Citations

Background: Vedolizumab (VDZ) is a gut-specific α4-β7 integrin antagonist that has demonstrated efficacy in Crohn’s disease (CD) and ulcerative colitis (UC). The safety of VDZ in the perioperative period remains unclear. The aim of this study was to evaluate postoperative complications and perioperative safety in VDZ-treated patients undergoing nonintestinal operations. Methods: A case-matched study was performed at two inflammatory bowel disease (IBD) referral centers. Adult patients with CD and UC who underwent a nonintestinal surgical procedure during treatment with VDZ were included. Patients who had their last VDZ infusion up to 12 weeks before the procedure were considered exposed and were matched in a 1:1 ratio to patients without VDZ therapy, according to type of surgical procedure, age, and sex. The primary outcome was overall risk of early postoperative infectious complications (up to 30 days after surgery), readmissions, reoperations, surgical site infections, and other infections. The VDZ and control groups were subsequently compared using the Pearson χ2 test and Wilcoxon rank sum. Results: We identified 34 patients treated with VDZ who underwent 36 nonintestinal surgical procedures. These patients were matched with 36 control procedures. Postoperative complications were not different between the VDZ-treated and control cohorts for all outcomes analyzed: infectious complications occurred in 14% versus 8% ( p = 0.45), superficial surgical site infections 6% versus 0% ( p = 0.15), reoperations 6% versus 3% ( p = 0.56) and readmissions 11% versus 6% ( p = 0.37). Conclusions: VDZ-treated patients with IBD undergoing nonintestinal procedures did not have an increased risk of overall postoperative infections or other complications compared with matched controls.

Background and Purpose— Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. Methods— We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P <5×10 − 8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0–2 versus 3–6) modified Rankin Scale using ordinal and logistic regression, respectively. Results— The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P =4.4×10 −8 ) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P =4.3×10 −8 ) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 ( P =0.04; meta-analysis P =2.5×10 −9 ; heterogeneity, P =0.16) but not for 22q13 ( P =0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P =0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P =0.045). Conclusions— We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

Abstract Introduction Precision medicine methodologies and approaches have advanced our understanding of the clinical presentation, development, progression, and management of Alzheimer's disease (AD) dementia. However, sex and gender have not yet been adequately integrated into many of these approaches. Methods The Society for Women's Health Research Interdisciplinary Network on AD, comprised of an expert panel of scientists and clinicians, reviewed ongoing and published research related to sex and gender differences in AD. Results The current review is a result of this Network's efforts and aims to: (1) highlight the current state‐of‐the‐science in the AD field on sex and gender differences; (2) address knowledge gaps in assessing sex and gender differences; and (3) discuss 12 priority areas that merit further research. Discussion The exclusion of sex and gender has impeded faster advancement in the detection, treatment, and care of AD across the clinical spectrum. Greater attention to these differences will improve outcomes for both sexes.

SummaryBackgroundPrimary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic biliary disease associated with inflammatory bowel disease (IBD) with no known cure.AimTo evaluate the effect of biological therapies on PSC progression in IBD patients.MethodsWe performed a retrospective cohort study of 88 cases (75 unique patients with 12 patients treated >1 biologics) of IBD (48 ulcerative colitis, 24 Crohn's disease and 3 indeterminate colitis) with concomitant PSC who received biological therapy (42 infliximab, 19 adalimumab, 27 vedolizumab) between June 2002 and October 2017. Hepatic biochemistries were compared using the paired t‐test (patients served as their own controls) ≤3 months before and 6‐8 and 12‐14 months after biological initiation. Radiographic information of biliary stenosis and liver fibrosis were obtained via abdominal ultrasound, abdominal magnetic resonance imaging and magnetic resonance elastography.ResultsUse of adalimumab was associated with a significant decrease in alkaline phosphatase (ALP) after 6‐8 months (P = 0.03; mean change −70 U/L, standard deviation [SD] 88 U/L) compared to vedolizumab (mean change +50 U/L, SD 142 U/L) or infliximab (mean change +37 U/L, SD 183 U/L) but the change was not significant after 12‐14 months (P = 0.24). No significant decreases were observed with AST, ALT, total or direct bilirubin, elastography score or radiographic imaging of biliary tree dilation/strictures with any biological therapy after 6‐8 or 12‐14 months.ConclusionsCurrent evidence suggests that biological therapies used for the treatment of IBD are not effective treatments for PSC. Further study is needed to elucidate any potential beneficial effect of adalimumab on PSC.

AbstractIntroductionIntrathecal interleukin (IL)‐10 delivered by plasmid or viral gene vectors has been proposed for clinical testing because it is effective for chronic pain in rodents, is a potential therapeutic for various human diseases, and was found to be nontoxic in dogs, when the human IL‐10 ortholog was tested. However, recent studies in swine testing porcine IL‐10 demonstrated fatal neurotoxicity. The present study aimed to deliver vector‐encoded human IL‐10 in swine, measure expression of the transgene in cerebrospinal fluid and monitor animals for signs of neurotoxicity.ResultsHuman IL‐10 levels peaked 2 weeks after vector administration followed by a rapid decline that occurred concomitant with the emergence of anti‐human IL‐10 antibodies in the cerebrospinal fluid and serum. Animals remained neurologically healthy throughout the study period.ConclusionsThe findings of the present study suggest that swine are not idiosyncratically sensitive to intrathecal IL‐10 because, recapitulating previous reports in dogs, they suffered no clinical neurotoxicity from the human ortholog. These results strongly infer that toxicity of intrathecal IL‐10 in large animal models was previously overlooked because of a species mismatch between transgene and host. The present study further suggests that swine were protected from interleukin‐10 by a humoral immune response against the xenogeneic cytokine. Future safety studies of IL‐10 or related therapeutics may require syngeneic large animal models.

Abstract Purpose: Virotherapies are maturing in the clinical setting. Adenoviruses (Ad) are excellent vectors for the manipulability and tolerance of transgenes. Poor tumor selectivity, off-target sequestration, and immune inactivation hamper clinical efficacy. We sought to completely redesign Ad5 into a refined, tumor-selective virotherapy targeted to αvβ6 integrin, which is expressed in a range of aggressively transformed epithelial cancers but nondetectable in healthy tissues. Experimental Design: Ad5NULL-A20 harbors mutations in each major capsid protein to preclude uptake via all native pathways. Tumor-tropism via αvβ6 targeting was achieved by genetic insertion of A20 peptide (NAVPNLRGDLQVLAQKVART) within the fiber knob protein. The vector's selectivity in vitro and in vivo was assessed. Results: The tropism-ablating triple mutation completely blocked all native cell entry pathways of Ad5NULL-A20 via coxsackie and adenovirus receptor (CAR), αvβ3/5 integrins, and coagulation factor 10 (FX). Ad5NULL-A20 efficiently and selectively transduced αvβ6+ cell lines and primary clinical ascites-derived EOC ex vivo, including in the presence of preexisting anti-Ad5 immunity. In vivo biodistribution of Ad5NULL-A20 following systemic delivery in non–tumor-bearing mice was significantly reduced in all off-target organs, including a remarkable 107-fold reduced genome accumulation in the liver compared with Ad5. Tumor uptake, transgene expression, and efficacy were confirmed in a peritoneal SKOV3 xenograft model of human EOC, where oncolytic Ad5NULL-A20–treated animals demonstrated significantly improved survival compared with those treated with oncolytic Ad5. Conclusions: Oncolytic Ad5NULL-A20 virotherapies represent an excellent vector for local and systemic targeting of αvβ6-overexpressing cancers and exciting platforms for tumor-selective overexpression of therapeutic anticancer modalities, including immune checkpoint inhibitors. Clin Cancer Res; 24(17); 4215–24. ©2018 AACR.