Intracerebral hemorrhage in CADASIL.

BACKGROUND: Intracerebral hemorrhage (ICH) has been reported in few cases of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), mostly in hypertensive patients. We aimed to assess the clinical and radiological characteristics of patients with CADASIL who presented with ICH. METHODS: A retrospective analysis of all neuroimaging exams of CADASIL patients hospitalized in our academic neurology department for acute cerebrovascular events was performed to find ICH. A systematic review of the literature was performed on this topic. RESULTS: Including our five patients, a total number of 52 subjects with CADASIL and ICH (mean age: 56 years, SD 11, 36-69%- male) were reported. Intracerebral hemorrhages were mainly deep (34 subjects), followed by lobar (8 subjects), infratentorial (6 subjects) and mixed locations (4 subjects). Three ICHs were asymptomatic. Fourteen patients were taking antithrombotic medication, 18 had no regular antiplatelet or anticoagulant treatment while in 20 patients medical treatment was not detailed. Arterial hypertension was present in 37 out of 51 patients with available information. Neuroimaging showed extensive FLAIR hyperintensities in all CADASIL subjects with ICH, cerebral microbleeds in all but three patients, and lacunar infarction in 19 out of 25 subjects with available information. CONCLUSIONS: Intracerebral hemorrhage represents a possible yet uncommon manifestation of CADASIL and should be considered as a possibility in patients with ICH associated with leukoencephalopathy and microbleeds, even in the absence of other clinical symptoms.

Stability of nivolumab in its original vials after opening and handing in normal saline bag for intravenous infusion.

OBJECTIVES: Nivolumab is an anti-programmed cell death-1 monoclonal antibody, approved for numerous indications in oncohaematological cancers. It is available as solution for infusion at 10 mg/ml. In accordance with the Summary of Product Characteristics (SmPCs), the product is stable for 24 h at 2-8 °C after dilution. However, to anticipate the needs and constraints related to the handling of the product, the aim was to obtain additional information that will contribute to the risk assessment in case of deviation. Potential changes in the stability of Opdivo® leftovers (10 mg/ml) and diluted nivolumab in normal saline solution (2 mg/ml) over a period exceeding 24 h, at different temperatures and after freezing/thawing cycles were studied. METHODS: Turbidimetry, Ultraviolet (UV)-spectroscopy, dynamic light scattering and chromatography were used to evaluate physicochemical stability. Potential pharmacological variations were monitored in vitro by a functional binding inhibition method. RESULTS: No change was detected after 1 month of storage at 2-8 °C neither after 7 days at 40 °C. Although slight changes were detected only after 3 months under 2-8 °C, major changes were found for the same period of time at 40 °C (variants in the distribution profile, slight increase in oligomers and fragments and UV spectral modifications). Physical instability was observed upon 3 freeze/thaw cycles, with the appearance of a new protein population associated with an increase in polydispersity index. CONCLUSION: In conclusion, our results provide additional rationale to the SmPCs, regarding the use of leftovers, reassignment of bags, pre-preparation or breaking the cold chain for Nivolumab.

Fluorescence in situ hybridization analysis of masked (8;21)(q22;q22) translocations.

The translocation (8;21)(q22;q22) is associated with acute myeloblastic leukemia (AML M2). The accurate detection of this chromosomal rearrangement is vital due to its association with a favorable prognosis. Variant translocations exist; these may be hidden within an unusual or complex karyotype. In such cases, it is often difficult to confirm the presence of t(8;21)(q22;q22) by conventional cytogenetic analysis alone. The molecular detection of the AML1/ETO fusion gene is possible by reverse transcriptase polymerase chain reaction (RT-PCR) or dual-color fluorescence in situ hybridization (FISH) using probes specific for AML1 and ETO. Four cases of AML M2, with unusual or complex structural chromosomal abnormalities, without cytogenetic evidence of the classical t(8;21)(q22;q22), were studied by FISH. Two were AML1/ETO positive by RT-PCR, one showed a rearrangement by AML1 by Southern analysis, and the fourth had morphological features characteristic of t(8;21). The FISH results showed a co-localization of one AML1 and one ETO signal in interphase and metaphase nuclei in all four cases, demonstrating the presence of variant t(8;21)(q22;q22) rearrangements. Therefore, FISH analysis with the AML1 and ETO probes is extremely valuable, in cases of AML M2, because of its ability to reveal masked t(8;21)(q22;q22) translocations and thus quickly confirm the diagnosis, allowing patients to be assigned to the correct risk group in terms of treatment.

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining.

The immune system is the site of intense DNA damage/modification, which occur during the development and maturation of B and T lymphocytes. V(D)J recombination is initiated by the Rag1 and Rag2 proteins and the formation of a DNA double-strand break (DNA dsb). This DNA lesion is repaired through the use of the non-homologous end-joining (NHEJ) pathway, several factors of which have been identified through the survey of immunodeficient conditions in humans and mice. Upon antigenic recognition in secondary lymphoid organs, mature B cells further diversify their repertoire through class switch recombination (CSR). CSR is a region-specific rearrangement process triggered by the activation-induced cytidine deaminase factor and also proceeds through the introduction of DNA dsb. However, unlike V(D)J recombination, CSR does not rely strictly on NHEJ for the repair of the DNA lesion. Instead, CSR, but not V(D)J recombination, requires the major factors of the DNA damage response. V(D)J recombination and CSR thus represent an interesting paradigm to study the regulation among the various DNA repair pathways.

Simultaneous detection of MYC, BVR1, and PVT1 translocations in lymphoid malignancies by fluorescence in situ hybridization.

The rapid detection of chromosome band 8q24 rearrangements, including classical translocations involving MYC and variant 3' translocations, is important for the accurate diagnosis and appropriate treatment of lymphoid malignancies. We have identified and characterized a CEPH YAC, 934e1, which extends from at least 190 kbp upstream to over 280 kbp downstream to MYC, allowing detection of classical t(8; 14)(q24;q32) and variant t(8;22)(q24;q11) and t(8;14)(q24;q11), extending distal to PVT1 and therefore, by extrapolation, to BVR1. This YAC also allowed clarification of complex chromosome 8 abnormalities and the identification of translocations in interphase nuclei. A second CEPH YAC, 904c3, previously shown to contain the PVT1 locus but not MYC, allowed distinction between translocations occurring centromeric and telomeric to MYC. Use of the 934e1 YAC will aid classification of a variety of lymphoid proliferations and further characterization of rearranged cases with the 904c3 YAC will simplify mapping of their diverse breakpoints.

Reassessment of childhood B-lineage lymphoblastic leukemia karyotypes using spectral analysis.

We studied a stratified cohort of 51 childhood B-lineage acute lymphoblastic leukemias (B-ALLs) to evaluate the efficiency of spectral karyotyping (SKY) in the detection of chromosome aberrations previously diagnosed using chromosome banding and/or reverse transcriptase polymerase chain reaction. Despite the small number of cases analyzed, several important features emerge from the study: (a) The result of banding analysis was revised in two-thirds of the cases. Eighty-three chromosome anomalies previously undetected or not characterized using chromosome banding were identified by spectral karyotyping, even in patients with apparently normal karyotypes. (b) All hyperdiploidy cases showed one or more extra copies of chromosomes X, 14, and 21. (c) Two hidden rearrangements, a t(7;12)(?p12;p13), and a new translocation, a t(9;12)(q31;p13), both involving the TEL gene, were characterized. (d) Some cryptic rearrangements, such as the der(21) t(12;21) translocation, remained undetected. (e) No new recurrent chromosome anomalies were discovered with this technique. In conclusion, the present study confirms the efficiency of the SKY technique in resolving and characterizing many complex chromosome anomalies seen in childhood B-ALLs, but it raises questions about the ability of this technique to detect cryptic rearrangements, such as the t(12;21) translocation.