Surgical strategies for older patients with glioblastoma.

OBJECTIVE: While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored. METHODS: Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed. RESULTS: The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores (<70) showed significant improvement at postoperative 6 weeks (P<0.0001). Patients with complications (P = 0.038) were more likely to have lower KPS at postoperative 6 weeks. CONCLUSIONS: Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care.

PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas.

Gene rearrangement in the form of an intragenic deletion is the primary mechanism of oncogenic mutation of the epidermal growth factor receptor (EGFR) gene in gliomas. However, the incidence of platelet-derived growth factor receptor-α (PDGFRA) gene rearrangement in these tumors is unknown. We investigated the PDGFRA locus in PDGFRA-amplified gliomas and identified two rearrangements, including the first case of a gene fusion between kinase insert domain receptor (KDR) (VEGFRII) and the PDGFRA gene, and six cases of PDGFRA(Δ8, 9), an intragenic deletion rearrangement. The PDGFRA(Δ8, 9) mutant was common, being present in 40% of the glioblastoma multiformes (GBMs) with PDGFRA amplification. Tumors with these two types of PDGFRA rearrangement displayed histologic features of oligodendroglioma, and the gene products of both rearrangements showed constitutively elevated tyrosine kinase activity and transforming potential that was reversed by PDGFR blockade. These results suggest the possibility that these PDGFRA mutants behave as oncogenes in this subset of gliomas, and that the prevalence of such rearrangements may have been considerably underestimated.

Histological changes associated with laser interstitial thermal therapy for radiation necrosis: illustrative cases.

BACKGROUND: Patients with lung cancer and melanoma remain the two largest groups to develop brain metastases. Immunotherapy has been approved for treatment of stage IV disease in both groups. Many of these patients are additionally treated with stereotactic radiosurgery for their brain metastases during ongoing immunotherapy. Use of immunotherapy has been reported to increase the rates of radiation necrosis (RN) after radiosurgery, causing neurological compromise due to growth of the enhancing lesion as well as worsening of associated cerebral edema. OBSERVATIONS: Laser interstitial thermal therapy (LITT) is a surgical approach that has been shown effective in the management of RN, especially given its efficacy in early reduction of perilesional edema. However, little remains known about the pathology of the post-LITT lesions and how LITT works in this condition. Here, we present two patients who needed surgical decompression after LITT for RN. Clinical, histopathological, and imaging features of both patients are presented. LESSONS: Criteria for selecting the best patients with RN for LITT therapy remains unclear. Given two similarly sized lesions and not too dissimilar clinical histories but with differing outcomes, further investigation is clearly needed to identify predictors of response to LITT in the setting of SRS and immunotherapy-induced RN.

Spinal Metastases and the Evolving Role of Molecular Targeted Therapy, Chemotherapy, and Immunotherapy.

Metastatic involvement of the spine is a common complication of systemic cancer progression. Surgery and external beam radiotherapy are palliative treatment modalities aiming to preserve neurological function, control pain and maintain functional status. More recently, with development of image guidance and stereotactic delivery of high doses of conformal radiation, local tumor control has improved; however recurrent or radiation refractory disease remains a significant clinical problem with limited treatment options. This manuscript represents a narrative overview of novel targeted molecular therapies, chemotherapies, and immunotherapy treatments for patients with breast, lung, melanoma, renal cell, prostate, and thyroid cancers, which resulted in improved responses compared to standard chemotherapy. We present clinical examples of excellent responses in spinal metastatic disease which have not been specifically documented in the literature, as most clinical trials evaluate treatment response based on visceral disease. This review is useful for the spine surgeons treating patients with metastatic disease as knowledge of these responses could help with timing and planning of surgical interventions, as well as promote multidisciplinary discussions, allowing development of an individualized treatment strategy to patients presenting with widespread multifocal progressive disease, where surgery could lead to suboptimal results.

Combination laser interstitial thermal therapy plus stereotactic radiotherapy increases time to progression for biopsy-proven recurrent brain metastases.

Background: Improved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases. Methods: A multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by "planned LITT+SRT" versus "LITT alone" versus "repeat SRT alone." Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Results: Fifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0-30.5), age of 60 years (range: 37-86), Karnofsky Performance Status (KPS) of 80 (range: 60-100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7-19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [P = .022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression (P = .004). Conclusions: These data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases.

Challenges and Advances in Diagnosis and Treatment of Leptomeningeal Disease (LMD).

Leptomeningeal disease (LMD) is a devastating category of CNS metastasis with a very poor prognosis and limited treatment options. With maximal aggressive therapy, survival times remain short and, without treatment, prognosis is measured in weeks. Both LMD diagnosis and treatment are challenging topics within neuro-oncology. In this review, we discuss the advances in LMD diagnosis with a focus on the role of circulating tumor DNA (ctDNA) and discuss the role of targeted and immunotherapy in LMD treatment.

Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma.

BACKGROUND: Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic region, affecting diencephalic structures, and characterized by shorter survival and high recurrence rates. Pilomyxoid astrocytoma management remains controversial, with pathologic tissue diagnosis and relief of mass effect being the main goals of surgery while avoiding treatment-related morbidity, including vision loss, panhypopituitarism, and hypothalamic dysfunction. Chemotherapy (typically vincristine and carboplatin) in all pediatric patients and radiation therapy in pediatric patients over 5 years of age are used for treatment. METHODS: We report clinical presentation, surgical management, and whole exome sequencing results in a pediatric patient with the subtotally resected pilomyxoid astrocytoma. RESULTS: We identified two somatic activating missense mutations affecting FGFR1, including FGFR1 p.K656E and FGFR1 p.V561M. While the former is a known hotspot mutation that is both activating and transforming, the latter has been described as a gatekeeper mutation imparting resistance to FGFR inhibitors. Interestingly, both mutations were present with similar variant allele frequency within the tumor. CONCLUSION: Similar variant allele frequencies of FGFR1 p.K656E and FGFR1 p.V561M mutations in our patient's tumor suggest that these mutations may have occurred at similar time points. Use of FGFR inhibitors in addition to STAT3 or PI3K/mTOR inhibition may prove a useful strategy in targeting our patient's pilomyxoid astrocytoma.

DNMT3A co-mutation in an IDH1-mutant glioblastoma.

Glioblastomas are highly aggressive, infiltrative, and genetically heterogeneous primary brain tumors that arise de novo or secondarily progress over time from low-grade tumors. Along with well-established signature mutational profiles, emerging research suggests that the epigenetic tumor landscape plays an important role in gliomagenesis via transcriptional regulation, DNA methylation, and histone modifications. The pursuit of targeted therapeutic approaches, based not only on expression profiles but also on somatic mutations, is fundamental to the effort of improving survival in patients with glioblastoma. Here, we describe a missense DNMT3A p.P904S mutation in an IDH1-mutant glioblastoma. Although never previously reported in gliomas, this mutation is predicted to be pathogenic and has been reported in several other malignancies. Our report suggests that elucidating epigenetic control is important to understanding glioblastoma biology and may likely unveil targets potentially important to glioblastoma treatment in an effort to improve survival.

Extent of resection of epidermoid tumors and risk of recurrence: case report and meta-analysis.

OBJECTIVE: Intracranial epidermoid tumors are slow-growing, histologically benign tumors of epithelial cellular origin that can be symptomatic because of their size and mass effect. Neurosurgical resection, while the treatment of choice, can be quite challenging due to locations where these lesions commonly occur and their association with critical neurovascular structures. As such, subtotal resection (STR) rather than gross-total resection (GTR) can often be performed, rendering residual and recurrent tumor potentially problematic. The authors present a case of a 28-year-old man who underwent STR followed by aggressive repeat resection for regrowth, and they report the results of the largest meta-analysis to date of epidermoid tumors to compare recurrence rates for STR and GTR. METHODS: The authors conducted a systemic review of PubMed, Web of Science, and the Cochrane Collaboration following the PRISMA guidelines. They then conducted a proportional meta-analysis to compare the pooled recurrence rates between STR and GTR in the included studies. The authors developed fixed- and mixed-effect models to estimate the pooled proportions of recurrence among patients undergoing STR or GTR. They also investigated the relationship between recurrence rate and follow-up time in the previous studies using linear regression and natural cubic spline models. RESULTS: Overall, 27 studies with 691 patients met the inclusion criteria; of these, 293 (42%) underwent STR and 398 (58%) received GTR. The average recurrence rate for all procedures was 11%. The proportional meta-analysis showed that the pooled recurrence rate after STR (21%) was 7 times greater than the rate after GTR (3%). The average recurrence rate for studies with longer follow-up durations (≥ 4.4 years) (17.4%) was significantly higher than the average recurrence rate for studies with shorter follow-up durations (< 4.4 years) (5.7%). The cutoff point of 4.4 years was selected based on the significant relationship between the recurrence rate of both STR and GTR and follow-up durations in the included studies (p = 0.008). CONCLUSIONS: STR is associated with a significantly higher rate of epidermoid tumor recurrence compared to GTR. Attempts at GTR should be made during the initial surgery with efforts to optimize success. Surgical expertise, as well as the use of adjuncts, such as intraoperative MRI and neuromonitoring, may increase the likelihood of completing a safe GTR and decreasing the long-term risk of recurrence. The most common surgical complications were transient cranial nerve palsies, occurring equally in STR and GTR cases when reported. In all postoperative epidermoid tumor cases, but particularly following STR, close follow-up with serial MRI, even years after surgery, is recommended.

Genomic alterations underlying spinal metastases in pediatric H3K27M-mutant pineal parenchymal tumor of intermediate differentiation: case report.

Pediatric midline tumors are devastating high-grade lesions with a dismal prognosis and no curative surgical options. Here, the authors report the clinical presentation, surgical management, whole-exome sequencing (WES), and clonality analysis of a patient with a radically resected H3K27M-mutant pineal parenchymal tumor (PPT) and spine metastases consistent with PPT of intermediate differentiation (PPTID). They identified somatic mutations in H3F3A (H3K27M), FGFR1, and NF1 both in the original PPT and in the PPTID metastases. They also found 12q amplification containing CDK4/MDM2 and chromosome 17 loss of heterozygosity overlapping with NF1 that resulted in biallelic NF1 loss. They noted a hypermutated phenotype with increased C>T transitions within the PPTID metastases and 2p amplification overlapping with the MYCN locus. Clonality analysis detected three founder clones maintained during progression and metastasis. Tumor clones present within the PPTID metastases but not the pineal midline tumor harbored mutations in APC and TIMP2.While the majority of H3K27M mutations are found in pediatric midline gliomas, it is increasingly recognized that this mutation is present in a wider range of lesions with a varied morphological appearance. The present case appears to be the first description of H3K27M mutation in PPTID. Somatic mutations in H3F3A, FGFR1, and NF1 have been suggested to be driver mutations in pediatric midline gliomas. Their clonality and presence in over 80% of tumor cells in our patient's PPTID are consistent with similarly crucial roles in early tumorigenesis, with progression mediated by copy number variations and chromosomal aberrations involving known oncogenes and tumor suppressors. The roles of APC and TIMP2 mutations in progression and metastasis remain to be investigated.

Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas.

OBJECTIVE: Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts. METHODS: Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher's exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features. RESULTS: Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among "mutation unknown" samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor's underlying driver mutation. CONCLUSIONS: Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.

Management of Subdural Hematomas: Part II. Surgical Management of Subdural Hematomas.

PURPOSE OF REVIEW: Management of patients with subdural hematomas starts with Emergency Neurological Life Support guidelines. Patients with acute or chronic subdural hematomas (SDHs) associated with rapidly deteriorating neurologic exam, unilaterally or bilaterally dilated nonreactive pupils, and extensor posturing are considered imminently surgical; likewise, SDHs more than 10 mm in size or those associated with more than 5-mm midline shift are deemed operative. RECENT FINDINGS: While twist drill craniostomy and placement of subdural evacuating vport system (SEPS) are quick, bedside procedures completed under local anesthesia and appropriate for patients with chronic SDH or patients that cannot tolerate anesthesia, these techniques are not optimal for patients with acute SDH or chronic SDH with septations. Burr hole SDH evacuation under conscious sedation or general anesthesia is an analogous technique; however, it requires basic surgical equipment and operating room staff, with a focus on a closed system with burr hole followed by rapid drain placement to avoid introduction of air into the subdural space, or multiple burr holes with extensive irrigation to reduce pneumocephalus and continue SDH evacuation via drain for several days. Acute SDH associated with significant mass effect and cerebral edema requires aggressive decompression via craniotomy with clot evacuation and frequently a craniectomy. Chronic SDHs that fail conservative management and progress clinically or radiographically are addressed with craniotomy with or without membranectomy. Surgical SDH management is variable depending on its characteristics and etiology, patient's functional status, comorbidities, goals of care, institutional preferences, and availability of specialized surgical equipment and adjunct therapies. Rapid access to surgical suites and trained staff to address surgical hemorrhages in a timely manner, with appropriate post-operative care by a specialized team including neurosurgeons and neurointensivists, is of paramount importance for successful patient outcomes. Here, we review various aspects of surgical SDH management.

Management of Subdural Hematomas: Part I. Medical Management of Subdural Hematomas.

PURPOSE OF REVIEW: Subdural hematomas (SDH) represent common neurosurgical problem associated with significant morbidity, mortality, and high recurrence rates. SDH incidence increases with age; numbers of patients affected by SDH continue to rise with our aging population and increasing number of people taking antiplatelet agents or anticoagulation. Medical and surgical SDH management remains a subject of investigation. RECENT FINDINGS: Initial management of patients with concern for altered mental status with or without trauma starts with Emergency Neurological Life Support (ENLS) guidelines, with a focus on maintaining ICP < 22 mmHg, CPP > 60 mmHg, MAP 80-110 mmHg, and PaO2 > 60 mmHg, followed by rapid sequence intubation if necessary, and expedited acquisition of imaging to identify a space-occupying lesion. Patients are administered anti-seizure medications, and their antiplatelet medications or anticoagulation may be reversed if neurosurgical interventions are anticipated, or until hemorrhage is stabilized on imaging. Medical SDH care focuses on (a) management of intracranial hypertension; (b) maintenance of adequate cerebral perfusion; (c) seizure prevention and treatment; (d) maintenance of normothermia, eucarbia, euglycemia, and euvolemia; and (e) early initiation of enteral feeding, mobilization, and physical therapy. Post-operatively, SDH patients require ICU level care and are co-managed by neurointensivists with expertise in treating increased intracranial pressure, seizures, and status epilepticus, as well as medical complications of critical illness. Here, we review various aspects of medical management with a brief overview of pertinent literature and clinical trials for patients diagnosed with SDH.

De novo MYH9 mutation in congenital scalp hemangioma.

Congenital hemangiomas are tumor-like vascular malformations with poorly understood pathogenesis. We report the case of a neonate with a massive congenital scalp hemangioma that required urgent neurosurgical removal on the second day of life because of concern for high-flow arteriovenous shunting. Exome sequencing identified a rare damaging de novo germline mutation in MYH9 (c.5308C>T, p.[Arg1770Cys]), encoding the MYH9 nonmuscle myosin IIA. MYH9 has a probability of loss-of-function intolerance (pLI) score of >0.99 and is highly intolerant to missense variation (z score = 5.59). The p.(Arg1770Cys) mutation substitutes an evolutionarily conserved amino acid in the protein's critical myosin tail domain and is predicted to be highly deleterious by SIFT, PolyPhen-2, MetaSVM, and CADD. MYH9 is a known regulator of cytokinesis, VEGF-regulated angiogenesis, and p53-dependent tumorigenesis. These findings reveal a novel association of germline de novo MYH9 mutation with congenital hemangioma.

Mouse models of brain tumors and their applications in preclinical trials.

Primary brain tumors, including gliomas and medulloblastomas, often represent the most devastating and difficult-to-treat tumors, and are thought to arise from glial cells and/or their precursors or the external granule cell layer, respectively. The majority of genetic alterations characteristic of the human brain tumors are thought to occur in genes encoding proteins involved in signal transduction or cell cycle regulation. Accurate recapitulation of these genetic alterations using genetically engineered mouse models allows for in vivo modeling of brain tumors with similar histopathology, etiology, and biology. These mouse models, in turn, increase our understanding of brain tumor initiation, formation, progression, and metastasis, providing an experimental system to discover novel therapeutic targets and test various therapeutic agents.

Platelet-derived growth factor-mediated gliomagenesis and brain tumor recruitment.

Platelet-derived growth factor (PDGF) is a growth factor family of ligands and receptors known to activate phosphatidylinositol 3-kinase, mitogen-activated protein kinase, Jak family kinase, Src family kinase, and phospholipase Cgamma signal transduction pathways, some of which have been causally linked to glioma formation. Extensive involvement of PDGF in development and its implication in a variety of pathologic conditions, including gliomagenesis, are mediated not only by autocrine effects but by paracrine effects. Many researchers view brain tumors as clonal entities derived from the cancer stem cell; however, recent documentation of the importance of the tumor microenvironment for glioma initiation and progression as well as the ability of neural stem or progenitor cells to migrate toward the sites of injury or tumor formation reveals additional complexities in brain tumorigenesis. Paracrine effects of PDGF in animal models of gliomagenesis, continued adult neurogenesis capable of increasing in response to brain injury, and the growth factor-rich environment of brain tumors suggest that recruitment may play a role in gliomagenesis. In this view, glioma formation involves recruitment of cells from the adjacent brain and possibly other sites.

Candidate pathways for promoting differentiation or quiescence of oligodendrocyte progenitor-like cells in glioma.

Platelet-derived growth factor receptor alpha-positive oligodendrocyte progenitor cells (OPC) located within the mature central nervous system may remain quiescent, proliferate, or differentiate into oligodendrocytes. Human glioblastoma multiforme tumors often contain rapidly proliferating oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells that resemble OPCs. In this study, we sought to identify candidate pathways that promote OPC differentiation or quiescence rather than proliferation. Gene expression profiling conducted in both normal murine OPCs and highly proliferative Olig2-positive glioma cells identified all the transcripts associated with the highly proliferative state of these cells and showed that among the various cell types found within the brain, Olig2-positive tumor cells are most similar to OPCs. We then subtracted OPC transcripts found in tumor samples from those found in normal brain samples and identified 28 OPC transcripts as candidates for promoting differentiation or quiescence. Systematic analysis of human glioma data revealed that these genes have similar expression profiles in human tumors and were significantly enriched in genomic deletions, suggesting an antiproliferative role. Treatment of primary murine glioblastoma cells with agonists of one candidate gene, Gpr17, resulted in a decreased number of neurospheres. Together, our findings show that comparison of the molecular phenotype of progenitor cells in tumors to the equivalent cells in the normal brain represents a novel approach for the identification of targeted therapies.

MEF promotes stemness in the pathogenesis of gliomas.

High-grade gliomas are aggressive and uniformly fatal tumors, composed of a heterogeneous population of cells that include many with stem-cell-like properties. The acquisition of stem-like traits might contribute to glioma initiation, growth, and recurrence. Here we investigated the role of the transcription factor myeloid Elf-1 like factor (MEF, also known as ELF4) in gliomas. We found that MEF is highly expressed in both human and mouse glioblastomas and its absence impairs gliomagenesis in a PDGF-driven glioma mouse model. We show that modulation of MEF levels in both mouse neural stem cells and human glioblastoma cells has a significant impact on neurosphere formation. Moreover, we identify Sox2 as a direct downstream target of MEF. Taken together, our studies implicate MEF as a previously unrecognized gatekeeper gene in gliomagenesis that promotes stem cell characteristics through Sox2 activation.