CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment.

PURPOSE: Glioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of cancer stem cells (CSCs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here, we identify CD70 as a potential therapeutic target for recurrent GBM CSCs. EXPERIMENTAL DESIGN: In the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We use CD70 knockdown studies, subsequent RNAseq pathway analysis, and in vivo xenotransplantation to validate CD70's role in GBM. Next, we developed and tested an anti-CD70 chimeric antigen receptor (CAR)-T therapy, which we validated in vitro and in vivo using our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples. RESULTS: CD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicity in vitro and in vivo. CD70 CAR-T therapy significantly improves prognosis in vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations, notably putative M1 macrophages and CD4 T cells. CONCLUSION: CD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable polytherapeutic avenue to co-target both GBM and its TIME.

Can the complete blood count be used as a reliable screening tool for obstructive sleep apnea?

PURPOSE: Since hypoxia increases erythropoietin production and inflammation, the complete blood count (CBC) has been proposed as an inexpensive alternative for obstructive sleep apnea (OSA) screening. The objective of this study was to determine whether or not intermittent hypoxia and OSA severity, as measured by the mean oxygen saturation (SpO2) and apnea-hypopnea index (AHI), affect parameters measured by the CBC. METHODS: This retrospective study included a total of 941 surgical patients who had a pre-operative home sleep study. The pre-operative CBC was extracted from the electronic patient records. Patients were stratified according to their AHI scores, into mild (AHI ≥ 5 - < 15), moderate (AHI ≥ 15 - < 30), and severe (AHI ≥ 30) OSA groups. RESULTS: There were 244 patients without OSA, 294 with mild, 223 with moderate, and 180 with severe OSA. Our analysis showed that hemoglobin (P = 0.010), hematocrit (P = 0.027), and basophils (P = 0.006) showed significant changes among the different severities of OSA. For mean SpO2, there were negative associations with body mass index (r = - 0.287; P < 0.001), age (r = - 0.077; P = 0.021), hemoglobin (r = - 0.208; P < 0.001), hematocrit (r = - 0.220; P < 0.001), red blood cells (r = - 0.107; P = 0.001), mean corpuscular volume (MCV) (r = - 0.159; P < 0.001), mean corpuscular hemoglobin (r = - 0.142; P < 0.001), and basophils (r = - 0.091; P = 0.007). All analyzed parameters remained within normal clinical range. Multivariable regression identified hemoglobin, MCV, and basophils to be independent predictors of mean SpO2 and AHI. CONCLUSION: Hemoglobin, MCV, and basophils were independently associated with intermittent hypoxia defined by mean SpO2 and AHI. Adding CBC parameters to other screening tools for OSA may have additional value due to its association with changes in mean SpO2.

The prevalence of obstructive sleep apnea in mild cognitive impairment: a systematic review.

BACKGROUND: Previous studies have shown that obstructive sleep apnea (OSA) is associated with a higher risk of cognitive impairment or dementia in the elderly, leading to deleterious health effects and decreasing quality of life. This systematic review aims to determine the prevalence of OSA in patients with mild cognitive impairment (MCI) and examine whether an association between OSA and MCI exists. METHODS: We searched Medline, PubMed, Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsychINFO, Scopus, the Web of Science, ClinicalTrials.gov and the International Clinical Trials Registry Platform for published and unpublished studies. We included studies in adults with a diagnosis of MCI that reported on the prevalence of OSA. Two independent reviewers performed the abstract and full-text screening, data extraction and the study quality critical appraisal. RESULTS: Five studies were included in the systematic review. Overall, OSA prevalence rates in patients with MCI varied between 11 and 71% and were influenced by OSA diagnostic methods and patient recruitment locations (community or clinic based). Among studies using the following OSA diagnostic measures- self-report, Home Sleep Apnea Testing, Berlin Questionnaire and polysomnography- the OSA prevalence rates in MCI were 11, 27, 59 and 71%, respectively. In a community-based sample, the prevalence of OSA in patients with and without MCI was 27 and 26%, respectively. CONCLUSIONS: Based on limited evidence, the prevalence of OSA in patients with MCI is 27% and varies based upon OSA diagnostic methods and patient recruitment locations. Our findings provide an important framework for future studies to prospectively investigate the association between OSA and MCI among larger community-based cohorts and implement a standardized approach to diagnose OSA in memory clinics. PROSPERO REGISTRATION: CRD42018096577.