Publications by authors named "Nicholas Butowski"

108 Publications

Modified RANO (mRANO), iRANO, and standard RANO response to convection-enhanced delivery of IL4R-targeted immunotoxin MDNA55 in recurrent glioblastoma.

Clin Cancer Res 2021 Apr 16. Epub 2021 Apr 16.

Medicenna BioPharma.

Purpose: The current study compared the modified radiographic response assessment in neuro-oncology (mRANO), immunotherapy RANO (iRANO), and standard RANO criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM).

Experimental Design: 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty (IRF), then standard RANO, iRANO, and mRANO criteria were applied.

Results: 41 of 47 patients (mean age 56{plus minus}11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared to iRANO (log-rank, <0.0001; =0.3) and mRANO (<0.0001;=0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (Local,=0.47;Central,=0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements (=0.017), but not central measurements (=0.18). 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local ( =0.66,<0.0001) and centrally-determined reads ( =0.57,=0.0007).

Conclusions: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0446DOI Listing
April 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 Apr 5. Epub 2021 Apr 5.

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

Background: Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas, 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 re-operation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes.

Results: Hypermutation was associated with high-grade disease at the time of re-operation (OR 12.0 95% CI 2.5-115.5, p=0.002) 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=0.024), 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=0.003). 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. 8-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
April 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

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 11 2;18(11):1537-1570. Epub 2020 Nov 2.

5The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.
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http://dx.doi.org/10.6004/jnccn.2020.0052DOI Listing
November 2020

Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma: A Randomized Clinical Trial.

JAMA Oncol 2020 12;6(12):1939-1946

Cleveland Clinic Foundation, Moffitt Cancer Center, Tampa, Florida.

Importance: New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma.

Objective: To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC).

Design, Setting, And Participants: A randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma.

Interventions: Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators' choice of single therapy: lomustine, temozolomide, or bevacizumab.

Main Outcomes And Measures: The primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS.

Results: All 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group.

Conclusions And Relevance: Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points.

Trial Registration: ClinicalTrials.gov Identifier: NCT02414165.
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http://dx.doi.org/10.1001/jamaoncol.2020.3161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596685PMC
December 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

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

Acta Neuropathol Commun 2020 08 28;8(1):151. Epub 2020 Aug 28.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.
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http://dx.doi.org/10.1186/s40478-020-01027-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456392PMC
August 2020

A systematic review and meta-analysis examining the effects of cannabis and its derivatives in adults with malignant CNS tumors.

Neurooncol Pract 2020 Jul 3;7(4):376-383. Epub 2020 Apr 3.

University of California, San Francisco, Neuro-Oncology Division.

Background: Primary CNS tumors constitute a heterogeneous group of neoplasms that share a considerable morbidity and mortality rate. To help control tumor growth and clinical outcomes (overall survival, progression-free survival, quality of life) symptoms, patients often resort to alternative therapies, including the use of cannabis. Despite rapidly growing popularity, cannabis and its impact on patients with primary malignant CNS tumors is understudied.

Methods: To shed light on the lack of scientific evidence in this field, in November 2018 we conducted a search and examination of cannabis in neuro-oncology in major journal databases and bibliographies of selected articles, and through abstracts of annual meetings using prespecified criteria in line with the Cochrane Collaboration guidelines.

Results: We identified 45 publications, of which 9 were selected. Five studies were included. Publication dates ranged from 2004 to 2018 and included varying histologies of primary brain tumors. The average survival at 1 year was 56.09% (95% CI: 48.28-63.9). There was no difference in risk ratio (RR) for death at 1 year between groups (RR: 1.069 [95% CI: 0.139-8.25]). We found strong evidence of heterogeneity (Q = 74.0%;  = .021). We found no statistical evidence of publication bias ( = .117; SD = 1.91).

Conclusions: There was limited moderate-quality evidence that supports the use of cannabinoids as adjuvant to the standard of care in the treatment of brain and CNS tumors. There was very low-quality evidence suggesting that cannabinoids were associated with adult-onset gliomas. Further prospective clinical trials are necessary to adequately evaluate the impact of cannabinoids on CNS tumors, specifically on survival and quality of life.
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http://dx.doi.org/10.1093/nop/npaa013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393278PMC
July 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

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

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE).

Neuro Oncol 2020 05;22(5):705-717

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

Background: Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.

Methods: This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).

Results: Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.

Conclusions: In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.

Clinical Trials Registration: NCT02511405.
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http://dx.doi.org/10.1093/neuonc/noz232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229248PMC
May 2020

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

Attitudes toward fertility and fertility preservation in women with glioma.

Neurooncol Pract 2019 May 26;6(3):218-225. Epub 2018 Sep 26.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, USA.

Background: No studies have examined the fertility priorities of women undergoing treatment for their glioma. Glioma patients frequently undergo chemotherapy as part of their treatment; however, it is unknown whether patients truly are aware of its possible effects on their fertility. Our objective was to assess the fertility priorities of glioma patients and ascertain whether female glioma patients are being effectively counseled on the effects of chemotherapy on their fertility prior to beginning treatment.

Methods: The sample was composed of female patients from the Neuro-oncology clinic of the University of California, San Francisco. Participants completed a cross-sectional survey between October 2010 and December 2013 exploring their attitudes toward fertility and their experience with fertility counseling prior to chemotherapy initiation.

Results: Seventy-two women completed the survey. Analysis of the survey results showed that 30% of women receiving chemotherapy reported having a discussion regarding fertility preservation prior to beginning treatment. Of those who reported having this discussion, 80% were aware that chemotherapy could negatively affect their fertility. Many women reported that while fertility preservation was not important to them at the time of diagnosis, it was a priority for them at the time of survey completion. Although interest in having children tended to decrease after cancer treatment, the majority of respondents reported wanting a child after treatment.

Conclusions: The data obtained in this study suggest a lack of understanding of reproductive priorities, which may be addressed with a more comprehensive fertility discussion prior to beginning treatment.
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http://dx.doi.org/10.1093/nop/npy036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656302PMC
May 2019

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Nat Med 2019 03 11;25(3):477-486. Epub 2019 Feb 11.

Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
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http://dx.doi.org/10.1038/s41591-018-0337-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408961PMC
March 2019

Risk factors of radiotherapy-induced cerebral microbleeds and serial analysis of their size compared with white matter changes: A 7T MRI study in 113 adult patients with brain tumors.

J Magn Reson Imaging 2019 09 20;50(3):868-877. Epub 2019 Jan 20.

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

Background: Although radiation therapy (RT) contributes to survival benefit in many brain tumor patients, it has also been associated with long-term brain injury. Cerebral microbleeds (CMBs) represent an important manifestation of radiation-related injury.

Purpose: To characterize the change in size and number of CMBs over time and to evaluate their relationship to white matter structural integrity as measured using diffusion MRI indices.

Study Type: Longitudinal, retrospective, human cohort.

Population: In all, 113 brain tumor patients including patients treated with focal RT (n = 91, 80.5%) and a subset of nonirradiated controls (n = 22, 19.5%).

Field Strength/sequence: Single and multiecho susceptibility-weighted imaging (SWI) and multiband, shell, and direction diffusion tensor imaging (DTI) at 7 T.

Assessment: Patients were scanned either once or serially. CMBs were detected and quantified on SWI images using a semiautomated approach. Local and global fractional anisotropy (FA) were measured from DTI data for a subset of 35 patients.

Statistical Tests: Potential risk factors for CMB development were determined by multivariate linear regression and using linear mixed-effect models. Longitudinal FA was quantitatively and qualitatively evaluated for trends.

Results: All patients scanned at 1 or more years post-RT had CMBs. A history of multiple surgical resections was a risk factor for development of CMBs. The total number and volume of CMBs increased by 18% and 11% per year, respectively, although individual CMBs decreased in volume over time. Simultaneous to these microvascular changes, FA decreased by a median of 6.5% per year. While the majority of nonirradiated controls had no CMBs, four control patients presented with fewer than five CMBs.

Data Conclusion: Identifying patients who are at the greatest risk for CMB development, with its likely associated long-term cognitive impairment, is an important step towards developing and piloting preventative and/or rehabilitative measures for patients undergoing RT.

Level Of Evidence: 3 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;50:868-877.
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http://dx.doi.org/10.1002/jmri.26651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642688PMC
September 2019

Advances in multidisciplinary therapy for meningiomas.

Neuro Oncol 2019 01;21(Suppl 1):i18-i31

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

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas.
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http://dx.doi.org/10.1093/neuonc/noy136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347080PMC
January 2019

Molecular features and clinical outcomes in surgically treated low-grade diffuse gliomas in patients over the age of 60.

J Neurooncol 2019 Jan 29;141(2):383-391. Epub 2018 Nov 29.

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

Purpose: WHO grade II gliomas are uncommon in patients over the age of 60, and there is a lack in consensus regarding their management. We present molecular tumor characteristics as well as clinical outcomes in patients over the age of 60 undergoing surgical resection of a WHO grade II glioma.

Methods: After receiving IRB approval, patients were identified through the UCSF Brain Tumor Center. Pathologic diagnosis was completed using WHO 2016 grading criteria.

Results: Twenty-six patients with a mean age of 66 years met inclusion criteria with a median follow-up of 5.2 years. Diagnoses included diffuse astrocytoma IDH-mutant (19.2%), diffuse astrocytoma IDH-wildtype (26.9%), Oligodendroglioma IDH-mutant and 1p/19q-codeleted (50%), and a rare case of mixed oligoastrocytoma (3.9%). 66% of astrocytoma IDH-wildtype tumors possessed TERT mutation. Median extent of resection was 75.4%. Progression-free (PFS) and overall survival (OS) were 23.5 and 62.6 months, respectively. Shorter PFS was associated with the astrocytoma IDH-wildtype subtype despite similar extent of resection and adjuvant treatment rates compared to the other subtypes. OS did not differ between subtypes. Malignant transformation and death were associated with larger preoperative and residual tumor volume.

Conclusions: Older patients with diffuse gliomas may safely undergo aggressive treatment with surgical resection and adjuvant therapy. Elderly patients with low grade gliomas have worse clinical outcomes compared to their younger counterparts. This may be due to an increased frequency of diffuse astrocytoma IDH-wildtype tumors in this age group.
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http://dx.doi.org/10.1007/s11060-018-03044-4DOI Listing
January 2019

Using genomics to guide treatment for glioblastoma.

Pharmacogenomics 2018 10 11;19(15):1217-1229. Epub 2018 Sep 11.

Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.

Glioblastoma has been shown to have many different genetic mutations found both within and between tumor samples. Molecular testing and genomic sequencing has helped to classify diagnoses and clarify difficult to interpret histopathological specimens. Genomic information also plays a critical role in prognostication for patients, with IDH mutations and MGMT methylation having significant impact of the response to chemotherapy and overall survival of patients. Unfortunately, personalized medicine and targeted therapy against specific mutations have not been shown to improve patient outcomes. As technology continues to improve, exome and RNA sequencing will play a role in the design of clinical trials, classification of patient subgroups and identification of rare mutations that can be targeted by small-molecule inhibitors and biologic agents.
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http://dx.doi.org/10.2217/pgs-2018-0078DOI Listing
October 2018

The genetic landscape of gliomas arising after therapeutic radiation.

Acta Neuropathol 2019 01 8;137(1):139-150. Epub 2018 Sep 8.

Department of Pathology, University of California, San Francisco, CA, USA.

Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.
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http://dx.doi.org/10.1007/s00401-018-1906-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589431PMC
January 2019

Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma.

J Neurooncol 2018 Nov 27;140(2):477-483. Epub 2018 Aug 27.

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

Introduction: Alterations in the CDK4/6-RB signaling pathway are common causes of cell cycle dysregulation in many cancers, including glioblastoma. Palbociclib is an oral inhibitor of CDK4/6, which leads to phosphorylation of RB1 and cell-cycle arrest. We conducted a two-arm study evaluating efficacy and tissue pharmacokinetics/pharmacodynamics of palbociclib in patients with recurrent glioblastoma.

Methods: Eligibility criteria included confirmation of RB1 proficiency by IHC; ≤ 3 relapses; KPS ≥ 60; no limit on prior treatments. Arm 1 received palbociclib for 7 days prior to indicated resection followed by adjuvant palbociclib. Arm 2 received palbociclib without resection. Primary objective was PFS6; secondary included toxicity, OS, and ORR. Exploratory aims included biomarker assessment and pharmacokinetic/pharmacodynamic effects in surgical patients.

Results: Total of 22 patients were enrolled; 6 on Arm 1 and 16 on Arm 2. Trial was stopped early secondary to lack of efficacy, with 95% of evaluable patients progressing within 6 months. Median PFS was 5.14 weeks (range 5 days-142 weeks) and median OS was 15.4 weeks (range 2-274 weeks). Two patients (10%) had related grade ≥ 3 AEs. In Arm 1, 5 patients had tissue concentrations of palbociclib felt to be sufficient for biological effect and paired samples available for RB1 IHC. There were no consistent changes in RB1 expression or cell proliferation in the paired tissue.

Conclusion: In this trial, despite adequate tissue PK, palbociclib monotherapy was not an effective treatment for recurrent glioblastoma. However, these were heavily pretreated patients and targeting the CDK4/6 pathway may still deserve further exploration.
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http://dx.doi.org/10.1007/s11060-018-2977-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239922PMC
November 2018

Primary brain tumours in adults.

Lancet 2018 08 27;392(10145):432-446. Epub 2018 Jul 27.

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

Primary CNS tumours refer to a heterogeneous group of tumours arising from cells within the CNS, and can be benign or malignant. Malignant primary brain tumours remain among the most difficult cancers to treat, with a 5 year overall survival no greater than 35%. The most common malignant primary brain tumours in adults are gliomas. Recent advances in molecular biology have improved understanding of glioma pathogenesis, and several clinically significant genetic alterations have been described. A number of these (IDH, 1p/19q codeletion, H3 Lys27Met, and RELA-fusion) are now combined with histology in the revised 2016 WHO classification of CNS tumours. It is likely that understanding such molecular alterations will contribute to the diagnosis, grading, and treatment of brain tumours. This progress in genomics, along with significant advances in cancer and CNS immunology, has defined a new era in neuro-oncology and holds promise for diagntic and therapeutic improvement. The challenge at present is to translate these advances into effective treatments. Current efforts are focused on developing molecular targeted therapies, immunotherapies, gene therapies, and novel drug-delivery technologies. Results with single-agent therapies have been disappointing so far, and combination therapies seem to be required to achieve a broad and durable antitumour response. Biomarker-targeted clinical trials could improve efficiencies of therapeutic development.
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http://dx.doi.org/10.1016/S0140-6736(18)30990-5DOI Listing
August 2018

Novel and Prospective Molecular Targets for Therapy of Intracranial Gliomas.

Prog Neurol Surg 2018 10;32:66-78. Epub 2018 Jul 10.

Multiple alterations in the expression levels of genes or proteins have been identified in gliomas, including activation of oncogenes and silencing of tumor suppressor genes. Illuminating these molecular mechanisms of tumorigenesis and treatment resistance is necessary for the development of new therapies. With the promise of better effectiveness and less toxicity, the emphasis in drug development has moved from cytotoxic, non-specific chemotherapies to molecular targeted agents. However, despite progress in other areas of oncology, targeted therapy success stories in cases of brain tumors remain all but absent. Nonetheless, experiences from previous clinical trials suggest that a small number of unselected patients may benefit from such treatment. An increasing knowledge about related factors and prospective enrichment strategies now shape research and clinical trial design in neuro-oncology and may lead to improved outcomes after molecular targeted therapies of gliomas.
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http://dx.doi.org/10.1159/000469681DOI Listing
October 2018

Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial.

Neuro Oncol 2019 01;21(1):106-114

NorthShore University Health System, Evanston, Illinois, USA.

Background: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM.

Methods: M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve.

Results: There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%.

Conclusions: Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).
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http://dx.doi.org/10.1093/neuonc/noy091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303422PMC
January 2019

Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma.

Neuro Oncol 2018 08;20(9):1240-1250

Department of Molecular Medicine, Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Background: In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS).

Methods: Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS.

Results: A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status.

Conclusion: Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.
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http://dx.doi.org/10.1093/neuonc/noy053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071654PMC
August 2018

A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle.

Nat Commun 2018 02 23;9(1):810. Epub 2018 Feb 23.

Department of Pathology, University of California, San Francisco, CA, 94143, USA.

Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.
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http://dx.doi.org/10.1038/s41467-018-02826-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824822PMC
February 2018

MRI Features and IDH Mutational Status of Grade II Diffuse Gliomas: Impact on Diagnosis and Prognosis.

AJR Am J Roentgenol 2018 Mar 20;210(3):621-628. Epub 2017 Dec 20.

1 Department of Radiology and Biomedical Imaging, University of California, San Francisco, 350 Parnassus, 370H, San Francisco, CA 94143.

Objective: Grade II diffuse gliomas (DGs) with isocitrate dehydrogenase (IDH) mutations are associated with better prognosis than their IDH wild-type counterparts. We sought to determine the MRI characteristics associated with IDH mutational status and ascertain whether MRI considered in combination with IDH mutational status can better predict the clinical outcomes of grade II DGs.

Materials And Methods: Preoperative MRI examinations were retrospectively studied for qualitative tumor characteristics, including location, extent, cortical involvement, margin sharpness, cystic component, mineralization or hemorrhage, and contrast enhancement. Quantitative diffusion and perfusion metrics were also assessed. Logistic regression and ROC analyses were used to evaluate the relationship between MRI features and IDH mutational status. The association between IDH mutational status, 1p19q codeletion, MRI features, extent of resection, and clinical outcomes was assessed by Kaplan-Meier and Cox proportional hazards models.

Results: Of 100 grade II DGs, 78 were IDH mutant and 22 were IDH wild type. IDH wild-type tumors were associated with older age, multifocality, brainstem involvement, lack of cystic change, and a lower apparent diffusion coefficient (ADC). Multivariable regression showed that age older than 45 years as well as low minimum ADC (ADC), mean ADC, and maximum ADC values were independently associated with IDH mutational status. Of these, an ADC threshold of 0.9 × 10 mm/s or less provided the greatest sensitivity and specificity (91% and 76%, respectively) in defining IDH wild-type grade II DGs. Combining low ADC with IDH wild-type status conferred worse outcomes than did IDH wild-type status alone.

Conclusion: IDH wild-type grade II DGs are associated with a lower ADC and poor clinical outcomes. Combining IDH mutational status and ADC may allow more accurate prediction of clinical outcomes for patients with grade II DGs.
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http://dx.doi.org/10.2214/AJR.17.18457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823758PMC
March 2018

Clinical trial endpoints for patients with gliomas.

Neurooncol Pract 2017 Dec 14;4(4):201-208. Epub 2017 Feb 14.

Department of Neurological Surgery, University of California San Francisco, San Francisco, California (J.W.T., A.M.M., N.B., M.P.).

Malignant glioma represents a diverse set of molecularly heterogeneous diseases. Few therapeutic agents have been approved despite decades of clinical trials research and pre-clinical investigation. Attempts to refine neuroimaging criteria and recent discovery of the genomic profiles linking tumor subsets to survival outcomes have spurred discussion on a variety of new approaches in clinical trial design and relevant endpoints. Here we focus on those endpoints in clinical trial design for patients with primary glioma and related issues still to be resolved.
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http://dx.doi.org/10.1093/nop/npw034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6655446PMC
December 2017