Leveraging single-cell sequencing to classify and characterize tumor subgroups in bulk RNA-sequencing data.

PURPOSE: Accurate classification of cancer subgroups is essential for precision medicine, tailoring treatments to individual patients based on their cancer subtypes. In recent years, advances in high-throughput sequencing technologies have enabled the generation of large-scale transcriptomic data from cancer samples. These data have provided opportunities for developing computational methods that can improve cancer subtyping and enable better personalized treatment strategies. METHODS: Here in this study, we evaluated different feature selection schemes in the context of meningioma classification. To integrate interpretable features from the bulk (n = 77 samples) and single-cell profiling (∼ 10 K cells), we developed an algorithm named CLIPPR which combines the top-performing single-cell models, RNA-inferred copy number variation (CNV) signals, and the initial bulk model to create a meta-model. RESULTS: While the scheme relying solely on bulk transcriptomic data showed good classification accuracy, it exhibited confusion between malignant and benign molecular classes in approximately ∼ 8% of meningioma samples. In contrast, models trained on features learned from meningioma single-cell data accurately resolved the sub-groups confused by bulk-transcriptomic data but showed limited overall accuracy. CLIPPR showed superior overall accuracy and resolved benign-malignant confusion as validated on n = 789 bulk meningioma samples gathered from multiple institutions. Finally, we showed the generalizability of our algorithm using our in-house single-cell (∼ 200 K cells) and bulk TCGA glioma data (n = 711 samples). CONCLUSION: Overall, our algorithm CLIPPR synergizes the resolution of single-cell data with the depth of bulk sequencing and enables improved cancer sub-group diagnoses and insights into their biology.

The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Clinical characteristics and outcomes after trigeminal schwannoma resection: a multi-institutional experience.

Given their rarity, the clinical course of patients undergoing trigeminal schwannoma (TS) resection remains understudied. The objective of this study is to describe clinical characteristics and outcomes in patients undergoing surgical resection for TS in a multi-institutional cohort. This is a retrospective study of patients undergoing TS resection at two institutions between 2004 and 2022. Patient, radiographic, and clinical characteristics were reviewed and analyzed with standard statistical methods. Thirty patients were included. The median patient age was 43 (IQR: 35-52) years, and 14 (47%) patients were female. Median clinical and radiographic follow-ups were 43 (IQR: 20-81) and 47 (IQR: 27-97) months respectively. The most common presenting symptoms were trigeminal hypesthesia (57%) and headaches (30%), diplopia (30%), and ataxia/cerebellar signs (30%). The median maximum tumor diameter was 3.3 (IQR: 2.5-5.4) cm. Most tumors were Samii type C (50%) and mixed cystic-solid (63%). Surgical approaches included endoscopic endonasal (33%), supratentorial (30%), combined/staged (20%), infratentorial (10%), and anterior petrosal (7%) approaches. Gross-total resection was achieved in 16 (53%) patients. Radiographic tumor recurrence was noted in four patients at a median of 79 (range 5-152) months. Twenty-six (87%) patients reported improvements in at least one symptom by last follow-up. The most common perioperative complication was new cranial nerve deficit, with 17% of patients having a transient deficit and 10% having a permanent cranial nerve deficit. Surgical resection of TS showed good progression-free survival and symptom improvement, but was associated with cranial nerve deficits.

Long-term antiseizure medication use in patients after meningioma resection: identifying predictors for successful weaning and failures.

OBJECTIVE: To define risk factors for meningioma-related seizures and predictors of successful weaning of antiseizure medications following meningioma resection. METHODS: This is a retrospective study of 95 patients who underwent meningioma resection at a single institution. Primary outcome analyzed was ability to achieve seizure freedom without the use of anti-seizure medication at 6-months, 1-year, and last known follow up. Secondary outcome was postoperative seizure freedom. RESULTS: Preoperative seizures (OR: 11.63, 95% CI [3.64, 37.17], p < 0.0001), non-skull base tumor location (OR: 3.01, 95% CI [1.29, 7.02], p = 0.0128), and modified STAMPE score of 3-5 (OR: 5.42, 95% CI [2.18, 13.52], p = 0.0003) were associated with greater likelihood of remaining on antiseizure medication at 6-month follow up. Preoperative seizures (OR: 4.93, 95% CI: [2.00, 12.16 ], p = 0.0008), intratumoral calcifications (OR: 4.19, 95% CI: [1.61, 14.46], p = 0.0055), modified STAMPE score of 3-5 (OR: 5.42, CI [2.18, 13.52], p = 0.0003), and Ki67 greater than 7% (OR: 5.68, CI [1.61, 20.10], p = 0.0060) were significant risk factors for inability to discontinue ASMs by last follow up. Preoperative seizures (OR: 4.33, 95% CI [1.59, 11.85], p = 0.0050) and modified STAMPE score of 3-5 (OR: 6.09, 95% CI [2.16, 17.20], p = 0.0007) were significant risk factors for postoperative seizures. CONCLUSIONS: Preoperative seizures, modified STAMPE2 score of 3-5, non-skull base tumor location, intratumoral calcifications, and Ki67 > 7% were significant risk factors for inability to achieve seizure freedom without ASMs. In addition, the modified STAMPE2 score successfully predicted increased seizure risk following meningioma resection for patients with a score of 3 or higher.

Outcomes following surgical resection of trigeminal schwannomas: a systematic review and meta-analysis.

Although typically benign, trigeminal schwannomas (TS) may require surgical resection when large or symptomatic and can cause significant morbidity. This study aims to summarize the literature and synthesize outcomes following surgical resection of TS. A systematic review was performed according to PRISMA guidelines. Data extracted included patient and tumor characteristics, surgical approaches, and postoperative outcomes. Odds ratios (OR) with corresponding 95% confidence intervals (CI) were used for outcome analysis. The initial search yielded 1838 results, of which 26 studies with 974 patients undergoing surgical resection of TS were included. The mean age was 42.9 years and 58.0% were female. The mean tumor diameter was 4.7 cm, with Samii type A, B, C, and D tumors corresponding to 33.4%, 15.8%, 37.2%, and 13.6%, respectively. Over a mean symptom duration of 29 months, patients presented with trigeminal hypesthesia (58.7%), headache (32.8%), trigeminal motor weakness (22.8%), facial pain (21.3%), ataxia (19.4%), diplopia (18.7%), and visual impairment (12.0%). Surgical approaches included supratentorial (61.4%), infratentorial (15.0%), endoscopic (8.6%), combined/staged (5.3%), and anterior (5.7%) or posterior (4.0%) petrosectomy. Postoperative improvement of facial pain (83.9%) was significantly greater than trigeminal motor weakness (33.0%) or hypesthesia (29.4%). The extent of resection (EOR) was reported as gross total (GTR), near total, and subtotal in 77.7%, 7.7%, and 14.6% of cases, respectively. Over a mean follow-up time of 62.6 months, recurrence/progression was noted in 7.4% of patients at a mean time to recurrence of 44.9 months. Patients with GTR had statistically significantly lower odds of recurrence/progression (OR: 0.07; 95% CI: 0.04-0.15) compared to patients with non-GTR. This systematic review and meta-analysis report patient outcomes following surgical resection of TS. EOR was found to be an important predictor of the risk of recurrence. Facial pain was more likely to improve postoperatively than facial hypesthesia. This work reports baseline rates of post-operative complications across studies, establishing benchmarks for neurosurgeons innovating and working to improve surgical outcomes for TS patients.

Radiotherapy for meningiomas.

Meningiomas are the most common primary central nervous system neoplasm. Despite promising recent progress in elucidating the genomic landscape and underlying biology of these histologically, molecularly, and clinically diverse tumors, the mainstays of meningioma treatment remain maximal safe resection and radiation therapy. The aim of this review of meningioma radiotherapy is to provide a concise summary of the history, current evidence, and future for application of radiotherapy in meningioma treatment.

Outcomes following stereotactic radiosurgery for foramen magnum meningiomas: a single-center experience and systematic review of the literature.

OBJECTIVE: Foramen magnum meningiomas (FMMs) pose a unique challenge given their intimate anatomical relationship with the craniovertebral junction. While resection has been studied extensively, much less has been reported about the use of stereotactic radiosurgery (SRS) for FMMs. This study includes what is to the authors' knowledge the first systematic review in the literature that summarizes patient and treatment characteristics and synthesizes outcomes following SRS for FMMs. METHODS: A retrospective chart review was conducted at a single major academic institution, and a systematic review was performed according to PRISMA guidelines. The initial search on the PubMed and Scopus databases yielded 530 results. Key data extracted from both databases included Karnofsky Performance Status (KPS) score and neurological deficits at presentation, tumor location, treatment indication, target volume, single versus multiple fractions, marginal and maximum doses, isodose line, clinical and radiographic follow-up times, and primary (clinical stability and local control at last follow-up) and secondary (mortality, adverse radiation events, time to regression, progression-free survival) outcomes. RESULTS: The study patients included 9 patients from the authors' institution and 165 patients across 4 studies who received SRS for FMMs. The weighted median age at treatment was 60.2 years, and 73.9% of patients were female. Common presenting symptoms included headache (33.9%), dizziness/ataxia (29.7%), cranial nerve deficit(s) (27.9%), numbness (22.4%), weakness (15.2%), and hydrocephalus (4.2%). Lateral/ventrolateral (64.2%) was the most common tumor location. SRS was utilized as the primary therapy in 63.6% of patients and as salvage (21.8%) or adjuvant (14.5%) therapy for the rest of the patients. Most patients (91.5%) were treated with a single fraction. A tumor with a weighted median target volume of 2.9 cm3 was treated with a weighted median marginal dose, maximum dose, and isodose line of 12.9 Gy, 22.8 Gy, and 58%, respectively. Clinical stability and local control at last follow-up were achieved in 98.8% and 97.0% of patients, respectively. Only one possible adverse radiation event occurred, and no mortality directly related to the tumor or SRS was reported. CONCLUSIONS: In this retrospective analysis and systematic review, the authors demonstrate SRS to be an effective and safe treatment option for carefully selected patients with FMMs.

Multidisciplinary Frontotemporal Orbitozygomatic Craniotomy for Spheno-orbital Meningiomas: Ophthalmic and Orbital Outcomes.

PURPOSE: Advances in surgical approaches have improved access for total or near-total resection of spheno-orbital meningiomas (SOM). Herein, the outcomes of multidisciplinary resection and reconstruction of SOM via frontotemporal orbitozygomatic craniotomy at a single institution are evaluated. METHODS: A retrospective chart review was performed of all patients with SOM who underwent joint neurosurgical and oculofacial plastic resection via frontotemporal orbitozygomatic craniotomy between January 1999 and December 2018. Demographic data, clinical presentation, risk factors for meningioma, radiographic imaging, pathology results, postoperative outcomes, and surgical complications were reviewed. The outcome measures assessed included visual acuity, pupillary function, color vision, ocular motility, visual fields, and proptosis. RESULTS: A total of 48 patients were identified having had multidisciplinary frontotemporal orbitozygomatic craniotomy for SOM of which 43 met inclusion criteria. A mean follow-up period of 23.9 ± 20.4 months (range 1-60) was observed. There were 35 patients who underwent primary resection and 8 patients who had prior surgical resection. The main presenting complaints were proptosis (88%), headache (44%), and reduced vision (12%). Gross total resection was achieved in 15 patients (35%) while near-total or subtotal resection was achieved in the remainder. Histologic analysis revealed World Health Organization grade I meningioma in 72% of tumors, grade II in 23%, and grade III in 5%. Mean visual acuity (Logarithm of the Minimum Angle of Resolution) improved from 0.24 ± 0.46 preoperatively to 0.09 ± 0.13 postoperatively (p = 0.03). Surgery improved proptosis, with a reduction in mean Hertel exophthalmometry from 22.37 ± 3.78 mm to 17.91 ± 3.84 mm (p < 0.001), of which 80% had no residual proptosis or developed subsequent recurrence. Exophthalmic index calculated by radiologic evaluation also improved from a mean preoperative value of 1.32 ± 0.19 to 1.12 ± 0.13 at the 6-month interval after surgery (p < 0.001). Before surgery, 19 (45%) patients had a relative afferent pupillary reaction with improvement in 9 (24%) after surgery. Of the 14 (33%) patients with preoperative ocular motility deficit, 7 (16%) had resolution of ocular motility deficit postoperatively. The most common surgical complications were temporalis muscle atrophy with temporal hollowing (14%), wound infection (7%), neurogenic strabismus secondary to trochlear nerve palsy (5%), restrictive strabismus (5%), and aponeurotic blepharoptosis (5%). CONCLUSIONS: Multidisciplinary frontotemporal orbitozygomatic for resection of SOM is a safe and effective means of tumor removal. It can provide improved visual acuity and proptosis metrics, as well as relief of optic neuropathy and ocular motility deficits.

Fertility treatment is associated with multiple meningiomas and younger age at diagnosis.

PURPOSE: Meningiomas are more common in females and 70-80% express the progesterone receptor, raising the possibility that high-dose exogenous estrogen/progesterone exposure, such as occurs during fertility treatments, may increase the risk of developing a meningioma. The goal of this study was to report the incidence of prior fertility treatment in a consecutive series of female meningioma patients. METHODS: A retrospective review (2015-2018) was performed of female patients with meningioma, and those with prior fertility treatment were compared to those without fertility treatment using standard statistical methods. RESULTS: Of 206 female patients with meningioma, 26 (12.6%) had a history of fertility treatments. Patients underwent various forms of assisted reproductive technology including: in vitro fertilization (50.0%), clomiphene with or without intrauterine insemination (34.6%), and unspecified (19.2%). Median follow up was 1.8 years. Tumors were WHO grade I (78.6%) or grade II (21.4%). Patients who underwent fertility treatments presented at significantly younger mean age compared to those who had not (51.8 vs. 57.3 years, p = 0.0135, 2-tailed T-test), and on multivariate analysis were more likely to have multiple meningiomas (OR 4.97, 95% CI 1.4-18.1, p = 0.0154) and convexity/falx meningiomas (OR 4.45, 95% CI 1.7-11.5, p = 0.0021). CONCLUSIONS: Patients in this cohort with a history of fertility treatment were more likely to present at a younger age and have multiple and convexity/falx meningiomas, emphasizing the importance of taking estrogen/progesterone exposure history when evaluating patients with meningioma. Future clinical studies at other centers in larger populations and laboratory investigations are needed to determine the role of fertility treatment in meningioma development.

Salvage therapy outcomes for atypical meningioma.

Atypical menginomas demonstrate increased clinical aggressiveness characterized by recurrence and diminished survival. The optimal management of atypical meningioma in the recurrent setting is especially not well defined. To characterize outcomes following salvage treatment of recurrent atypical meningioma and to identify risk factors for further recurrence. Retrospective chart review was performed on 65 patients who underwent salvage treatment of atypical meningioma at a single institution. Data were analyzed using the Kaplan-Meier method and Cox proportional hazards modeling. Sixty-five patients with recurrent atypical meningioma and median imaging follow-up of 4.0 years (range 1.9-6.6 years) underwent 62 surgeries and 114 radiation treatments (RT) for salvage therapy. Salvage modality was surgery (21%), surgery/RT (25%), or RT alone (54%), associated with 2 year local freedom from recurrence (LFFR) of 36, 59, and 73%, respectively (P = 0.01). Twenty percent of patients experienced CTCAE grade ≥ 3 toxicity with salvage therapy. Thirty-nine percent of patients experienced ≥ 3 recurrences. The median disease-free survival intervals after first and second salvage treatments were 2.9 and 1.3 years, respectively. On univariate Cox analysis, prior subtotal resection, prior RT, tumor diameter > 2.5 cm, and multifocal local recurrence were associated with recurrence after salvage therapy. On multivariate logistic regression, only multifocal local recurrence was associated with further recurrence. Recurrent atypical meningioma is clinically and pathologically more aggressive than primary atypical meningioma, and the likelihood of durable local control with salvage therapy is lower. Future efforts should identify patients at risk of recurrence, and aggressive upfront treatment should be employed.

Relationship between tumor location, size, and WHO grade in meningioma.

OBJECTIVE Prior studies have investigated preoperative risk factors for meningioma; however, no association has been shown between meningioma tumor size and tumor grade. The objective of this study was to investigate the relationship between tumor size and grade in a large single-center study of patients undergoing meningioma resection. METHODS A retrospective chart review of patients undergoing meningioma resection at the University of California, San Francisco, between 1985 and 2015 was performed. Patients with incomplete information, spinal meningiomas, multiple meningiomas, or WHO grade III meningiomas were excluded. The largest tumor dimension was used as a surrogate for tumor size. Univariate and multivariate logistic regression models were used to investigate the relationship between tumor grade and tumor size. A recursive partitioning analysis was performed to identify groups at higher risk for atypical (WHO grade II) meningioma. RESULTS Of the 1113 patients identified, 905 (81%) had a WHO grade I tumor and in 208 (19%) the tumors were WHO grade II. The median largest tumor dimension was 3.6 cm (range 0.2-13 cm). Tumors were distributed as follows: skull base (n = 573, 51%), convexity/falx/parasagittal (n = 431, 39%), and other (n = 109, 10%). On univariate regression, larger tumor size (p < 0.001), convexity/falx/parasagittal location (p < 0.001), and male sex (p < 0.001) were significant predictors of WHO grade II pathology. After controlling for interactions, multivariate regression found male sex (OR 1.74, 95% CI 1.25-2.43), size 3-6 cm (OR 1.69, 95% CI 1.08-2.66), size > 6 cm (OR 3.01, 95% CI 1.53-5.94), and convexity/falx/parasagittal location (OR 1.83, 95% CI 1.19-2.82) to be significantly associated with WHO grade II. Recursive partitioning analysis identified male patients with tumors > 3 cm as a high-risk group (32%) for WHO grade II meningioma. CONCLUSIONS Larger tumor size is associated with a greater likelihood of a meningioma being WHO grade II, independent of tumor location and male sex, which are known risk factors.

Tuberculum sellae meningiomas: grading scale to assess surgical outcomes using the transcranial versus transsphenoidal approach.

OBJECTIVE Tuberculum sellae meningiomas (TSMs) are surgically challenging tumors that can severely impair vision. Debate exists regarding whether the transcranial (TC) or endoscopic transsphenoidal (TS) approach is best for resecting these tumors, and there are few large series comparing these approaches. METHODS A retrospective chart review was performed at 2 academic centers comparing TC and TS approaches with respect to vision, extent of resection, recurrence, and complications. The authors report surgical outcomes and propose a simple preoperative tumor grading scale that scores tumor size (1-2), optic canal invasion (0-2), and arterial encasement (0-2). The authors performed univariate, multivariate, and recursive partitioning analysis (RPA) to evaluate outcomes. RESULTS The TSMs were resected in 139 patients. The median follow-up was 29 months. Ninety-five (68%) cases were resected via a TC and 44 (32%) via a TS approach. Tumors treated via a TC approach had a higher tumor (p = 0.0007), artery (p < 0.0001), and total score (p = 0.0012) on the grading scale. Preoperative visual deficits were present in 87% of patients. Vision improved in 47%, stayed the same in 35%, declined in 10%, and was not recorded in 8%. The extent of resection was 65% gross-total resection, 23% near-total resection (95%-99% resection), and 12% subtotal resection (< 95%). A lower tumor score was significantly associated with better or stable vision postoperatively (p = 0.0052). The RPA confirmed low tumor score as the key predictor of postoperative visual improvement or stability. Multivariate analysis and RPA demonstrate that lower canal score (p < 0.0001) and TC approach (p = 0.0019) are associated with gross-total resection. Complications occurred in 20 (14%) patients, including CSF leak (5%) and infection (4%). There was no difference in overall complication rates between TC and TS approaches; however, the TS approach had more CSF leaks (OR 5.96, 95% CI 1.10-32.04). The observed recurrence rate was 10%, and there was no difference between the TC and TS approaches. CONCLUSIONS Tuberculum sellae meningiomas can be resected using either a TC or TS approach, with low morbidity and good visual outcomes in appropriately selected patients. The simple proposed grading scale provides a standard preoperative method to evaluate TSMs and can serve as a starting point for selection of the surgical approach. Higher scores were associated with worsened visual outcomes and subtotal resection, regardless of approach. The authors plan a multicenter review of this grading scale to further evaluate its utility.

Mini-open anterior approach for cervicothoracic junction fracture: technical note.

Elderly patients with diffuse idiopathic skeletal hyperostosis are at high risk for falls, and 3-column unstable fractures present multiple challenges. Unstable fractures across the cervicothoracic junction are associated with significant morbidity and require fixation, which is commonly performed through a posterior open or percutaneous approach. The authors describe a novel, navigated, mini-open anterior approach using intraoperative cone-beam CT scanning to place lag screws followed by an anterior plate in a 97-year-old patient. This approach is less invasive and faster than an open posterior approach and can be considered as an option for management of cervicothoracic junction fractures in elderly patients with high perioperative risk profile who cannot tolerate being placed prone during surgery.

Resection of falx and parasagittal meningioma: complication avoidance.

Falx and parasagittal meningiomas are common locations for meningiomas of the cranial vault. Many of these tumors are now discovered incidentally during cranial imaging for other reasons. Therefore, in the calculation of the risks and benefits of surgery it behooves the surgeon to do all he/she can to avoid surgical complications. This is a heavily experience based article based off the senior author's experience with over 1200 intracranial meningiomas. We present three cases to illustrate some of the decision-making and techniques used to reduce complications in the management of these cases treated with an open operation.

Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma.

While immunotherapy may offer promising new approaches for high grade meningiomas, little is currently known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment and a potentially targetable antigen mesothelin across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors. Immunohistochemistry was performed using antibodies against CD3, CD8, CD20, CD68, PD-L1, and mesothelin. Dual staining using anti-PD-L1 and anti-CD68 antibodies was performed, and automated cell detection and positive staining detection algorithms were utilized. Greater degree of PD-L1 expression was found in higher grade tumors. More specifically, higher grade tumors contained increased numbers of intratumoral CD68-, PD-L1+ cells (p = 0.022), but did not contain higher numbers of infiltrating CD68+, PD-L1+ cells (p = 0.30). Higher PD-L1+/CD68- expression was independently predictive of worse overall survival in our cohort when accounting for grade, performance status, extent of resection, and recurrence history (p = 0.014). Higher expression of PD-L1+/CD68- was also present in tumors that had undergone prior radiotherapy (p = 0.024). Approximately quarter of meningiomas overexpressed mesothelin to levels equivalent to those found in pancreatic carcinomas and malignant mesotheliomas. The association with poor survival outcomes in our study suggests that PD-L1 may play a significant biologic role in the aggressive phenotype of higher grade meningiomas. Thus, immunotherapeutic strategies such as checkpoint inhibition may have clinical utility in PD-L1 overexpressing meningiomas.

Neurogenic thoracic outlet syndrome: current diagnostic criteria and advances in MRI diagnostics.

Neurogenic thoracic outlet syndrome (nTOS) is caused by compression of the brachial plexus as it traverses from the thoracic outlet to the axilla. Diagnosing nTOS can be difficult because of overlap with other complex pain and entrapment syndromes. An nTOS diagnosis is made based on patient history, physical exam, electrodiagnostic studies, and, more recently, interpretation of MR neurograms with tractography. Advances in high-resolution MRI and tractography can confirm an nTOS diagnosis and identify the location of nerve compression, allowing tailored surgical decompression. In this report, the authors review the current diagnostic criteria, present an update on advances in MRI, and provide case examples demonstrating how MR neurography (MRN) can aid in diagnosing nTOS. The authors conclude that improved high-resolution MRN and tractography are valuable tools for identifying the source of nerve compression in patients with nTOS and can augment current diagnostic modalities for this syndrome.

Molecularly targeted therapies for recurrent glioblastoma: current and future targets.

OBJECT: Glioblastoma is the most aggressive and diffusely infiltrative primary brain tumor. Recurrence is expected and is extremely difficult to treat. Over the past decade, the accumulation of knowledge regarding the molecular and genetic profile of glioblastoma has led to numerous molecularly targeted therapies. This article aims to review the literature and highlight the mechanisms and efficacies of molecularly targeted therapies for recurrent glioblastoma. METHODS: A systematic search was performed with the phrase "(name of particular agent) and glioblastoma" as a search term in PubMed to identify all articles published up until 2014 that included this phrase in the title and/or abstract. The references of systematic reviews were also reviewed for additional sources. The review included clinical studies that comprised at least 20 patients and reported results for the treatment of recurrent glioblastoma with molecular targeted therapies. RESULTS: A total of 42 articles were included in this review. In the treatment of recurrent glioblastoma, various targeted therapies have been tested over the past 10-15 years. The targets of interest include epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Ras pathway, protein kinase C, mammalian target of rapamycin, histone acetylation, and integrins. Unfortunately, the clinical responses to most available targeted therapies are modest at best. Radiographic responses generally range in the realm of 5%-20%. Progression-free survival at 6 months and overall survival were also modest with the majority of studies reporting a 10%-20% 6-month progression-free survival and 5- to 8-month overall survival. There have been several clinical trials evaluating the use of combination therapy for molecularly targeted treatments. In general, the outcomes for combination therapy tend to be superior to single-agent therapy, regardless of the specific agent studied. CONCLUSIONS: Recurrent glioblastoma remains very difficult to treat, even with molecular targeted therapies and anticancer agents. The currently available targeted therapy regimens have poor to modest activity against recurrent glioblastoma. As newer agents are actively being developed, combination regimens have provided the most promising results for improving outcomes. Targeted therapies matched to molecular profiles of individual tumors are predicted to be a critical component necessary for improving efficacy in future trials.