Discovering rare diseases: chloroma

http://www.ajronline.org/doi/full/10.2214/ajr.178.2.1780319

Granulocytic sarcoma, also known as chloroma or extramedullary myeloblastoma, is a rare solid tumor composed of primitive precursors of the granulocytic series of WBC that include myeloblasts, promyelocytes, and myelocytes [1]. This tumor was first described by Burns in 1811. In 1853, King initially called it chloroma, because typical forms have a green color caused by high levels of myeloperoxidase in these immature cells. Rappaport renamed it granulocytic sarcoma in 1966, because not all of the cells are green; 30% are white, gray, or brown, depending on the state of oxidation of the pigmented enzyme or the different cellular enzyme concentrations [1, 2]. Radiologic descriptions of granulocytic sarcomas are rare in the literature and consist mainly of case reports. The aim of this article is to present an overview of the most common imaging findings of granulocytic sarcoma.

Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome

Objective: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs).

Methods: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing.

Results: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay.

Conclusions: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.
Neurology September 2013

Dedicato ad una Collega

Dedichiamo questa pagina del nostro blog ad una giovane ma brillante Collega che ha dato la vita per la propria professione.
Un esempio per tutti noi. 

Grazie di cuore, Dr.ssa Eleonora.

Evidence-based guideline update: Vagus nerve stimulation for the treatment of epilepsy

Objective: To evaluate the evidence since the 1999 assessment regarding efficacy and safety of vagus nerve stimulation (VNS) for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients >12 years.

Methods: We reviewed the literature and identified relevant published studies. We classified these studies according to the American Academy of Neurology evidence-based methodology.

Results: VNS is associated with a >50% seizure reduction in 55% (95% confidence interval [CI] 50%–59%) of 470 children with partial or generalized epilepsy (13 Class III studies). VNS is associated with a >50% seizure reduction in 55% (95% CI 46%–64%) of 113 patients with Lennox-Gastaut syndrome (LGS) (4 Class III studies). VNS is associated with an increase in ≥50% seizure frequency reduction rates of ∼7% from 1 to 5 years postimplantation (2 Class III studies). VNS is associated with a significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies). Infection risk at the VNS implantation site in children is increased relative to that in adults (odds ratio 3.4, 95% CI 1.0–11.2). VNS is possibly effective for seizures (both partial and generalized) in children, for LGS-associated seizures, and for mood problems in adults with epilepsy. VNS may have improved efficacy over time.

Recommendations: VNS may be considered for seizures in children, for LGS-associated seizures, and for improving mood in adults with epilepsy (Level C). VNS may be considered to have improved efficacy over time (Level C). Children should be carefully monitored for site infection after VNS implantation.

Neurology 2013

L-Selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients

Objective: To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment.

Methods: Patients were recruited from 10 European and US cohorts. Of 289 patients with multiple sclerosis (MS), 224 had been treated with natalizumab (18–80 months), 21 received other immune-modulatory treatments, and 28 were untreated. We had access to samples from 16 natalizumab PML patients. Eight of these patients had given blood before the diagnosis of PML. We also analyzed non-natalizumab-treated patients who developed PML (n = 10) and age- and sex-matched healthy donors (n = 31). All flow cytometric assessments were done on previously cryopreserved, viable peripheral blood mononuclear cells.

Results: The percentage of L-selectin-expressing CD4+ T cells was significantly lower in patients treated long-term with natalizumab (40.2%) when compared with patients not receiving natalizumab treatment (47.2%; p = 0.016) or healthy controls (61.0%; p < 0.0001). An unusually low percentage (9-fold lower; 4.6%) was highly correlated with the risk of developing PML in the patient group with available pre-PML samples when compared with non-PML natalizumab-treated patients (p ≤ 0.0001). Samples were gathered between 4 and 26 months before PML diagnosis.

Conclusions: The cell-based assessment of the percentage of L-selectin-expressing CD4 T cells could provide an urgently needed biomarker for individual PML risk assessment.

Neurology 2013

Breaking News: Mutations in ATXN2 increase the risk of amyotrophic lateral sclerosis

Abstract

CAG repeat expansions in the ataxin-2 gene (ATXN2) cause spinocerebellar ataxia type 2, and could have a role in amyotrophic lateral sclerosis (ALS). Through haplotyping and DNA sequencing in an ALS pedigree, Laffita-Mesa et al.de novoCAG expansions in ATXN2 alleles in three patients with autosomal dominant ALS.

Nature Reviews Neurology 2013

Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome

Introduction

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency characterized by eczema, thrombocytopenia, infections, and a high risk of developing autoimmunity and cancer. In a recent clinical trial, a γ-retroviral vector was used to introduce a functional WAS gene into autologous hematopoietic stem/progenitor cells (HSCs), followed by reinfusion of the gene-corrected HSCs into the patients. This strategy provided clinical benefit but resulted in expansion and malignant transformation of hematopoietic clones carrying vector insertions near oncogenes, thus increasing leukemia risk. We have developed a clinical protocol for WAS based on lentiviral vector (LV) gene transfer into HSCs.

Analysis of common insertion sites (CIS) in gene therapy trials using lentiviral versus γ-retroviral vectors. Word clouds show the intensity of insertion sites clustering in each of the CIS genes (the larger the gene name, the larger the number of insertion sites within or in the proximity of that gene). The names of the CIS genes detected in both gene therapy trials are reported at the intersection between the circles. Analysis of common insertion sites (CIS) in gene therapy trials using lentiviral versus γ-retroviral vectors. Word clouds show the intensity of insertion sites clustering in each of the CIS genes (the larger the gene name, the larger the number of insertion sites within or in the proximity of that gene). The names of the CIS genes detected in both gene therapy trials are reported at the intersection between the circles.

Methods

Three patients with WAS were treated in a phase I/II clinical trial with gene-corrected HSCs after pretreatment with a reduced-intensity myeloablative regimen. Autologous CD34+ cells were transduced with an optimized LV carrying the WAS gene under the control of its endogenous promoter. Patients were monitored for up to 2.5 years after gene therapy by molecular, immunological, and clinical tests. We also investigated the genomic distribution of LV integration sites in the patients’ bone marrow and peripheral blood cell lineages.

Results

Administration of autologous HSCs transduced with LV at high efficiency (>90%) resulted in robust (25 to 50%), stable, and long-term engraftment of gene-corrected HSCs in the patients’ bone marrow. WAS protein expression was detected in myeloid cells at similar rates and in nearly all circulating platelets and lymphoid cells. In vitro T cell proliferative responses, natural killer cell cytotoxic activity, immune synapsis formation, and suppressive function of T regulatory cells were normalized. In all three patients, we observed improved platelet counts, protection from bleeding and severe infections, and resolution of eczema. Vector integration analyses on >35,000 unique insertion sites showed distinct waves of HSC clonal output, resulting in highly polyclonal multilineage hematopoietic reconstitution. In contrast to ©-retroviral gene therapy, our LV-based therapy did not induce in vivo selection of clones carrying integrations near oncogenes. Consistent with this, we did not see evidence of clonal expansions in the patients for up to 20 to 32 months after gene therapy.

Discussion

Our gene transfer protocol provided efficient stem cell transduction in vitro, resulting in robust and stable in vivo gene marking. WAS expression was restored to near-physiological levels in the patients, resulting in immunological and hematological improvement and clinical benefit. Clonal tracking of stem cell dynamics by vector insertions showed details of hematopoietic reconstitution after gene therapy. Comparison with clinical data from ©-retroviral gene therapy in the same disease setting strongly suggests that LV gene therapy offers safety advantages, but a longer follow-up time is needed for validation. Collectively, our findings support the use of LV gene therapy to treat patients with WAS and other hematological disorders.

Science 2013