Tel Aviv Sourasky Medical Center Research Articles

Characterizing CRP dynamics during acute infections.

C-reactive protein (CRP) is a common proxy of inflammation, but accurate characterizations of its dynamics during acute infections are scant. The goal of this study was to examine C-reactive protein (CRP) trajectories in hospitalized patients with viral infections, confirmed bacteremia (stratified by Gram-negative or Gram-positive bacteria), and non-bacteremic infections/inflammations, considering antibiotic treatment. Electronic medical records from Tel Aviv Sourasky Medical Center (July 2007-May 2023) were analyzed. Patients with blood cultures or positive viral tests were included. CRP levels were modeled using generalized additive mixed-effects models (GAMMs) and observed up to 150h after initial infection diagnosis. Patients with initial CRP levels > 31.9 were excluded, to remove individuals already in a highly active inflammatory process. The shapes of the CRP curves were characterized and peak CRP as well as area under the CRP curve were the primary variables of interest. Viral infections had the lowest and flattest CRP curves. Non-bacteremic infections showed intermediate levels, while bacteremia (especially Gram-negative under antibiotic treatment) had the highest CRP peaks. For instance, peak CRP ranged from 15.4mg/L in viral infections without antibiotics to 140.9mg/L in Gram-negative bacteremia with antibiotics. CRP trajectories significantly differ based on infection type and antibiotic treatment. Frequent CRP measurement could be a valuable diagnostic and risk stratification tool in hospitalized patients.

Long-Term Quality of Life Among Patients Undergoing Endoscopic Pituitary Gland Surgery.

Introduction/Objectives: The endoscopic approach to skull base lesions is widely regarded as less invasive and associated with reduced morbidity, offering favorable outcomes, particularly in terms of short-term quality of life (QOL). However, to date, long-term assessments of both nasal function and tumor-related QOL remain limited. To evaluate patients' long-term nasal- and tumor-related QOL after endoscopic endonasal resection of pituitary tumors and to detect predictors for poor postoperative QOL. Study Design: This study was a prospective cohort study. Methods: All patients with pituitary adenomas who underwent trans-sphenoidal surgery at Tel Aviv Sourasky Medical Center between 2014 and 2021 were recruited. Recruited patients completed the Anterior Skull Base Disease-Specific QOL (ASBS-Q) questionnaire and the Sinonasal Outcome Test 22 (SNOT-22) questionnaire before surgery and 1, 2, and 3-5 years after surgery. Clinical data were collected and analyzed. Results: The study included 43 patients (18 women). No significant decrease was observed in tumor-related quality of life (QOL) scores, measured by ASBS-Q and SNOT-22, throughout the 5-year follow-up period. SNOT-22 score differences from the preoperative baseline at years 1, 3, and 5 were 0.81 [-4.84-6.58], 3.35 [-4.32-11.02], and 3.73 [-2.22-9.68], respectively, with no statistically significant changes. ASBS-Q scores similarly showed no significant changes over time. Subgroup analyses revealed that tumor characteristics (secreting vs. non-secreting, size), surgical factors (intraoperative cerebrospinal fluid leak, gross tumor resection, use of nasoseptal flap), and endocrine remission did not significantly impact QOL (p > 0.05 for all variables). Conclusions: Our study demonstrated that patients who underwent endoscopic pituitary lesion resection maintained high nasal- and tumor-related quality of life over a 5-year follow-up period. However, given the limitations of our study, further multi-center studies with larger patient populations are warranted to validate these results.

Adherence to the mediterranean diet among oncological outpatients in Tel Aviv Sourasky Medical Center

Adherence to the mediterranean diet among oncological outpatients in Tel Aviv Sourasky Medical Center

Routine Ankle-Brachial Index (ABI) measurement: a window into atherosclerosis and early left ventricular dysfunction in patients diagnosed with cancer

BackgroundCancer therapy is considered to cause accelerated ischemia. Ankle-Brachial Index (ABI) measurement is an inexpensive, simple, available test for the early diagnosis of peripheral artery disease (PAD); however, it is not performed routinely. We aimed to evaluate the role of routine ABI measurement for the diagnosis of PAD among patients diagnosed with cancer and whether it correlates with left ventricular (LV) dysfunction.MethodsA retrospective, single-center study including patients diagnosed with cancer at Tel Aviv Sourasky Medical Center. The cohort included patients performing routine ABI and LV global longitudinal strain (GLS) echocardiography. The primary endpoint was the prevalence of PAD and whether it correlates with LV dysfunction, defined by LV GLS absolute value < 19%. The secondary composite endpoint evaluated the association between reduced ABI to LV dysfunction and all-cause mortality.ResultsAmong 226 patients, PAD was diagnosed in 14 patients (6%). We revealed a positive correlation between ABI and LV GLS (r = 0.22, p < 0.01) with a reduced mean ABI score among patients with reduced LV GLS. A reduced mean ABI was observed among the positive composite endpoint group; however, it was not statistically significant (p = 0.35).ConclusionsWe report, for the first time to our knowledge, the routine use of ABI testing among patients diagnosed with cancer. ABI showed a significant correlation to LV GLS, implying a potential tool in the early diagnosis of atherosclerosis and cardiotoxicity. Considering its low cost and availability, future prospective trials are needed to integrate its role in routine assessment.

Epidemiology of autoimmune encephalitis and comparison to infectious causes-Experience from a tertiary center.

The incidence of autoimmune encephalitis (AIE) has risen in the last decade, yet recent studies are lacking. We compared the epidemiology of autoimmune and infectious encephalitis cases in Tel-Aviv Sourasky Medical Center (TASMC) between 2010 and 2020. All encephalitis cases, aged 18 and above, admitted to TASMC between the years 2010 and 2020 were reviewed for demographic, clinical, laboratory, and imaging data and categorized based on etiology. Two hundred and twenty-five patients with encephalitis were identified. The most common identifiable cause was viral (42%), followed by autoimmune encephalitis (35%), bacterial (18%), and fungal/parasitic (5%). The incidence of AIE cases out of the yearly admitted cases increased substantially, from 3.8/100 K in 2010 to 18.8/100 K in 2020. The incidence of viral cases also increased while those of bacterial and fungal/parasitic infections remained stable. Patients with AIE were younger compared to infectious patients (p-value <0.001) and had lower markers of systemic and cerebrospinal fluid inflammation (p-value for all <0.001). Seizures were more common among AIE patients (p-value <0.001), yet one-year mortality rates were higher among infectious patients (p-value <0.001). AIE incidence has risen significantly in our institution during the past decade, with current rates comparable to those of all infectious causes combined. Based on this cohort, clinical clues for an autoimmune etiology include a non-inflammatory cerebrospinal fluid profile, the presence of seizures, and temporal lobe imaging abnormalities (also common in herpetic encephalitis). In light of its rising incidence and the importance of early treatment, AIE should be considered in the differential diagnosis of all encephalitis cases.

Body and mind and self-consciousness awareness workshops: Improving quality of life in patients with cancer.

e24081 Background: Cancer patients, commonly experience disease and treatment related stress, anxiety and difficulties coping with life. Data suggests that body and mind are interrelated and can influences patients' quality of life (QOL). Objectives: The study aimed to evaluate the impact of patients body and mind work developing self consciousness awareness and changing behavioral patterns of women’s cancer patients, on quality of life and coping abilities. By evaluation of QOL, sleep disorders and anxiety tests done during and following our workshop. Methods: The study conducted at the Women's Cancer Center of Tel Aviv Sourasky Medical Center in Tel Aviv Israel between 2022-2024. Female cancer patients and survivors, were enrolled in workshops teaching self consciousness awareness development according to the Metaism methodology. Each workshop with groups of 10-15 patients was conducted weekly for three months, The groups were led by dedicated moderators and supervised by a psychiatrist. Patients completed a validated QOL questionnaire, sleep disorder evaluation and anxiety questionnaires, upon enrollment and every month during the workshop and up to a year from completion of the workshop. Results: one-hundred and twofemale patients diagnosed with cancer and treated at multiple cancer centers were included in the study. Patient mean age was 57 (26-75) years. Patient diagnoses included breast, ovarian, uterine, cervical, and other cancers (58%, 22%, 7%, 5%, respectively). Significant improvement was observed in the QOL assessment at the 5th week of the workshop, overall educational well-being indicator at the 3rd week of the workshop, emotional well being at the 3rd week of the workshop, physical well-being at the end of follow up. Conclusions: The study demonstrated that integrating the metaism methodology of self consciousness awareness development workshops significantly improved patient coping ability and QOL. Further investigation of larger cohorts is warranted.

Long COVID-19 Enigma: Unmasking the Role of Distinctive Personality Profiles as Risk Factors.

Background: The COVID-19 (Coronavirus disease 2019) pandemic has prompted extensive research into lingering effects, especially in 'Long COVID' patients. Despite exploration, contributing factors remain elusive; Objective: This study explores the potential link between distinctive personality profiles, particularly type D personality, and an increased risk of Long COVID; Methods: A retrospective cross-sectional study at Tel-Aviv Sourasky Medical Center's Post-COVID clinic analyzed data from 373 Long COVID patients through comprehensive questionnaires covering Long COVID syndrome, Fibromyalgia criteria, personality assessments, social support, and subjective evaluations of cognitive decline, health and life quality. In total, 116 out of 373 patients completed the questionnaire, yielding a 31% participation rate; Results: Cluster analysis revealed two groups, with Cluster 1 (N = 58) exhibiting Type D personality traits while Cluster 2 (N = 56) not meeting criteria for Type D personality. In comparison to Cluster 2, Cluster 1 patients reported heightened anxiety, depression, reduced social support, increased pain symptoms, manifestations of fibromyalgia, cognitive decline, and poor sleep quality, contributing to a diminished quality-of-life perception; Conclusions: findings highlight diverse personality profiles among Long COVID patients, emphasizing the need for tailored care. This approach shows potential for improving Long COVID patient care, aligning with the evolving personalized medicine paradigm.

Therapeutic drug monitoring in pregnancy: Levetiracetam.

Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020-2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1-2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope = .85), with no significant change in the 2nd trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester. LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period.

BlastAssist: a deep learning pipeline to measure interpretable features of human embryos.

BlastAssist: a deep learning pipeline to measure interpretable features of human embryos.

National Rapid Genome Sequencing in Neonatal Intensive Care

National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates. To evaluate the feasibility, diagnostic efficacy, and clinical utility of rtGS in neonatal intensive care units (NICUs) throughout Israel. This prospective, public health care-based, multicenter cohort study was conducted from October 2021 to December 2022 with the Community Genetics Department of the Israeli Ministry of Health and all Israeli medical genetics institutes (n = 18) and NICUs (n = 25). Critically ill neonates suspected of having a genetic etiology were offered rtGS. All sequencing, analysis, and interpretation of data were performed in a central genomics center at Tel-Aviv Sourasky Medical Center. Rapid results were expected within 10 days. A secondary analysis report, issued within 60 days, focused mainly on cases with negative rapid results and actionable secondary findings. Pathogenic, likely pathogenic, and highly suspected variants of unknown significance (VUS) were reported. Diagnostic rate, including highly suspected disease-causing VUS, and turnaround time for rapid results. Clinical utility was assessed via questionnaires circulated to treating neonatologists. A total of 130 neonates across Israel (70 [54%] male; 60 [46%] female) met inclusion criteria and were recruited. Mean (SD) age at enrollment was 12 (13) days. Mean (SD) turnaround time for rapid report was 7 (3) days. Diagnostic efficacy was 50% (65 of 130) for disease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidate (1%). Disease-causing variants included 12 chromosomal and 52 monogenic disorders as well as 1 neonate with uniparental disomy. Overall, the response rate for clinical utility questionnaires was 82% (107 of 130). Among respondents, genomic testing led to a change in medical management for 24 neonates (22%). Results led to immediate precision medicine for 6 of 65 diagnosed infants (9%), an additional 2 (3%) received palliative care, and 2 (3%) were transferred to nursing homes. In this national cohort study, rtGS in critically ill neonates was feasible and diagnostically beneficial in a public health care setting. This study is a prerequisite for implementation of rtGS for ill neonates into routine care and may aid in design of similar studies in other public health care systems.

The differential regulation of placenta trophoblast bisphosphoglycerate mutase in fetal growth restriction: preclinical study in mice and observational histological study of human placenta.

Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown. Pregnant mice were subjected to acute or chronic hypoxia (12.5% O2) resulting in reduced fetal weight. Placenta oxygen transport was assessed by blood oxygenation level dependent (BOLD) contrast magnetic resonance imaging (MRI). The placentae were analyzed via immunohistochemistry and in situ hybridization. Human placentae were selected from FGR and matched controls and analyzed by immunohistochemistry (IHC). Maternal and cord sera were analyzed by mass spectrometry. We show that murine acute and chronic gestational hypoxia recapitulates FGR phenotype and affects placental structure and morphology. Gestational hypoxia decreased labyrinth area, increased the incidence of red blood cells (RBCs) in the labyrinth while expanding the placental spiral arteries (SpA) diameter. Hypoxic placentae exhibited higher hemoglobin-oxygen affinity compared to the control. Placental abundance of Bisphosphoglycerate mutase (BPGM) was upregulated in the syncytiotrophoblast and spiral artery trophoblast cells (SpA TGCs) in the murine gestational hypoxia groups compared to the control. Hif1α levels were higher in the acute hypoxia group compared to the control. In contrast, human FGR placentae exhibited reduced BPGM levels in the syncytiotrophoblast layer compared to placentae from healthy uncomplicated pregnancies. Levels of 2,3 BPG, the product of BPGM, were lower in cord serum of human FGR placentae compared to control. Polar expression of BPGM was found in both human and mouse placentae syncytiotrophoblast, with higher expression facing the maternal circulation. Moreover, in the murine SpA TGCs expression of BPGM was concentrated exclusively in the apical cell side, in direct proximity to the maternal circulation. This study suggests a possible involvement of placental BPGM in maternal-fetal oxygen transfer, and in the pathophysiology of FGR. This work was supported by the Weizmann Krenter Foundation and the Weizmann - Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.

Do We Still Need to Perform Bone Marrow Examination in All Subjects Suspected of MDS? Evaluation and Validation of Non-Invasive (Web-Based) Algorithm

Background : The gold standard of diagnosing myelodysplastic syndromes (MDS) still requires a bone marrow examination (BME), an old invasive procedure, with possible associated pain and bleeding, and subjective interpretation with 20-25% inter-observer variability. We first developed a logistic regression formula [Oster HS et al., Leuk Res 2018], and then a non-invasive web-based diagnostic algorithm [Oster HS et al., Bld Adv 2021]. The app requires input of 10 readily available clinical and laboratory parameters (age, gender, Hb, MCV, WBC, ANC, monocytes, PLT, glucose, creatinine), resulting in diagnosing or excluding MDS, perhaps obviating the BME (Figure). Here, we performed external validation of the model, using data of MDS patients and non-MDS controls, who had not been included in the development of the model. Methods: The BM registry of Tel Aviv Sourasky Medical Center (1/2017-12/2021) was reviewed. Inclusion criteria for the MDS group were BME diagnosis, and for the controls, age &amp;gt;50yr, and unexplained anemia requiring BME. We excluded patients with other causes of anemia (renal failure; B12/folic acid or iron deficiency), active malignancy and other hematologic diseases. The relevant parameters were entered into the online model (at https://shiny.york.ac.uk/mds/) and the results of both groups were compared. In a sub-analysis, the model performance was tested in patients with lower risk (LR, IPSS-R&amp;lt;3.5) and higher risk (HR, IPSS-R≥3.5) MDS. Results: In total, 204 patients were included and compared, 103 with MDS, and 101 anemic non-MDS control patients, all with BME. The analysis of model performance (Table, upper portion) showed a sensitivity of 85.6%, specificity of 92.3%, positive predictive value (PPV) of 90.3% and a negative predictive value (NPV) of 88.4%. The algorithm was indeterminate in 26.2% of patients with MDS (BME proven), compared with 9.9% in the control group. In the sub-analysis (Table, lower portion), the model performance in the patients with LR-MDS (n=61) demonstrated sensitivity 85.1%, specificity 92.3%, PPV 90.3% and NPV 88.1%. The performance in HR-MDS (n=32), was 89.3%, 92.3%, 90.6% and 91.1%, respectively. Conclusions : This study validates the potential role of this non-invasive, easy-to-use model to assist in diagnosis, and mainly exclusion of MDS, perhaps allowing to avoid bone marrow examination in some patients. This might be especially relevant for patients suspected to have LR-MDS. Emerging technologies with data generated from peripheral blood (genetics, morphometrics) may be incorporated in the model in the future.

A Novel Approach to Epigenetic Profiling in Acute Myeloid Leukemia: Mapping Methylation and Hydroxymethylation in Genomic and Cell-Free DNA

Introduction: Acute Myeloid Leukemia (AML) is marked by uncontrolled growth of undifferentiated myeloid cells. DNA methylation patterns in AML have been thoroughly researched, however, studies on hydroxy methylation patterns, indicating active DNA methylation erasure, are still evolving. Our principal goal was to detect differential methylation and hydroxy methylation regions between AML and non-malignant samples. We proposed that simultaneous profiling of blood cells and circulating cell-free DNA would offer more insights into the disease mechanism. Therefore, we combined these data sources to provide a comprehensive epigenetic picture, assuming that this dual approach could reveal new AML biomarkers and enhance our understanding regarding AML pathobiology. Methods: We collected peripheral blood samples from 16 newly diagnosed AML patients (median age 64, age range 36-85) treated at Tel Aviv Sourasky Medical Center, Israel, and 33 age-matched healthy volunteers (NCT05735704). We utilized novel microarray technology to examine methylation and hydroxy methylation patterns in both genomic and cell-free DNA. Following differential methylation region extraction, we used DAVID functional annotation tool to interpret our results' biological significance. Results: This report presents the preliminary methylation data results. Methylation analysis unveiled 474 and 475 differentially methylated regions between AML and controls in genomic and cell-free DNA analysis, respectively, with only 18 common regions. The clear AML-control distinction is displayed in hierarchical clustering heatmaps (Figure 1a, 1b). Further DAVID tool analysis revealed enrichment in biological processes such as aging, cell cycle regulation, cell morphogenesis, and MAP kinase activity - processes closely linked with AML. Notably, genomic data analysis showed significant enrichment of the ‘transcriptional misregulation in cancer’ pathway, involving genes encoding vital transcription factors for cell development and differentiation. Figure 2 demonstrates the biological pathways for genomic and cell free data analysis. Conclusions: This research underscores the importance of combined epigenetic data from malignant tissue and its microenvironment, obtained by examining genomic and cell-free DNA. Both datasets exhibit striking differences between AML and control samples. We detected enrichment of AML-related biological pathways within differential regions. Our findings of enriched biological pathways align with existing literature, reinforce our analysis validity, and support our combined view of methylation patterns in genomic and cell-free DNA. By suggesting a combined view of these two types of DNA, we provide a more comprehensive perspective on AML's complex epigenetic landscape. It underscores the value of such integrative epigenetic profiling in shedding new light on the intricacies of AML development and progression, which may eventually guide the discovery of novel therapeutic targets.

Unraveling the Mechanism of Action of Bispecific T-Cell Engagers in B-Cell Acute Lymphoblastic Leukemia Using Advanced Single-Cell Multiomics

Background Bispecific T-cell engagers (BiTEs) stimulate T lymphocytes proximate to tumor cells, inducing T-cell stimulation and tumor killing. Blinatumomab, an anti CD3-CD19, was the first to be approved with overall response rates of up to 80% in refractory B-cell Acute Lymphoblastic Leukemia (B-ALL). To overcome resistance and to develop next-generation BiTEs, we need to build on blinatumomab's success and better understand BiTEs mode of action and interaction with the tumor microenvironment (TME). Here, we apply advanced multiomics to examine blinatumomab's activation signatures and the sustained dynamics in the tumor and bone marrow (BM) immune TME. Methods Physically interacting Cells sequencing (PIC-seq) is an advanced multiomics technology deciphering the crosstalk between the cellular components of an immunological synapse (Cohen et al., 2022; Giladi et al., 2020). To assess Immediate activation signatures, we applied PIC-seq on a model of B-ALL cell lines (RS4;11, NALM-6) and lymphocytes obtained from healthy subjects, activated by blinatumomab, compared to no-treatment and activation with anti CD3-CD28 antibodies. To examine the Sustained effects on the immune TME, we performed a longitudinal single-cell RNA sequencing of the bone BM of adult B-ALL patients, before and after treatment with blinatumomab in the Division of Hematology in the Tel Aviv Sourasky Medical Center in 2021-22. Results Immediate activation Applying PIC-seq on n=16,543 CD3 and CD19+ cells, we identified the distinct gene expression of ‘blinatumomab-activated lymphocytes’ (Figure 1). Blinatumomab induced cellular synapses composed of specific T lymphocytes subsets along the activation continuum, namely: effector T cells (CCL5, GNLY, NKG7), early IFN-G activation (IRF1, GBP5), activated cytotoxic (Xcl1-2, IFN-G) and proliferating T cells (CD69, CCND2) . ‘Blinatumomab-activated lymphocytes’ were characterized by a unique activation signature: upregulation of cytotoxicity (Xcl1, IFN-G, GNLY), co-stimulation and B-T cells crosstalk (CD40, CD27, TNFRSF18), immune recruitment (CXCL10, CCL4) and antigen-presentation (TNFSF14, ITGB2) pathways. Late synapses also expressed immunoregulatory molecules (TNFAIP8L2). This signature differed from classical anti CD3-CD28 induced activation and is independent of the donor and the target-cell identity. The malignant cells' response varied: RS4;11 cells manifested cellular senescence, while NALM-6 upregulated INFG-induced apoptotic pathways, suggesting indirect killing in the mechanism of action of BiTEs. Data on the introduction of primary B-ALL patients' cells will be presented at the ASH. Sustained effects We profiled &amp;gt;11,000 cells from three patients: Patient 1, 31-year-old (y/o) female, primary refractory B-ALL (50% BM blasts), attaining transient MRD negativity. Patient 2, 71-y/o male, primary refractory Ph+ B-ALL (74% BM blasts) achieving reduction in MRD following first cycle. Patient 3, 71 y/o, Ph+ B-ALL, treated as consolidation therapy, achieving MRD negativity. Blinatumomab induced a dramatic perturbation in the lymphocytic and myeloid compartments of the BM and was highly patient-specific ( Figure 2). The BM lymphocytic compartment prior to initiation of blinatumomab in molecular remission (patient 3) was characterized by active T and Natural Killer cell states, compared to an abundancy of naïve lymphocytes in active disease (patients 1 and 2). There were no signs of T-cell exhaustion pre or post treatment in all patients. Post-treatment, CD8 T-Central Memory cells proliferated in all patients. Patients treated for active disease (patients 2 and 3), had an expansion of the Tregs population post-treatment. In the myeloid compartment, patients with active disease had more non-classical monocytes, known to correlate with poor prognosis. These were replaced by classical monocytes following treatment, in addition to the emergence of a macrophage-precursor population. Data on the BM and peripheral blood dynamics of an additional six patients will be presented at the ASH. Conclusions We present an advanced single cell dissection of blinatumomab-induced target-effector interaction, providing novel insights into the mechanism of action and TME dynamics to guide patient selection and next generation BiTEs. A larger patients' cohort and introduction of patients' cells to the PIC-seq in vitro model will be presented at the ASH.

Outcomes of Acute Myeloid Leukemia Patients Suffering from an Additional Active Malignancy Treated with Venetoclax and Azacitidine: A Single Center Experience

Introduction: Venetoclax (ven) and azacitidine (aza) has become the standard of care for the treatment of patients (pts) with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy on the basis of the phase III VIALE-A trial, which showed prolonged overall survival with ven-aza vs. placebo-aza. Pts with active additional malignancies (AM) at the time of AML diagnosis are often unfit for intensive chemotherapy but are excluded from clinical trials, including VIALE-A. We aim to compare the characteristics and outcomes of AML patients with AM vs without AM (non-AM), all treated in a real world setting. Methods: A retrospective analysis including all AML pts diagnosed between Jan 2019 and Apr 2023 and treated with ven-aza in Tel Aviv Sourasky Medical Center. We defined active malignancy as any malignancy additional to AML that was diagnosed within 2 years prior to or concomitantly with the diagnosis of AML, or receiving active treatment at the time of the diagnosis of AML. We excluded prior MDS, MPN and basal cell or localized squamous cell carcinomas of the skin. We defined patients eligible for registration trial (RTE) as pts meeting the inclusion criteria for the VIALE-A trial. We compared categorical and continuous variables as appropriate, and examined survival outcomes by a Kaplan Meier and Log-Rank test. Event free survival (EFS) was defined as time until treatment failure (2 courses of ven-aza without achievement of response), relapse, or death. Results: We analyzed 113 pts diagnosed with AML and treated with ven-aza. 17 patients had an additional AM; 11 solid and 6 hematological, at the time of AML diagnosis. Six pts had more than one additional malignancy. Six patients had newly diagnosed AM, 6 had AM in remission and were treated with maintenance therapy at the time of AML diagnosis, and 5 had an active relapsed / progressive AM. Five patients received treatment for AM concomitantly or alternating with ven-aza, including surgery, letrozole, olaparib, arabiterone acetate, pazopanib, and trabectedin. We compared the baseline characteristics and outcomes of AML pts with AM to AML pts treated with ven-aza who did not have AM (96 pts, non-AM) and pts who met inclusion criteria for the registration VIALE-A trial (57 pts, RTE). Pts with AM were younger than non-AM pts or RTE pts (11.8% over the age of 75 vs. 67% and 68%; respectively, p&amp;lt;0.001), and had a slightly higher baseline creatinine level than RTE pts (median=1.1 range 0.6-1.4 mg/dL vs. median=0.9 range 0.5-1.3 mg/dL; p=0.01). ECOG functional status, ELN risk category, and baseline cell counts were similar between all groups. Treatment with ven-aza was initiated within a median of 6 days from diagnosis in AM pts (range 1-20). 58.2% of AM pts achieved CR/CRi vs. 57% of non-AM pts and 68% of RTE pts (p=0.9 and p=0.46, respectively). The 30 day mortality rate for AM pts was 17.6% vs 7.3% for non-AM pts (p=0.17) and 3.5% for RTE pts (p=0.07). Causes of early mortality among AM patients were non-responsive/progressive AML (2 pts) and sepsis (1 pt). Overall, 13 of 17 AM pts died, 7 from progressive AML, 3 from progressive additional malignancy and 3 from treatment complications. Six of the AM pts underwent allogeneic stem cell transplant (35%) vs. 14 non-AM pts (14.5%, p=0.07) and 11 RTE pts (19.2%, p=0.19). Median length of follow-up was 23.8 months (95% CI, 12.9-34.7). Overall survival (OS) EFS, and relapse free survival (RFS) were similar between AM and non-AM pts. (Figure 1A). ECOG score other than 0 (p=0.009, HR=2.2 95% CI 1.2-4.1) and secondary AML type (p=0.049, HR=1.8, 95% CI 1.001-3.124) but not AM (p=0.354, HR=1.42, 95% CI 0.67-3.03) were associated with reduced overall survival in a multivariate analysis which included age, sex and ELN risk category. A trend for worse survival outcomes in AM vs. RTE pts was noted (HR=1.82, CI 0.95-3.46 p = 0.068) (Figure 1B). EFS and RFS were similar between AM and RTE pts. Conclusions: Among pts diagnosed with AML and an additional active malignancy, treatment with ven-aza in the real world setting resulted in similar response and survival rates as in patients without active malignancies, but with a trend for worse overall survival and higher early mortality than pts who meet the eligibility criteria of the VIALE-A trial. 21.8% of AM pts were alive at 24 months. These results imply that treatment for AML for pts with active malignancy with ven-aza is feasible, and should not be withheld from these pts.

FRI542 Long-term Metabolic Outcomes In Graves’ Disease: Is There A Difference Between Oral Anti-thyroid Medications And Radioactive Iodine Treatment?

Abstract Disclosure: E. Shemesh: None. T. Kolitz: None. A. Nathan: None. K.M. Tordjman: None. Y. Greenman: None. E. Izkhakov: None. Introduction: The treatment of hyperthyroidism in patients with Graves’ disease (GD) is associated with various metabolic comorbidities, including weight gain and an increased risk of cardiovascular and cerebrovascular diseases. Few studies have assessed the potential differences in metabolic outcomes between radioactive iodine (RAI) and oral anti-thyroid drug (ATD) therapies. Aim: We sought to investigate the long-term (&amp;gt;10 years) metabolic effects of RAI versus ATD therapy in GD. We also compared the occurrence rates following long-term use to those with short-term (&amp;lt;5 years) use in order to explore a potential "legacy effect". Hypothesis: RAI and oral ATD treatment will differ in their associated risk of metabolic sequelae, including the occurrence of hypertension, dyslipidemia, obesity, and diabetes. Methods: Patients attending the Institute of Endocrinology at the Tel Aviv Sourasky Medical Center filled in a questionnaire on post-RAI or post-ATD treatment for GD. Results: In total, 143 participants had been followed-up for 5 years, and 87 of them (age range 31-88 years, 65 females [74.7%]) had completed &amp;gt;10 years of follow-up (mean follow-up period 14±1 years). During the initial 5-year follow-up period, RAI treatment was associated with a significantly increased rate of obesity and dyslipidemia in the short-term, but no comparable differences persisted into the &amp;gt;10-year follow-up period. However, mean fasting glucose concentrations were higher among RAI recipients compared to ATD recipients (106 and 91 mg/dL, respectively, p=0.037) even after 10 years, and the mean triglyceride concentration was also higher in the former (127 and 88 mg/dL, respectively, p=0.02). There were no significant group differences in the rates of diabetes mellitus or dyslipidemia in the &amp;gt;10-year follow-up period. Conclusions: RAI therapy is associated with long-term higher glucose and triglyceride levels compered to ATD therapy in patients with GD. Clinical metabolic diagnosis are comparable. The significant group differences in the occurrence of metabolic morbidities that had been observed after the first 5 years of follow-up persisted to a greater or lesser extent into the extended &amp;gt;10-year follow-up period, as evidenced by fasting glucose and triglycerides concentrations Presentation: Friday, June 16, 2023

FRI544 Serological Profile In Rheumatoid Arthritis And Its Interplay With Autoimmune Thyroid Diseases

Abstract Disclosure: T. Kolitz: None. S. Kivity: None. I. Tessler: None. Y. Marcus-Perlman: None. E. Izkhakov: None. I. Yaish: None. Y. Greenman: None. Objective: Autoimmune thyroid diseases (AITD) are the most common organ-specific autoimmune disorders, with an estimated prevalence of 5%. AITD encompass the clinical scope of Hashimoto’s thyroiditis (HT) and Graves’s disease (GD). Rheumatoid arthritis (RA) is a relatively common non-organ-specific autoimmune disease with an estimated global prevalence of 0.5-1%. Numerous studies have investigated the association of thyroid disorders and RA in various populations, but results were inconsistent. This study is aimed to assess the rate of AITD in RA patients and to further investigate these rates in subgroups of patients with seronegative RA, seropositive RA and dual-positive RA antibodies [i.e., positive anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF)]. Methods: We used a big-data platform (MDClone Ltd., Israel) to create a cohort of RA patients with and without coexistent AITD. The cohort included 1316 patients who were treated in the Tel Aviv Sourasky Medical Center for any diagnosis between January 2008 and December 2022. Results: There were 340 men (25.8%) and 976 (74.2%) women in the cohort. The mean age at time of initial coding of RA diagnosis in our referral center was 62.5±15 years. AITD was found in 15.5% of the entire RA cohort. Hypothyroidism was the most common thyroid-associated diagnosis (in 95.8% of patients with RA and AITD). When RA patients were further sub-classified to seronegative, seropositive, and dual-positive RA, the rates of AITD were 11.8%, 17.6% and 25%, respectively (p=0.007). AITD rates in seropositive women and men were 20.6% and 8%, respectively (p&amp;lt;0.001). In the RA-seronegative subgroup, the rate of AITD was 15.6% in women and 2.7% in men (p&amp;lt;0.001). The mortality rates in RA-seronegative patients, RA-seronegative patients with AITD, RA-seropositive patients and RA-seropositive patients with AITD were 5.5%, 8.3%, 21.6% and 29.5%, respectively (p=0.05). Conclusion: Our findings suggest that the prevalence of AITD in patients with RA is associated with the specific serological profile, with highest rates in RA patients who are positive for both anti-CCP and RF. Randomized prospective studies are required to explore any cause-and-effect correlation and to delineate the impact of AITD on RA outcome and mortality rates. Presentation: Friday, June 16, 2023

The COVID-19 pfizer BioNTech mRNA vaccine and the frequency of seizures

ObjectiveA nationwide vaccination operation against Coronavirus disease 2019 (COVID-19) using the BNT162b2 mRNA vaccine commenced in Israel in December 2020. People older than 60 were prioritized, and most were vaccinated shortly after. Seizures are not infrequently attributed to the vaccine despite a lack of supporting evidence. People with epilepsy (PWE) are often reluctant to get the vaccine due to concerns of seizure aggravation. We aim to examine the effect of the vaccine effort on the frequency of both new-onset seizures and recurrent seizures in PWE. Methods: All adults who presented to the emergency department (ED) of Tel Aviv Sourasky Medical Center between January 1st and May 31st, 2017–2021, and were diagnosed with seizures were included. Demographic, clinical, and vaccination status parameters were collected using MDClone, a data acquisition tool. Vaccination rates in the general population were obtained from official governmental publications. Statistics included a sub-analysis of patients with the highest vaccination rate, people older than 60. Results: 1675 cases were included. The numbers of ED visits and hospital admissions due to seizures in 2021 were comparable to preceding years after adjusting for the total number of ED visits at the same time. Out of 339 cases in 2021, 134 patients older than 60 years old presented to the ED (39.5%) compared to 124–151 in 2017–2019 (37–44%) and 103 in 2020 (33%). The vaccination rate among patients hospitalized due to seizures was similar to the general population of the same age group during the same period in Israel. There was no temporal relation between vaccination and hospitalization due to a seizure. Significance: Despite very high vaccination rates in the general population in Israel and especially among people older than 60 years, no increase was observed in ED presentations due to seizures. No temporal relation was observed between vaccination and hospitalization due to a seizure. We conclude that the mass vaccination with the Pfizer BioNTech mRNA vaccine is not associated with increased seizure propensity.

Transitioning from having no metabolic abnormality nor obesity to metabolic impairment in a cohort of apparently healthy adults

IntroductionThe global prevalence of metabolic syndrome and its association with increased morbidity and mortality has been rigorously studied. However, the true prevalence of “metabolic health”, i.e. individuals without any metabolic abnormalities is not clear. Here, we sought to determine the prevalence of “metabolically healthy” individuals and characterize the “transition phase” from metabolic health to development of dysfunction over a follow-up period of 5 years.MethodsWe included 20,507 individuals from the Tel Aviv Sourasky Medical Center Inflammation Survey (TAMCIS) which comprises apparently healthy individuals attending their annual health survey. A second follow-up visit was documented after 4.8 (± 0.6) years. We defined a group of metabolically healthy participants without metabolic abnormalities nor obesity and compared their characteristics and change in biomarkers over time to participants who developed metabolic impairment on their follow-up visit. The intersections of all metabolic syndrome components and elevated high sensitivity C-reactive protein (hs-CRP) were also analyzed.ResultsA quarter of the cohort (5379 individuals, (26.2%) did not fulfill any metabolic syndrome criteria during their baseline visit. A total of 985 individuals (12.7% of returning participants) developed metabolic criteria over time with hypertension being the most prevalent component to develop among these participants. Individuals that became metabolically impaired over time demonstrated increased overlap between metabolic syndrome criteria and elevated hs-CRP levels. The group that became metabolically impaired over time also presented higher delta values of WBC, RBC, liver biomarkers, and uric acid compared with participants who were consistently metabolically impaired. LDL-C (low-density lipoprotein cholesterol) delta levels were similar.ConclusionsRoughly one-quarter of apparently healthy adults are defined as “metabolically healthy” according to current definitions. The transition from health to metabolic dysfunction is accompanied with active inflammation and several non-metabolic syndrome biomarkers. Aggressive screening for these biomarkers, blood pressure and hs-CRP might help identify apparently healthy individuals at increased risk of developing metabolic syndrome over time.

Circadian clock gene disruption in white blood cells of patients with celiac disease

Clock gene disruption has been reported in inflammatory and autoimmune diseases. Specifically, it has been shown that clock gene expression is down-regulated in intestinal tissue and peripheral blood mononuclear cells of patients with inflammatory bowel disease (IBD). We aimed to determine the systemic expression of the circadian clock genes in newly diagnosed untreated, young patients with celiac disease (CeD). We prospectively enrolled patients younger than 20 years old who underwent diagnostic endoscopic procedures either for CeD diagnosis or due to other gastrointestinal complaints, at the pediatric and adult gastroenterology units, the Tel Aviv Sourasky Medical Center from 8/2016–8/2022. Demographic data, anthropometric parameters, and endoscopic macroscopic and microscopic findings were obtained. Blood samples were obtained to determine tissue transglutaminase (tTG) and core clock gene (CLOCK, BMAL1, PER1, PER2, CRY1, CRY2) expression in white blood cells (WBC). Thirty individuals were analyzed (18 with newly diagnosed CeD and 12 controls). Expression of the clock genes CLOCK, BMAL1, CRY2, PER1 and PER2 was significantly reduced in CeD patients compared to controls, while CRY1 did not differ between the groups. In conclusion, newly diagnosed, untreated, young patients with CeD have reduced clock gene expression in WBC compared to controls. These results suggest that, in CeD, the inflammatory response is associated with systemic disruption of clock gene expression, as is manifested in other inflammatory and autoimmune diseases. ClinicalTrials.gov identifierNCT03662646.