Neuro-oncology Practice Research Articles

Hospital teaching status associated with reduced inpatient mortality and perioperative complications in surgical neuro-oncology.

Studies have demonstrated that higher surgical volumes correlate with improved neurosurgical outcomes yet none exist evaluating the effects of hospital teaching status on the surgical neuro-oncology patient. We present the first analysis comparing brain tumor surgery perioperative outcomes at academic and non-teaching centers. Brain tumor surgeries in the Nationwide Inpatient Sample (NIS) from 1998 to 2014 were identified. A teaching hospital, defined by the NIS, must have ≥ 1 Accreditation Council of Graduate Medical Education (ACGME) approved residency programs, Council of Teaching Hospitals membership, or have a ratio ≥ 0.25 of full-time residents to hospital beds. Annual treatment trends were stratified by hospital teaching status, assessing yearly caseload with linear regression. Multivariable logistic regression determined predictors of inpatient mortality/complications. Hospitals were further divided into quartiles by case volume and teaching status was compared in each. Teaching hospitals (THs) exhibited an average annual increase in brain tumor surgeries (+ 1057/year, p < 0.0001). In multivariable analysis, teaching status was associated with decreased risk of mortality (OR 0.82, p = 0.0003) and increased likelihood of discharge home (OR 1.21, p < 0.0001). In subgroup analysis, within the highest hospital quartile by caseload, higher mortality rates and lower routine discharges were again seen at non-teaching hospitals (NTHs) (p = 0.0002 and p = 0.0016, respectively). THs are performing more brain tumor surgeries over time with lower rates of inpatient mortality and perioperative complications even after controlling for hospital case volume. These results suggest a shift in neuro-oncology practice patterns favoring THs to optimize patient outcomes especially at the highest volume centers.

The central nervous system tumor methylation classifier changes neuro-oncology practice for challenging brain tumor diagnoses and directly impacts patient care

BackgroundMolecular signatures are being increasingly incorporated into cancer classification systems. DNA methylation-based central nervous system (CNS) tumor classification is being recognized as having the potential to aid in cases of difficult histopathological diagnoses. Here, we present our institutional clinical experience in integrating a DNA-methylation-based classifier into clinical practice and report its impact on CNS tumor patient diagnosis and treatment.MethodsProspective case review was undertaken at CNS tumor board discussions over a 3-year period and 55 tumors with a diagnosis that was not certain to two senior neuropathologists were recommended for methylation profiling based on diagnostic needs. Tumor classification, calibrated scores, and copy number variant (CNV) plots were obtained for all 55 cases. These results were integrated with histopathological findings to reach a final diagnosis. We retrospectively reviewed each patient's clinical course to determine final neuro-pathology diagnoses and the impact of methylation profiling on their clinical management, with a focus on changes that were made to treatment decisions.ResultsFollowing methylation profiling, 46 of the 55 (84%) challenging cases received a clinically relevant diagnostic alteration, with two-thirds having a change in the histopathological diagnosis and the other one-third obtaining clinically important molecular diagnostic or subtyping alterations. WHO grading changed by 27% with two-thirds receiving a higher grade. Patient care was directly changed in 15% of all cases with major changes in clinical decision-making being made for these patients to avoid unnecessary or insufficient treatment.ConclusionsThe integration of methylation-based CNS tumor classification into diagnostics has a substantial clinical benefit for patients with challenging CNS tumors while also avoiding unnecessary health care costs. The clinical impact shown here may prompt the expanded use of DNA methylation profiling for CNS tumor diagnostics within prominent neuro-oncology centers globally.

ACTR-41. AN ARGUMENT THAT MORE ADJUVANT TEMOZOLOMIDE THERAPY IS BETTER FOR GLIOMA PATIENTS

Abstract Current guidelines for adjuvant temozolomide (TMZ) treatment of glioma patients advocates 6 to 12 monthly cycles. Is that best? Will patients who receive &gt; 12 cycles live longer? To find out, we conducted a 10-year (2006–2016) chart review of 1300 glioma patients treated at NorCal Kaiser Permanente facilities to determine the impact of dose-week (AUC) quartiles and duration of TMZ therapy quartiles on median overall survival (mOS) in new low- and mid-grade gliomas (Group A) and glioblastoma (Group B) patients. Group A had 357 patients with WHO grade II and III astrocytic and oligodendroglial tumors; Group B had 943 patients with glioblastoma. The median AUC in Group A was 337 mg/m2 (IQR 129, 1095) and the median weeks of TMZ 15 (IQR 1, 42). In Group B, median AUC was 210 mg/m2 (IQR 79,581) and median weeks of TMZ 24 (IQR 9. 45). Based on quartile ranking of AUC, a higher AUC was found to be associated with longer mOS in Group A and B. In Group A, for increasing AUC quartiles, mOS was 134, 146, 369, and 397 weeks (p=0.0014); for Group B, mOs were 30, 48, 74, and 117 weeks (p&lt; 0.0001). Based on increasing quartiles for TMZ treatment duration for quartiles 2–4, Group A patient mOS increased from 122 weeks to 431 weeks (p = ns) and Group B patients, increased mOS from 51 to 143 weeks (p&lt; 0.0001). This retrospective analysis of 10-years of neuro-oncology practice brings into question limiting TMZ dose in WHO grade 2–3 glioma and WHO grade 4 glioblastoma patients as higher dose toleration and longer duration of treatment appears to be associated with longer mOS in both groups. Or does it show that patients who do well elect to take TMZ longer and maybe these findings reflect reverse causality?

Introducing Fluorescence Guided Surgery into Neuro-Oncology Practice and Getting It Right First Time

Abstract Introduction Fluorescence Guided Surgery (FGS) using 5-ALA is recommended for patients undergoing resection of suspected high grade glioma and this type of surgery is increasingly being used in more units throughout the UK. We report on our experience of introducing 5-ALA guided surgery for suspected HGG in a regional neurosciences unit. Methods Consecutive series of the first 24 patients in our unit to receive 5-ALA guided surgery for suspected HGG from June 2017 to October 2018. Data was prospectively collected. Results 5-ALA fluorescence guided surgery was used for a range of histologically confirmed WHO grade III-IV gliomas. All but 1 tumour (GBM) fluoresced with 5-ALA, with strong fluorescence in recurrent GBM and anaplastic foci of grade 3 tumours. EOR varied according to the eloquence of the lesion with 70% of cases achieving gross total resection. 40% of cases used awake mapping or intraoperative neurophysiology. 5 patients (20.8%) had temporary neurological deficits which resolved in all cases. Individual surgeon learning curves resulted in 2 styles of practice- complete FGS with fluorescence used throughout the case, and intermittent use of fluorescence as an adjunct often at the end of debulking under white light. Conclusions Adopting 5-ALA use comes with specific challenges in terms of service organisation, learning curves and complication avoidance. Our experience is that it is useful both to improve EOR and as an adjunct to identify tumour tissue in eloquent region tumours with monitoring of function. This is possible through a day admission pathway in line with GIRFT.

Neuro-Oncology Practice Clinical Debate: stereotactic radiosurgery or fractionated stereotactic radiotherapy following surgical resection for brain metastasis.

The treatment of resected brain metastasis has shifted away from the historical use of whole-brain radiotherapy (WBRT) toward adjuvant radiosurgery (stereotactic radiosurgery [SRS]) based on a recent prospective clinical trial demonstrating less cognitive decline with the use of SRS alone and equivalent survival as compared with WBRT. Whereas all level 1 evidence to date concerns single-fraction SRS for postoperative brain metastasis, there is emerging evidence that fractionated stereotactic radiotherapy (FSRT) may improve local control at the resected tumor bed. The lack of direct comparative data for SRS vs FSRT results in a diversity in clinical practice. In this article, Greenspoon and Roberge defend the use of SRS as the standard of care for resected brain metastasis, whereas Palmer and Brown argue for FSRT.

Neuro-Oncology Practice Clinical Debate: targeted therapy vs conventional chemotherapy in pediatric low-grade glioma.

The treatment of children with low-grade glioma has evolved over the last several decades, beginning initially with focal radiotherapy, which has now been largely replaced by systemic treatment with conventional chemotherapy agents or more recently molecularly targeted therapeutics. A consensus standard of care is not well defined, leaving clinicians and parents to choose from an increasing number of options, often without complete information concerning the associated risks and benefits. Issues critical to this topic include timing of interventions (when to treat), preservation of neurological function (goals of treatment), choice of initial therapy strategy (conventional cytotoxic chemotherapy vs molecularly targeted therapy), duration of treatment (how long, and what clinical or imaging endpoints to consider), and perhaps most important, risk reduction relative to anticipated benefit. The groups from the University of California, San Francisco and Dana Farber Cancer Institute, moderated by Michael Prados, herein debate the merits of cytotoxic chemotherapy and targeted therapeutics as initial treatment strategies in pediatric low-grade glioma, a topic discussed daily in Tumor Boards across the United States and abroad. Prospective, randomized, phase 3 trials comparing the 2 strategies, conducted within homogenous disease settings, with consistently evaluated functional and imaging endpoints, are not available to guide the risks/benefit discussion. As is often the case in rare biologically diverse diseases, in a vulnerable population, therapy decisions are frequently based on incomplete data, physician experience, bias to some degree, and patient/family preference.

Comparison of Epidemiology and Outcomes in Neuro-Oncology Between the East and the West: Challenges and Opportunities

Although neoplasms of the brain and central nervous system (CNS) are relatively uncommon, comprising only 1–2% of the overall cancer burden, they represent a substantial source of morbidity and mortality worldwide. The age-adjusted annual incidence of CNS tumours is reportedly low; however, there is substantial global variability in its incidence, with nearly a five-fold difference between regions with the highest rates in developed countries in the West and those with the lowest rates in developing countries in South-East Asia, including India, possibly attributable to key differences in environmental factors, genetic susceptibilities and cultural practices, as well as resource constraints in low–middle income countries precluding precise ascertainment and accurate diagnosis. The burden of CNS tumours is further compounded by the fact that they require highly specialised and skilled multidisciplinary care, including access to modern neuroimaging, neurosurgery, neuropathology and molecular biology, radiotherapy, chemotherapy and rehabilitation services, which may not be widely available in an integrated manner in large parts of the world with a large variation in clinical pathways, non-uniformity of care and resultant heterogeneity in clinical outcomes. CNS tumours encompass a heterogeneous spectrum of histopathological entities with differences in presentation, distinct molecular/genetic alterations, diverse biological behaviour and varying clinical outcomes. Survival is highly dependent on histology, grade and molecular biology, but varies widely across continents, even for the same tumour type and grade. In general, survival is higher in children with primary brain tumours than in adults, largely due to the differences in histological distribution across age groups. However, there is widespread variability, with 5-year survival for paediatric brain tumours being <40% in some low–middle income countries compared with 70–80% in the developed world. This review compares the descriptive epidemiology and clinical outcomes of primary brain tumours between the East and the West that pose unique challenges but also provide new opportunities in contemporary neuro-oncological practice.

Molecular profiling and targeted therapy in pediatric gliomas: review and consensus recommendations.

As the field of neuro-oncology makes headway in uncovering the key oncogenic drivers in pediatric glioma, the role of precision diagnostics and therapies continues to rapidly evolve with important implications for the standard of care for clinical management of these patients. Four studies at major academic centers were published in the last year outlining the clinically integrated molecular profiling and targeting of pediatric brain tumors; all 4 demonstrated the feasibility and utility of incorporating sequencing into the care of children with brain tumors, in particular for children and young adults with glioma. Based on synthesis of the data from these studies and others, we provide consensus recommendations for the integration of precision diagnostics and therapeutics into the practice of pediatric neuro-oncology. Our primary consensus recommendation is that next-generation sequencing should be routinely included in the workup of most pediatric gliomas.

Use of steroids in neuro-oncology

Corticosteroids are widely used in routine clinical practice in neuro-oncology. However, despite their widespread use, there is no established consensus on their indications, dosages and dosage schedule. This article reviews the mechanism of action of corticosteroids, their indications for use, side effects and the appropriate management, dosage and duration of therapy, as well as the role of new treatments currently being use to treat cerebral oedema. The most widely used corticosteroid in neuro-oncology is dexamethasone, probably due to its low mineralocorticoid effect and its long half-life. Its effect on cerebral oedema is fundamental in the symptomatic control of patients with brain tumours. It is recommended to start treatment only in symptomatic patients, in doses of 4-8 mg/24 h, always seeking the minimum effective dosage. Side effects associated with corticosteroid use are common and have a negative impact on patients' quality of life.

Joint EANM/EANO/RANO practice guidelines/SNMMI procedure standards for imaging of gliomas using PET with radiolabelled amino acids and [18F]FDG: version 1.0

These joint practice guidelines, or procedure standards, were developed collaboratively by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the working group for Response Assessment in Neurooncology with PET (PET-RANO). Brain PET imaging is being increasingly used to supplement MRI in the clinical management of glioma. The aim of these standards/guidelines is to assist nuclear medicine practitioners in recommending, performing, interpreting and reporting the results of brain PET imaging in patients with glioma to achieve a high-quality imaging standard for PET using FDG and the radiolabelled amino acids MET, FET and FDOPA. This will help promote the appropriate use of PET imaging and contribute to evidence-based medicine that may improve the diagnostic impact of this technique in neurooncological practice. The present document replaces a former version of the guidelines published in 2006 (Vander Borght et al. Eur J Nucl Med Mol Imaging. 33:1374–80, 2006), and supplements a recent evidence-based recommendation by the PET-RANO working group and EANO on the clinical use of PET imaging in patients with glioma (Albert et al. Neuro Oncol. 18:1199–208, 2016). The information provided should be taken in the context of local conditions and regulations.

A Critical Overview of Targeted Therapies for Glioblastoma.

Over the past century, treatment of malignant tumors of the brain has remained a challenge. Refinements in neurosurgical techniques, discovery of powerful chemotherapeutic agents, advances in radiotherapy, applications of biotechnology, and improvements in methods of targeted delivery have led to some extension of length of survival of glioblastoma patients. Refinements in surgery are mentioned because most of the patients with glioblastoma undergo surgery and many of the other innovative therapies are combined with surgery. However, cure of glioblastoma has remained elusive because it requires complete destruction of the tumor. Radical surgical ablation is not possible in the brain and even a small residual tumor leads to rapid recurrence that eventually kills the patient. Blood-brain barrier (BBB) comprising brain endothelial cells lining the cerebral microvasculature, limits delivery of drugs to the brain. Even though opening of the BBB in tumor core occurs locally, BBB limits systemic chemotherapy especially at the tumor periphery, where tumor cells invade normal brain structure comprising intact BBB. Comprehensive approaches are necessary to gain maximally from promising targeted therapies. Common methods used for critical evaluation of targeted therapies for glioblastoma include: (1) novel methods for targeted delivery of chemotherapy; (2) strategies for delivery through BBB and blood-tumor barriers; (3) innovations in radiotherapy for selective destruction of tumor; (4) techniques for local destruction of tumor; (5) tumor growth inhibitors; (6) immunotherapy; and (7) cell/gene therapies. Suggestions for improvements in glioblastoma therapy include: (1) controlled targeted delivery of anticancer therapy to glioblastoma through the BBB using nanoparticles and monoclonal antibodies; (2) direct introduction of genetically modified bacteria that selectively destroy cancer cells but spare the normal brain into the remaining tumor after resection; (3) use of better animal models for preclinical testing; and (4) personalized/precision medicine approaches to therapy in clinical trials and translation into practice of neurosurgery and neurooncology. Advances in these techniques suggest optimism for the future management of glioblastoma.

Development of a Professional Practice Model for Neuro-oncology Advanced Practitioners at an Academic Medical Center: A Quality Improvement Project

In medicine, neuro-oncology practice falls outside the scope of established practice requirements for the specialties of neurology, medical oncology, and neurosurgery, justifying the prerequisite of specialized training to practice neuro-oncology. Neuro-oncology advanced practitioners (AP) also require specialization beyond the scope of population-based generalist training and education. This quality improvement project's primary purpose was to develop a professional practice model (PPM) for APs employed at an academic medical center (AMC) ambulatory neuro-oncology practice. Using the focus, analyze, develop, execute, and evaluate (FADE) quality improvement methodology, the authors (1) reviewed literature and relevant professional organizations to identify possible professional competencies for neuro-oncology APs; (2) analyzed data to develop evidence-based practice domains; (3) used purposive sampling to recruit an interprofessional team of neuro-oncology experts; and (4) conducted a Delphi study with an interprofessional team of experts to gain consensus on practice domains and professional competencies. Twenty-three participants (n = 23) were recruited for the Delphi study, which was executed via electronic transmission using the Web-based software Qualtrics. After two rounds of the Delphi survey, the expert team reached consensus on six domains of practice, with 50 corresponding competency statements. Through interprofessional collaboration and consensus, this quality improvement project successfully created a PPM for an AMC neuro-oncology AP team. The PPM supports neuro-oncology APs by validating the unique set of skills that combines several specialties. The PPM provided the framework to standardize orientation and training, evaluate performance, and support the professional development of an AMC neuro-oncology AP team.

Integrating Genomics Into Neuro-Oncology Clinical Trials and Practice.

Important advances in our understanding of the molecular biology of brain tumors have resulted in a rapid evolution in the taxonomy of central nervous system (CNS) tumors, which culminated in the revised 2016 World Health Organization classification of CNS tumors that incorporates an integrated molecular/histologic diagnostic approach. Our expanding understanding of brain tumor genomics and molecular evolution during the disease course has started to impact clinical management. Furthermore, incorporation of genomic information in ongoing and planned neuro-oncology clinical trials is expected to lead to improved outcomes and result in personalized treatment options for patients with CNS malignancies.

Diffusion Weighted/Tensor Imaging, Functional MRI and Perfusion Weighted Imaging in Glioblastoma-Foundations and Future.

In this article, we review the basics of diffusion tensor imaging and functional MRI, their current utility in preoperative neurosurgical mapping, and their limitations. We also discuss potential future applications, including implementation of resting state functional MRI. We then discuss perfusion and diffusion-weighted imaging and their application in advanced neuro-oncologic practice. We explain how these modalities can be helpful in guiding surgical biopsies and differentiating recurrent tumor from treatment related changes.

How does one do next-generation sequencing for brain tumors in the clinical laboratories?

The newly released World Health Organization Classification of Tumors of the Central Nervous System 2016 has implemented molecular information in the classification of brain tumors. A number of large-scale retrospective studies have indicated that molecular data are of diagnostic and prognostic relevance in neuro-oncology. Incorporation of molecular studies has become a prerequisite in standard-of-care practice of neuro-oncology. Next-generation sequencing (NGS) or massively parallel sequencing allows simultaneously sequencing millions of DNA fragments in an acceptable period. The technique allows examination of a number of genes and gene regions simultaneously and is capable of detecting a wide variety of molecular alterations. NGS has been rapidly adopted in cancer studies to identify mutational landscape, copy number variation, novel fusion genes, and others. With its rapidly declining cost, NGS is slowly replacing conventional molecular techniques in cancer diagnosis. In this review, we will review the development of NGS and common sequencing strategies in oncology laboratories. We will then discuss the application of NGS in detecting genetic aberrations in neuro-oncology.

Social and structural conditions for the avoidance of advance care planning in neuro-oncology: a qualitative study

BackgroundPrimary brain tumours newly affect >260 000 people each year worldwide. In the UK, every year >10 000 people are diagnosed with a brain tumour while >5000 die annually from...

Advanced Magnetic Resonance Imaging in Glioblastoma: A Review

In 2017, it is estimated that 26,070 patients will be diagnosed with a malignant primary brain tumor in the United States, with more than half having the diagnosis of glioblas- toma (GBM).1 Magnetic resonance imaging (MRI) is a widely utilized examination in the diagnosis and post-treatment management of patients with glioblastoma; standard modalities available from any clinical MRI scanner, including T1, T2, T2-FLAIR, and T1-contrast-enhanced (T1CE) sequences, provide critical clinical information. In the last decade, advanced imaging modalities are increasingly utilized to further charac- terize glioblastomas. These include multi-parametric MRI sequences, such as dynamic contrast enhancement (DCE), dynamic susceptibility contrast (DSC), diffusion tensor imaging (DTI), functional imaging, and spectroscopy (MRS), to further characterize glioblastomas, and significant efforts are ongoing to implement these advanced imaging modalities into improved clinical workflows and personalized therapy approaches. A contemporary review of standard and advanced MR imaging in clinical neuro-oncologic practice is presented.

NIMG-24. PATHOLOGY CONFIRMED RADIOGRAPHIC DIAGNOSIS OF TRUE PROGRESSION AND PSEUDO-PROGRESSION MADE BY ADVANCED BRAIN TUMOR IMAGING

Differentiation of true tumor progression verse pseudo-pregresion in glioblastomas patients by routine MRI is a challenging task, in part because T1 enhancement and timeline similarities where pseudo-progression can happen within first 3-6 months post chemoradiation. We performed a retrospective data analysis of Advanced Brain Tumor Imaging (ABTI) protocol as a differentiating tool. 29 Patients, ages from 21 to 79 years old with18 Male and 11 females, were included in this study and their MRI showed evidence of new enhancement by RANO or McDonald criteria. ABTI protocol was performed 4 weeks later, including DSC and ASL perfusion, DTI, SWI, MRS and T1 WI delayed post contrast sequences with wash-in/wash-out maps (WIWOM). Eight patients underwent subsequent craniotomy and pathology reports are available for ABTI correlation. Patients were divided in three groups by pathology and ABTI results: a) 15 as pseudo-progression, featuring significant delay wash-in on WIWOM, low Cho/Cr, Naa and Cho, with/wo high lipids on MRS, low ASL/CBF and low DSC/r CBV. b) 9 patients as true progression, featuring significant areas of early wash-out on WIWOM, high Cho/Cr on MRS, high ASL/CBF on and DSC/r CBV. c) 6 cases as mixed responses displaying both pseudo-progression and true progression in separate areas. For patient with pseudo-progression group, original treatment was continued, with subsequent proven stability or lesion regression by MRI. Reports were rectified by pathology in 6 cases. Data analysis with pathological correlation indicates a high predictive value for the ABTI based pseudo-progression diagnosis, posing the proposed ABTI algorithm as a useful tool scrutinizing alleged conventional imaging based tumor progression diagnosis. Significant delay contrast wash-in, low Cho/Cr and low ASL/DSC perfusion parameters, are highly suggestive of treatment response/pseudo-progression, supporting ABTI routine utilization in the modern neurooncological practice to be further validated by a larger sample study.

Advanced magnetic resonance imaging in glioblastoma: a review.

Glioblastoma, the most common and most rapidly progressing primary malignant tumor of the central nervous system, continues to portend a dismal prognosis, despite improvements in diagnostic and therapeutic strategies over the last 20 years. The standard of care radiographic characterization of glioblastoma is magnetic resonance imaging (MRI), which is a widely utilized examination in the diagnosis and post-treatment management of patients with glioblastoma. Basic MRI modalities available from any clinical scanner, including native T1-weighted (T1w) and contrast-enhanced (T1CE), T2-weighted (T2w), and T2-fluid-attenuated inversion recovery (T2-FLAIR) sequences, provide critical clinical information about various processes in the tumor environment. In the last decade, advanced MRI modalities are increasingly utilized to further characterize glioblastomas more comprehensively. These include multi-parametric MRI sequences, such as dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE), higher order diffusion techniques such as diffusion tensor imaging (DTI), and MR spectroscopy (MRS). Significant efforts are ongoing to implement these advanced imaging modalities into improved clinical workflows and personalized therapy approaches. Functional MRI (fMRI) and tractography are increasingly being used to identify eloquent cortices and important tracts to minimize postsurgical neuro-deficits. A contemporary review of the application of standard and advanced MRI in clinical neuro-oncologic practice is presented here.

Tumor Treating Fields in Neuro-Oncological Practice.

Electric fields are known to produce biological effects. Depending on specific frequency, they can stimulate healing, directly damage tissues, or produce anti-mitotic activity. Frequencies of 100-300KHz have been shown to disrupt mitosis and lead to cellular death. Growth of cancer cell lines, both in vitro and in vivo, was shown to be inhibited by application of the electric fields. In the clinical setting, electric fields are available for treatment of brain tumors, specifically glioblastoma (GBM), through a portable device producing so-called tumor treating fields (TTF). Clinical trials conducted in patients with recurrent and newly diagnosed GBM indicated that this novel treatment modality is active and associated with minimal toxicity. This manuscript will review the available evidence supporting the use of TTF in neuro-oncologic practice.