Abstract BACKGROUND Both radiation and temozolomide (TMZ) have meaningful single-modality anti-tumor activity against low-grade gliomas. ECOG-ACRIN E3F05 tested whether combined therapy with radiation and temozolomide is more effective than radiation alone in patients with grade II gliomas. METHODS Patients with grade II gliomas (central pathology review performed post hoc), no prior radiation/chemotherapy, and either age > 40, uncontrolled symptoms/seizures, or progression after initial observation were randomized 1:1 to radiation 50.4 Gy alone in 28 fractions (Arm A) versus radiation 50.4 Gy with concomitant and 12 four-week cycles of post-radiation TMZ (Arm B). Randomization was stratified by 1p/19q codeletion status, age, KPS, pre-operative tumor diameter, and contrast enhancement. The primary endpoint was progression-free survival (PFS); overall survival (OS), quality of life, cognition, severe toxicities, and impact of codeletion status were secondary objectives. RESULTS The trial opened 1/09. Accrual was stopped in 1/14 after RTOG 9802 reported benefit from the addition of PCV chemotherapy to radiation in grade II gliomas. A total of 172 subjects were enrolled. Median age was 44 (range 19-78) and 54% male. 1p/19q codeletion was present in 44%. NCI CTCAE (version 4) grade 3+ toxicity was more common in participants treated with TMZ: thrombocytopenia (11%) and neutropenia (5%) versus none in the radiation alone arm. With a median follow-up of 117 months, OS was superior in Arm B (HR 0.54, 95% CI 0.31-0.95, stratified log-rank p value 0.03). OS HRs were 0.56 and 0.53 for subjects with and without 1p/19q codeleted tumors, respectively. PFS did not differ between Arms A and B (HR 0.76, 95% CI 0.44-1.28, p = 0.30). Five and ten-year OS were 78% and 70% in Arm B versus 70% and 47% in Arm A. CONCLUSION The addition of temozolomide to radiation improves overall survival in both co-deleted and non-co-deleted grade II gliomas.

To assess the comparative safety of patent foramen ovale (PFO) closure for secondary stroke prevention in a population of patients aged 60 or older in the United States.

Evaluate the clinical outcomes of patients with acute ischemic stroke treated with Tenecteplase.

Background: Unlike other stimulants, methamphetamine (meth) is highly addictive and can be injected, snorted, smoked, or ingested orally. Due to increased access, its use has increased globally. Recent studies have shown that there was no significant difference in hospital outcomes between ICH positive patients who utilize meth versus those who do not. However, there has not been a comprehensive evaluation of methamphetamine related ICH in recent times. Our objective is to determine if meth use impacts ICU length of stay/need for sedating agents, and if meth use varies by ethnicity in the ICH population. Methods: This is an IRB approved retrospective review of all patients with acute ICH at a large academic stroke center from 2017 to 2023. Data collected and analyzed include demographics, ICH score/size, intraventricular hemorrhage, location of hematoma, surgical intervention, GCS/NIHSS scores, ICU length of stay (LOS), and discharge destiny. Statistics used include Pearson’s Chi-squared test and Wilcoxon rank sum test. Results: Of 70 ICH patients with all data elements, 32 (46%) were meth users, with an average age of meth positive patients at 59. In our Hispanic population, significant meth use was seen (41% v 13%, p = 0.009). ICH patients had significant NICU LOS (10.1 v 6.1 days, p < 0.001), with longer hospital mean LOS (12.4 v 7.8 days, p = 0.007). They also required more sedatives (63% v 37%, p = 0.032). Meth use was not associated with larger ICH size (15.7 v 29.2, p = 0.406), but was associated with higher discharge mRS (4.7 v 4.3, p = 0.788). Conclusions: Our study demonstrates that in ICH positive patients, meth-use was associated with increased use of sedatives and increased length of stay, as well as higher discharge mRS. However, it was not associated with larger ICH size. Hispanic ethnicity and ICH also appear to have a relationship, although that relationship needs to be further elucidated. Discussion: Methamphetamine is easily and relatively inexpensive to make, with over-the-counter ingredients such as pseudoephedrine. With over 35 million people using meth worldwide, our data found that the average user was older than previously thought. As ICH is one of the major complications of meth use, ICH has a major impact on complexity of care and health economics.

Background: Endovascular thrombectomy (EVT) for treatment of acute ischemic stroke (AIS) in the proximal cerebrovasculature has, since its inception, become part of the standard of care when addressing AIS. Overall, one in six individuals treated has improved neurologic and functional outcomes. Reperfusion following thrombectomy in the anterior cerebral circulation has long been graded by the modified Thrombolysis in Cerebral Infarction (mTICI) scale-and the score of mTICI (2b, or, “partial filling of more than 50% of the affected vascular territory” is considered the benchmark for “good” outcomes in EVT. It remains unclear whether this score at time of reperfusion reliably predicts a sustained improvement in neurologic or functional outcome. Method: This is a retrospective review of all anterior AIS patients with large vessel occlusion (LVO) at Barrow Neurological Institute between 01/01/2018 and 12/31/2022 who underwent EVT with mTICI 2b or greater. The study was approved by the local IRB. Demographic data of patients between the ages of 18 and 95 who had AIS with LVO in the anterior Circle of Willis or its supplying vessels were collected. Other variables collected and analyzed include mTICI score, and modified Rankin Score (mRS) at discharge and 90 days. The TICI grade was obtained via digital cerebral angiography post EVT. Descriptive statistics was used to examine the differences of mRS scores at 90 days. Results: Of 81 cases reviewed, 52 (65%) had a TICI 2b score and their average mRS was 3.7, 20 (25%) had a TICI 2c and their average mRS was 3.6, and 4 (5%) had a TICI 3 with mRS 3 at discharge. At 90 days, the average mRS for TICI 2b patients was 3.2, for TICI 2c patients 2.9 and for TICI 3 patients 2.3. No difference in the rate of intracerebral hemorrhage (ICH) following reperfusion between the TICI 2 and 3 groups (17%). Conclusion: Our results demonstrated that patients with a mTICI of 2b had a higher mean mRS at discharge and minimal improvement of mRS at 90 days compared against patients with a mTICI of 2c or 3 (average change in score was -0.6, -0.7 and -1.3 in the TICI 2b, 2c and 3 groups respectively). Therefore, a reperfusion score of mTICI 2b may not be sufficient to indicate a high probability of a good functional outcome. With EVT, reaching a TICI 3 should be attempted.

Figure A2 from Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial

Figure A3 from Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial

Figure A1 from Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial

BACKGROUND:Three- and five-year progression-free survival (PFS) for low-risk meningioma managed with surgery and observation reportedly exceeds 90%. Herewith we summarize outcomes for low-risk meningioma patients enrolled on NRG/RTOG 0539. METHODS:This phase II trial allocated patients to one of three groups per World Health Organization grade, recurrence status, and resection extent. Low-risk patients had either gross total (GTR) or subtotal resection (STR) for a newly diagnosed grade 1 meningioma and were observed after surgery. The primary endpoint was 3-year PFS. Adverse events (AEs) were scored using Common Terminology Criteria for Adverse Events (CTCAE) version 3. RESULTS:Among 60 evaluable patients, the median follow-up was 9.1 years. The 3-, 5-, and 10-year rates were 91.4% (95% CI, 84.2 to 98.6), 89.4% (95% CI, 81.3 to 97.5), 85.0% (95% CI, 75.3 to 94.7) for PFS and 98.3% (95% CI, 94.9 to 100), 98.3%, (95% CI, 94.9 to 100), 93.8% (95% CI, 87.0 to 100) for overall survival (OS), respectively. With centrally confirmed GTR, 3/5/10y PFS and OS rates were 94.3/94.3/87.6% and 97.1/97.1/90.4%. With STR, 3/5/10y PFS rates were 83.1/72.7/72.7% and 10y OS 100%. Five patients reported one grade 3, four grade 2, and five grade 1 AEs. There were no grade 4 or 5 AEs. CONCLUSIONS:These results prospectively validate high PFS and OS for low-risk meningioma managed surgically but raise questions regarding optimal management following STR, a subcohort that could potentially benefit from adjuvant therapy.

Web Extra Material - 2 tables and 3 figures

Background:A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma. Methods:Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided Z test for 2 proportions. Adverse events (AEs) were evaluated per CTCAE version 4. Results:One hundred and fifty-eight patients were randomized, out of which 9 were ineligible and 12 were not evaluable for the primary endpoint, leaving 137 eligible and evaluable. 6-month PFS was 46.6% in the cediranib arm versus 24.5% in the placebo arm (P = .005). There was no significant difference in overall survival between the 2 arms. There was more grade ≥ 3 AEs in the cediranib arm than in the placebo arm (P = .02). Conclusions:This study met its primary endpoint of prolongation of 6-month PFS with cediranib in combination with radiation and temozolomide versus placebo in combination with radiation and temozolomide. There was no difference in overall survival between the 2 arms.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

Abstract BACKGROUND Novel therapies are needed in newly diagnosed glioblastoma as nearly all patients experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ), including patients with tumors with methylated MGMT promoter, a positive prognostic factor and predictor of benefit with TMZ. Here, we report the final analysis of progression-free survival (PFS), overall survival (OS), and safety from an international randomized, single-blind phase-3 study of nivolumab (NIVO)+RT+TMZ in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter (CheckMate 548; NCT02667587). METHODS Patients (N=716) aged ≥ 18y were randomized 1:1 regardless of tumor PD-L1 expression to NIVO (240 mg Q2W×8, then 480 mg Q4W) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 QD during RT, then 4-week break, then 150–200 mg/m2 QD on days 1–5 of every 28-day cycle for 6 cycles) or placebo (PBO)+RT+TMZ. The dual-primary endpoints were PFS by blinded independent central review and OS, both overall and without baseline corticosteroids. RESULTS As of December 22, 2020, median PFS was 10.6 months (95% CI, 8.9–11.8) with NIVO+RT+TMZ and 10.3 months (95% CI, 9.7–12.5) with PBO+RT+TMZ (HR, 1.06 [95% CI, 0.90–1.25]). Median OS was 28.9 months (95% CI, 24.4–31.6) with NIVO+RT+TMZ and 32.1 months (95% CI, 29.4–33.8) with PBO+RT+TMZ (HR, 1.10 [95% CI, 0.91–1.33]). Among patients without baseline corticosteroids, median OS was 31.3 months (95% CI, 28.6–34.8) with NIVO+RT+TMZ and 33.0 months (95% CI, 31.0–35.1) with PBO+RT+TMZ (HR, 1.12 [95% CI, 0.87–1.43]). Grade 3–4 treatment-related adverse events were 52.4% and 33.6% with NIVO+RT+TMZ and PBO+RT+TMZ, respectively. CONCLUSIONS NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter. No new safety signals were observed with NIVO. The role of immunotherapy in this treatment landscape remains an area for further investigation.

Background/purpose Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. Methods This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. Results Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. Conclusions A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here— https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ .

Abstract BACKGROUND Tectal gliomas (TG) are rare tumors occurring primarily in children but also found in adults during workup of various neurological symptoms. Surgery is not required in asymptomatic cases, so histopathological information is sparse. No consensus on timing of imaging surveillance or management has been established. OBJECTIVE We seek to standardize neuroimaging, including MRI protocol and surveillance time intervals, and clinical management of symptoms and disease progression, including surgery, radiotherapy, and chemotherapy. METHODS At our institution, patients with TG were identified through a search of radiology reports and clinic notes between 1989 and 2020. Initial and serial MRI exams were evaluated for tumor size, enhancement, edema, hydrocephalus, and other radiographic features. When tissue was available, cellularity, mitotic activity, and morphology were described. We documented neurological symptoms and signs potentially related to the tumor. RESULTS 37 cases were identified: 22 female, 15 male; 5 children, 32 adults. Age of diagnosis ranged from 7 to 69 years. Presenting symptoms included headache (59%), visual symptoms (35%), and imbalance (14%), less commonly: seizure, weakness, nausea/vomiting, and dizziness. Surgical procedures included biopsy (9), resection (7), endoscopic third ventriculostomy (15), and shunt placement (11). Eight patients received radiotherapy, including IMRT, CyberKnife, GammaKnife, and Zap-X (all adults; 4 at diagnosis, 3 at progression, 1 at diagnosis and again at progression). Four patients received chemotherapy (all adults; 1 at diagnosis, 3 at progression), all with temozolomide. One additionally received bevacizumab for radionecrosis. Three patients died with progressive disease, two following treatment and one without. Of interest, 5 adult patients developed signs of parkinsonism during their follow-up period. CONCLUSION Management of TG encompasses both neoplastic progression and symptom control, either from local compression or infiltrative disease. We have developed an algorithm for imaging surveillance and treatment, including MRI protocol, definition of progressive disease, and indications for antineoplastic therapies.