CNS Infiltration Research Articles

ALL-017 Adult T-Cell Acute Lymphoblastic Leukemia With Transducin-Like Enhancer Gene Expression

Transducin-like enhancer of split 1 (TLE1) is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. The aim of this study was to evaluate the prognostic role of TLE1 gene expression in patients with T-cell acute lymphoblastic leukemia (T-ALL). This study was conducted on 97 newly diagnosed T-ALL patients admitted to the Mansoura University oncology center (59 males and 38 females) with median age 33 years, in addition to 102 apparently healthy individuals who served as a control group. TLE1 gene expression was measured in both patients and control groups by real time - PCR. The calculation of relative gene expression was done using the AACt method. TEL1 gene expression was significantly down regulated in T-ALL cases (median 2.83) as compared to controls (median 84.65) (p < 0.001). Low TEL1 gene expression was significantly associated with CNS infiltration, failure to achieve 1st complete remission and higher relapse rate (p< 0.001, 0.001 and 0.023, respectively). Early T-cell precursor (ETP)-ALL/LBL subtype was found to be significantly associated with low TEL1 gene expression (P 0.04), however there was no relation between TEL1 gene expression and TCR rearrangement or other available molecular abnormalities. Likewise, low TEL1 gene expression was significantly associated with shorter overall survival (OS) and disease-free survival (DFS) (P= 0.012 and 0.011, respectively). Furthermore, Low TEL1 gene expression was considered a risk predictor of relapse with OR 3.636(CI.1.422-9.295) (P =0.007); and OR 0.803(CI. 0.609-0.96) (P=0.021) and an independent predictor of T-ALL patients' outcomes with OR 0.619 (CI. 0.44-0.872) (P=0.006). TLE1 gene expression was significantly down regulated in T-ALL as compared with controls. Low TLE1 expression is an independent predictor of the T-ALL patient's outcome and could open the way for further risk stratification and targeted therapy in T-ALL.

Neurological Involvement in Pediatric Patients with Acute Leukemia: A Retrospective Cohort.

Acute leukemia (AL) is an important cause of morbidity and mortality in children, and neurological manifestations (NM) are frequent. The objective of this study was to analyze neurological manifestations in children with acute leukemia from cases attended in the last five years at the Centro Médico Nacional “20 de Noviembre”. Methods: Conducting a retrospective and analytical study from 1 January 2015 to 31 December 2020 in children with AL classified according to sex, age range and AL type. Participants were grouped according the presence of NM. Results: We analyzed 607 patients: 54.85% boys and 44.14% girls, with a mean age of 7.27 ± 4.54 years. When comparing groups, the NM group was significantly older (p = 0.01), and the highest prevalence was between 6 and 12 years old. ALL was predominant over the other lineages (p ≤ 0.01). The most frequent NM was CNS infiltration, seizures, headache and neuropathy. Death outcomes occurred in 18.7% of children with AML, 11.8% with ALL and 50% with MPAL (p ≤ 0.002). The NM group was associated with higher mortality during a follow-up time of 77.9 ± 49 months (44.4% vs. 8.9% deaths, NM vs. non-NM, respectively; OR = 3.3; 95% CI 2.4 to 4.6; p ≤ 0.0001). Conclusions: ALL was the most prevalent leukemia type. CNS infiltration, seizures, headache, neuropathy and PRES were the most frequent symptoms in the NM group. NM was associated with a higher mortality rate.

The Prevalence of Dizziness and Vertigo in COVID-19 Patients: A Systematic Review.

Clinical manifestations of COVID-19 include symptoms of vertigo and dizziness, which is rather unsurprising, since SARS-CoV-2 neurotropism may inflict a broad spectrum of neuropathic effects. The widespread nature of central and peripheral audiovestibular pathways suggests that there may be several probable pathophysiological mechanisms. The cytokine storm, CNS infiltration of the virus through ACE 2 receptors, and other systemic factors can be responsible for the significant number of COVID-19 patients reported to experience symptoms of vertigo and dizziness. In this paper, we present a systematic review of clinical studies reporting the detection of dizziness and vertigo as clinical manifestations of COVID-19 and discuss their etiopathogenesis.

Therapeutic Effect of Anti-CD52 Monoclonal Antibody in Multiple Sclerosis and Its Animal Models Is Mediated via T Regulatory Cells.

The objective of this study is to determine the mechanism of action of anti-CD52 mAb treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Experimental autoimmune encephalomyelitis (EAE), an animal model of the disease, was used to address the role of T regulatory cells (Tregs) in the anti-CD52 mAb-induced suppression of the disease. In vitro studies on PBMCs from RRMS patients and matched healthy controls determined the effect of IL-7 on the expansion of CD4+CD25+CD127- Tregs and induction of their suppressive phenotype. This study using EAE animal models of MS has shown that mouse anti-CD52 mAb suppression of clinical disease was augmented by coadministration of IL-7 and partially reversed by anti-IL-7 mAb. In vitro human studies showed that IL-7 induced expansion of CD4+CD25+CD127- Tregs and increased their FOXP3, GITIR, CD46, CTLA-4, granzyme B, and perforin expression. Anti-CD52 mAb treatment of mice with relapsing-remitting EAE induced expansion of Foxp3+CD4+ Tregs and the suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in peripheral immune organs and CNS infiltrates. The effect was detected immediately after the treatment and maintained over long-term follow-up. Foxp3+CD4+ Treg-mediated suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in the spinal cord infiltrates was reversed after inducible Foxp3 depletion. Our results demonstrated that the therapeutic effect of U.S. Food and Drug Administration-approved anti-CD52 mAb is dependent on the presence of Tregs.

Biological aging of CNS-resident cells alters the clinical course and immunopathology of autoimmune demyelinating disease.

Biological aging is the strongest factor associated with the clinical phenotype of multiple sclerosis (MS). Relapsing-remitting MS typically presents in the third or fourth decade, whereas the mean age of presentation of progressive MS (PMS) is 45 years old. Here, we show that experimental autoimmune encephalomyelitis (EAE), induced by the adoptive transfer of encephalitogenic CD4+ Th17 cells, was more severe, and less likely to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils were more abundant, while B cells were relatively sparse, in CNS infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrated that radio-resistant, nonhematopoietic cells played a dominant role in shaping age-dependent features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of PMS, EAE in middle-aged adoptive transfer recipients was characterized by widespread microglial activation. Microglia from older mice expressed a distinctive transcriptomic profile suggestive of enhanced chemokine synthesis and antigen presentation. Collectively, our findings suggest that drugs that suppress microglial activation, and acquisition or expression of aging-associated properties, may be beneficial in the treatment of progressive forms of inflammatory demyelinating disease.

HTLV-1 encephalomyelitis; a case report of a treatable manifestation of HTLV-1 infection

IntroductionHuman T-cell lymphotropic virus type-1 (HTLV-1) infection remains asymptomatic in &gt;90% of the 20-million people infected worldwide. However in 3%, chronic inflammation within the thoracic spinal cord leads to progressive spastic paraparesis; HTLV-1 associated myelopathy (HAM). This pathological process is not limited to the thoracic cord. We present a case of HTLV-1 encephalomyelitis.CaseA 53-year-old woman with HAM of 9 years duration presented with subacute cerebellar dysfunc- tion, being unable to feed herself, 3-months after cessation of methotrexate. Investigations demonstrated extensive T2-hyperintensity within the brainstem, cortical and subcortical white matter with punctate contrast enhancement; lymphocytic CSF; and high blood (36%) and CSF (72%) HTLV-1 proviral load (DNA copies per 100 lymphocytes). We diagnosed HTLV-1 encephalomyelitis and commenced high dose methylprednisolone with slow steroid taper following which functional independence in the upper limbs was regained.DiscussionRisk of HAM rises exponentially once HTLV-1 proviral load exceeds 1%, while CSF:blood proviral load ratio ≥2:1 indicates CNS infiltration of HTLV-1 infected lymphocytes. This patient’s high HTLV-1 proviral load and widespread MRI changes indicated HTLV-1 associated inflammation of the brain and spine. Prompt immunosuppression resulted in significant recovery and highlights the importance of early rec- ognition and management of extraspinal manifestations of HTLV-1 infection.j.king-robson@nhs.net

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Isolated CNS Hemophagocytic Lymphohistiocytosis in Children:What We Know, What We Don't Know ?

The presence of central nervous system involvement has a profound impact on the prognosis, treatment, and clinical outcome of the primary hemophagocytic lymphohistiocytosis (pHLH). However, isolated CNS-HLH is a challenging disease with a high mortality and morbidity , possibly resulting from a spsecific neuroinflammation that leads to isolated disease only without systemic activation under some additional genetic modifiers. In this study, we retrospectively reviewed our isolated CNS-HLH cases and there were 73 patients (36 male, 37 female) with a median age of 20 months (range, 1- 226 months) diagnosed as primary hemophagocytic lymphohistiocytosis at Hacettepe University Faculty of Medicine, between January 2005 and June 2021. Among these, 39 (53%) patients had central nervous system involvement either on admission or during the recurrence. On admission, the number of patients who had both CNS and sytemic involvement was 19 (49%), moreover 2 had CNS infiltration both initially and during the course of relapse. 8 patient did show CNS involvement only during the relapse. Ten (25%) patients (5 male, 5 female) with isolated CNS involvement are the main subject of this study and none of them had infectious trigger. What we know is they were presented with mostly unexplained neurological findings and /or cranial nerve paralysis. In this group median age at presentation was 101 months ( range 6 - 180 months). They all had primary HLH associated patogenic mutation and in some of them diagnosed was also confirmed by brain biopsy. Neither family history and /or consanguinity nor HLH criteria are fullfilling in this devastating disorder. Cranial MRI gives many clues during admission in experienced hands. Two of our published cases were initially diagnosed as lymphomatoid granulomatosis and acute disseminated encephalomyelitis ; they were diagnosed as hemophagocytic lymphohistiocytosis after developing systemic symptoms 3 and 12 months later. Interestingly 6 of 10 patients in this group never developed systemic symptomps, 7 patients underwent allogeneic bone marrow transplantation. Spinal cord involvement was determined in 8 patients(20%), including 4 at diagnosis and 4 during follow up ; including one previously published case, 4 out of 8 had isolated cases did show spinal involvement as well. Even though few number of cases with isolated CNS-HLH has been reported in the recent years, we believe that the number of such cases is not limited to those who have been reported because it is rather difficult to diagnose patients with isolated CNS symptoms, which leads to misdiagnosis and/or mistreatment. What we don't know is how to specifically treat patients with CNS directed therapy, and exactly which mutations are associated with isolated CNS-HLH or whether there is a known tendency in this group and perhaps unknown mutations ? Does it have a facilitating effect ? DisclosuresNo relevant conflicts of interest to declare.

Chronic Lymphocytic Leukaemia: Rare Involvement of the Central Nervous System.

Involvement of the central nervous system, although uncommon, is one of the most frequent extramedullary manifestations of chronic lymphocytic leukaemia (CLL). Various conditions can lead to neurological symptoms in CLL patients and distinguishing between clinically significant CLL involvement of the CNS and other aetiologies can be challenging.The authors report the case of a 90-year-old woman with a previous diagnosis of low-risk CLL who presented to the emergency room with altered mental status. After the most frequent causes were ruled out and considering the underlying disease, CNS infiltration by clonal B-cells was hypothesised and later confirmed. Treatment was initiated, but the patient died soon afterwards.LEARNING POINTSCentral nervous system involvement in chronic lymphocytic leukaemia (CLL) is rare and characterized by a heterogeneous clinical presentation.CNS localisation of CLL should be considered in patients with any neurological symptom, irrespective of the stage and activity of CLL.Brain imaging and cerebrospinal fluid examination should be performed.

P-123: Extramedullary expansion of Myeloma plasma cells into CNS

Background Multiple myeloma (MM) is characterised by a presence of clonal plasma cell (a-PC) which are usually localised in bone marrow (BM) as a heterogeneous suspension, not often as solitary lesion. A BM microenvironment dependency is lost in a subset of patients and a-PCs spread out of BM, probably because of changes in adhesive molecules expression. Circulating myeloma PCs (cPCs) were detected in peripheral blood of almost all MM. Moreover, primary and/or secondary extramedullary disease (soft tissue and/or bone-related) was revealed in many patients. On the other hand, presence of a-PCs in cerebrospinal fluid (CSF) is relatively rare. Aim Detection of a-PCs in CSF and comparison of their phenotype with other compartments. Methods CSF of 15 relapsed MM patients was analysed by polychromatic flow cytometry (FC). Centrifuged samples were immediately incubated with MoAb (mostly CD38/CD138/CD45/CD19/CD56/CD14/CD5/CD27), lysed by NH4Cl and analysed. Results Whole group of analysed CSF has median of leukocytes 231 with range 19-6013. Myeloma a-PC infiltration was detected in 26.7 % (4/15). Only a-PCs were detected, these were always CD19- and in 50% CD56+. Phenotype profile in CSF, bone marrow, peripheral blood and tumour was similar according to CD19 and CD56. Flow cytometry is a highly efficient method for a-PCs detection. Conclusion Unfortunately, for these small samples more markers have to be analysed simultaneously to perform diagnostics and to analyse a-PCs as well, so only 8-colour FC is relatively insufficient in term of detail a-PC phenotype assess. All CSF+ patients were almost refractory to the treatment and they have cPCs in peripheral blood, extramedullary relapse was detected in 2 patients as well. It is evident, that prognosis of patients with CNS infiltration is generally poor. Supported by Ministry of Health of the Czech Republic, grant nr. 17-29343A. Multiple myeloma (MM) is characterised by a presence of clonal plasma cell (a-PC) which are usually localised in bone marrow (BM) as a heterogeneous suspension, not often as solitary lesion. A BM microenvironment dependency is lost in a subset of patients and a-PCs spread out of BM, probably because of changes in adhesive molecules expression. Circulating myeloma PCs (cPCs) were detected in peripheral blood of almost all MM. Moreover, primary and/or secondary extramedullary disease (soft tissue and/or bone-related) was revealed in many patients. On the other hand, presence of a-PCs in cerebrospinal fluid (CSF) is relatively rare. Detection of a-PCs in CSF and comparison of their phenotype with other compartments. CSF of 15 relapsed MM patients was analysed by polychromatic flow cytometry (FC). Centrifuged samples were immediately incubated with MoAb (mostly CD38/CD138/CD45/CD19/CD56/CD14/CD5/CD27), lysed by NH4Cl and analysed. Whole group of analysed CSF has median of leukocytes 231 with range 19-6013. Myeloma a-PC infiltration was detected in 26.7 % (4/15). Only a-PCs were detected, these were always CD19- and in 50% CD56+. Phenotype profile in CSF, bone marrow, peripheral blood and tumour was similar according to CD19 and CD56. Flow cytometry is a highly efficient method for a-PCs detection. Unfortunately, for these small samples more markers have to be analysed simultaneously to perform diagnostics and to analyse a-PCs as well, so only 8-colour FC is relatively insufficient in term of detail a-PC phenotype assess. All CSF+ patients were almost refractory to the treatment and they have cPCs in peripheral blood, extramedullary relapse was detected in 2 patients as well. It is evident, that prognosis of patients with CNS infiltration is generally poor. Supported by Ministry of Health of the Czech Republic, grant nr. 17-29343A.

ALL-234: TLE1 Gene Expression in Adult T-Cell Acute Lymphoblastic Leukemia

<h3>Background:</h3> Transducin-like enhancer of split 1 (TLE1) is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. The aim of this study was to evaluate the prognostic role of TLE1 gene expression in patients with T-cell acute lymphoblastic leukemia (T-ALL). <h3>Method:</h3> This study was conducted on 97 newly diagnosed T-ALL patients admitted to the Mansoura University Oncology Center (59 males and 38 females), with a median age of 33 years, in addition to 102 apparently healthy individuals who served as a control group. TLE1 gene expression was measured in both the patient and control groups by real-time PCR. The calculation of relative gene expression was done using the δδCt: method. <h3>Results:</h3> TEL1 gene expression was significantly downregulated in T-ALL cases (median 2.83) compared to controls (median 84.65; P<0.001). Low TEL1 gene expression was significantly associated with CNS infiltration, failure to achieve the first complete remission, and a higher relapse rate (P<0.001, 0.001, and 0.023, respectively). The early T-cell precursor (ETP)-ALL/LBL subtype was found to be significantly associated with low TEL1 gene expression (P=0.04); however, no relations between TEL1 gene expression and TCR rearrangement or other known molecular abnormalities were found. Likewise, low TEL1 gene expression was significantly associated with shorter OS and DFS (P=0.012 and 0.011, respectively). Furthermore, low TEL1 gene expression was considered a risk predictor of relapse, with OR 3.636 (CI: 1.422–9.295; P=0.007) in univariate analysis and OR 0.803 (CI: 0.609–0.96; P=0.021) in multivariate analysis, and an independent predictor of T-ALL patient outcomes, with OR 0.619 (CI:0 .44–0.872; P=0.006). <h3>Conclusion:</h3> TLE1 gene expression was significantly downregulated in T-ALL compared with controls. Low TLE1 expression is an independent predictor of T-ALL patient outcomes and could open avenues for further risk stratification and targeted therapy in T-ALL.

High-parameter cytometry unmasks microglial cell spatio-temporal response kinetics in severe neuroinflammatory disease

BackgroundDifferentiating infiltrating myeloid cells from resident microglia in neuroinflammatory disease is challenging, because bone marrow-derived inflammatory monocytes infiltrating the inflamed brain adopt a ‘microglia-like’ phenotype. This precludes the accurate identification of either cell type without genetic manipulation, which is important to understand their temporal contribution to disease and inform effective intervention in its pathogenesis. During West Nile virus (WNV) encephalitis, widespread neuronal infection drives substantial CNS infiltration of inflammatory monocytes, causing severe immunopathology and/or death, but the role of microglia in this remains unclear.MethodsUsing high-parameter cytometry and dimensionality-reduction, we devised a simple, novel gating strategy to identify microglia and infiltrating myeloid cells during WNV-infection. Validating our strategy, we (1) blocked the entry of infiltrating myeloid populations from peripheral blood using monoclonal blocking antibodies, (2) adoptively transferred BM-derived monocytes and tracked their phenotypic changes after infiltration and (3) labelled peripheral leukocytes that infiltrate into the brain with an intravenous dye. We demonstrated that myeloid immigrants populated only the identified macrophage gates, while PLX5622 depletion reduced all 4 subsets defined by the microglial gates.ResultsUsing this gating approach, we identified four consistent microglia subsets in the homeostatic and WNV-infected brain. These were P2RY12hi CD86−, P2RY12hi CD86+ and P2RY12lo CD86− P2RY12lo CD86+. During infection, 2 further populations were identified as 'inflammatory' and 'microglia-like' macrophages, recruited from the bone marrow. Detailed kinetic analysis showed significant increases in the proportions of both P2RY12lo microglia subsets in all anatomical areas, largely at the expense of the P2RY12hi CD86− subset, with the latter undergoing compensatory proliferation, suggesting replenishment of, and differentiation from this subset in response to infection. Microglia altered their morphology early in infection, with all cells adopting temporal and regional disease-specific phenotypes. Late in disease, microglia produced IL-12, downregulated CX3CR1, F4/80 and TMEM119 and underwent apoptosis. Infiltrating macrophages expressed both TMEM119 and P2RY12 de novo, with the microglia-like subset notably exhibiting the highest proportional myeloid population death.ConclusionsOur approach enables detailed kinetic analysis of resident vs infiltrating myeloid cells in a wide range of neuroinflammatory models without non-physiological manipulation. This will more clearly inform potential therapeutic approaches that specifically modulate these cells.

Upregulated Cholesterol Biosynthesis Is a Biomarker for Isolated Central Nervous System Relapse in Acute Lymphoblastic Leukaemia

Background:Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer. In early trials CNS relapse was a common occurrence, and the introduction of CNS-directed therapy in the 1960s-70s resulted in the largest single improvement in outcome for childhood ALL. Today, despite universal intensive CNS-directed therapy - with significant associated toxicity - the CNS is involved in around 50% of ALL relapses, with 50% of these being isolated CNS (iCNS) relapse. Whilst many factors appear to increase risk of CNS relapse, few are specific for CNS relapse. Discovery of biomarkers for CNS relapse would allow increased therapy for children at high risk, and potentially less CNS-directed therapy for those at low risk.Despite the clinical significance of CNS infiltration, relatively little is known about the biological differences between systemic and CNS ALL. In the CNS, leukaemic cells form plaques adherent to the leptomeninges, bathed in low-nutrient, low-oxygen CSF. It was hypothesised that leukaemic cells adapt metabolically to this nutritionally poor CNS microenvironment, and these adaptations may be targetable as specific biomarkers for CNS relapse.Findings:Human precursor-B ALL cell lines (SEM (t(4;11) and REH (t(12;21)) were purified from the CNS and spleen after xenotransplantation into immunodeficient (NSG) mice, and transcriptomic analysis was carried out using RNASeq. Gene Set Enrichment Analysis (GSEA), showed upregulation of the cholesterol biosynthesis pathway in the CNS compared with systemic ALL (adj. p<0.0001). This finding was confirmed in publicly available microarray data of human ALL cells retrieved from CNS and bone marrow samples (GEO dataset GSE60926; p=006). To further validate this finding, metabolic analysis of xenografted SEM cells was performed using HPLC-mass spectrometry, showing an increase in intracellular abundance of cholesterol-precursor mevalonate (p=0.003) in SEM cells in the CNS compared with spleen.To confirm lack of cholesterol as a key metabolic challenge for ALL cells in the CNS, total cholesterol was quantified in CSF and plasma from normal human controls and NSG mice, with and without leukaemia. To investigate the effect of leukaemia on CSF cholesterol abundance in humans, CSF from patients at diagnosis (i.e. with untreated ALL) and during maintenance therapy was analysed. In control samples from humans, there was approximately 1000-fold lower total cholesterol in CSF compared to plasma (in murine CSF there was approx. 500-fold lower cholesterol). In addition, plasma cholesterol was around 33% lower in mice xenografted with SEM cells (p=0.02), with a trend towards a similar reduction in CSF cholesterol (p=0.08). In humans there was an approx. 2-fold increase in CSF cholesterol between samples taken at diagnosis compared with samples taken during maintenance chemotherapy (i.e. CSF cholesterol was lower in children with untreated ALL, p=0.03).Having shown upregulated cholesterol biosynthesis to be an adaptation to the CNS microenvironment, the utility of finding this signature in the bone marrow of children at diagnosis as a biomarker of CNS relapse was assessed. Publicly available data from GEO dataset GSE11877/NCI TARGET program was analysed for association between upregulated cholesterol biosynthesis and CNS relapse. Upregulation of 2 or more genes in the cholesterol biosynthetic pathway, determined using a z-score approach, (n=44 upregulated, n=163 not upregulated) was associated with a 3-fold increased risk of isolated CNS but not bone marrow relapse (28.5% absolute risk of iCNS relapse compared with 9.5% after 14 years follow up, p=0.0007). This increase in CNS relapse risk remained after multivariate analysis. Early validation using data from the NOPHO ALL2008 trial of all risk groups (n=163) showed that both children with iCNS relapse had upregulation of cholesterol synthesis by these criteria. Further validation in additional independent cohorts is ongoing.Conclusions:These findings suggest that cholesterol biosynthesis is a key metabolic pathway for childhood ALL cells infiltrating the CNS. This is in keeping with very low levels of cholesterol detected in the CSF, particularly in the presence of leukaemia. Upregulated cholesterol synthesis genes in diagnostic bone marrow are associated with increased risk of CNS relapse in high risk ALL, with supporting evidence of a similar association in standard-risk ALL. DisclosuresHalsey:Jazz Pharmaceuticals: Consultancy, Other: Support to attend educational meetings.

Prognostic Value of TLE1 Gene Expression in Patients with T-cell Acute Lymphoblastic Leukemia.

Background:Transducin-like enhancer of split 1 (TLE1( is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. The aim of this study was to evaluate the prognostic role of TLE1 gene expression in patients with T-cell acute lymphoblastic leukemia (T-ALL). Method:This study was conducted on 97 newly diagnosed T-ALL patients admitted to the Mansoura University oncology center (59 males and 38 females) with median age (33 years) in addition to 102 apparently healthy individuals served as a control group. TLE1 gene expression was measured in both patients and control groups by real time – PCR. The calculation of relative gene expression was done using the ΔΔCt method. Results: TEL1 gene expression was significantly down regulated in T-ALL cases (median 2.83) as compared to controls (median 84.65) (p < 0.001). The low TEL1 gene expression was significantly associated with CNS infiltration, non-remission and higher relapse rate (p< 0.001, 0.001 and 0.023 respectively). Likewise, Low TEL1 gene expression was significantly associated with shorter OS and DFS (P= 0.012 and 0.011 respectively). Furthermore, Low TEL1 gene expression was considered as risk predictor of relapse with OR 3.636(CI.1.422-9.295) (P =0.007); and OR 0.803(CI. 0.609-0.96) (P=0.021) and independent predictor of T-ALL patient’s outcome with OR 0.619 (CI. 0.44-0.872) (P=0.006). Conclusion:TLE1 gene expression was significantly down regulated in T-ALL cases as compared with controls. Low TLE1 expression is independent predictor of the T-ALL patient’s outcome.

CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS.

ObjectiveB cells have emerged as a therapeutic target for MS. Anti-CD20 antibodies, which deplete B cells, are effective therapies for MS. However, atacicept (TACI-Fc), which blocks BAFF and APRIL and reduces B cells, unexpectedly exacerbates MS. We tested the hypothesis that B cell maturation antigen (BCMA), a receptor for BAFF and APRIL, plays a role in the paradoxical effects of anti-CD20 antibody and TACI-Fc using experimental autoimmune encephalomyelitis (EAE).MethodsEAE was induced in wild-type (BCMA+/+) and BCMA-deficient (BCMA−/−) mice with an immunization of rodent myelin oligodendrocyte glycoprotein (MOG)35–55 peptide. Treatment with anti-CD20 antibody, TACI-Fc, and isotype controls was administered by intraperitoneal injections. CNS infiltration was evaluated by histology; immune cell phenotypes were evaluated by flow cytometry; MOG-specific antibodies were determined by ELISA. Mixed bone marrow chimeras and cell culture assays were used to identify the specific subsets of immune cells affected by BCMA deficiency.ResultsFirst, we found that BCMA−/− mice had more severe EAE compared with BCMA+/+ mice and the increased disease was associated with elevated anti-MOG B-cell responses. Second, we found that anti-CD20 therapy attenuated EAE in BCMA−/− mice but not in BCMA+/+ mice. Third, TACI-Fc attenuated EAE in BCMA+/+ mice but not in BCMA−/− mice. Mixed bone marrow chimeric and cell culture experiments demonstrated that BCMA deficiency elevates inflammatory B-cell responses but inhibits inflammatory responses in macrophages.ConclusionsBCMA has multifaceted roles during inflammation that affects therapeutic efficacies of anti-CD20 and TACI-Fc in EAE. Our results from BCMA-deficient mice provide insights into the failure of atacicept in MS.

Ocular radiological findings in Children with Acute Lymphoblastic Leukemia: a cross sectional study

Background:Ophthalmic complications in pediatric acute lymphoblastic leukemia (ALL) have become serious and recognition of ocular manifestations of leukemia is fundamental. In this study, we aimed to detect radiological findings among ALL patients.Patients and methods:This cross sectional study was conducted in Pediatric Oncology Unit and Ophthalmology Department; Faculty of Medicine; Zagazig University with a total of 45 patients diagnosed with ALL (18 patients were denovo ALL, 14 patients were receiving treatment of leukemia and 13 patients finished their treatment protocol and were on follow up schedule). Detailed radiological work up was done including MRI of brain and both orbits, fundus photography, fluorescein angiography (FA), optical coherence tomography (OCT) and orbital CT.Results:Ocular manifestations were detected in 35.6% of ALL patients by ophthalmic examinations. 44.4% of ALL patients had abnormal brain MRI and most commonly, ischemic changes, post-radiation leukomalacia and CNS infiltration were detected. Twenty-two percent of the studied cases reported abnormal orbital MRI and most common abnormalities were sutural metastasis and optic nerve affection. Fundus photographs were done for selected patients. Optic nerve head leukemic infiltration, choroidal, retinal and vitreal infiltration were detected (4.44%). Moreover, CMV retinitis was detected in one patient.Conclusions:Several ocular abnormalities are present in pediatric ALL and the most common are retinal lesions. Knowledge about ocular problems in children with ALL could be beneficial to reduce morbidity and mortality.

Treatment of Aggressive T Cell Lymphoblastic Lymphoma/leukemia Using Anti-CD5 CAR T Cells

While treatment for B-cell malignancies has been revolutionized through the advent of CAR immunotherapy, similar strategies for T-cell malignancies have been limited. Additionally, T-cell leukemias and lymphomas can commonly metastasize to the CNS, where outcomes are poor and treatment options are associated with severe side effects. Consequently, the development of safer and more effective alternatives for targeting malignant T cells that have invaded the CNS remains clinically important. CD5 CAR has previously been shown to effectively target various T-cell cancers in preclinical studies. As IL-15 strengthens the anti-tumor response, we have modified CD5 CAR to secrete an IL-15/IL-15sushi complex. In a Phase I clinical trial, these CD5-IL15/IL15sushi CAR T cells were tested for safety and efficacy in a patient with refractory T-LBL with CNS infiltration. CD5-IL15/IL15sushi CAR T cells were able to rapidly ablate the CNS lymphoblasts within a few weeks, resulting in the remission of the patient’s lymphoma. Despite the presence of CD5 on normal T cells, the patient only experienced a brief, transient T-cell aplasia. These results suggest that CD5-IL15/IL15sushi CAR T cells may be a safe and useful treatment of T-cell malignancies and may be particularly beneficial for patients with CNS involvement.Graphical

Evaluation of Neurological Disorder Using Computed Tomography and Magnetic Resonance Imaging

Background: The integration of different imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) assists clinicians in diagnosing several neurological diseases at an initial stage, thereby inhibiting their development into serious medical conditions. With respect to the severity of neurological diseases and the increasing popularity of imaging tools, the current study has evaluated the findings of CT and MRI in examining neurological disorders. Methods: A retrospective study was conducted at the faculty of applied medical sciences, King Abdul-Aziz University from September 2017 to 2018 including details of 43 patients with complaints of potential neurological disturbances such as headache, oligodendroglioma, CNS infiltration, hypoxia, weakness, epilepsy and multiple sclerosis. The history of patients including their age, gender, reason for examination and findings of CT and MRI was evaluated in the study. Results: The results showed that patients in the age group of 21 to 40 years were more prone to developing neurological disorders. The major reasons for neurological examination in individuals were found to be headaches (n = 7), multiple sclerosis (n = 5) and epilepsy (n = 3). The evaluation of patients’ records revealed that only 4 patients underwent CT scans; however, all of them went through the MRI. Statistically significant results were obtained for the patients scanned and examined through MRI rather than CT. Conclusions: The results revealed MRI as more successful in diagnosing different neurological conditions in comparison with CT scan. The study further suggests that MRI can be used as an integral diagnostic approach for neurological understanding of major diseases of the central nervous system.

Nalfurafine reduces neuroinflammation and drives remyelination in models of CNS demyelinating disease.

ObjectivesMultiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to the myelin sheath, resulting in physical and cognitive disability. There is currently no cure for MS, and finding effective treatments to prevent disease progression has been challenging. Recent evidence suggests that activating kappa opioid receptors (KOR) has a beneficial effect on the progression of MS. Although many KOR agonists like U50,488 are not suitable for clinical use because of a poor side‐effect profile, nalfurafine is a potent, clinically used KOR agonist with a favorable side‐effect profile.MethodsUsing the experimental autoimmune encephalomyelitis (EAE) model, the effect of therapeutically administered nalfurafine or U50,488 on remyelination, CNS infiltration and peripheral immune responses were compared. Additionally, the cuprizone model was used to compare the effects on non‐immune demyelination.ResultsNalfurafine enabled recovery and remyelination during EAE. Additionally, it was more effective than U50,488 and promoted disease reduction when administered after chronic demyelination. Blocking KOR with the antagonist, nor‐BNI, impaired full recovery by nalfurafine, indicating that nalfurafine mediates recovery from EAE in a KOR‐dependent fashion. Furthermore, nalfurafine treatment reduced CNS infiltration (especially CD4+ and CD8+ T cells) and promoted a more immunoregulatory environment by decreasing Th17 responses. Finally, nalfurafine was able to promote remyelination in the cuprizone demyelination model, supporting the direct effect on remyelination in the absence of peripheral immune cell invasion.ConclusionsOverall, our findings support the potential of nalfurafine to promote recovery and remyelination and highlight its promise for clinical use in MS.

Low Prevalence of T-Cell Lymphoblastic Leukemia/Lymphoma in an Adult Hispanic Population: A Report of the Acute Leukemia Working Group (GTLA)

Introduction: The proportion of Acute lymphoblastic T cell leukemia/lymphoma (T-ALL/LBL) in Latinamerica (LA) is about 13% [Quiroz, 2018], compared with 25% of other publications [Litzow,2015]. In the largest leukemia series of adult Mexican population, the incidence of T-ALL was merely 2.9% with a -SG. The main objective of this study was to describe the epidemiological characteristic and survival of T-ALL in 4 reference oncology centers in Mexico. Methods: Retrospective cohort study from 2014 to 2019 in all consecutive, newly diagnosed T-ALL patients defined by flow cytometry (FC). The primary end point was to assess the survival of T-ALL in a Hispanic population. Baseline characteristics were grouped in tables and summarized as medians and ranges. Sub-groups were compared using chi-square test for binary variables and Mann-Whitney U test for quantitative variables. The Overall Survival (OS) analysis was made using Kaplan-Meier curves and comparison between groups was performed using the log-rank test with a significant P value less than 0.05 with 95% confidence interval. Results: A total of 47 patients were identified, which represent 11.1% of all acute leukemia the median of age was 30 years. The 83.7% being identified in the adolescent young-adult (AYA) group. Counterintuitively a 44.9% had a previous comorbidity (diabetes, hypertension, dyslipidemia) considering the range of age. The 85% had a low risk of mortality using the modified Charlson index, the median count of leukocytes was 36 x 109 (range 6.78-117) and 28% presented with initial hyperleukocytosis, the median LDH was 605 UI/l (range 343-1451). Applying the European Group for the Immunological Classification of Leukemias criteria: 28% were cortical T, 41.7% were mature and approximately 30% were be classified as early. Applying the early T-P (ETP) definition a total of 10 cases were identified (22.2% prevalence). The use of hyperCVAD and pediatric inspired regimens shared the same rate (41.3%), strikingly there is still a 17.4% of patients that received other type of chemotherapy for diverse reasons (economic, shortage of treatment, patient or physician preference) being the CHOP-inspired schemes the most used. The rate of complete response (CR) at 4 weeks after induction was 68.2% with 54.2% having a negative minimal residual disease (MRD). After 8 weeks a total of 34 (77.3%) patients achieved CR, with 63.6% and 66.7 % maintaining negative MRD at 16 weeks and after consolidations, respectively. Only 38.3% were able to complete the full induction treatment without a dose adjustment due to toxicity. A total of 8 (19.5%) were refractory to initial frontline treatment and eventually 23 (60.5%) relapsed, with a total of 10 patients presenting with CNS infiltration at relapse. A total of 6 patients received an allogenic stem cell transplant (ASCT), with 4 of them being alive and in CR at the 100 days cutoff. The median OS was 16 months (CI 95% 11.4-21.09) and 38.8% of our population was alive at the 24 months cutoff. This time period was drastically reduced for the non-AYA population who had a OS of 7.69 months (CI 95% 0-21.24) and 21.9% a 24 months progression free survival (PFS), compared with 16.6 months (CI 7.41-25.81) and 41.6% 24 months PFS. In the univariate analysis refractoriness to induction (p 0.039) and higher number of cycles (p 0.02) were associated with worse outcome. Conclusions: The T-ALL predominantly affects AYA populations while its incidence in our country appears to be lower even in large oncologic concentration centers. The proportion of ETP was slightly higher than that reported in other studies. Lower CR rates with a low frequency of ASCT in comparison to those reported in high income countries was observed, probably associated with the delay in implementation of pediatric-inspired regimens and lack of access to ASCT. Disclosures No relevant conflicts of interest to declare.