Olson, Jeffrey J.

Glioma incidence is highest in non‐Hispanic Whites, and to date, glioma genome‐wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case–Control Study and GliomaSE Case–Control Study previously estimated to have <80% EA, or self‐identify as non‐White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR ≥0.4 ), and ≥15% NAA (AMR ≥0.15 ), genome‐wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10 −4 ; 11p11.12, p = 7.0 × 10 −4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR ≥0.4 . In addition, we identified a peak at rs1620291 ( p = 4.36 × 10 −6 ) in 7q21.3. Among AMR ≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10 −4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10 −4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.

Abstract Glioma incidence is highest in non-Hispanic Whites, where it occurs ~2x as frequently compared with other race/ethnicity groups. Glioma GWAS to date have included European ancestry populations only, and it is unknown whether variants identified by these analyses are associated with glioma in non- European ancestry populations. African Americans and Hispanics are admixed populations with varying proportions of European ancestry. While global ancestry may be similar within admixed groups, the proportion of European ancestry at each allele can vary across the genome. As glioma is more common in European ancestry populations, the presence of increased local European ancestry in these admixed populations could be used to identify glioma risk loci. Here we assessed whether excess European ancestry at established risk loci (Melin et al, Nature Genetics, 2017) was associated with glioma risk in non-European ancestry populations. Global ancestry was estimated using fastStructure, and local ancestry was estimated using RFMix. Both methods used 1,000 genomes project reference populations (African: YRI; European: CEU; East Asian: CHB/JPT; and Native American: CLM/PEL/MXL). We evaluated differences in local European ancestry between cases and controls using logistic regression conditioned on global European ancestry within 500kb of 25 previously identified risk variants among individuals with ≥50% African ancestry, and ≥30% Native American ancestry for all gliomas, and for grade IV glioblastoma (GBM) and grade II-III non-GBM. There were 347 individuals (184 cases and 163 controls) with ≥50% global African ancestry, and 277 individuals (153 cases and 124 controls) with ≥30% global American ancestry. There was no significant difference in proportion of global European ancestry between cases and controls with ≥50% global African ancestry (cases: 18.2%, controls: 17.7%, p=0.6834), and no significant difference in proportion of global European ancestry between cases and controls with ≥30% global American ancestry (cases: 51.1%, controls: 49.0%, p=0.2123). Among individuals with &gt;50% African ancestry, we observed a nominally significant association between all glioma and increased local European ancestry at 7p11.2 (EGFR, pmin=0.0070) and between GBM and increased local European ancestry at 22q13.1 (CSNK1E, pmin=0.0098), both near SNPs previously associated with glioblastoma in majority European-ancestry populations. The dataset used for this analysis represents the largest collection of genotyped non-European glioma cases. These results suggest that glioma risk in African Americans may be associated with an increased local European ancestry variants at glioma risk loci previously identified in majority European ancestry populations (7p11.2 and 22q13.1). Citation Format: Quinn T. Ostrom, Kathleen M. Egan, L. Burt Nabors, Travis Gerke, Reid C. Thompson, Jeffrey J. Olson, Renato LaRocca, Sajeel Chowdhary, Jeanette E. Eckel-Passow, Georgina Armstrong, John K. Wiencke, Christopher I. Amos, Jonine L. Bernstein, Elizabeth B. Claus, Dora Il'yasova, Christoffer Johansen, Daniel H. Lachance, Rose Lai, Ryan T. Merrell, Sara H. Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, Richard S. Houlston, Robert B. Jenkins, Beatrice Melin, Melissa L. Bondy, Jill S. Barnholtz-Sloan. Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 233.

Abstract MEDICAL THERAPY Target Population Adults with histologically proven or suspected vestibular schwannomas with neurofibromatosis type 2 (NF2). Question What is the role of bevacizumab in the treatment of patients with vestibular schwannomas? Recommendations Level 3: It is recommended that bevacizumab be administered in order to radiographically reduce the size or prolong tumor stability in patients with NF2 without surgical options. Level 3: It is recommended that bevacizumab be administered to improve hearing or prolong time to hearing loss in patients with NF2 without surgical options. Question Is there a role for lapatinib, erlotinib, or everolimus in the treatment of patients with vestibular schwannomas? Recommendations Level 3: Lapatinib may be considered for use in reducing vestibular schwannoma size and improvement in hearing in NF2. Level 3: Erlotinib is not recommended for use in reducing vestibular schwannoma size or improvement in hearing in patients with NF2. Level 3: Everolimus is not recommended for use in reducing vestibular schwannoma size or improvement in hearing in NF2. Question What is the role of aspirin, to augment inflammatory response, in the treatment of patients with vestibular schwannomas? Target Population Any patient with a vestibular schwannoma undergoing observation. Recommendation Level 3: It is recommended that aspirin administration may be considered for use in patients undergoing observation of their vestibular schwannomas. Question Is there a role for treatment of vasospasm, ie, nimodipine or hydroxyethyl starch, perioperatively to improve facial nerve outcomes in patients with vestibular schwannomas? Target Population Adults with histologically proven or suspected vestibular schwannomas. Recommendation Level 3: Perioperative treatment with nimodipine (or with the addition of hydroxyethyl starch) should be considered to improve postoperative facial nerve outcomes and may improve hearing outcomes. PREHABILITATION Question Is there a role for preoperative vestibular rehab or vestibular ablation with gentamicin for patients surgically treated for vestibular schwannomas? Target Population Adults with histologically proven or suspected vestibular schwannomas. Recommendations Level 3: Preoperative vestibular rehabilitation is recommended to aid in postoperative mobility after vestibular schwannoma surgery. Level 3: Preoperative gentamicin ablation of the vestibular apparatus should be considered to improve postoperative mobility after vestibular schwannoma surgery. SURGICAL THERAPY Question Does endoscopic assistance make a difference in resection or outcomes in patients with vestibular schwannomas? Target Population Vestibular schwannoma patients, who are surgical candidates. Inclusion in this analysis required resection utilizing the endoscope, either as the primary operative visualization or microscopic assistance with more than 20 patients treated. Recommendation Level 3: Endoscopic assistance is a surgical technique that the surgeon may choose to use in order to aid in visualization. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_9.

Abstract TARGET POPULATION Adults diagnosed with vestibular schwannomas. QUESTION 1 What is the prognostic significance of Antoni A vs B histologic patterns in vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 2 What is the prognostic significance of mitotic figures seen in vestibular schwannoma specimens? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 3 Are there other light microscopic features that predict clinical behavior of vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 4 Does the KI-67 labeling index predict clinical behavior of vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 5 Does the proliferating cell nuclear antigen labeling index predict clinical behavior of vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 6 Does degree of vascular endothelial growth factor expression predict clinical behavior of vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_6.

Abstract FACIAL NERVE MONITORING Question 1 Does intraoperative facial nerve monitoring during vestibular schwannoma surgery lead to better long-term facial nerve function? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery regardless of tumor characteristics. Recommendation Level 3: It is recommended that intraoperative facial nerve monitoring be routinely utilized during vestibular schwannoma surgery to improve long-term facial nerve function. Question 2 Can intraoperative facial nerve monitoring be used to accurately predict favorable long-term facial nerve function after vestibular schwannoma surgery? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery. Recommendation Level 3: Intraoperative facial nerve can be used to accurately predict favorable long-term facial nerve function after vestibular schwannoma surgery. Specifically, the presence of favorable testing reliably portends a good long-term facial nerve outcome. However, the absence of favorable testing in the setting of an anatomically intact facial nerve does not reliably predict poor long-term function and therefore cannot be used to direct decision-making regarding the need for early reinnervation procedures. Question 3 Does an anatomically intact facial nerve with poor electromyogram (EMG) electrical responses during intraoperative testing reliably predict poor long-term facial nerve function? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery. Recommendation Level 3: Poor intraoperative EMG electrical response of the facial nerve should not be used as a reliable predictor of poor long-term facial nerve function. COCHLEAR NERVE MONITORING Question 4 Should intraoperative eighth cranial nerve monitoring be used during vestibular schwannoma surgery? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery with measurable preoperative hearing levels and tumors smaller than 1.5 cm. Recommendation Level 3: Intraoperative eighth cranial nerve monitoring should be used during vestibular schwannoma surgery when hearing preservation is attempted. Question 5 Is direct monitoring of the eighth cranial nerve superior to the use of far-field auditory brain stem responses? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery with measurable preoperative hearing levels and tumors smaller than 1.5 cm. Recommendation Level 3: There is insufficient evidence to make a definitive recommendation. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-manage-ment-patients-vestibular-schwannoma/chapter_4.

Abstract Please see the full-text version of this guideline (https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_8) for the target population of each recommendation listed below. QUESTION 1 What surgical approaches for vestibular schwannomas (VS) are best for complete resection and facial nerve (FN) preservation when serviceable hearing is present? RECOMMENDATION There is insufficient evidence to support the superiority of either the middle fossa (MF) or the retrosigmoid (RS) approach for complete VS resection and FN preservation when serviceable hearing is present. QUESTION 2 Which surgical approach (RS or translabyrinthine [TL]) for VS is best for complete resection and FN preservation when serviceable hearing is not present? RECOMMENDATION There is insufficient evidence to support the superiority of either the RS or the TL approach for complete VS resection and FN preservation when serviceable hearing is not present. QUESTION 3 Does VS size matter for facial and vestibulocochlear nerve preservation with surgical resection? RECOMMENDATION Level 3: Patients with larger VS tumor size should be counseled about the greater than average risk of loss of serviceable hearing. QUESTION 4 Should small intracanalicular tumors (<1.5 cm) be surgically resected? RECOMMENDATION There are insufficient data to support a firm recommendation that surgery be the primary treatment for this subclass of VSs. QUESTION 5 Is hearing preservation routinely possible with VS surgical resection when serviceable hearing is present? RECOMMENDATION Level 3: Hearing preservation surgery via the MF or the RS approach may be attempted in patients with small tumor size (<1.5 cm) and good preoperative hearing. QUESTION 6 When should surgical resection be the initial treatment in patients with neurofibromatosis type 2 (NF2)? RECOMMENDATION There is insufficient evidence that surgical resection should be the initial treatment in patients with NF2. QUESTION 7 Does a multidisciplinary team, consisting of neurosurgery and neurotology, provides the best outcomes of complete resection and facial/vestibulocochlear nerve preservation for patients undergoing resection of VSs? RECOMMENDATION There is insufficient evidence to support stating that a multidisciplinary team, usually consisting of a neurosurgeon and a neurotologist, provides superior outcomes compared to either subspecialist working alone. QUESTION 8 Does a subtotal surgical resection of a VS followed by stereotactic radiosurgery (SRS) to the residual tumor provide comparable hearing and FN preservation to patients who undergo a complete surgical resection? RECOMMENDATION There is insufficient evidence to support subtotal resection (STR) followed by SRS provides comparable hearing and FN preservation to patients who undergo a complete surgical resection. QUESTION 9 Does surgical resection of VS treat preoperative balance problems more effectively than SRS? RECOMMENDATION There is insufficient evidence to support either surgical resection or SRS for treatment of preoperative balance problems. QUESTION 10 Does surgical resection of VS treat preoperative trigeminal neuralgia more effectively than SRS? RECOMMENDATION Level 3: Surgical resection of VSs may be used to better relieve symptoms of trigeminal neuralgia than SRS. QUESTION 11 Is surgical resection of VSs more difficult (associated with higher facial neuropathies and STR rates) after initial treatment with SRS? RECOMMENDATION Level 3: If microsurgical resection is necessary after SRS, it is recommended that patients be counseled that there is an increased likelihood of a STR and decreased FN function. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_8.

Abstract Please see the full-text version of this guideline (https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_3) for the target population of each recommendation listed below. STEREOTACTIC RADIOSURGERY Question 1 What is the overall probability of maintaining serviceable hearing following stereotactic radiosurgery utilizing modern dose planning, at 2, 5, and 10 yr following treatment? Recommendation Level 3 : Individuals who meet these criteria and are considering stereotactic radiosurgery should be counseled that there is moderately high probability (>50%-75%) of hearing preservation at 2 yr, moderately high probability (>50%-75%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 2 Among patients with AAO-HNS (American Academy of Otolaryngology-Head and Neck Surgery hearing classification) class A or GR (Gardner-Robertson hearing classification) grade I hearing at baseline, what is the overall probability of maintaining serviceable hearing following stereotactic radiosurgery, utilizing modern dose planning, at 2, 5, and 10 yr following treatment? Recommendation Level 3 : Individuals who meet these criteria and are considering stereotactic radiosurgery should be counseled that there is a high probability (>75%-100%) of hearing preservation at 2 yr, moderately high probability (>50%-75%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 3 What patient- and tumor-related factors influence progression to nonserviceable hearing following stereotactic radiosurgery using ≤13 Gy to the tumor margin? Recommendation Level 3: Individuals who meet these criteria and are considering stereotactic radiosurgery should be counseled regarding the probability of successful hearing preservation based on the following prognostic data: the most consistent prognostic features associated with maintenance of serviceable hearing are good preoperative word recognition and/or pure tone thresholds with variable cut-points reported, smaller tumor size, marginal tumor dose ≤12 Gy, and cochlear dose ≤4 Gy. Age and sex are not strong predictors of hearing preservation outcome. MICROSURGERY Question 4 What is the overall probability of maintaining serviceable hearing following microsurgical resection of small to medium-sized sporadic vestibular schwannomas early after surgery, at 2, 5, and 10 yr following treatment? Recommendation Level 3 : Individuals who meet these criteria and are considering microsurgical resection should be counseled that there is a moderately low probability (>25%-50%) of hearing preservation immediately following surgery, moderately low probability (>25%-50%) of hearing preservation at 2 yr, moderately low probability (>25%-50%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 5 Among patients with AAO-HNS class A or GR grade I hearing at baseline, what is the overall probability of maintaining serviceable hearing following microsurgical resection of small to medium-sized sporadic vestibular schwannomas early after surgery, at 2, 5, and 10 yr following treatment? Recommendation Level 3: Individuals who meet these criteria and are considering microsurgical resection should be counseled that there is a moderately high probability (>50%-75%) of hearing preservation immediately following surgery, moderately high probability (>50%-75%) of hearing preservation at 2 yr, moderately high probability (>50%-75%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 6 What patient- and tumor-related factors influence progression to nonserviceable hearing following microsurgical resection of small to medium-sized sporadic vestibular schwannomas? Recommendation Level 3: Individuals who meet these criteria and are considering microsurgical resection should be counseled regarding the probability of successful hearing preservation based on the following prognostic data: the most consistent prognostic features associated with maintenance of serviceable hearing are good preoperative word recognition and/or pure tone thresholds with variable cut-points reported, smaller tumor size commonly less than 1 cm, and presence of a distal internal auditory canal cerebrospinal fluid fundal cap. Age and sex are not strong predictors of hearing preservation outcome. CONSERVATIVE OBSERVATION Question 7 What is the overall probability of maintaining serviceable hearing with conservative observation of vestibular schwannomas at 2, 5, and 10 yr following diagnosis? Recommendation Level 3: Individuals who meet these criteria and are considering observation should be counseled that there is a high probability (>75%-100%) of hearing preservation at 2 yr, moderately high probability (>50%-75%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 8 Among patients with AAO-HNS class A or GR grade I hearing at baseline, what is the overall probability of maintaining serviceable hearing with conservative observation at 2 and 5 yr following diagnosis? Recommendation Level 3: Individuals who meet these criteria and are considering stereotactic radiosurgery should be counseled that there is a high probability (>75%-100%) of hearing preservation at 2 yr, and moderately high probability (>50%-75%) of hearing preservation at 5 yr. Insufficient data were available to determine the probability of hearing preservation at 10 yr for this population subset. Question 9 What patient and tumor-related factors influence progression to nonserviceable hearing during conservative observation? Recommendation Level 3: Individuals who meet these criteria and are considering observation should be counseled regarding probability of successful hearing preservation based on the following prognostic data: the most consistent prognostic features associated with maintenance of serviceable hearing are good preoperative word recognition and/or pure tone thresholds with variable cut-points reported, as well as nongrowth of the tumor. Tumor size at the time of diagnosis, age, and sex do not predict future development of nonserviceable hearing during observation. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-manage-ment-patients-vestibular-schwannoma/chapter_3.

Abstract QUESTION 1 What is the expected diagnostic yield for vestibular schwannomas when using a magnetic resonance imaging (MRI) to evaluate patients with previously published definitions of asymmetric sensorineural hearing loss? TARGET POPULATION These recommendations apply to adults with an asymmetric sensorineural hearing loss on audiometric testing. RECOMMENDATION Level 3: On the basis of an audiogram, it is recommended that MRI screening on patients with ≥10 decibels (dB) of interaural difference at 2 or more contiguous frequencies or ≥15 dB at 1 frequency be pursued to minimize the incidence of undiagnosed vestibular schwannomas. However, selectively screening patients with ≥15 dB of interaural difference at 3000 Hz alone may minimize the incidence of MRIs performed that do not diagnose a vestibular schwannoma. QUESTION 2 What is the expected diagnostic yield for vestibular schwannomas when using an MRI to evaluate patients with asymmetric tinnitus, as defined as either purely unilateral tinnitus or bilateral tinnitus with subjective asymmetry? TARGET POPULATION These recommendations apply to adults with subjective complaints of asymmetric tinnitus. RECOMMENDATION Level 3: It is recommended that MRI be used to evaluate patients with asymmetric tinnitus. However, this practice is low yielding in terms of vestibular schwannoma diagnosis (<1%). QUESTION 3 What is the expected diagnostic yield for vestibular schwannomas when using an MRI to evaluate patients with a sudden sensorineural hearing loss? TARGET POPULATION These recommendations apply to adults with a verified sudden sensorineural hearing loss on an audiogram. RECOMMENDATION Level 3: It is recommended that MRI be used to evaluate patients with a sudden sensorineural hearing loss. However, this practice is low yielding in terms of vestibular schwannoma diagnosis (<3%). The full guideline can be found at: https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_2.

Abstract Purpose: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma. Experimental Design: Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749). Tumor expression of the gene that contained the identified prognostic SNP was examined in three separate data sets (total n = 619). Genotype imputation was used to estimate hazard ratios (HR) for SNPs that had not been directly genotyped. Results: From the discovery and validation analyses, we identified a variant in single-stranded DNA-binding protein 2 (SSBP2) on 5q14.1 associated with overall survival in combined analyses (HR, 1.64; P = 1.3 × 10−6). Expression of SSBP2 in tumors from three independent data sets also was significantly related to patient survival (P = 5.3 × 10−4). Using genotype imputation, the SSBP2 SNP rs17296479 had the strongest statistically significant genome-wide association with poorer overall patient survival (HR, 1.79; 95% CI, 1.45-2.22; P = 1.0 × 10−7). Conclusion: The minor allele of SSBP2 SNP rs17296479 and the increased tumor expression of SSBP2 were statistically significantly associated with poorer overall survival among glioblastoma patients. With further confirmation, previously unrecognized inherited variations influencing survival may warrant inclusion in clinical trials to improve randomization. Unaccounted for genetic influence on survival could produce unwanted bias in such studies. Clin Cancer Res; 18(11); 3154–62. ©2012 AACR.