Barriers to Accrual and Enrollment in Brain Tumor Trials

Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next five years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions

An Assessment of the Compliance and Utility of a Home Exercise DVD for Caregivers of Children and Adolescents With Brachial Plexus Palsy: A Pilot Study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146875/1/pmr2190.pd

8‐Year‐Old Boy with Progressive Headache

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99694/1/bpa12074.pd

The Role of CD 133+ Cells in a Recurrent Embryonal Tumor with Abundant Neuropil and True Rosettes ( ETANTR )

Embryonal tumor with abundant neuropil and true rosettes ( ETANTR ) is a recently described embryonal neoplasm of the central nervous system, consisting of a well‐circumscribed embryonal tumor of infancy with mixed features of ependymoblastoma (multilayer ependymoblastic rosettes and pseudorosettes) and neuroblastoma (neuroblastic rosettes) in the presence of neuropil‐like islands. We present the case of a young child with a very aggressive tumor that rapidly recurred after gross total resection, chemotherapy and radiation. Prominent vascular sclerosis and circumscribed tumor led to the diagnosis of malignant astroblastoma; however, rapid recurrence and progression of this large tumor after gross total resection prompted review of the original pathology. ETANTR is histologically distinct with focal glial fibrillary acid protein ( GFAP ) and synaptophysin expression in the presence of neuronal and ependymoblastic rosettes with focal neuropil islands. These architectural features, combined with unique chromosome 19q13.42 amplification, confirmed the diagnosis. In this report, we describe tumor stem cell ( TSC ) marker CD 133, CD 15 and nestin alterations in ETANTR before and after chemotherapy. We found that TSC marker CD 133 was richly expressed after chemotherapy in recurrent ETANTR , while CD 15 is depleted compared with that expressed in the original tumor, suggesting that CD 133+ cells likely survived initial treatment, further contributing to formation of the recurrent tumor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102077/1/bpa12079.pd

T2 FLAIR hyperintensity volume Is associated with cognitive function and quality of life in clinically stable patients with lower grade gliomas

Survival outcomes for patients with lower grade gliomas (LrGG) continue to improve. However, damage caused both by tumor growth and by the consequences of treatment often leads to significantly impaired cognitive function and quality of life (QoL). While neuropsychological testing is not routine, serial clinical MRIs are standard of care for patients with LrGG. Thus, having a greater understanding of MRI indicators of cognitive and QoL impairment risk could be beneficial to patients and clinicians. In this work we sought to test the hypothesis that in clinically stable LrGG patients, T2 FLAIR hyperintensity volumes at the time of cognitive assessment are associated with impairments of cognitive function and QoL and could be used to help identify patients for cognitive and QoL assessments and interventions. We performed anatomical MR imaging, cognitive testing and QoL assessments cross-sectionally in 30 clinically stable grade 2 and 3 glioma patients with subjective cognitive concerns who were 6 or more months post-treatment. Larger post-surgical T2 FLAIR volume at testing was significantly associated with lower cognitive performance, while pre-surgical tumor volume was not. Older patients had lower cognitive performance than younger patients, even after accounting for normal age-related declines in performance. Patients with Astrocytoma, IDH mutant LrGGs were more likely to show lower cognitive performance than patients with Oligodendroglioma, IDH mutant 1p19q co-deleted LrGGs. Previous treatment with combined radiation and chemotherapy was associated with poorer self-reported QoL, including self-reported cognitive function. This study demonstrates the importance of appreciating that LrGG patients may experience impairments in cognitive function and QoL over their disease course, including during periods of otherwise sustained clinical stability. Imaging factors can be helpful in identifying vulnerable patients who would benefit from cognitive assessment and rehabilitation

Preclinical modeling of lower-grade gliomas

Models for human gliomas prove critical not only to advancing our understanding of glioma biology but also to facilitate the development of therapeutic modalities. Specifically, creating lower-grade glioma (LGG) models has been challenging, contributing to few investigations and the minimal progress in standard treatment over the past decade. In order to reliably predict and validate the efficacies of novel treatments, however, LGG models need to adhere to specific standards that recapitulate tumor genetic aberrations and micro-environment. This underscores the need to revisit existing models of LGG and explore prospective models that may bridge the gap between preclinical insights and clinical translation. This review first outlines a set of criteria aimed to address the current challenges hindering model development. We then evaluate the strengths and weaknesses of existing preclinical models of LGG with respect to these established standards. To conclude, the review discusses potential future directions for integrating existing models to maximize the exploration of disease mechanisms and therapeutics development

Health Related Quality of Life in Adult Low and High-Grade Glioma Patients Using the National Institutes of Health Patient Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL Assessments

Health related quality of life (HRQOL) measures have become increasingly important in the management of glioma patients in both research and clinical practice settings. Functional impairment is common in low-grade and high-grade glioma patients as the disease has both oncological and neurological manifestations. Natural disease history as well as medical or surgical treatment can negatively influence HRQOL. There are no universal standards for HRQOL assessment in glioma patients. In this study, we examine patient perspectives on functional outcome domains and report the prevalence of impairments rates using the National Institutes of Health (NIH) Patient Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL item banks as measures of HRQOL. Retrospective analysis of a prospectively collected dataset involving 79 glioma patients reveals that quality of life concerns are the most important consideration behind making decisions about treatment in 80.7% of patients. The prevalence of functional impairment by PROMIS and NEURO-QOL assessment is high, ranging from 28.6% in the physical function domain to 43.9% in the cognitive function domain. Pain and anxiety related to physical decline is higher in LGG patients compared to HGG patients. Aphasia severity also impacts HRQOL. The results of this study suggest that the PROMIS and NEURO-QOL assessments may be important HRQOL metrics for future use in larger clinical research and clinical trial settings

Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas

BACKGROUND. Long-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy. METHODS. We conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor. RESULTS. A total of 17 eligible patients were enrolled — 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident–like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination. CONCLUSION. The regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies

Artificial-intelligence-based molecular classification of diffuse gliomas using rapid, label-free optical imaging

Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. However, timely molecular diagnostic testing for patients with brain tumors is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. In this study, we developed DeepGlioma, a rapid ($< 90$ seconds), artificial-intelligence-based diagnostic screening system to streamline the molecular diagnosis of diffuse gliomas. DeepGlioma is trained using a multimodal dataset that includes stimulated Raman histology (SRH); a rapid, label-free, non-consumptive, optical imaging method; and large-scale, public genomic data. In a prospective, multicenter, international testing cohort of patients with diffuse glioma ($n=153$) who underwent real-time SRH imaging, we demonstrate that DeepGlioma can predict the molecular alterations used by the World Health Organization to define the adult-type diffuse glioma taxonomy (IDH mutation, 1p19q co-deletion and ATRX mutation), achieving a mean molecular classification accuracy of $93.3\pm 1.6\%$. Our results represent how artificial intelligence and optical histology can be used to provide a rapid and scalable adjunct to wet lab methods for the molecular screening of patients with diffuse glioma.Comment: Paper published in Nature Medicin

On the cutting edge of glioblastoma surgery:where neurosurgeons agree and disagree on surgical decisions

OBJECTIVE: The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity. Standards are lacking for surgical decision-making, and previous studies indicate treatment variations. These shortcomings reflect the need to evaluate larger populations from different care teams. In this study, the authors used probability maps to quantify and compare surgical decision-making throughout the brain by 12 neurosurgical teams for patients with glioblastoma. METHODS: The study included all adult patients who underwent first-time glioblastoma surgery in 2012-2013 and were treated by 1 of the 12 participating neurosurgical teams. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to identify and compare patient treatment variations. Brain regions with different biopsy and resection results between teams were identified and analyzed for patient functional outcome and survival. RESULTS: The study cohort consisted of 1087 patients, of whom 363 underwent a biopsy and 724 a resection. Biopsy and resection decisions were generally comparable between teams, providing benchmarks for probability maps of resections and biopsies for glioblastoma. Differences in biopsy rates were identified for the right superior frontal gyrus and indicated variation in biopsy decisions. Differences in resection rates were identified for the left superior parietal lobule, indicating variations in resection decisions. CONCLUSIONS: Probability maps of glioblastoma surgery enabled capture of clinical practice decisions and indicated that teams generally agreed on which region to biopsy or to resect. However, treatment variations reflecting clinical dilemmas were observed and pinpointed by using the probability maps, which could therefore be useful for quality-of-care discussions between surgical teams for patients with glioblastoma