Making Waves in the Brain: What Are Oscillations, and Why Modulating Them Makes Sense for Brain Injury.

Traumatic brain injury (TBI) can result in persistent cognitive, behavioral and emotional deficits. However, the vast majority of patients are not chronically hospitalized; rather they have to manage their disabilities once they are discharged to home. Promoting recovery to pre-injury level is important from a patient care as well as a societal perspective. Electrical neuromodulation is one approach that has shown promise in alleviating symptoms associated with neurological disorders such as in Parkinson's disease (PD) and epilepsy. Consistent with this perspective, both animal and clinical studies have revealed that TBI alters physiological oscillatory rhythms. More recently several studies demonstrated that low frequency stimulation improves cognitive outcome in models of TBI. Specifically, stimulation of the septohippocampal circuit in the theta frequency entrained oscillations and improved spatial learning following TBI. In order to evaluate the potential of electrical deep brain stimulation for clinical translation we review the basic neurophysiology of oscillations, their role in cognition and how they are changed post-TBI. Furthermore, we highlight several factors for future pre-clinical and clinical studies to consider, with the hope that it will promote a hypothesis driven approach to subsequent experimental designs and ultimately successful translation to improve outcome in patients with TBI

Characterization of Inpatient Moyamoya in the United States: 1988–2004

Background and Purpose: Moyamoya disease has been classically described by the Asian experience, yet clinical aspects of moyamoya phenomena in the United States remain vastly undefined. The multifocal occlusive arterial disorder may be linked with numerous conditions; however, later stages of this syndrome share common vascular pathophysiology. This study is aimed at characterizing inpatient moyamoya cases in the United States over a broad time span. Methods: A comprehensive analysis of the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project (Releases 1–13, 1988–2004) based on ICD-9-CM code 437.5 was performed. Annual percentages and trends analyses were conducted for demographic variables, admission characteristics, co-morbidities, and procedures. Result: 2247 admissions of moyamoya cases were analyzed from a wide geographic distribution throughout the United States between 1988 and 2004. Age at admission varied considerably (mean 29.6 ± 18.5 years), affecting women more frequently than men (61.9%). Various racial groups were identified (35.4% White, 19.7% African American, 5.6% Hispanic, 8.3% Asian or Pacific Islander, 1.4% Native American). Admissions were typically emergent (38.8%) or urgent (18.7%), although elective admissions occurred (24.4%). Aside from moyamoya, sickle cell disease was diagnosed in 13.6%, ischemic stroke in 20.7%, intracerebral hemorrhage in 7.4%, transient ischemic attack in 3.4%, and subarachnoid hemorrhage in 3.1%. Cerebral angiography was performed in 24.9% while extracranial–intracranial bypass was done in 8.4% of patients. Conclusion: Moyamoya in the United States is a heterogeneous condition affecting individuals of all ages across a diverse racial spectrum and wide geographic distribution. Further recognition of moyamoya syndrome may facilitate ongoing research and future therapeutic approaches

Stereotactic guidance for navigated percutaneous sacroiliac joint fusion.

Arthrodesis of the sacroiliac joint (SIJ) for surgical treatment of SIJ dysfunction has regained interest among spine specialists. Current techniques described in the literature most often utilize intraoperative fluoroscopy to aid in implant placement; however, image guidance for SIJ fusion may allow for minimally invasive percutaneous instrumentation with more precise implant placement. In the following cases, we performed percutaneous stereotactic navigated sacroiliac instrumentation using O-arm® multidimensional surgical imaging with StealthStation® navigation (Medtronic, Inc. Minneapolis, MN). Patients were positioned prone and an image-guidance reference frame was placed contralateral to the surgical site. O-arm® integrated with StealthStation® allowed immediate auto-registration. The skin incision was planned with an image-guidance probe. An image-guided awl, drill and tap were utilized to choose a starting point and trajectory. Threaded titanium cage(s) packed with autograft and/or allograft were then placed. O-arm® image-guidance allowed for implant placement in the SIJ with a small skin incision. However, we could not track the cage depth position with our current system, and in one patient, the SIJ cage had to be revised secondary to the anterior breach of sacrum

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

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