Alpha thalassemia-myelodysplastic syndrome (ATMDS) is one of the possible complications related to the genetic instability typical of clonal hemopoietic disorders such as myelodysplastic syndromes ...(MDS). Hemoglobin H acquisition, which is hemoglobin without alpha chains and with 4 beta chains is the hallmark of this disease.
An 86-year-old male with chronic, microcytic anemia was referred due to a fall in his hemoglobin level. The blood smear was remarkable for intense anisocytoses and poikilocytosis. Bone marrow analysis was followed by a diagnosis of MDS with a good prognostic score. Peripheral blood coloration with brilliant cresyl blue showed "golf ball-like" erythrocytes. Hemoglobin electrophoresis is notable for the presence of H hemoglobin. The new generation sequencing confirmed the diagnosis of ATMDS showing a non-sense mutation in the gene ATRX.
The diagnosis of ATMDS should be considered in the presence of the association of MDS, microcytic anemia and marked blood smear abnormalities such as anisocytosis and poikilocytosis. A little less than 10% of all MDS are complicated by ATMDS.
Abstract
BACKGROUND
Primary CNS lymphoma (PCNSL) is a rare disease accounting for around 3% of the primary brain tumors. In the vast majority of cases, PCNSL are classified as diffuse large B-cell ...lymphoma according to the WHO classification. The diagnosis is based on cranial MRI, in combination with a brain biopsy. In case of classical MRI findings, the identification of lymphoma cells in the cerebrospinal (CSF) or vitreous fluid by cytology and flow cytometry might obviate brain biopsy. The presence of the somatic mutation p.Leu265Pro (L265P) in MYD88 is detectable in 50 to 80% of PCNSL, and might also be helpful to confirm the diagnosis. The aim of our study was to evaluate the contribution of a highly sensitive digital droplet PCR, targeting the mutation L265P MYD88, for the detection of tumoral circulating DNA from CSF supernatant.
MATERIAL AND METHODS
We identified 9 PCNSL expressing the L265P mutation at diagnosis or relapse. The mutation was found by an allele specific PCR technique either on biopsy or in CSF cells. Circulating DNA was isolated from CSF supernatant with the « QiaAmp® circulating nucleic acid» kit. The quantity of DNA collected was estimated by quantitative PCR for a reference gene (albumine) with 7900HT (Life technologies™) device. Subsequently, the L265P MYD88 mutation was quantified by digital droplet PCR Biorad™: The droplets generated were amplified by PCR, detected with the QX200 Reader, and analyzed with the QuantaSoft™ software.
RESULTS
The circulating DNA concentration was low, varying between 0 and 2.2 ng/mL of CSF. However, the mutation was detected in the circulating DNA from CSF supernatant in 6 out of 9 cases (66%). The fractional abundance varied from 2.6 to 85%. In 3 cases, the mutation was detected even though cytology and flow cytometry did not reveal leptomeningeal disease. For 3 other cases, the mutation was not detected: The genome copy number was below 1 copy/µL, indicating a low analytical sensitivity for theses samples.
CONCLUSION
This study shows that circulating DNA is present in low concentration in CSF and can be amplified by a sensitive digital PCR for the L265P MYD88 mutation. The detection of circulating PCNSL DNA in CSF is possible and might be used to improve the non-invasive diagnosis of PCNSL. It might also help to select patients for targeted therapies.
Abstract
BACKGROUND
Interleukin (IL)-6 is a dual pro and anti-inflammatory cytokine and its presence in the cerebrospinal fluid (CSF) is considered as a marker of central nervous system (CNS) ...inflammation. Our aim was to analyze the diagnostic significance of CSF IL-6 levels among various CNS pseudotumoral inflammatory lesions (PIL) and primary CNS lymphoma (PCNSL).
MATERIAL AND METHODS
We retrospectively analyzed the CSF IL-6 concentrations in 43 patients with a differential diagnosis of PCNSL. Finally, 28 patients were positively diagnosed with PCNSL and 15 with other inflammatory CNS disorders. We verified the results with CSF IL-10, a biomarker for PCNSL. IL concentrations were measured by flow cytometry using the cytometric bead array (CBA) technique (BD Biosciences) with a detection limit set at 2.5 pg/ml.
RESULTS
In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5 - 18.5. For the patients with other PIL the median concentration was of 70 pg/ml, IQR 5 - 1368. A group comparison disclosed significantly higher CSF IL-6 levels in patients with PIL compared to the group with PCNSL (p=0.032). Moreover, IL-6 was correlated with CSF cell count for the whole cohort (r=0.45, p=0.002), as well as for the PIL group (r=0.56, p=0.028), but not for the PCNSL group (r=0.3, p=0.13). We found significantly higher CSF IL-10 levels in patients with PCNSL compared to the group with other CNS inflammatory lesions (p<0.001).
CONCLUSION
Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the diagnosis of CNS PIL that may mimic PCNSL.
L’alpha thalassémie-syndrome myélodysplasique (ATSMD) est une complication possible associée à l’instabilité génétique des hémopathies clonales telles que les syndromes myélodysplasiques (SMD). Cette ...pathologie est caractérisée par la production d’une hémoglobine dite H constituée d’un tétramère de chaînes bêta du fait de l’incapacité à synthétiser des globines alpha.
Un patient de 86 ans avec une anémie chronique et microcytaire non carentielle, aggravait soudainement son anémie avec une anisocytose et une poïkilocytose marquées. L’examen cytologique de la moelle osseuse et le caryotype étaient en faveur d’un SMD avec dysplasie multilignée de bon pronostic. La coloration du sang périphérique au Bleu de Crésyl montrait des hématies « en balle de golf ». L’électrophorèse de l’hémoglobine montrait une hémoglobine H. Le diagnostic d’ATSMD était porté du fait d’une mutation non-sens du gène ATRX mise en évidence au séquençage de nouvelle génération.
L’association SMD, anémie microcytaire avec anisocytose et poïkilocytose doit faire évoquer le diagnostic de ATSMD, qui complique moins de 10 % des SMD.
Alpha thalassemia-myelodysplastic syndrome (ATMDS) is one of the possible complications related to the genetic instability typical of clonal hemopoietic disorders such as myelodysplastic syndromes (MDS). Hemoglobin H acquisition, which is hemoglobin without alpha chains and with 4 beta chains is the hallmark of this disease.
An 86-year-old male with chronic, microcytic anemia was referred due to a fall in his hemoglobin level. The blood smear was remarkable for intense anisocytoses and poikilocytosis. Bone marrow analysis was followed by a diagnosis of MDS with a good prognostic score. Peripheral blood coloration with brilliant cresyl blue showed “golf ball-like” erythrocytes. Hemoglobin electrophoresis is notable for the presence of H hemoglobin. The new generation sequencing confirmed the diagnosis of ATMDS showing a non-sense mutation in the gene ATRX.
The diagnosis of ATMDS should be considered in the presence of the association of MDS, microcytic anemia and marked blood smear abnormalities such as anisocytosis and poikilocytosis. A little less than 10% of all MDS are complicated by ATMDS.
Background
Interleukin 6 (IL-6) is a pleomorphic cytokine that can be found in the cerebrospinal fluid (CSF) in a wide spectrum of inflammatory pathologies of the central nervous system (CNS).
...Objective
Our aim was to characterize the diagnostic significance of CSF IL-6 among various CNS inflammatory diseases with pseudotumoral lesions (CNSID) and primary CNS lymphoma (PCNSL).
Methods
We retrospectively analyzed the CSF IL-6 concentrations in 43 consecutive patients with suspected PCNSL. A total of 28 patients were positively diagnosed with PCNSL and 15 with CNSID. We verified the results with CSF IL-10, an established biomarker for PCNSL.
Results
In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5–18.5. For the patients with CNSID, the median concentration was 70 pg/ml, IQR 5–1368. A group comparison showed significantly higher CSF IL-6 levels in patients with CNSID than in those with PCNSL (
p
= 0.032). Moreover, IL-6 was correlated with CSF cell count in the CNSID group (
r
= 0.56,
p
= 0.028), but not in the PCNSL group (
r
= 0.3,
p
= 0.13).
We found significantly higher CSF IL-10 levels in patients with PCNSL than in patients with CNS inflammatory lesions (
p
< 0.001).
Discussion and conclusions
Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the differential diagnosis of CNSID and suspected PCNSL.
Aripiprazole is a second-generation antipsychotic, efficacious in patients with schizophrenia during acute episodes. Due to its pharmacological profile, aripiprazole may be of interest in patients ...with specific clinical profiles who have not been studied extensively in randomised clinical trials.
To capture experience with aripiprazole in everyday psychiatric practice using the Delphi method in order to inform decision-making on the use of aripiprazole for the treatment of patients with schizophrenia in clinical situations where robust evidence from clinical trials is lacking.
The scope of the survey was defined as the management of schizophrenia in adults. A systematic literature review was performed to identify the different clinical situations in which aripiprazole has been studied, and to describe the level of clinical evidence. Clinical profiles to include in the Delphi survey were selected if there was a clear interest in terms of medical need but uncertainty over the efficacy of aripiprazole. For each clinical profile retained, five to seven specific statements were generated and included in a questionnaire. The final 41-item questionnaire was proposed to a panel of 406 French psychiatrists with experience in the treatment of schizophrenia. Panellists rated their level of agreement using a Likert scale. A second round of voting on eleven items was organised to clarify points for which a consensus was not obtained in the first round.
Five clinical profiles were identified in the literature review (persistent negative symptoms, pregnancy, cognitive dysfunction, addictive comorbidity and clozapine resistance). Sixty-two psychiatrists participated in the first round of the Delphi survey and 33 in the second round. A consensus was obtained for 11 out of 41 items in the first round and for 9/11 items in the second round. According to the panellists' clinical experience, aripiprazole can be used as maintenance treatment for pregnant women, is relevant to preserve cognitive function and can be considered an option in patients with a comorbid addictive disorder or with persistent negative symptoms.
These findings may help physicians in choosing relevant ways to use aripiprazole and highlight areas where more research is needed to widen the evidence base.
Major depressive disorder is one of the leading causes of disability worldwide. Although most international guidelines recommend psychological and psychosocial interventions as first-line treatment ...for mild to moderate depression, access remains limited in France due to the limited availability of trained clinicians, high costs for patients in the context of nonreimbursement, and the fear of stigmatization. Therefore, online blended psychological treatment such as Deprexis could improve access to care for people with depression. It has several advantages, such as easy accessibility and scalability, and it is supported by evidence.
This study aims to evaluate the real-life acceptability of Deprexis for people with depression in France outside of a reimbursement pathway.
Deprexis Acceptability Study Measure in Real Life (DARE) was designed as a multicenter cross-sectional study in which Deprexis was offered to any patient meeting the inclusion criteria during the fixed inclusion period (June 2022-March 2023). Inclusion criteria were (1) depression, (2) age between 18 and 65 years, (3) sufficient French language skills, and (4) access to the internet with a device to connect to the Deprexis platform. Exclusion criteria were previous or current diagnoses of bipolar disorder, psychotic symptoms, and suicidal thoughts during the current episode. The primary objective was to measure the prospective acceptability of Deprexis, a new digital therapy. Secondary objectives were to examine differences in acceptability according to patient and clinician characteristics and to identify reasons for refusal. All investigators received video-based training on Deprexis before enrollment to ensure that they all had the same level of information and understanding of the program.
A total of 245 patients were eligible (n=159, 64.9% were women and n=138, 56.3% were single). The mean age was 40.7 (SD 14.1) years. A total of 78% (n=191) of the patients had moderate to severe depression (according to the Patient Health Questionnaire-9 PHQ-9). More than half of the population had another psychiatric comorbidity (excluding bipolar disorder, psychotic disorders, and suicidal ideation). A total of 33.9% (n=83) of patients accepted the idea of using Deprexis; the main reason for refusal was financial at 83.3% (n=135). Multivariate logistic regression identified factors that might favor the acceptability of Deprexis. Among these, being a couple, being treated with an antidepressant, or having a low severity level favored the acceptance of Deprexis.
DARE is the first French study aiming at evaluating the prospective acceptability of digital therapy in the treatment of depression. The main reason for the refusal of Deprexis was financial. DARE will allow better identification of factors influencing acceptability in a natural setting. This study highlights the importance of investigating factors that may be associated with the acceptability of digital interventions, such as marital status, medication use, and severity of depression.
Abstract 5233
In Activated B-Cell like Diffuse Large B-Cell Lymphomas (ABC DLBCLs) the most commonly affected gene is TNFAIP3, which encodes A20, an ubiquitin modifying enzyme involved in the ...negative regulation of NF-κB signaling. A20 is itself a target gene of NF-κB and needs to be induced in order to exert its negative feedback effect on NF-κB. Mutations resulting in the inactivation of A20 have been found in a significant proportion of ABC DLBCL cases (Compagno M et al, Nature 2009). The tumor suppressor role of A20 was established by the reintroduction of wild-type A20 in some mutant A20 lymphoma B-cell lines promoting apoptosis, supposedly due to the loss of the ability to inactivate NF-κB. However, a protective effect of A20 against apoptotic stimuli was demonstrated in some cell types. In endothelial cells, A20 protects from TNF- and Fas-mediated apoptosis by inhibiting caspase-8 activation (Daniel S et al, Blood 2004). We thus wanted to understand the relationship between A20 expression, NF-κB activation and protection against apoptosis in B-cells.
We have cloned cDNAs coding for wild-type A20 (A20wt), for IκBαS32,36A (constitutively active form of IκBα), and for luciferase (as a control) into a doxycycline double-inducible episomal vector pRT-1, and stably transfected these vectors into an EBV positive lymphoblastoid B-cells line. Induction of p53 mediated apoptosis was performed by treatment of cells with Fludarabine*, whereas induction of caspase-8 dependant was performed with agonist antibodies against Fas (CD95).
Both A20 and IκBαS32,36A overexpression suppressed NF-κB activity with downregulation of NF-κB target genes. Loss of NF-κB activation by induction of IκBαS32,36A led to increase of spontaneous apoptosis. Oppositely, loss of NF-κB activation by induction of A20 led to decrease of spontaneous apoptosis. Compared with luciferase transfected cells, no effect of A20 overexpression was seen after treatment of cells with anti-CD95 antibodies. Caspase-9 cleavage was significantly decreased and increase of TP53 protein levels was lower in A20 overexpressing cells after Fludarabine* treatment. By contrast, Fludarabine* treatment of IκBαS32,36A expressing cells led to an increase of both TP53 protein levels and caspase-9 cleavage. Therefore, A20 negatively modulated mitochondrial apoptosis pathway despite NF-κB downregulation.
These results suggest that A20 may exert an anti-apoptotic effect on its own independently of NF-κB activation. We are now looking after the functional properties of A20 natural mutants. Indeed, we can hypothesize that A20 mutants described in ABC DLBCLs have lost their negative feedback effect on NF-κB, but not their protective effect against apoptosis. So, A20 mutants may actively contribute to oncogenesis through their own protective effect on tumor cells.
No relevant conflicts of interest to declare.
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