Search

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

Background The mainstay treatment for petrous apicitis (Gradenigo’s syndrome) is medical management with antibiotics, steroids, and placement of pressure equalization tubes. The role for surgery is limited as second-line treatment if conservative methods have failed. Case Description We report 2 cases of medically refractory petrous apicitis presenting with progressive cranial neuropathies who underwent petrous apex resection and debridement via an anterior petrosal (Kawase) approach. Both patients had improvement of their preoperative cranial nerve deficits within 24–48 hours of surgery, that previously did not improve after 2 weeks of medical management. Conclusions To our knowledge, the use of the Kawase approach for petrous apicitis has not been previously reported. In addition, we postulate that surgical intervention can potentially result in quicker recovery of preexisting cranial nerve deficits in medically refractory petrous apicitis. This raises the potential role of earlier surgical intervention.

Background Rathke cleft cysts (RCCs) are sellar-based cystic lesions that are often found incidentally but occasionally become symptomatic with significant visual and/or endocrine deficits. The standard of treatment is surgery, but rare cases of multiply recurrent RCCs can be refractory to surgical drainage, leading to significant morbidity. Objective To demonstrate the safety and feasibility of fractionated stereotactic radiotherapy (SRT) as salvage therapy in multiply recurrent RCCs refractory to surgical drainage. Methods An IRB-approved retrospective review at a single institution was conducted to identify and describe patients with multiply recurrent RCCs refractory to surgical drainage who underwent SRT. Results From 1994 to 2015, 6 patients (5 female) who underwent SRT for recurrent RCCs were identified. A total of 4 presented with visual deficits, and 2 presented with endocrine dysfunction and severe headaches prior to their initial drainage. All patients had initial postoperative improvement but then developed multiple, symptomatic recurrences. Median number of surgical drainage procedures prior to radiotherapy was 3. A total of 3 patients underwent LINAC-based SRT, and 3 had proton-based SRT. Treatment doses were 45 Gy over 25 fractions (n = 5) and 50.4 Gy over 28 fractions (n = 1). Median follow-up after radiation therapy was 69 mo (range 24-154 mo). In the follow-up period, stabilization of the RCC was achieved, although 2 patients required additional drainage procedures. Only 1 patient developed new hypothyroidism and hypoadrenalism after SRT. Conclusion In rare cases of multiply recurrent RCCs refractory to repeat surgical drainage, stereotactic fractionated radiation therapy is a safe and effective salvage therapy.

BACKGROUND: Recurrent atypical and malignant meningiomas have poor outcomes with surgical therapy alone. Neither adjuvant chemotherapy nor postoperative radiation therapy remedies this problem. OBJECTIVE: To evaluate our experience with the treatment of 15 patients treated with I-125 or Cs-131 brachytherapy radiation seeds as an adjuvant in these difficult cases. METHODS: Patients with high-grade recurrent meningioma who underwent resection and intraoperative placement of brachytherapy seeds at our institution from 2002 to 2014 were identified and studied by retrospective chart review. RESULTS: Fifteen patients with median age of 68.8 yr were treated with I-125 (n = 13) or Cs-131 (n = 2) brachytherapy seeds for cases of recurrent, grade II (n = 8), or grade III (n = 7) meningioma at our institution from 2002 to 2014. These lesions originated from a variety of locations including, convexity (3), falcine (3), frontal (2), occipital (1), parietal (2), 2 sphenoid wing (2), and temporal (2), based recurrent meningiomas. Patients had a median of 2 prior open surgical interventions and received local radiation therapy with a median dose of 55 Gy prior to brachytherapy. Survival at 2.5 yr was 56% for grade II and 17% for grade III lesions. Survival was significantly associated with patient age but not tumoral pathology. Forty percent of patients required reoperations for wound complications following brachytherapy. CONCLUSION: Brachytherapy with implantation of permanent radiation seeds provides a viable alternative treatment for recurrent meningioma while carrying a significant clinical risk of wound infection and need for reoperation.

2000 Background: Craniopharyngiomas, a rare brain tumor along the pituitary-hypothalamic axis, can cause significant clinical sequelae. Surgery and radiation, the only effective treatments, can cause significant morbidity. Genetic analysis of craniopharyngiomas revealed that 95% of papillary craniopharyngiomas (PCP) have BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). We evaluated the efficacy of BRAF/MEK inhibition in patients (pts) with previously untreated PCP. Methods: Eligible pts without prior radiation whose PCP screened positively for BRAF mutations were treated with oral vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of response rate (RR) based on centrally determined volumetric data was evaluated in 16 pts, where a partial response was defined as >20% decrease in volume. This single arm, Simon two-stage phase 2 trial had 89% power to detect a true RR of at least 30% (vs. the null RR 5%; alpha=0.04). In this design, 3 or more observed volumetric responses in 16 evaluable pts would be considered promising activity. Results: In the 16 pts evaluated, 56% were female, and the median age was 49.5 years. Median follow-up was 22 months (95% CI: 16-26.5) and median number of treatment cycles was 8. Three patients progressed after therapy was discontinued and none have died. Based on volumetric response criteria, 14 of 15 pts with volumetric data available for central review had response to therapy (93%; 95% CI: 68% to 99.8%). Of 16 patients evaluable based on local review, 15 had response to therapy (93.75%; 95% CI: 70% to 99.8%). The median tumor reduction was -83% (range: -52% to -99%). The one nonresponder received 2 days of treatment before coming off therapy due to toxicity. Median progression-free survival was not reached. Grade 3 toxicities at least possibly related to treatment occurred in 12 pts (rash in 6 pts). Grade 4 toxicities were observed in two pts: hyperglycemia (n=1) and increased CPK (n=1). Three pts discontinued treatment for adverse events. Conclusions: Vemurafenib/cobimetinib resulted in an objective response in all pts who received 1 or more cycles of therapy. Our study indicates that BRAF/MEK inhibitors could be a powerful tool in the treatment of previously untreated PCP and warrants further evaluation in larger studies. A second arm of this study is enrolling pts with progressive PCP after prior radiotherapy. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; https://acknowledgments.alliancefound.org. Clinical trial information: NCT03224767.

Background Posterior fossa surgery is particularly prone to cerebrospinal fluid (CSF) leakage. Several methods have been introduced to address and/or prevent this complication. However, to the best of our knowledge, the use of a vascularized fascial flap based on the occipital artery for the purpose of reconstruction has not been reported. We introduce the occipital fascial flap (OFF) for reconstruction of a craniectomy defect after the retrosigmoid approach. Methods A 57-year-old woman with a large cerebellar metastasis underwent gross total resection of the mass followed by reconstruction of the craniectomy defect using OFF. Results Postoperative imaging showed flap viability and no CSF leak occurred during follow-up. Conclusions We report the first use of OFF for reconstruction of a craniectomy defect in a retrosigmoid approach. The vascularized fascial flap in posterior fossa surgery is a potentially helpful technique to reduce the risk of CSF leak in high-risk patients.

Background: While there are reports of acute ischemic stroke (AIS) in COVID-19 patients, the overall incidence of acute ischemic stroke and clinical characteristics of large vessel occlusion in such patient remains to be established. Methods: A retrospective, international multicenter study of large vessel occlusion (LVO) was undertaken from March 1 to May 1, 2020 at 12 stroke centers from 4 countries. Detailed data were collected on consecutive LVOs in hospitalized patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the incidence of AIS/LVO was measured. Among patients who underwent mechanical thrombectomy, stroke outcomes along with COVID-19 symptoms were reported. Results: Out of a total of 6698 COVID-19 patients admitted to 10 stroke centers, the incidence of stroke was found to be 1.3% (range 0.6-2.6%). The median age of patients who presented with LVO was 51 years (range 27-87) and in the US centers, African Americans comprised 28% of all patients. Ten patients (16 %) were less than 50 years of age with no significant risk factors for LVOs the vast majority. Among the LVOs eligible for MT, the average time to presentation from symptom onset to presentation was 9.3 hours. Successful revascularization was achieved in 81% of patients and the intracranial hemorrhage rate was 14% with no symptomatic hemorrhages. Twenty-one (50%) patients were either discharged to home or to acute rehabilitation facilities. Conclusion: LVOs was predominant in patients with AIS and COVID-19, occurring at a significantly younger age and affecting African Americans disproportionately.

BackgroundThe neutrophil–lymphocyte ratio (NLR) is emerging as an important biomarker of acute physiologic stress in a myriad of medical conditions, and is a confirmed poor prognostic indicator in COVID-19.ObjectiveWe sought to describe the role of NLR in predicting poor outcome in COVID-19 patients undergoing mechanical thrombectomy for acute ischemic stroke.MethodsWe analyzed NLR in COVID-19 patients with large vessel occlusion (LVO) strokes enrolled into an international 12-center retrospective study of laboratory-confirmed COVID-19, consecutively admitted between March 1, 2020 and May 1, 2020. Increased NLR was defined as ≥7.2. Logistic regression models were generated.ResultsIncidence of LVO stroke was 38/6698 (.57%). Mean age of patients was 62 years (range 27–87), and mortality rate was 30%. Age, sex, and ethnicity were not predictive of mortality. Elevated NLR and poor vessel recanalization (Thrombolysis in Cerebral Infarction (TICI) score of 1 or 2a) synergistically predicted poor outcome (likelihood ratio 11.65, p = .003). Patients with NLR > 7.2 were 6.8 times more likely to die (OR 6.8, CI95% 1.2–38.6, p = .03) and almost 8 times more likely to require prolonged invasive mechanical ventilation (OR 7.8, CI95% 1.2–52.4, p = .03). In a multivariate analysis, NLR > 7.2 predicted poor outcome even when controlling for the effect of low TICI score on poor outcome (NLR p = .043, TICI p = .070).ConclusionsWe show elevated NLR in LVO patients with COVID-19 portends significantly worse outcomes and increased mortality regardless of recanalization status. Severe neuro-inflammatory stress response related to COVID-19 may negate the potential benefits of successful thrombectomy.

BackgroundThe transradial approach (TRA) is frequently used for neurointerventional procedures as it is safer, improves patient comfort, and decreases costs and procedural time in comparison with the transfemoral approach (TFA). Patients with arteria lusoria, or an aberrant right subclavian artery (ARSA), provide a unique challenge for cerebral angiography and interventions when using the TRA.ObjectiveTo examine the hypothesis that the extreme angulation encountered while accessing the great vessels from the right TRA could be overcome by reversing the approach to the left distal TRA (dTRA).MethodsA prospectively maintained database of transradial neurointerventional cases since 2018 was searched. Six cases from 850 were identified, in which the left dTRA was used. Three cases were for patients with an ARSA. For the three cases of interest, patient history, pathology, imaging, and access techniques were reviewed.ResultsTwo diagnostic cerebral angiography cases and one intervention were successfully performed through a left dTRA.ConclusionsProper positioning of the left wrist and familiarity with forming the Simmons catheter can overcome this anatomical challenge. This technique and results further demonstrate that the left distal radial artery is a feasible access site for catheterization of bilateral carotid, left vertebral, and right subclavian arteries for patients with an ARSA.

Importance: Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is a global pandemic that has been an i

PURPOSE Standard of care for craniopharyngiomas is surgery with or without radiotherapy (RT). Cohort A of Alliance A071601 evaluated the efficacy of BRAF/MEK inhibition with vemurafenib/cobimetinib in patients with previously untreated papillary craniopharyngiomas (PCP), which carry the BRAF V600E mutation. Cohort B is currently enrolling patients with recurrence after RT. In a correlative analysis, we examined changes in RT volumes after BRAF/MEK therapy in Cohort A. METHODS Previously unirradiated patients with BRAF-mutated PCP were treated with vemurafenib/cobimetinib. Sixteen patients had scans available before starting vemurafenib/cobimetinib (“pre-therapy”) and after completing therapy (“post-therapy”). Two patients went off study treatment after 8 and 9 days due to side-effects and were excluded for this analysis. Gross target volumes (GTV) were contoured on pre-therapy and post-therapy scans. On post-therapy scans, an additional target comprising gross disease and at-risk regions for microscopic residual disease (GTV-micro) was defined and considered the treatment volume. Clinical target volume (CTV) was a 5-mm uniform expansion on pre-therapy GTV and post-therapy GTV-micro. Volumes were independently reviewed by two radiation oncologists. Changes in volumes from pre- versus post-therapy were compared using the Wilcoxon signed rank test. RESULTS In 14 patients evaluated, 57% were female and median age at enrollment was 49.5 years (range 33-83). Median time on treatment was 8.9 months (range 4.0-18.0). Median GTV pre-therapy was 3.8 mL (range 0.2-23.4) versus 0.3 mL (range 0.0-3.2) post-therapy (p=0.0001) and 1.7 mL (range 0.1-8.0) post-therapy GTV-micro (p=0.0001). Median CTV pre-therapy was 13.7 mL (range 2.8-51.8) versus 9.1 mL (range 2.2-27.5) post-therapy (p=0.0001). All tumors abutted the optic chiasm pre-therapy, only 6 did post-therapy. CONCLUSIONS Vemurafenib/cobimetinib resulted in smaller RT volumes. BRAF/MEK inhibitors could reduce RT volumes and spare dose to surrounding normal structures. Enrollment to Cohort B of Alliance A071601 should be considered for patients with recurrent tumors after RT. SUPPORT https://acknowledgments.alliancefound.org

BACKGROUND While there are reports of acute ischemic stroke (AIS) in coronavirus disease 2019 (COVID-19) patients, the overall incidence of AIS and clinical characteristics of large vessel occlusion (LVO) remain unclear. OBJECTIVE To attempt to establish incidence of AIS in COVID-19 patients in an international cohort. METHODS A cross-sectional retrospective, multicenter study of consecutive patients admitted with AIS and COVID-19 was undertaken from March 1 to May 1, 2020 at 12 stroke centers from 4 countries. Out of those 12 centers, 9 centers admitted all types of strokes and data from those were used to calculate the incidence rate of AIS. Three centers exclusively transferred LVO stroke (LVOs) patients and were excluded only for the purposes of calculating the incidence of AIS. Detailed data were collected on consecutive LVOs in hospitalized patients who underwent mechanical thrombectomy (MT) across all 12 centers. RESULTS Out of 6698 COVID-19 patients admitted to 9 stroke centers, the incidence of stroke was found to be 1.3% (interquartile range [IQR] 0.75%-1.7%). The median age of LVOs patients was 51 yr (IQR 50-75 yr), and in the US centers, African Americans comprised 28% of patients. Out of 66 LVOs, 10 patients (16%) were less than 50 yr of age. Among the LVOs eligible for MT, the average time from symptom onset to presentation was 558 min (IQR 82-695 min). A total of 21 (50%) patients were either discharged to home or discharged to acute rehabilitation facilities. CONCLUSION LVO was predominant in patients with AIS and COVID-19 across 2 continents, occurring at a significantly younger age and affecting African Americans disproportionately in the USA., Graphical Abstract Graphical Abstract

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.

We present a case of the spinal accessory nerve traversing a fenestrated internal jugular vein. Awareness of this variant may be important in neurosurgical procedures that involve upper cervical exposures.

Intracranial aneurysms pose a significant clinical challenge for cerebrovascular and endovascular neurosurgeons both in treatment decision-making and in the technical aspects. The most important question is whether the aneurysm has ruptured, thereby necessitating urgent treatment. In the unruptured ophthalmic artery aneurysm case with vision loss, the decision to treat rests on understanding the risk of hemorrhage, the success in addressing neurological deficits, and the morbidity of any potential treatment. Computed tomography angiography, conventional angiography, and magnetic resonance imaging are critical and complementary in the diagnosis and management of ophthalmic artery aneurysms, which have also been termed paraclinoid or junctional aneurysms. Due to technological advances, multiple treatment methods are possible, including surgical clipping, endovascular coiling, and flow diversion. Flow diversion is emerging as an effective, less invasive technique with good vision outcomes. This chapter discusses the data behind decision-making, reviews the surgical technique of flow diversion, and emphasizes important aspects of perioperative management.

Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.

Meningiomas are the most common primary intracranial neoplasms in adults. Current histopathological grading schemes do not consistently predict their natural history. Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. Furthermore, the recent application of unbiased next-generation sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine.

Cerebral arteriovenous malformations (AVM) are traditionally considered primary congenital lesions that result from embryological aberrations in vasculogenesis. Recent insights, however, suggest that these lesions may be secondary to a vascular insult such as ischemia or trauma. Herein, the authors present a rare case of a secondary cerebral AVM, occurring in a young girl who received prior cranial radiation therapy. At age 3years, she underwent surgical resection, chemotherapy, and photon radiation therapy for treatment of a fourth ventricular ependymoma. At age 19years, she developed new onset seizures and was found to have a left medial temporal lobe AVM. Her seizures were managed successfully with anti-epileptic medications and the AVM was treated with proton radiation therapy. This case highlights a rare but possible vascular sequela of radiation therapy and adds to the growing body of evidence that cerebral AVM may arise as secondary lesions.

// Michael B. Miller 1, * , Wenya Linda Bi 2, 3, 10 , * , Lori A. Ramkissoon 4 , Yun Jee Kang 4 , Malak Abedalthagafi 1 , David S. Knoff 4 , Pankaj K. Agarwalla 3, 5 , Patrick Y. Wen 4, 10 , David A. Reardon 4, 10 , Brian M. Alexander 6, 7, 10 , Edward R. Laws Jr. 2, 10 , Ian F. Dunn 2, 10 , Rameen Beroukhim 3, 4, 8, 10 , Keith L. Ligon 1, 4, 8, 9, 10 , Shakti H. Ramkissoon 1, 4, 9, 10 1 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA 2 Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 5 Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA 6 Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA 7 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 8 Broad Institute of MIT and Harvard, Cambridge, MA, USA 9 Department of Pathology, Boston Children’s Hospital, Boston, MA, USA 10 Harvard Medical School, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Shakti H. Ramkissoon, e-mail: sramkissoon@partners.org Keith L. Ligon, e-mail: keith_ligon@dfci.harvard.edu Keywords: spindle cell oncocytoma, pituitary, MAPK, HRAS, genomics Received: February 08, 2016 Accepted: April 16, 2016 Published: May 09, 2016 ABSTRACT Pituitary spindle cell oncocytoma (SCO) is an uncommon primary pituitary neoplasm that presents with mass effect on adjacent neurovascular structures, similar to non-hormone-producing pituitary adenomas. To determine the molecular etiology of SCO, we performed exome sequencing on four SCO cases, with matched normal controls, to assess somatic mutations and copy number alterations. Our analysis revealed a low mutation rate and a copy-neutral profile, consistent with the low-grade nature of this tumor. However, we identified a co-occurring somatic HRAS (p.Q61R) activating point mutation and MEN1 frameshift mutation (p.L117fs) present in a primary and recurrent tumor from one patient. Other SCOs demonstrated mutations in SND1 and FAT1 , which are associated with MAPK pathway activation. Immunohistochemistry across the SCO cohort demonstrated robust MAPK activity in all cases (n=4), as evidenced by strong phospho-ERK staining, while phospho-AKT levels suggested only basal levels of PI3K pathway activation. Taken together, this identifies the MAPK signaling pathway as a novel therapeutic target for spindle cell oncocytoma, which may offer a powerful adjunct for aggressive tumors refractory to surgical resection.

Background Zygomatic osteotomy, an adjunct to middle cranial fossa (MCF) surgical approaches, improves the superior-inferior angle of approach and minimizes temporal lobe retraction. However, a decision-making algorithm for selective use of the zygomatic osteotomy and the impact of the zygomatic osteotomy on surgical complications have not been well documented. Objective We described an algorithm for deciding whether to use a zygomatic osteotomy in MCF surgery and evaluated complications associated with a zygomatic osteotomy. Methods A retrospective review of MCF cases over 11 years at our academic tertiary referral center was conducted. Demographic variables, tumor characteristics, surgical details, and postoperative complications were extracted. Results Of the 87 patients included, 15 (17%) received a zygomatic osteotomy. Surgical trajectory oriented from anterior to posterior (A-P) was significantly correlated with the use of the zygomatic osteotomy. Among the cases approached from A-P, we found (receiver-operating characteristic curve) that the cut-off tumor size that predicted a zygomatic osteotomy was 30 mm. Of the 87 cases included, 15 patients had a complication. The multivariate logistic regression model failed to reveal any significant correlation between complications and zygomatic osteotomies. Conclusions We found that the most important factor determining the use of a zygomatic osteotomy was anticipated trajectory. A-P approaches were most highly correlated with zygomatic osteotomy. Within those cases, a lesion size cut-off of 30 mm was the secondary predicting factor of zygomatic osteotomy use. The odds of suffering a surgical complication were not significantly increased by use of zygomatic osteotomy.

Object Moyamoya disease/syndrome (MMD/S) is a progressive, occlusive vasculopathy of the intracranial vasculature that leads to ischemic and hemorrhagic strokes. Significant debate exists regarding the role of indirect cerebrovascular bypass surgery in its management. The authors review their institution's experience with indirect bypass in the surgical management of patients with MMD/S. Methods The authors conducted a retrospective review of patients with MMD/S who underwent encephaloduroarteriosynangiosis (EDAS), a form of indirect bypass, from 1996 to 2013. Results A total of 37 patients (52 hemispheres) underwent an EDAS procedure for MMD/S; 21 patients received revascularization of both hemispheres. Patients presented with the following: 49% with stroke, 35% with transient ischemic attack, 13% with hemorrhage, and 3% with seizure. The mean Suzuki grade was 3.46. The number of patients with a modified Rankin Scale score of 0–1 improved from 21 to 29 (p = 0.002) from the time of surgery to the time of last follow-up. The number of neurological events (i.e., transient ischemic attacks, strokes, and hemorrhages) decreased from a mean of 1.7 events per patient to 0.14 (p < 0.001). The mean length of follow-up was 32.8 months. Conclusions This series demonstrates that EDAS is an effective procedure for MMD/S in a North American cohort of patients.

Background and importance Persistent trigeminal artery (PTA) is a rare but important anatomic variant that contributes to trigeminal neuralgia (TN). Microvascular decompression (MVD) of the responsible vessel(s) away from the trigeminal nerve provides the most complete and durable relief from TN. The role and technique of MVD for TN associated with a PTA has not been fully defined in the literature. Furthermore, assessment of PTA anatomy intraoperatively with a microscope is challenging. We report the first 3-dimensional (3D) microscopic video and first intraoperative endoscopic video of a successful MVD of the trigeminal nerve in a patient who suffered TN from a tortuous, compressive PTA. Clinical presentation A 66-yr-old right-handed female presented with right facial pain in V2 and V3 distributions with a clinical picture of TN. Imaging demonstrated trigeminal nerve compression secondary to a PTA and MVD was performed with a 3D operative microscope and an endoscope. The PTA appeared to compress the nerve directly at the trigeminal porus and also had compressive superior cerebellar artery variant branches. The nerve was decompressed at all points of compression with Teflon pledgets along its entire cisternal length. Postoperatively, she is free with trigeminal pain episodes at 4-mo follow-up. Conclusion In cases of TN associated with a PTA, we recommend decompression along the entire length of the nerve wherever there is compression. Furthermore, we find both the operative microscope and particularly the endoscope useful to assess vascular anatomy intraoperatively.

High-grade meningiomas frequently recur and are associated with high rates of morbidity and mortality. To determine the factors that promote the development and evolution of these tumors, we analyzed the genomes of 134 high-grade meningiomas and compared this information with data from 587 previously published meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any statistically significant mutated genes aside from

High-grade meningiomas frequently recur and are associated with high rates of morbidity and mortality. To determine the factors that promote the development and evolution of these tumors, we analyzed the genomes of 134 high-grade meningiomas and compared this information with data from 595 previously published meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any significantly mutated genes aside from NF2. High-grade meningiomas also possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22. Meningiomas previously treated with adjuvant radiation had significantly more copy number alterations than radiation-induced or radiation-naïve meningiomas. Across serial recurrences, genomic disruption preceded the emergence of nearly all mutations, remained largely uniform across time, and when present in low-grade meningiomas correlated with subsequent progression to a higher grade. In contrast to the largely stable copy number alterations, mutations were strikingly heterogeneous across tumor recurrences, likely due to extensive geographic heterogeneity in the primary tumor. While high-grade meningiomas harbored significantly fewer overtly targetable alterations than low-grade meningiomas, they contained numerous mutations that are predicted to be neoantigens, suggesting that immunologic targeting may be of therapeutic value., Brain tumors: uncovering genomic disruption in meningiomas Meningiomas, which arise from the tissue surrounding the brain and spinal cord, are the most common primary brain tumor in adults. The majority of these are slow-growing and amenable to surgical resection, if treatment is indicated. However, a subset of aggressive meningiomas are considered high-grade, producing significantly worse mortality. In a first study of its kind, Drs. Wenya Linda Bi, Ian Dunn, Sandro Santagata, Rameen Beroukhim, and colleagues at Harvard Medical School sequenced the genomes of 134 high-grade meningiomas and compared their makeup with lower-grade meningiomas. They found that aggressive tumors were more likely to harbor mutations in the NF2 gene and exhibit widespread genomic disruption. They also harbored an elevated rate of predicted immunogenic mutations, with implications for the use of immuno-modulatory therapies.

Background. Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making. Methods. To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas. Results. The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome. Conclusion. We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.

Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency., National Cancer Institute (U.S.) (R01 CA188228), National Cancer Institute (U.S.) (U01 CA176058), National Cancer Institute (U.S.) (F30 CA192725)

OBJECTIVE Vascular malformations of the spine represent rare clinical entities with profound neurological implications. Previously reported studies on management strategies for spinal dural arteriovenous fistulas (sDAVFs) appeared before the advent of modern liquid embolic agents. Authors of the present study review their institutional experience with endovascularly and surgically treated sDAVFs. METHODS The authors performed a retrospective, observational, single-center case series on sDAVFs treated with endovascular embolization, microsurgical occlusion, or both between 2004 and 2013. The mode, efficacy, and clinical effect of treatment were evaluated. RESULTS Forty-seven patients with spinal arteriovenous malformations were evaluated using spinal angiography, which demonstrated 34 Type I sDAVFs (thoracic 20, lumbar 12, and cervical 2). Twenty-nine of the patients (85%) were male, and the median patient age was 63.3 years. Twenty patients underwent primary endovascular embolization (16 Onyx, 4 N-butyl cyanoacrylate [NBCA]), and 14 underwent primary surgical clipping. At a mean follow-up of 36 weeks, according to angiography or MR angiography, 5 patients treated with endovascular embolization demonstrated persistent arteriovenous shunting, whereas none of the surgically treated patients showed lesion persistence (p = 0.0237). Thirty patients (88%) experienced some resolution of their presenting symptoms (embolization 17 [85%], surgery 13 [93%], p = 1.00). CONCLUSIONS Microsurgical occlusion remains the most definitive treatment modality for sDAVFs, though modern endovascular techniques remain a viable option for the initial treatment of anatomically amenable lesions. Treatment of these lesions usually results in some clinical improvement.