Cumulative Intracranial Tumor Volume as a Prognostic Factor in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery.

Approximately 25-35% of all cancer patients suffer from brain metastases (BM), and many of them-in particular, those with a limited number of intracranial tumors-are treated with stereotactic radiosurgery (SRS). Accurate prediction of survival remains a key clinical challenge in this population. Several prognostic scales have been developed to facilitate this prognostication, including the Recursive Partitioning Analysis (RPA) classification, the modified Recursive Partitioning Analysis (mRPA) subclassifications, the Basic Score for Brain Metastases (BS-BM), the Score Index for Radiosurgery (SIR), the Graded Prognostic Assessment (GPA), and the diagnosis-specific Graded Prognostic Assessment (dsGPA). However, none of these scales include consideration of the cumulative intracranial tumor volume (CITV), which is defined as the sum of all intracranial tumor volumes. Since there is mounting evidence that the CITV carries significant prognostic value in SRS-treated patients with BM, this variable should be considered during survival prognostication, along with other pertinent clinical, pathological, and molecular characteristics.

Survival trends of oligodendroglial tumor patients and associated clinical practice patterns: a SEER-based analysis.

There is limited information on the management strategies and survival trends for oligodendroglioma patients. Here we used the Surveillance, Epidemiology and End Results (SEER, 1999-2012) database to analyze the historical trends of oligodendroglioma patient survival and correlate these trends to evolving clinical practice of radiation therapy (RT) use and surgical practice of gross total resection (GTR). We identified 2689 World Health Organization (WHO) grade II oligodendroglioma (abbreviated as O2) and 1191 WHO grade III oligodendroglioma (abbreviated as O3). Time-trend analyses were performed for overall survival, radiation treatment (RT) use, and extent of surgical resection (EOR). In multivariable Cox models that accounted for age, race, sex, tumor size, tumor location, EOR, and RT status, the hazard of dying from O3 has significantly decreased over the study period (p  <  0.01), while the hazard of dying from O2 has remained largely unchanged. A search of the published literature revealed articles reporting results largely supportive of these observations. The pattern of surgical practice and RT for O3 patients remained unchanged throughout the study period, suggesting that the survival improvement may be related to evolving patterns of medical management. Results from the SEER database indicate significant gains have been made in survival for O3 patients between 1999 and 2012. Such gains were not observed for O2 patients during this study period.

Safety of stereotactic laser ablations performed as treatment for glioblastomas in a conventional magnetic resonance imaging suite.

OBJECTIVE Stereotactic laser ablation (SLA) is typically performed in the setting of intraoperative MRI or in a staged manner in which probe insertion is performed in the operating room and thermal ablation takes place in an MRI suite. METHODS The authors describe their experience, in which SLA for glioblastoma (GBM) treatment was performed entirely within a conventional MRI suite using the SmartFrame stereotactic device. RESULTS All 10 patients with GBM (2 with isocitrate dehydrogenase 1 mutation [mIDH1] and 8 with wild-type IDH1 [wtIDH1]) were followed for > 6 months. One of these patients underwent 2 independent SLAs approximately 12 months apart. Biopsies were performed prior to SLA for all patients. There were no perioperative morbidities, wound infections, or unplanned 30-day readmissions. The average time for a 3-trajectory SLA (n = 3) was 436 ± 102 minutes; for a 2-trajectory SLA (n = 4) was 321 ± 85 minutes; and for a single-trajectory SLA (n = 4) was 254 ± 28 minutes. No tumor recurrence occurred within the blue isotherm line ablation zone, although 2 patients experienced recurrence immediately adjacent to the blue isotherm ablation line. Overall survival for the patient cohort averaged 356 days, with the 2 patients who had mIDH1 GBMs exhibiting the longest survival (811 and 654 days). CONCLUSIONS Multitrajectory SLA for treatment of GBM can be safely performed using the SmartFrame stereotactic device in a conventional MRI suite.

Stereotactic laser ablation as treatment for brain metastases that recur after stereotactic radiosurgery: a multiinstitutional experience.

OBJECTIVE Therapeutic options for brain metastases (BMs) that recur after stereotactic radiosurgery (SRS) remain limited. METHODS The authors provide the collective experience of 4 institutions where treatment of BMs that recurred after SRS was performed with stereotactic laser ablation (SLA). RESULTS Twenty-six BMs (in 23 patients) that recurred after SRS were treated with SLA (2 patients each underwent 2 SLAs for separate lesions, and a third underwent 2 serial SLAs for discrete BMs). Histological findings in the BMs treated included the following: breast (n = 6); lung (n = 6); melanoma (n = 5); colon (n = 2); ovarian (n = 1); bladder (n = 1); esophageal (n = 1); and sarcoma (n = 1). With a median follow-up duration of 141 days (range 64-794 days), 9 of the SLA-treated BMs progressed despite treatment (35%). All cases of progression occurred in BMs in which < 80% ablation was achieved, whereas no disease progression was observed in BMs in which ≥ 80% ablation was achieved. Five BMs were treated with SLA, followed 1 month later by adjuvant SRS (5 Gy daily × 5 days). No disease progression was observed in these patients despite ablation efficiency of < 80%, suggesting that adjuvant hypofractionated SRS enhances the efficacy of SLA. Of the 23 SLA-treated patients, 3 suffered transient hemiparesis (13%), 1 developed hydrocephalus requiring temporary ventricular drainage (4%), and 1 patient who underwent SLA of a 28.9-cm3 lesion suffered a neurological deficit requiring an emergency hemicraniectomy (4%). Although there is significant heterogeneity in corticosteroid treatment post-SLA, most patients underwent a 2-week taper. CONCLUSIONS Stereotactic laser ablation is an effective treatment option for BMs in which SRS fails. Ablation of ≥ 80% of BMs is associated with decreased risk of disease progression. The efficacy of SLA in this setting may be augmented by adjuvant hypofractionated SRS.

Standalone middle meningeal artery embolization versus middle meningeal artery embolization with concurrent surgical evacuation for chronic subdural hematomas: a multicenter propensity score matched analysis of clinical and radiographic outcomes.

BACKGROUND: Middle meningeal artery embolization (MMAE) has emerged as a promising therapy for chronic subdural hematomas (cSDHs). The efficacy of standalone MMAE compared with MMAE with concurrent surgery is largely unknown. METHODS: cSDH patients who underwent successful MMAE from 14 high volume centers with at least 30 days of follow-up were included. Clinical and radiographic variables were recorded and used to perform propensity score matching (PSM) of patients treated with standalone MMAE or MMAE with concurrent surgery. Multivariable logistic regression models were used for additional covariate adjustments. The primary outcome was recurrence requiring surgical rescue, and the secondary outcome was radiographic failure defined as <50% reduction of cSDH thickness. RESULTS: 722 MMAE procedures in 588 cSDH patients were identified. After PSM, 230 MMAE procedures remained (115 in each group). Median age was 73 years, 22.6% of patients were receiving anticoagulation medication, and 47.9% had no preoperative functional disability. Median midline shift was 4 mm and cSDH thickness was 16 mm, representing modestly sized cSDHs. Standalone MMAE and MMAE with surgery resulted in similar rates of surgical rescue (7.8% vs 13.0%, respectively, P=0.28; adjusted OR (aOR 0.73 (95% CI 0.20 to 2.40), P=0.60) and radiographic failure (15.5% vs 13.7%, respectively, P=0.84; aOR 1.08 (95% CI 0.37 to 2.19), P=0.88) with a median follow-up duration of 105 days. These results were similar across subgroup analyses and follow-up durations. CONCLUSIONS: Standalone MMAE led to similar and durable clinical and radiographic outcomes as MMAE combined with surgery in select patients with moderately sized cSDHs and mild clinical disease.

Neuroanatomy of cranial dural vessels: implications for subdural hematoma embolization.

Adoption of middle meningeal artery embolization in the management of chronic subdural hematomas has led to a renewed interest in dural vascular anatomy. The readily identifiable major dural arteries and potential hazards associated with their embolization are well described. Less emphasized are several levels of intrinsic dural angioarchitecture, despite their more direct relationship to dural based diseases, such as subdural hematoma and dural fistula. Fortunately, microvascular aspects of dural anatomy, previously limited to ex vivo investigations, are becoming increasingly accessible to in vivo visualization, setting the stage for synthesis of the old and the new, and providing a rationale for the endovascular approach to subdural collections in particular. In contrast with traditional anatomical didactics, where descriptions advance from larger trunks to smaller pedicles, we present a strategic approach that proceeds from a fundamental understanding of the dural microvasculature and its relationship to larger vessels.

The impact of the COVID-19 pandemic on cerebrovascular disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a systemic disease that affects nearly all organ systems through infection and subsequent dysregulation of the vascular endothelium. One of the most striking phenomena has been a coronavirus disease 2019 (COVID-19)-associated coagulopathy. Given these findings, questions naturally emerged about the prothrombotic impact of COVID-19 on cerebrovascular disease and whether ischemic stroke is a clinical feature specific to COVID-19 pathophysiology. Early reports from China and several sites in the northeastern United States seemed to confirm these suspicions. Since these initial reports, many cohort studies worldwide observed decreased rates of stroke since the start of the pandemic, raising concerns for a broader impact of the pandemic on stroke treatment. In this review, we provide a comprehensive assessment of how the pandemic has affected stroke presentation, epidemiology, treatment, and outcomes to better understand the impact of COVID-19 on cerebrovascular disease. Much evidence suggests that this decline in stroke admissions stems from the global response to the virus, which has made it more difficult for patients to get to the hospital once symptoms start. However, there does not appear to be a demonstrable impact on quality metrics once patients arrive at the hospital. Despite initial concerns, there is insufficient evidence to ascribe a causal relationship specific to the pathogenicity of SARS-CoV-2 on the cerebral vasculature. Nevertheless, when patients infected with SARS-CoV-2 present with stroke, their presentation is likely to be more severe, and they have a markedly higher rate of in-hospital mortality than patients with either acute ischemic stroke or COVID-19 alone.

Severe, Intolerable Fatigue Associated with Hyperresponse to Clopidogrel.

OBJECTIVE: Clopidogrel is a commonly used antiplatelet agent for the prevention of thromboembolic complications following neuroendovascular procedures, but anecdotal data have raised concern for the possibility that clopidogrel may induce severe, intolerable fatigue. The purpose of this study is to systematically investigate this phenomenon. METHODS: We performed a dual-institution, 9-year, retrospective study of patients undergoing clopidogrel therapy for neuroendovascular procedures. Patients were included only if their response to clopidogrel was assessed by platelet function testing using the VerifyNow P2Y12 (VNP) assay. Hyperresponse to clopidogrel was defined as P2Y12 reaction units ≤60. Patients were considered to have had clopidogrel-induced severe fatigue if the onset of symptoms followed the initiation of clopidogrel therapy; symptoms improved following a reduction in the dose of clopidogrel; and symptoms could not be attributed to any other medical explanation. RESULTS: Data were collected on 349 patients. Five patients (1.4%) met criteria for clopidogrel-induced severe fatigue. All 5 patients were female, ages 39-68. VNP assessments obtained while patients were symptomatic revealed hyperresponse to clopidogrel (0-22 P2Y12 reaction units). Symptoms improved in all 5 patients when the dose of clopidogrel was reduced by half. Notably, 30% of patients (n = 103) demonstrated a hyperresponse to clopidogrel on at least 1 VNP assessment, but 98 of these patients did not suffer from severe fatigue. CONCLUSIONS: A syndrome of severe fatigue and other constitutional symptoms is a rare but clinically significant side effect of hyperresponse to clopidogrel in patients undergoing neuroendovasular intervention.

Smoking As a Risk Factor for Postcraniotomy 30-Day Mortality.

BACKGROUND: There is limited information on the impact of smoking on postcraniotomy mortality. In this study we used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) to examine this issue. METHODS: We identified 16,280 postcraniotomy patients in the ACS-NSQIP database. Indications for surgery were categorized by vascular, trauma, epilepsy, malignant tumor, and benign tumor. Univariate and multivariable logistic regression analyses were used to identify risk factors associated with mortality. RESULTS: In the ACS-NSQIP dataset, postcraniotomy mortality within 30 days of surgery was 5.03%. An area under the curve analysis indicated 30 pack-years as the optimal discriminating threshold for risk stratification in terms of 30-day postcraniotomy mortality. Using this threshold, multivariate analyses revealed 3 variables that were closely associated with 30-day post-craniotomy mortality: male gender (P = 0.002), indication for operation (P < 0.001), and a smoking history of ≥30 pack-years (P < 0.001). In subsequent stratified analyses, smoking-associated mortality risk was observed only in males (odds ratio of 2.33 comparing males with ≥30 and <30 pack-years of smoking history; 97.5% confidence interval 1.36-4.03). When the analysis was further stratified by surgical indications, the mortality association with smoking was found only in male patients who underwent craniotomy as treatment for neurovascular diseases (odds ratio 3.88, 97.5% confidence interval 1.39-11.65). Such an association was not seen in patients who underwent craniotomy for traumatic brain injury, malignant tumors, benign tumors, or epilepsy. CONCLUSIONS: This study identified ≥30 pack-years as a risk factor for male patients undergoing craniotomy as treatment for neurovascular diseases.

Isocitrate Dehydrogenase Mutations in Low-Grade Gliomas Correlate With Prolonged Overall Survival in Older Patients.

BACKGROUND: Older age has been associated with worse outcomes in low-grade gliomas (LGGs). Given their rarity in the older population, determining optimal treatment plans and patient outcomes remains difficult. OBJECTIVE: To retrospectively study LGG survival outcomes in an older population stratified by molecular genetic profiles. METHODS: We included patients age ≥40 yr with pathologically confirmed World Health Organization grade II gliomas treated at a single institution between 1995 and 2015. We collected tumor genomic information when available. RESULTS: Median overall survival for the entire group (n = 111, median age 51 yr, range 40-77 yr) was 15.75 yr with 5- and 10-yr survival rates of 84.3% and 67.7%, respectively. On univariate analysis, patients with isocitrate dehydrogenase (IDH) mutation had significantly increased survival compared to IDH wildtype (hazard ratio [HR] 0.17 [0.07-0.45], P < .001). Older age, seizure at presentation, larger tumor size, IDH wildtype, biopsy only, chemotherapy, and radiation were significantly associated with shorter survival based on univariate analyses. In patients with known IDH status (n = 73), bivariate analysis of IDH mutation status and age showed only IDH status significantly influenced overall survival (HR 0.22 [0.07-0.68], P = .008). Greater surgical resection was predictive of survival, although extent of resection significantly correlated with IDH mutation status (odds ratio 7.5; P < .001). CONCLUSION: We show that genomic alterations in LGG patients ≥40 occur at high rates like the younger population and predict a similar survival advantage. Maximizing surgical resection may have survival benefit, although feasibility of resection is often linked to IDH status. Given the importance of molecular genetics, a redefinition of prognostic factors associated with these tumors is likely to emerge.

Prognostic Importance of Age, Tumor Location, and Tumor Grade in Grade II Astrocytomas: An Integrated Analysis of the Cancer Genome Atlas and the Surveillance, Epidemiology, and End Results Database.

BACKGROUND: Previous work in anaplastic astrocytoma (AA) demonstrated that the survival benefit from gross total resection (GTR) is modified by age and tumor location. Here, we determined the influence of age and tumor location on survival benefit from GTR in diffuse astrocytoma (DA). METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database (1999-2010). We used Kaplan-Meier curves and Cox survival models to determine the survival benefit from GTR in populations stratified by age and tumor location. We determined the prevalence of the mutated isocitrate dehydrogenase (mIDH) using The Cancer Genome Atlas (TCGA). RESULTS: We identified 1980 patients with DA. For frontal DAs, GTR resulted in improved survival relative to subtotal resection in all ages (age ≤50 years hazard ratio [HR], 0.56; P = 0.002; age >50 years HR, 0.41; P < 0.001). For nonfrontal DAs, only patients ≤50 years experienced improved survival with GTR (age ≤50 years HR, 0.55; P = 0.002; age >50 years HR, 0.78; P = 0.114). For patients ≤50 years with frontal tumors, survival was comparable between DA and AA after GTR (75% survival DA: 80 months, AA: 89 months, P = 0.973). In TCGA, these tumors were nearly uniformly mIDH (DA: 98%; AA: 90%, P = 0.11). However, for patients ≤50 years with nonfrontal tumors, there was a survival difference after GTR (75% survival DA: 80 months, AA: 30 months, P = 0.001) despite comparable mIDH prevalence (DA: 82%, AA: 75%, P = 0.49). CONCLUSIONS: Age and tumor location modify the survival benefit derived from GTR in DA. Survival patterns in SEER imperfectly correlated with mIDH prevalence in TCGA, suggesting that tumor grade and mIDH status convey nonredundant prognostic information in select clinical contexts.

Intraoperative Magnetic Resonance Imaging-Guided Biopsy in the Diagnosis of Suprasellar Langerhans Cell Histiocytosis.

BACKGROUND: Magnetic resonance imaging (MRI)-guided biopsy is an emerging diagnostic technique that holds great promise for otherwise difficult to access neuroanatomy. CASE DESCRIPTION: Here we describe MRI-guided biopsy of a suprasellar lesion located posterior and superior to the pituitary stalk. The approach was implemented successfully in a 38-year-old woman who had developed progressive visual deterioration. CONCLUSION: Intraoperative MRI revealed the need for trajectory adjustment due to an unintended, minor deviation in the burr hole entry point, demonstrating the benefit of an MRI-guided approach. Langerhans cell histiocytosis was diagnosed after biopsy, and the lesion regressed after cladribine treatment. Technical nuances of the case are reviewed in the context of the available literature.

Cost-effectiveness Analysis of Nivolumab for Treatment of Platinum-Resistant Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck.

Background: The CheckMate 141 trial found that nivolumab improved survival for patients with recurrent or metastatic head and neck cancer (HNC). Despite the improved survival, nivolumab is much more expensive than standard therapies. This study assesses the cost-effectiveness of nivolumab for the treatment of HNC. Methods: We constructed a Markov model to simulate treatment with nivolumab or standard single-agent therapy for patients with recurrent or metastatic platinum-refractory HNC. Transition probabilities, including disease progression, survival, and probability of toxicity, were derived from clinical trial data, while costs (in 2017 US dollars) and health utilities were estimated from the literature. Incremental cost-effectiveness ratios (ICERs), expressed as dollar per quality-adjusted life-year (QALY), were calculated, with values of less than $100 000/QALY considered cost-effective from a health care payer perspective. We conducted one-way and probabilistic sensitivity analyses to assess model uncertainty. Results: Our base case model found that treatment with nivolumab increased overall cost by $117 800 and improved effectiveness by 0.400 QALYs compared with standard therapy, leading to an ICER of $294 400/QALY. The model was most sensitive to the cost of nivolumab, though nivolumab only became cost-effective if the cost per cycle decreased from $13 432 to $3931. The model was not particularly sensitive to assumptions about survival. If one assumed that all patients alive at the end of the CheckMate 141 trial were cured of their disease, nivolumab was still not cost-effective (ICER $244 600/QALY). Conclusion: While nivolumab improves overall survival, at its current cost it would not be considered a cost-effective treatment option for patients with HNC.

Interaction Between the Contributions of Tumor Location, Tumor Grade, and Patient Age to the Survival Benefit Associated with Gross Total Resection.

BACKGROUND: Gross total resection (GTR) in patients with glioblastoma (GB) and anaplastic astrocytoma (AA) is associated with improved survival. We examined how tumor location, tumor grade, and age affected this benefit. METHODS: We selected patients with lobar AA or GB in the Surveillance, Epidemiology, and End Results database from 1999 to 2010. Survival analyses were performed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: We identified and studied 1429 patients with lobar AA and 12,537 patients with lobar GB in the Surveillance, Epidemiology, and End Results database. In multivariate Cox proportional hazards analysis, GTR of frontal lobe AA was associated with approximately 50% reduction in risk of death compared with subtotal resection (STR) (hazard ratio 0.51; 95% confidence interval, 0.36-0.73; P < 0.001). This hazard ratio corresponds to a median increase in overall survival of >8 years with GTR compared with STR. In nonfrontal AAs, there was no survival difference between GTR and STR (hazard ratio 0.79; 95% confidence interval, 0.58-1.08; P = 0.143). Location-specific survival benefit from GTR in AAs was significant in patients ≤50 years old but was not evident in patients >50 years old. In patients with GB, no location-dependent survival benefit with GTR was observed. CONCLUSIONS: Our results demonstrate complex interaction between tumor grade, frontal lobe location, and age in their various contributions to survival benefit gained from GTR. The greatest survival benefit of GTR relative to STR was observed in patients ≤50 years old with frontal AAs.

Oligodendroglioma resection: a Surveillance, Epidemiology, and End Results (SEER) analysis.

OBJECTIVE The available evidence suggests that the clinical benefits of extended resection are limited for chemosensitive tumors, such as primary CNS lymphoma. Oligodendroglioma is generally believed to be more sensitive to chemotherapy than astrocytoma of comparable grades. In this study the authors compare the survival benefit of gross-total resection (GTR) in patients with oligodendroglioma relative to patients with astrocytoma. METHODS Using the Surveillance, Epidemiology, and End Results (SEER) Program (1999-2010) database, the authors identified 2378 patients with WHO Grade II oligodendroglioma (O2 group) and 1028 patients with WHO Grade III oligodendroglioma (O3 group). Resection was defined as GTR, subtotal resection, biopsy only, or no resection. Kaplan-Meier and multivariate Cox regression survival analyses were used to assess survival with respect to extent of resection. RESULTS Cox multivariate analysis revealed that the hazard of dying from O2 and O3 was comparable between patients who underwent biopsy only and GTR (O2: hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.73-1.53; O3: HR 1.18, 95% CI 0.80-1.72). A comprehensive search of the published literature identified 8 articles without compelling evidence that GTR is associated with improved overall survival in patients with oligodendroglioma. CONCLUSIONS This SEER-based analysis and review of the literature suggest that GTR is not associated with improved survival in patients with oligodendroglioma. This finding contrasts with the documented association between GTR and overall survival in anaplastic astrocytoma and glioblastoma. The authors suggest that this difference may reflect the sensitivity of oligodendroglioma to chemotherapy as compared with astrocytomas.

Effect of Gross Total Resection in World Health Organization Grade II Astrocytomas: SEER-Based Survival Analysis.

INTRODUCTION: We sought to compare the survival benefit associated with gross total resection (GTR) in World Health Organization grade II astrocytomas (A2) with those of grade III (A3) and grade IV (glioblastoma) astrocytomas. METHODS: Using the Surveillance, Epidemiology, and End Results program database (1999-2010), we identified 4113 A2 patients. Surgical resection was defined as GTR, subtotal resection (STR), or no resection. Kaplan-Meier and multivariate Cox proportional hazards analyses were used to assess survival with respect to extent of resection. Results were compared with the benefit of GTR over STR in 2755 A3 and 21,962 glioblastoma patients from the same database. RESULTS: A multivariate Cox proportional hazards analysis indicated that A2 patients who underwent a GTR had a 28.3% reduction in the hazard of death relative to A2 patients who underwent STR. Similar risk reductions were observed in A2 patients age <50 and ≥50. However, because of differences in the natural history of these cohorts, the relative hazard reduction translated into distinct overall survival profiles. For A2 patients ≥50 years old, the GTR-associated survival benefit was approximately 6 months, resembling that observed in glioblastoma patients. In contrast, GTR in A2 patients <50 years old was associated with survival profiles superior to those observed in A3 patients. CONCLUSIONS: In the Surveillance, Epidemiology, and End Results (SEER) program database, GTR-associated survival benefit in A2 patients ≥50 years old resembled that observed in glioblastoma, while GTR in A2 patients <50 years old was associated with a distinctly more favorable survival profile.

Management and Survival Patterns of Patients with Gliomatosis Cerebri: A SEER-Based Analysis.

OBJECTIVE: We used the SEER (Surveillance Epidemiology and End Results) database (1999-2010) to analyze the clinical practice patterns and overall survival in patients with gliomatosis cerebri (GC), or glioma involving 3 or more lobes of the cerebrum. METHODS: We identified 111 patients (age ≥18 years) with clinically or microscopically diagnosed GC in the SEER database. Analyses were performed to determine clinical practice patterns for these patients and whether these practices were associated with survival. RESULTS: Fifty-eight percent of the 111 patients with GC received microscopic confirmation of their diagnosis. Of the remaining patients, 40% were diagnosed via imaging or laboratory tests, and 2% had unknown methods of diagnosis. Seven percent of patients who did not have microscopic confirmation of their diagnosis received radiation therapy. Radiation therapy and surgery were not associated with survival. The only variable significantly associated with overall survival was age at diagnosis. Patients aged 18-50 years showed improved survival relative to patients aged >50 years (median survival, 11 and 6 months, respectively; P = 0.03). For patients aged >50 years, improved overall survival was observed in the post-temozolomide era (2005-2010) relative to those treated in the pre-temozolomide era (1999-2004) (median survival, 9 and 4 months, respectively; P = 0.005). CONCLUSIONS: In the SEER database, ∼40% of the patients with glioma with imaging findings of GC do not receive microscopic confirmation of their diagnosis. We propose that tissue confirmation is warranted in patients with GC, because genomic analysis of these specimens may provide insights that will contribute to meaningful therapeutic intervention.

Survival Patterns of 5750 Stereotactic Radiosurgery-Treated Patients with Brain Metastasis as a Function of the Number of Lesions.

BACKGROUND: The number of brain metastases (BMs) plays an important role in the decision between stereotactic radiosurgery (SRS) and whole-brain radiation therapy. METHODS: We analyzed the survival of 5750 SRS-treated patients with BM as a function of BM number. Survival analyses were performed with Kaplan-Meier analysis as well as univariate and multivariate Cox proportional hazards models. RESULTS: Patients with BMs were first categorized as those with 1, 2-4, and 5-10 BMs based on the scheme proposed by Yamamoto et al. (Lancet Oncology 2014). Median overall survival for patients with 1 BM was superior to those with 2-4 BMs (7.1 months vs. 6.4 months, P = 0.009), and survival of patients with 2-4 BMs did not differ from those with 5-10 BMs (6.4 months vs. 6.3 months, P = 0.170). The median survival of patients with >10 BMs was lower than those with 2-10 BMs (6.3 months vs. 5.5 months, P = 0.025). In a multivariate model that accounted for age, Karnofsky Performance Score, systemic disease status, tumor histology, and cumulative intracranial tumor volume, we observed a ∼10% increase in hazard of death when comparing patients with 1 versus 2-10 BMs (P < 0.001) or 10 versus >10 BMs (P < 0.001). When BM number was modeled as a continuous variable rather than using the classification by Yamamoto et al., we observed a step-wise 4% increase in the hazard of death for every increment of 6-7 BM (P < 0.001). CONCLUSIONS: The contribution of BM number to overall survival is modest and should be considered as one of the many variables considered in the decision between SRS and whole-brain radiation therapy.

Coevolution of Peer-Reviewed Literature and Clinical Practice in High-Grade Glioma Resection.

BACKGROUND: The paradigm of evidence-based medicine dictates that clinical practice should reflect the shifting landscape of the peer-reviewed literature. Here, we examined the extent to which this premise is fulfilled as it pertains to the surgical resection of high-grade gliomas (HGGs). OBJECTIVE: We assessed trends in published literature regarding HGG survival after resection in conjunction with trends in clinical practice patterns of HGG resection. METHODS: We performed a comprehensive PubMed search to identify articles that examined whether gross total resection (GTR) improves HGG survival. Temporal trends in the literature were compared with rates of GTR in the Surveillance Epidemiology and End Results (SEER) database, the Veterans Health Administration database, and published data series from academic neuro-oncology centers. RESULTS: Before 2000, the ratio of articles supporting survival benefit of GTR relative to those not supporting it ranged from approximately 1:5 to 1:1. Since 2000, this ratio has steadily increased such that by the post-2013 period, 32 of the 33 published articles (>30:1) supported the survival benefit of GTR. Although the frequency of GTR increased during the 2000-2004 period in the SEER and Veterans Health Administration database, no further increase in the frequency of GTR was observed thereafter. In contrast, resection rates in academic neuro-oncology centers continued to increase subsequent to 2004. CONCLUSIONS: Our results indicate that clinical practice patterns mirror publication patterns for HGG resection, suggesting that neurosurgical oncology is a field in which clinical practice is informed by the peer-reviewed literature.

Inhibition of cereal rust fungi by both class I and II defensins derived from the flowers of Nicotiana alata.

Defensins are a large family of small, cysteine-rich, basic proteins, produced by most plants and plant tissues. They have a primary function in defence against fungal disease, although other functions have been described. This study reports the isolation and characterization of a class I secreted defensin (NaD2) from the flowers of Nicotiana alata, and compares its antifungal activity with the class II defensin (NaD1) from N. alata flowers, which is stored in the vacuole. NaD2, like all other class I defensins, lacks the C-terminal pro-peptide (CTPP) characteristic of class II defensins. NaD2 is most closely related to Nt-thionin from N. tabacum (96% identical) and shares 81% identity with MtDef4 from alfalfa. The concentration required to inhibit in vitro fungal growth by 50% (IC50 ) was assessed for both NaD1 and NaD2 for the biotrophic basidiomycete fungi Puccinia coronata f. sp. avenae (Pca) and P. sorghi (Ps), the necrotrophic pathogenic ascomycetes Fusarium oxysporum f. sp. vasinfectum (Fov), F. graminearum (Fgr), Verticillium dahliae (Vd) and Thielaviopsis basicola (Tb), and the saprobe Aspergillus nidulans. NaD1 was a more potent antifungal molecule than NaD2 against both the biotrophic and necrotrophic fungal pathogens tested. NaD2 was 5-10 times less effective at killing necrotrophs, but only two-fold less effective on Puccinia species. A new procedure for testing antifungal proteins is described in this study which is applicable to pathogens with spores that are not amenable to liquid culture, such as rust pathogens. Rusts are the most damaging fungal pathogens of many agronomically important crop species (wheat, barley, oats and soybean). NaD1 and NaD2 inhibited urediniospore germination, germ tube growth and germ tube differentiation (appressoria induction) of both Puccinia species tested. NaD1 and NaD2 were fungicidal on Puccinia species and produced stunted germ tubes with a granular cytoplasm. When NaD1 and NaD2 were sprayed onto susceptible oat plants prior to the plants being inoculated with crown rust, they reduced the number of pustules per leaf area, as well as the amount of chlorosis induced by infection. Similar to observations in vitro, NaD1 was more effective as an antifungal control agent than NaD2. Further investigation revealed that both NaD1 and NaD2 permeabilized the plasma membranes of Puccinia spp. This study provides evidence that both secreted (NaD2) and nonsecreted (NaD1) defensins may be useful for broad-spectrum resistance to pathogens.