Polymorphous low-grade neuroepithelial tumor of the young with FGFR3-TACC3 fusion mimicking high-grade glioma: case report and series of high-grade correlates.

Background: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described entity that can mimic high-grade glioma (HGG) in histologic and molecular features; however, factors predicting aggressive behavior in these tumors are unclear. Methods: We present an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of HGG, and a series of adult patients with HGG harboring FGFR3-TACC3 fusions are also presented for comparison. Results: Pathology in the case patient revealed low-grade cytomorphology, microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34+ and harbored an FGFR3-TACC3 fusion and TERT promoter mutation. A diagnosis of PLNTY was therefore favored and the patient was observed with no progression at 15-month follow-up. In patients with HGG with FGFR3-TACC3 fusions, molecular findings included IDH-wildtype status, absence of 1p19q codeletion, CDKN2A loss, TERT promoter mutations and lack of MGMT promoter methylation. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. Conclusion: PLNTY is a rare low-grade entity that can display characteristics of HGG, particularly in adults. Presence of FGFR3-TACC3 fusions and other high-grade features should raise concern for a more malignant precursor lesion when a diagnosis of PLNTY is considered.

Foundations of the Diagnosis and Management of Low-Grade Gliomas.

In the past, low-grade gliomas-World Health Organization (WHO) grade I and II tumors-were generally expected to have a much better prognosis than higher-grade (WHO grade III and IV) gliomas. However, diffuse gliomas (WHO grade II), unlike WHO grade I gliomas, are by definition infiltrative, limiting resection and potentially contributing to poor outcomes like those seen with malignant gliomas. Rapid progress in the understanding of the pathogenesis of these tumors indicates that specific molecular factors, especially isocitrate dehydrogenase mutation status and the presence or absence of the 1p/19q codeletion (deletion of the short arm of chromosome 1 and long arm of chromosome 19), are much more important than grade in determining prognosis and response to treatment. These molecular characteristics outweigh the histologic distinctions and have been quickly incorporated into the WHO classification of gliomas. Management of these tumors with surgery, radiation, and chemotherapy has similarly been transformed by these developments, highlighting the need for a customized approach for patients with low-grade gliomas.

Challenges in the Diagnosis and Management of Low-Grade Gliomas.

Low-grade gliomas are clinically challenging entities. Patients with these tumors tend to be relatively young at presentation, and lesions are often incidental findings or are identified because the patient presents with a seizure. Rapidly emerging and evolving molecular classifications of gliomas have influenced treatment paradigms. Importantly, low-grade gliomas can be classified on the basis of IDH mutation status, whereby low-grade astrocytomas harbor the IDH mutation, while oligodendrogliomas are defined by both IDH mutant status and 1p/19q co-deletion. Given the importance of molecular classification for diagnosis, treatment planning, and prognostication, tissue samples are necessary for proper management. Literature supports improved overall survival and outcomes with increased extent of resection for low-grade glioma. Awake craniotomies and resection of insular low-grade gliomas both have been demonstrated as safe and improve outcomes for patients with lesions located in eloquent areas. Given the younger age at diagnosis of these lesions compared with higher-grade gliomas, fertility, fertility preservation, and potential malignant transformation should be discussed with patients of childbearing age.

Innovations in the Diagnosis and Surgical Management of Low-Grade Gliomas.

Low-grade gliomas are a broad category of tumors that can manifest at different stages of life. As a group, their prognosis has historically been considered to be favorable, and surgery is a mainstay of treatment. Advances in the molecular characterization of individual lesions has led to newer classification systems, a better understanding of the biological behavior of different neoplasms, and the identification of previously unrecognized entities. New prospective genetic and molecular data will help delineate better treatment paradigms and will continue to change the taxonomy of central nervous system tumors in the coming years. Advances in the field of radiomics will help predict the molecular profile of a particular tumor through noninvasive testing. Similarly, more precise methods of intraoperative tumor tissue analysis will aid surgical planning. Improved surgical outcomes propelled by novel surgical techniques and intraoperative adjuncts and emerging forms of medical treatment in the field of immunotherapy have enriched the management of these lesions. We review the contemporary management and innovations in the treatment of low-grade gliomas.

Novel approaches to the management of patients with 5-15 brain metastases: a narrative review.

BACKGROUND AND OBJECTIVE: The management of metastatic disease has been greatly influenced by molecular-based tumor classification and associated therapeutic targets, leading to a significant improvement in survival in many cases. This improvement, in both progression free survival and overall survival, has led to an increased incidence of brain metastases (BM) in a population with systemically well controlled disease or patients with promising therapeutic options available. Within this review, we discuss the paradigm of treatment for 5 to 15 BM, and how the treatment has evolved away from short-term palliation towards providing long term intracranial control. METHODS: A review of literature pertaining to treatment of multiple BM was performed. We searched in PubMed to identify literature on treatment of multiple brain metastases. Only English literature published until February 1st, 2022 was reviewed. KEY CONTENT AND FINDINGS: The management of 5-15 BM include multi-modality treatment pathways that are tailored towards each individual's primary cancer and burden of disease. Surgical resection of a dominant metastasis is still reserved for large symptomatic lesions, and is combined with post-operative local disease control. Overall, there is a shift away from whole brain radiation therapy (WBRT) due to side effect profile towards stereotactic radiosurgery (SRS). However, advances in WBRT continue to be studied, as well as the use of immunotherapy, targetable mutations, and synergistic effects between SRS and targeted therapies. CONCLUSIONS: The use of SRS to treat 5 to 15 BM is an increasingly acceptable and well-regarded practice, along with a combinatorial approach taking into account systemic options during all treatment timepoints.

Acromegaly: Medical and Surgical Considerations.

Acromegaly results from excessive secretion of insulinlike growth factor-1 and growth hormone, which most commonly occurs because of pituitary somatotrophinoma. Diagnostic features of acromegaly include elevated insulinlike growth factor-1 and growth hormone; lesion on brain MRI; and clinically dysmorphic features, such as soft tissue swelling, jaw prognathism, and acral overgrowth. Transsphenoidal resection is the primary therapy for individuals with acromegaly, even in the cases where gross total resection is not possible because of parasellar extension and cavernous sinus involvement. For recurrent or persistent disease after resection, systemic medications and stereotactic radiosurgery are used.

Characterization of Hemorrhagic and Ischemic Stroke in a Diverse Cohort of COVID-19 Patients.

BACKGROUND AND PURPOSE: COVID-19 is a known risk factor for stroke. There is limited data on the influence of demographics, risk factors, and hematologic function on outcomes in COVID-19 stroke patients. METHODS: All patients with acute ischemic or hemorrhagic stroke tested for COVID-19 and treated from March 13 through May 19, 2020 were retrospectively analyzed. COVID+ patients were compared to COVID- patients and a historical cohort from 2019. RESULTS: 84 patients with radiographic acute stroke from the 2020 study period and 152 patients in the historical cohort were included. Stroke incidence in COVID+ patients was 1.5%, with a significant decline in total stroke presentations during this period compared to 2019. 37 patients were COVID+ and 47 patients were COVID-. 32% of COVID+ stroke patients were Hispanic compared to 15% and 18% in the COVID- and 2019 cohorts respectively (p = 0.069 and 0.07). COVID+ stroke patients were younger, had higher rates of hemorrhagic conversion (p = 0.034), higher initial NIHSS (p < 0.001), increased cryptogenic stroke mechanism (p = 0.02), and higher mortality independent of COVID-19 severity. COVID+ patients had higher rates of thrombocytopenia (p = 0.02), and were less likely to be on antiplatelet therapy (p = 0.025). In multivariable analysis, only COVID-19 status independently predicted mortality. CONCLUSIONS: COVID status, independent of severity, was significantly associated with higher mortality in stroke patients. COVID+ stroke patients were younger and less likely to be on antiplatelets, with higher rates of thrombocytopenia, suggesting a possible role for antiplatelet use in this population.

Impact of the COVID-19 pandemic on neuro-oncology outcomes.

INTRODUCTION: The Coronavirus disease 2019 (COVID-19) pandemic has uprooted healthcare systems worldwide, disrupting care and increasing dependence on alternative forms of health care delivery. It is yet to be determined how the pandemic affected neuro-oncology patient outcomes, given that the majority of even "elective" neurosurgical oncology procedures are time-sensitive. This study quantifies changes in neuro-oncological care during the height of the pandemic and investigates patient outcomes in 2020 compared to a historical control. METHODS: We performed a retrospective review of patients with malignant brain tumor diagnoses who were seen at our institution between March 13 and May 1 of 2020 and 2019. Alterations in care, including shift from in-person to telehealth, delays in evaluation and intervention, and treatment modifications were evaluated. These variables were analyzed with respect to brain tumor control and mortality. RESULTS: 112 patients from 2020 to 166 patients from 2019 were included. There was no significant difference in outcomes between the cohorts, despite significantly more treatment delays (p = 0.0160) and use of telehealth (p < 0.0001) in 2020. Patients in 2020 who utilized telehealth visits had significantly more stable tumor control than those who had office visits (p = 0.0124), consistent with appropriate use of in-person visits for patients with progression. CONCLUSIONS: Our study showed that use of telehealth and selective alterations in neuro-oncological care during the COVID-19 pandemic did not lead to adverse patient outcomes. This suggests that adaptive physician-led changes were successful and may inform management during the ongoing pandemic, especially with the emergence of the Delta variant.

COVID-19: A Time Like No Other in (the Department of) Neurological Surgery.

Coronavirus disease 2019 (COVID-19) has disrupted lives and indelibly impacted the practice of medicine since emerging as a pandemic in March 2020. For neurosurgery departments throughout the United States, the pandemic has created unique challenges across subspecialties in devising methods of triage, workflow, and operating room safety. Located in New York City, at the early epicenter of the COVID-19 crisis, the Weill Cornell Medicine Department of Neurological Surgery was disrupted and challenged in many ways, requiring adaptations in clinical operations, workforce management, research, and education. Through our department's collective experience, we offer a glimpse at how our faculty and administrators overcame obstacles, and transformed in the process, at the height of the COVID-19 pandemic.

Neurosurgery in COVID-19 Ground Zero: The Weill Cornell Medicine Experience.

The mobilization of subspecialty departments in reaction to the unique demands of the onset of the coronavirus disease 2019 (COVID-19) pandemic in New York City was swift and left little time for reflection and commemoration. The early days of the pandemic brought unprecedented stressors on the medical system that necessitated a restructuring of hospitals, reallocation of health care workers, and a shift in care and education paradigms to meet patient care demands and public health needs. As the number of cases, intensive care unit patients, and deaths skyrocketed in New York City, many struggled with a somewhat paradoxical difficulty in perceiving the human value of what these numbers mean. Easily lost in the statistics are the stories and experiences of the physicians and trainees who were counted on to halt their own clinical practices and adapt their skillsets to tackle the pandemic. In this article, we present 10 brief narratives from the student members of the Neurosurgery Publication Group at Weill Cornell Medical College and members of the Weill Cornell Medicine Neurological Surgery Residency Program and Department of Neurological Surgery faculty. Reflecting on these individual experiences gives us an opportunity to simultaneously contribute to a history of New York City's reaction to COVID-19 and commemorate the individuals who were impacted by or succumbed to this disease.

Updates on Surgical Management and Advances for Brain Tumors.

PURPOSE OF REVIEW: This review summarizes the modern approach to surgical management of malignant brain tumors, highlighting new technology and multimodal treatment paradigms. RECENT FINDINGS: Outcomes in patients with glioblastoma are strongly correlated with extent of initial surgical resection. Intraoperative MRI, 5-ALA, and neuronavigation are surgical tools that can help achieve a maximal safe resection. Stereotactic radiosurgery and brachytherapy can be used to enhance local control for brain metastases in conjunction with surgery, while combinatorial approaches are increasingly employed in patients with multiple metastases. Advances in surgical techniques allow for minimally invasive approaches, including the use of tubular retractors, endoscopes, and laser interstitial thermal therapy. Primary and metastatic brain tumors require a multimodal, multidisciplinary approach to treatment. Surgical resection can be paired with radiation for metastases to maximize tumor control, expanding systemic options. Technological innovations have improved the safety of surgical resection, while expanding the surgical options and indications for treatment.

Molecular Engineering of Ultrasmall Silica Nanoparticle-Drug Conjugates as Lung Cancer Therapeutics.

PURPOSE: Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects. EXPERIMENTAL DESIGN: Ultrasmall (<8 nm) core-shell silica nanoparticles, C' dots, were molecularly engineered to function as multivalent drug delivery vehicles for significantly improving key in vivo biological and therapeutic properties of a prototype epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib. Novel surface chemical components were used to conjugate gefitinib-dipeptide drug-linkers and deferoxamine (DFO) chelators for therapeutic delivery and PET imaging labels, respectively. RESULTS: Gefitinib-bound C' dots (DFO-Gef-C' dots), synthesized using the gefitinib analogue, APdMG, at a range of drug-to-particle ratios (DPR; DPR = 11-56), demonstrated high stability for DPR values≤ 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 = 6.21 nmol/L vs. 3 µmol/L, respectively). In human non-small cell lung cancer mice, efficacious Gef-C' dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 µmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C' dot-treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wild-type EGFR target inhibition, unlike free drug. CONCLUSIONS: Results underscore the clinical potential of DFO-Gef-C' dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose.

Radiographic and clinical outcomes using intraoperative magnetic resonance imaging for transsphenoidal resection of pituitary adenomas.

OBJECTIVE: The utility and safety of intraoperative MRI (iMRI) for resection of pituitary adenomas is not clearly established in the context of advances in endoscopic approaches. The goal in this study was to evaluate the safety and efficacy of iMRI for pituitary adenoma resection, with endoscopic transsphenoidal (ETS) versus microscopic transsphenoidal (MTS) approaches. METHODS: Radiographic and clinical outcomes of all pituitary adenomas resected using iMRI between 2008 and 2017 at a single institution were retrospectively evaluated. RESULTS: Of 212 tumors treated, 131 (62%) underwent further resection based on iMRI findings, resulting in a significant increase in gross-total resection on postoperative MRI compared with iMRI (p = 0.0001) in both ETS and MTS groups. iMRI increased rates of gross-total resection for cavernous sinus invasion Knosp grades 1 and 2, but not in Knosp ≥ 3 across treatment groups (p < 0.0001). The extent of resection on postoperative MRI was significantly correlated with increased progression-free survival (p < 0.0001). Initial hormone remission off medical therapy was achieved in 64%, with a significantly higher rate of remission in tumors resected via the ETS approach (81%) compared with the MTS approach (55%) (p = 0.02). The rate of persistent new hormone deficit was low at 8%, including a 2.8% rate of permanent diabetes insipidus, and 45% of patients had improvement in preoperative hormone deficit following surgery. Serious postoperative complications including CSF leaks requiring reoperation were rare at 1%, with no postoperative infections. CONCLUSIONS: These results suggest that iMRI is a safe and effective method of increasing the extent of resection for pituitary adenomas while preserving hormone function. When paired with the endoscope, iMRI may offer the ability to tailor more aggressive removal of tumors while optimizing pituitary function, resulting in high rates of secretory hormone remission. Secretory tumors and adenomas with Knosp grade < 3 cavernous sinus invasion may benefit most from the use of iMRI.

Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model.

PURPOSE: Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood-brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy. EXPERIMENTAL DESIGN: Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood-brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle-drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC. RESULTS: Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition. CONCLUSIONS: These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.

A Multidisciplinary Team Approach to Brain and Spine Stereotactic Radiosurgery Conferences: A Unique Institutional Model.

OBJECTIVE: The use of multidisciplinary teams (MDTs) comprised of all members of the patient care team is becoming increasingly popular in the field of oncology. We present a single-center experience exploring the utility and uniqueness of an MDT in the care of patients undergoing brain and spine stereotactic radiosurgery (SRS). METHODS: The weekly SRS conference brought together neurosurgeons, radiation oncologists, neuroradiologists, physicists, dosimetrists, therapists, advanced practice providers, and trainees in these fields as well as researchers from a variety of disciplines with a goal of optimizing patient care. A survey of 20 conference attendees from 7 different facets of the MDT was conducted for feedback. RESULTS: The survey results revealed that most respondents believed the SRS conference increased educational opportunities, provided opportunities for research and collaborations, helped streamline patient care, and was beneficial to their practice. CONCLUSIONS: We present our institutional MDT model, a framework and workflow that can be incorporated at other large academic centers. We believe that the SRS conference has educational, academic, and patient care value.

Magnetic Resonance Thermometry and Laser Interstitial Thermal Therapy for Brain Tumors.

Recent technological advancements in intraoperative imaging are shaping the way for a new era in brain tumor surgery. Magnetic resonance thermometry has provided intraoperative real-time imaging feedback for safe and effective application of laser interstitial thermal therapy (LITT) in neuro-oncology. Thermal ablation has also established itself as a surgical option in epilepsy surgery and is currently used in spine oncology with promising results. This article reviews the principles and rationale as well as the clinical application of LITT for brain tumors. It also discusses the technical nuances of the current commercially available systems.

Updated response assessment criteria for high-grade glioma: beyond the MacDonald criteria.

High-grade glioma continues to be a challenging disease with few effective treatment options and a poor prognosis, necessitating intensive research into alternate therapies. The Response Assessment in Neuro-Oncology (RANO) committee was formed to create a robust endpoint assessment criteria in Neuro-Oncology in order to streamline the assessment of new therapies in a uniform fashion. The aim of this committee is to create standardized guidelines to assess clinical and imaging response in the treatment of brain tumors, which can then be applied in clinical trials. Since the first RANO report was published in 2010, its criteria have been widely adopted and utilized in clinical trials worldwide. Standardized application of the RANO response assessment criteria in clinical trials will result in the generation of strong clinical data, which can subsequently be pooled and analyzed to attain a more accurate assessment of treatment efficacy. In this review, we summarize the current RANO guidelines in patients with high-grade glioma, highlighting the key clinical and imaging criteria used for RANO evaluation and introducing the role of newer imaging and biomarkers.

Gamma Knife radiosurgery for intracranial hemangioblastoma.

Gamma knife radiosurgery (GKRS) has become a treatment option for intracranial hemangioblastomas, especially in patients with poor clinical status and also high-risk surgical candidates. The objective of this study was to analyze clinical outcome and tumor control rates. Retrospective chart review revealed 12 patients with a total of 20 intracranial hemangioblastomas treated with GKRS from May 1998 until December 2014. Kaplan-Meier plots were used to calculate the actuarial local tumor control rates and rate of recurrence following GKRS. Univariate analysis, including log rank test and Wilcoxon test were used on the Kaplan-Meier plots to evaluate the predictors of tumor progression. Two-tailed p value of <0.05 was considered as significant. Median follow-up was 64months (2-184). Median tumor volume pre-GKRS was 946mm(3) (79-15970), while median tumor volume post-GKRS was 356mm(3) (30-5404). Complications were seen in two patients. Tumor control rates were 100% at 1year, 90% at 3years, and 85% at 5years, using the Kaplan-Meier method. There were no statistically significant univariate predictors of progression identified, although there was a trend towards successful tumor control in solid tumors (p=0.07). GKRS is an effective and safe option for treating intracranial hemangioblastoma with favorable tumor control rates.

Current Management and Treatment Modalities for Intramedullary Spinal Cord Tumors.

OPINION STATEMENT: Intramedullary spinal cord tumors are rare central nervous system tumors with unique challenges due to the eloquence of the surrounding tissue. Their treatment and prognosis is largely dependent on tumor histology and patient functionality. The introduction and advancement of microsurgical techniques have made surgery the mainstay of treatment for intramedullary tumors. Tumors that are well demarcated (e.g., ependymomas, hemangioblastomas) can be resected for cure, while more infiltrative tumors (e.g., high-grade astrocytomas) are typically managed with biopsies or limited resections in order to minimize the significant risk of damage to the spinal cord. The use of more aggressive surgical resection for astrocytoma is controversial but may have an increasing role in select cases. The use of intraoperative neurophysiologic monitoring and intraoperative ultrasound may help guide the extent of surgery while minimizing damage to normal tissue. Advances in MRI technology have greatly aided the diagnosis and preoperative planning of intramedullary tumors. Further advances in intraoperative MRI may make this a useful tool in guiding extent of resection. Preoperative functional status is the most important predictor of neurologic outcome, while histology and extent of resection are the most important predictors of progression-free survival. The use of adjuvant radiation and chemotherapy is dependent on patient age and histology but is largely reserved for high-grade tumor histologies or systemic involvement. Children are particularly at risk of radiation-induced injury, and these cases may benefit from more focused stereotactic radiation where necessary. Further studies are needed to support new surgical strategies minimizing destabilization and to investigate new forms of adjuvant therapy to minimize toxicity.