A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Evaluating Transcranial Photobiomodulation as Treatment for Concussion.

INTRODUCTION: Literature indicating that transcranial photobiomodulation (tPBM) may enable the brain to recover normal function after concussion, resulting in symptoms reduction, and improved cognitive function after concussion is limited by small sample sizes and lack of controls. METHODS: We conducted a randomized, double-blind, placebo-controlled trial examining the effect of 6 wk of tPBM in patients 11 yr or older who received care for persistent postconcussion symptoms between September 2012 and December 2015. Our primary outcome measure was the mean difference in Postconcussion Symptom Scale total score and the raw Immediate Postconcussion Assessment and Cognitive Testing composite scores between study entry and treatment completion. Participants received two, 10-min sessions either with tPBM units or via two placebo units, three times per week. We screened for potential confounding variables using univariable analyses. We entered covariables that differed between the two groups on univariable screening into a regression analysis. We considered adjusted odds ratio that did not cross one statistically significant. RESULTS: Forty-eight participants completed the study. Most were female (63%), and a majority sustained their injury during sports or exercise (71%). Despite randomization, those that received tPBM therapy reported a greater number of previous concussions. After adjusting for the effect of previous concussions and multiple comparisons, there were no significant differences between tPBM and placebo groups at 3 or 6 wk of treatment. CONCLUSIONS: Despite showing promise in previous investigations, our study did not show benefit to tPBM over placebo therapy in patients experiencing persistent postconcussion symptoms. Further investigation is needed to determine if varying the dose or timing alters the efficacy of tPBM after concussion.

Oncologic Outcomes of Definitive Treatments for Low- and Intermediate-Risk Prostate Cancer After a Period of Active Surveillance.

BACKGROUND: To compare oncologic outcomes of different definitive treatment (DT) modalities in a cohort of patients with prostate cancer (PCa) after active surveillance (AS). METHODS: We identified 237 patients with National Comprehensive Cancer Network (NCCN) low- and intermediate-risk prostate cancer diagnosed from 1990 to 2012 who did not undergo immediate DT within 12 months of diagnosis (ie, AS patients as well as watchful waiting and those refusing DT). Charts were examined for clinical/pathologic data and type of DT: surgery (RP), radiation including brachytherapy (XRT), cryotherapy, and androgen deprivation therapy monotherapy (ADT). The impact of DT on oncologic outcomes of biochemical recurrence (BCR), metastasis, disease-specific (DSS), and overall survival (OS) was examined with the Cox proportional hazards model, along with the Kaplan-Meier method and log-rank test. RESULTS: After median time on AS of 63.4 months, 40% of patients underwent DT: 47% XRT, 28% RP, 14% ADT, and 11% cryotherapy. On multivariable analysis, the use of XRT predicted higher BCR (hazard ratio [HR] 6.1, P = .001) and worse overall mortality (HR 2.1, P = .03) compared with other treatments, controlling for age, Charlson Comorbidity Index (CCI), stage, Gleason score, and NCCN risk category. Median follow-up was 71.7 months. On Kaplan-Meier analysis, 10-year OS was superior for RP versus XRT among patients with prostatic specific antigen (PSA) velocity >2.0 ng/mL/y. CONCLUSIONS: Low- and intermediate-risk patients with PCa who progress to DT after AS may be inadequately treated with radiation therapy compared with other DT modalities, especially when pretreatment PSA velocity is > 2 ng/mL/y.

Low-level laser therapy for closed-head traumatic brain injury in mice: effect of different wavelengths.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) affects millions worldwide and is without effective treatment. One area that is attracting growing interest is the use of transcranial low-level laser therapy (LLLT) to treat TBI. The fact that near-infrared light can penetrate into the brain would allow non-invasive treatment to be carried out with a low likelihood of treatment-related adverse events. LLLT may treat TBI by increasing respiration in the mitochondria, causing activation of transcription factors, reducing inflammatory mediators and oxidative stress, and inhibiting apoptosis. STUDY DESIGN/MATERIALS AND METHODS: We tested LLLT in a mouse model of closed-head TBI produced by a controlled weight drop onto the skull. Mice received a single treatment with continuous-wave 665, 730, 810, or 980 nm lasers (36 J/cm(2) delivered at 150 mW/cm(2)) 4-hour post-TBI and were followed up by neurological performance testing for 4 weeks. RESULTS: Mice with moderate-to-severe TBI treated with 665 and 810 nm laser (but not with 730 or 980 nm) had a significant improvement in Neurological Severity Score that increased over the course of the follow-up compared to sham-treated controls. Morphometry of brain sections showed a reduction in small deficits in 665 and 810 nm laser treated mouse brains at 28 days. CONCLUSIONS: The effectiveness of 810 nm agrees with previous publications, and together with the effectiveness of 660 nm and non-effectiveness of 730 and 980 nm can be explained by the absorption spectrum of cytochrome oxidase, the candidate mitochondrial chromophore in transcranial LLLT.

Low-level laser light therapy improves cognitive deficits and inhibits microglial activation after controlled cortical impact in mice.

Low-level laser light therapy (LLLT) exerts beneficial effects on motor and histopathological outcomes after experimental traumatic brain injury (TBI), and coherent near-infrared light has been reported to improve cognitive function in patients with chronic TBI. However, the effects of LLLT on cognitive recovery in experimental TBI are unknown. We hypothesized that LLLT administered after controlled cortical impact (CCI) would improve post-injury Morris water maze (MWM) performance. Low-level laser light (800 nm) was applied directly to the contused parenchyma or transcranially in mice beginning 60-80 min after CCI. Injured mice treated with 60 J/cm² (500 mW/cm²×2 min) either transcranially or via an open craniotomy had modestly improved latency to the hidden platform (p<0.05 for group), and probe trial performance (p<0.01) compared to non-treated controls. The beneficial effects of LLLT in open craniotomy mice were associated with reduced microgliosis at 48 h (21.8±2.3 versus 39.2±4.2 IbA-1+ cells/200×field, p<0.05). Little or no effect of LLLT on post-injury cognitive function was observed using the other doses, a 4-h administration time point and 7-day administration of 60 J/cm². No effect of LLLT (60 J/cm² open craniotomy) was observed on post-injury motor function (days 1-7), brain edema (24 h), nitrosative stress (24 h), or lesion volume (14 days). Although further dose optimization and mechanism studies are needed, the data suggest that LLLT might be a therapeutic option to improve cognitive recovery and limit inflammation after TBI.

Expression of cellular FLICE inhibitory proteins (cFLIP) in normal and traumatic murine and human cerebral cortex.

Cellular Fas-associated death domain-like interleukin-1-beta converting enzyme (FLICE) inhibitory proteins (cFLIPs) are endogenous caspase homologues that inhibit programmed cell death. We hypothesized that cFLIPs are differentially expressed in response to traumatic brain injury (TBI). cFLIP-alpha and cFLIP-delta mRNA were expressed in normal mouse brain-specifically cFLIP-delta (but not cFLIP-alpha) protein was robustly expressed. After controlled cortical impact (CCI), cFLIP-alpha expression increased initially then decreased to control levels at 12 h, increasing again at 24-72 h (P<0.05). cFLIP-delta expression was decreased in brain homogenates by 12 h after CCI, then increased again at 24 to 72 h (P<0.05). cFLIP-delta immunostaining was markedly reduced in injured cortex, but not hippocampus, at 3 to 72 h after CCI. In cortex, reduced cFLIP-delta staining was found in TUNEL-positive cells, but in hippocampus TUNEL-positive cells expressed cFLIP-delta immunoreactivity. cFLIP-delta was increased in a subset of reactive astrocytes in pericontusional cortex and hippocampus at 48 to 72 h. Low levels of both cFLIP isoforms were detected in human cortical tissue with no TBI, from four patients undergoing brain surgery for epilepsy and <24 h post mortem from three patients without CNS pathologic assessment. In cortical tissue surgically removed <18 h after severe TBI (n=3), cFLIP-alpha expression was increased relative to epilepsy controls (P<0.05) but not relative to post-mortem controls. The data suggest differential spatial and temporal regulation of cFLIP-alpha and cFLIP-delta expression that may influence the magnitude of cell death and further implicate programmed mechanisms of cell death after TBI.

Effect of granulocyte colony-stimulating factor on functional and histopathologic outcome after traumatic brain injury in mice.

OBJECTIVE: Granulocyte colony-stimulating factor has been used to reduce the risk of sepsis in patients with traumatic brain injury. However, granulocyte colony-stimulating factor exerts potent pro- and anti-inflammatory effects that could influence secondary injury, and outcome, after traumatic brain injury. Our objective was to determine the effect of granulocyte colony-stimulating factor on histopathologic, motor, and cognitive outcome after experimental traumatic brain injury in mice. DESIGN: Experimental study. SETTING: Research laboratory at the Massachusetts General Hospital, Boston, MA. SUBJECTS: Forty-eight adult male C57Bl/6 mice. INTERVENTIONS: Mice (8 wks of age, n = 16/group) were administered granulocyte colony-stimulating factor or saline subcutaneously twice per day for 7 days after controlled cortical impact or sham injury (n = 16). Absolute neutrophil counts, motor function, Morris water maze performance, and lesion volume were determined after controlled cortical impact or sham injury. MEASUREMENTS AND MAIN RESULTS: At the time of controlled cortical impact, body weight, brain and body temperature, and systemic absolute neutrophil counts did not differ between groups. Compared with control, systemic absolute neutrophil count was increased more than ten-fold in granulocyte colony-stimulating factor-treated mice on posttrauma days 2 and 7 (p < .05, repeated-measures analysis of variance) but did not differ between groups by day 14. There were no differences between groups in tests of motor function or histopathologic outcome. However, compared with control, mice given granulocyte colony-stimulating factor had improved Morris water maze performance after controlled cortical impact (p < .05, repeated-measures analysis of variance) but not sham injury. CONCLUSIONS: The data suggest a small beneficial effect of granulocyte colony-stimulating factor on functional outcome after traumatic brain injury in adult mice but do not show differences in histopathology or motor outcome between treated and control groups.