Publications by authors named "Annette M Molinaro"

135 Publications

External Controls to Improve on Glioblastoma Clinical Trials.

Neuro Oncol 2021 Oct 29. Epub 2021 Oct 29.

Department of Neurological Surgery, UCSF, San Francisco CA.

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http://dx.doi.org/10.1093/neuonc/noab251DOI Listing
October 2021

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

Interactions of Age and Blood Immune Factors and Non-Invasive Prediction of Glioma Survival.

J Natl Cancer Inst 2021 Oct 1. Epub 2021 Oct 1.

Department of Neurological Surgery, UCSF, San Francisco, CA, USA.

Background: Tumor-based classification of human glioma portends patient prognosis; however, 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.

Methods: We evaluated immune-cell fractions and epigenetic age in archived blood from the University of California San Francisco Adult Glioma Study, including a training set of 197 IDH-wildtype, 1p19q intact, TERT wildtype (IDH/1p19q/TERT-WT) glioma patients, an evaluation set of 350 patients with other subtypes of glioma, and 454 subjects without glioma.

Results: IDH/1p19q/TERT-WT patients had lower lymphocyte fractions (CD4+T, CD8+T, natural killer, and B cells) and higher neutrophil fractions than subjects without glioma. Recursive partitioning analysis delineated four statistically significantly different survival groups for IDH/1p19q/TERT-WT patients based on an interaction between chronological age and two blood immune factors, CD4+T cells, and neutrophils with median overall survival ranging from 0.76 years [95% confidence intervaI = 0.55 to 0.99] for the worst survival group (n = 28) to 9.72 years [95% confidence intervaI = 6.18 to NA] for the best (n = 33). The Recursive partitioning analysis also statistically significantly delineated four risk groups in patients with other glioma subtypes.

Conclusion: The 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 impact survival. The ability of DNA methylation-based markers of immune status to capture diverse, clinically relevant information may facilitate non-invasive personalized patient evaluation in the neuro-oncology clinic.
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http://dx.doi.org/10.1093/jnci/djab195DOI Listing
October 2021

Correlation of natural language assessment results with health-related quality of life in adult glioma patients.

J Neurosurg 2021 Jul 30:1-7. Epub 2021 Jul 30.

1Department of Neurological Surgery and.

Objective: Impairments of speech are common in patients with glioma and negatively impact health-related quality of life (HRQoL). The benchmark for clinical assessments is task-based measures, which are not always feasible to administer and may miss essential components of HRQoL. In this study, the authors tested the hypothesis that variations in natural language (NL) correlate with HRQoL in a pattern distinct from task-based measures of language performance.

Methods: NL use was assessed using audio samples collected unobtrusively from 18 patients with newly diagnosed low- and high-grade glioma. NL measures were calculated using manual segmentation and correlated with Quality of Life in Neurological Disorders (Neuro-QoL) outcomes. Spearman's rank-order correlation was used to determine relationships between Neuro-QoL scores and NL measures.

Results: The distribution of NL measures across the entire patient cohort included a mean ± SD total time speaking of 11.5 ± 2.20 seconds, total number of words of 27.2 ± 4.44, number of function words of 10.9 ± 1.68, number of content words of 16.3 ± 2.91, and speech rate of 2.61 ± 0.20 words/second. Speech rate was negatively correlated with functional domains (rho = -0.62 and p = 0.007 for satisfaction with social roles; rho = -0.74 and p < 0.001 for participation in social roles) but positively correlated with impairment domains (rho = 0.58 and p = 0.009 for fatigue) of Neuro-QoL.

Conclusions: Assessment of NL at the time of diagnosis may be a useful measure in the context of treatment planning and monitoring outcomes for adult patients with glioma.
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http://dx.doi.org/10.3171/2021.1.JNS203387DOI Listing
July 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

Detection of glioma infiltration at the tumor margin using quantitative stimulated Raman scattering histology.

Sci Rep 2021 06 9;11(1):12162. Epub 2021 Jun 9.

Department of Neurological Surgery, University of California, 505 Parnassus Ave., Rm. M-779, San Francisco, CA, 94143-0112, USA.

In the management of diffuse gliomas, the identification and removal of tumor at the infiltrative margin remains a central challenge. Prior work has demonstrated that fluorescence labeling tools and radiographic imaging are useful surgical adjuvants with macroscopic resolution. However, they lose sensitivity at the tumor margin and have limited clinical utility for lower grade histologies. Fiber-laser based stimulated Raman histology (SRH) is an optical imaging technique that provides microscopic tissue characterization of unprocessed tissues. It remains unknown whether SRH of tissues taken from the infiltrative glioma margin will identify microscopic residual disease. Here we acquired glioma margin specimens for SRH, histology, and tumor specific tissue characterization. Generalized linear mixed models were used to evaluate agreement. We find that SRH identified residual tumor in 82 of 167 margin specimens (49%), compared to IHC confirming residual tumor in 72 of 128 samples (56%), and H&E confirming residual tumor in 82 of 169 samples (49%). Intraobserver agreements between all 3 modalities were confirmed. These data demonstrate that SRH detects residual microscopic tumor at the infiltrative glioma margin and may be a promising tool to enhance extent of resection.
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http://dx.doi.org/10.1038/s41598-021-91648-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190264PMC
June 2021

Relationship between 7T MR-angiography features of vascular injury and cognitive decline in young brain tumor patients treated with radiation therapy.

J Neurooncol 2021 May 24;153(1):143-152. Epub 2021 Apr 24.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, Byers Hall, 1700 4th Street, Suite 303D, Box 2532, San Francisco, CA, 94158-2330, USA.

Purpose: Although radiation therapy (RT) is a common treatment for pediatric brain tumors, it is associated with detrimental long-term effects such as impaired cognition, vascular injury, and increased stroke risk. This study aimed to develop metrics that describe vascular injury and relate them to the presence of cerebral microbleeds (CMBs) and cognitive performance scores.

Methods: Twenty-five young adult survivors of pediatric brain tumors treated with either whole-brain (n = 12), whole-ventricular (n = 7), or no RT (n = 6) underwent 7T MRI and neurocognitive testing. Simultaneously acquired MR angiography and susceptibility-weighted images were used to segment CMBs and vessels and quantify their radii and volume.

Results: Patients treated with whole-brain RT had significantly lower arterial volumes (p = 0.003) and a higher proportion of smaller vessels (p = 0.003) compared to the whole-ventricular RT and non-irradiated control patients. Normalized arterial volume decreased with increasing CMB count (R = - 0.66, p = 0.003), and decreasing trends were observed with time since RT and at longitudinal follow-up. Global cognition and verbal memory significantly decreased with smaller normalized arterial volume (p ≤ 0.05).

Conclusions: Arterial volume is reduced with increasing CMB presence and is influenced by the total brain volume exposed to radiation. This work highlights the potential use of vascular-derived metrics as non-invasive markers of treatment-induced injury and cognitive impairment in pediatric brain tumor patients.
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http://dx.doi.org/10.1007/s11060-021-03753-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172069PMC
May 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

Identification of a foetal epigenetic compartment in adult human kidney.

Epigenetics 2021 Mar 30:1-21. Epub 2021 Mar 30.

Department of Epidemiology, Department of Pathology and Laboratory Medicine, Brown University School of Public Health, Providence, RI, USA.

The mammalian kidney has extensive repair capacity; however, identifying adult renal stem cells has proven elusive. We applied an epigenetic marker of foetal cell origin (FCO) in diverse human tissues as a probe for developmental cell persistence, finding a 5.4-fold greater FCO proportion in kidney. Normal kidney FCO proportions averaged 49% with extensive interindividual variation. FCO proportions were significantly negatively correlated with immune-related gene expression and positively correlated with genes expressed in the renal medulla, including those involved in renal organogenesis (e.g., . FCO associated genes also mapped to medullary nephron segments in mouse and rat, suggesting evolutionary conservation of this cellular compartment. Renal cancer patients whose tumours contained non-zero FCO scores survived longer. The kidney appears unique in possessing substantial foetal epigenetic features. Further study of FCO-related gene methylation may elucidate regenerative regulatory programmes in tissues without apparent discrete stem cell compartments.
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http://dx.doi.org/10.1080/15592294.2021.1900027DOI Listing
March 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

The Relationship Between Stimulation Current and Functional Site Localization During Brain Mapping.

Neurosurgery 2021 05;88(6):1043-1050

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

Background: Gliomas are often in close proximity to functional regions of the brain; therefore, electrocortical stimulation (ECS) mapping is a common technique utilized during glioma resection to identify functional areas. Stimulation-induced seizure (SIS) remains the most common reason for aborted procedures. Few studies have focused on oncological factors impacting cortical stimulation thresholds.

Objective: To examine oncological factors thought to impact stimulation threshold in order to understand whether a linear relationship exists between stimulation current and number of functional cortical sites identified.

Methods: We retrospectively reviewed single-institution prospectively collected brain mapping data of patients with dominant hemisphere gliomas. Comparisons of stimulation threshold were made using t-tests and ANOVAs. Associations between oncologic factors and stimulation threshold were made using multivariate regressions. The association between stimulation current and number of positive sites was made using a Poisson model.

Results: Of the 586 patients included in the study, SIS occurred in 3.92% and the rate of SIS events differed by cortical location (frontal 8.5%, insular 1.6%, parietal 1.3%, and temporal 2.8%; P = .009). Stimulation current was lower when mapping frontal cortex (P = .002). Stimulation current was not associated with tumor plus peritumor edema volume, world health organization) (WHO grade, histology, or isocitrate dehydrogenase (IDH) mutation status but was associated with tumor volume within the frontal lobe (P = .018). Stimulation current was not associated with number of positive sites identified during ECS mapping (P = .118).

Conclusion: SISs are rare but serious events during ECS mapping. SISs are most common when mapping the frontal lobe. Greater stimulation current is not associated with the identification of more cortical functional sites during glioma surgery.
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http://dx.doi.org/10.1093/neuros/nyaa364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117445PMC
May 2021

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

Clin Cancer Res 2021 02 16;27(4):1048-1057. Epub 2020 Nov 16.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: VEGF 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 Methods: Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, = 50) or pembrolizumab monotherapy (cohort B, = 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.

Results: Pembrolizumab 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 , unmethylated , and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.

Conclusions: Pembrolizumab 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284901PMC
February 2021

Consensus-based perioperative protocols during the COVID-19 pandemic.

J Neurosurg Spine 2020 Oct 2:1-9. Epub 2020 Oct 2.

Departments of1Neurological Surgery.

Objective: During the COVID-19 pandemic, quaternary-care facilities continue to provide care for patients in need of urgent and emergent invasive procedures. Perioperative protocols are needed to streamline care for these patients notwithstanding capacity and resource constraints.

Methods: A multidisciplinary panel was assembled at the University of California, San Francisco, with 26 leaders across 10 academic departments, including 7 department chairpersons, the chief medical officer, the chief operating officer, infection control officers, nursing leaders, and resident house staff champions. An epidemiologist, an ethicist, and a statistician were also consulted. A modified two-round, blinded Delphi method based on 18 agree/disagree statements was used to build consensus. Significant disagreement for each statement was tested using a one-sided exact binomial test against an expected outcome of 95% consensus using a significance threshold of p < 0.05. Final triage protocols were developed with unblinded group-level discussion.

Results: Overall, 15 of 18 statements achieved consensus in the first round of the Delphi method; the 3 statements with significant disagreement (p < 0.01) were modified and iteratively resubmitted to the expert panel to achieve consensus. Consensus-based protocols were developed using unblinded multidisciplinary panel discussions. The final algorithms 1) quantified outbreak level, 2) triaged patients based on acuity, 3) provided a checklist for urgent/emergent invasive procedures, and 4) created a novel scoring system for the allocation of personal protective equipment. In particular, the authors modified the American College of Surgeons three-tiered triage system to incorporate more urgent cases, as are often encountered in neurosurgery and spine surgery.

Conclusions: Urgent and emergent invasive procedures need to be performed during the COVID-19 pandemic. The consensus-based protocols in this study may assist healthcare providers to optimize perioperative care during the pandemic.
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http://dx.doi.org/10.3171/2020.6.SPINE20777DOI Listing
October 2020

Rate of radiation-induced microbleed formation on 7T MRI relates to cognitive impairment in young patients treated with radiation therapy for a brain tumor.

Radiother Oncol 2021 01 20;154:145-153. Epub 2020 Sep 20.

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

Background: Radiation therapy (RT) is essential to the management of many brain tumors, but has been known to lead to cognitive decline and vascular injury in the form of cerebral microbleeds (CMBs).

Purpose: In a subset of children, adolescents, and young adults recruited from a larger trial investigating arteriopathy and stroke risk after RT, we evaluated the prevalence of CMBs after RT, examined risk factors for CMBs and cognitive impairment, and related their longitudinal development to cognitive performance changes.

Methods: Twenty-five patients (mean 17 years, range: 10-25 years) underwent 7-Tesla MRI and cognitive assessment. Nineteen patients were treated with whole-brain or focal RT 1-month to 20-years prior, while 6 non-irradiated patients with posterior-fossa tumors served as controls. CMBs were detected on 7T susceptibility-weighted imaging (SWI) using semi-automated software, a first use in this population.

Results: CMB detection sensitivity with 7T SWI was higher than previously reported at lower field strengths, with one or more CMBs detected in 100% of patients treated with RT at least 1-year prior. CMBs were localized to dose-targeted brain volumes with risk factors including whole-brain RT (p = 0.05), a higher RT dose (p = 0.01), increasing time since RT (p = 0.03), and younger age during RT (p = 0.01). Apart from RT dose, these factors were associated with impaired memory performance. Follow-up data in a subset of patients revealed a proportional increase in CMB count with worsening verbal memory performance (r = -0.85, p = 0.03).

Conclusions: Treatment with RT during youth is associated with the chronic development of CMBs that evolve with memory impairment over time.
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http://dx.doi.org/10.1016/j.radonc.2020.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208731PMC
January 2021

Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma.

J Clin Invest 2020 12;130(12):6325-6337

Department of Neurosurgery and.

BACKGROUNDPatients with diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+, H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine.METHODSNewly diagnosed patients, aged 3-21 years, with HLA-A*02.01+ and H3.3K27M+ status were enrolled in stratum A (DIPG) or stratum B (nonpontine DMG). Vaccine was administered in combination with polyinosinic-polycytidylic acid-poly-I-lysine carboxymethylcellulose (poly-ICLC) every 3 weeks for 8 cycles, followed by once every 6 weeks. Immunomonitoring and imaging were performed every 3 months. Imaging was centrally reviewed. Immunological responses were assessed in PBMCs using mass cytometry.RESULTSA total of 19 patients were enrolled in stratum A (median age,11 years) and 10 in stratum B (median age, 13 years). There were no grade-4 treatment-related adverse events (TRAEs). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22%-73%) for patients in stratum A and 39% (95% CI, 16%-93%) for patients in stratum B. The median OS was 16.1 months for patients who had an expansion of H3.3K27M-reactive CD8+ T cells compared with 9.8 months for their counterparts (P = 0.05). Patients with DIPG with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared with their counterparts (P < 0.01). Immediate pretreatment dexamethasone administration was inversely associated with H3.3K27M-reactive CD8+ T cell responses.CONCLUSIONAdministration of the H3.3K27M-specific vaccine was well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared with nonresponders.TRIAL REGISTRATIONClinicalTrials.gov NCT02960230.FUNDINGThe V Foundation, the Pacific Pediatric Neuro-Oncology Consortium Foundation, the Pediatric Brain Tumor Foundation, the Mithil Prasad Foundation, the MCJ Amelior Foundation, the Anne and Jason Farber Foundation, Will Power Research Fund Inc., the Isabella Kerr Molina Foundation, the Parker Institute for Cancer Immunotherapy, and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R35NS105068).
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http://dx.doi.org/10.1172/JCI140378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685729PMC
December 2020

Phase I study of vemurafenib in children with recurrent or progressive BRAF mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002).

Oncotarget 2020 May 26;11(21):1942-1952. Epub 2020 May 26.

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

BRAF mutation is present in a subset of pediatric brain tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of BRAF kinase. The goal of this multi-center study conducted through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs) in children < 18 years with recurrent or progressive BRAF mutant brain tumors. Nineteen eligible patients were enrolled. Eleven patients had received three or more prior therapies. Data reported are from the start of treatment for the first patient (April 30 2014) through August 31 2019. The RP2D was defined as 550 mg/m twice daily after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events included secondary keratoacanthoma ( = 1); rash ( =16); and fever ( = 5). Subjects received a median of 23 cycles (range 3-63). Four patients remain on treatment. Centrally reviewed best radiographic responses included 1 complete response, 5 partial responses, and 13 stable disease. The steady-state area under the curve (AUCmedian) was 604 mg*h/L (range 329-1052). Vemurafenib was given starting at 550 mg/m, twice daily which corresponds to the adult RP2D. Adverse events were graded using the NIH Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Central imaging review was performed. Pharmacokinetic sampling was performed. Vemurafenib has promising anti-tumor activity in recurrent V600E-positive brain tumors with manageable toxicity. A phase 2 study is ongoing (NCT01748149).
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http://dx.doi.org/10.18632/oncotarget.27600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260122PMC
May 2020

Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C.

Neuro Oncol 2020 11;22(11):1602-1613

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype.

Methods: A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10-8.

Results: Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10-10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10-8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10-9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10-10).

Conclusions: Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.
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http://dx.doi.org/10.1093/neuonc/noaa117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690366PMC
November 2020

The influence of race and socioeconomic status on therapeutic clinical trial screening and enrollment.

J Neurooncol 2020 May 29;148(1):131-139. Epub 2020 Apr 29.

Department of Neurological Surgery, University of California, 505 Parnassus Ave., Rm. M-779, San Francisco, CA, 94143-0112, USA.

Purpose: Under-enrollment in clinical trials significantly limits valid analyses of clinical interventions and generalizability of findings. Often it results in premature study termination, with estimates of 22% to 50% of clinical trials terminated due to poor accrual. Currently, there are limited reports addressing the influence of race/ethnicity and socioeconomic status on clinical trial enrollment in adult glioma patients. The goal of this study was to test the hypothesis that race and socioeconomic status negatively impact therapeutic clinical trial enrollment.

Methods: 988 adult patients were identified from the UCSF Tumor Board Registry and analyzed to determine the rate of therapeutic clinical trial screening and study enrollment.

Results: At initial diagnosis, 43.6% and 17.5% of glioma patients were screened and enrolled in a therapeutic clinical trial, respectively. At recurrence, 49.8% and 26.3% of patients were screened and enrolled in a clinical trial, respectively. Thirty-three percent of the study population belonged to a NIH-designated underrepresented minority group; Asian/Pacific-Islander comprised 19.6% of the overall cohort. On univariate analysis, only in-state location, distance to the hospital, and WHO grade were associated with enrollment at initial diagnosis and recurrence. Minority status, insurance type, median household income, and percent below poverty were not associated with clinical trial enrollment.

Conclusion: Minority and socioeconomic status did not impact adult glioma clinical trial enrollment. Proximity to the tertiary care cancer center may be an important consideration for minority patients. Patient screening should be carefully considered in order to avoid bias based on minority and socioeconomic status.
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http://dx.doi.org/10.1007/s11060-020-03503-xDOI Listing
May 2020

The impact of obesity on perioperative complications in patients undergoing anterior lumbar interbody fusion.

J Neurosurg Spine 2020 Apr 24:1-10. Epub 2020 Apr 24.

1Department of Neurological Surgery, University of California, San Francisco.

Objective: Anterior approaches to the lumbar spine provide wide exposure that facilitates placement of large grafts with high fusion rates. There are limited data on the effects of obesity on perioperative complications.

Methods: Data from consecutive patients undergoing anterior lumbar interbody fusion (ALIF) from 2007 to 2016 at a single academic center were analyzed. The primary outcome was any perioperative complication. Complications were divided into those occurring intraoperatively and those occurring postoperatively. Multivariate logistic regression was used to assess the association of obesity and other variables with these complications. An estimation table was used to identify a body mass index (BMI) threshold associated with increased risk of postoperative complication.

Results: A total of 938 patients were identified, and the mean age was 57 years; 511 were females (54.5%). The mean BMI was 28.7 kg/m2, with 354 (37.7%) patients classified as obese (BMI ≥ 30 kg/m2). Forty patients (4.3%) underwent a lateral transthoracic approach, while the remaining 898 (95.7%) underwent a transabdominal retroperitoneal approach. Among patients undergoing transabdominal retroperitoneal ALIF, complication rates were higher for obese patients than for nonobese patients (37.0% vs 28.7%, p = 0.010), a difference that was driven primarily by postoperative complications (36.1% vs 26.0%, p = 0.001) rather than intraoperative complications (3.2% vs 4.3%, p = 0.416). Obese patients had higher rates of ileus (11.7% vs 7.2%, p = 0.020), wound complications (11.4% vs 3.4%, p < 0.001), and urinary tract infections (UTI) (5.0% vs 2.5%, p = 0.049). In a multivariate model, age, obesity, and number of ALIF levels fused were associated with an increased risk of postoperative complication. An estimation table including 19 candidate cut-points, odds ratios, and adjusted p values found a BMI ≥ 31 kg/m2 to have the highest association with postoperative complication (p = 0.012).

Conclusions: Obesity is associated with increased postoperative complications in ALIF, including ileus, wound complications, and UTI. ALIF is a safe and effective procedure. However, patients with a BMI ≥ 31 kg/m2 should be counseled on their increased risks and warrant careful preoperative medical optimization and close monitoring in the postoperative setting.
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http://dx.doi.org/10.3171/2020.2.SPINE191418DOI Listing
April 2020

Recurrent tumor and treatment-induced effects have different MR signatures in contrast enhancing and non-enhancing lesions of high-grade gliomas.

Neuro Oncol 2020 10;22(10):1516-1526

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

Background: Differentiating treatment-induced injury from recurrent high-grade glioma is an ongoing challenge in neuro-oncology, in part due to lesion heterogeneity. This study aimed to determine whether different MR features were relevant for distinguishing recurrent tumor from the effects of treatment in contrast-enhancing lesions (CEL) and non-enhancing lesions (NEL).

Methods: This prospective study analyzed 291 tissue samples (222 recurrent tumor, 69 treatment-effect) with known coordinates on imaging from 139 patients who underwent preoperative 3T MRI and surgery for a suspected recurrence. 8 MR parameter values were tested from perfusion-weighted, diffusion-weighted, and MR spectroscopic imaging at each tissue sample location for association with histopathological outcome using generalized estimating equation models for CEL and NEL tissue samples. Individual cutoff values were evaluated using receiver operating characteristic curve analysis with 5-fold cross-validation.

Results: In tissue samples obtained from CEL, elevated relative cerebral blood volume (rCBV) was associated with the presence of recurrent tumor pathology (P < 0.03), while increases in normalized choline (nCho) and choline-to-NAA index (CNI) were associated with the presence of recurrent tumor pathology in NEL tissue samples (P < 0.008). A mean CNI cutoff value of 2.7 had the highest performance, resulting in mean sensitivity and specificity of 0.61 and 0.81 for distinguishing treatment-effect from recurrent tumor within the NEL.

Conclusion: Although our results support prior work that underscores the utility of rCBV in distinguishing the effects of treatment from recurrent tumor within the contrast enhancing lesion, we found that metabolic parameters may be better at differentiating recurrent tumor from treatment-related changes in the NEL of high-grade gliomas.
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http://dx.doi.org/10.1093/neuonc/noaa094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566399PMC
October 2020

MGMT promoter methylation level in newly diagnosed low-grade glioma is a predictor of hypermutation at recurrence.

Neuro Oncol 2020 11;22(11):1580-1590

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

Background: Emerging data suggest that a subset of patients with diffuse isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG) who receive adjuvant temozolomide (TMZ) recur with hypermutation in association with malignant progression to higher-grade tumors. It is currently unclear why some TMZ-treated LGG patients recur with hypermutation while others do not. MGMT encodes O6-methylguanine-DNA methyltransferase, a DNA repair protein that removes cytotoxic and potentially mutagenic lesions induced by TMZ. Here, we hypothesize that epigenetic silencing of MGMT by promoter methylation facilitates TMZ-induced mutagenesis in LGG patients and contributes to development of hypermutation at recurrence.

Methods: We utilize a quantitative deep sequencing assay to characterize MGMT promoter methylation in 109 surgical tissue specimens from initial tumors and post-treatment recurrences of 37 TMZ-treated LGG patients. We utilize methylation arrays to validate our sequencing assay, RNA sequencing to assess the relationship between methylation and gene expression, and exome sequencing to determine hypermutation status.

Results: Methylation level at the MGMT promoter is significantly higher in initial tumors of patients that develop hypermutation at recurrence relative to initial tumors of patients that do not (45.7% vs 34.8%, P = 0.027). Methylation level in initial tumors can predict hypermutation at recurrence in univariate models and multivariate models that incorporate patient age and molecular subtype.

Conclusions: These findings reveal a mechanistic basis for observed differences in patient susceptibility to TMZ-driven hypermutation. Furthermore, they establish MGMT promoter methylation level as a potential biomarker to inform clinical management of LGG patients, including monitoring and treatment decisions, by predicting risk of hypermutation at recurrence.
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http://dx.doi.org/10.1093/neuonc/noaa059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444710PMC
November 2020

Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma.

JAMA Oncol 2020 04;6(4):495-503

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

Importance: Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non-contrast-enhanced (NCE) disease is poorly understood.

Objective: To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery.

Design, Setting, And Participants: This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019.

Main Outcomes And Measures: Overall survival.

Results: Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients with IDH-wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients with IDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients with IDH-wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients with IDH-wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients with IDH-wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase.

Conclusions And Relevance: This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless of IDH status, and among patients with IDH-wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma.
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http://dx.doi.org/10.1001/jamaoncol.2019.6143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042822PMC
April 2020

Longitudinal molecular trajectories of diffuse glioma in adults.

Nature 2019 12 20;576(7785):112-120. Epub 2019 Nov 20.

Fondazione IRCCS Istituto Neurologico Besta, Milano, Italy.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
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http://dx.doi.org/10.1038/s41586-019-1775-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897368PMC
December 2019

An independently validated nomogram for isocitrate dehydrogenase-wild-type glioblastoma patient survival.

Neurooncol Adv 2019 May-Dec;1(1):vdz007. Epub 2019 May 30.

Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Background: In 2016, the World Health Organization reclassified the definition of glioblastoma (GBM), dividing these tumors into isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant GBM, where the vast majority of GBMs are IDH-wild-type. Nomograms are useful tools for individualized estimation of survival. This study aimed to develop and independently validate a nomogram for IDH-wild-type patients with newly diagnosed GBM.

Methods: Data were obtained from newly diagnosed GBM patients from the Ohio Brain Tumor Study (OBTS) and the University of California San Francisco (UCSF) for diagnosis years 2007-2017 with the following variables: age at diagnosis, sex, extent of resection, concurrent radiation/temozolomide (TMZ) status, Karnofsky Performance Status (KPS), O-methylguanine-DNA methyltransferase (MGMT) methylation status, and IDH mutation status. Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using the OBTS data and independently validated using the UCSF data. Models were internally validated using 10-fold cross-validation and externally validated by plotting calibration curves.

Results: A final nomogram was validated for IDH-wild-type newly diagnosed GBM. Factors that increased the probability of survival included younger age at diagnosis, female sex, having gross total resection, having concurrent radiation/TMZ, having a high KPS, and having methylation.

Conclusions: A nomogram that calculates individualized survival probabilities for IDH-wild-type patients with newly diagnosed GBM could be useful to physicians for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free software for implementing this nomogram is provided: https://gcioffi.shinyapps.io/Nomogram_For_IDH_Wildtype_GBM_H_Gittleman/.
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http://dx.doi.org/10.1093/noajnl/vdz007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777501PMC
May 2019

Reirradiation of recurrent high-grade glioma and development of prognostic scores for progression and survival.

Neurooncol Pract 2019 Sep 12;6(5):364-374. Epub 2019 Apr 12.

Department of Radiation Oncology, University of California San Francisco.

Background: Optimal techniques and patient selection for salvage reirradiation of high-grade glioma (HGG) are unclear. In this study, we identify prognostic factors for freedom from progression (FFP) and overall survival (OS) after reirradiation, risk factors for high-grade toxicity, and validate clinical prognostic scores.

Methods: A total of 116 patients evaluated between 2000 and 2018 received reirradiation for HGG (99 WHO grade IV, 17 WHO grade III). Median time to first progression after initial therapy was 10.6 months. Salvage therapies before reirradiation included surgery (31%) and systemic therapy (41%). Sixty-five patients (56%) received single-fraction stereotactic radiosurgery (SRS) as reirradiation. The median biologically effective dose (BED) was 47.25 Gy, and the median planning target volume (PTV) was 4.8 cc for SRS and 95.0 cc for non-SRS treatments. Systemic therapy was given concurrently to 52% and adjuvantly to 74% of patients.

Results: Median FFP was 4.9 months, and median OS was 11.0 months. Significant multivariable prognostic factors for FFP were performance status, time to initial progression, and BED; for OS they were age, time to initial progression, and PTV volume at recurrence. High-grade toxicity was correlated to PTV size at recurrence. Three-level prognostic scores were generated for FFP and OS, with cross-validated receiver operating characteristic area under the curve (AUC) of 0.640 and 0.687, respectively.

Conclusions: Clinical variables at the time of reirradiation for HGG can be used to prognosticate FFP and OS.
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http://dx.doi.org/10.1093/nop/npz017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753361PMC
September 2019

Reirradiation of recurrent high-grade glioma and development of prognostic scores for progression and survival.

Neurooncol Pract 2019 Sep 12;6(5):364-374. Epub 2019 Apr 12.

Department of Radiation Oncology, University of California San Francisco.

Background: Optimal techniques and patient selection for salvage reirradiation of high-grade glioma (HGG) are unclear. In this study, we identify prognostic factors for freedom from progression (FFP) and overall survival (OS) after reirradiation, risk factors for high-grade toxicity, and validate clinical prognostic scores.

Methods: A total of 116 patients evaluated between 2000 and 2018 received reirradiation for HGG (99 WHO grade IV, 17 WHO grade III). Median time to first progression after initial therapy was 10.6 months. Salvage therapies before reirradiation included surgery (31%) and systemic therapy (41%). Sixty-five patients (56%) received single-fraction stereotactic radiosurgery (SRS) as reirradiation. The median biologically effective dose (BED) was 47.25 Gy, and the median planning target volume (PTV) was 4.8 cc for SRS and 95.0 cc for non-SRS treatments. Systemic therapy was given concurrently to 52% and adjuvantly to 74% of patients.

Results: Median FFP was 4.9 months, and median OS was 11.0 months. Significant multivariable prognostic factors for FFP were performance status, time to initial progression, and BED; for OS they were age, time to initial progression, and PTV volume at recurrence. High-grade toxicity was correlated to PTV size at recurrence. Three-level prognostic scores were generated for FFP and OS, with cross-validated receiver operating characteristic area under the curve (AUC) of 0.640 and 0.687, respectively.

Conclusions: Clinical variables at the time of reirradiation for HGG can be used to prognosticate FFP and OS.
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http://dx.doi.org/10.1093/nop/npz017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753361PMC
September 2019

EGFR amplification status for clinical trial inclusion: where do we draw the line?

Neuro Oncol 2019 10;21(10):1215-1216

Departments of Neurological Surgery and Pathology, University of California, San Francisco, California.

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http://dx.doi.org/10.1093/neuonc/noz146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784265PMC
October 2019

A historical cohort of temporal lobe surgery for medically refractory epilepsy: a systematic review and meta-analysis to guide future nonrandomized controlled trial studies.

J Neurosurg 2019 Jun 28:1-8. Epub 2019 Jun 28.

1Department of Neurological Surgery and.

Objective: Recent trials for temporal lobe epilepsy (TLE) highlight the challenges of investigating surgical outcomes using randomized controlled trials (RCTs). Although several reviews have examined seizure-freedom outcomes from existing data, there is a need for an overall seizure-freedom rate estimated from level I data as investigators consider other methods besides RCTs to study outcomes related to new surgical interventions.

Methods: The authors performed a systematic review and meta-analysis of the 3 RCTs of TLE in adults and report an overall surgical seizure-freedom rate (Engel class I) composed of level I data. An overall seizure-freedom rate was also collected from level II data (prospective cohort studies) for validation. Eligible studies were identified by filtering a published Cochrane meta-analysis of epilepsy surgery for RCTs and prospective studies, and supplemented by searching indexed terms in MEDLINE (January 1, 2012-April 1, 2018). Retrospective studies were excluded to minimize heterogeneity in patient selection and reporting bias. Data extraction was independently reverified and pooled using a fixed-effects model. The primary outcome was overall seizure freedom following surgery. The historical benchmark was applied in a noninferiority study design to compare its power to a single-study cohort.

Results: The overall rate of seizure freedom from level I data was 72.4% (55/76 patients, 3 RCTs), which was nearly identical to the overall seizure-freedom rate of 71.7% (1325/1849 patients, 18 studies) from prospective cohorts (z = 0.134, p = 0.89; z-test). Seizure-freedom rates from level I and II studies were consistent over the years of publication (R2 < 0.01, p = 0.73). Surgery resulted in markedly improved seizure-free outcomes compared to medical management (RR 10.82, 95% CI 3.93-29.84, p < 0.01; 2 RCTs). Noninferiority study designs in which the historical benchmark was used had significantly higher power at all difference margins compared to using a single cohort alone (p < 0.001, Bonferroni's multiple comparison test).

Conclusions: The overall rate of seizure freedom for temporal lobe surgery is approximately 70% for medically refractory epilepsy. The small sample size of the RCT cohort underscores the need to move beyond standard RCTs for epilepsy surgery. This historical seizure-freedom rate may serve as a useful benchmark to guide future study designs for new surgical treatments for refractory TLE.
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http://dx.doi.org/10.3171/2019.4.JNS183235DOI Listing
June 2019

Residual Tumor Volume and Location Predict Progression After Primary Subtotal Resection of Sporadic Vestibular Schwannomas: A Retrospective Volumetric Study.

Neurosurgery 2020 03;86(3):410-416

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

Background: Preservation of functional integrity during vestibular schwannoma surgery has become critical in the era of patient-centric medical decision-making. Subtotal tumor removal is often necessary when dense adhesions between the tumor and critical structures are present. However, it is unclear what the rate of tumor control is after subtotal resection (STR) and what factors are associated with recurrence.

Objective: To determine the rate of residual tumor growth after STR and identify clinical and radiographic predictors of tumor progression.

Methods: A single-institution retrospective study was performed on all sporadic vestibular schwannomas that underwent surgical resection between January 1, 2002 and December 31, 2015. Clinical charts, pathology, radiology, and operative reports were reviewed. Volumetric analysis was performed on all pre- and postoperative MR imaging. Univariate and multivariate logistic regression was performed to identify predictors of the primary endpoint of tumor progression. Kaplan-Meier analysis was performed to compare progression free survival between 2 groups of residual tumor volumes and location.

Results: In this cohort of 66 patients who underwent primary STR, 30% had documented progression within a median follow up period of 3.1 yr. Greater residual tumor volume (OR 2.0 [1.1-4.0]) and residual disease within the internal auditory canal (OR 3.7 [1.0-13.4]) predicted progression on multivariate analysis.

Conclusion: These longitudinal data provide insight into the behavior of residual tumor, helping clinicians to determine if and when STR is an acceptable surgical strategy and to anchor expectations during shared medical decision-making consultation with patients.
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http://dx.doi.org/10.1093/neuros/nyz200DOI Listing
March 2020

Genetic and molecular epidemiology of adult diffuse glioma.

Nat Rev Neurol 2019 07 21;15(7):405-417. Epub 2019 Jun 21.

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

The WHO 2007 glioma classification system (based primarily on tumour histology) resulted in considerable interobserver variability and substantial variation in patient survival within grades. Furthermore, few risk factors for glioma were known. Discoveries over the past decade have deepened our understanding of the molecular alterations underlying glioma and have led to the identification of numerous genetic risk factors. The advances in molecular characterization of glioma have reframed our understanding of its biology and led to the development of a new classification system for glioma. The WHO 2016 classification system comprises five glioma subtypes, categorized by both tumour morphology and molecular genetic information, which led to reduced misclassification and improved consistency of outcomes within glioma subtypes. To date, 25 risk loci for glioma have been identified and several rare inherited mutations that might cause glioma in some families have been discovered. This Review focuses on the two dominant trends in glioma science: the characterization of diagnostic and prognostic tumour markers and the identification of genetic and other risk factors. An overview of the many challenges still facing glioma researchers is also included.
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http://dx.doi.org/10.1038/s41582-019-0220-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286557PMC
July 2019
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