Publications by authors named "Manish K Aghi"

203 Publications

Socioeconomic predictors of case presentations and outcomes in 225 nonfunctional pituitary adenoma resections.

J Neurosurg 2021 Oct 1:1-12. Epub 2021 Oct 1.

4Department of Neurological Surgery, University of California, San Francisco; and.

Objective: Clinical presentations and outcomes of nonfunctional pituitary adenoma (NFPA) resections can vary widely, and very little prior research has analyzed this variance through a socioeconomic lens. This study sought to determine whether socioeconomic status (SES) influences NFPA presentations and postoperative outcomes, as these associations could aid physicians in understanding case prognoses and complications.

Methods: The authors retrospectively analyzed 225 NFPA resections from 2012 to 2019 at their institution. Race, ethnicity, insurance status, estimated income, and having a primary care provider (PCP) were collected as 5 markers of SES. These markers were correlated with presenting tumor burden, presenting symptoms, surgical outcomes, and long-term clinical outcomes.

Results: All 5 examined SES markers influenced variance in patient presentation or outcome. Insurance status's effects on patient presentations disappeared when examining only patients with PCPs. Having a PCP was associated with significantly smaller tumor size at diagnosis (effect size = 0.404, p < 0.0001). After surgery, patients with PCPs had shorter postoperative hospital lengths of stay (p = 0.043) and lower rates of readmission within 30 days of discharge (OR 0.256, p = 0.047). Despite continuing follow-up for longer durations (p = 0.0004), patients with PCPs also had lower rates of tumor recurrence (p < 0.0001). Higher estimated income was similarly associated with longer follow-up (p = 0.002) and lower rates of tumor recurrence (p = 0.013). Among patients with PCPs, income was not associated with recurrence.

Conclusions: This study found that while all 5 variables (race, ethnicity, insurance, PCP status, and estimated income) affected NFPA presentations and outcomes, having a PCP was the single most important of these socioeconomic factors, impacting hospital lengths of stay, readmission rates, follow-up adherence, and tumor recurrence. Having a PCP even protected low-income patients from experiencing increased rates of tumor recurrence. These protective findings suggest that addressing socioeconomic disparities may lead to better NFPA presentations and outcomes.
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http://dx.doi.org/10.3171/2021.4.JNS21907DOI Listing
October 2021

The Evolving Role of Neurosurgical Intervention for Central Nervous System Tumors.

Hematol Oncol Clin North Am 2021 Sep 23. Epub 2021 Sep 23.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Hale Building for Transformative Medicine, 60 Fenwood Road, Boston, MA 02115, USA; Department of Radiology, Brigham and Women's Hospital/Harvard Medical School, Hale Building for Transformative Medicine, 60 Fenwood Road, Boston, MA 02115, USA.

Since its inception, greater than a century ago, neurosurgery has represented the fundamental trait-d'union between clinical management, scientific investigation, and therapeutic advancements in the field of brain tumors. During the years, oncological neurosurgery has evolved as a self-standing subspecialty, due to technical progress, equipment improvement, evolution of therapeutic paradigms, and the progressively crucial role that it plays in the execution of complex therapeutic strategies and modern clinical trials.
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http://dx.doi.org/10.1016/j.hoc.2021.08.003DOI Listing
September 2021

Geographic landscape of foreign medical graduates in US neurosurgery training programs from 2007 to 2017.

Clin Neurol Neurosurg 2021 Oct 24;209:106891. Epub 2021 Aug 24.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94131, USA. Electronic address:

Objective: Although foreign medical graduates (FMGs) have been essential to the US physician workforce, the increasing competitiveness has made it progressively challenging for FMGs to match in US neurosurgery programs. We describe geographic origins and characteristics associated with successful match into US neurosurgery training programs.

Methods: Retrospective review of AANS membership data (2007-2017). Scopus was used to collect bibliometrics.

Results: From 2009 neurosurgical residents, 165 (8.2%) were FMGs. Most were male (n = 148; 89.6%) with a median age of 34.0 years. Top six feeder countries (TFC) included India (13.9%; n = 23), Lebanon and Pakistan (9.1%; n = 15), Caribbean Region (7.2%; n = 12), Mexico (6.67%; n = 11), and Greece (3.6%; n = 6). Compared to FMGs from non-top feeder countries (NTFC), TFC FMGs had higher H-indices (2 vs 4, p = 0.049), greater number of publications (2 vs 5, p = 0.04), were more likely to have an MBBS/MBBCh (n = 38 vs n = 17, p = 0.03), and had twice as many candidates from major feeder medical schools that successfully matched into a US neurosurgery program (n = 43 vs NTFC = 20, p < 0.001). NTFC FMGs were almost 3-times more likely to match at an affiliated neurosurgery program (8 vs TFC = 3, p = 0.03), while TFC FMGs were 1.5-times more likely to match at an NIH Top-40 program (33 vs NTFC = 21, p = 0.03).

Conclusions: TFC graduates have higher bibliometrics, frequently come from major feeder schools, and have greater match success at a broader selection of programs and NIH top-40 programs. Future studies characterizing FMG country and medical school origins may enable foreign students to geographically target institutions of interest and could allow US programs to better evaluate foreign training environments.
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http://dx.doi.org/10.1016/j.clineuro.2021.106891DOI Listing
October 2021

Mouse models of glioblastoma for the evaluation of novel therapeutic strategies.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab100. Epub 2021 Jul 26.

Department of Neurological Surgery, University of California, San Francisco, California, USA.

Glioblastoma (GBM) is an incurable brain tumor with a median survival of approximately 15 months despite an aggressive standard of care that includes surgery, chemotherapy, and ionizing radiation. Mouse models have advanced our understanding of GBM biology and the development of novel therapeutic strategies for GBM patients. However, model selection is crucial when testing developmental therapeutics, and each mouse model of GBM has unique advantages and disadvantages that can influence the validity and translatability of experimental results. To shed light on this process, we discuss the strengths and limitations of 3 types of mouse GBM models in this review: syngeneic models, genetically engineered mouse models, and xenograft models, including traditional xenograft cell lines and patient-derived xenograft models.
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http://dx.doi.org/10.1093/noajnl/vdab100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403483PMC
July 2021

Trends in physician reimbursements and procedural volumes for radiosurgery versus open surgery in brain tumor care: an analysis of Medicare data from 2009 to 2018.

J Neurosurg 2021 Jul 30:1-12. Epub 2021 Jul 30.

7Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Objective: Given its minimally invasive nature and effectiveness, stereotactic radiosurgery (SRS) has become a mainstay for the multimodal treatment of intracranial neoplasm. However, no studies have evaluated recent trends in the use of SRS versus those of open resection for the management of brain tumor or trends in the involvement of neurosurgeons in SRS (which is primarily delivered by radiation oncologists). Here, the authors used publicly available Medicare data from 2009 to 2018 to elucidate trends in the treatment of intracranial neoplasm and to compare reimbursements between these approaches.

Methods: By using CPT Professional 2019, the authors identified 10 open resection and 9 SRS codes (4 for neurosurgery and 5 for radiation oncology) for the treatment of intracranial neoplasm. Medicare payments (inflation adjusted) and allowed services (number of reimbursed procedures) for each code were abstracted from the Centers for Medicare and Medicaid Services Part B National Summary Data File (2009-2018). Payments per procedure and procedures per 100,000 Medicare enrollees were analyzed with linear regression and compared with tests for equality of slopes (α = 0.05). The average payment per procedure over the study period was compared by using the 2-tailed Welsh unequal variances t-test, and more granular comparisons were conducted by using ANOVA with post hoc Tukey honestly significant difference (HSD) tests.

Results: From 2009 to 2018, the number of SRS treatments per 100,000 Medicare enrollees for intracranial neoplasm increased by 3.97 cases/year (R2 = 0.99, p < 0.001), while comparable open resections decreased by 0.34 cases/year (R2 = 0.85, p < 0.001) (t16 = 7.5, p < 0.001). By 2018, 2.6 times more SRS treatments were performed per 100,000 enrollees than open resections (74.9 vs 28.7 procedures). However, neurosurgeon involvement in SRS treatment declined over the study period, from 23.4% to 11.5% of SRS treatments; simultaneously, the number of lesions treated per session increased from 1.46 to 1.84 (R2 = 0.98, p < 0.001). Overall, physician payments from 2013 to 2018 averaged $1816.08 (95% CI $1788.71-$1843.44) per SRS treatment and $1565.59 (95% CI $1535.83-$1595.34) per open resection (t10 = 15.9, p < 0.001). For neurosurgeons specifically, reimbursements averaged $1566 per open resection, but this decreased to $1031-$1198 per SRS session; comparatively, radiation oncologists were reimbursed even less (average $359-$898) per SRS session (p < 0.05 according to the Tukey HSD test for all comparisons).

Conclusions: Over a decade, the number of open resections for intracranial neoplasm in Medicare enrollees declined slightly, while the number of SRS procedures increased greatly. This latter expansion is largely attributable to radiation oncologists; meanwhile, neurosurgeons have shifted their involvement in SRS toward sessions for the management of multiple lesions.
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http://dx.doi.org/10.3171/2020.11.JNS202284DOI Listing
July 2021

Metabolic Drivers of Invasion in Glioblastoma.

Front Cell Dev Biol 2021 1;9:683276. Epub 2021 Jul 1.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States.

Glioblastoma is a primary malignant brain tumor with a median survival under 2 years. The poor prognosis glioblastoma caries is largely due to cellular invasion, which enables escape from resection, and drives inevitable recurrence. While most studies to date have focused on pathways that enhance the invasiveness of tumor cells in the brain microenvironment as the primary driving forces behind GBM's ability to invade adjacent tissues, more recent studies have identified a role for adaptations in cellular metabolism in GBM invasion. Metabolic reprogramming allows invasive cells to generate the energy necessary for colonizing surrounding brain tissue and adapt to new microenvironments with unique nutrient and oxygen availability. Historically, enhanced glycolysis, even in the presence of oxygen (the Warburg effect) has dominated glioblastoma research with respect to tumor metabolism. More recent global profiling experiments, however, have identified roles for lipid, amino acid, and nucleotide metabolism in tumor growth and invasion. A thorough understanding of the metabolic traits that define invasive GBM cells may provide novel therapeutic targets for this devastating disease. In this review, we focus on metabolic alterations that have been characterized in glioblastoma, the dynamic nature of tumor metabolism and how it is shaped by interaction with the brain microenvironment, and how metabolic reprogramming generates vulnerabilities that may be ripe for exploitation.
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http://dx.doi.org/10.3389/fcell.2021.683276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281286PMC
July 2021

Detection of glioma infiltration at the tumor margin using quantitative stimulated Raman scattering histology.

Sci Rep 2021 06 9;11(1):12162. Epub 2021 Jun 9.

Department of Neurological Surgery, University of California, 505 Parnassus Ave., Rm. M-779, San Francisco, CA, 94143-0112, USA.

In the management of diffuse gliomas, the identification and removal of tumor at the infiltrative margin remains a central challenge. Prior work has demonstrated that fluorescence labeling tools and radiographic imaging are useful surgical adjuvants with macroscopic resolution. However, they lose sensitivity at the tumor margin and have limited clinical utility for lower grade histologies. Fiber-laser based stimulated Raman histology (SRH) is an optical imaging technique that provides microscopic tissue characterization of unprocessed tissues. It remains unknown whether SRH of tissues taken from the infiltrative glioma margin will identify microscopic residual disease. Here we acquired glioma margin specimens for SRH, histology, and tumor specific tissue characterization. Generalized linear mixed models were used to evaluate agreement. We find that SRH identified residual tumor in 82 of 167 margin specimens (49%), compared to IHC confirming residual tumor in 72 of 128 samples (56%), and H&E confirming residual tumor in 82 of 169 samples (49%). Intraobserver agreements between all 3 modalities were confirmed. These data demonstrate that SRH detects residual microscopic tumor at the infiltrative glioma margin and may be a promising tool to enhance extent of resection.
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http://dx.doi.org/10.1038/s41598-021-91648-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190264PMC
June 2021

Role of c-Met/β1 integrin complex in the metastatic cascade in breast cancer.

JCI Insight 2021 Jun 22;6(12). Epub 2021 Jun 22.

Department of Neurological Surgery, UCSF, San Francisco, California, USA.

Metastases cause 90% of human cancer deaths. The metastatic cascade involves local invasion, intravasation, extravasation, metastatic site colonization, and proliferation. Although individual mediators of these processes have been investigated, interactions between these mediators remain less well defined. We previously identified a complex between receptor tyrosine kinase c-Met and β1 integrin in metastases. Using cell culture and in vivo assays, we found that c-Met/β1 complex induction promoted intravasation and vessel wall adhesion in triple-negative breast cancer cells, but did not increase extravasation. These effects may have been driven by the ability of the c-Met/β1 complex to increase mesenchymal and stem cell characteristics. Multiplex transcriptomic analysis revealed upregulated Wnt and hedgehog pathways after c-Met/β1 complex induction. A β1 integrin point mutation that prevented binding to c-Met reduced intravasation. OS2966, a therapeutic antibody disrupting c-Met/β1 binding, decreased breast cancer cell invasion and mesenchymal gene expression. Bone-seeking breast cancer cells exhibited higher levels of c-Met/β1 complex than parental controls and preferentially adhered to tissue-specific matrix. Patient bone metastases demonstrated higher c-Met/β1 complex than brain metastases. Thus, the c-Met/β1 complex drove intravasation of triple-negative breast cancer cells and preferential affinity for bone-specific matrix. Pharmacological targeting of the complex may have prevented metastases, particularly osseous metastases.
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http://dx.doi.org/10.1172/jci.insight.138928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262466PMC
June 2021

Meningioma surgical outcomes and complications in patients aged 75 years and older.

J Clin Neurosci 2021 Jun 1;88:88-94. Epub 2021 Apr 1.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94131, USA. Electronic address:

Objective: Meningioma incidence increases with age, yet limited data exist on how comorbidities impact complication rates in elderly patients undergoing meningioma resection. The objective of this study was to report surgical outcomes and identify risk factors for perioperative complications.

Methods: We performed a retrospective study of patients 75 years and older undergoing meningioma resection. Outcomes included survival and complications. Major complications were those requiring surgical intervention or causing permanent neurological deficit. Recursive partitioning, Kaplan-Meier survival, univariate and multi-variate (MVA) analyses were performed.

Results: From 1996 to 2014, 103 patients with a median age of 79 years (IQR 77-83 years) underwent cranial meningioma resection. Median follow-up was 5.8 years (IQR 1.7-8.7 years). Median actuarial survival was 10.5 years. Complications occurred in 32 patients (31.1%), and 13 patients (12.6%) had multiple complications. Major complications occurred in 16 patients (15.5%). Increasing age was not a significant predictor of any (p = 0.6408) or major complication (p = 0.8081). On univariate analysis, male sex, Charlson Comorbidity Index greater than 8, and cardiovascular comorbidities were significantly associated with major complications. On MVA only cardiovascular comorbidities (OR 3.94, 95% CI 1.05-14.76, p = 0.0238) were significantly associated with any complication. All patients with major complications had cardiovascular comorbidities, and on MVA male gender (OR 3.78, 95%CI 1.20-11.93, p = 0.0212) was associated with major complications.

Conclusions: Cardiovascular comorbidities and male gender are significant risk factors for complications after meningioma resection in patients aged 75 years and older. While there is morbidity associated with meningioma resection in this cohort, there is also excellent long-term survival.
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http://dx.doi.org/10.1016/j.jocn.2021.03.032DOI Listing
June 2021

Are preoperative chlorhexidine gluconate showers associated with a reduction in surgical site infection following craniotomy? A retrospective cohort analysis of 3126 surgical procedures.

J Neurosurg 2021 Apr 30:1-9. Epub 2021 Apr 30.

Departments of1Neurological Surgery.

Objective: Surgical site infection (SSI) is a complication linked to increased costs and length of hospital stay. Prevention of SSI is important to reduce its burden on individual patients and the healthcare system. The authors aimed to assess the efficacy of preoperative chlorhexidine gluconate (CHG) showers on SSI rates following cranial surgery.

Methods: In November 2013, a preoperative CHG shower protocol was implemented at the authors' institution. A total of 3126 surgical procedures were analyzed, encompassing a time frame from April 2012 to April 2016. Cohorts before and after implementation of the CHG shower protocol were evaluated for differences in SSI rates.

Results: The overall SSI rate was 0.6%. No significant differences (p = 0.11) were observed between the rate of SSI of the 892 patients in the preimplementation cohort (0.2%) and that of the 2234 patients in the postimplementation cohort (0.8%). Following multivariable analysis, implementation of preoperative CHG showers was not associated with decreased SSI (adjusted OR 2.96, 95% CI 0.67-13.1; p = 0.15).

Conclusions: This is the largest study, according to sample size, to examine the association between CHG showers and SSI following craniotomy. CHG showers did not significantly alter the risk of SSI after a cranial procedure.
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http://dx.doi.org/10.3171/2020.10.JNS201255DOI Listing
April 2021

Modified RANO, Immunotherapy RANO, and Standard RANO Response to Convection-Enhanced Delivery of IL4R-Targeted Immunotoxin MDNA55 in Recurrent Glioblastoma.

Clin Cancer Res 2021 Jul 16;27(14):3916-3925. Epub 2021 Apr 16.

Medicenna BioPharma, Houston, Texas.

Purpose: The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM).

Patients And Methods: A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied.

Results: A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, < 0.0001; = 0.3) and mRANO ( < 0.0001; = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, = 0.47; central, = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements ( = 0.017), but not central measurements ( = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local ( = 0.66, < 0.0001) and centrally determined reads ( = 0.57, = 0.0007).

Conclusions: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282697PMC
July 2021

Plurihormonal PIT-1-Positive Pituitary Adenomas: A Systematic Review and Single-Center Series.

World Neurosurg 2021 07 20;151:e185-e191. Epub 2021 Apr 20.

Department of Neurological Surgery, University of California, San Francisco, School of Medicine, San Francisco, California, USA. Electronic address:

Objective: The 2017 World Health Organization classification of pituitary adenomas identified the plurihormonal PIT-1-positive (PP1) adenoma as a distinct subtype. The reported data suggest that PP1 adenomas encompass the former class of silent subtype 3 (SS3) adenomas and might have an aggressive phenotype. In the present study, we summarized the current clinical data on PP1 and SS3 adenomas and compared the reported data with the data from a single institutional cohort.

Methods: Medline and Google Scholar were searched from 1990 to 2020 for clinical series of PP1 and SS3 adenomas in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies were included if they had reported pituitary pathology as PP1 or SS3 adenomas and had reported the clinical outcomes after surgical intervention. To better define the PP1 phenotype compared with non-PP1 adenomas, we also reviewed the adenomas treated surgically at our institution from 2012 to 2019.

Results: Of all the tumors reported in the studies as PP1 or SS3, 99% were macroadenomas and 18% were giant adenomas (>4 cm). Of the reported patients, 31.8% had received radiotherapy, and 22.9% had undergone multiple surgeries for their pituitary tumor. In our single-center experience, 20 patients had an adenoma that met the criteria for a PP1 adenoma. Compared with the 1146 non-PP1 tumors, the PP1 tumors did not show statistically significant differences in the extent of resection, size, number of previous surgeries, future reoperations, rate of radiotherapy, p53 staining, or MIB-1 labeling index.

Conclusions: The findings from the present large, single-center study comparing PP1 and non-PP1 adenomas do not suggest that PP1 tumors are more aggressive. Further work is warranted to identify the pathologic subtypes of pituitary adenomas that are consistently more clinically aggressive.
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http://dx.doi.org/10.1016/j.wneu.2021.04.003DOI Listing
July 2021

The Role of Cancer-Associated Fibroblasts in Tumor Progression.

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.
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http://dx.doi.org/10.3390/cancers13061399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003545PMC
March 2021

Convection-enhanced drug delivery for glioblastoma: a review.

J Neurooncol 2021 Feb 21;151(3):415-427. Epub 2021 Feb 21.

Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, New York, NY, USA.

Introduction: Convection-enhanced delivery (CED) is a method of targeted, local drug delivery to the central nervous system (CNS) that bypasses the blood-brain barrier (BBB) and permits the delivery of high-dose therapeutics to large volumes of interest while limiting associated systemic toxicities. Since its inception, CED has undergone considerable preclinical and clinical study as a safe method for treating glioblastoma (GBM). However, the heterogeneity of both, the surgical procedure and the mechanisms of action of the agents studied-combined with the additional costs of performing a trial evaluating CED-has limited the field's ability to adequately assess the durability of any potential anti-tumor responses. As a result, the long-term efficacy of the agents studied to date remains difficult to assess.

Materials And Methods: We searched PubMed using the phrase "convection-enhanced delivery and glioblastoma". The references of significant systematic reviews were also reviewed for additional sources. Articles focusing on physiological and physical mechanisms of CED were included as well as technological CED advances.

Results: We review the history and principles of CED, procedural advancements and characteristics, and outcomes from key clinical trials, as well as discuss the potential future of this promising technique for the treatment of GBM.

Conclusion: While the long-term efficacy of the agents studied to date remains difficult to assess, CED remains a promising technique for the treatment of GBM.
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http://dx.doi.org/10.1007/s11060-020-03408-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034832PMC
February 2021

Beyond guidelines: analysis of current practice patterns of AANS/CNS tumor neurosurgeons.

J Neurooncol 2021 Feb 21;151(3):361-366. Epub 2021 Feb 21.

Department of Neurological Surgery, Weill Medical College of Cornell University, 525 E. 68th St, Box 99, New York, NY, 10065, USA.

Introduction: Evidence-based medicine guidelines are increasingly published and sanctioned by organized neurosurgery. However, implementation, interpretation, and use of clinical guidelines may vary substantially on a regional, national and international basis. Survey research can help bridge the gap by providing a snapshot of neurosurgeon attitudes, knowledge, and practices. The American Association of Neurological Surgeons/Congress of Neurological Surgeons (AANS/CNS) Section on Tumors formed a Survey Committee to formalize the process by which surveys are submitted and reviewed before distribution to our membership. The goal of this committee is to provide peer-review so that collected information will be scientifically robust and useful to the neurosurgical community.

Methods: Surveys submitted to the AANS/CNS tumor section between 2015 and 2019 were reviewed and metrics such as response rate and publication status assessed.

Results: Six surveys were submitted to the Survey Committee of the AANS/CNS section on tumors between 2015 and 2019. Four have been circulated to section members, of which three have been published. Response rate has averaged 19% (range 16-23%), a majority of respondents (mean 70%) practice in academic settings.

Conclusions: The AANS/CNS Section on Tumors Survey Committee has and continues to help promote and improve the practice of surveying our community to answer important questions that can advance future training, research, and practice. There remains significant room for improvement in response rates, but ongoing tumor section efforts to increase member engagement will likely improve these numbers.
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http://dx.doi.org/10.1007/s11060-020-03389-9DOI Listing
February 2021

Introduction to special issue dedicated to the 35th anniversary of the joint section on tumors.

J Neurooncol 2021 Feb 21;151(3):341-343. Epub 2021 Feb 21.

UCSF Neurosurgery, UCSF Department of Neurological Surgery, 505 Parnassus Avenue Room M779, San Francisco, CA, USA.

The American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Joint Section on Tumors was formed in December of 1984 as the first professional organization devoted to the study and treatment of brain tumors. One year earlier, the Journal of Neuro-Oncology had been established and went on to be sponsored by the Joint Section on Tumors. To celebrate the 35th anniversary of the founding of the Section, we are thrilled to bring you this special issue of Journal of Neuro-Oncology in which current leaders of the Joint Section on Tumors highlight their work and the work of others that have led to significant recent advances in the management of tumors of the central nervous system.
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http://dx.doi.org/10.1007/s11060-020-03518-4DOI Listing
February 2021

Using viral vectors to deliver local immunotherapy to glioblastoma.

Neurosurg Focus 2021 02;50(2):E4

The treatment for glioblastoma (GBM) has not seen significant improvement in over a decade. Immunotherapies target the immune system against tumor cells and have seen success in various cancer types. However, the efficacy of immunotherapies in GBM thus far has been limited. Systemic immunotherapies also carry with them concerns surrounding systemic toxicities as well as penetration of the blood-brain barrier. These concerns may potentially limit their efficacy in GBM and preclude the use of combinatorial immunotherapy, which may be needed to overcome the severe multidimensional immune suppression seen in GBM patients. The use of viral vectors to deliver immunotherapies directly to tumor cells has the potential to improve immunotherapy delivery to the CNS, reduce systemic toxicities, and increase treatment efficacy. Indeed, preclinical studies investigating the delivery of immunomodulators to GBM using viral vectors have demonstrated significant promise. In this review, the authors discuss previous studies investigating the delivery of local immunotherapy using viral vectors. They also discuss the future of these treatments, including the reasoning behind immunomodulator and vector selection, patient safety, personalized therapies, and the need for combinatorial treatment.
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http://dx.doi.org/10.3171/2020.11.FOCUS20859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011938PMC
February 2021

Postoperative diffusion-weighted imaging and neurological outcome after convexity meningioma resection.

J Neurosurg 2021 Jan 29:1-8. Epub 2021 Jan 29.

Departments of1Neurological Surgery and.

Objective: Convexity meningiomas are commonly managed with resection. Motor outcomes and predictors of new deficits after surgery are poorly studied. The objective of this study was to determine whether postoperative diffusion-weighted imaging (DWI) was associated with neurological deficits after convexity meningioma resection and to identify the risk factors for postoperative DWI restriction.

Methods: A retrospective review of patients who had undergone convexity meningioma resection from 2014 to 2018 was performed. Univariate and multivariate logistic regressions were performed to identify variables associated with postoperative neurological deficits and a DWI signal. The amount of postoperative DWI signal was measured and was correlated with low apparent diffusion coefficient maps to confirm ischemic injury.

Results: The authors identified 122 patients who had undergone a total of 125 operations for convexity meningiomas. The median age at surgery was 57 years, and 70% of the patients were female. The median follow-up was 26 months. The WHO grade was I in 62% of cases, II in 36%, and III in 2%. The most common preoperative deficits were seizures (24%), extremity weakness/paralysis (16%), cognitive/language/memory impairment (16%), and focal neurological deficit (16%). Following resection, 89% of cases had no residual deficit. Postoperative DWI showed punctate or no diffusion restriction in 78% of cases and restriction > 1 cm in 22% of cases. An immediate postoperative neurological deficit was present in 14 patients (11%), but only 8 patients (7%) had a deficit at 3 months postoperatively. Univariate analysis identified DWI signal > 1 cm (p < 0.0001), tumor diameter (p < 0.0001), preoperative motor deficit (p = 0.0043), older age (p = 0.0113), and preoperative embolization (p = 0.0171) as risk factors for an immediate postoperative deficit, whereas DWI signal > 1 cm (p < 0.0001), tumor size (p < 0.0001), and older age (p = 0.0181) were risk factors for deficits lasting more than 3 months postoperatively. Multivariate analysis revealed a DWI signal > 1 cm to be the only significant risk factor for deficits at 3 months postoperatively (OR 32.42, 95% CI 3.3-320.1, p = 0.0002). Further, estimated blood loss (OR 1.4 per 100 ml increase, 95% CI 1.1-1.7, p < 0.0001), older age (OR 1.1 per year older, 95% CI 1.0-1.1, p = 0.0009), middle third location in the sagittal plane (OR 16.9, 95% CI 1.3-216.9, p = 0.0026), and preoperative peritumoral edema (OR 4.6, 95% CI 1.2-17.7, p = 0.0249) were significantly associated with a postoperative DWI signal > 1 cm.

Conclusions: A DWI signal > 1 cm is significantly associated with postoperative neurological deficits, both immediate and long-lasting. Greater estimated blood loss, older age, tumor location over the motor strip, and preoperative peritumoral edema increase the risk of having a postoperative DWI signal > 1 cm, reflective of perilesional ischemia. Most immediate postoperative deficits will improve over time. These data are valuable when preoperatively communicating with patients about the risks of surgery and when postoperatively discussing prognosis after a deficit occurs.
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http://dx.doi.org/10.3171/2020.8.JNS193537DOI Listing
January 2021

Immunologic aspects of viral therapy for glioblastoma and implications for interactions with immunotherapies.

J Neurooncol 2021 Mar 3;152(1):1-13. Epub 2021 Jan 3.

Department of Neurological Surgery, University of California, 505 Parnassus Ave, M-779, San Francisco, CA, 94143-0112, USA.

Introduction: The treatment for glioblastoma (GBM) has remained unchanged for the past decade, with only minimal improvements in patient survival. As a result, novel treatments are needed to combat this devastating disease. Immunotherapies are treatments that stimulate the immune system to attack tumor cells and can be either local or systemically delivered. Viral treatments can lead to direct tumor cell death through their natural lifecycle or through the delivery of a suicide gene, with the potential to generate an anti-tumor immune response, making them interesting candidates for combinatorial treatment with immunotherapy.

Methods: We review the current literature surrounding the interactions between oncolytic viruses and the immune system as well as the use of oncolytic viruses combined with immunotherapies for the treatment of GBM.

Results: Viral therapies have exhibited preclinical efficacy as single-agents and are being investigated in that manner in clinical trials. Oncolytic viruses have significant interactions with the immune system, although this can also vary depending on the strain of virus. Combinatorial treatments using both oncolytic viruses and immunotherapies have demonstrated promising preclinical findings.

Conclusions: Studies combining viral and immunotherapeutic treatment modalities have provided exciting results thus far and hold great promise for patients with GBM. Additional studies assessing the clinical efficacy of these treatments as well as improved preclinical modeling systems, safety mechanisms, and the balance between treatment efficacy and immune-mediated viral clearance should be considered.
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http://dx.doi.org/10.1007/s11060-020-03684-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011939PMC
March 2021

Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa142. Epub 2020 Oct 22.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Background: "Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited.

Methods: Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis.

Results: Median patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus ( = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the gene and an absence of mutations in , which are present in approximately one-third of pediatric DMGs. Accompanying mutations in , , , , and were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults.

Conclusions: Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.
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http://dx.doi.org/10.1093/noajnl/vdaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739048PMC
October 2020

Incorporating Tumor-Associated Macrophages into Engineered Models of Glioma.

iScience 2020 Dec 5;23(12):101770. Epub 2020 Nov 5.

University of California, Berkeley - University of California, San Francisco Graduate Program in Bioengineering, Berkeley, CA 94720, USA.

Tumor progression is profoundly influenced by interactions between cancer cells and the tumor microenvironment (TME). Among the various non-neoplastic cells present, immune cells are critical players in tumor development and have thus emerged as attractive therapeutic targets. Malignant gliomas exhibit a unique immune landscape characterized by high numbers of tumor-associated macrophages (TAMs). Despite encouraging preclinical results, targeting TAMs has yielded limited clinical success as a strategy for slowing glioma progression. The slow translational progress of TAM-targeted therapies is due in part to an incomplete understanding of the factors driving TAM recruitment, differentiation, and polarization. Furthermore, the functions that TAMs adopt in gliomas remain largely unknown. Progress in addressing these gaps requires sophisticated culture platforms capable of capturing key cellular and physical TME features. This review summarizes the current understanding of TAMs in gliomas and highlights the utility of TME models for investigating TAM-cancer cell cross talk.
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http://dx.doi.org/10.1016/j.isci.2020.101770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695970PMC
December 2020

Comparative Analysis of Survival Outcomes and Prognostic Factors of Supratentorial versus Cerebellar Glioblastoma in the Elderly: Does Location Really Matter?

World Neurosurg 2021 02 7;146:e755-e767. Epub 2020 Nov 7.

Department of Neurosurgery, Memorial Hermann Hospital-TMC, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, USA. Electronic address:

Background: Cerebellar glioblastomas (cGBMs) are rare tumors that are uncommon in the elderly. In this study, we compare survival outcomes and identify prognostic factors of cGBM compared with the supratentorial (stGBM) counterpart in the elderly.

Methods: Data from the SEER 18 registries were used to identify patients with a glioblastoma (GBM) diagnosis between 2000 and 2016. The log-rank method and a multivariable Cox proportional hazards regression model were used for analysis.

Results: Among 110 elderly patients with cGBM, the median age was 74 years (interquartile range [IQR], 69-79 years), 39% were female and 83% were white. Of these patients, 32% underwent gross total resection, 73% radiotherapy, and 39% chemotherapy. Multivariable analysis of the unmatched and matched cohort showed that tumor location was not associated with survival; in the unmatched cohort, insurance status (hazard ratio [HR], 0.11; IQR, 0.02-0.49; P = 0.004), gross total resection (HR, 0.53; IQR, 0.30-0.91; P = 0.022), and radiotherapy (HR, 0.33; IQR, 0.18-0.61; P < 0.0001) were associated with better survival. Patients with cGBM and stGBM undergoing radiotherapy (7 months vs. 2 months; P < 0.001) and chemotherapy (10 months vs. 3 months; P < 0.0001) had improved survival. Long-term mortality was lower for cGBM in the elderly at 24 months compared with the stGBM cohort (P = 0.007).

Conclusions: In our study, elderly patients with cGBM and stGBM have similar outcomes in overall survival, and those undergoing maximal resection with adjuvant therapies, independent of tumor location, have improved outcomes. Thus, aggressive treatment should be encouraged for cGBM in geriatric patients to confer the same survival benefits seen in stGBM. Single-institutional and multi-institutional studies to identify patient-level prognostic factors are warranted to triage the best surgical candidates.
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http://dx.doi.org/10.1016/j.wneu.2020.11.003DOI Listing
February 2021

In Reply to the Letter to the Editor "Regarding the Path to U.S. Neurosurgical Residency for Foreign Medical Graduates: Trends from a Decade 2007-2017".

World Neurosurg 2020 11;143:625

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. Electronic address:

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http://dx.doi.org/10.1016/j.wneu.2020.08.107DOI Listing
November 2020

Higher cytolytic score correlates with an immunosuppressive tumor microenvironment and reduced survival in glioblastoma.

Sci Rep 2020 10 16;10(1):17580. Epub 2020 Oct 16.

Department of Neurological Surgery, University of California San Francisco, San Francisco, USA.

Cytolytic score (CYT), calculated from mRNA expression levels of granzyme and perforin, positively correlates with CD8+ T cell infiltration/activity in a variety of cancers. Unlike other cancers, higher CYT has been associated with worse prognosis in glioblastoma (GBM). To address this discrepancy, we sought to investigate the relationship between CYT and immune checkpoint gene score (ICGscore), as well as their correlation with patient survival and tumor immune cell infiltration. Clinical and RNA-sequencing data for patients with newly diagnosed GBM were obtained from The Cancer Genome Atlas. Maximally-selected rank statistics was used to dichotomize subgroups. CIBERSORT was used to estimate abudence of immune cell-types. Spearman correlation was used to characterize the relationship between CYT and ICGscore. Kaplan-Meier curves were generated for survival analysis. Overall, 28/151 patients had high CYT. High CYT was associated with a mesenchymal subtype (p < 0.001) and worse survival (7.45 vs. 12.2 months, p < 0.001). There were no differences in patient demographics, IDH/MGMT mutation status, or treatment. On subgroup analysis, patients with high CYT/ICGscore had significantly increased CD8+ infiltration (p < 0.001), as expected, and worse survival (HR 0.445, p < 0.01). Furthermore, CYT strongly correlated with ICGscore (R = 0.675, p < 0.001). The high CYT/ICGscore subgroup was associated with greater infiltration of M2 macrophages (p = 0.011) and neutrophils (p = 0.055). Our study highlights a multidimensional immunosuppressive GBM microenvironment in patients with higher CYT and potentially identifies patients with high CYT/ICGscore as a subgroup that may particularly benefit from multi-faceted immunotherapies, given their already elevated tumor CD8+ T cell levels.
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http://dx.doi.org/10.1038/s41598-020-73793-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567862PMC
October 2020

Clinical characteristics and outcomes in elderly patients undergoing transsphenoidal surgery for nonfunctioning pituitary adenoma.

Neurosurg Focus 2020 10;49(4):E19

Departments of2Neurological Surgery and.

Objective: Life expectancy has increased over the past century, causing a shift in the demographic distribution toward older age groups. Elderly patients comprise up to 14% of all patients with pituitary tumors, with most lesions being nonfunctioning pituitary adenomas (NFPAs). Here, the authors evaluated demographics, outcomes, and postoperative complications between nonelderly adult and elderly NFPA patients.

Methods: A retrospective review of 908 patients undergoing transsphenoidal surgery (TSS) for NFPA at a single institution from 2007 to 2019 was conducted. Clinical and surgical outcomes and postoperative complications were compared between nonelderly adult (age ≥ 18 and ≤ 65 years) and elderly patients (age > 65 years).

Results: There were 614 and 294 patients in the nonelderly and elderly groups, respectively. Both groups were similar in sex (57.3% vs 60.5% males; p = 0.4), tumor size (2.56 vs 2.46 cm; p = 0.2), and cavernous sinus invasion (35.8% vs 33.7%; p = 0.6). Regarding postoperative outcomes, length of stay (1 vs 2 days; p = 0.5), extent of resection (59.8% vs 64.8% gross-total resection; p = 0.2), CSF leak requiring surgical revision (4.3% vs 1.4%; p = 0.06), 30-day readmission (8.1% vs 7.3%; p = 0.7), infection (3.1% vs 2.0%; p = 0.5), and new hypopituitarism (13.9% vs 12.0%; p = 0.3) were similar between both groups. Elderly patients were less likely to receive adjuvant radiation (8.7% vs 16.3%; p = 0.009), undergo future reoperation (3.8% vs 9.5%; p = 0.003), and experience postoperative diabetes insipidus (DI) (3.7% vs 9.4%; p = 0.002), and more likely to have postoperative hyponatremia (26.7% vs 16.4%; p < 0.001) and new cranial nerve deficit (1.9% vs 0.0%; p = 0.01). Subanalysis of elderly patients showed that patients with higher Charlson Comorbidity Index scores had comparable outcomes other than higher DI rates (8.1% vs 0.0%; p = 0.006). Elderly patients' postoperative sodium peaked and troughed on postoperative day 3 (POD3) (mean 138.7 mEq/L) and POD9 (mean 130.8 mEq/L), respectively, compared with nonelderly patients (peak POD2: mean 139.9 mEq/L; trough POD8: mean 131.3 mEq/L).

Conclusions: The authors' analysis revealed that TSS for NFPA in elderly patients is safe with low complication rates. In this cohort, more elderly patients experienced postoperative hyponatremia, while more nonelderly patients experienced postoperative DI. These findings, combined with the observation of higher DI in patients with more comorbidities and elderly patients experiencing later peaks and troughs in serum sodium, suggest age-related differences in sodium regulation after NFPA resection. The authors hope that their results will help guide discussions with elderly patients regarding risks and outcomes of TSS.
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http://dx.doi.org/10.3171/2020.7.FOCUS20524DOI Listing
October 2020

WHO Grade I Meningioma Recurrence: Identifying High Risk Patients Using Histopathological Features and the MIB-1 Index.

Front Oncol 2020 28;10:1522. Epub 2020 Aug 28.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States.

In this study, we identify clinical, radiographic, and histopathologic prognosticators of overall, early, and post-median recurrence in World Health Organization (WHO) grade I meningiomas. We also determine a clinically relevant cutoff for MIB-1 to identify patients at high risk for recurrence. A retrospective review of WHO grade I meningioma patients with available MIB-1 index data who underwent treatment at our institution from 2007 to 2017 was performed. Univariate and multivariate analyses, and recursive partitioning analysis (RPA), were used to identify risk factors for overall, early (within 24 months), and post-median (>24 months post-treatment) recurrence. A total of 239 patients were included. The mean age was 60.0 years, and 69.5% of patients were female. The average follow-up was 41.1 months. All patients received surgery and 2 patients each received either adjuvant radiotherapy (2/239) or gamma knife treatment (2/239). The incidence of recurrence was 10.9% (26/239 patients), with an average time to recurrence of 33.2 months (6-105 months). Posterior fossa tumor location ( = 0.004), MIB-1 staining ( = 0.008), nuclear atypia ( = 0.003), and STR ( < 0.001) were independently associated with an increased risk of recurrence on cox-regression analysis. RPA for overall recurrence highlighted extent of resection, and after gross total resection (GTR), a MIB-1 index cutoff of 4.5% as key prognostic factors for recurrence. Patients with a GTR and MIB-1 >4.5% had a similar incidence of recurrence as those with STR (18.8 vs. 18.6%). Variables independently associated with early recurrence on binary logistic regression modeling included STR ( = 0.002) and nuclear atypia ( = 0.019). RPA confirmed STR as associated with early recurrence. STR, posterior fossa location, nuclear atypia, and elevated MIB-1 index are prognostic factors for WHO grade I meningioma recurrence. Moreover, MIB-1 index >4.5% is prognostic for recurrence in patients with GTR. Verification of our findings in larger, multi-institutional studies could enable risk stratification and recommendations for adjuvant radiotherapy following resection of WHO grade I meningiomas.
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http://dx.doi.org/10.3389/fonc.2020.01522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483477PMC
August 2020

Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma.

Nat Commun 2020 09 23;11(1):4803. Epub 2020 Sep 23.

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA.

Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology.
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http://dx.doi.org/10.1038/s41467-020-18582-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511976PMC
September 2020

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

Acta Neuropathol Commun 2020 08 28;8(1):151. Epub 2020 Aug 28.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.
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http://dx.doi.org/10.1186/s40478-020-01027-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456392PMC
August 2020

Letter to the Editor Regarding "Global Diversity and Academic Success of Foreign-Trained Academic Neurosurgeons in the United States".

World Neurosurg 2020 07;139:704-705

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. Electronic address:

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http://dx.doi.org/10.1016/j.wneu.2020.04.144DOI Listing
July 2020
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