Neurogenesis in the subventricular zone and hippocampus following cell therapy in a non-human primate model of cortical damage

Approximately 795,000 Americans experience a new or recurrent stroke each year (American Heart Association 2016; Mozaffarian et al. 2016). However, the only experimental therapeutic to have gained FDA approval for treatment of stroke in humans is the thrombolytic agent tPA that can dissolve clots and restore blood flow, if given within a narrow therapeutic window of a few hours following stroke onset (AHA 2016, Li et al. 2016). Nevertheless, in many cases with or without tPA there is significant residual impairment, and there are currently no FDA approved therapeutic agents that facilitate functional recovery following stroke (Zhang L et al. 2012). Recent studies have suggested that neural plasticity and neurogenesis following stroke may play a role in recovery of function, and promising findings have been demonstrated with cell therapies for enhancing recovery after stroke (Kokaia and Darasalia, 2015; Kozorovitskiy et al, 2013; Zhao et al, 2012). Our recent study (Moore et al. 2013) showed significant recovery of function following a reproducible ischemic lesion limited to the hand representation of the motor cortex in non-human primates (NHPs) treated with the investigational cell drug product CNTO 0007, that contains human umbilical tissue-derived cells (hUTC). While the treatment group in this study demonstrated significantly better recovery of motor function, the mechanism of recovery remains unclear. Previous studies conducted with brain tissue from these monkeys have suggested that functional recovery may be related to cortical reorganization induced by the hUTC treatment. To explore the possibility that neurogenesis may have also played a role in the enhanced recovery, these same monkeys received an injection of the thymidine analog Bromodeoxyuridine (BrdU), which was visualized in the brain tissue to investigate cell proliferation in the subventricular zone and hippocampus. Results show that there is no significant difference in the number of BrdU positive cells in the hUTC treated vs. untreated monkeys, however there is a trend towards significant increase in BrdU labeling in the granule cell layer of the hippocampus of the hUTC treated animals. Clusters of proliferating cells were also found in the GCL of treated monkeys, but not in the untreated monkeys. These findings support the hypothesis that enhanced recovery of function may be related to a combination of reorganization of undamaged cortical motor regions and generation of new cells in the brain

The clinical effectiveness of different surveillance strategies to prevent colorectal cancer in people with intermediate-grade colorectal adenomas: a retrospective cohort analysis, and psychological and economic evaluations

Background: The UK guideline recommends 3-yearly surveillance for patients with intermediate-risk (IR) adenomas. No study has examined whether or not this group has heterogeneity in surveillance needs. Objectives To examine the effect of surveillance on colorectal cancer (CRC) incidence; assess heterogeneity in risk; and identify the optimum frequency of surveillance, the psychological impact of surveillance, and the cost-effectiveness of alternative follow-up strategies. Design: Retrospective multicentre cohort study. Setting: Routine endoscopy and pathology data from 17 UK hospitals (n = 11,944), and a screening data set comprising three pooled cohorts (n = 2352), followed up using cancer registries. Subjects: Patients with IR adenoma(s) (three or four small adenomas or one or two large adenomas). Primary outcomes: Advanced adenoma (AA) and CRC detected at follow-up visits, and CRC incidence after baseline and first follow-up. Methods: The effects of surveillance on long-term CRC incidence and of interval length on findings at follow-up were examined using proportional hazards and logistic regression, adjusting for patient, procedural and polyp characteristics. Lower-intermediate-risk (LIR) subgroups and higher-intermediate-risk (HIR) subgroups were defined, based on predictors of CRC risk. A model-based cost–utility analysis compared 13 surveillance strategies. Between-group analyses of variance were used to test for differences in bowel cancer worry between screening outcome groups (n = 35,700). A limitation of using routine hospital data is the potential for missed examinations and underestimation of the effect of interval and surveillance. Results: In the hospital data set, 168 CRCs occurred during 81,442 person-years (pys) of follow-up [206 per 100,000 pys, 95% confidence interval (CI) 177 to 240 pys]. One surveillance significantly lowered CRC incidence, both overall [hazard ratio (HR) 0.51, 95% CI 0.34 to 0.77] and in the HIR subgroup (n = 9265; HR 0.50, 95% CI 0.34 to 0.76). In the LIR subgroup (n = 2679) the benefit of surveillance was less clear (HR 0.62, 95% CI 0.16 to 2.43). Additional surveillance lowered CRC risk in the HIR subgroup by a further 15% (HR 0.36, 95% CI 0.20 to 0.62). The odds of detecting AA and CRC at first follow-up (FUV1) increased by 18% [odds ratio (OR) 1.18, 95% CI 1.12 to 1.24] and 32% (OR 1.32, 95% CI 1.20 to 1.46) per year increase in interval, respectively, and the odds of advanced neoplasia at second follow-up increased by 22% (OR 1.22, 95% CI 1.09 to 1.36), after adjustment. Detection rates of AA and CRC remained below 10% and 1%, respectively, with intervals to 3 years. In the screening data set, 32 CRCs occurred during 25,745 pys of follow-up (124 per 100,000 pys, 95% CI 88 to 176 pys). One follow-up conferred a significant 73% reduction in CRC incidence (HR 0.27, 95% CI 0.10 to 0.71). Owing to the small number of end points in this data set, no other outcome was significant. Although post-screening bowel cancer worry was higher in people who were offered surveillance, worry was due to polyp detection rather than surveillance. The economic evaluation, using data from the hospital data set, suggested that 3-yearly colonoscopic surveillance without an age cut-off would produce the greatest health gain. Conclusions: A single surveillance benefited all IR patients by lowering their CRC risk. We identified a higher-risk subgroup that benefited from further surveillance, and a lower-risk subgroup that may require only one follow-up. A surveillance interval of 3 years seems suitable for most IR patients. These findings should be validated in other studies to confirm whether or not one surveillance visit provides adequate protection for the lower-risk subgroup of intermediate-risk patients