Comparison of pre-mortem 2D-3D ultrasound examination to post-mortem micro-CT of carotid arteries - first experiences.

Background and purpose:

A prerequisite for the treatment of carotid atherosclerosis is the accurate measurement of the stenosis, that is most commonly evaluated by duplex ultrasonography. In this study, we aimed to verify the reliability of 2D and 3D ultrasonography, comparing the data to results of post-mortem micro-CT examination.

Neurological patients with any life-threatening, presumably fatal neurological disease were enrolled. Ultrasound examinations were performed with a Philips Epiq 5G machine, using a VL13-5 broadband linear volume array transducer. Plaque length, diameter and vessel area reduction (stenosis) were calculated using the 2D images. Finally, the stenosis was reassessed using automatized, 3D application as well. After the death of the patient, autopsy was performed, during which the previously examined carotid artery was removed. The samples were examined with micro-CT. Similar to the ultrasound examination, plaque length, diameter and vessel area reduction (stenosis) were determined.

Ten vessels of seven patients were eligible for complex comparison. Plaque diameter and length measured by CT did not correlate with the ultrasound data. CT-measured axial plaque and vessel areas showed no correlation with ultrasound results either. While determining the strength of correlation between stenoses measured by the different modalities, significant correlation was found between the results measured by ultrasound (2D) and CT (Pearson r: 0.902, P<0.001).

Three-dimensional ultrasound analysis is a spectacular method for examining carotid plaques, as it can assist in a more detailed evaluation of the plaque morphology and composition, thereby identifying plaques with a particularly high risk of stroke. Micro-CT is an excellent tool for the exact determination of calcified plaque areas, but ultrasound images are not suitable yet for such a precise examination due to acoustic shadowing and artifacts.

Role of carotid duplex in the assessment of carotid artery restenosis after endarterectomy or stenting.

Introduction: Redo carotid endarterectomy (CEA) and carotid stenting (CAS) are often performed when there is evidence of post-procedural restenosis. The incidence of restenosis after carotid reconstruction is not negligible, ranging from 5 to 33%. The diagnosis of significant internal carotid artery (ICA) restenosis is usually based on duplex ultrasound (US) criteria, mostly on peak-systolic flow velocity (PSV). However, there have been no generally accepted duplex US criteria for carotid restenosis after CAS or CEA. Methods: In this systematic review, the PubMed/ Medline and Scopus databases were screened to find trials that reported duplex US criteria for significant restenosis after CEA and/or CAS. Only those reports were analyzed in which the restenoses were also assessed by CT/MR or digital subtraction angiography as comparators for duplex US. Results: Fourteen studies met the predetermined search criteria and were included in this review. In most studies, PSV thresholds for significant in-stent ICA restenosis after CAS were higher than those for significant stenosis in non-procedurally treated (native) ICA. Many fewer studies investigated the US criteria for ICA restenosis after CEA. Despite the heterogeneous data, there is a consensus to use higher flow velocity thresholds for assessment of stenosis in stented ICA than in native ICA; however, there have been insufficient data about the flow velocity criteria for significant restenosis after CEA. Although the flow velocity thresholds for restenosis after CAS and CEA seem to be different, the large studies used the same duplex criteria to define restenosis after the two procedures. Moreover, different studies used different flow velocity thresholds to define ICA restenosis, leading to variable restenosis rates. Discussion: We conclude that (1) further examinations are warranted to determine appropriate duplex US criteria for restenosis after CAS and CEA, (2) single duplex US parameter cannot be used to reliably determine the degree of ICA restenosis, (3) inappropriate US criteria used in large studies may have led to false restenosis rates, and (4) studies are required to determine if there is a benefit from redo carotid artery procedure, such as redo-CEA or redo-CAS, starting with prospective risk stratification studies using current best practice non-invasive care alone.

Seasonal patterns in the epidemiology of Bell's palsy in Hungary.

Introduction: Epidemiological data on Bell's palsy are vital for elucidating disease prevalence and enhancing therapeutic options. Our objective was to explore the prevalence and possible risk factors associated with Bell's palsy recurrence in the Clinical Center of the University of Debrecen service area. Secondary data analysis was performed using hospital discharge data, including patient information and comorbidities. Methods: Data was obtained from the Clinical Center of the University of Debrecen, on Bell's palsy patients who were treated at the hospital between January 1, 2015 and December 31, 2021. Multiple logistic regression analysis was used to examine the factors associated with Bell's palsy recurrence. Results: Of the 613 patients analyzed, 5.87% had recurrent paralysis, and the median time interval between episodes was 315 days. Hypertension was significantly associated with Bell's palsy recurrence. Moreover, seasonal distribution analysis revealed that the number of Bell's palsy episodes was higher in colder seasons, with spring and winter having a significantly higher number of episodes than summer and autumn. Discussion: This study provides insights into the prevalence and associated risk factors of Bell's palsy recurrence, which could aid in its management and help reduce the long-term consequences of the disease. Further research is necessary to determine the precise mechanisms underlying these findings.

PersonALL: a genetic scoring guide for personalized risk assessment in pediatric B-cell precursor acute lymphoblastic leukemia.

BACKGROUND: Recurrent genetic lesions provide basis for risk assessment in pediatric acute lymphoblastic leukemia (ALL). However, current prognostic classifiers rely on a limited number of predefined sets of alterations. METHODS: Disease-relevant copy number aberrations (CNAs) were screened genome-wide in 260 children with B-cell precursor ALL. Results were integrated with cytogenetic data to improve risk assessment. RESULTS: CNAs were detected in 93.8% (n = 244) of the patients. First, cytogenetic profiles were combined with IKZF1 status (IKZF1normal, IKZF1del and IKZF1plus) and three prognostic subgroups were distinguished with significantly different 5-year event-free survival (EFS) rates, IKAROS-low (n = 215): 86.3%, IKAROS-medium (n = 27): 57.4% and IKAROS-high (n = 18): 37.5%. Second, contribution of genetic aberrations to the clinical outcome was assessed and an aberration-specific score was assigned to each prognostically relevant alteration. By aggregating the scores of aberrations emerging in individual patients, personalized cumulative values were calculated and used for defining four prognostic subgroups with distinct clinical outcomes. Two favorable subgroups included 60% of patients (n = 157) with a 5-year EFS of 96.3% (excellent risk, n = 105) and 87.2% (good risk, n = 52), respectively; while 40% of patients (n = 103) showed high (n = 74) or ultra-poor (n = 29) risk profile (5-year EFS: 67.4% and 39.0%, respectively). CONCLUSIONS: PersonALL, our conceptually novel prognostic classifier considers all combinations of co-segregating genetic alterations, providing a highly personalized patient stratification.

Chromosomal breakage tests in the differential diagnosis of Fanconi anemia and aplastic anemia.

BACKGROUND: FA patients are hypersensitive to preconditioning of bone marrow transplantation. OBJECTIVE: Assessment of the power of mitomycin C (MMC) test to assign FA patients. METHODS: We analysed 195 patients with hematological disorders using spontaneous and two types of chromosomal breakage tests (MMC and bleomycin). In case of presumed Ataxia telangiectasia (AT), patients' blood was irradiated in vitro to determine the radiosensitivity of the patients. RESULTS: Seven patients were diagnosed as having FA. The number of spontaneous chromosomal aberrations was significantly higher in FA patients than in aplastic anemia (AA) patients including chromatid breaks, exchanges, total aberrations, aberrant cells. MMC-induced ≥10 break/cell was 83.9 ± 11.4% in FA patients and 1.94 ± 0.41% in AA patients (p < .0001). The difference in bleomycin-induced breaks/cell was also significant: 2.01 ± 0.25 (FA) versus 1.30 ± 0.10 (AA) (p = .019). Seven patients showed increased radiation sensitivity. Both dicentric + ring, and total aberrations were significantly higher at 3 and 6 Gy compared to controls. CONCLUSIONS: MMC and Bleomycin tests together proved to be more informative than MMC test alone for the diagnostic classification of AA patients, while in vitro irradiation tests could help detect radiosensitive-as such, individuals with AT.

Next-Generation Sequencing-Based Genomic Profiling of Children with Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) represents a major cause of childhood leukemic mortality, with only a limited number of studies investigating the molecular landscape of the disease. Here, we present an integrative analysis of cytogenetic and molecular profiles of 75 patients with pediatric AML from a multicentric, real-world patient cohort treated according to AML Berlin-Frankfurt-Münster protocols. Targeted next-generation sequencing of 54 genes revealed 17 genes that were recurrently mutated in >5% of patients. Considerable differences were observed in the mutational profiles compared with previous studies, as BCORL1, CUX1, KDM6A, PHF6, and STAG2 mutations were detected at a higher frequency than previously reported, whereas KIT, NRAS, and KRAS were less frequently mutated. Our study identified novel recurrent mutations at diagnosis in the BCORL1 gene in 9% of the patients. Tumor suppressor gene (PHF6, TP53, and WT1) mutations were found to be associated with induction failure and shorter event-free survival, suggesting important roles of these alterations in resistance to therapy and disease progression. Comparison of the mutational landscape at diagnosis and relapse revealed an enrichment of mutations in tumor suppressor genes (16.2% versus 44.4%) and transcription factors (35.1% versus 55.6%) at relapse. Our findings shed further light on the heterogeneity of pediatric AML and identify previously unappreciated alterations that may lead to improved molecular characterization and risk stratification of pediatric AML.

Daily serum phosphate increase as early and reliable indicator of kidney injury in children with leukemia and lymphoma developing tumor lysis syndrome.

BACKGROUND: Tumor lysis syndrome (TLS) and its most serious complication, acute kidney injury (AKI) are one of the emergency conditions in onco-hematology. It is difficult to predict the degree of kidney involvement. Therefore, we studied children with leukemia and lymphoma treated in four Hungarian tertiary centers (inpatient university clinics) retrospectively (2006-2016) from a nephrological aspect. METHOD: Data of 31 pediatric patients were obtained from electronic- and paper-based medical records. Physical status, laboratory test results, treatments, and outcomes were assessed. Patients were analyzed according to both "traditional" TLS groupings, as laboratory TLS or clinical TLS, and nephrological aspect based on pRIFLE classification, as mild or severe AKI. RESULTS: Significant differences were found between the changes in parameters of phosphate homeostasis and urea levels in both classifications. Compared to age-specific normal phosphate ranges, before the development of TLS, hypophosphatemia was common (19/31 cases), while in the post-TLS period, hyperphosphatemia was observed (26/31 cases) most frequently. The rate of daily change in serum phosphate level was significant in the nephrological subgroups, but peaks of serum phosphate level show only a moderate increase. The calculated cut-off value of daily serum phosphate level increased before AKI was 0.32 mmol/L per ROC analysis for severe TLS-AKI. The 24-h urinalysis data of eight patients revealed transiently increased phosphate excretion only in those patients with TLS in whom serum phosphate was elevated in parallel. CONCLUSION: Daily serum phosphate level increase can serve as a prognostic factor for the severity of pediatric TLS, as well as predict the severity of kidney involvement. A higher resolution version of the Graphical abstract is available as Supplementary information.

Real-world performance analysis of a novel computational method in the precision oncology of pediatric tumors.

BACKGROUND: The utility of routine extensive molecular profiling of pediatric tumors is a matter of debate due to the high number of genetic alterations of unknown significance or low evidence and the lack of standardized and personalized decision support methods. Digital drug assignment (DDA) is a novel computational method to prioritize treatment options by aggregating numerous evidence-based associations between multiple drivers, targets, and targeted agents. DDA has been validated to improve personalized treatment decisions based on the outcome data of adult patients treated in the SHIVA01 clinical trial. The aim of this study was to evaluate the utility of DDA in pediatric oncology. METHODS: Between 2017 and 2020, 103 high-risk pediatric cancer patients (< 21 years) were involved in our precision oncology program, and samples from 100 patients were eligible for further analysis. Tissue or blood samples were analyzed by whole-exome (WES) or targeted panel sequencing and other molecular diagnostic modalities and processed by a software system using the DDA algorithm for therapeutic decision support. Finally, a molecular tumor board (MTB) evaluated the results to provide therapy recommendations. RESULTS: Of the 100 cases with comprehensive molecular diagnostic data, 88 yielded WES and 12 panel sequencing results. DDA identified matching off-label targeted treatment options (actionability) in 72/100 cases (72%), while 57/100 (57%) showed potential drug resistance. Actionability reached 88% (29/33) by 2020 due to the continuous updates of the evidence database. MTB approved the clinical use of a DDA-top-listed treatment in 56 of 72 actionable cases (78%). The approved therapies had significantly higher aggregated evidence levels (AELs) than dismissed therapies. Filtering of WES results for targeted panels missed important mutations affecting therapy selection. CONCLUSIONS: DDA is a promising approach to overcome challenges associated with the interpretation of extensive molecular profiling in the routine care of high-risk pediatric cancers. Knowledgebase updates enable automatic interpretation of a continuously expanding gene set, a "virtual" panel, filtered out from genome-wide analysis to always maximize the performance of precision treatment planning.

Low α2-Plasmin Inhibitor Antigen Levels on Admission Are Associated With More Severe Stroke and Unfavorable Outcomes in Acute Ischemic Stroke Patients Treated With Intravenous Thrombolysis.

Background: Intravenous administration of recombinant tissue plasminogen activator (rt-PA) fails to succeed in a subset of acute ischemic stroke (AIS) patients, while in approximately 6-8% of cases intracerebral hemorrhage (ICH) occurs as side effect. Objective: Here, we aimed to investigate α2-plasmin inhibitor (α2-PI) levels during thrombolysis and to find out whether they predict therapy outcomes in AIS patients. Patients/Methods: In this prospective, observational study, blood samples of 421 AIS patients, all undergoing i.v. thrombolysis by rt-PA within 4.5 h of their symptom onset, were taken before and 24 h after thrombolysis. In a subset of patients (n = 131), blood was also obtained immediately post-lysis. α2-PI activity and antigen levels were measured by chromogenic assay and an in-house ELISA detecting all forms of α2-PI. α2-PI Arg6Trp polymorphism was identified in all patients. Stroke severity was determined by NIHSS on admission and day 7. Therapy-associated ICH was classified according to ECASSII. Long-term outcomes were defined at 3 months post-event by the modified Rankin Scale (mRS). Results: Median α2-PI activity and antigen levels showed a significant drop immediately post-lysis and increased to subnormal levels at 24 h post-event. Admission α2-PI levels showed a significant negative stepwise association with stroke severity. Patients with favorable long-term outcomes (mRS 0-1) had significantly higher admission α2-PI antigen levels (median:61.6 [IQR:55.9-70.5] mg/L) as compared to patients with poor outcomes (mRS 2-5: median:59.7 [IQR:54.5-69.1] and mRS 6: median:56.0 [IQR:48.5-61.0] mg/L, p < 0.001). In a Kaplan-Meier survival analysis, patients with an α2-PI antigen in the highest quartile on admission showed significantly better long-term survival as compared to those with α2-PI antigen in the lowest quartile (HR: 4.54; 95%CI:1.92-10.8, p < 0.001); however, in a multivariate analysis, a low admission α2-PI antigen did not prove to be an independent risk factor of poor long-term outcomes. In patients with therapy-related ICH (n = 34), admission α2-PI antigen levels were significantly, but only marginally, lower as compared to those without hemorrhage. Conclusions: Low α2-PI antigen levels on admission were associated with more severe strokes and poor long-term outcomes in this cohort. Our results suggest that in case of more severe strokes, α2-PI may be involved in the limited efficacy of rt-PA thrombolysis.

High Neutrophil-Lymphocyte Ratio and Low Lymphocyte-Monocyte Ratio Combination after Thrombolysis Is a Potential Predictor of Poor Functional Outcome of Acute Ischemic Stroke.

(1) Background: Ischemic stroke is one of the leading causes of death and disability. An inflammatory response is observed in multiple stages of cerebral ischemia, particularly in the acute phase. Recent publications revealed that the neutrophil−lymphocyte ratio (NLR) and lymphocyte−monocyte ratio (LMR) may be used to predict long-term prognosis in acute ischemic stroke (AIS) after thrombolysis. To test whether there is a relationship between the combination of these parameters and long-term prognosis, we analyzed the NLR−LMR combination in AIS patients treated with intravenous recombinant tissue plasminogen activator (rtPA); (2) Methods: The study included 285 adults with a diagnosis of AIS and rtPA treatment within a 4.5 h time window. Blood samples were obtained at admission and 24 h after thrombolysis to calculate pre- and post-thrombolysis NLR and LMR. Clinical data, including NIHSS was registered on admission and day 1. The long-term outcome was defined 90 days post-event by the modified Rankin Scale (mRS). Therapy-associated intracranial hemorrhage (ICH) was classified according to ECASS II. Receiver operating characteristic curve (ROC) analysis was performed to determine optimal cutoffs of NLR and LMR as predictors of therapy outcomes; (3) Results: Patients were stratified by cutoffs of 5.73 for NLR and 2.08 for LMR. The multivariate logistic regression model, including all possible confounders, displayed no significant association between NLR or LMR with 3-months functional prognosis. The combination of high NLR−low LMR vs. low NRL−high LMR as obtained 24 h after thrombolysis was found to be an independent predictor of poor 3-months functional outcome (mRS ≥ 2; OR 3.407, 95% CI 1.449 to 8.011, p = 0.005). The proportion of patients between low NLR−high LMR and high NLR−low LMR groups from admission to day 1 showed no significant change in the good outcome group. On the other hand, in the poor outcome group (mRS ≥ 2), low NLR−high LMR and high NLR−low LMR groups displayed a significant shift in patient proportions from 67% and 21% at admission (p = 0.001) to 36% and 49% at 24 h after thrombolysis (p < 0.001), respectively; (4) Conclusions: Our study demonstrated for the first time that a high NLR−low LMR combination as observed at 24 h after thrombolysis can serve as an independent predictor of 3-months poor outcome in AIS patients. This simple and readily available data may help clinicians to improve the prognostic estimation of patients and may provide guidance in selecting patients for personalized and intensified care post-thrombolysis.

The role of urinary N-acetyl-ß-D-glucosaminidase in early detection of acute kidney injury among pediatric patients with neoplastic disorders in a retrospective study.

BACKGROUND: The 1-year cumulative incidence of AKI reportedly is high (52%) in pediatric neoplastic disorders. About half of these events occur within 2 weeks. However, subclinical AKI episodes may remain unrecognized by the conventional creatinine-based approaches. We investigated the diagnostic value of urinary N-acetyl-ß-D-glucosaminidase (uNAG) as an early marker of acute kidney injury (AKI). METHODS: In our retrospective study, 33 children with neoplastic disorders were inculded who had serial uNAG tests (at least 5 samples/patient) with a total of 367 uNAG measurements. Renal function was determined by cystatin-C and creatinine based GFR, and relative increase of uNAG index (uNAGRI). We focused on detecting both clinical and subclinical AKI episodes (according to Biomarker-Guided Risk Assessment using pRIFLE criteria and /or elevated uNAG levels) and the incidence of chronic kidney damage. RESULTS: Sixty episodes in 26 patients, with positivity at least in one parameter of kidney panel, were identified during the observation period. We detected 18/60 clinical and 12/60 subclinical renal episodes. In 27/60 episodes only uNAG values was elevated with no therapeutic consequence at presentation. Two patients were detected with decreased initial creatinine levels with 3 "silent" AKI. In 13 patients, modest elevation of uNAG persisted suggesting mild, reversible tubular damage, while chronic tubuloglomerular injury occurred in 5 patients. Based on ROC analysis for the occurence of AKI, uNAGRI significantly indicated the presence of AKI, the sensitivity and specificity are higher than the changes of GFRCreat. Serial uNAG measurements are recommended for  the reduction of the great amount of false positive uNAG results, often due to overhydratation. CONCLUSION: Use of Biomarker-guided Risk Assessment for AKI identified 1.5 × more clinical and subclinical AKI episodes than with creatinine alone in our pediatric cancer patients. Based on the ROC curve for the occurence of AKI, uNAGRI has relatively high sensitivity and specificity comparable to changes of GFRCysC. The advantage of serial uNAG measurements is to decrease the number of false positive results. TRIAL REGISTRATION: The consent to participate is not applicable because it was not reqired for ethical approval and it is a retrospectiv study.

Case Report: A Child With Hemophilia A Serves as Donor for Hematopoietic Stem Cell Transplantation to Cure His Brother's Severe Aplastic Anemia.

The first-line treatment of severe aplastic anemia is allogeneic hematopoietic stem cell transplantation with a matched sibling donor. However, co-morbidities of the identical donor can make donation difficult. We present a transplantation where in parallel with the patient's conditioning treatment, the preparation of the donor with severe hemophilia A required a special management with perioperative factor VIII substitution. Donation was successful without complications, and 18 months after transplantation, the patient and his donor are well without any long-term sequelae. To our knowledge, this is the first reported succesfull transplantation with hemophilic child serving as a bone marrow donor. The procedure did not mean a significant risk to donor health, so donors with hemophilia should not be excluded from donation.

Clinical Course of COVID-19 Disease in Children Treated With Neoplastic Diseases in Hungary.

We report on children with cancer in Hungary suffering from COVID-19, surveying a 13-months-long period of time. We performed a retrospective clinical trial studying the medical documentation of children treated in seven centers of the Hungarian Pediatric Oncology-Hematology Group. About 10% of children admitted to tertiary hemato-oncological centers for anti-neoplastic treatment or diagnosis for de novo malignancies were positive for SARS-CoV-2 infection. Nearly two-thirds of the infected patients were asymptomatic or had only mild symptoms but showed seropositivity by 1-4.5 months after positive PCR. One third of the SARS-CoV-2-positive children were hospitalized due to symptomatic COVID-19. Five children required antiviral treatment with remdesivir. One child was referred to the intensive care unit, requiring intubation and mechanical ventilation. Delay in the scheduled anti-cancer treatment did not exceed 2 weeks in the majority (89%) of cases. There was only one patient requiring treatment deferral longer than a month. There was no COVID-19-related death in patients under 18 years of age, and nor was multisystem inflammatory syndrome diagnosed. In conclusion, SARS-CoV-2 infection did not represent an untoward risk factor among children with cancer in Hungary.

Peripheral Vascular Resistance in Cerebral Arteries in Patients With Carotid Atherosclerosis - Substudy Results of the Atherosclerotic Plaque Characteristics Associated With a Progression Rate of the Plaque and a Risk of Stroke in Patients With the Carotid Bifurcation Plaque Study (ANTIQUE).

OBJECTIVES: Transcranial color-coded duplex sonography (TCCS) enables to measure blood flow characteristics in cerebral vessels, including vascular resistance and pulsatility. The study aims to identify factors influencing pulsatility (PI) and resistance (RI) indices measured using TCCS in patients with carotid atherosclerosis. METHODS: Self-sufficient patients with atherosclerotic plaque causing 20-70% carotid stenosis were consecutively enrolled to the study. All patients underwent duplex sonography of cervical arteries and TCCS with measurement of PI and RI in the middle cerebral artery, neurological, and physical examinations. Following data were recorded: age, gender, height, weight, body mass index, systolic and diastolic blood pressure, occurrence of current and previous diseases, surgery, medication, smoking, and daily dose of alcohol. Univariant and multivariant logistic regression analysis were used for identification of the factors influencing RI and PI. RESULTS: Totally 1863 subjects were enrolled to the study: 139 healthy controls (54 males, age 55.52 ± 7.05 years) in derivation cohort and 1724 patients (777 males, age 68.73 ± 9.39 years) in validation cohort. The cut off value for RI was 0.63 and for PI 1.21. Independent factors for increased RI/PI were age (odds ratio [OR] = 1.108/1.105 per 1 year), occurrence of diabetes mellitus (OR = 1.767/2.170), arterial hypertension (OR = 1.700 for RI only), width of the carotid plaque (OR = 1.260 per 10% stenosis for RI only), and male gender (OR = 1.530 for PI only; P ˂.01 in all cases). CONCLUSIONS: The independent predictors of increased cerebral arterial resistance and/or pulsatility in patients with carotid atherosclerosis were age, arterial hypertension, diabetes mellitus, carotid plaque width, and male gender.

A Novel Method for the Evaluation of Bone Marrow Samples from Patients with Pediatric B-Cell Acute Lymphoblastic Leukemia-Multidimensional Flow Cytometry.

Multicolor flow cytometry (FC) evaluation has a key role in the diagnosis and prognostic stratification of ALL. Our aim was to create new analyzing protocols using multidimensional dot-plots. Seventy-two pediatric patients with ALL were included in this single-center study. Data of a normal BM sample and three BM samples of patients with BCP-ALL were merged, then all B cell populations of the four samples were presented in a single radar dot-plot, and those parameters and locations were selected in which the normal and pathological cell populations differed from each other the most. The integrated profile of immunophenotype resulted in a simple, rapid, and accurate method. There were no significant differences between the percentages of lymphoblasts in the detection of minimal residual disease (MRD) by multidimensional or conventional FC method (p = 0.903 at Day 15 and p = 0.155 at Day 33). Furthermore, we found associations between the position and the number of clusters of blast cells in the radar plots and cytogenetic properties (p = 0.002 and p < 0.0001 by the position and p = 0.02 by the number of subclones). FC analysis based on multidimensional dot-plots is not only a rapid, easy-to-use method, but can also provide additional information to screen cases which require detailed genetic examination.

Recent Advances in the Management of Pediatric Acute Myeloid Leukemia-Report of the Hungarian Pediatric Oncology-Hematology Group.

Outcome measures of pediatric acute myeloid leukemia (AML) improved considerably between 1990 and 2011 in Hungary. Since 2012, efforts of the Hungarian Pediatric Oncology-Hematology Group (HPOG) included the reduction in the number of treatment centers, contemporary diagnostic procedures, vigorous supportation, enhanced access to hematopoietic stem cell transplantation (HSCT), and to targeted therapies. The major aim of our study was to evaluate AML treatment results of HPOG between 2012 and 2019 with 92 new patients registered (52 males, 40 females, mean age 7.28 years). Two periods were distinguished: 2012-2015 and 2016-2019 (55 and 37 patients, respectively). During these periods, 2 y OS increased from 63.6% to 71.4% (p = 0.057), and the 2 y EFS increased significantly from 56.4% to 68.9% (p = 0.02). HSCT was performed in 37 patients (5 patients received a second HSCT). We demonstrate advances in the diagnosis and treatment of acute promyelocytic leukemia (APL) in two cases. Early diagnosis and follow-up were achieved by multidimensional flow cytometry and advanced molecular methods. Both patients were successfully treated with all-trans retinoic acid and arsenic-trioxide, in addition to chemotherapy. In order to meet international standards of pediatric AML management, HPOG will further centralize treatment centers and diagnostic facilities and join efforts with international study groups.

Decreased clot burden is associated with factor XIII Val34Leu polymorphism and better functional outcomes in acute ischemic stroke patients treated with intravenous thrombolysis.

BACKGROUND: Intravenous thrombolysis using recombinant tissue plasminogen activator remains the mainstay treatment of acute ischemic stroke (AIS), although endovascular treatment is becoming standard of care in case of large vessel occlusions (LVO). To quantify the thrombus burden in LVO, a semiquantitative CT angiography (CTA) grading system, the clot burden score (CBS) can be used. Here we aimed to study the association between CBS and various hemostasis parameters, and to evaluate which parameters are major determinants of thrombolysis outcome. METHODS: In this single-centered prospective observational case-control study, 200 anterior circulation AIS patients receiving intravenous thrombolysis treatment without thrombectomy were enrolled: 100 AIS patients with LVO (CBS 0-9) and 100 age- and sex-matched AIS patients without LVO (CBS 10). Fibrinogen, α2-plasmin inhibitor, plasminogen, factor XIII and D-dimer were assessed from blood samples taken before and 24 h after thrombolysis, and FXIII-A Val34Leu was genotyped. CBS was calculated using admission CTA. Short-term outcomes were defined based on the change in NIHSS by day 7, long-term outcomes were assessed according to the modified Rankin scale at 3 months post-event. RESULTS: Poor outcomes were significantly more frequent in the CBS 0-9 group. Plasminogen activity on admission was significantly higher in the CBS 0-9 group. In a univariate analysis, significant protective effect of the Leu34 allele against developing larger clots (CBS 0-9) could be demonstrated (OR:0.519; 95%CI:0.298-0.922, p = 0.0227). Multivariate regression analysis revealed that CBS is an independent predictor of short- and long-term functional outcomes, while such effect of the studied hemostasis parameters could not be demonstrated. CONCLUSIONS: CBS was found to be a significant independent predictor of thrombolysis outcomes. FXIII-A Leu34 carrier status was associated with smaller thrombus burden, which is consistent with the in vitro described whole blood clot mass reducing effects of the allele, but the polymorphism had no effect on thrombolysis outcomes.

Comparing Endovascular Treatment Methods in Acute Ischemic Stroke Due to Tandem Occlusion Focusing on Clinical Aspects.

INTRODUCTION: Acute ischemic strokes (AIS) due to tandem occlusion (TO) of intracranial anterior large vessel and concomitant extracranial internal carotid artery (EICA) are represent in 15-20% of all ischemic strokes. The endovascular treatment (EVT) strategy for those patients is still unclear. Although the intracranial mechanical thrombectomy (MT) is considered as a standard treatment approach, the EICA lesion stent necessity remains a matter of debate. We sought to assess the efficacy and safety of EVT in tandem lesions, particularly the EICA stenting management. METHODS: We retrospectively analyzed all patients with anterior circulation stroke associated with EICA lesion and receiving EVT in the three participated stroke centers between November 2017 and December 2020. Patients' data were collected from our prospective stroke registry (STAY ALIVE). Patients enrolled in our study were divided into two groups depending on whether acute carotid stenting (ACS) or balloon angioplasty only (BAO) technique was used. Our primary outcome was the 90-day functional outcome assessed by modified Rankin scale (mRS). Mortality at 90 days and symptomatic intracranial hemorrhage (sICH) were considered as secondary outcomes. RESULTS: A total of 101 patients (age: 67 ± 10 years, 38.6% female) were enrolled in our study, including 29 (28.3%) BAO cases, and 72 (71.3%) patients treated with ACS. Patients in the BAO group were slightly older (70 ± 9 years vs. 66 ± 10 years, p = 0.054), and had higher prevalence of comorbidities such as hypertension (100.0% vs. 59.4%, p < 0.001). There was no significant difference in favorable outcomes (51.7% vs. 54.4%, p = 0.808) between the groups. However, we observed a trend towards higher rates of sICH (8.3% vs. 3.4%, p = 0.382) and 90-day mortality (23.5% vs. 13.8%, p = 0.278) with significantly higher frequency of distal embolization (39.1% vs. 17.9%, p = 0.043) in patients with ACS. In the overall population age (p = 0.013), atrial fibrillation (AF) (p = 0.008), National Institutes of Health Stroke Scale (NIHSS) baseline (p = 0.029), and successful recanalization (p = 0.023) were associated with favorable outcome. CONCLUSION: Endovascular approach of EICA in addition to MT was safe and effective in tandem occlusion of anterior circulation. Furthermore, our results suggest that balloon angioplasty technique without acute stenting shows a comparable favorable outcome rate to ACS with moderately less hemorrhagic events and mortality rates.

A modified in vitro clot lysis assay predicts outcomes and safety in acute ischemic stroke patients undergoing intravenous thrombolysis.

The outcome of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is only favorable in ≈ 40% of acute ischemic stroke (AIS) patients. Moreover, in ≈ 6-8% of cases, intracerebral hemorrhage (ICH) develops. We tested whether a modification of clot lysis assay (CLA), might predict therapy outcomes and safety. In this prospective observational study, blood samples of 231 AIS patients, all receiving intravenous rt-PA, were taken before thrombolysis. Cell-free DNA (cfDNA), CLA and CLA supplemented with cfDNA and histones (mCLA) were determined from the blood samples. Stroke severity was determined by NIHSS on admission. ICH was classified according to ECASSII. Short- and long-term outcomes were defined at 7 and 90 days post-event according to ΔNIHSS and by the modified Rankin Scale, respectively. Stroke severity demonstrated a step-wise positive association with cfDNA levels, while a negative association was found with the time to reach 50% lysis (50%CLT) parameter of CLA and mCLA. ROC analysis showed improved diagnostic performance of the mCLA. Logistic regression analysis proved that 50%CLT is a predictor of short-term therapy failure, while the AUC parameter predicts ICH occurrence. A modified CLA, supplemented with cfDNA and histones, might be a promising tool to predict short-term AIS outcomes and post-lysis ICH.