Citations

Background: To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported. Objective: To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical–scientific integrity. Methods: We assessed the “standard of care” for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design. Results: The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide. Conclusion: The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path.

Background: Different clinical syndromes can arise from Alzheimer’s disease (AD) neuropathology, including dementia of the Alzheimer’s type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA). Objective: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD. Methods: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups. Results: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum. Conclusion: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology.

Abstract Purpose: There is a clear need to improve risk stratification and to identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets. Experimental Design: We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4 years). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score. Results: Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell-cycle progression signature, and CAPRA-S). Conclusions: To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes. Clin Cancer Res; 22(7); 1777–86. ©2015 AACR.

Injection of autologous adipose tissue removed via liposuction has been used clinically for facial contouring, the aging face, furrows, facial atrophy, acne scars, nasolabial folds, chin, and various other surgical defects. Survival rates for autografts of fat have been quoted anywhere from 30% to 80%. Our study uses a reproducible rabbit animal model for autotransplantation of adipose tissue and examines the histopathologic changes that occur to the graft over time. Autogenous subcutaneous fat was removed from a dorsal scapular donor site, treated to stimulate cannula damage as in liposuction, then reinjected at the base of the ear. Histologic examination of the grafts were made at 5, 10, 15, 20, 40, and 100 days after transplantation. Hematoxylin‐eosin sections were graded on degree of fibrosis present (0 to 4+), viable fat (1 to 10), degree of inflammation (0 to 4+), and neovascularization (+ or ‐). Viability of fat decreased from 8.5 to 10 at 5 days to 2 viability at 40 days. Acute inflammation peaked at 10 days, followed by the chronic inflammatory response with macrophages and multinucleated giant cells scavenging the dying fat graft. Neovascularization began at 5 days, peaked at 10 days, and remained constant thereafter only at the edge of the graft. Microcysts appeared at 15 days and increased in number in proportion to the decrease in viable fat. In summary, the temporal histologic events are progressive fibrosis; decreased amount of viable fat; inflammation beginning with a neutrophilic response, later a macrophage and giant cell response; and neovascularization at the periphery of the graft insufficient to maintain graft viability. In our animal model, autografts of fat appear to have limited long‐term viability and are replaced by fibrous tissue. This may have clinical implications in autografting of fat in facial plastic and reconstructive surgery.

Objectives/HypothesisThe primary goals of microsurgery for vestibular schwannoma (VS) include preservation of neural function and complete tumor removal. In a subset of patients, adherent tumor remnant may be intentionally left behind in order to minimize risk of new neurologic deficits. It is not well established if residual tumor volume predicts likelihood of tumor remnant growth.MethodsPatients with sporadic VS who underwent near‐total (NTR) or subtotal (STR) VS resection between 2000 and 2014 were reviewed. Postoperative tumor remnants were volumetrically contoured using T1‐weighted gadolinium‐enhanced magnetic resonance imaging obtained within 3 months of surgery.ResultsA total of 103 patients met study criteria, and the median duration of radiographic follow‐up was 41 months (mean 56.1 months, range 12–150 months). Fifty patients underwent NTR and 53 received STR. Overall 14 (13.6%) tumors recurred at a median of 41.0 months. Patients who underwent STR were over 13 times more likely to recur compared with those treated with NTR (hazard ratio 13.31; 95% confidence interval 1.71–103.91; P = 0.014). The median time to recurrence following NTR was 124 months compared to 32 months after STR (P < 0.001).ConclusionsLong‐term follow‐up in patients undergoing incomplete resection is essential. Near‐total resection has a significantly lower rate of recurrence compared to STR. Maximal surgical resection should be the goal in VS microsurgery. The decision to pursue less than complete resection should be based on intraoperative impression, when it is felt that continued dissection of adherent disease would compromise neurologic outcome.Level of Evidence4. Laryngoscope, 126:1877–1882, 2016

AbstractBackgroundThe pemphigus group is characterized by the presence of circulating immunoglobulins against desmosomes. IgG/IgA pemphigus is defined by the presence of IgG and IgA cell surface deposits upon direct immunofluorescence (DIF) and/or circulating IgG and IgA autoantibodies upon indirect immunofluorescence. Previous reports of patients with IgG/IgA pemphigus are sparse. Whether IgG/IgA pemphigus is best classified as a subtype of IgG (classic) pemphigus or IgA pemphigus, or as a distinct entity, has yet to be determined.ObjectivesWe compared the features of patients with IgG/IgA pemphigus to those of IgG pemphigus and IgA pemphigus.MethodsRetrospective clinicopathologic study of patients with IgG, IgG/IgA, and IgA pemphigus evaluated at our clinic (1993–2013).ResultsWe included 26, 13, and seven patients with IgG, IgG/IgA, and IgA pemphigus, respectively. Patients with IgG/IgA pemphigus did not differ significantly from patients with IgG pemphigus in terms of clinical and microscopic features, DIF findings, anti‐desmoglein antibody values, and treatments required. However, patients with IgG/IgA pemphigus were significantly different from patients with IgA pemphigus regarding intertriginous distribution (P = 0.038) and pustular lesions (P < 0.001), acantholysis (P = 0.043), and presence of intercellular C3 deposits on DIF (P < 0.001).ConclusionComparative clinicopathologic data imply that IgG/IgA pemphigus may best be regarded as a variant of IgG pemphigus and distinct from IgA pemphigus.

Abstract Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. Cancer Discov; 6(2); 154–65. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109