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Background Temozolomide is an oral alkylating agent with schedule-dependent antitumor activity against high-grade malignancies including high-grade glioma. Increasingly, reports have suggested that temozolomide may have activity as a salvage therapy for aggressive, recurrent pituitary adenomas or carcinomas that fail surgery, radiation and other pharmacotherapy. To our knowledge, temozolomide retreatment following initial responsiveness has not previously been demonstrated. Case report A woman was diagnosed with a prolactin-secreting pituitary adenoma in 1995 (age 44). Despite bromocriptine therapy, transphenoidal resection, radiotherapy, and cabergoline treatment she experienced continued clinico-radiographic progression, and temozolomide was initiated in 2011. She received three treatment cycles with rapid, dramatic clinico-radiographic response, and 99.3% reduction in serum prolactin. After three years of close observation, she developed recurrent radiographic progression and prolactin elevation. She was re-initiated on temozolomide, and after four cycles, clinical, radiographic and hormonal response was observed with a 92.2% reduction in serum prolactin. Conclusions/Summary Temozolomide is an increasingly described treatment option for refractory pituitary adenomas and carcinomas. In the current report, we document rapid biochemical response following retreatment with temozolomide in aggressive pituitary adenoma. When “off label” salvage therapy with temozolomide is offered for patients with recurrent prolactinomas, retreatment at the time of recurrence can be considered. [ABSTRACT FROM AUTHOR]

We investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial ( NCT03107780 ) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact. Sequencing of three recurrent tumors revealed an absence of TP53 -inactivating mutations, indicating alternative mechanisms of resistance. In patient-derived GBM models, the lower range of clinically achieved navtemadlin concentrations induced partial tumor cell death as monotherapy. However, combining navtemadlin with temozolomide increased apoptotic rates while sparing normal bone marrow cells in vitro, which in return underwent reversible growth arrest. These results indicate that clinically achievable doses of navtemadlin generate significant pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy is a route to durable survival benefits., Statement of Significance: Tissue sampling during this clinical trial allowed us to assess mechanisms of response and resistance associated with navtemadlin treatment in recurrent GBM. We report that clinically achievable doses of navtemadlin induce pharmacodynamic effects in tumor tissue, and suggest combinations with standard-of-care chemotherapy for durable clinical benefit.

Objective: To assess the effectiveness of an educational program leveraging technology-enhanced learning and retrieval practice to teach trainees how to correctly identify interictal epileptiform discharges (IEDs)., Methods: This was a bi-institutional prospective randomized controlled educational trial involving junior neurology residents. The intervention consisted of three video tutorials focused on the six IFCN criteria for IED identification and rating 500 candidate IEDs with instant feedback either on a web browser (intervention 1) or an iOS app (intervention 2). The control group underwent no educational intervention ("inactive control"). All residents completed a survey and a test at the onset and offset of the study. Performance metrics were calculated for each participant., Results: Twenty-one residents completed the study: control (n = 8); intervention 1 (n = 6); intervention 2 (n = 7). All but two had no prior EEG experience. Intervention 1 residents improved from baseline (mean) in multiple metrics including AUC (.74; .85; p < .05), sensitivity (.53; .75; p < .05), and level of confidence (LOC) in identifying IEDs/committing patients to therapy (1.33; 2.33; p < .05). Intervention 2 residents improved in multiple metrics including AUC (.81; .86; p < .05) and LOC in identifying IEDs (2.00; 3.14; p < .05) and spike-wave discharges (2.00; 3.14; p < .05). Controls had no significant improvements in any measure., Significance: This program led to significant subjective and objective improvements in IED identification. Rating candidate IEDs with instant feedback on a web browser (intervention 1) generated greater objective improvement in comparison to rating candidate IEDs on an iOS app (intervention 2). This program can complement trainee education concerning IED identification., (© 2024 International League Against Epilepsy.)

Objective: We published a list of "must-know" routine EEG (rEEG) findings for trainees based on expert opinion. Here, we studied the accuracy and inter-rater agreement (IRA) of these "must-know" rEEG findings among international experts., Methods: A previously validated online rEEG examination was disseminated to EEG experts. It consisted of a survey and 30 multiple-choice questions predicated on the previously published "must-know" rEEG findings divided into four domains: normal, abnormal, normal variants, and artifacts. Questions contained de-identified 10-20-s epochs of EEG that were considered unequivocal examples by five EEG experts., Results: The examination was completed by 258 international EEG experts. Overall mean accuracy and IRA (AC1) were 81% and substantial (0.632), respectively. The domain-specific mean accuracies and IRA were: 76%, moderate (0.558) (normal); 78%, moderate (0.575) (abnormal); 85%, substantial (0.678) (normal variants); 85%, substantial (0.740) (artifacts). Academic experts had a higher accuracy than private practice experts (82% vs. 77%; p = .035). Country-specific overall mean accuracies and IRA were: 92%, almost perfect (0.836) (U.S.); 86%, substantial (0.762) (Brazil); 79%, substantial (0.646) (Italy); and 72%, moderate (0.496) (India). In conclusion, collective expert accuracy and IRA of "must-know" rEEG findings are suboptimal and heterogeneous., Significance: We recommend the development and implementation of pragmatic, accessible, country-specific ways to measure and improve the expert accuracy and IRA., (© 2023 International League Against Epilepsy.)

The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System, utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young adult glioblastomas. The authors relate these molecular classes to current World Health Organization guidelines and reference current literature to give therapeutic and prognostic descriptions where possible., (© The Author(s) 2023. Published by Oxford University Press.)

Introduction: Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM., Methods: A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 C min ), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR., Results: Of the 24 enrolled patients, median age was 62.1 (38.7-76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6-2.5) and OS was 7.7 months (95% CI 4.9-12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R 2  = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence., Conclusions: PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Laser interstitial thermal therapy (LITT) in the setting of post-SRS radiation necrosis (RN) for patients with brain metastases has growing evidence for efficacy. However, questions remain regarding hospitalization, local control, symptom control, and concurrent use of therapies., Methods: Demographics, intraprocedural data, safety, Karnofsky performance status (KPS), and survival data were prospectively collected and then analyzed on patients who consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 US centers. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan-Meier estimated survival., Results: Ninety patients met the inclusion criteria. Four patients underwent 2 ablations on the same day. Median hospitalization time was 32.5 hours. The median time to corticosteroid cessation after LITT was 13.0 days (0.0, 1229.0) and cumulative incidence of lesional progression was 19% at 1 year. Median post-procedure overall survival was 2.55 years [1.66, infinity] and 77.1% at one year as estimated by KaplanMeier. Median KPS remained at 80 through 2-year follow-up. Seizure prevalence was 12% within 1-month post-LITT and 7.9% at 3 months; down from 34.4% within 60-day prior to procedure., Conclusions: LITT for RN was not only again found to be safe with low patient morbidity but was also a highly effective treatment for RN for both local control and symptom management (including seizures). In addition to averting expected neurological death, LITT facilitates ongoing systemic therapy (in particular immunotherapy) by enabling the rapid cessation of steroids, thereby facilitating maximal possible survival for these patients., Competing Interests: We declare that the company Monteris, which funded the trial, is also paying the publication fees for this manuscript. This may create a conflict of interest, as the company has a financial interest in the outcome of the study. However, we confirm that the study was conducted independently and that the results were not influenced by the funding source. We have disclosed all potential conflicts of interest to the journal and are committed to maintaining the integrity and objectivity of our research., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: B-cell primary central nervous system (CNS) lymphoma (PCL) is diffuse large B-cell lymphoma (DLBCL) confined to the CNS. Less than 50% of patients with PCL achieve complete remission with current therapies. We describe the findings from comprehensive genomic profiling (CGP) of a cohort of 69 patients with PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL to highlight their differences and characterize the PCL cohort. In addition, we highlight the differences in frequency of germinal center B-cell like (GCB) and non-GCB subtypes and molecular subtypes, particularly MCD and EZH subtypes, between PCL and DLBCL., Materials and Methods: Sixty-nine cases of B-cell PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL were evaluated by CGP of 405 genes via DNAseq and 265 genes via RNAseq for fusions (FoundationOne Heme). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA., Results: Genomic alterations with significant differences between PCL and DLBCL included MYD88, ETV6, PIM1, PRDM1, CXCR4, TP53, and CREBBP, while only MYD88 was significantly different between SCL and DLBCL. PCL cases were significantly enriched for the MCD molecular subtypes, which have an excellent response to BTKi. We report a patient with a durable complete response to BTKi consistent with their genomic profile. EBV status, CD274 amplification, and TMB status suggest that 38% of PCL patients may benefit from ICPI; however further study is warranted., Conclusion: CGP of PCLs reveals biomarkers, genomic alterations, and molecular classifications predictive of BTKi efficacy and potential ICPI efficacy. Given the limitations of standard of care for PCL, CGP is critical to identify potential therapeutic approaches for patients in this rare form of lymphoma., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: Data on the efficacy and safety of stereotactic radiosurgery (SRS) for treatment of radiation-induced meningiomas (RIMs) are limited., Methods: A single institution database of Cobalt-60 SRS cases from 08/1999 to 10/2020 was reviewed. Radiation-induced meningiomas were identified using Cahan's criteria. Endpoints included overall survival (OS), progression free survival (PFS), local control (LC), treatment failure, and treatment toxicity. Univariate and multivariate analyses were performed using cox proportional hazard models., Results: A total of 29 patients with 86 RIM lesions were identified. Median follow-up after SRS was 59 months. The median dose prescribed to the 50% isodose line was 14 Gy (range 12-20 Gy). The actuarial 5-yr OS and PFS were 96% and 68%, respectively. Patients treated for recurrent RIMs had a significantly lower PFS (45% vs 94% at 3 yr, p < 0.005) than patients treated in the upfront setting. Patients with presumed or WHO grade I RIMs had a significantly greater PFS (3-year PFS 96% vs 20%) than patients with WHO grade II RIMs (p < 0.005). On a per-lesion basis, local control (LC) at 1-, 3-, and 5-yrs was 82%, 76%, 74%, respectively. On multivariate analysis, female gender was associated with improved LC (p < 0.001), while marginal doses > 14 Gy were associated with worse local control (p < 0.001). Grade I-III toxicity following treatment was 9.0%., Conclusions: Stereotactic radiosurgery is a safe and effective treatment option for radiographic RIMs, WHO grade I RIMs, or lesions treated in the upfront setting. WHO grade II lesions and recurrent lesions are at increased risk for disease progression., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Wrist drop is a common presentation in neurology. To localize the lesion, clinicians can focus on testing finger extension, elbow flexion with semipronated forearm, and elbow extension among other muscle groups and identifying dermatomes of numbness. Once the lesion is localized, electrophysiology or imaging can guide to an underlying etiology. Here, we describe a case that illustrates the importance of using a stepwise approach to diagnose the etiology of wrist drop in a patient with a cancer history. A 65-year-old woman with diffuse large B-cell lymphoma in remission presented with new onset wrist drop, severe pain, numbness, and tingling concerning for peripheral nerve injury. Imaging findings from PET, venous ultrasound, nerve conduction velocity study, and MRI were conflicting favoring deep venous thrombosis, cancer recurrence, or peripheral nerve sheath tumor. A biopsy was ultimately required to confirm the diagnosis., (© 2022 American Academy of Neurology.)

The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ's effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer and suppressed the progression of established tGLI1-positive BCBM without liver toxicities. We further developed six KCZ derivatives, two of which (KCZ-5 and KCZ-7) retained tGLI1-selectivity in vitro. KCZ-7 exhibited higher blood-brain barrier penetration than KCZ/KCZ-5 and more effectively reduced the BCBM frequency. In contrast, itraconazole, another FDA-approved antifungal, failed to suppress BCBM. The mechanistic studies suggest that KCZ and KCZ-7 inhibit tGLI1's ability to bind to DNA, activate its target stemness genes Nanog and OCT4, and promote tumor proliferation and angiogenesis. Our study establishes the rationale for using KCZ and KCZ-7 for treating and preventing BCBM and identifies their mechanism of action.

Background: Re-irradiation for recurrent gliomas is a controversial treatment option with no clear standard dose or concurrent systemic therapy., Methods: This series represents a single-institution retrospective review of patients treated with re-irradiation for recurrent high-grade glioma. After 2012, patients were commonly offered concurrent bevacizumab as a cytoprotective agent against radiation necrosis. Kaplan-Meier method was used to estimate overall survival and progression-free survival. Cox proportional hazards regression was used to identify factors associated with overall survival and progression-free survival., Results: Between 2001 and 2021, 52 patients underwent re-irradiation for a diagnosis of recurrent high-grade glioma. 36 patients (69.2%) had a histologic diagnosis of glioblastoma at the time of re-irradiation. The median BED10 (biological equivalent dose 10 Gy) of re-irradiation was 53.1 Gy. Twenty-one patients (40.4%) received concurrent bevacizumab with re-irradiation. Median survival for the entire cohort and for glioblastoma at the time of recurrence patients was 6.7 months and 6.0 months, respectively. For patients with glioblastoma at the time of recurrence, completing re-irradiation (HR 0.03, P < .001), use of concurrent bevacizumab (HR 0.3, P = .009), and the BED10 (HR 0.9, P = .005) were predictive of overall survival. Nine patients developed grade 3-5 toxicity; of these, 2 received concurrent bevacizumab and 7 did not ( P = .15)., Conclusion: High dose re-irradiation with concurrent bevacizumab is feasible in patients with recurrent gliomas. Concurrent bevacizumab and increasing radiation dose may improve survival in patients with recurrent glioblastoma., (Published by Oxford University Press 2022.)

Purpose: To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults., Methods: ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature., Results: Fifty-nine randomized trials focusing on therapeutic management were identified., Recommendations: Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMT promoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines., Competing Interests: Reprint Requests: 2318 Mill Road, Suite 800, Alexandria, VA 22314; guidelines@asco.org. Nimish A. MohileResearch Funding: Vascular Biogenics, Boston Biomedical, Quell, Tocagen Na Tosha GatsonHonoraria: NovocureConsulting or Advisory Role: NovocureTravel, Accommodations, Expenses: Novocure Andreas F. HottingerConsulting or Advisory Role: Ideogen (Inst), Bayer Roche (Inst), Novocure (Inst)Research Funding: Novocure (Inst)Travel, Accommodations, Expenses: Celgene, Novocure, Bristol Myers Squibb, Karyopharm Therapeutics Andrew LassmanHonoraria: Abbott MolecularConsulting or Advisory Role: Karyopharm Therapeutics, Sapience Therapeutics, QED Therapeutics, FORMA Therapeutics, Bayer, Orbus Therapeutics, BioClinica, Novocure, Elsevier, Vivacitas OncologyResearch Funding: AbbVie (Inst), Novartis (Inst), Genentech/Roche (Inst), Aeterna Zentaris (Inst), Celldex (Inst), Kadmon (Inst), BeiGene (Inst), VBI Vaccines (Inst), Pfizer (Inst), Millennium (Inst), Oncoceutics (Inst), Karyopharm Therapeutics (Inst), Bayer (Inst), QED Therapeutics (Inst), Agios (Inst), Orbus Therapeutics (Inst), BMS (Inst), RTOG Foundation (Inst)Patents, Royalties, Other Intellectual Property: ElsevierTravel, Accommodations, Expenses: AbbVie, BioClinica, Abbott Molecular, FORMA Therapeutics, Karyopharm Therapeutics, QED Therapeutics, Bayer, Novartis, Pfizer, VBI Vaccines Douglas NeyConsulting or Advisory Role: DNAtrixResearch Funding: Orbus Therapeutics, Denovo Biopharma (Inst) Phioanh Leia NghiemphuConsulting or Advisory Role: AbbVieResearch Funding: Novartis Adriana OlarConsulting or Advisory Role: Guardant Health, Anuncia Inc Jeffery OlsonConsulting or Advisory Role: American Cancer Society David SchiffConsulting or Advisory Role: Orbus Therapeutics, GlaxoSmithKline, PRAResearch Funding: Bayer (Inst) Helen A. ShihHonoraria: UpToDate Roy StrowdConsulting or Advisory Role: Monteris Medical, NovocureResearch Funding: Southeastern Brain Tumor Foundation, Jazz Pharmaceuticals, NIH, American Board of Psychiatry and Neurology, Alpha Omega AlphaOther Relationship: American Academy of Neurology (AAN) Martin van den BentThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Employment: AstraZeneca (I)Consulting or Advisory Role: AbbVie, Bristol Myers Squibb, Celgene, Agios, Boehringer Ingelheim, Bayer, Carthera, Genenta Science, Nerviano Medical Sciences, Boston PharmaceuticalsResearch Funding: AbbVie (Inst) Mateo ZiuStock and Other Ownership Interests: Gilead Sciences Jaishri BlakeleyConsulting or Advisory Role: AbbVie, AstraZeneca, Astellas Pharma, Exelixis, VertexResearch Funding: GlaxoSmithKline (Inst), Lilly (Inst), Sanofi (Inst), Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: ExelixisUncompensated Relationships: SpringWorks Therapeutics (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/747718No other potential conflicts of interest were reported.

Background: As medical education shifted to a virtual environment during the early coronavirus disease 2019 (COVID-19) pandemic, we evaluated how neurology podcasting may have been utilized during this period, and which features of podcasts have been more highly sought by a medical audience., Methods: We conducted a retrospective analysis of neurology-themed blogs and/or podcasts between April 2019 and May 2020. Programs were eligible if they reported mean monthly downloads > 2000, were affiliated with an academic society, or offered continuing medical education credit. Thirty-day download counts were compared between study months, with adjustment for multiple testing. Exploratory analyses were performed to determine which podcast features were associated with higher downloads., Results: Of the 12 neurology podcasts surveyed, 8 completed the survey and 5 met inclusion criteria. The median monthly download count was 2865 (IQR 869-7497), with significant variability between programs (p < 0.001). While there was a 358% increase in downloads during April 2020 when compared to the previous month, this was not significant (median 8124 [IQR 2913-14,177] vs. 2268 [IQR 540-6116], p adj  = 0.80). The non-significant increase in overall downloads during April 2020 corresponded to an increase in unique episodes during that month (r = 0.48, p = 0.003). There was no difference in 30-day downloads among episodes including COVID-19 content versus not (median 1979 [IQR 791-2873] vs. 1171 [IQR 405-2665], p = 0.28)., Conclusions: In this unique, exploratory study of academic neurology-themed podcasts, there was no significant increase in episode downloads during the early COVID-19 pandemic. A more comprehensive analysis of general and subspecialty medical podcasts is underway., (© 2021. Fondazione Società Italiana di Neurologia.)

Background: Among patients with breast carcinoma who have metastatic disease, 15%-30% will eventually develop brain metastases. We examined the genomic landscape of a large cohort of patients with breast carcinoma brain metastases (BCBMs) and compared it with a cohort of patients with primary breast carcinomas (BCs)., Material and Methods: We retrospectively analyzed 733 BCBMs tested with comprehensive genomic profiling (CGP) and compared them with 10,772 primary breast carcinomas (not-paired) specimens. For a subset of 16 triple-negative breast carcinoma (TNBC)-brain metastasis samples, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) was performed concurrently., Results: A total of 733 consecutive BCBMs were analyzed. Compared with primary BCs, BCBMs were enriched for genomic alterations in TP53 (72.0%, 528/733), ERBB2 (25.6%, 188/733), RAD21 (14.1%, 103/733), NF1 (9.0%, 66/733), BRCA1 (7.8%, 57/733), and ESR1 (6.3%,46/733) (p < .05 for all comparisons). Immune checkpoint inhibitor biomarkers such as high tumor mutational burden (TMB-high; 16.2%, 119/733); high microsatellite instability (1.9%, 14/733); CD274 amplification (3.6%, 27/733); and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutational signature (5.9%, 43/733) were significantly higher in the BCBM cohort compared with the primary BC cohort (p < .05 for all comparisons). When using both CGP and PD-L1 IHC, 37.5% (6/16) of patients with TNBC brain metastasis were eligible for atezolizumab based on PD-L1 IHC, and 18.8% (3/16) were eligible for pembrolizumab based on TMB-high status., Conclusion: We found a high prevalence of clinically relevant genomic alterations in patients with BCBM, suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for CGP in addition to CGP of the primary tumor may be clinically warranted., Implications for Practice: This study found a high prevalence of clinically relevant genomic alterations in patients with breast carcinoma brain metastasis (BCBM), suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for comprehensive genomic profiling (CGP) in addition to CGP of the primary tumor may be clinically warranted. In addition, this study identified higher positive rates for FDA-approved immunotherapy biomarkers detected by CGP in patients with BCBM, opening a possibility of new on-label treatments. Last, this study noted limited correlation between tumor mutational burden and PD-L1 immunohistochemistry (IHC), which shows the importance of testing patients with triple-negative BCBM for immune checkpoint inhibitor eligibility with both PD-L1 IHC and CGP., (© 2021 AlphaMed Press.)

JAK2-STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining-confocal microscopy and immunoprecipitation-Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA-STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA-STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC . The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2-STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.

Purpose: Accurate recording of diagnosis (DX) data in electronic health records (EHRs) is important for clinical practice and learning health care. Previous studies show statistically stable patterns of data entry in EHRs that contribute to inaccurate DX, likely because of a lack of data entry support. We conducted qualitative research to characterize the preferences of oncological care providers on cancer DX data entry in EHRs during clinical practice., Methods: We conducted semistructured interviews and focus groups to uncover common themes on DX data entry preferences and barriers to accurate DX recording. Then, we developed a survey questionnaire sent to a cohort of oncologists to verify the generalizability of our initial findings. We constrained our participants to a single specialty and institution to ensure similar clinical backgrounds and clinical experience with a single EHR system., Results: A total of 12 neuro-oncologists and thoracic oncologists were involved in the interviews and focus groups. The survey developed from these two initial thrusts was distributed to 19 participants yielding a 94.7% survey response rate. Clinicians reported similar user interface experiences, barriers, and dissatisfaction with current DX entry systems including repetitive entry operations, difficulty in finding specific DX options, time-consuming interactions, and the need for workarounds to maintain efficiency. The survey revealed inefficient DX search interfaces and challenging entry processes as core barriers., Conclusion: Oncologists seem to be divided between specific DX data entry and time efficiency because of current interfaces and feel hindered by the burdensome and repetitive nature of EHR data entry. Oncologists' top concern for adopting data entry support interventions is ensuring that it provides significant time-saving benefits and increasing workflow efficiency. Future interventions should account for time efficiency, beyond ensuring data entry effectiveness., Competing Interests: Roy StrowdConsulting or Advisory Role: Monteris Medical, NovocureResearch Funding: Southeastern Brain Tumor Foundation, Jazz Pharmaceuticals, NIH, American Board of Psychiatry and Neurology, Alpha Omega AlphaOther Relationship: American Academy of Neurology (AAN) Thomas W. LycanTravel, Accommodations, Expenses: IncyteOpen Payments Link: https://openpaymentsdata.cms.gov/physician/4354581https://openpaymentsdata.cms.gov/physician/4354581 Brian J. WellsResearch Funding: Boehringer Ingelheim Umit TopalogluStock and Other Ownership Interests: CareDirectionsNo other potential conflicts of interest were reported.

Objective. To teach interprofessional communication and teamwork skills to health professions students through a standardized patient simulation on acute patient stabilization and measure the impact on learners' perceptions of interprofessional collaboration. Methods. Medical and pharmacy students in their final year and post-licensure nurses in their initial six-month probationary period worked together to stabilize a simulated acutely ill standardized patient. Perceptions of IPE were assessed pre- and post-simulation using the Student Perceptions of Interprofessional Clinical Education-Revised Instrument, version 2 (SPICE-R2). Medical student participants' scores were compared to those of a concurrently enrolled cohort of medical students who did not participate in the simulation. Results. Eighty learners participated in the simulation and all completed pre and post SPICE-R2 assessments. Learners' perceptions increased significantly in all domains, including understanding of roles in collaborative practice, interprofessional teamwork and team-based practice, and patient outcomes from collaborative practice. Compared to the control cohort, participants' perceptions of team-based practice and the impact on patient outcomes improved significantly, while a statistically similar improvement in scores for understanding of roles and responsibilities was seen. The SPICE-R2 scores increased similarly among students in each profession. Repeat exposure to the simulation continued to improve perceptions but not as robustly as the initial simulation. Conclusion. This simulation changed learners' perceptions of how interprofessional collaboration affects patient care, which supports the incorporation of standardized patient-based interprofessional education even in the late-stage education of health professionals., (© 2021 American Association of Colleges of Pharmacy.)

Background: Experts in the field of medical education emphasized the need for curricula that improve students' attitudes toward the underserved. However, some studies have shown that medical education tends to worsen these attitudes in students. We aimed at systematically reviewing the literature assessing the change in medical students' attitudes toward the underserved and intention to work with the underserved throughout medical education, the sociodemographic and educational factors associated with favorable medical student attitudes toward and/or intention to work with the underserved and the effectiveness of educational interventions to improve medical student attitudes toward and/or intention to work with the underserved., Method: We conducted a systematic review on MEDLINE, Scopus, and Web of Science databases. Three investigators independently conducted the electronic search. We assessed the change in medical students attitudes toward the underserved by computing a weighted mean effect size of studies reporting scores from validated scales. The research team performed a meta-analysis for the sociodemographic and educational factors associated with medical students attitudes toward and/or intention to work with the underserved., Results: Fifty-five articles met the inclusion criteria, including a total of 109,647 medical students. The average response rate was 73.2%. Most of the studies were performed in the USA (n = 45). We observed a significant decline of medical students attitudes toward the underserved throughout medical education, in both US and non-US studies. A moderate effect size was observed between the first and fourth years (d = 0.51). Higher favorable medical students attitudes toward or intention to work with the underserved were significantly associated with female gender, being from an underserved community or ethnic minority, exposure to the underserved during medical education and intent to practice in primary care. Regarding educational interventions, the effectiveness of experiential community-based learning and curricula dedicated to social accountability showed the most positive outcome., Conclusions: Medical students attitudes toward the underserved decline throughout medical education. Educational interventions dedicated to improving the attitudes or intentions of medical students show encouraging but mixed results. The generalizability of our results is impeded by the high number of studies from the global-North included in the review.

Despite advances in systemic therapies for solid tumors, the development of brain metastases remains a significant contributor to overall cancer mortality and requires improved methods for diagnosing and treating these lesions. Similarly, the prognosis for malignant primary brain tumors remains poor with little improvement in overall survival over the last several decades. In both primary and metastatic central nervous system (CNS) tumors, the challenge from a clinical perspective centers on detecting CNS dissemination early and understanding how CNS lesions differ from the primary tumor, in order to determine potential treatment strategies. Acquiring tissue from CNS tumors has historically been accomplished through invasive neurosurgical procedures, which restricts the number of patients to those who can safely undergo a surgical procedure, and for which such interventions will add meaningful value to the care of the patient. In this review we discuss the potential of analyzing cell free DNA shed from tumor cells that is contained within the cerebrospinal fluid (CSF) as a sensitive and minimally invasive method to detect and characterize primary and metastatic tumors in the CNS., (Copyright © 2020 Ramkissoon, Pegram, Haberberger, Danziger, Lesser, Strowd, Dahiya, Cummings, Bi, Abedalthagafi, Sathyan, McGregor, Reddy, Severson, Williams, Lin, Edgerly, Huang, Hemmerich, Creeden, Brown, Venstrom, Hegde, Ross, Alexander, Elvin and Ramkissoon.)

Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and associated with unfavorable prognosis. TNBC lacks effective treatments. HER2-positive tumors have treatment options but often acquire resistance to HER2-targeted therapy after initial response. To address these challenges, we determined whether novel combinations of JAK2-STAT3 and SMO-GLI1/tGLI1 inhibitors synergistically target TNBC and HER2 breast cancer since these two pathways are concurrently activated in both tumor types and enriched in metastatic tumors. Herein, we show that novel combinations of JAK2 inhibitors (ruxolitinib and pacritinib) with SMO inhibitors (vismodegib and sonidegib) synergistically inhibited in vitro growth of TNBC and HER2-positive trastuzumab-resistant BT474-TtzmR cells. Synergy was also observed against breast cancer stem cells. To determine if the combination is efficacious in inhibiting metastasis, we treated mice with intracardially inoculated TNBC cells and found the combination to inhibit lung and liver metastases, and prolong host survival without toxicity. The combination inhibited orthotopic growth, VEGF-A expression, and tumor vasculature of both TNBC and HER2-positive trastuzumab-refractory breast cancer. Lung metastasis of orthotopic BT474-TtzmR xenografts was suppressed by the combination. Together, our results indicated that dual targeting of JAK2 and SMO resulted in synergistic suppression of breast cancer growth and metastasis, thereby supporting future clinical testing.

Purpose: Diagnosis (DX) information is key to clinical data reuse, yet accessible structured DX data often lack accuracy. Previous research hints at workflow differences in cancer DX entry, but their link to clinical data quality is unclear. We hypothesized that there is a statistically significant relationship between workflow-describing variables and DX data quality., Methods: We extracted DX data from encounter and order tables within our electronic health records (EHRs) for a cohort of patients with confirmed brain neoplasms. We built and optimized logistic regressions to predict the odds of fully accurate (ie, correct neoplasm type and anatomic site), inaccurate, and suboptimal (ie, vague) DX entry across clinical workflows. We selected our variables based on correlation strength of each outcome variable., Results: Both workflow and personnel variables were predictive of DX data quality. For example, a DX entered in departments other than oncology had up to 2.89 times higher odds of being accurate ( P < .0001) compared with an oncology department; an outpatient care location had up to 98% fewer odds of being inaccurate ( P < .0001), but had 458 times higher odds of being suboptimal ( P < .0001) compared with main campus, including the cancer center; and a DX recoded by a physician assistant had 85% fewer odds of being suboptimal ( P = .005) compared with those entered by physicians., Conclusion: These results suggest that differences across clinical workflows and the clinical personnel producing EHR data affect clinical data quality. They also suggest that the need for specific structured DX data recording varies across clinical workflows and may be dependent on clinical information needs. Clinicians and researchers reusing oncologic data should consider such heterogeneity when conducting secondary analyses of EHR data.

The COVID-19 outbreak is posing unprecedented risks and challenges for all communities and healthcare systems, worldwide. There are unique considerations for many adult patients with gliomas who are vulnerable to the novel coronavirus due to older age and immunosuppression. As patients with terminal illnesses, they present ethical challenges for centers that may need to ration access to ventilator care due to insufficient critical care capacity. It is urgent for the neuro-oncology community to develop a pro-active and coordinated approach to the care of adults with gliomas in order to provide them with the best possible oncologic care while also reducing their risk of viral infection during times of potential healthcare system failure. In this article, we present an approach developed by an international multi-disciplinary group to optimize the care of adults with gliomas during this pandemic. We recommend measures to promote strict social distancing and minimize exposures for patients, address risk and benefit of all therapeutic interventions, pro-actively develop end of life plans, educate patients and caregivers and ensure the health of the multi-disciplinary neuro-oncology workforce. This pandemic is already changing neuro-oncologic care delivery around the globe. It is important to highlight opportunities to maximize the benefit and minimize the risk of glioma management during this pandemic and potentially, in the future., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mechanisms for breast cancer metastasis remain unclear. Whether truncated glioma-associated oncogene homolog 1 (TGLI1), a transcription factor known to promote angiogenesis, migration and invasion, plays any role in metastasis of any tumor type has never been investigated. In this study, results of two mouse models of breast cancer metastasis showed that ectopic expression of TGLI1, but not GLI1, promoted preferential metastasis to the brain. Conversely, selective TGLI1 knockdown using antisense oligonucleotides led to decreased breast cancer brain metastasis (BCBM) in vivo. Immunohistochemical staining showed that TGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that TGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. TGLI1 activation is associated with a shortened time to develop BCBM and enriched in HER2-enriched and triple-negative breast cancers. Radioresistant BCBM cell lines and specimens expressed higher levels of TGLI1, but not GLI1, than radiosensitive counterparts. Since cancer stem cells (CSCs) are radioresistant and metastasis-initiating cells, we examined TGLI1 for its involvement in breast CSCs and found TGLI1 to transcriptionally activate stemness genes CD44, Nanog, Sox2, and OCT4 leading to CSC renewal, and TGLI1 outcompetes with GLI1 for binding to target promoters. We next examined whether astrocyte-priming underlies TGLI1-mediated brain tropism and found that TGLI1-positive CSCs strongly activated and interacted with astrocytes in vitro and in vivo. These findings demonstrate, for the first time, that TGLI1 mediates breast cancer metastasis to the brain, in part, through promoting metastasis-initiating CSCs and activating astrocytes in BCBM microenvironment.

Background and Purpose: Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks., Materials and Methods: Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients., Results: At baseline, the ketone bodies acetone and β-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and β-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not β-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and β-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones ( r = 0.87, P = .001) and lower fasting glucose ( r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks., Conclusions: This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used., (© 2019 by American Journal of Neuroradiology.)