Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters

Background: Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined. Methodology/Principal Findings: In the present study, we investigated whether experimental ‘jet lag ’ (i.e., phase advances of the light:dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function. Conclusions/Significance: Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learnin

Central zone lesions on magnetic resonance imaging: Should we be concerned?

The Prostate Imaging Reporting and Data System (PI-RADS) score was developed to evaluate lesions in the peripheral and transition zone on multiparametric magnetic resonance imaging (mpMRI) of the prostate. We aim to determine if the PI-RADS scoring system can be used to evaluate central zone lesions on mpMRI. A retrospective review of 73 patients who underwent mpMRI/ultrasound (US) fusion-guided biopsy of 143 suspicious lesions between February 2014 and October 2015 was performed. All patients underwent a 3T mpMRI. Indications for mpMRI included an abnormal digital rectal examination, PSA velocity >0.75ng/dl/y, and patients on active surveillance. The mpMRI sequence involved T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast enhancement. Using 3-dimensional model software (Invivo Corporation, Gainesville, FL, USA), a minimum of 3 magnetic resonance imaging (MRI)/US fusion-guided biopsy samples were taken from each prostate lesion seen on mpMRI irrespective of PI-RADS score, using local anesthesia in an outpatient clinic setting. A total of 73 patients underwent MRI/US fusion-guided biopsy of 85 peripheral zone lesions, 31 transitional zone lesions, and 27 central zone lesions. Only 2 (7%) of central zone lesions were positive for prostate cancer. Both patients had lesions which were graded as PI-RADS 3. Both the patients had multifocal lesions that encompassed≥50% of the central and transition zones on the sagittal view MRI images. Both patients previously had transrectal US-guided biopsy of the prostate which was negative for cancer. Both patients underwent a robotic-assisted laparoscopic prostatectomy, each revealing high-grade cancer. Lesions involving only the central gland/zone seen on MRI are less concerning for malignancy and should not be given equal weight as peripheral zone lesions. In this series, no lesions involving solely the central gland/zone, regardless of PI-RADS score, was positive for malignancy on MRI/US fusion-guided biopsy. Consideration of a modified PI-RADS scoring system should be given to help identify central zone lesions with malignant potential. •Central zone (CZ) lesions are more likely to be benign.•CZ lesions that overlap with the peripheral zone are concerning malignancy.•High PSA values may be a predictor for CZ lesions concerning for malignancy

Multi-parametric MRI guided dose escalated radiotherapy for treatment of localized prostate cancer (PCa): Initial toxicity results of a prospective phase II trial

25 Background: Multi-parametric MRI (mpMRI) of PCa uses advanced sequences to detect aggressive, high grade and bulky lesions. Given known advantages of hypofractionated radiotherapy (RT) to treat PCa (low a/b ratio), we conducted a phase II trial to escalate a high dose to mpMRI lesion(s) via Image-Guided (IG)-RT/Volumetric Arc Therapy (VMAT)/Stereotactic Body Radiotherapy (SBRT) technology. We present the acute toxicity results of this novel approach. Methods: 22 pts with mpMRI lesion(s) were prospectively treated to a course of IGRT/VMAT to the prostate & seminal vesicle +/- pelvic lymph nodes (PLN) to a dose of 45 Gy in 25 fractions followed by SBRT boost, 18 Gy in 3 fraction to the prostate with a simultaneous integrated boost 21 Gy in 3 fractions (EQD2 = 85.2 Gy using a/b 3 or 93.4 Gy using a/b 1.5) to the mpMRI prostatic lesion(s). Placement of 3 polymer based fiducial markers visible in both CT and MRI for image co-registration and treatment guidance was performed. Genitourinary (GU) and gastrointestinal (GI) adverse events (AE) were scored using CTCAE v4. DSMC approved reporting of acute AE results prior to completion of trial accrual as an interim safety assessment prior to final trial accrual. Results: Median age was 66.5 years (range: 57-80). All patients had PI-RADS grade 3-5 mpMRI lesion(s); 41.0%, 45.4% and 13.6% having 1, 2 and 3 lesions respectively. Ten (45%) pts had Gleason Score (GS) 8-10 and 12 had GS 7 disease. Median PSA was 8.97 (range: 4.0-77.9). Eleven (50%), 10 (46%), and 1 (5%) pts had stage T1, T2, and T3 tumor, respectively. Nine pts received treatment to the PLN and 15 received androgen deprivation therapy. All patients completed the protocol treatment without reporting acute GI or GU AEs grade ≥3 during treatment or at follow up. Grade 2 GI (diarrhea) and GU toxicity (frequency) was seen in 2 (9%) and 9 (41%) pts, respectively, during treatment. Of the 16 pts (71%) with least 3 months follow-up all grade 2 GI and 55.5% GU toxicities had resolved. Conclusions: Early results of this prospective Phase II study suggest that high-dose RT for localized PCa via mpMRI-guided RT/VMAT and SBRT boost is tolerable with a favorable acute toxicity profile