Determining venous thromboembolism risk in patients with adult-type diffuse glioma.

Venous thromboembolism (VTE) is a life-threating condition that is common in patients with adult-type diffuse gliomas, yet thromboprophylaxis is controversial because of possible intracerebral hemorrhage. Effective VTE prediction models exist for other cancers, but not glioma. Our objective was to develop a VTE prediction tool to improve glioma patient care, incorporating clinical, blood-based, histologic, and molecular markers. We analyzed preoperative arterial blood, tumor tissue, and clinical-pathologic data (including next-generation sequencing data) from 258 patients with newly diagnosed World Health Organization (WHO) grade 2 to 4 adult-type diffuse gliomas. Forty-six (17.8%) experienced VTE. Tumor expression of tissue factor (TF) and podoplanin (PDPN) each positively correlated with VTE, although only circulating TF and D-dimers, not circulating PDPN, correlated with VTE risk. Gliomas with mutations in isocitrate dehydrogenase 1 (IDH1) or IDH2 (IDHmut) caused fewer VTEs; multivariable analysis suggested that this is due to IDHmut suppression of TF, not PDPN. In a predictive time-to-event model, the following predicted increased VTE risk in newly diagnosed patients with glioma: (1) history of VTE; (2) hypertension; (3) asthma; (4) white blood cell count; (5) WHO tumor grade; (6) patient age; and (7) body mass index. Conversely, IDHmut, hypothyroidism, and MGMT promoter methylation predicted reduced VTE risk. These 10 variables were used to create a web-based VTE prediction tool that was validated in 2 separate cohorts of patients with adult-type diffuse glioma from other institutions. This study extends our understanding of the VTE landscape in these tumors and provides evidence-based guidance for clinicians to mitigate VTE risk in patients with glioma.

Racial and ethnic disparities in surgery for kidney cancer: a SEER analysis, 2007-2014.

BACKGROUND AND OBJECTIVES: Compared with White patients, Black and American Indian/Alaskan Native (AI/AN) patients experience higher rates of kidney cancer incidence, and Black, AI/AN, and Hispanic patients face later stages of disease at diagnosis, poorer survival rates, and greater risk of mortality. Despite the importance that appropriate treatment has in ensuring positive outcomes, little is known about the association between race and ethnicity and receipt of treatment for kidney cancer. Accordingly, the aim of this study was to explore differences in receipt of treatment and patterns of refusal of recommended treatment by race and ethnicity. DESIGN: 96,745 patients ages 45-84 with kidney cancer were identified in the Surveillance, Epidemiology, and End Results (SEER) program between 2007 and 2014. Logistic regression models were used to examine the association of race and ethnicity with treatment and with patient refusal of recommended treatment. Outcomes of interest were (1) receiving any surgical procedure, and (2) refusing recommended surgery. RESULTS: Relative to White patients, Black and AI/AN patients had lower odds of undergoing any surgical procedure (OR = 0.76; 95% CI: 0.72-0.81; p < 0.001, and OR = 0.92; 95% CI: 0.76-1.10; p = 0.36, respectively) after adjusting for gender, age, insurance status, stage at diagnosis, unemployment status, education status, and income as additive effects. Black and AI/AN patients also had higher odds of refusing recommended surgery (OR = 1.93; 95% CI: 1.56-2.39; p < 0.001, and OR = 1.99; 95% CI: 1.05-3.76; p = 0.035, respectively). Hispanic patients had slightly higher odds of undergoing any surgical procedure (OR = 1.10; 95% CI: 1.04-1.17; p = 0.001) and lower odds of refusal (OR = 0.67; 95% CI: 0.50-0.90; p = 0.007, respectively). CONCLUSIONS: Compared with White patients, Black patients were less likely to receive potentially life-saving surgery, and both Black and AI/AN patients were more likely to refuse recommended surgery.

Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial.

BACKGROUND: Malignant glioma is the most common and lethal primary brain tumour, with dismal survival rates and no effective treatment. We examined the safety and activity of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma. METHODS: This was a first-in-human, open-label, phase 1, dose-escalation trial done to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received a dose starting at 6·25 × 1010 viral particles administered by 5·00 × 107 NSCs, the second cohort a dose of 1·25 × 1011 viral particles administered by 1·00 × 108 NSCs, and the third cohort a dose of 1·875 × 1011 viral particles administered by 1·50 × 108 NSCs. No further dose escalation was planned. Within 10-14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT03072134. FINDINGS: Between April 24, 2017, and Nov 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. The median follow-up was 18 months (IQR 14-22). One patient receiving 1·50 × 108 NSCs loading 1·875 × 1011 viral particles developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Otherwise, treatment was safe as no formal dose-limiting toxicity was reached, so 1·50 × 108 NSCs loading 1·875 × 1011 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5-not reached) and median overall survival was 18·4 months (15·7-not reached). INTERPRETATION: NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase 2/3 clinical trial. FUNDING: US National Institutes of Health.

Bridging the gaps: using an NHP model to predict single dose radiation absorption in humans.

Purpose: Design and characterization of a radiation biodosimetry device are complicated by the fact that the requisite data are not available in the intended use population, namely humans exposed to a single, whole-body radiation dose. Instead, one must turn to model systems. We discuss our studies utilizing healthy, unexposed humans, human bone marrow transplant patients undergoing total body irradiation (TBI), non-human primates subjected to the same irradiation regimen received by the human TBI patients and NHPs given a single, whole-body dose of ionizing radiation.Materials and Methods: We use Bayesian linear mixed models to characterize the association between NHP and human expression patterns in radiation response genes when exposed to a common exposure regimen and across exposure regimens within the same species.Results: We show that population average differences in expression of our radiation response genes from one to another model system are comparable to typical differences between two randomly sampled members of a given model system and that these differences are smaller, on average, for linear combinations of the probe data and for the model-based combinations employed for dose prediction as part of a radiation biodosimetry device.Conclusions: Our analysis suggests that dose estimates based on our gene list will be accurate when applied to humans who have received a single, whole-body exposure to ionizing radiation.