, Jasmine, Lupo, Janine, Clarke, Jennifer, Villanueva-Meyer, Javier, Oberheim-Bush, Nancy Ann, Chang, Susan, Xu, Duan, Larson, Peder, Vigneron, Daniel, and Li, Yan

Subjects
Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Abstract INTRODUCTION Mutations in isocitrate dehydrogenase (IDH) have been investigated as a prognostic biomarker in glioma. The presence of the IDH mutation (IDHm) is associated with 2-hydroxyglutarate (2HG) production and inhibition of glutamate synthesis (McBrayer, Cell 2018). Hyperpolarized carbon-13 (HP-13C) MRI enables dynamic measurements of in-vivo metabolism using a [2-13C]pyruvate labeled probe that undergoes conversion to [2-13C]lactate and [5-13C]glutamate. Here, we present HP [2-13C]pyruvate data from healthy volunteers and patients with IDHm diffuse glioma. Due to its intrinsic low signal-to-noise ratio (SNR), we demonstrate the ability of post-processing denoising to improve its utility and aid in detection of metabolic changes associated with IDHm. METHODS Dynamic HP 13C data were acquired following intravenous injection of [2-13C]pyruvate from five healthy volunteers and one patient with IDHm grade III astrocytoma. A novel multi-resolution frequency specific multislice EPI sequence was used to obtain [2-13C]pyruvate, [5-13C]glutamate, and downfield and upfield [2-13C]lactate signals (3s temporal resolution, pyruvate/lactate/glutamate spatial resolutions = 0.75x0.75cm2/ 2.25x2.25cm2/ 2.25x2.25cm2, 5 slices 3cm thick). Following phase correction, patch-based tensor decomposition denoising was applied to metabolite images. Metabolite differences between normal-appearing white matter (NAWM) and T2 lesion were examined for the patient data. RESULTS HP [2-13C]pyruvate imaging is able to simultaneously probe glycolytic ([2-13C]lactate) and oxidative ([5-13C]glutamate) metabolism. Denoised pyruvate/lactate/glutamate signals achieved a 4-9/3-6/3-7 fold increase in SNR. T2 lesion exhibited decreased glutamate-to-pyruvate and glutamate-to-lactate AUC ratios versus contralateral NAWM (p< 0.018, p < 1.5e-5), consistent with IDH mutant status. CONCLUSION We successfully demonstrated the feasibility of applying variable resolution HP [2-13C]pyruvate metabolic imaging to detect IDHm specific metabolism. This technique addresses a major hurdle in HP 13C MRI by improving SNR while permitting robust metabolism quantification. Future studies will optimize methods for acquiring and processing data to evaluate further data acquired from IDHm glioma patients. Supported by NIH T32 CA151022, P01 CA118816, and NICO.

Published
2021

42. Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I TrialVorasidenib in Recurrent or Progressive Glioma

Author

Mellinghoff, Ingo K, Penas-Prado, Marta, Peters, Katherine B, Burris, Howard A, Maher, Elizabeth A, Janku, Filip, Cote, Gregory M, de la Fuente, Macarena I, Clarke, Jennifer L, Ellingson, Benjamin M, Chun, Saewon, Young, Robert J, Liu, Hua, Choe, Sung, Lu, Min, Le, Kha, Hassan, Islam, Steelman, Lori, Pandya, Shuchi S, Cloughesy, Timothy F, and Wen, Patrick Y

Subjects
Neurosciences, Orphan Drug, Cancer, Brain Cancer, Brain Disorders, Clinical Research, Clinical Trials and Supportive Activities, Rare Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Adult, Aged, Brain Neoplasms, Diamines, Disease Progression, Female, Glioma, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Mutation, Neoplasm Recurrence, Local, Pyridines, Young Adult, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeLower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.Patients and methodsWe conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.ResultsVorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.ConclusionsVorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.

Published
2021

43. NGMA-6. Quantitative MGMT Promoter Methylation Index Indicates Non-Linear, Prognostic Effect in Glioblastoma

Author

Gibson, David, Ravi, Akshay, Rodriguez, Eduardo, Chang, Susan, Bush, Nancy, Taylor, Jennie, Clarke, Jennifer, Solomon, David, Scheffler, Aaron, Witte, John, Okada, Hideho, Berger, Mitchel, Chehab, Farid, and Butowski, Nicholas

Abstract

Abstract Background Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative methods of measuring methylation, allowing for clearer insights into methylation’s functional relationship with survival. Methods A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point MGMT promoter methylation index derived from the number of methylated CpG sites. Retrospective review of 242 newly diagnosed GBM patients was performed in order to discern how risk for mortality transforms as promoter methylation increases. Non-linearities were captured by fitting splines to Cox proportional hazard models, plotting smoothed residuals, and creating survival plots. Covariates included age, KPS, IDH1 mutation, and extent of resection. Results Median follow-up time and progression free survival were 15.9 and 9 months, respectively. 176 subjects experienced death. A one-unit increase in CpG methylation resulted in a 4% reduction in hazard (95% CI 0.93–0.99, P

Published
2021

44. A single institution retrospective analysis on survival based on treatment paradigms for patients with anaplastic oligodendroglioma

Author

Bush, Nancy Ann Oberheim, Young, Jacob S, Zhang, Yalan, Dalle Ore, Cecilia L, Molinaro, Annette M, Taylor, Jennie, Clarke, Jennifer, Prados, Michael, Braunstein, Steve E, Raleigh, David R, Chang, Susan M, Berger, Mitchel S, and Butowski, Nicholas A

Subjects
Brain Disorders, Clinical Research, Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 6.4 Surgery, Astrocytoma, Brain Neoplasms, Humans, Oligodendroglioma, Retrospective Studies, Glioma, Anaplastic Oligodendroglioma, Chemotherapy, Radiation, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

IntroductionAnaplastic oligodendrogliomas are high-grade gliomas defined molecularly by 1p19q co-deletion. There is no curative therapy, and standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone has not been demonstrated in a randomized control trial. Given the potential long-term consequences of radiation therapy, such as cognitive impairment, arteriopathy, endocrinopathy, and hearing/visual impairment, there is an effort to balance longevity with radiation toxicity.MethodsWe performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years.Results159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996 and 2016. Of those, 40 patients were found to have AO at original diagnosis and had documented 1p19q co-deletion with a median of 7.1 years of follow-up (range: 0.6-16.7 years). After surgery, 45 % of patients were treated with radiation and chemotherapy at diagnosis, and 50 % were treated with adjuvant chemotherapy alone. The group treated with chemotherapy alone had a trend of receiving more cycles of chemotherapy than patients treated with radiation and chemotherapy upfront (p = 0.051). Median overall survival has not yet been reached. The related risk of progression in the upfront, adjuvant chemotherapy only group was almost 5-fold higher than the patients who received radiation and chemotherapy (hazard ratio = 4.85 (1.74-13.49), p = 0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p = 0.8). Univariate analysis of age, KPS, extent of resection, or upfront versus delayed radiation was not associated with improved survival.ConclusionsInitial treatment with adjuvant chemotherapy alone, rather than radiation and chemotherapy, may be an option for some patients with anaplastic oligodendroglioma, as it is associated with similar overall survival despite shorter progression free survival.

Published
2021

45. Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma

Author

Nayak, Lakshmi, Molinaro, Annette M, Peters, Katherine, Clarke, Jennifer L, Jordan, Justin T, de Groot, John, Nghiemphu, Leia, Kaley, Thomas, Colman, Howard, McCluskey, Christine, Gaffey, Sarah, Smith, Timothy R, Cote, David J, Severgnini, Mariano, Yearley, Jennifer H, Zhao, Qing, Blumenschein, Wendy M, Duda, Dan G, Muzikansky, Alona, Jain, Rakesh K, Wen, Patrick Y, and Reardon, David A

Subjects
Brain Disorders, Brain Cancer, Rare Diseases, Clinical Research, Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Biomarkers, Tumor, Brain Neoplasms, Drug Monitoring, Female, Glioblastoma, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Prognosis, Progression-Free Survival, Prospective Studies, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeVEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.Patients and methodsEighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, n = 50) or pembrolizumab monotherapy (cohort B, n = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.ResultsPembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.ConclusionsPembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.

Published
2021

46. Current Advances in Immunotherapy for Glioblastoma

Author

Mende, Abigail L, Schulte, Jessica D, Okada, Hideho, and Clarke, Jennifer L

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Brain Cancer, Cancer, Rare Diseases, Neurosciences, Biotechnology, Orphan Drug, Brain Disorders, Vaccine Related, Immunization, Immunotherapy, 5.1 Pharmaceuticals, Good Health and Well Being, Brain Neoplasms, Cancer Vaccines, Combined Modality Therapy, Glioblastoma, Humans, Oncolytic Virotherapy, Cancer vaccine, CAR-T, Oncolytic virus, Checkpoint inhibitor, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Purpose of reviewThis review seeks to inform oncology clinicians and researchers about the development of novel immunotherapies for the treatment of glioblastoma. An enumeration of ongoing and recently completed clinical trials will be discussed with special attention given to current technologies implemented to overcome central nervous system-specific challenges including barriers to the peripheral immune system, impaired antigen presentation, and T cell dysfunction.Recent findingsThe success of immunotherapy in other solid cancers has served as a catalyst to explore its application in glioblastoma, which has limited response to other treatments. Recent developments include multi-antigen vaccines that seek to overcome the heterogeneity of glioblastoma, as well as immune checkpoint inhibitors, which could amplify the adaptive immune response and may have promise in combinatorial approaches. Additionally, oncolytic and retroviruses have opened the door to a plethora of combinatorial approaches aiming to leverage their immunogenicity and/or ability to carry therapeutic transgenes. Treatment of glioblastoma remains a serious challenge both with regard to immune-based as well as other therapeutic strategies. The disease has proven to be highly resistant to treatment due to a combination of tumor heterogeneity, adaptive expansion of resistant cellular subclones, evasion of immune surveillance, and manipulation of various signaling pathways involved in tumor progression and immune response. Immunotherapeutics that are efficacious in other cancer types have unfortunately not enjoyed the same success in glioblastoma, illustrating the challenging and complex nature of this disease and demonstrating the need for development of multimodal treatment regimens utilizing the synergistic qualities of immune-mediated therapies.

Published
2021

47. Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.

Author

Muster, Rachel, Ko, Nerissa, Smith, Wade, Su, Hua, Dickey, Melissa A, Nelson, Jeffrey, McCulloch, Charles E, Sneed, Patricia K, Clarke, Jennifer L, Saloner, David A, Eisenmenger, Laura, Kim, Helen, and Cooke, Daniel L

Subjects
cerebrovascular, neurosurgery, pharmacology, stroke, Patient Safety, Clinical Research, Congenital Structural Anomalies, Neurosciences, Pediatric, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals
Abstract

Brain arteriovenous malformations (bAVMs) are relatively rare, although their potential for secondary intracranial haemorrhage (ICH) makes their diagnosis and management essential to the community. Currently, invasive therapies (surgical resection, stereotactic radiosurgery and endovascular embolisation) are the only interventions that offer a reduction in ICH risk. There is no designated medical therapy for bAVM, although there is growing animal and human evidence supporting a role for bevacizumab to reduce the size of AVMs. In this single-arm pilot study, two patients with large bAVMs (deemed unresectable by an interdisciplinary team) received bevacizumab 5 mg/kg every 2 weeks for 12 weeks. Due to limitations of external funding, the intended sample size of 10 participants was not reached. Primary outcome measure was change in bAVM volume from baseline at 26 and 52 weeks. No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment. No clinically important adverse events were observed during the 52-week study period. There were no observed instances of ICH. Sera vascular endothelial growth factor levels were reduced at 26 weeks and returned to baseline at 52 weeks. This pilot study is the first to test bevacizumab for patients with bAVMs. Bevacizumab therapy was well tolerated in both subjects. No radiographic changes were observed over the 52-week study period. Subsequent larger clinical trials are in order to assess for dose-dependent efficacy and rarer adverse drug effects. Trial registration number: NCT02314377.

Published
2021

48. Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium (EORTC 1419)

Author

Hertler, Caroline, Felsberg, Jörg, Gramatzki, Dorothee, Le Rhun, Emilie, Clarke, Jennifer, Soffietti, Riccardo, Wick, Wolfgang, Chinot, Olivier, Ducray, François, Roth, Patrick, McDonald, Kerrie, Hau, Peter, Hottinger, Andreas F., Reijneveld, Jaap, Schnell, Oliver, Marosi, Christine, Glantz, Michael, Darlix, Amélie, Lombardi, Giuseppe, Krex, Dietmar, Glas, Martin, Reardon, David A., van den Bent, Martin, Lefranc, Florence, Herrlinger, Ulrich, Razis, Evangelia, Carpentier, Antoine F., Phillips, Samuel, Rudà, Roberta, Wick, Antje, Tabouret, Emeline, Meyronet, David, Maurage, Claude-Alain, Rushing, Elisabeth, Rapkins, Robert, Bumes, Elisabeth, Hegi, Monika, Weyerbrock, Astrid, Aregawi, Dawit, Gonzalez-Gomez, Christian, Pellerino, Alessia, Klein, Martin, Preusser, Matthias, Bendszus, Martin, Golfinopoulos, Vassilis, von Deimling, Andreas, Gorlia, Thierry, Wen, Patrick Y., Reifenberger, Guido, and Weller, Michael

Published
2023
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49. Association of Country Income Level With the Characteristics and Outcomes of Critically Ill Patients Hospitalized With Acute Kidney Injury and COVID-19

Author

Abdukahil, heryl Ann, Abdulkadir, Nurul Najmee, Abe, Ryuzo, Abel, Laurent, Abrous, Amal, Absil, Lara, Acker, Andrew, Adachi, Shingo, Adrião, Diana, Al Ageel, Saleh, Ahmed, Shakeel, Ainscough, Kate, Airlangga, Eka, Aisa, Tharwat, Hssain, Ali Ait, Tamlihat, Younes Ait, Akimoto, Takako, Akmal, Ernita, Akwani, Chika, Al Qasim, Eman, Alalqam, Razi, Alberti, Angela, Al-dabbous, Tala, Alegesan, Senthilkumar, Alessi, Marta, Alex, Beatrice, Alexandre, Kévin, Al-Fares, Abdulrahman, Alfoudri, Huda, Ali, Imran, Alidjnou, Kazali Enagnon, Aliudin, Jeffrey, Alkhafajee, Qabas, Allavena, Clotilde, Allou, Nathalie, Alves, João, Alves, Rita, Alves, João Melo, Cabrita, Joana Alves, Amaral, Maria, Amira, Nur, Ampaw, Phoebe, Andini, Roberto, Andréjak, Claire, Angheben, Andrea, Angoulvant, François, Ansart, Séverine, Anthonidass, Sivanesen, Antonelli, Massimo, Antunes de Brito, Carlos Alexandre, Apriyana, Ardiyan, Arabi, Yaseen, Aragao, Irene, Arancibia, Francisco, Araujo, Carolline, Arcadipane, Antonio, Archambault, Patrick, Arenz, Lukas, Arlet, Jean-Benoît, Arnold-Day, Christel, Arora, Lovkesh, Arora, Rakesh, Artaud-Macari, Elise, Aryal, Diptesh, Asensio, Angel, Ashraf, Muhammad, Assie, Jean Baptiste, Asyraf, Amirul, Atif, Minahel, Atique, Anika, Auchabie, Johann, Aumaitre, Hugues, Auvet, Adrien, Azemar, Laurène, Azoulay, Cecile, Bach, Benjamin, Bachelet, Delphine, Badr, Claudine, Baillie, J. Kenneth, Baird, J Kevin, Bak, Erica, Bakakos, Agamemnon, Bakar, Nazreen Abu, Bal, Andriy, Balakrishnan, Mohanaprasanth, Balan, Valeria, Bani-Sadr, Firouzé, Barbalho, Renata, Barbosa, Nicholas Yuri, Barclay, Wendy S., Barnett, Saef Umar, Barnikel, Michaela, Barrelet, Audrey, Barrigoto, Cleide, Bartoli, Marie, Baruch, Joaquín, Basmaci, Romain, Hassin Basri, Muhammad Fadhli, Battaglini, Denise, Bauer, Jules, Bautista Rincon, Diego Fernando, Beane, Abigail, Bedossa, Alexandra, Bee, Ker Hong, Begum, Husna, Behilill, Sylvie, Beishuizen, Albertus, Beljantsev, Aleksandr, Bellemare, David, Beltrame, Anna, Beltrão, Beatriz Amorim, Beluze, Marine, Benech, Nicolas, Benjiman, Lionel Eric, Benkerrou, Dehbia, Bennett, Suzanne, Benny, Binny, Bento, Luís, Berdal, Jan-Erik, Bergeaud, Delphine, Bergin, Hazel, Bernal Sobrino, José Luis, Bertoli, Giulia, Bertolino, Lorenzo, Bessis, Simon, Bevilcaqua, Sybille, Bezulier, Karine, Bhatt, Amar, Bhavsar, Krishna, Bianco, Claudia, Bidin, Farah Nadiah, Singh, Moirangthem Bikram, Humaid, Felwa Bin, Bin Kamarudin, Mohd Nazlin, Bisoffi, Zeno, Bissuel, François, Biston, Patrick, Bitker, Laurent, Bitton, Jonathan, Blanco-Schweizer, Pablo, Blier, Catherine, Bloos, Frank, Blot, Mathieu, Blumberg, Lucille, Boccia, Filomena, Bodenes, Laetitia, Bogaert, Debby, Boivin, Anne-Hélène, Bolaños, Isabela, Bolze, Pierre-Adrien, Bompart, François, Borges, Diogo, Borie, Raphaël, Botelho-Nevers, Elisabeth, Bouadma, Lila, Bouchaud, Olivier, Bouchez, Sabelline, Bouhmani, Dounia, Bouhour, Damien, Bouiller, Kévin, Bouillet, Laurence, Bouisse, Camile, Boureau, Anne-Sophie, Bourke, John, Bouscambert, Maude, Bousquet, Aurore, Bouziotis, Jason, Boxma, Bianca, Boyer-Besseyre, Marielle, Boylan, Maria, Bozza, Fernando Augusto, Braconnier, Axelle, Braga, Cynthia, Monteiro, Filipa Brás, Brazzi, Luca, Breen, Patrick, Breen, Dorothy, Brewster, David, Brickell, Kathy, Browne, Shaunagh, Brusse-Keizer, Marjolein, Bryda, Petra, Buchtele, Nina, Bugaeva, Polina, Buisson, Marielle, Burhan, Erlina, Burrell, Aidan, Bustos, Ingrid G., Butnaru, Denis, Cabie, André, Cabral, Susana, Caceres, Eder, Cadoz, Cyril, Garcês, Rui Caetano, Calligy, Kate, Calvache, Jose Andres, Camões, João, Campana, Valentine, Campbell, Paul, Campisi, Josie, Cantero, Mireia, Caraux-Paz, Pauline, Cardellino, Chiara Simona, Cardoso, Sofia, Cardoso, Filipe, Cardoso, Filipa, Cardoso, Nelson, Carelli, Simone, Carlier, Nicolas, Carmoi, Thierry, Carney, Gayle, Carqueja, Inês, Carret, Marie-Christine, Carrier, François Martin, Carroll, Ida, Carson, Gail, Casanova, Maire-Laure, Cascão, Mariana, Casey, Siobhan, Casimiro, José, Cassandra, Bailey, Castanheira, Nidyanara, Castor-Alexandre, Guylaine, Castro, Ivo, Catarino, Ana, Catherine, François-Xavier, Cattaneo, Paolo, Cavalin, Roberta, Cavayas, Alexandros, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chakveatze, Catherine, Chan, Adrienne, Chand, Meera, Chantalat Auger, Christelle, Chapplain, Jean-Marc, Charpentier, Charlotte, Chas, Julie, Chávez Iñiguez, Jonathan Samuel, Chen, Anjellica, Chen, Yih-Sharng, Chenard, Léo, Cheng, Matthew Pellan, Cheret, Antoine, Chiarabini, Thibault, Chica, Julian, Chidambaram, Suresh Kumar, Tho, Leong Chin, Chirouze, Catherine, Chiumello, Davide, Cho, Sung-Min, Cholley, Bernard, Chopin, Marie-Charlotte, Chow, Ting Soo, Chow, Yock Ping, Chua, Hiu Jian, Chua, Jonathan, Cidade, Jose Pedro, Citarella, Barbara Wanjiru, Ciullo, Anna, Clarke, Jennifer, Claure-Del Granado, Rolando, Clohisey, Sara, Cobb, Perren J., Codan, Cassidy, Cody, Caitriona, Coelho, Alexandra, Coles, Megan, Coles, Jennifer, Colin, Gwenhaël, Collins, Michael, Colombo, Sebastiano Maria, Combs, Pamela, Connolly, Jennifer, Connor, Marie, Conrad, Anne, Conway, Elaine, Cooke, Graham S., Copland, Mary, Cordel, Hugues, Corley, Amanda, Cornelis, Sabine, Cornet, Alexander Daniel, Corpuz, Arianne Joy, Cortegiani, Andrea, Corvaisier, Grégory, Couffignal, Camille, Couffin-Cadiergues, Sandrine, Courtois, Roxane, Cousse, Stéphanie, Croonen, Sabine, Crowl, Gloria, Crump, Jonathan, Cruz, Claudina, Cruz Bermúdez, Juan Luis, Rojo, Jaime Cruz, Csete, Marc, Cullen, Ailbhe, Curley, Gerard, Curlier, Elodie, Curran, Colleen, Custodio, Paula, da Silva Filipe, Ana, Da Silveira, Charlene, Dabaliz, Al-Awwab, Dai, Danyang, Dagens, Andrew, Dahly, Darren, Dalton, Heidi, Dalton, Jo, Daly, Seamus, Damas, Juliana, Daneman, Nick, Daniel, Corinne, Dankwa, Emmanuelle A., Dantas, Jorge, de Loughry, Gillian, De Montmollin, Etienne, Freitas de Oliveira França, Rafael, De Rosa, Rosanna, de Silva, Thushan, de Vries, Peter, Dean, David, Debard, Alexa, DeBenedictis, Bianca, Debray, Marie-Pierre, DeCastro, Nathalie, Dechert, William, Deconninck, Lauren, Decours, Romain, Defous, Eve, Delacroix, Isabelle, Delaveuve, Eric, Delavigne, Karen, Dell'Amore, Andrea, Delmas, Christelle, Delobel, Pierre, Delsing, Corine, Demonchy, Elisa, Denis, Emmanuelle, Deplanque, Dominique, Depuydt, Pieter, Desai, Mehul, Descamps, Diane, Desvallées, Mathilde, Dewayanti, Santi, Dhanger, Pathik, Diallo, Alpha, Diamantis, Sylvain, Da Silva, Fernanda Dias, Diaz, Juan Jose, Diaz, Rodrigo, Didier, Kévin, Diehl, Jean-Luc, Dieperink, Wim, Dimet, Jérôme, Dinot, Vincent, Diop, Fara, Diouf, Alphonsine, Dishon, Yael, Djossou, Félix, Docherty, Annemarie B., Doherty, Helen, Donnelly, Maria, Donnelly, Christl A., Donohue, Sean, Donohue, Yoann, Donohue, Chloe, Doran, Peter, Dorival, Céline, D'Ortenzio, Eric, Douglas, James Joshua, Dournon, Nathalie, Downer, Triona, Downey, Joanne, Downing, Mark, Drake, Tom, Driscoll, Aoife, Dryden, Murray, Fonseca, Claudio Duarte, Dubee, Vincent, Dubos, François, Ducancelle, Alexandre, Duculan, Toni, Dudman, Susanne, Duggal, Abhijit, Dunand, Paul, Dunning, Jake, Duplaix, Mathilde, Durante-Mangoni, Emanuele, Durham, Lucian, III, Dussol, Bertrand, Duthoit, Juliette, Duval, Xavier, Dyrhol-Riise, Anne Margarita, Ean, Sim Choon, Echeverria-Villalobos, Marco, Edwards, Eleanor, Egan, Siobhan, El Sanharawi, Mohammed, Elapavaluru, Subbarao, Elharrar, Brigitte, Eloy, Philippine, Elshazly, Tarek, Enderle, Isabelle, Endo, Tomoyuki, Eng, Chan Chee, Engelmann, Ilka, Enouf, Vincent, Epaulard, Olivier, Escher, Martina, Esperatti, Mariano, Esperou, Hélène, Santo, Catarina Espírito, Esposito-Farese, Marina, Estevão, João, Etienne, Manuel, Ettalhaoui, Nadia, Everding, Anna Greti, Evers, Mirjam, Fabre, Marc, Fabre, Isabelle, Faheem, Amna, Fahy, Arabella, Fairfield, Cameron J., Faria, Pedro, Fateena, Hanan, Fatoni, Arie Zainul, Faure, Karine, Favory, Raphaël, Fayed, Mohamed, Feely, Niamh, Feeney, Laura, Fernandes, Jorge, Fernandes, Marília Andreia, Fernandes, Susana, Ferrand, François-Xavier, Devouge, Eglantine Ferrand, Ferrão, Joana, Ferraz, Mário, Ferreira, Sílvia, Ferreira, Bernardo, Ferreira, Benigno, Ferriere, Nicolas, Ficko, Céline, Figueiredo-Mello, Claudia, Fiorda, Juan, Flament, Thomas, Flanagan, Emily, Flateau, Clara, Fletcher, Tom, Florence, Aline-Marie, Florio, Letizia Lucia, Flynn, Deirdre, Foley, Jean, Fomin, Victor, Fonseca, Tatiana, Forsyth, Simon, Foster, Denise, Foti, Giuseppe, Fourn, Erwan, Fowler, Robert A., Fraher, Marianne, Franch-Llasat, Diego, Fraser, John F., Fraser, Christophe, Freire, Marcela Vieira, Ribeiro, Ana Freitas, Friedrich, Caren, Fritz, Ricardo, Fry, Stéphanie, Fuentes, Nora, Fukuda, Masahiro, G, Argin, Gaborieau, Valérie, Gaci, Rostane, Gagliardi, Massimo, Gagnard, Jean-Charles, Gagneux-Brunon, Amandine, Gaião, Sérgio, Skeie, Linda Gail, Gallagher, Phil, Gamble, Carrol, Gani, Yasmin, Garan, Arthur, Garcia, Rebekha, Barrio, Noelia García, Garcia-Gallo, Esteban, Garot, Denis, Garrait, Valérie, Gault, Nathalie, Gavin, Aisling, Gavrylov, Anatoliy, Gaymard, Alexandre, Gebauer, Johannes, Geraud, Eva, Morlaes, Louis Gerbaud, Germano, Nuno, Ghosn, Jade, Giani, Marco, Gibson, Jess, Gigante, Tristan, Gilg, Morgane, Gilroy, Elaine, Giordano, Guillermo, Girvan, Michelle, Gissot, Valérie, Glikman, Daniel, Glybochko, Petr, Gnall, Eric, Goehringer, François, Goffard, Jean-Christophe, Goh, Jin Yi, Golob, Jonathan, Gominet, Marie, Gonzalez, Alicia, Gordon, Patricia, Gorenne, Isabelle, Gormley, Conor, Goubert, Laure, Goujard, Cécile, Goulenok, Tiphaine, Grable, Margarite, Grandin, Edward Wilson, Granier, Pascal, Grasselli, Giacomo, Green, Christopher A., Greenhalf, William, Greffe, Segolène, Grieco, Domenico Luca, Griffee, Matthew, Griffiths, Fiona, Grigoras, Ioana, Groenendijk, Albert, Gruner, Heidi, Gu, Yusing, Guedj, Jérémie, Guego, Martin, Guellec, Dewi, Guerreiro, Daniela, Guery, Romain, Guillaumot, Anne, Guilleminault, Laurent, Guimarães de Castro, Maisa, Guimard, Thomas, Haalboom, Marieke, Haber, Daniel, Habraken, Hannah, Hachemi, Ali, Hadri, Nadir, Hakak, Sheeba, Hall, Adam, Hall, Matthew, Halpin, Sophie, Hamer, Ansley, Hamers, Raph L., Hamidfar, Rebecca, Hammond, Terese, Hammond, Naomi, Han, Lim Yuen, Hao, Kok Wei, Hardwick, Hayley, Harrison, Ewen M., Harrison, Janet, Hartman, Alan, Hashmi, Junaid, Hayes, Ailbhe, Hays, Leanne, Heerman, Jan, Heggelund, Lars, Hendry, Ross, Hennessy, Martina, Hentzien, Maxime, Hernandez, Diana, Hershey, Andrew, Hesstvedt, Liv, Higgins, Eibhlin, Higgins, Dawn, Higgins, Rupert, Hinchion, Rita, Hinton, Samuel, Hiraiwa, Hiroaki, Hitoto, Hikombo, Ho, Antonia, Ho, Yi Bin, Hoctin, Alexandre, Hoffmann, Isabelle, Hoh, Wei Han, Hoiting, Oscar, Holt, Rebecca, Holter, Jan Cato, Horby, Peter, Hoshino, Kota, Houas, Ikram, Hough, Catherine L., Houltham, Stuart, Ming-Yang Hsu, Jimmy, Hulot, Jean-Sébastien, Hurd, Abby, Ijaz, Samreen, Ikram, M. 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Eduardo, Martin-Loeches, Ignacio, Martinot, Martin, Martins, João, Martins, Ana, Rego, Caroline Martins, Martucci, Gennaro, Martynenko, Olga, Marwali, Eva Miranda, Marzukie, Marsilla, Maslove, David, Mason, Sabina, Mat Nor, Mohd Basri, Matan, Moshe, Mathieu, Daniel, Mattei, Mathieu, Maulin, Laurence, Maxwell, Michael, Mazzoni, Thierry, Sweeney, Lisa Mc, McArthur, Colin, McCanny, Peter, McCarthy, Anne, McCarthy, Aine, McCloskey, Colin, McConnochie, Rachael, McDermott, Sherry, McDonald, Sarah E., McElroy, Aine, McElwee, Samuel, McEneany, Victoria, McEvoy, Natalie, McGeer, Allison, McKay, Chris, McKeown, Johnny, McLean, Kenneth A., McNicholas, Bairbre, McPartlan, Elaine, Meaney, Edel, Mear-Passard, Cécile, Mechlin, Maggie, Mehkri, Omar, Mele, Ferruccio, Menon, Kusum, Mentré, France, Mentzer, Alexander J., Mercier, Noémie, Mercier, Emmanuelle, Merckx, Antoine, Mergeay-Fabre, Mayka, Mergler, Blake, Merson, Laura, Mesquita, António, Metwally, Osama, Meybeck, Agnès, Meyer, Dan, Meynert, Alison M., Meysonnier, Vanina, Meziane, Amina, Mezidi, Mehdi, Michelanglei, Céline, Michelet, Isabelle, Mihelis, Efstathia, Mihnovit, Vladislav, Miller, Jennene, Misnan, Nor Arisah, Mohamed, Tahira Jamal, Eliza Mohamed, Nik Nur, Moin, Asma, Molinos, Elena, Molloy, Brenda, Monahan, Sinead, Mone, Mary, Monteiro, Agostinho, Montes, Claudia, Montrucchio, Giorgia, Moore, Shona C., Moore, Sarah, Cely, Lina Morales, Moro, Lucia, Motherway, Catherine, Motos, Ana, Mouquet, Hugo, Perrot, Clara Mouton, Moyet, Julien, Mudara, Caroline, Muh, Ng Yong, Muhamad, Dzawani, Mullaert, Jimmy, Müller, Fredrik, Müller, Karl Erik, Munblit, Daniel, Murphy, Aisling, Murphy, Lorna, Murray, Patrick, Murris, Marlène, Murthy, Srinivas, Musaab, Himed, Muyandy, Gugapriyaa, Myrodia, Dimitra Melia, Nagpal, Dave, Nagrebetsky, Alex, Narasimhan, Mangala, Narayanan, Nageswaran, Neant, Nadège, Necsoi, Coca, Nekliudov, Nikita, Neto, Raul, Neumann, Emily, Ng, Pauline Yeung, Ng, Wing Yiu, Nghi, Anthony, Nguyen, Duc, Choileain, Orna Ni, Leathlobhair, Niamh Ni, Nichol, Alistair D., Nitayavardhana, Prompak, Nonas, Stephanie, Mohd Noordin, Nurul Amani, Noret, Marion, Izzati Norharizam, Nurul Faten, Norman, Lisa, Notari, Alessandra, Noursadeghi, Mahdad, Nseir, Saad, Nusantara, Dwi Utomo, Nyamankolly, Elsa, Brien, Fionnuala O., Callaghan, Annmarie O., O'Callaghan, Annmarie, Occhipinti, Giovanna, OConnor, Derbrenn, Ogura, Takayuki, O'Halloran, Sophie, O'Hearn, Katie, Ohshimo, Shinichiro, Oliveira, João, Olliaro, Piero L., O'Neil, Conar, Ong, David S.Y., Ong, Jee Yan, Oosthuyzen, Wilna, Opavsky, Anne, Openshaw, Peter, Orozco-Chamorro, Claudia Milena, Ortoleva, Jamel, Osatnik, Javier, O'Shea, Linda, O'Sullivan, Miriam, Othman, Siti Zubaidah, Ouamara, Nadia, Ouissa, Rachida, Oziol, Eric, Pagadoy, Maïder, Pages, Justine, Palmarini, Massimo, Panarello, Giovanna, Panda, Prasan Kumar, Pang, Lai Hui, Panigada, Mauro, Pansu, Nathalie, Papadopoulos, Aurélie, Parke, Rachael, Pasquier, Jérémie, Pastene, Bruno, Patauner, Fabian, Pathmanathan, Mohan Dass, Patricio, Patricia, Patrier, Juliette, Patterson, Lisa, Paul, Mical, Paul, Christelle, Paulos, Jorge, Paxton, William A., Payen, Jean-François, Peake, Sandra L., Peariasamy, Kalaiarasu, Jiménez, Miguel Pedrera, Peek, Giles J., Peelman, Florent, Peiffer-Smadja, Nathan, Peigne, Vincent, Pejkovska, Mare, Pelosi, Paolo, Peltan, Ithan D., Pereira, Rui, Perez, Daniel, Periel, Luis, Perpoint, Thomas, Pesenti, Antonio, Pestre, Vincent, Petrou, Lenka, Petrovic, Michele, Petrov-Sanchez, Ventzislava, Pettersen, Frank Olav, Peytavin, Gilles, Pharand, Scott, Piagnerelli, Michael, Picard, Walter, Picone, Olivier, Pierobon, Carola, Piersma, Djura, Pimentel, Carlos, Piquard, Valentine, Pires, Catarina, Pironneau, Isabelle, Piroth, Lionel, Pitaloka, Ayodhia, Piubelli, Chiara, Pius, Riinu, Plantier, Laurent, Png, Hon Shen, Poissy, Julien, Pokeerbux, Ryadh, Poli, Sergio, Pollakis, Georgios, Ponscarme, Diane, Porto, Diego Bastos, Post, Andra-Maris, Postma, Douwe F., Povoa, Pedro, Póvoas, Diana, Powis, Jeff, Prapa, Sofia, Preau, Sébastien, Prebensen, Christian, Preiser, Jean-Charles, Prinssen, Anton, Proença, Lucia, Pudota, Sravya, Puéchal, Oriane, Semedi, Bambang Pujo, Purcell, Gregory, Quesada, Luisa, González, Víctor Quirós, Quist-Paulsen, Else, Quraishi, Mohammed, Qutishat, Fadi, Rabaud, Christian, Rafael, Aldo, Rafiq, Marie, Rahardjani, Mutia, Rahimi, Amir Kamel, Rahman, Rozanah Abd, Haji Ab Rahman, Ahmad Kashfi, Rainieri, Fernando, Rajahram, Giri Shan, Ramakrishnan, Nagarajan, Ramalho, José, Ramli, Ahmad Afiq, Rammaert, Blandine, Ramos, Grazielle Viana, Ranjan, Ritika, Rapp, Christophe, Rasmin, Menaldi, Rätsep, Indrek, Ravi, Tharmini, Real, Andre, Rebaudet, Stanislas, Redl, Sarah, Reeve, Brenda, Reid, Liadain, Reikvam, Dag Henrik, Reis, Renato, Remy, Martine, Ren, Hongru, Resseguier, Anne-Sophie, Revest, Matthieu, Rewa, Oleksa, Reyes, Tiago, Reyes, Luis Felipe, Ribeiro, Maria Ines, Richardson, David, Richardson, Denise, Richier, Laurent, Atikah Ahmad Ridzuan, Siti Nurul, Rios, Ana L., Rishu, Asgar, Rispal, Patrick, Risso, Karine, Rizer, Nicholas, Robba, Chiara, Roberto, André, Roberts, Stephanie, Robertson, David L., Robineau, Olivier, Roche-Campo, Ferran, Rodari, Paola, Rodeia, Simão, Roessler, Bernhard, Roger, Pierre-Marie, Rojek, Amanda, Romaru, Juliette, Roncon-Albuquerque, Roberto, Jr., Roriz, Mélanie, Rosa-Calatrava, Manuel, Rose, Michael, Rosenberger, Dorothea, Rossanese, Andrea, Rossetti, Matteo, Rossignol, Bénédicte, Rossignol, Patrick, Rousset, Stella, Roy, Carine, Roze, Benoît, Russell, Clark D., Ryan, Maria, Ryan, Maeve, Ryckaert, Steffi, Holten, Aleksander Rygh, Saba, Isabela, Sadat, Musharaf, Sahraei, Valla, Saint-Gilles, Maximilien, Sakiyalak, Pranya, Salazar, Leonardo, Sales, Gabriele, Sallaberry, Stéphane, Gandonniere, Charlotte Salmon, Salvator, Hélène, Sanchez, Emely, Sanchez, Olivier, Sanchez-Miralles, Angel, Sancho-Shimizu, Vanessa, Sandhu, Gyan, Sandhu, Zulfiqar, Sandrine, Pierre-François, Sandulescu, Oana, Santos, Marlene, Sarfo-Mensah, Shirley, Sarmiento, Iam Claire E., Sarton, Benjamine, Satyapriya, Sree, Satyawati, Rumaisah, Saviciute, Egle, Saw, Yen Tsen, Schaffer, Justin, Schermer, Tjard, Scherpereel, Arnaud, Schneider, Marion, Schroll, Stephan, Schwameis, Michael, Scott, Janet T., Scott-Brown, James, Sedillot, Nicholas, Seitz, Tamara, Selvarajoo, Mageswari, Semaille, Caroline, Semple, Malcolm G., Senian, Rasidah Bt, Senneville, Eric, Sepulveda, Claudia, Sequeira, Filipa, Sequeira, Tânia, Neto, Ary Serpa, Balazote, Pablo Serrano, Shadowitz, Ellen, Shahidan, Syamin Asyraf, Shamsah, Mohammad, Shankar, Anuraj, Sharjeel, Shaikh, Sharma, Pratima, Shaw, Catherine A., Shaw, Victoria, Sheenan, John Robert, Shi, Haixia, Shime, Nobuaki, Shimizu, Hiroaki, Shimizu, Keiki, Shrapnel, Sally, Shum, Hoi Ping, Mohammed, Nassima Si, Siang, Ng Yong, Sibiude, Jeanne, Siddiqui, Atif, Sigfrid, Louise, Sillaots, Piret, Silva, Catarina, Silva, Rogério, Silva, Maria Joao, Lim Heng, Benedict Sim, Sin, Wai Ching, Singh, Punam, Singh, Budha Charan, Sitompul, Pompini Agustina, Sivam, Karisha, Skogen, Vegard, Smith, Sue, Smood, Benjamin, Smyth, Coilin, Smyth, Michelle, Snacken, Morgane, So, Dominic, Soh, Tze Vee, Solomon, Joshua, Solomon, Tom, Somers, Emily, Sommet, Agnès, Song, Rima, Song, Myung Jin, Song, Tae, Chia, Jack Song, Sotto, Albert, Soum, Edouard, Sousa, Marta, Sousa, Ana Chora, Uva, Maria Sousa, Souza-Dantas, Vicente, Sperry, Alexandra, Spinuzza, Elisabetta, Sriskandan, Shiranee, Stabler, Sarah, Staudinger, Thomas, Stecher, Stephanie-Susanne, Steinsvik, Trude, Stienstra, Ymkje, Stiksrud, Birgitte, Stolz, Eva, Stone, Amy, Streinu-Cercel, Adrian, Streinu-Cercel, Anca, Stuart, Ami, Stuart, David, Su, Richa, Subekti, Decy, Suen, Gabriel, Suen, Jacky Y., Sukumar, Prasanth, Sultana, Asfia, Summers, Charlotte, Supic, Dubravka, Suppiah, Deepashankari, Surovcová, Magdalena, Svistunov, Suwarti; Andrey, Syahrin, Sarah, Syrigos, Konstantinos, Sztajnbok, Jaques, Szuldrzynski, Konstanty, Tabrizi, Shirin, Taccone, Fabio S., Tagherset, Lysa, Taib, Shahdattul Mawarni, Taleb, Sara, Talsma, Jelmer, Tampubolon, Maria Lawrensia, Tan, Kim Keat, Tan, Yan Chyi, Tanaka, Hiroyuki, Tanaka, Taku, Taniguchi, Hayato, Tardivon, Coralie, Tattevin, Pierre, Taufik, M Azhari, Tawfik, Hassan, Tedder, Richard S., Tee, Tze Yuan, Teixeira, João, Tellier, Marie-Capucine, Teoh, Sze Kye, Teotonio, Vanessa, Téoulé, François, Terpstra, Pleun, Terrier, Olivier, Terzi, Nicolas, Tessier-Grenier, Hubert, Tey, Adrian, Mohd Thabit, Alif Adlan, Tham, Zhang Duan, Thangavelu, Suvintheran, Theron, Elmi, Thibault, Vincent, Thiberville, Simon-Djamel, Thill, Benoît, Thirumanickam, Jananee, Thompson, Shaun, Thomson, David, Thomson, Emma C., Thorpe, Mathew, Thanga Thurai, Surain Raaj, Thwaites, Ryan S., Tierney, Paul, Tieroshyn, Vadim, Timashev, Peter S., Timsit, Jean-François, Tissot, Noémie, Toal, Fiona, Yang Toh, Jordan Zhien, Toki, Maria, Tonby, Kristian, Tonnii, Sia Loong, Torre, Marta, Torres, 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Rizo-Topete, Lilia, Pole, Jason D., and Johnson, David W.

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2023
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50. Thrombotic and hemorrhagic complications of COVID-19 in adults hospitalized in high-income countries compared with those in adults hospitalized in low- and middle-income countries in an international registry

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Abdukahil, Sheryl Ann, Abdulkadir, Nurul Najmee, Abe, Ryuzo, Abel, Laurent, Abrous, Amal, Absil, Lara, Acker, Andrew, Adam, Elisabeth, Adrião, Diana, Al Ageel, Saleh, Ahmed, Shakeel, Ainscough, Kate, Aisa, Tharwat, Hssain, Ali Ait, Tamlihat, Younes Ait, Akimoto, Takako, Akmal, Ernita, Akwani, Chika, Al Qasim, Eman, Alalqam, Razi, Alberti, Angela, Al-dabbous, Tala, Alegesan, Senthilkumar, Alessi, Marta, Alex, Beatrice, Alexandre, Kévin, Al-Fares, Abdulrahman, Alfoudri, Huda, Ali, Imran, Alidjnou, Kazali Enagnon, Aliudin, Jeffrey, Alkhafajee, Qabas, Allavena, Clotilde, Allou, Nathalie, Alves, João, Alves, Rita, Alves, João Melo, Cabrita, Joana Alves, Amaral, Maria, Amira, Nur, Ampaw, Phoebe, Andini, Roberto, Andréjak, Claire, Angheben, Andrea, Angoulvant, François, Ansart, Séverine, Anthonidass, Sivanesen, Antonelli, Massimo, de Brito, Carlos Alexandre Antunes, Apriyana, Ardiyan, Arabi, Yaseen, Aragao, Irene, Arancibia, Francisco, Araujo, Carolline, Arcadipane, Antonio, Archambault, Patrick, Arenz, Lukas, Arlet, Jean-Benoît, Arnold-Day, Christel, Arora, Lovkesh, Arora, Rakesh, Artaud-Macari, Elise, Aryal, Diptesh, Asensio, Angel, Ashraf, Muhammad, Assie, Jean Baptiste, Asyraf, Amirul, Atif, Minahel, Atique, Anika, Auchabie, Johann, Aumaitre, Hugues, Auvet, Adrien, Azemar, Laurène, Azoulay, Cecile, Bach, Benjamin, Bachelet, Delphine, Badr, Claudine, Baig, Nadia, Baillie, J. Kenneth, Bak, Erica, Bakakos, Agamemnon, Bakar, Nazreen Abu, Bal, Andriy, Balakrishnan, Mohanaprasanth, Balan, Valeria, Bani-Sadr, Firouzé, Barbalho, Renata, Barbosa, Nicholas Yuri, Barclay, Wendy S., Barnett, Saef Umar, Barnikel, Michaela, Barrasa, Helena, Barrelet, Audrey, Barrigoto, Cleide, Bartoli, Marie, Baruch, Joaquín, Basmaci, Romain, Basri, Muhammad Fadhli Hassin, Battaglini, Denise, Bauer, Jules, Rincon, Diego Fernando Bautista, Beane, Abigail, Bedossa, Alexandra, Hong Bee, Ker, Begum, Husna, Behilill, Sylvie, Beishuizen, Albertus, Beljantsev, Aleksandr, Bellemare, David, Beltrame, Anna, Beltrão, Beatriz Amorim, Beluze, Marine, Benech, Nicolas, Benjiman, Lionel Eric, Benkerrou, Dehbia, Bennett, Suzanne, Benny, Binny, Bento, Luís, Berdal, Jan-Erik, Bergeaud, Delphine, Bergin, Hazel, Sobrino, José Luis Bernal, Bertoli, Giulia, Bertolino, Lorenzo, Bessis, Simon, Bevilcaqua, Sybille, Bezulier, Karine, Bhatt, Amar, Bhavsar, Krishna, Bianco, Claudia, Bidin, Farah Nadiah, Singh, Moirangthem Bikram, Humaid, Felwa Bin, Kamarudin, Mohd Nazlin Bin, Bisoffi, Zeno, Bissuel, François, Bitker, Laurent, Bitton, Jonathan, Blanco-Schweizer, Pablo, Blier, Catherine, Bloos, Frank, Blot, Mathieu, Blumberg, Lucille, Boccia, Filomena, Bodenes, Laetitia, Bogaert, Debby, Boivin, Anne-Hélène, Bolaños, Isabela, Bolze, Pierre-Adrien, Bompart, François, Borges, Diogo, Borie, Raphaël, Bosse, Hans Martin, Botelho-Nevers, Elisabeth, Bouadma, Lila, Bouchaud, Olivier, Bouchez, Sabelline, Bouhmani, Dounia, Bouhour, Damien, Bouiller, Kévin, Bouillet, Laurence, Bouisse, Camile, Boureau, Anne-Sophie, Bourke, John, Bouscambert, Maude, Bousquet, Aurore, Bouziotis, Jason, Boxma, Bianca, Boyer-Besseyre, Marielle, Boylan, Maria, Bozza, Fernando Augusto, Braconnier, Axelle, Braga, Cynthia, Brandenburger, Timo, Monteiro, Filipa Brás, Brazzi, Luca, Breen, Patrick, Breen, Dorothy, Brewster, David, Brickell, Kathy, Browne, Shaunagh, Browne, Alex, Brozzi, Nicolas, Brusse-Keizer, Marjolein, Bryda, Petra, Buchtele, Nina, Buisson, Marielle, Burhan, Erlina, Burrell, Aidan, Bustos, Ingrid G., Cabie, André, Cabral, Susana, Caceres, Eder, Cadoz, Cyril, Garcês, Rui Caetano, Calligy, Kate, Calvache, Jose Andres, Camões, João, Campana, Valentine, Campbell, Paul, Campisi, Josie, Canepa, Cecilia, Cantero, Mireia, Caraux-Paz, Pauline, Cárcel, Sheila, Cardellino, Chiara Simona, Cardoso, Sofia, Cardoso, Filipe, Cardoso, Filipa, Cardoso, Nelson, Carelli, Simone, Carlier, Nicolas, Carmoi, Thierry, Carney, Gayle, Carqueja, Inês, Carret, Marie-Christine, Carrier, François Martin, Carroll, Ida, Carson, Gail, Casanova, Maire-Laure, Cascão, Mariana, Casey, Siobhan, Casimiro, José, Cassandra, Bailey, Castañeda, Silvia, Castanheira, Nidyanara, Castor-Alexandre, Guylaine, Castro, Ivo, Catarino, Ana, Catherine, François-Xavier, Cattaneo, Paolo, Cavalin, Roberta, Cavayas, Alexandros, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chakveatze, Catherine, Chan, Adrienne, Chand, Meera, Chantalat Auger, Christelle, Chapplain, Jean-Marc, Charpentier, Charlotte, Chas, Julie, Chávez Iñiguez, Jonathan Samuel, Chen, Anjellica, Chen, Yih-Sharng, Chenard, Léo, Cheng, Matthew Pellan, Cheret, Antoine, Chiarabini, Thibault, Chica, Julian, Chidambaram, Suresh Kumar, Chin Tho, Leong, Chirouze, Catherine, Chiumello, Davide, Cho, Sung-Min, Cholley, Bernard, Chopin, Marie-Charlotte, Chow, Ting Soo, Chua, Hiu Jian, Chua, Jonathan, Cidade, Jose Pedro, Cisneros Herreros, José Miguel, Citarella, Barbara Wanjiru, Ciullo, Anna, Clarke, Jennifer, Clarke, Emma, Claure-Del Granado, Rolando, Clohisey, Sara, Codan, Cassidy, Cody, Caitriona, Coelho, Alexandra, Coles, Megan, Coles, Jennifer, Colin, Gwenhaël, Collins, Michael, Colombo, Sebastiano Maria, Combs, Pamela, Connolly, Jennifer, Connor, Marie, Conrad, Anne, Conway, Elaine, Cooke, Graham S., Copland, Mary, Cordel, Hugues, Corley, Amanda, Cornelis, Sabine, Cornet, Alexander Daniel, Corpuz, Arianne Joy, Cortegiani, Andrea, Corvaisier, Grégory, Costigan, Emma, Couffignal, Camille, Couffin-Cadiergues, Sandrine, Courtois, Roxane, Cousse, Stéphanie, Cregan, Rachel, Cristella, Cosimo, Croonen, Sabine, Crowl, Gloria, Crump, Jonathan, Cruz, Claudina, Cruz Bermúdez, Juan Luis, Cruz Rojo, Jaime, Csete, Marc, Cullen, Ailbhe, Cummings, Matthew, Curley, Gerard, Curlier, Elodie, Curran, Colleen, Custodio, Paula, da Silva Filipe, Ana, Da Silveira, Charlene, Dabaliz, Al-Awwab, Dagens, Andrew, Dahly, Darren, Dalton, Heidi, Dalton, Jo, Daly, Seamus, Damas, Juliana, Daneman, Nick, Daniel, Corinne, Dankwa, Emmanuelle A., Dantas, Jorge, D'Aragon, Frédérick, de Jong, Menno, de Loughry, Gillian, De Montmollin, Etienne, de Oliveira França, Rafael Freitas, de Pinho Oliveira, Ana Isabel, De Rosa, Rosanna, de Silva, Thushan, de Vries, Peter, Dean, David, Debard, Alexa, DeBenedictis, Bianca, Debray, Marie-Pierre, DeCastro, Nathalie, Dechert, William, Deconninck, Lauren, Decours, Romain, Defous, Eve, Delacroix, Isabelle, Delaveuve, Eric, Delavigne, Karen, Delfos, Nathalie M., Deligiannis, Ionna, Dell'Amore, Andrea, Delmas, Christelle, Delobel, Pierre, Delsing, Corine, Demonchy, Elisa, Denis, Emmanuelle, Deplanque, Dominique, Depuydt, Pieter, Desai, Mehul, Descamps, Diane, Desvallées, Mathilde, Dewayanti, Santi, Dhanger, Pathik, Diallo, Alpha, Diamantis, Sylvain, Dias, André, Da Silva, Fernanda Dias, Diaz, Juan Jose, Diaz, Rodrigo, Diaz, Priscila, Didier, Kévin, Diehl, Jean-Luc, Dieperink, Wim, Dimet, Jérôme, Dinot, Vincent, Diop, Fara, Diouf, Alphonsine, Dishon, Yael, Djossou, Félix, Docherty, Annemarie B., Doherty, Helen, Donnelly, Maria, Donnelly, Christl A., Donohue, Sean, Donohue, Yoann, Donohue, Chloe, Doran, Peter, Dorival, Céline, D'Ortenzio, Eric, Douglas, James Joshua, Dournon, Nathalie, Downer, Triona, Downey, Joanne, Downing, Mark, Drake, Tom, Driscoll, Aoife, Dryden, Murray, Fonseca, Claudio Duarte, Dubee, Vincent, Dubos, François, Ducancelle, Alexandre, Duculan, Toni, Dudman, Susanne, Duggal, Abhijit, Dunand, Paul, Dunning, Jake, Duplaix, Mathilde, Durante-Mangoni, Emanuele, Durham, Lucian, III, Dussol, Bertrand, Duthoit, Juliette, Duval, Xavier, Dyrhol-Riise, Anne Margarita, Ean, Sim Choon, Echeverria-Villalobos, Marco, Egan, Siobhan, Eira, Carla, El Sanharawi, Mohammed, Elapavaluru, Subbarao, Elharrar, Brigitte, Ellerbroek, Jacobien, Eloy, Philippine, Elshazly, Tarek, Enderle, Isabelle, Endo, Tomoyuki, Eng, Chan Chee, Engelmann, Ilka, Enouf, Vincent, Epaulard, Olivier, Escher, Martina, Esperatti, Mariano, Esperou, Hélène, Santo, Catarina Espírito, Esposito-Farese, Marina, Estevão, João, Etienne, Manuel, Ettalhaoui, Nadia, Everding, Anna Greti, Evers, Mirjam, Fabre, Isabelle, Fabre, Marc, Faheem, Amna, Fahy, Arabella, Fairfield, Cameron J., Faria, Pedro, Fateena, Hanan, Fatoni, Arie Zainul, Faure, Karine, Favory, Raphaël, Fayed, Mohamed, Feely, Niamh, Feeney, Laura, Fernandes, Jorge, Fernandes, Marília Andreia, Fernandes, Susana, Ferrand, François-Xavier, Devouge, Eglantine Ferrand, Ferrão, Joana, Ferraz, Mário, Ferreira, Sílvia, Ferreira, Bernardo, Ferreira, Benigno, Ferreira, Isabel, Ferriere, Nicolas, Ficko, Céline, Figueiredo-Mello, Claudia, Fiorda, Juan, Flament, Thomas, Flateau, Clara, Fletcher, Tom, Florence, Aline-Marie, Florio, Letizia Lucia, Flynn, Deirdre, Foley, Claire, Foley, Jean, Fonseca, Tatiana, Forsyth, Simon, Foster, Denise, Foti, Giuseppe, Fourn, Erwan, Fowler, Robert A., Fraher, Marianne, Franch-Llasat, Diego, Fraser, John F., Fraser, Christophe, Freire, Marcela Vieira, Ribeiro, Ana Freitas, Fritz, Ricardo, Fry, Stéphanie, Fuentes, Nora, Fukuda, Masahiro, Gaborieau, Valérie, Gaci, Rostane, Gagliardi, Massimo, Gagnard, Jean-Charles, Gagneux-Brunon, Amandine, Gaião, Sérgio, Skeie, Linda Gail, Gallagher, Phil, Gamble, Carrol, Gani, Yasmin, Garan, Arthur, Garcia, Rebekha, Barrio, Noelia García, Garcia-Gallo, Esteban, Garot, Denis, Garrait, Valérie, Gault, Nathalie, Gavin, Aisling, Gavrylov, Anatoliy, Gaymard, Alexandre, Gebauer, Johannes, Geraud, Eva, Morlaes, Louis Gerbaud, Germano, Nuno, Ghosn, Jade, Giani, Marco, Gibson, Jess, Gigante, Tristan, Gilg, Morgane, Gilroy, Elaine, Giordano, Guillermo, Girvan, Michelle, Gissot, Valérie, Glikman, Daniel, Gnall, Eric, Goehringer, François, Goepel, Siri, Goffard, Jean-Christophe, Goh, Jin Yi, Golob, Jonathan, Gómez-Junyent, Joan, Gominet, Marie, Gonzalez, Alicia, Gordon, Patricia, Gorenne, Isabelle, Gormley, Conor, Goubert, Laure, Goujard, Cécile, Goulenok, Tiphaine, Grable, Margarite, Graf, Jeronimo, Grandin, Edward Wilson, Granier, Pascal, Grasselli, Giacomo, Green, Christopher A., Greene, Courtney, Greenhalf, William, Greffe, Segolène, Grieco, Domenico Luca, Griffee, Matthew, Griffiths, Fiona, Grigoras, Ioana, Groenendijk, Albert, Gruner, Heidi, Gu, Yusing, Guedj, Jérémie, Guego, Martin, Guellec, Dewi, Guerreiro, Daniela, Guery, Romain, Guillaumot, Anne, Guilleminault, Laurent, de Castro, Maisa Guimarães, Guimard, Thomas, Haalboom, Marieke, Haber, Daniel, Habraken, Hannah, Hachemi, Ali, Hadri, Nadir, Hakak, Sheeba, Hall, Adam, Hall, Matthew, Halpin, Sophie, Hamer, Ansley, Hamidfar, Rebecca, Hammond, Terese, Hammond, Naomi, Han, Lim Yuen, Haniffa, Rashan, Hao, Kok Wei, Hardwick, Hayley, Harrison, Ewen M., Harrison, Janet, Ekow Harrison, Samuel Bernard, Hartman, Alan, Hashmi, Junaid, Hayes, Ailbhe, Hays, Leanne, Heerman, Jan, Heggelund, Lars, Hendry, Ross, Hennessy, Martina, Henriquez-Trujillo, Aquiles, Hentzien, Maxime, Hernandez, Diana, Hernandez-Montfort, Jaime, Hershey, Andrew, Hesstvedt, Liv, Higgins, Eibhlin, Higgins, Dawn, Higgins, Rupert, Hinchion, Rita, Hinton, Samuel, Hiraiwa, Hiroaki, Hitoto, Hikombo, Ho, Antonia, Ho, Yi Bin, Hoctin, Alexandre, Hoffmann, Isabelle, Hoh, Wei Han, Hoiting, Oscar, Holt, Rebecca, Holter, Jan Cato, Horby, Peter, Horcajada, Juan Pablo, Hoshino, Koji, Houas, Ikram, Hough, Catherine L., Houltham, Stuart, Ming-Yang Hsu, Jimmy, Hulot, Jean-Sébastien, Hurd, Abby, Ijaz, Samreen, Ikram, M. Arfan, Illes, Hajnal-Gabriela, Imbert, Patrick, Inácio, Hugo, Infante Dominguez, Carmen, Ing, Yun Sii, Iosifidis, Elias, Ippolito, Mariachiara, Isgett, Sarah, Isidoro, Tiago, Ismail, Nadiah, Isnard, Margaux, Itai, Junji, Ivulich, Daniel, Jaafar, Danielle, Jaafoura, Salma, Jabot, Julien, Jackson, Clare, Janes, Victoria, Jaquet, Pierre, Jassat, Waasila, Jaud-Fischer, Coline, Jaureguiberry, Stéphane, Jaworsky, Denise, Jego, Florence, Jelani, Anilawati Mat, Jenum, Synne, Jimbo-Sotomayor, Ruth, Joe, Ong Yiaw, Jorge García, Ruth N., Joseph, Cédric, Joseph, Mark, Jourdain, Mercé, Jouvet, Philippe, Jung, Anna, Jung, Hanna, Juzar, Dafsah, Kafif, Ouifiya, Kaguelidou, Florentia, Kaisbain, Neerusha, Kaleesvran, Thavamany, Kali, Sabina, Kalomoiri, Smaragdi, Ayadi Kamaluddin, Muhammad Aisar, Che Kamaruddin, Zul Amali, Kamarudin, Nadiah, Kandamby, Darshana Hewa, Kandel, Chris, Kang, Kong Yeow, Karpayah, Pratap, Kartsonaki, Christiana, Kasugai, Daisuke, Kataria, Anant, Katz, Kevin, Kaur, Aasmine, Kay, Christy, Kayyali, Lamees, Keane, Hannah, Keating, Seán, Kelly, Claire, Kelly, Yvelynne, Kelly, Andrea, Kelly, Niamh, Kelly, Aoife, Kelly, Sadie, Kelsey, Maeve, Kennedy, Ryan, Kennon, Kalynn, Kernan, Maeve, Kerroumi, Younes, Keshav, Sharma, Khalid, Imrana, Khalil, Antoine, Khan, Coralie, Khan, Irfan, Kho, Michelle E., Khoo, Saye, Khoo, Ryan, Khoo, Denisa, Kiat, Khor How, Kida, Yuri, Kiiza, Peter, Granerud, Beathe Kiland, Kildal, Anders Benjamin, Kimmoun, Antoine, Kindgen-Milles, Detlef, King, Alexander, Kitamura, Nobuya, Klenerman, Paul, Klont, Rob, Bekken, Gry Kloumann, Knight, Stephen R., Vasconcelos, Malte Kohns, Komatsu, Mamoru, Kosgei, Caroline, Kpangon, Arsène, Krawczyk, Karolina, Krishnan, Sudhir, Krishnan, Vinothini, Kruglova, Oksana, Kumar, Deepali, Kumar, Ganesh, Vecham, Pavan Kumar, Kuriakose, Dinesh, Kurtzman, Ethan, Kutsogiannis, Demetrios, Kutsyna, Galyna, Kyriakoulis, Konstantinos, Lachatre, Marie, Lacoste, Marie, Laffey, John G., Lafhej, Nadhem, Lagrange, Marie, Laine, Fabrice, Lairez, Olivier, Lalueza, Antonio, Lambert, Marc, Lamontagne, François, Langelot-Richard, Marie, Langlois, Vincent, Lantang, Eka Yudha, Lanza, Marina, Laouénan, Cédric, Laribi, Samira, Lariviere, Delphine, Lasry, Stéphane, Launay, Odile, Laureillard, Didier, Lavie-Badie, Yoan, Law, Andy, Lawrence, Teresa, Lawrence, Cassie, Le, Minh, Le Bihan, Clément, Le Bris, Cyril, Le Falher, Georges, Le Fevre, Lucie, Le Hingrat, Quentin, Le Maréchal, Marion, Mestre, Soizic Le, Le Moal, Gwenaël, Le Moing, Vincent, Le Nagard, Hervé, LeTurnier, Paul, Leal, Ema, Santos, Marta Leal, Lee, Todd C., Lee, Su Hwan, Lee, James, Lee, Jennifer, Lee, Heng Gee, Lee, Biing Horng, Lee, Yi Lin, Leeming, Gary, Lefebvre, Bénédicte, Lefebvre, Laurent, Lefèvre, Benjamin, LeGac, Sylvie, Lelievre, Jean-Daniel, Lellouche, François, Lemaignen, Adrien, Lemee, Véronique, Lemeur, Anthony, Lemmink, Gretchen, Lene, Ha Sha, Lennon, Jenny, León, Rafael, Leone, Marc, Leone, Michela, Lepiller, Quentin, Lescure, François-Xavier, Lesens, Olivier, Lesouhaitier, Mathieu, Lester-Grant, Amy, Letrou, Sophie, Levy, Bruno, Levy, Yves, Levy-Marchal, Claire, Lewandowska, Katarzyna, L'Her, Erwan, Bassi, Gianluigi Li, Liegeon, Geoffrey, Lim, Wei Shen, Lim, Kah Chuan, Lima, Chantre, Lina, Bruno, Lina, Lim, Lind, Andreas, Lingas, Guillaume, Lion-Daolio, Sylvie, Lissauer, Samantha, Liu, Keibun, Livrozet, Marine, Lizotte, Patricia, Lolong, Navy, Loon, Leong Chee, Lopes, Diogo, Lopez-Colon, Dalia, Loschner, Anthony L., Loubet, Paul, Loufti, Bouchra, Louis, Guillame, Lourenco, Silvia, Lee Low, Lee, Lowik, Marije, Loy, Jia Shyi, Lucet, Jean-Christophe, Bermejo, Carlos Lumbreras, Luna, Carlos M., Lungu, Olguta, Luong, Liem, Luque, Nestor, Luton, Dominique, Lwin, Nilar, Lyons, Ruth, Maasikas, Olavi, Mabiala, Oryane, Machado, Moïse, Machado, Sara, Macheda, Gabriel, Madiha, Hashmi, de la Calle, Guillermo Maestro, Mahieu, Rafael, Mahy, Sophie, Maia, Ana Raquel, Maier, Lars S., Maillet, Mylène, Maitre, Thomas, Malfertheiner, Maximilian, Malik, Nadia, Mallon, Paddy, Maltez, Fernando, Malvy, Denis, Manda, Victoria, Mandelbrot, Laurent, Manetta, Frank, Mankikian, Julie, Manning, Edmund, Manuel, Aldric, Sant`Ana Malaque, Ceila Maria, Marino, Flávio, Markowicz, Samuel, Marques, Ana, Marquis, Catherine, Marsh, Brian, Marsh, Laura, Marshal, Megan, Marshall, John, Martelli, Celina Turchi, Martin, Emily, Martin-Blondel, Guillaume, Martinez, F. Eduardo, Martin-Loeches, Ignacio, Martinot, Martin, Martins, João, Martins, Ana, Martins, Nuno, Rego, Caroline Martins, Martucci, Gennaro, Martynenko, Olga, Marwali, Eva Miranda, Marzukie, Marsilla, Maslove, David, Mason, Sabina, Mat Nor, Mohd Basri, Matan, Moshe, Mathieu, Daniel, Mattei, Mathieu, Maulin, Laurence, Maxwell, Michael, Maynar, Javier, Mazzoni, Thierry, Sweeney, Lisa Mc, McArthur, Colin, McCanny, Peter, McCarthy, Anne, McCarthy, Aine, McCloskey, Colin, McConnochie, Rachael, McDermott, Sherry, McDonald, Sarah E., McElroy, Aine, McElwee, Samuel, McEneany, Victoria, McEvoy, Natalie, McGeer, Allison, McKay, Chris, McKeown, Johnny, McLean, Kenneth A., McNally, Paul, McNicholas, Bairbre, McPartlan, Elaine, Meaney, Edel, Mear-Passard, Cécile, Mechlin, Maggie, Mehkri, Omar, Mele, Ferruccio, Melo, Luis, Mendes, Joao Joao, Menon, Kusum, Mentré, France, Mentzer, Alexander J., Mercier, Emmanuelle, Mercier, Noémie, Merckx, Antoine, Mergeay-Fabre, Mayka, Mergler, Blake, Merson, Laura, Mesquita, António, Metwally, Osama, Meybeck, Agnès, Meyer, Dan, Meynert, Alison M., Meysonnier, Vanina, Meziane, Amina, Mezidi, Mehdi, Michelanglei, Céline, Michelet, Isabelle, Mihelis, Efstathia, Mihnovit, Vladislav, Miller, Jennene, Miranda-Maldonado, Hugo, Misnan, Nor Arisah, Mohamed, Tahira Jamal, Eliza Mohamed, Nik Nur, Moin, Asma, Molinos, Elena, Molloy, Brenda, Monahan, Sinead, Mone, Mary, Monteiro, Agostinho, Montes, Claudia, Montrucchio, Giorgia, Moore, Shona C., Moore, Sarah, Cely, Lina Morales, Moro, Lucia, Morton, Ben, Motherway, Catherine, Motos, Ana, Mouquet, Hugo, Perrot, Clara Mouton, Moyet, Julien, Mudara, Caroline, Muh, Ng Yong, Muhamad, Dzawani, Mullaert, Jimmy, Müller, Fredrik, Müller, Karl Erik, Murphy, Aisling, Murphy, Lorna, Murray, Patrick, Murris, Marlène, Murthy, Srinivas, Musaab, Himed, Muyandy, Gugapriyaa, Myrodia, Dimitra Melia, Nagpal, Dave, Nagrebetsky, Alex, Narasimhan, Mangala, Narayanan, Nageswaran, Nazerali-Maitland, Alasdair, Neant, Nadège, Neb, Holger, Neto, Raul, Neumann, Emily, Ng, Pauline Yeung, Ng, Wing Yiu, Nghi, Anthony, Nguyen, Duc, Choileain, Orna Ni, Leathlobhair, Niamh Ni, Nichol, Alistair D., Nitayavardhana, Prompak, Nonas, Stephanie, Mohd Noordin, Nurul Amani, Noret, Marion, Izzati Norharizam, Nurul Faten, Norman, Lisa, Noursadeghi, Mahdad, Nowinski, Adam, Nseir, Saad, Nunez, Jose I., Nyamankolly, Elsa, Brien, Fionnuala O., Callaghan, Annmarie O., O'Callaghan, Annmarie, Occhipinti, Giovanna, OConnor, Derbrenn, O'Donnell, Max, Ogston, Tawnya, Ogura, Takayuki, Oh, Tak-Hyuk, O'Halloran, Sophie, O'Hearn, Katie, Ohshimo, Shinichiro, Oliveira, João, Oliveira, Larissa, Olliaro, Piero L., Ong, David S.Y., Ong, Jee Yan, Oosthuyzen, Wilna, Opavsky, Anne, Openshaw, Peter, Orozco-Chamorro, Claudia Milena, Ortoleva, Jamel, Osatnik, Javier, O'Shea, Linda, O'Sullivan, Miriam, Othman, Siti Zubaidah, Ouamara, Nadia, Ouissa, Rachida, Oziol, Eric, Pagadoy, Maïder, Pages, Justine, Palacios, Amanda, Palmarini, Massimo, Panarello, Giovanna, Panda, Prasan Kumar, Pang, Lai Hui, Panigada, Mauro, Pansu, Nathalie, Papadopoulos, Aurélie, Parke, Rachael, Pasquier, Jérémie, Pastene, Bruno, Patauner, Fabian, Pathmanathan, Mohan Dass, Patrão, Luís, Patricio, Patricia, Patrier, Juliette, Patterson, Lisa, Paul, Christelle, Paul, Mical, Paulos, Jorge, Paxton, William A., Payen, Jean-François, Peake, Sandra L., Peariasamy, Kalaiarasu, Jiménez, Miguel Pedrera, Peek, Giles J., Peelman, Florent, Peiffer-Smadja, Nathan, Peigne, Vincent, Pejkovska, Mare, Pelosi, Paolo, Peltan, Ithan D., Pereira, Rui, Perez, Daniel, Periel, Luis, Perpoint, Thomas, Pesenti, Antonio, Pestre, Vincent, Petrou, Lenka, Petrovic, Michele, Petrov-Sanchez, Ventzislava, Pettersen, Frank Olav, Peytavin, Gilles, Pharand, Scott, Picard, Walter, Picone, Olivier, de Piero, Maria, Pierobon, Carola, Piersma, Djura, Pimentel, Carlos, Pinto, Raquel, Piquard, Valentine, Pires, Catarina, Pironneau, Isabelle, Piroth, Lionel, Piubelli, Chiara, Pius, Riinu, Plantier, Laurent, Png, Hon Shen, Poissy, Julien, Pokeerbux, Ryadh, Poli, Sergio, Pollakis, Georgios, Ponscarme, Diane, Porto, Diego Bastos, Post, Andra-Maris, Postma, Douwe F., Povoa, Pedro, Póvoas, Diana, Powis, Jeff, Prapa, Sofia, Preau, Sébastien, Prebensen, Christian, Preiser, Jean-Charles, Prinssen, Anton, Pritchard, Mark G., Proença, Lucia, Pudota, Sravya, Puéchal, Oriane, Semedi, Bambang Pujo, Purcell, Gregory, Quesada, Luisa, González, Víctor Quirós, Quist-Paulsen, Else, Quraishi, Mohammed, Qutishat, Fadi, Rabaud, Christian, Rafael, Aldo, Rafiq, Marie, Rahman, Rozanah Abd, Haji Ab Rahman, Ahmad Kashfi, Rainieri, Fernando, Rajahram, Giri Shan, Ramakrishnan, Nagarajan, Ramalho, José, Ramli, Ahmad Afiq, Rammaert, Blandine, Ramos, Grazielle Viana, Ranjan, Ritika, Rapp, Christophe, Rasmin, Menaldi, Rätsep, Indrek, Ravi, Tharmini, Real, Andre, Rebaudet, Stanislas, Redl, Sarah, Reeve, Brenda, Reid, Liadain, Reikvam, Dag Henrik, Reis, Renato, Rello, Jordi, Remppis, Jonathan, Remy, Martine, Ren, Hongru, Renk, Hanna, Resseguier, Anne-Sophie, Revest, Matthieu, Rewa, Oleksa, Reyes, Tiago, Reyes, Luis Felipe, Ribeiro, Maria Ines, Richardson, David, Richardson, Denise, Richier, Laurent, Atikah Ahmad Ridzuan, Siti Nurul, Rios, Ana L., Rishu, Asgar, Rispal, Patrick, Risso, Karine, Rizer, Nicholas, Robba, Chiara, Roberto, André, Roberts, Stephanie, Robertson, David L., Robineau, Olivier, Roche-Campo, Ferran, Rodari, Paola, Rodeia, Simão, Roessler, Bernhard, Roger, Pierre-Marie, Roger, Claire, Roilides, Emmanuel, Rojek, Amanda, Romaru, Juliette, Roncon-Albuquerque, Roberto, Jr., Roriz, Mélanie, Rosa-Calatrava, Manuel, Rose, Michael, Rosenberger, Dorothea, Rossanese, Andrea, Rossetti, Matteo, Rossignol, Bénédicte, Rossignol, Patrick, Rousset, Stella, Roy, Carine, Roze, Benoît, Russell, Clark D., Ryan, Maria, Ryan, Maeve, Ryckaert, Steffi, Holten, Aleksander Rygh, Saba, Isabela, Sadat, Musharaf, Sahraei, Valla, Saint-Gilles, Maximilien, Sakiyalak, Pranya, Salazar, Leonardo, Sales, Gabriele, Sallaberry, Stéphane, Gandonniere, Charlotte Salmon, Salvator, Hélène, Sanchez, Olivier, Sanchez, Emely, Sanchez-Miralles, Angel, Sancho-Shimizu, Vanessa, Sandhu, Gyan, Sandhu, Zulfiqar, Sandrine, Pierre-François, Sandulescu, Oana, Santos, Marlene, Sarfo-Mensah, Shirley, Sarmento Banheiro, Bruno, Sarmiento, Iam Claire E., Sarton, Benjamin, Satyapriya, Sree, Satyawati, Rumaisah, Saviciute, Egle, Savvidou, Parthena, Saw, Yen Tsen, Schaffer, Justin, Schermer, Tjard, Scherpereel, Arnaud, Schneider, Marion, Schroll, Stephan, Schwameis, Michael, Scicluna, Brendan, Scott, Janet T., Scott-Brown, James, Sedillot, Nicholas, Seitz, Tamara, Selvarajoo, Mageswari, Semaille, Caroline, Semple, Malcolm G., Senian, Rasidah Bt, Senneville, Eric, Sepulveda, Claudia, Sequeira, Filipa, Sequeira, Tânia, Neto, Ary Serpa, Balazote, Pablo Serrano, Shadowitz, Ellen, Shahidan, Syamin Asyraf, Shamsah, Mohammad, Sharjeel, Shaikh, Sharma, Pratima, Shaw, Catherine A., Shaw, Victoria, Sheenan, John Robert, Shi, Haixia, Shime, Nobuaki, Shimizu, Keiki, Shrapnel, Sally, Shum, Hoi Ping, Mohammed, Nassima Si, Siang, Ng Yong, Sibiude, Jeanne, Siddiqui, Atif, Sigfrid, Louise, Sillaots, Piret, Silva, Catarina, Silva, Rogério, Silva, Maria Joao, Lim Heng, Benedict Sim, Sin, Wai Ching, Singh, Punam, Singh, Budha Charan, Sitompul, Pompini Agustina, Sivam, Karisha, Skogen, Vegard, Smith, Sue, Smood, Benjamin, Smyth, Coilin, Smyth, Michelle, Snacken, Morgane, So, Dominic, Soh, Tze Vee, Solomon, Joshua, Solomon, Tom, Somers, Emily, Sommet, Agnès, Song, Rima, Song, Myung Jin, Song, Tae, Chia, Jack Song, Sonntagbauer, Michael, Soom, Azlan Mat, Sotto, Albert, Soum, Edouard, Sousa, Marta, Sousa, Ana Chora, Uva, Maria Sousa, Souza-Dantas, Vicente, Sperry, Alexandra, Spinuzza, Elisabetta, Sriskandan, Shiranee, Stabler, Sarah, Staudinger, Thomas, Stecher, Stephanie-Susanne, Steinsvik, Trude, Stienstra, Ymkje, Stiksrud, Birgitte, Stolz, Eva, Stone, Amy, Streinu-Cercel, Adrian, Streinu-Cercel, Anca, Stuart, 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2023
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