Continuous ASL perfusion fMRI investigation of higher cognition: Quantification of tonic CBF changes during sustained attention and working memory tasks

Arterial spin labeling (ASL) perfusion fMRI is an emerging method in clinical neuroimaging. Its non-invasiveness, absence of low frequency noise, and ability to quantify the absolute level of cerebral blood flow (CBF) make the method ideal for longitudinal designs or low frequency paradigms. Despite the usefulness in the study of cognitive dysfunctions in clinical populations, perfusion activation studies to date have been conducted for simple sensorimotor paradigms or with single-slice acquisition, mainly due to technical challenges. Using our recently developed amplitude-modulated continuous ASL (CASL) perfusion fMRI protocol, we assessed the feasibility of a higher level cognitive activation study in twelve healthy subjects. Taking advantage of the ASL noise properties, we were able to study tonic CBF changes during uninterrupted 6-min continuous performance of working memory and sustained attention tasks. For the visual sustained attention task, regional CBF increases (6–12 ml/100 g/min) were detected in the right middle frontal gyrus, the bilateral occipital gyri, and the anterior cingulate/medial frontal gyri. During the 2-back working memory task, significantly increased activations (7–11 ml/100 g/min) were found in the left inferior frontal/precentral gyri, the left inferior parietal lobule, the anterior cingulate/medial frontal gyri, and the left occipital gyrus. Locations of activated and deactivated areas largely concur with previous PET and BOLD fMRI studies utilizing similar paradigms. These results demonstrate that CASL perfusion fMRI can be successfully utilized for the investigation of the tonic CBF changes associated with high level cognitive operations. Increased applications of the method to the investigation of cognitively impaired populations are expected to follow

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Statin Medications Are Associated With a Lower Probability of Having an Abnormal Screening Prostate-specific Antigen Result

ObjectiveTo investigate how statin use is associated with the probability of having an abnormal screening prostate-specific antigen (PSA) result according to common PSA thresholds for biopsy (&gt;2.5, &gt;4.0, and &gt;6.5 ng/mL).MethodsWe conducted a cross-sectional study of 323,426 men aged ≥65 years who had a screening PSA test in 2003 at a Veterans Affairs facility. The primary predictor was the use of statin medications at the time of index screening PSA test. The main outcome was the screening PSA value. Poisson regressions were performed to calculate adjusted relative risks for having an abnormal screening PSA result according to statin usage.ResultsPercentages of men with PSA results exceeding commonly used thresholds of &gt;2.5, &gt;4.0, and &gt;6.5 ng/mL were 21.0%, 7.6%, and 1.6%, respectively. These percentages decreased with statin use, increasing statin dose, duration of statin use, and potency of the statin. For example, after adjusting for age, the percentage of men having a PSA level &gt;4.0 ng/mL ranged from 8.2% in non-statin users to 6.2% in men prescribed with &gt;40 mg of simvastatin dose. Adjusted relative risks of having a PSA level &gt;4.0 ng/mL were 0.89 (95% confidence interval [CI], 0.86-0.93), 0.87 (95% CI, 0.84-0.91), and 0.83 (95% CI, 0.80-0.87), respectively for men on simvastatin dose of 5-20, &gt;20-40, and &gt;40 mg vs non-statin users.ConclusionStatin use is associated with a reduction in the probability that an older man will have an abnormal screening PSA result, regardless of the PSA threshold. This reduction is more pronounced with higher statin dose, longer statin duration, and higher statin potency

Age, comorbidity, life expectancy, and pulmonary nodule follow-up in older veterans

<div><p>Background</p><p>Pulmonary nodule guidelines do not indicate how to individualize follow-up according to comorbidity or life expectancy.</p><p>Objectives</p><p>To characterize comorbidity and life expectancy in older veterans with incidental, symptom-detected, or screen-detected nodules in 2008–09 compared to 2013–14. To determine the impact of these patient factors on four-year nodule follow-up among the 2008–09 subgroup.</p><p>Design</p><p>Retrospective cohort study.</p><p>Setting</p><p>Urban Veterans Affairs Medical Center.</p><p>Participants</p><p>243 veterans age ≥65 with newly diagnosed pulmonary nodules in 2008–09 (followed for four years through 2012 or 2013) and 446 older veterans diagnosed in 2013–14.</p><p>Measurements</p><p>The primary outcome was receipt of any follow-up nodule imaging and/or biopsy within four years after nodule diagnosis. Primary predictor variables included age, Charlson-Deyo Comorbidity Index (CCI), and life expectancy. Favorable life expectancy was defined as age 65–74 with CCI 0 while limited life expectancy was defined as age ≥85 with CCI ≥1 or age ≥65 with CCI ≥4. Interaction by nodule size was also examined.</p><p>Results</p><p>From 2008–09 to 2013–14, the number of older veterans diagnosed with new pulmonary nodules almost doubled, including among those with severe comorbidity and limited life expectancy. Overall among the 2008–09 subgroup, receipt of nodule follow-up decreased with increasing comorbidity (CCI ≥4 versus 0: adjusted RR 0.61, 95% CI 0.39–0.95) with a trend towards decreased follow-up among those with limited life expectancy (adjusted RR 0.69, 95% CI 0.48–1.01). However, we detected an interaction effect with nodule size such that comorbidity and life expectancy were associated with decreased follow-up only among those with nodules ≤6 mm.</p><p>Conclusions</p><p>We found some individualization of pulmonary nodule follow-up according to comorbidity and life expectancy in older veterans with smaller nodules only. As increased imaging detects nodules in sicker patients, guidelines need to be more explicit about how to best incorporate comorbidity and life expectancy to maximize benefits and minimize harms for patients with nodules of all sizes.</p></div

Patient and baseline pulmonary nodule characteristics in veterans age ≥65 with newly diagnosed pulmonary nodule(s) by diagnosis year group (N = 689).

<p>Patient and baseline pulmonary nodule characteristics in veterans age ≥65 with newly diagnosed pulmonary nodule(s) by diagnosis year group (N = 689).</p