Systemic Therapy for Melanoma Brain and Leptomeningeal Metastases.

OPINION STATEMENT: Melanoma has a high propensity to metastasize to the brain which portends a poorer prognosis. With advanced radiation techniques and targeted therapies, outcomes however are improving. Melanoma brain metastases are best managed in a multi-disciplinary approach, including medical oncologists, neuro-oncologists, radiation oncologists, and neurosurgeons. The sequence of therapies is dependent on the number and size of brain metastases, status of systemic disease control, prior therapies, performance status, and neurological symptoms. The goal of treatment is to minimize neurologic morbidity and prolong both progression free and overall survival while maximizing quality of life. Surgery should be considered for solitary metastases, or large and/or symptomatic metastases with edema. Stereotactic radiosurgery offers a benefit over whole-brain radiation attributed to the relative radioresistance of melanoma and reduction in neurotoxicity. Thus far, data supports a more durable response with systemic therapy using combination immunotherapy of ipilimumab and nivolumab, though targeting the presence of BRAF mutations can also be utilized. BRAF inhibitor therapy is often used after immunotherapy failure, unless a more rapid initial response is needed and then can be done prior to initiating immunotherapy. Further trials are needed, particularly for leptomeningeal metastases which currently require the multi-disciplinary approach to determine best treatment plan.

Predicting access to postoperative treatment after glioblastoma resection: an analysis of neighborhood-level disadvantage using the Area Deprivation Index (ADI).

PURPOSE: Social determinants of health (SDoH)-socioeconomic and environmental factors-impact outcomes. The Area Deprivation Index (ADI), a composite of seventeen SDoH factors, has been correlated with poorer outcomes. We aimed to compare outcomes and treatment access for glioblastoma, a universally fatal malignant brain tumor, in patients more (ADI 34-100%) versus less disadvantaged (ADI 0-33%). METHODS: A 5-year retrospective study of Rhode Island Hospital and Mayo Clinic databases was conducted from 2012 to 2017 for patients ≥ 18 years with glioblastoma. Patient addresses were matched to ADI percentiles and grouped into more (top 66% ADI) and less disadvantaged. Adjusted multivariable regressions were used to compare outcomes between groups. RESULTS: A total of 434 patients met inclusion; 92.9% were insured, 56.2% were more disadvantaged (n = 244), and the more disadvantaged cohort was younger on average (62 years). After adjustment, the more disadvantaged group had decreased odds of receiving gross total resection (adjusted odds ratio (aOR) 0.43, 95% CI [0.27-0.68]; p < 0.001). This cohort also had decreased odds of undergoing chemotherapy (aOR 0.51[0.26-0.98]), radiation (aOR 0.39[0.20-0.77]), chemoradiation (aOR 0.42[0.23-0.77]), tumor-treating fields (aOR 0.39[0.16-0.93]), and clinical trial participation (aOR 0.47[0.25-0.91]). No differences in length of survival or postoperative Karnofsky Performance Status Scale were observed. CONCLUSION: More disadvantaged glioblastoma patients had decreased odds of receiving gross total resection. They also exhibited decreased odds of receiving standard of care like chemoradiation as well as participating in a clinical trial, compared to the less disadvantaged group. More research is needed to identify modifiable SDoH barriers to post-operative treatment in disadvantaged patients with glioblastoma.

The early infiltrative phase of GBM hypothesis: are molecular glioblastomas histological glioblastomas in the making? A preliminary multicenter study.

PURPOSE: The presence of necrosis or microvascular proliferation was previously the hallmark for glioblastoma (GBM) diagnosis. The 2021 WHO classification now considers IDH-wildtype diffuse astrocytic tumors without the histological features of glioblastoma (that would have otherwise been classified as grade 2 or 3) as molecular GBM (molGBM) if they harbor any of the following molecular abnormalities: TERT promoter mutation, EGFR amplification, or chromosomal + 7/-10 copy changes. We hypothesize that these tumors are early histological GBM and will eventually develop the classic histological features. METHODS: Medical records from 65 consecutive patients diagnosed with molGBM at three tertiary-care centers from our institution were retrospectively reviewed from November 2017-October 2021. Only patients who underwent reoperation for tumor recurrence and whose tissue at initial diagnosis and recurrence was available were included in this study. The detailed clinical, histopathological, and radiographic scenarios are presented. RESULTS: Five patients were included in our final cohort. Three (60%) patients underwent reoperation for recurrence in the primary site and 2 (40%) underwent reoperation for distal recurrence. Microvascular proliferation and pseudopalisading necrosis were absent at initial diagnosis but present at recurrence in 4 (80%) patients. Radiographically, all tumors showed contrast enhancement, however none of them showed the classic radiographic features of GBM at initial diagnosis. CONCLUSIONS: In this manuscript we present preliminary data for a hypothesis that molGBMs are early histological GBMs diagnosed early in their natural history of disease and will eventually develop necrosis and microvascular proliferation. Further correlative studies are needed in support of this hypothesis.

The survival outcomes of molecular glioblastoma IDH-wildtype: a multicenter study.

PURPOSE: Histological diagnosis of glioblastoma (GBM) was determined by the presence of necrosis or microvascular proliferation (histGBM). The 2021 WHO classification now considers IDH-wildtype diffuse astrocytic tumors without the histological features of glioblastoma (that would have otherwise been classified as grade 2 or 3) as molecular GBM (molGBM, WHO grade 4) if they harbor any of the following molecular abnormalities: TERT promoter mutation, EGFR amplification, or chromosomal + 7/- 10 copy changes. The objective of this study was to explore and compare the survival outcomes between histGBM and molGBM. METHODS: Medical records for patients diagnosed with GBM at the three tertiary care academic centers of our institution from November 2017 to October 2021. Only patients who underwent adjuvant chemoradiation were included. Patients without molecular feature testing or with an IDH mutation were excluded. Univariable and multivariable analyses were performed to evaluate progression-free (PFS) and overall- survival (OS). RESULTS: 708 consecutive patients were included; 643 with histGBM and 65 with molGBM. Median PFS was 8 months (histGBM) and 13 months (molGBM) (p = 0.0237) and median OS was 21 months (histGBM) versus 26 months (molGBM) (p = 0.435). Multivariable analysis on the molGBM sub-group showed a worse PFS if there was contrast enhancement on MRI (HR 6.224 [CI 95% 2.187-17.714], p < 0.001) and a superior PFS on patients with MGMT methylation (HR 0.026 [CI 95% 0.065-0.655], p = 0.007). CONCLUSIONS: molGBM has a similar OS but significantly longer PFS when compared to histGBM. The presence of contrast enhancement and MGMT methylation seem to affect the clinical behavior of this subset of tumors.

How much time do we have? Longitudinal perception of prognosis in newly-diagnosed high grade glioma patients and caregivers compared to clinicians.

PURPOSE: Discordant prognostic awareness (PA) can cause distress, impact goals of care and future planning, especially in patients with high grade glioma (pwHGG) who have limited survival. We aimed to evaluate the feasibility of assessing PA of pwHGG, caregivers and clinicians using a single question and to evaluate these responses for discord, alignment and fluctuation over time. METHODS: This is a sub-study of an IRB-approved pilot study evaluating early palliative care and longitudinal symptom monitoring via a smart-device tool in 16 pwHGG and their caregivers receiving treatment at the Mayo Clinic Arizona (United States). Eligible patients were ≥ 18 years, English-speaking, newly-diagnosed, and had a willing caregiver. Participants answered a multiple-choice question asking for an estimate of their own or their loved one's survival on a monthly basis. RESULTS: All except one patient/caregiver dyad answered the question each time it was asked. The question did not appear to cause discomfort or increase conversations with clinicians around prognosis. PA of patients and caregivers fluctuated monthly, ranging from dismal to overtly optimistic, with a discordance frequency of 68%. Patients tended to be more optimistic than caregivers, and a higher QOL correlated to a more optimistic response. Clinicians' were more hopeful; their prediction tended to fluctuate less than those of patients and caregivers. CONCLUSIONS: PA may be assessed in pwHGG and caregivers with a single, frank question. There is clear discordance between PA of patients, their caregivers and clinicians. Understanding fluctuates longitudinally through disease and treatment course. Additional studies on timing and ways of discussing prognosis in this population are needed. CLINICAL TRIAL REGISTRATION: NCT04630379.

A Mechanistic Investigation into Ischemia-Driven Distal Recurrence of Glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor with a short median survival. Tumor recurrence is a clinical expectation of this disease and usually occurs along the resection cavity wall. However, previous clinical observations have suggested that in cases of ischemia following surgery, tumors are more likely to recur distally. Through the use of a previously established mechanistic model of GBM, the Proliferation Invasion Hypoxia Necrosis Angiogenesis (PIHNA) model, we explore the phenotypic drivers of this observed behavior. We have extended the PIHNA model to include a new nutrient-based vascular efficiency term that encodes the ability of local vasculature to provide nutrients to the simulated tumor. The extended model suggests sensitivity to a hypoxic microenvironment and the inherent migration and proliferation rates of the tumor cells are key factors that drive distal recurrence.

Updated Imaging Features of Dysplastic Cerebellar Gangliocytoma.

OBJECTIVE: The aim of this study was to perform an updated review of the imaging features of dysplastic cerebellar gangliocytoma (DCG). METHODS: Imaging findings were retrospectively reviewed in 14 patients with DCG. The analysis included size, location, cyst formation, calcification, intralesional hemorrhage, enhancement pattern, and apparent diffusion coefficient (ADC). RESULTS: In addition to revisiting many well-established imaging features of DCG, enhancement was much more common (64.3%) than previously reported, and small enhancing veins were also frequently encountered within or along the periphery of the lesions (50%). Dysplastic cerebellar gangliocytomas had an elevated ADC compared with normal cerebellum (967.8 ± 115.7 vs 770.4 ± 47.3 × 10 mm/s; P < 0.0001). CONCLUSIONS: Enhancement on magnetic resonance imaging within DCG should be an accepted imaging finding rather than being viewed as uncommon or atypical. Dysplastic cerebellar gangliocytomas typically have an elevated ADC compared with normal cerebellum, which may assist in differentiation from other posterior fossa neoplasms.

Socioeconomic status and glioblastoma risk: a population-based analysis.

PURPOSE: Socioeconomic status (SES) is associated with risk of various cancer types because of correlation between SES and causal factors or increased case ascertainment, or both. Studies evaluating the association between glioblastoma and occupational or SES factors have yielded inconsistent results. We evaluated the association between SES and glioblastoma risk using a large, population-based cancer registry dataset. METHODS: Data of the Surveillance, Epidemiology, and End Results Program were used to evaluate the impact of SES on glioblastoma risk. SES was divided into quintiles on the basis of census tract of residence. Census tracts are small, geographically defined areas with relatively homogeneous population characteristics. RESULTS: Higher SES was strongly associated with increased risk of glioblastoma (p < .001). Relative to persons living in census tracts of the lowest SES quintile, the highest SES quintile had a rate ratio of 1.45 (95 % CI 1.39-1.51) (p < .001). Similar associations were seen in population subgroups defined by age, sex, and race. CONCLUSIONS: The strong association between higher SES and greater glioblastoma risk is unlikely to represent an ascertainment effect because glioblastoma is rapidly progressive and ultimately fatal. A number of previously proposed glioma risk factors may be correlated with SES, including atopy and allergy rates, cellular telephone use, and body morphometric measures. Further research is needed to define the mechanism of this association.

Defining interventions and metrics to improve diversity in CNS clinical trial participation: A SNO and RANO effort.

Despite major strides in cancer research and therapy, these advances have not been equitable across race and ethnicity. Historically marginalized groups (HMG) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black, Hispanic, and Indigenous people represent 30% of the population but only 9% of oncology clinical trial participants. As a result, HMGs lack equitable access to novel therapies, contradicting the principle of distributive justice, as enshrined in the Belmont report, which demands the equitable selection of subjects in research involving human subjects. The lack of clinical trial diversity also leads to low generalizability and potentially harmful medical practices. Specifically, patients with brain cancer face unique barriers to clinical trial enrollment and completion due to disease-specific neurologic and treatment-induced conditions. Collectively, the intersection of these disease-specific conditions with social determinants of health fosters a lack of diversity in clinical trials. To ameliorate this disparity in neuro-oncology clinical trial participation, we present interventions focused on improving engagement of HMGs. Proposals range from inclusive trial design, decreasing barriers to care, expanding trial eligibility, access to tumor profiling for personalized medical trials, setting reasonable metrics and goals for accrual, working with patient community stakeholders, diversifying the neuro-oncology workforce, and development of tools to overcome biases with options to incentivize equity. The diversification of participation amongst neuro-oncology clinical trials is imperative. Equitable access and inclusion of HMG patients with brain tumors will not only enhance research discoveries but will also improve patient care.

Neurologic Complications of Cancer Treatment.

OBJECTIVE: Advances in cancer treatment have led to extended survival and increased risk of neurologic complications in an aging population. This review summarizes potential neurologic complications in patients who have undergone treatment for neurologic and systemic malignancies. LATEST DEVELOPMENTS: Radiation and cytotoxic chemotherapy along with other targeted therapies continue to be the mainstay of cancer treatment. These advances in cancer care have led to improved outcomes and increased the need to understand the spectrum of neurologic complications that may arise from treatment. While radiation and older therapies including cytotoxic chemotherapies have side effect profiles that are widely known and well understood, this article serves as a review of the more commonly associated neurologic complications of both traditional and newer treatments being offered to this patient population. ESSENTIAL POINTS: Neurotoxicity is a common complication of cancer-directed treatment. In general, neurologic complications of radiation therapy are more common in central nervous system malignancies, and neurologic complications of chemotherapy are more common in non-neurologic malignancies. Attempts at prevention, early detection, and intervention remain paramount in the reduction of neurologic morbidity.

Molecular Profiling in Neuro-Oncology: Where We Are, Where We're Heading, and How We Ensure Everyone Can Come Along.

Advances in molecular profiling have led to improved understanding of glioma heterogeneity. Results have been used to inform diagnostic classification and targeted treatment strategies. Validation of these tests is necessary in the development of biomarkers that can aid in treatment decision, allowing for personalized medicine in neuro-oncologic diseases. Although not all populations have benefitted equally from awareness of and access to testing, opportunities arise regarding incorporating this testing into the standard of care for patients with glioma.

Clinical Outcomes of Stereotactic Radiosurgery-Related Radiation Necrosis in Patients with Intracranial Metastasis from Melanoma.

Background: Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population. Methods: Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation. Results: Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients. Conclusions: Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted.

Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures.

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

Image-localized biopsy mapping of brain tumor heterogeneity: A single-center study protocol.

Brain cancers pose a novel set of difficulties due to the limited accessibility of human brain tumor tissue. For this reason, clinical decision-making relies heavily on MR imaging interpretation, yet the mapping between MRI features and underlying biology remains ambiguous. Standard (clinical) tissue sampling fails to capture the full heterogeneity of the disease. Biopsies are required to obtain a pathological diagnosis and are predominantly taken from the tumor core, which often has different traits to the surrounding invasive tumor that typically leads to recurrent disease. One approach to solving this issue is to characterize the spatial heterogeneity of molecular, genetic, and cellular features of glioma through the intraoperative collection of multiple image-localized biopsy samples paired with multi-parametric MRIs. We have adopted this approach and are currently actively enrolling patients for our 'Image-Based Mapping of Brain Tumors' study. Patients are eligible for this research study (IRB #16-002424) if they are 18 years or older and undergoing surgical intervention for a brain lesion. Once identified, candidate patients receive dynamic susceptibility contrast (DSC) perfusion MRI and diffusion tensor imaging (DTI), in addition to standard sequences (T1, T1Gd, T2, T2-FLAIR) at their presurgical scan. During surgery, sample anatomical locations are tracked using neuronavigation. The collected specimens from this research study are used to capture the intra-tumoral heterogeneity across brain tumors including quantification of genetic aberrations through whole-exome and RNA sequencing as well as other tissue analysis techniques. To date, these data (made available through a public portal) have been used to generate, test, and validate predictive regional maps of the spatial distribution of tumor cell density and/or treatment-related key genetic marker status to identify biopsy and/or treatment targets based on insight from the entire tumor makeup. This type of methodology, when delivered within clinically feasible time frames, has the potential to further inform medical decision-making by improving surgical intervention, radiation, and targeted drug therapy for patients with glioma.

Secondary intramedullary spinal cord non-Hodgkin's lymphoma.

Intramedullary spinal cord metastases of solid neoplasms are associated with poor long-term survival. As the characteristics of secondary intramedullary spinal cord non-Hodgkin's lymphoma (NHL) are not well understood, we sought to describe its clinical features and outcome. We retrospectively reviewed the Mayo Clinic patient database, lymphoma database, and pathology records from 1996 to 2010 and identified patients with clinical myelopathy and neuroimaging evidence of secondary intramedullary spinal cord involvement from pathologically confirmed systemic NHL. Seven patients were included in this study. The median age was 61 years (range, 41-81). Symptom onset was subacute (≤8 weeks) in six. Four patients were wheelchair-dependent at diagnosis. Spinal cord NHL was diagnosed by cerebrospinal fluid cytology in four; Positron emission tomography hypermetabolism in two; or MRI features alone. Myelopathy developed in five patients at a median 8 months (range, 1-58) following systemic NHL diagnosis, while myelopathy was the heralding symptom of NHL in two patients. Spinal cord MRI lesions were characteristically gadolinium enhancing and expansile. Four patients had co-existing MRI brain lesions. Six patients had B-cell NHL and one patient T-cell NHL. Six of the seven were treated (high dose intravenous methotrexate in three; radiation therapy in two; and R-CHOP in one). Median survival was 11.5 months (range, 1-28) with a 33% 2-year survival compared to historical median survival estimates of spinal cord metastases due to solid tumors of 3 months. In secondary intramedullary spinal cord involvement of NHL early neurological morbidity is common, but overall survival compares favorably to previously reported survival in spinal cord metastases from solid tumors.

Case Report: Opsoclonus-Myoclonus Syndrome Associated With Contactin-Associated Protein-Like 2 and Acetylcholine Receptor Autoantibodies in the Setting of Non-Small Cell Lung Carcinoma.

Opsoclonus myoclonus syndrome (OMS) is a rare immune-mediated paraneoplastic or para/-post-infectious syndrome characterized by "dancing" eye movements, myoclonus, and ataxia. Neuropsychiatric symptoms have also been reported. Without treatment, OMS may progress to further neurological impairment and even death. Autoimmune attack of CNS structures in OMS is most commonly mediated by anti-Ri (also known as ANNA2) IgG antibodies, with additional findings implicating antibodies targeting various neurotransmitter receptors. Prompt immunotherapy and neoplasm treatment may result in improvement. We report a novel association of Contactin-Associated Protein-Like 2 (Caspr2) antibodies occurring in association with paraneoplastic OMS. While breast cancer and small cell lung cancer (SCLC) are more commonly associated with OMS among adults, we characterize a novel association between Caspr2 antibody in a patient with mixed non-small cell and small cell lung carcinoma.

A population study of clinical trial accrual for women and minorities in neuro-oncology following the NIH Revitalization Act.

BACKGROUND: The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate progress made in all phase therapeutic clinical trials for neuroepithelial CNS tumors stratified by demographic-specific age-adjusted disease incidence and mortality. Additionally, we identify workforce characteristics associated with clinical trials meeting established accrual benchmarks. METHODS: Registry study of published clinical trials for World Health Organization defined neuroepithelial CNS tumors between January 2000 and December 2019. Study participants were obtained from PubMed and ClinicalTrials.gov. Population-based data originated from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and χ 2 tests were used for data analysis. RESULTS: Among 662 published clinical trials representing 49 907 participants, 62.5% of participants were men and 37.5% women (P < .0001) representing a mortality specific over-accrual for men (P = .001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with mortality, Blacks (47% of expected mortality, P = .008), Hispanics (17% of expected mortality, P < .001) and Asians (33% of expected mortality, P < .001) were underrepresented compared with Whites (114% of expected mortality, P < .001). Clinical trials meeting accrual benchmarks for race included minority authorship. CONCLUSIONS: Following the Revitalization Act, minorities and women remain underrepresented in therapeutic clinical trials for neuroepithelial tumors, relative to disease incidence and mortality. Study accrual has improved with time. This study provides a framework for clinical trial accrual efforts and offers guidance regarding workforce considerations associated with enrollment of underserved patients.

Efficacy of Treatment With Armodafinil for Cancer-Related Fatigue in Patients With High-grade Glioma: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: Nearly 96% of patients with high-grade glioma (HGG) report moderate-to-severe fatigue. Armodafinil is a psychostimulant that might help cancer-related fatigue in patients with HGG. OBJECTIVE: To determine whether armodafinil reduces fatigue in patients with HGG and moderate-to-severe fatigue. DESIGN, SETTING, AND PARTICIPANTS: In this randomized multicenter, phase 3, double-blinded, placebo-controlled clinical trial, adults with HGG and moderate-to-severe fatigue who were clinically stable at least 4 weeks after completing radiation therapy were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo over 8 weeks. A score of at least 6 out of 10 on severity scale for the brief fatigue inventory scale, with 10 being the worst, was required to suggest moderate-to-severe fatigue. Patients were allowed stable doses of corticosteroids but were excluded if they required increasing amounts of corticosteroids, were receiving some other treatment for fatigue, or had an uncontrolled seizure disorder. The study was conducted from June 2013 to December 15, 2019. INTERVENTIONS: Patients were randomized to 150 mg of armodafinil, 250 mg of armodafinil, or placebo for a total of 8 weeks with assessments at weeks 4 and 8. MAIN OUTCOMES AND MEASURES: The primary outcome was efficacy in treating cancer-related fatigue. Secondary outcomes included safety, neurocognitive function, and quality of life. Patients were evaluated at baseline and at weeks 4 and 8. Efficacy between the placebo and the 2 doses of study drug was determined by an improvement by 2 points on the 0 to 10 brief fatigue inventory scale. Kruskal-Wallis and χ2 tests were used and followed by confirmatory analyses. RESULTS: A total of 328 patients were enrolled, of whom 297 had evaluable end point data. Of these, 103 received 150 mg of armodafinil (mean [SD] age, 58.5 [11.9] years; 42 women [40.8%]), 97 250 mg of armodafinil (mean [SD] age, 56.6 [12.5] years; 37 women [38.1%]), and 97 placebo (mean [SD] age, 57.1 [12.5] years; 39 women [40.2%]). There was no difference in the proportion of patients who achieved clinically meaningful fatigue reduction between arms (28% [95% CI 20%-30%] for 150 mg of armodafinil, 28% [95% CI 19%-38%] for 250 mg of armodafinil, and 30% [95% CI 21%-40%] for placebo). There was a statistically significant reduction in global fatigue for corticosteroid users compared with nonusers (-0.7 [95% CI, -1.5 to -0.3] vs -1.7 [95% CI, -2.1 to -1.3]; P < .001). More patients (2 vs 7) reported insomnia with treatment with 250 mg of armodafinil. CONCLUSIONS AND RELEVANCE: The results of this randomized clinical trial found no meaningful benefit of using treatment with armodafinil to reduce cancer-related fatigue in patients with HGG. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01781468.

IDH-wild-type glioblastoma cell density and infiltration distribution influence on supramarginal resection and its impact on overall survival: a mathematical model.

OBJECTIVE: Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH-wild-type glioblastoma (GBM) to further improve patients' overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH-wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile). METHODS: Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3)2/3 × (6.106/[VT21/1 - VT11/1])2, where VT2 and VT1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse. RESULTS: A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98-0.99; p = 0.02; and HR 0.98, 95% CI 0.96-0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively. CONCLUSIONS: The impact of SMR on OS for patients with IDH-wild-type GBM is influenced by the degree of tumor invasiveness. The authors' results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH-wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.