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Introduction Surgical resection has long been the treatment of choice for meningiomas and is considered curative in many cases. Indeed, the extent of resection (EOR) remains a significant factor in determining disease recurrence and outcome optimization for patients undergoing surgery. Although the Simpson Grading Scale continues to be widely accepted as the measure of EOR and is used to predict symptomatic recurrence, its utility is under increasing scrutiny. The influence of surgery in the definitive management of meningioma is being re-appraised considering the rapid evolution of our understanding of the biology of meningioma. Discussion Although historically considered “benign” lesions, meningioma natural history can vary greatly, behaving with unexpectedly high recurrence rates and growth which do not always behave in accordance with their WHO grade. Histologically confirmed WHO grade 1 tumors may demonstrate unexpected recurrence, malignant transformation, and aggressive behavior, underscoring the molecular complexity and heterogeneity. Conclusion As our understanding of the clinical predictive power of genomic and epigenomic factors matures, we here discuss the importance of surgical decision-making paradigms in the context of our rapidly evolving understanding of these molecular features.

PURPOSE Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Chondrosarcoma and chordoma are often grouped together because of their similar anatomic locations, clinical presentations, histopathological and radiological findings, and growth patterns. In the present study, we investigated the clinical and prognostic differences of chondrosarcomas and chordomas of the skull base and spine.We accessed the Surveillance, Epidemiology, and End Results database to search for patients from 2000 to 2018 with chondrosarcomas and chordomas of the skull base and spine for inclusion in the present study.We included 1346 and 1536 cases of chondrosarcoma and chordoma for analysis, respectively. Chondrosarcomas of the cranial base and spine were seen in younger patients and were associated with a larger tumor size compared with chordomas. Among the tumors of the skull base, chondrosarcomas were more common in women, with a male predominance found for chordomas. We also observed a male predilection for both spinal chondrosarcomas and chordomas. Distinct metastatic patterns were found for chondrosarcomas versus chordomas, and spinal chondrosarcomas showed a greater risk of distant metastases at presentation compared with spinal chordomas. Cranial base chondrosarcomas were associated with superior outcomes compared with chordomas. However, we demonstrated an opposite survival pattern for spinal chondrosarcomas and chordomas.Chondrosarcomas and chordomas have divergent clinical manifestations and prognoses depending on the anatomic location.

Objective While the transcondylar approach is technically challenging, it provides generous ventral and caudal exposure to the craniovertebral junction. This approach requires navigation around multiple eloquent neurovascular structures including the lower cranial nerves, vertebral artery and its branches, and the brainstem. Superficial exposure, including incision location and muscle dissection, can dramatically affect the surgical angle and maneuverability at depth. Methods We demonstrate the transcondylar approach in a step-by-step fashion in a formalin-embalmed, latex-injected cadaver head. Dissection within each layer of the suboccipital muscles was performed. A small cohort with an illustrative case is also included herein. Results The sternocleidomastoid (SCM) muscle was retracted anteriorly; the splenium capitis, semispinalis capitis, and longissimus capitis muscles were disconnected from the superior nuchal line and reflected inferomedially. The suboccipital muscle group was fully exposed. The superior and inferior oblique muscles were disconnected from the transverse process of C1. The superior oblique and the rectus capitis posterior major muscles were then dissected off the inferior nuchal line, and the suboccipital muscle group was retracted inferomedially en bloc. The greater auricular nerve was retracted laterally with the SCM, and the greater occipital nerve was retracted inferomedially with the suboccipital muscle group. Conclusions This technique avoids the obstructive muscle bulk that results from a myocutaneous approach while maximizing deep exposure. Understanding the detailed muscular anatomical relationship with the insertion location and suboccipital nerves is key to complete and safe extracranial dissection. Diligent dissection helps minimize postoperative pain and muscle spasm while optimizing the closure technique.

Summary of clinically informative (TARGET) genes.

Supplementary Methods, Figures S1 - S20. Figure S1. Branched evolution leads to tissue-sampling bias in primary tumor samples. Figure S2. Results of ABSOLUTE on samples from patient 418. Figure S3. 2D Bayesian clustering analysis of point-mutation CCF distributions in case 418. Figure S4. Bayesian clustering of private point-mutation CCF distributions in all sequenced tissue samples from case 418. Figure S5. Genetic alterations supporting phylogeny construction in case 418. Figure S6. Phylogenetic tree for case 418 Figure S7. Evolutionary relationships between primary tumor-samples and brain metastasis samples Figure S8. Detection of homozygous deletion in CDKN2A in the brain metastasis of case 24. Figure S9. Amplification of FGFR1 and MYC detected in the brain metastasis of case 331. Figure S10. Additional alterations under investigation for association with various targeted therapies. Figure S11. Power for paired-detection of somatic mutations. Figure S12. Amplification of CCNE1 detected in the brain metastasis of case 314. Figure S13. Amplification of EGFR detected in the brain metastasis of case 314. Figure S14. Amplification of MYC detected in the brain metastasis of case 308. Figure S15. Amplification of MYC detected in the brain metastasis of case 138. Figure S16. Amplifications of CDK6 and MET detected in the brain metastasis of case 138. Figure S17. Amplifications of CCNE1 and AKT2 detected in the brain metastasis of case 138. Figure S18. Amplification of EGFR detected in a regional lymph node from case 296. Figure S19. Power for somatic mutation detection in 86 matched primary-tumor and brain-metastasis samples. Figure S20. Calling of amplifications in primary-tumor samples and paired brain metastases.

BACKGROUND Skull base chordomas are typically extradural and present with cranial nerve deficits, headache, and visual disturbances. Clival chordoma involving the dura and presenting as a spontaneous cerebrospinal fluid (CSF) leak is extremely rare and can be mistaken for other skull base lesions. Here the authors present a case of chordoma with an unusual presentation. OBSERVATIONS A 43-year-old female who presented with clear nasal drainage was diagnosed with CSF rhinorrhea secondary to a clival defect previously thought to be ecchordosis physaliphora. The patient subsequently developed bacterial meningitis and underwent endoscopic, endonasal, transclival gross-total resection of the lesion with repair of the dural defect. Pathology revealed brachyury-positive chordoma. She received adjuvant proton beam radiotherapy and has remained stable for 2 years. LESSONS Spontaneous CSF rhinorrhea can occur as a rare primary presentation of clival chordoma, requiring careful radiological interpretation and a high index of suspicion for diagnosis. Chordoma cannot be reliably differentiated from benign notochordal lesions based on imaging alone; thus, intraoperative exploration and immunohistochemistry play key roles. Clival lesions presenting with CSF rhinorrhea should undergo prompt resection to facilitate diagnosis and prevent complications. Future studies on connections between chordoma and benign notochordal lesions may help to establish management guidelines.

Supplementary File 1. Power for detection of somatic point mutations in coding exons of TARGET genes. The description for the plots in Supplementary File 1 can be found in the Legend of Supplementary Figure S1.

Supplementary File 3. Detailed plots of the data used for phylogenetic inference in each case. The description for the plots in Supplementary File 3 can be found in the Legend of Supplementary Figure S13-S17.

Supplementary File 2. Detailed plots of SCNA calls in TARGET genes. The description for the plots in Supplementary File 2 can be found in the Legend of Supplementary Figure S3.

List of genes in signature of disruption along with disruption scores for functional adenomas

Comparison of gene expression levels

All nonsynonymous mutations detected in WES samples

Histopathologic characteristics of 42 pituitary adenomas

Characteristics of 87 pituitary adenomas from validation cohort

Arm-level SCNAs from paired or imputed copy number data

Imputed copy-number profiles from expression data

Purpose: Pituitary adenomas are the second most common primary brain tumor, yet their genetic profiles are incompletely understood.Experimental Design: We performed whole-exome sequencing of 42 pituitary macroadenomas and matched normal DNA. These adenomas included hormonally active and inactive tumors, ones with typical or atypical histology, and ones that were primary or recurrent.Results: We identified mutations, insertions/deletions, and copy-number alterations. Nearly one-third of samples (29%) had chromosome arm-level copy-number alterations across large fractions of the genome. Despite such widespread genomic disruption, these tumors had few focal events, which is unusual among highly disrupted cancers. The other 71% of tumors formed a distinct molecular class, with somatic copy number alterations involving less than 6% of the genome. Among the highly disrupted group, 75% were functional adenomas or atypical null-cell adenomas, whereas 87% of the less-disrupted group were nonfunctional adenomas. We confirmed this association between functional subtype and disruption in a validation dataset of 87 pituitary adenomas. Analysis of previously published expression data from an additional 50 adenomas showed that arm-level alterations significantly impacted transcript levels, and that the disrupted samples were characterized by expression changes associated with poor outcome in other cancers. Arm-level losses of chromosomes 1, 2, 11, and 18 were significantly recurrent. No significantly recurrent mutations were identified, suggesting no genes are altered by exonic mutations across large fractions of pituitary macroadenomas.Conclusions: These data indicate that sporadic pituitary adenomas have distinct copy-number profiles that associate with hormonal and histologic subtypes and influence gene expression. Clin Cancer Res; 23(7); 1841–51. ©2016 AACR.

Legend for supplementary materials

OBJECTIVE: The hemicraniectomy is a common technique used in a variety of pathologies including some traumatic brain injury and malignant stroke. A novel technique of performing hemicraniectomies using a retro-auricular incision can avoid transgressing the temporalis muscle and superficial temporal artery while providing adequate hemicranial exposure. METHODS: This technique was reproduced in a skull base lab using a cadaveric head. The key steps of this approach were illustrated in step-by-step fashion. A post-approach CT scan of the cadaver was performed to evaluate the decompression exposure. RESULTS: This approach can provide sufficient middle fossa decompression and area of exposure, while preserving the temporalis along with the superficial temporal artery. A step-by-step technical illustration is demonstrated in the present note. CONCLUSIONS: The modified retro-auricular myocutaneous flap is a novel technique in hemicraniectomy which can provide sufficient middle fossa decompression and exposure while sparing the temporalis muscle and superficial temporal artery during the approach.

The COMMD (copper metabolism MURR1 domain containing) family includes ten structurally conserved proteins (COMMD1 to COMMD10) in eukaryotic multicellular organisms that are involved in a diverse array of cellular and physiological processes, including endosomal trafficking, copper homeostasis, and cholesterol metabolism, among others. To understand the role of COMMD10 in embryonic development, we used Commd10Tg(Vav1-icre)A2Kio/J mice, where the Vav1-cre transgene is integrated into an intron of the Commd10 gene, creating a functional knockout of Commd10 in homozygous mice. Breeding heterozygous mice produced no COMMD10-deficient (Commd10Null) offspring, suggesting that COMMD10 is required for embryogenesis. Analysis of Commd10Null embryos demonstrated that they displayed stalled development by embryonic day 8.5 (E8.5). Transcriptome analysis revealed that numerous neural crest-specific gene markers had lower expression in mutant versus wild-type (WT) embryos. Specifically, Commd10Null embryos displayed significantly lower expression levels of a number of transcription factors, including a major regulator of the neural crest, Sox10. Moreover, several cytokines/growth factors involved in early embryonic neurogenesis were also lower in mutant embryos. On the other hand, Commd10Null embryos demonstrated higher expression of genes involved in tissue remodeling and regression processes. Taken together, our findings show that Commd10Null embryos die by day E8.5 due to COMMD10-dependent neural crest failure, revealing a new and critical role for COMMD10 in neural development.

IntroductionWe investigated the clinicopathological features and prognoses of the new molecularly defined entities in latest edition of the World Health Organization (WHO) classification of sinonasal carcinoma (SNC)MethodsIntegrated data were combined into an individual patient data (IPD) meta-analysis.ResultsWe included 61 studies with 278 SNCs including 25 IDH2-mutant, 41 NUT carcinoma, 187 SWI/SNF loss, and 25 triple negative SNCs (without IDH2 mutation, NUTM1 rearrangement, and SWI/SNF inactivation) for analyses. Compared to other molecular groups, NUT carcinoma was associated with a younger age at presentation and an inferior disease-specific survival. Among SNCs with SWI/SNF inactivation, SMARCB1-deficient tumors presented later in life and were associated with a higher rate of radiotherapy administration. SMARCA4-deficiency was mostly found in teratocarcinosarcoma while SMARCB1-deficient tumors were associated with undifferentiated carcinoma and non-keratinizing squamous cell carcinoma.ConclusionOur study facilitates our current understanding of this developing molecular-defined spectrum of tumors and their prognoses.

Venous thromboembolism (VTE), encompassing deep venous thrombosis (DVT) and pulmonary embolism (PE), causes postoperative morbidity and mortality in neurosurgical patients. The use of pharmacological prophylaxis for DVT prevention in the immediate postoperative period carries increased risk of intracranial hemorrhage, especially after skull base surgeries.To investigate the impact of routine Doppler ultrasound monitoring in prevention and tiered management of VTE after skull base surgery.We retrospectively analyzed a large cohort of consecutive adult patients who were prospectively and uniformly managed with routine monitoring by Doppler ultrasound for DVT after resection of a skull base tumor.A total of 389 patients who underwent 459 surgeries for intracranial tumor resection were analyzed. Skull base meningioma was the most common pathology. Forty-four (9.59%) postoperative VTEs were detected: 9 (1.96%) with PE with or without DVT and 35 (7.63%) with DVT alone. Four cases of subsegmental PE were diagnosed without evidence of lower extremity DVT, possibly in the setting of peripherally inserted central catheters maintenance. One patient had a preoperative proximal DVT and underwent a prophylactic inferior vena cava filter but expired from PE after discharge. Prior history of VTE (risk ratio [RR] 5.13; 95% CI 2.76-7.18; P.01), anesthesia duration (RR 1.14; 95% CI 1.03-1.27; P = .02), and blood transfusion (RR 1.95; 95% CI 1.01-3.37; P = .04) were associated with VTE development on multivariate analysis.Routine postoperative venous ultrasound monitoring detects asymptomatic DVT guiding management. This is an alternative strategy to prescribing pharmacological VTE prophylaxis immediately after lengthy surgeries for intracranial tumors. Peripherally inserted central catheters were associated with subsegmental PE.

Neurosurgery at the University of Oklahoma has played a pivotal role in the development of the specialty in the state. Its history spans nearly 90 years, beginning in 1931 when Dr. Harry Wilkins established the first neurosurgical practice in the state at the University of Oklahoma. Together with his first trainee, Dr. Jess Herrmann, Wilkins established the Division of Neurosurgery and its training program in 1946. Through their tireless work, the division and its residency program gained renown for its patient care and teaching, and this tradition was carried forward by its subsequent leaders. The Department of Neurosurgery was established in 1993. From humble beginnings, neurosurgery at the University of Oklahoma has grown a comprehensive residency program with an intensive curriculum, leveraging the clinical and academic breadth afforded by relationships with the College of Medicine, the University of Oklahoma Health Sciences Center, and allied clinical and research partners. Here, the authors recount the history of neurosurgery at the University of Oklahoma, the flagship academic neurosurgical program in the state.

Meningiomas are largely indolent tumors with a benign clinical course, but a minority exhibit aggressive behavior characterized by rapid growth, neurologic deficits, and increased mortality. Identifying high-risk patients requiring intervention is challenging, but recent insights into meningioma biology provide a useful guide for decision making. Standard of care for recurrent or biologically aggressive tumors consists of surgery and radiation therapy. Systemic therapies targeting vascular endothelial growth factor signaling and somatostatin analogues are potential options for those with refractory disease but display only modest activity. New paradigms in meningioma clinical trial design provide hope for improved options in the future.

Purpose To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature. Results Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. Recommendations Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non–small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy. Additional information is available at www.asco.org/neurooncology-guidelines.

Introduction: H3K27M-mutated diffuse midline gliomas (H3-DMGs) are aggressive tumors with a fatal outcome. This study integrating individual patient data (IPD) from published studies aimed to investigate the prognostic impact of different genetic alterations on survival of these patients.Methods: We accessed PubMed and Web of Science to search for relevant articles. Studies were included if they have available data of follow-up and additional molecular investigation of H3-DMGs. For survival analysis, Kaplan-Meier analysis and Cox regression models were utilized, and corresponding hazard ratios (HR) and 95% confidence intervals (CI) were computed to analyze the impact of genetic events on overall survival (OS).Result: We included 30 studies with 669 H3-DMGs. TP53 mutations were the most common second alteration among these neoplasms. In univariate Cox regression model, TP53 mutation was an indicator of shortened survival (HR = 1.446; 95% CI = 1.143-1.829) whereas ACVR1 (HR = 0.712; 95% CI = 0.518-0.976) and FGFR1 mutations (HR = 0.408; 95% CI = 0.208-0.799) conferred prolonged survival. In addition, ATRX loss was also associated with a better OS (HR = 0.620; 95% CI = 0.386-0.996). Adjusted for age, gender, tumor location, and the extent of resection, the presence of TP53 mutations, the absence of ACVR1 or FGFR1 mutations remained significantly poor prognostic factors.Conclusions: We outlined the prognostic importance of additional genetic alterations in H3-DMGs and recommended that these neoplasms should be further molecularly segregated. It could help neuro-oncologists better evaluate the risk stratification of patients and consider pertinent treatments.

Objective The vidian nerve can be accessed in transcranial approaches in carefully selected patients to ensure its preservation and to serve as a landmark for sphenoid sinus entry. This report is to review a technique, evaluate it in laboratory settings, and present two illustrative cases. Design The study involves cadaveric dissection and illustrative cases. Setting The study conducted in a cadaveric dissection laboratory. Participants The object of the study is one cadaveric head and two illustrative clinical cases. Main Outcome Measures Two cases using this approach were illustrated, and a cadaver dissection was performed in a step-by-step fashion. Results: The vidian canal can be accessed by drilling the anterolateral triangle. Two illustrated cases were presented; in one, the vidian nerve was used as part of a corridor to access the sphenoid sinus for tumor delivery, and in the other, the technique was used to find and preserve the vidian nerve during transcranial resection. Conclusion Careful identification of the vidian canal in transcranial surgery is a beneficial technique in carefully selected cases which allows identification of the nerve both for its preservation in selected cases and to create the vidian–maxillary corridor for tumor resection. Knowing the anatomy and pneumatization variants is important in the surgical approach.

Background Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management. Methods We evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms. Results We developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score. Conclusion We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.

Gliosarcoma is an aggressive brain tumor with histologic features of glioblastoma (GBM) and soft tissue sarcoma. Despite its poor prognosis, its rarity has precluded analysis of its underlying biology. We used a multi-center database to characterize the genomic landscape of gliosarcoma. Sequencing data was obtained from 35 gliosarcoma patients from Genomics Evidence Neoplasia Information Exchange (GENIE) 5.0, a database curated by the American Association of Cancer Research (AACR). We analyzed genomic alterations in gliosarcomas and compared them to GBM (n = 1,449) and soft tissue sarcoma (n = 1,042). 30 samples were included (37% female, median age 59 [IQR: 49–64]). Nineteen common genes were identified in gliosarcoma, defined as those altered in > 5% of samples, including TERT Promoter (92%), PTEN (66%), and TP53 (60%). Of the 19 common genes in gliosarcoma, 6 were also common in both GBM and soft tissue sarcoma, 4 in GBM alone, 0 in soft tissue sarcoma alone, and 9 were more distinct to gliosarcoma. Of these, BRAF harbored an OncoKB level 1 designation, indicating its status as a predictive biomarker of response to an FDA-approved drug in certain cancers. EGFR, CDKN2A, NF1, and PTEN harbored level 4 designations in solid tumors, indicating biological evidence of these biomarkers predicting a drug-response. Gliosarcoma contains molecular features that overlap GBM and soft tissue sarcoma, as well as its own distinct genomic signatures. This may play a role in disease classification and inclusion criteria for clinical trials. Gliosarcoma mutations with potential therapeutic indications include BRAF, EGFR, CDKN2A, NF1, and PTEN.

Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship withEligible patients whose tumors screened positively forOf 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients withGSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive

BACKGROUND Olfactory neuroblastomas are rare sinonasal tumors that arise from the olfactory epithelium. The authors presented a case of an olfactory neuroblastoma with extensive cranial invasion that demonstrated dramatic response to sorafenib, a tyrosine kinase inhibitor. OBSERVATIONS A 54-year-old man with history of prostate cancer and melanoma presented with left-sided proptosis and was found to have a 6.5-cm Kadish stage D olfactory neuroblastoma with cranial invasion that was refractory to chemotherapy and everolimus. However, it demonstrated dramatic response to sorafenib, causing extensive skull base defects that prompted operative repair. Genomic analysis of the tumor revealed mutations in TSC1 and SUFU. The patient developed disease progression with liver metastases 35 months after starting sorafenib, prompting a change to lenvatinib. He experienced progression of his olfactory neuroblastoma 10 months following this change and died in hospice 1 month later. LESSONS The authors reviewed the clinical presentation and management of a large olfactory neuroblastoma with dramatic response to sorafenib. They highlighted prior uses of targeted therapy in the management of refractory olfactory neuroblastoma within the context of current standard treatment regimens. Targeted therapies may play a vital role in the management of refractory olfactory neuroblastoma.

Background Programmed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy. Methods Twenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale. Results Enrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO. Conclusion Nivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.

Esthesioneuroblastoma (ENB) is an uncommon primary sinonasal tumor which can extend intracranially. Exactly how to classify them pathologically still remains discrepant; the Hyams grading system, for example, has not been universally adopted. This individual patient data (IPD) meta-analysis aimed to investigate the prognostic implication of each Hyams grade on patient outcomes. We accessed two electronic databases including PubMed and Web of Science. Raw patient data from potential articles were extracted. To examine the associations of various clinicopathological factors with the Hyams grades, we utilized Chi-square, t-test, and Mann–Whitney, as appropriate. Log-rank test and Cox regression analysis were used to elucidate the impact of the Hyams grades on recurrence-free survival (RFS), metastasis-free survival (MFS), and overall survival (OS) of ENB patients. We included 33 studies with 492 ENB patients. We found significant associations of Kadish stages, Dulguerov stages, rates of recurrence, metastasis, and patient mortality with Hyams grade. Log-rank tests and Cox regression models demonstrated significant differences in RFS and OS of Hyams grade I – II, grade III, and grade IV patients. There was no statistical difference in RFS and OS of Hyams grade I and II. Radiotherapy was only effective in grade III – IV ENBs and chemotherapy showed no benefits to patients. We verify that the Hyams grading system appears to be a reliable prognostic indicator to assess ENB patient outcomes. Consolidating the Hyams grading system into a three-tier system based on similar clinical outcomes of grades I and II may simplify this classification schema.