Publications by authors named "Susan M Chang"

283 Publications

Intracranial mesenchymal tumors with FET-CREB fusion are composed of at least two epigenetic subgroups distinct from meningioma and extracranial sarcomas.

Brain Pathol 2021 Nov 25:e13037. Epub 2021 Nov 25.

Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.

'Intracranial mesenchymal tumor, FET-CREB fusion-positive' occurs primarily in children and young adults and has previously been termed intracranial angiomatoid fibrous histiocytoma (AFH) or intracranial myxoid mesenchymal tumor (IMMT). Here we performed genome-wide DNA methylation array profiling of 20 primary intracranial mesenchymal tumors with FET-CREB fusion to further study their ontology. These tumors resolved into two distinct epigenetic subgroups that were both divergent from all other analyzed intracranial neoplasms and soft tissue sarcomas, including meningioma, clear cell sarcoma of soft tissue (CCS), and AFH of extracranial soft tissue. The first subgroup (Group A, 16 tumors) clustered nearest to but independent of solitary fibrous tumor and AFH of extracranial soft tissue, whereas the second epigenetic subgroup (Group B, 4 tumors) clustered nearest to but independent of CCS and also lacked expression of melanocytic markers (HMB45, Melan A, or MITF) characteristic of CCS. Group A tumors most often occurred in adolescence or early adulthood, arose throughout the neuroaxis, and contained mostly EWSR1-ATF1 and EWSR1-CREB1 fusions. Group B tumors arose most often in early childhood, were located along the cerebral convexities or spinal cord, and demonstrated an enrichment for tumors with CREM as the fusion partner (either EWSR1-CREM or FUS-CREM). Group A tumors more often demonstrated stellate/spindle cell morphology and hemangioma-like vasculature, whereas Group B tumors more often demonstrated round cell or epithelioid/rhabdoid morphology without hemangioma-like vasculature, although robust comparison of these clinical and histologic features requires future study. Patients with Group B tumors had inferior progression-free survival relative to Group A tumors (median 4.5 vs. 49 months, p = 0.001). Together, these findings confirm that intracranial AFH-like neoplasms and IMMT represent histologic variants of a single tumor type ('intracranial mesenchymal tumor, FET-CREB fusion-positive') that is distinct from meningioma and extracranial sarcomas. Additionally, epigenomic evaluation may provide important prognostic subtyping for this unique tumor entity.
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http://dx.doi.org/10.1111/bpa.13037DOI Listing
November 2021

Isocitrate Dehydrogenase Mutant Grade II and III Glial Neoplasms.

Hematol Oncol Clin North Am 2022 02 25;36(1):95-111. Epub 2021 Oct 25.

Department of Neuro-onoclogy, Brain Tumor Center at Erasmus MC Cancer Institute, Nt-542, Dr Molenwaterplein 40, Rotterdam 3015 GD, The Netherlands. Electronic address:

Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors.
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http://dx.doi.org/10.1016/j.hoc.2021.08.008DOI Listing
February 2022

Improving the noninvasive classification of glioma genetic subtype with deep learning and diffusion-weighted imaging.

Neuro Oncol 2021 Oct 15. Epub 2021 Oct 15.

Department of Radiology & Biomedical Imaging, University of California San Francisco.

Background: Diagnostic classification of diffuse gliomas now requires an assessment of molecular features, often including IDH-mutation and 1p19q-codeletion status. Because genetic testing requires an invasive process, an alternative noninvasive approach is attractive, particularly if resection is not recommended. The goal of this study was to evaluate the effects of training strategy and incorporation of biologically relevant images on predicting genetic subtypes with deep learning.

Methods: Our dataset consisted of 384 patients with newly-diagnosed gliomas who underwent preoperative MR imaging with standard anatomical and diffusion-weighted imaging, and 147 patients from an external cohort with anatomical imaging. Using tissue samples acquired during surgery, each glioma was classified into IDH-wildtype (IDHwt), IDH-mutant/1p19q-noncodeleted (IDHmut-intact), and IDH-mutant/1p19q-codeleted (IDHmut-codel) subgroups. After optimizing training parameters, top performing convolutional neural network (CNN) classifiers were trained, validated, and tested using combinations of anatomical and diffusion MRI with either a 3-class or tiered structure. Generalization to an external cohort was assessed using anatomical imaging models.

Results: The best model used a 3-class CNN containing diffusion-weighted imaging as an input, achieving 85.7% (95% CI:[77.1,100]) overall test accuracy and correctly classifying 95.2%, 88.9%, 60.0% of the IDHwt, IDHmut-intact, and IDHmut-codel tumors. In general, 3-class models outperformed tiered approaches by 13.5-17.5%, and models that included diffusion-weighted imaging were 5-8.8% more accurate than those that used only anatomical imaging.

Conclusion: Training a classifier to predict both IDH-mutation and 1p19q-codeletion status outperformed a tiered structure that first predicted IDH-mutation, then1p19q-codeletion. Including ADC, a surrogate marker of cellularity, more accurately captured differences between subgroups.
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http://dx.doi.org/10.1093/neuonc/noab238DOI Listing
October 2021

Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma.

Clin Cancer Res 2021 Sep 24. Epub 2021 Sep 24.

Duke University, Durham, North Carolina.

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2681DOI Listing
September 2021

Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement.

Clin Cancer Res 2021 Sep 24. Epub 2021 Sep 24.

Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as "recruiting" or "not yet recruiting" as of February 2021.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2750DOI Listing
September 2021

Cognitive, psychosocial, and behaviour gains at age 31 years from the Jamaica early childhood stimulation trial.

J Child Psychol Psychiatry 2021 Aug 17. Epub 2021 Aug 17.

Institute of Child Health, University College London, London, UK.

Background: There is little evidence on adult benefits from early childhood interventions in low and middle-income countries. We assessed adult cognition, psychosocial skills and behaviour from a stimulation trial conducted in Jamaica.

Methods: Children with stunted growth (height-for age <-2SD of references) aged 9-24 months were enrolled in a two-year randomised-controlled trial of nutritional supplementation and/or stimulation. At mean age 31.79 (SD 0.40) years, 95 of 127 participants (74.8%; 53.7% male) were assessed. Children without stunted growth were also followed as a comparison group (64 of 84 participants, 76.2%). Measurements included IQ, executive function, mental health, psychosocial skills, personality traits and risk behaviours. A block permutation test, valid for small sample sizes, was used. Analyses accounted for the randomisation protocol, multiple hypothesis testing and attrition.

Results: Treatment group participants (stimulation intervention with or without supplementation, n = 48) had significantly greater IQ (Hedges g effect size 0. 57; 95%CI 0.20, 0.95) and cognitive flexibility (0.61; 0.25, 0.98) compared with no-treatment (no-intervention and supplementation only, n = 47). They also had reduced depressive symptoms (0.61; 0.28, 1.00), increased grit (0.53; 0.16, 0.92) and conscientiousness (0.66; 0.31, 1.07), lower substance use (rank mean score, 0.45; 0.08, 0.81) and risk taking related to health and work (0.64; 0.27, 1.00). There were 18 significant outcomes of 33 assessed. Comparison participants had higher IQ than no-treatment (1.17; 0.81, 1.54) and treatment groups (0.62; 0.18, 1.07); and better executive function, lower social inhibition and risk taking than the no-treatment group.

Conclusions: The wide-ranging benefits at 31 years from the stimulation intervention supports investment in larger scale programmes to promote early childhood development in disadvantaged children. The lower IQ in the treatment group compared with comparison participants, emphasises the need for continued efforts to prevent early childhood growth retardation.
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http://dx.doi.org/10.1111/jcpp.13499DOI Listing
August 2021

Physical activity and disordered eating behaviours: Are Caribbean adolescents at risk?

Int J Psychol 2021 Aug 16. Epub 2021 Aug 16.

Caribbean Institute for Health Research, The University of the West Indies, Mona, Jamaica.

Excessive physical activity (PA) has been linked to increased risk for disordered eating behaviours and eating disorders. This study investigates the relationship between PA and disordered eating behaviours and attitudes (DEBAs) among Jamaican adolescents. This cross-sectional study included 521 adolescents, 12-19 years. Anthropometric measurements were collected, and adolescents completed questionnaires on disordered eating behaviours (EAT-26), physical activity, self-esteem and affect. Associations were assessed using sex-specific mixed-effect linear and logistic regression models. Participants reported exercising an average of 3 days per week. Adolescents who exercised for a longer duration had greater odds of having elevated EAT-26 scores (at least 1 hour-OR = 2.04; 95% CI = 1.03, 4.06; p = .042), while a higher exercise frequency among males (3-5 days per week) was protective against DEBAs (OR 0.38; 95% CI = 0.16, 0.88; p = .025). Female adolescents reported higher prevalence of elevated EAT-26 scores than males (p < .01). Increased negative affect increased odds of an elevated EAT-26 score. Exercise duration and frequency play a role in disordered eating behaviours in Jamaican adolescents and vary by gender. Our findings have implications for weight management interventions and policies, encouraging healthcare providers to monitor PA levels as well as negative affect in adolescents who display disordered eating behaviours.
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http://dx.doi.org/10.1002/ijop.12802DOI Listing
August 2021

Systematic review on the use of patient-reported outcome measures in brain tumor studies: part of the Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) initiative.

Neurooncol Pract 2021 Aug 13;8(4):417-425. Epub 2021 Feb 13.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: The Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.

Methods: A systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living [(I)ADL] or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.

Results: A total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORTC QLQ-C30 and QLQ-BN20 (n = 286 and n = 247), and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).

Conclusion: Many different PRO measures assessing symptoms, (I)ADL or HRQoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their scales/items exhibit good content validity and other measurement properties for use in brain tumor patients.
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http://dx.doi.org/10.1093/nop/npab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278354PMC
August 2021

Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.

J Immunother Cancer 2021 07;9(7)

Duke Cancer Institute, Duke University, Durham, North Carolina, USA

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
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http://dx.doi.org/10.1136/jitc-2021-002459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256733PMC
July 2021

Denoising of hyperpolarized C MR images of the human brain using patch-based higher-order singular value decomposition.

Magn Reson Med 2021 11 25;86(5):2497-2511. Epub 2021 Jun 25.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.

Purpose: To improve hyperpolarized C (HP- C) MRI by image denoising with a new approach, patch-based higher-order singular value decomposition (HOSVD).

Methods: The benefit of using a patch-based HOSVD method to denoise dynamic HP- C MR imaging data was investigated. Image quality and the accuracy of quantitative analyses following denoising were evaluated first using simulated data of [1- C]pyruvate and its metabolic product, [1- C]lactate, and compared the results to a global HOSVD method. The patch-based HOSVD method was then applied to healthy volunteer HP [1- C]pyruvate EPI studies. Voxel-wise kinetic modeling was performed on both non-denoised and denoised data to compare the number of voxels quantifiable based on SNR criteria and fitting error.

Results: Simulation results demonstrated an 8-fold increase in the calculated SNR of [1- C]pyruvate and [1- C]lactate with the patch-based HOSVD denoising. The voxel-wise quantification of k (pyruvate-to-lactate conversion rate) showed a 9-fold decrease in standard errors for the fitted k after denoising. The patch-based denoising performed superior to the global denoising in recovering k information. In volunteer data sets, [1- C]lactate and [ C]bicarbonate signals became distinguishable from noise across captured time points with over a 5-fold apparent SNR gain. This resulted in >3-fold increase in the number of voxels quantifiable for mapping k (pyruvate-to-bicarbonate conversion rate) and whole brain coverage for mapping k .

Conclusions: Sensitivity enhancement provided by this denoising significantly improved quantification of metabolite dynamics and could benefit future studies by improving image quality, enabling higher spatial resolution, and facilitating the extraction of metabolic information for clinical research.
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http://dx.doi.org/10.1002/mrm.28887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530853PMC
November 2021

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

J Neurooncol 2021 Jul 14;153(3):447-454. Epub 2021 Jun 14.

Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, CA, USA.

Introduction: Anaplastic 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.

Methods: We performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years.

Results: 159 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.

Conclusions: Initial 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.
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http://dx.doi.org/10.1007/s11060-021-03781-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279971PMC
July 2021

Maternal characteristics influence infant feeding styles in Caribbean women.

Public Health Nutr 2021 Dec 28;24(18):6034-6045. Epub 2021 May 28.

Caribbean Institute for Health Research, The University of the West Indies, Kingston 7, Jamaica.

Objective: To examine associations between maternal characteristics and feeding styles in Caribbean mothers.

Design: Participants were mother-child pairs enrolled in a cluster randomised trial of a parenting intervention in three Caribbean islands. Maternal characteristics were obtained by questionnaires when infants were 6-8 weeks old. Items adapted from the Toddler Feeding Behaviour Questionnaire were used to assess infant feeding styles at the age of 1 year. Feeding styles were identified using factor analysis and associations with maternal characteristics assessed using multilevel linear regression.

Setting: Health clinics in St. Lucia (n 9), Antigua (n 10) and Jamaica (n 20).

Participants: A total of 405 mother-child pairs from the larger trial.

Results: Maternal depressive symptoms were associated with uninvolved (β = 0·38, 95 % CI (0·14, 0·62)), restrictive (β = 0·44, 95 % CI (0·19, 0·69)) and forceful (β = 0·31, 95 % CI (0·06, 0·57)) feeding and inversely associated with responsive feeding (β = -0·30, 95 % CI (-0·56, -0·05)). Maternal vocabulary was inversely associated with uninvolved (β = -0·31, 95 % CI (-0·57, -0·06)), restrictive (β = -0·30, 95 % CI (-0·56, -0·04)), indulgent (β = -0·47, 95 % CI (-0·73, -0·21)) and forceful (β = -0·54, 95 % CI (-0·81, -0·28)) feeding. Indulgent feeding was negatively associated with socio-economic status (β = -0·27, 95 % CI (-0·53, -0·00)) and was lower among mothers ≥35 years (β = -0·32, 95 % CI (-0·62, -0·02)). Breast-feeding at 1 year was associated with forceful feeding (β = 0·41, 95 % CI (0·21, 0·61)). No significant associations were found between maternal education, BMI, occupation and feeding styles.

Conclusion: Services to identify and assist mothers with depressive symptoms may benefit infant feeding style. Interventions to promote responsive feeding may be important for less educated, younger and socio-economically disadvantaged mothers.
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http://dx.doi.org/10.1017/S1368980021002391DOI Listing
December 2021

The state of neuro-oncology during the COVID-19 pandemic: a worldwide assessment.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab035. Epub 2021 Feb 20.

Departments of Medicine and Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

Background: It remains unknown how the COVID-19 pandemic has changed neuro-oncology clinical practice, training, and research efforts.

Methods: We performed an international survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents, April 24-May 17, 2020. We assessed clinical practice and research environments, institutional preparedness and support, and perceived impact on patients.

Results: Of 582 respondents, 258 (45%) were US-based and 314 (55%) international. Ninety-four percent of participants reported changes in their clinical practice. Ninety-five percent of respondents converted at least some practice to telemedicine. Ten percent of practitioners felt the need to see patients in person, specifically because of billing concerns and pressure from their institutions. Sixty-seven percent of practitioners suspended enrollment for at least one clinical trial, including 62% suspending phase III trial enrollments. More than 50% believed neuro-oncology patients were at increased risk for COVID-19. Seventy-one percent of clinicians feared for their own personal safety or that of their families, specifically because of their clinical duties; 20% had inadequate personal protective equipment. While 69% reported increased stress, 44% received no psychosocial support from their institutions. Thirty-seven percent had salary reductions and 63% of researchers temporarily closed their laboratories. However, the pandemic created positive changes in perceived patient satisfaction, communication quality, and technology use to deliver care and mediate interactions with other practitioners.

Conclusions: The pandemic has changed treatment schedules and limited investigational treatment options. Institutional lack of support created clinician and researcher anxiety. Communication with patients was satisfactory. We make recommendations to guide clinical and scientific infrastructure moving forward and address the personal challenges of providers and researchers.
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http://dx.doi.org/10.1093/noajnl/vdab035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928618PMC
February 2021

Loneliness and symptom burden in oncology patients during the COVID-19 pandemic.

Cancer 2021 09 27;127(17):3246-3253. Epub 2021 Apr 27.

School of Medicine, University of California, San Francisco, California.

Background: Loneliness and social isolation are significant public health problems that are being exacerbated during the coronavirus disease 2019 pandemic. Little is known about the associations between loneliness and symptom burden in oncology patients before and during the pandemic. Study purposes include determining the prevalence of loneliness in a sample of oncology patients; evaluating for differences in demographic, clinical, and symptom characteristics between lonely and nonlonely patients; and determining which demographic, clinical, and symptom characteristics were associated with membership in the lonely group.

Methods: A convenience sample (n = 606) completed online surveys that evaluated the severity of loneliness, social isolation, and common symptoms (ie, anxiety, depression, fatigue, sleep disturbance, cognitive dysfunction, and pain) in oncology patients. Parametric and nonparametric tests were used to evaluate for differences in scores between the lonely and nonlonely groups. Logistic regression analysis was used to determine risk factors for membership in the loneliness group.

Results: Of the 606 patients, 53.0% were categorized in the lonely group. The lonely group reported higher levels of social isolation, as well as higher symptom severity scores for all of the symptoms evaluated. In the multivariate model, being unmarried, having higher levels of social isolation, as well as higher levels of anxiety and depressive symptoms were associated with membership in the lonely group.

Conclusions: Study findings suggest that a significant number of oncology patients are experiencing loneliness, most likely as a result of mandate social distancing and isolation procedures. The symptom burden of these patients is extremely high and warrants clinical evaluation and interventions.
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http://dx.doi.org/10.1002/cncr.33603DOI Listing
September 2021

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

Neuro Oncol 2021 11;23(11):1872-1884

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Background: Chemotherapy 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.

Methods: We 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.

Results: Hypermutation 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.

Conclusions: TMZ-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.
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http://dx.doi.org/10.1093/neuonc/noab081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563321PMC
November 2021

Report of National Brain Tumor Society roundtable workshop on innovating brain tumor clinical trials: building on lessons learned from COVID-19 experience.

Neuro Oncol 2021 08;23(8):1252-1260

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

On July 24, 2020, a workshop sponsored by the National Brain Tumor Society was held on innovating brain tumor clinical trials based on lessons learned from the COVID-19 experience. Various stakeholders from the brain tumor community participated including the US Food and Drug Administration (FDA), academic and community clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and representatives from the Society for Neuro-Oncology and the National Cancer Institute. This report summarizes the workshop and proposes ways to incorporate lessons learned from COVID-19 to brain tumor clinical trials including the increased use of telemedicine and decentralized trial models as opportunities for practical innovation with potential long-term impact on clinical trial design and implementation.
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http://dx.doi.org/10.1093/neuonc/noab082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083574PMC
August 2021

Are Benefits From a Parenting Intervention Delivered Through the Health Services Sustainable? Follow-Up of a Randomized Evaluation in Jamaica.

Acad Pediatr 2021 May-Jun;21(4):638-645. Epub 2021 Jan 9.

Caribbean Institute for Health Research, The University of the West Indies (JA Smith, SM Chang, and SP Walker), Kingston, Jamaica.

Objective: An innovative low-cost parenting intervention, implemented through health services in Jamaica showed benefits to children's cognitive development at 18 months and parent's attitudes concerning childcare. We assessed the impact of the intervention on child and parent outcomes at 6 years of age.

Methods: A cluster randomized trial of 2 parenting interventions was conducted through 20 health centers in Jamaica. Interventions were implemented from age 3 to 18 months and each intervention benefited cognitive development at 18 months (effect size 0.34-0.38 standard deviation). Children were reassessed at 6 years (n = 262, 80.1% of those assessed at 18 months) to determine any benefits to cognition, behavior, and parenting behavior. Loss to follow-up was not significantly different by treatment. Inverse probability weighting and Lee bounds were used to adjust for loss to follow-up, and multilevel regression analyses conducted with random effects at the health center level.

Results: There were no significant benefits to any child outcomes at age 6 years or to parenting behavior. Results are robust using the wild cluster bootstrap procedure and using Lee bounds for attrition. The initial trial benefits were reproduced with the current sample and methods.

Conclusion: Lack of sustained benefits may be related to the initial effect size and low intensity of the intervention that ended very young at age 18 months. It may also be related to lack of initial impact on home environment and fade-out of effects in a country with near universal preschool. The findings have implications for intervention design and targeting.
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http://dx.doi.org/10.1016/j.acap.2021.01.003DOI Listing
July 2021

Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa142. Epub 2020 Oct 22.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Background: "Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited.

Methods: Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis.

Results: Median patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus ( = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the gene and an absence of mutations in , which are present in approximately one-third of pediatric DMGs. Accompanying mutations in , , , , and were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults.

Conclusions: Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.
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http://dx.doi.org/10.1093/noajnl/vdaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739048PMC
October 2020

Continuing to raise awareness of current practice and research opportunities in neuro-oncology.

Authors:
Susan M Chang

Neurooncol Pract 2020 Dec 4;7(6):581-582. Epub 2020 Dec 4.

University of California at San Francisco Department of Neurological Surgery, San Francisco, CA, United States.

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http://dx.doi.org/10.1093/nop/npaa070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716179PMC
December 2020

Proceedings of the Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) Oligodendroglioma Workshop.

Neurooncol Adv 2020 Jan-Dec;2(1):vdz048. Epub 2019 Dec 6.

Neuro-Oncology Branch/National Cancer Institute, Bethesda, Maryland.

Background: Oligodendroglioma is a rare primary central nervous system (CNS) tumor with highly variable outcome and for which therapy is usually not curative. At present, little is known regarding the pathways involved with progression of oligodendrogliomas or optimal biomarkers for stratifying risk. Developing new therapies for this rare cancer is especially challenging. To overcome these challenges, the neuro-oncology community must be particularly innovative, seeking multi-institutional and international collaborations, and establishing partnerships with patients and advocacy groups thereby ensuring that each patient enrolled in a study is as informative as possible.

Methods: The mission of the National Cancer Institute's NCI-CONNECT program is to address the challenges and unmet needs in rare CNS cancer research and treatment by connecting patients, health care providers, researchers, and advocacy organizations to work in partnership. On November 19, 2018, the program convened a workshop on oligodendroglioma, one of the 12 rare CNS cancers included in its initial portfolio. The purpose of this workshop was to discuss scientific progress and regulatory challenges in oligodendroglioma research and develop a call to action to advance research and treatment for this cancer.

Results: The recommendations of the workshop include a multifaceted and interrelated approach covering: biology and preclinical models, data sharing and advanced molecular diagnosis and imaging; clinical trial design; and patient outreach and engagement.

Conclusions: The NCI-CONNECT program is well positioned to address challenges in oligodendroglioma care and research in collaboration with other stakeholders and is developing a list of action items for future initiatives.
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http://dx.doi.org/10.1093/noajnl/vdz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212866PMC
December 2019

Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a 3-arm sequential accrual clinical trial: NABTC 05-02.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa124. Epub 2020 Sep 17.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs.

Methods: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6).

Results: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated.

Conclusion: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.
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http://dx.doi.org/10.1093/noajnl/vdaa124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668489PMC
September 2020

Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.

Brain Pathol 2021 07 28;31(4):e12918. Epub 2021 Jan 28.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.
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http://dx.doi.org/10.1111/bpa.12918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089120PMC
July 2021

Patient-derived cells from recurrent tumors that model the evolution of -mutant glioma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa088. Epub 2020 Jul 16.

Department of Neurological Surgery, University of California, San Francisco, California, USA.

Background: mutant lower-grade gliomas (LGGs) evolve under the selective pressure of therapy, but well-characterized patient-derived cells (PDCs) modeling evolutionary stages are lacking. -mutant LGGs may develop therapeutic resistance associated with chemotherapy-driven hypermutation and malignant progression. The aim of this study was to establish and characterize PDCs, single-cell-derived PDCs (scPDCs), and xenografts (PDX) of -mutant recurrences representing distinct stages of tumor evolution.

Methods: We derived and validated cell cultures from mutant recurrences of astrocytoma and oligodendroglioma. We used exome sequencing and phylogenetic reconstruction to examine the evolutionary stage represented by PDCs, scPDCs, and PDX relative to corresponding spatiotemporal tumor tissue and germline DNA. PDCs were also characterized for growth and tumor immortality phenotypes, and PDX were examined histologically.

Results: The integrated astrocytoma phylogeny revealed 2 independent founder clonal expansions of hypermutated (HM) cells in tumor tissue that are faithfully represented by independent PDCs. The oligodendroglioma phylogeny showed more than 4000 temozolomide-associated mutations shared among tumor samples, PDCs, scPDCs, and PDX, suggesting a shared monoclonal origin. The PDCs from both subtypes exhibited hallmarks of tumorigenesis, retention of subtype-defining genomic features, production of 2-hydroxyglutarate, and subtype-specific telomere maintenance mechanisms that confer tumor cell immortality. The oligodendroglioma PDCs formed infiltrative intracranial tumors with characteristic histology.

Conclusions: These PDCs, scPDCs, and PDX are unique and versatile community resources that model the heterogeneous clonal origins and functions of recurrent -mutant LGGs. The integrated phylogenies advance our knowledge of the complex evolution and immense mutational load of -mutant HM glioma.
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http://dx.doi.org/10.1093/noajnl/vdaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462278PMC
July 2020

The immunohistochemical, DNA methylation, and chromosomal copy number profile of cauda equina paraganglioma is distinct from extra-spinal paraganglioma.

Acta Neuropathol 2020 12 6;140(6):907-917. Epub 2020 Sep 6.

Division of Neuropathology, Department of Pathology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA.

Paragangliomas are neuroendocrine tumors of the autonomic nervous system that are variably clinically functional and have a potential for metastasis. Up to 40% occur in the setting of a hereditary syndrome, most commonly due to germline mutations in succinate dehydrogenase (SDHx) genes. Immunohistochemically, paragangliomas are characteristically GATA3-positive and cytokeratin-negative, with loss of SDHB expression in most hereditary cases. In contrast, the rare paragangliomas arising in the cauda equina (CEP) or filum terminale region have been shown to be hormonally silent, clinically indolent, and have variable keratin expression, suggesting these tumors may represent a separate pathologic entity. We retrospectively evaluated 17 CEPs from 11 male and 6 female patients with a median age of 38 years (range 21-82), none with a family history of neuroendocrine neoplasia. Six of the 17 tumors demonstrated prominent gangliocytic or ganglioneuromatous differentiation. By immunohistochemistry, none of the CEPs showed GATA3 positivity or loss of SDHB staining; all 17 CEPs were cytokeratin positive. Genome-wide DNA methylation profiling was performed on 12 of the tumors and compared with publicly available genome-wide DNA methylation data. Clustering analysis showed that CEPs form a distinct epigenetic group, separate from paragangliomas of extraspinal sites, pheochromocytomas, and other neuroendocrine neoplasms. Copy number analysis revealed diploid genomes in the vast majority of CEPs, whereas extraspinal paragangliomas were mostly aneuploid with recurrent trisomy 1q and monosomies of 1p, 3, and 11, none of which were present in the cohort of CEP. Together, these findings indicate that CEPs likely represent a distinct entity. Future genomic studies are needed to further elucidate the molecular pathogenesis of these tumors.
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http://dx.doi.org/10.1007/s00401-020-02221-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682537PMC
December 2020

Simultaneous multi-slice spin- and gradient-echo dynamic susceptibility-contrast perfusion-weighted MRI of gliomas.

NMR Biomed 2021 01 25;34(1):e4399. Epub 2020 Aug 25.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

Although combined spin- and gradient-echo (SAGE) dynamic susceptibility-contrast (DSC) MRI can provide perfusion quantification that is sensitive to both macrovessels and microvessels while correcting for T -shortening effects, spatial coverage is often limited in order to maintain a high temporal resolution for DSC quantification. In this work, we combined a SAGE echo-planar imaging (EPI) sequence with simultaneous multi-slice (SMS) excitation and blipped controlled aliasing in parallel imaging (blipped CAIPI) at 3 T to achieve both high temporal resolution and whole brain coverage. Two protocols using this sequence with multi-band (MB) acceleration factors of 2 and 3 were evaluated in 20 patients with treated gliomas to determine the optimal scan parameters for clinical use. ΔR *(t) and ΔR (t) curves were derived to calculate dynamic signal-to-noise ratio (dSNR), ΔR *- and ΔR -based relative cerebral blood volume (rCBV), and mean vessel diameter (mVD) for each voxel. The resulting SAGE DSC images acquired using MB acceleration of 3 versus 2 appeared visually similar in terms of image distortion and contrast. The difference in the mean dSNR from normal-appearing white matter (NAWM) and that in the mean dSNR between NAWM and normal-appearing gray matter were not statistically significant between the two protocols. ΔR *- and ΔR -rCBV maps and mVD maps provided unique contrast and spatial heterogeneity within tumors.
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http://dx.doi.org/10.1002/nbm.4399DOI Listing
January 2021

Characterization of serial hyperpolarized C metabolic imaging in patients with glioma.

Neuroimage Clin 2020 24;27:102323. Epub 2020 Jun 24.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, USA. Electronic address:

Background: Hyperpolarized carbon-13 (HP-C) MRI is a non-invasive imaging technique for probing brain metabolism, which may improve clinical cancer surveillance. This work aimed to characterize the consistency of serial HP-C imaging in patients undergoing treatment for brain tumors and determine whether there is evidence of aberrant metabolism in the tumor lesion compared to normal-appearing tissue.

Methods: Serial dynamic HP [1-C]pyruvate MRI was performed on 3 healthy volunteers (6 total examinations) and 5 patients (21 total examinations) with diffuse infiltrating glioma during their course of treatment, using a frequency-selective echo-planar imaging (EPI) sequence. HP-C imaging at routine clinical timepoints overlapped treatment, including radiotherapy (RT), temozolomide (TMZ) chemotherapy, and anti-angiogenic/investigational agents. Apparent rate constants for [1-C]pyruvate conversion to [1-C]lactate (k) and [C]bicarbonate (k) were simultaneously quantified based on an inputless kinetic model within normal-appearing white matter (NAWM) and anatomic lesions defined from H MRI. The inter/intra-subject consistency of k and k was measured in terms of the coefficient of variation (CV).

Results: When excluding scans following anti-angiogenic therapy, patient values of k and k were 0.020 s ± 23.8% and 0.0058 s ± 27.7% (mean ± CV) across 17 HP-C MRIs, with intra-patient serial k/k CVs ranging 6.8-16.6%/10.6-40.7%. In 4/5 patients, these values (0.018 s ± 13.4% and 0.0058 s ± 24.4%; n = 13) were more similar to those from healthy volunteers (0.018 s ± 5.0% and 0.0043 s ± 12.6%; n = 6) (mean ± CV). The anti-angiogenic agent bevacizumab was associated with global elevations in apparent rate constants, with maximum k in 2 patients reaching 0.047 ± 0.001 and 0.047 ± 0.003 s (±model error). In 3 patients with progressive disease, anatomic lesions showed elevated k relative to k of 0.024 ± 0.001 s (±model error) in the absence of gadolinium enhancement, and 0.032 ± 0.008, 0.040 ± 0.003 and 0.041 ± 0.009 s with gadolinium enhancement. The lesion k in patients was reduced to unquantifiable values compared to k.

Conclusion: Serial measures of HP [1-C]pyruvate metabolism displayed consistency in the NAWM of healthy volunteers and patients. Both k and k were globally elevated following bevacizumab treatment, while progressive disease demonstrated elevated k in gadolinium-enhancing and non-enhancing lesions. Larger prospective studies with homogeneous patient populations are planned to evaluate metabolic changes following treatment.
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http://dx.doi.org/10.1016/j.nicl.2020.102323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334458PMC
June 2021
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