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Thromboinflammation/immunothrombosis plays a role in several diseases including thrombotic thrombocytopenic purpura (TTP) and COVID-19. Unlike the extensive research that has been conducted on COVID-19 cytokine storms, the baseline and acute phase cytokine profiles of TTP are poorly characterized. Moreover, we compared the cytokine profiles of TTP and COVID-19 to identify the disease-specific/general characteristics of thromboinflammation/immunothrombosis. Plasma concentrations of 33 soluble mediators (SMs: cytokines, chemokines, soluble receptors, and growth factors) were measured by multiplex bead-based LEGENDplex™ immunoassay from 32 COVID-19 patients (32 non-vaccinated patients in three severity groups), 32 TTP patients (remission/acute phase pairs of 16 patients), and 15 control samples. Mainly, the levels of innate immunity-related SMs changed in both diseases. In TTP, ten SMs decreased in both remission and acute phases compared to the control, one decreased, and two increased only in the acute phase compared to remission, indicating mostly anti-inflammatory changes. In COVID-19, ten pro-inflammatory SMs increased, whereas one decreased with increasing severity compared to the control. In severe COVID-19, sixteen SMs exceeded acute TTP levels, with only one higher in TTP. PCA identified CXCL10, IL-1RA, and VEGF as the main discriminators among their cytokine profiles. The innate immune response is altered in both diseases. The cytokine profile of TTP suggests a distinct pathomechanism from COVID-19 and supports referring to TTP as thromboinflammatory rather than immunothrombotic, emphasizing thrombosis over inflammation as the driving force of the acute phase.

Abstract TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next‐generation sequencing (NGS)‐based studies have identified frequent low‐burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low‐burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS‐based mutation analysis in a ‘real‐world’ cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high‐burden mutations, while 52% were low‐burden TP53 mutations. Low‐burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low‐burden TP53 mutation. Patients harbouring low‐burden TP53 mutations had significantly lower time to first treatment compared to patients with wild‐type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low‐burden TP53 mutations. By demonstrating that patients with sole low‐burden TP53 variants represent more than one‐third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

Abstract Choosing the optimal device during cardiac resynchronization therapy (CRT) upgrade can be challenging. Therefore, we sought to provide a solution for identifying patients in whom upgrading to a CRT-defibrillator (CRT-D) is associated with better long-term survival than upgrading to a CRT-pacemaker (CRT-P). To this end, we first applied topological data analysis to create a patient similarity network using 16 clinical features of 326 patients without prior ventricular arrhythmias who underwent CRT upgrade. Then, in the generated circular network, we delineated three phenogroups exhibiting significant differences in clinical characteristics and risk of all-cause mortality. Importantly, only in the high-risk phenogroup was upgrading to a CRT-D associated with better survival than upgrading to a CRT-P (hazard ratio: 0.454 (0.228–0.907), p = 0.025). Finally, we assigned each patient to one of the three phenogroups based on their location in the network and used this labeled data to train multi-class classifiers to enable the risk stratification of new patients. During internal validation, an ensemble of 5 multi-layer perceptrons exhibited the best performance with a balanced accuracy of 0.898 (0.854–0.942) and a micro-averaged area under the receiver operating characteristic curve of 0.983 (0.980–0.986). To allow further validation, we made the proposed model publicly available ( https://github.com/tokmarton/crt-upgrade-risk-stratification ).

Not available.

Abstract Background Recent reports suggested a different predictive value for TyG index compared to HOMA-IR in coronary artery calcification (CAC) and other atherosclerotic outcomes, despite that both indices are proposed as surrogate markers of insulin resistance. We hypothesized a key role for liver pathology as an explanation and therefore assessed the relationship among the two indices and the intrahepatic lipid content stratified by PNPLA3 rs738409 genotypes as a known non-alcoholic fatty liver disease (NAFLD) genetic risk. Methods Thirty-nine women from a prior GDM-genetic study were recalled with PNPLA3 rs738409 CC and GG genotypes for metabolic phenotyping and to assess hepatic triglyceride content (HTGC). 75 g OGTT was performed, fasting lipid, glucose, insulin levels and calculated insulin resistance indices (TyG and HOMA2-IR) were used. HTGC was measured by MR based methods. Mann–Whitney-U, χ2 and for the correlation analysis Spearman rank order tests were applied. Results The PNPLA3 rs738409 genotype had a significant effect on the direct correlation between the HOMA2-IR and TyG index: the correlation (R = 0.52, p = 0.0054) found in the CC group was completely abolished in those with the GG (NAFLD) risk genotype. In addition, the HOMA2-IR correlated with HTGC in the entire study population (R = 0.69, p

Abstract Background TCF7L2 rs7903146 and PNPLA3 rs738409 gene variants confer the strongest risk for type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), respectively. Pancreatic triacylglycerol content (PTGC) was reported to have a role in T2DM development. We aimed to assess the correlation between PTGC and hepatic triacylglycerol content (HTGC) stratified by PNPLA3 rs738409 genotype and subsequently interactions between PTGC and gene variants associated with β-cell dysfunction (TCF7L2, WFS1) and visceral adiposity (11ΒHSD1) on β-cell function were also tested. Methods PTGC and HTGC were assessed using MR in a post-hoc analysis of a genotype-based (PNPLA3 rs738409) recall study of 39 (lipid- and glucose lowering) drug-naïve women. Oral glucose tolerance test, HbA1c, insulin indices, anthropometric data were evaluated. The effect of minor allele carrying of TCF7L2 (rs7903146); WFS1 (rs1801214) and 11ΒHSD1 (rs4844880) variants in combination with PTGC was studied on surrogate markers of β-cell function. We used Spearman’s rank-order, Mann-Whitney-U tests, and linear regression models. Results PTGC and HTGC values were correlated after stratification by the rs738409 variant (only in CC genotype group R = 0.67, p = 10− 4). PTGC and HbA1c values correlated in the entire study population (R = 0.58, p = 10− 4). Insulin resistance, sensitivity and disposition indices were correlated with PTGC (HOMA2-IR: R = 0.42, p = 0.008; TyG: R = 0.38, p = 0.018; Matsuda: R= − 0.48, p = 0.002; DIbasal: R=−0.33, p = 0.039; ISSI-2: R=−0.35, p = 0.028). Surrogate markers of β-cell function (HOMA2-B, AUCinsulin/AUCglucose) correlated significantly with PTGC in subjects with the following genotypes rs7903146: CC R = 0.51, p = 0.022; rs18001214: CT + CC R = 0.55, p = 0.013; rs4844880: TA + AA R = 0.56, p = 0.016. The strongest interactions were found between PTGC and TCF7L2 rs7903146 effect on HOMA2-B (p = 0.001) and AUCinsulin/AUCglucose (p = 0.013). Conclusions The PNPLA3 rs738409 genotype has a major effect on the correlation between PTGC and HTGC. Furthermore we first report the combined effect of PTGC and individual risk gene variants of TCF7L2, WFS1 and 11ΒHSD1 on β-cell dysfunction. The correlation between pancreatic lipid accumulation and HbA1c also indicates an important role for the latter pathology.

Objective: Response to treatment in multiple myeloma (MM) is routinely measured by serum and urine M-protein and free light chain (FLC), as described by the International Myeloma Working Group (IMWG) consensus statement. A non-negligible subgroup of patients however present without measurable biomarkers, others become oligo or non-secretory during recurrent relapses. The aim of our research was to evaluate soluble B-cell maturation antigen (sBCMA) as a monitoring marker measured concurrent with the standard monitoring in MM patients at diagnosis, at relapse and during follow up, in order to establish its potential usefulness in oligo and non-secretory disease.Method: sBCMA levels were measured in 149 patients treated for plasma cell dyscrasia (3 monoclonal gammopathy of unknown significance, 5 smoldering myeloma, 7 plasmacytoma, 8 AL amyloidosis and 126 MM) and 16 control subjects using a commercial ELISA kit. In 43 newly diagnosed patients sBCMA levels were measured at multiple timepoints during treatment, and compared to conventional IMWG response and progression free survival (PFS).Results: sBCMA levels among control subjects were significantly lower than among newly diagnosed or relapsed MM patients [20.8 (14.7–38.7) ng/mL vs. 676 (89.5–1,650) and 264 (20.7–1,603) ng/mL, respectively]. Significant correlations were found between sBCMA and the degree of bone marrow plasma cell infiltration. Out of the 37 newly diagnosed patients who have reached partial response or better per IMWG criteria, 33 (89%) have had at least a 50% drop in sBCMA level by therapy week 4. Cohorts made similarly to IMWG response criteria—achieving a 50% or 90% drop in sBCMA levels compared to level at diagnosis—had statistically significant differences in PFS.Conclusion: Our results confirmed that sBCMA levels are prognostic at important decision points in myeloma, and the percentage of BCMA change is predictive for PFS. This highlights the great potential use of sBCMA in oligo- and non-secretory myeloma.

IntroductionWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.MethodsWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.ResultsWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p

The letter to the editor discusses the results of the VENICE-II trial, which evaluated the impact of venetoclax monotherapy on health-related quality of life (HRQoL) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). The trial showed significant improvements in HRQoL, with sustained benefits observed up to week 108. Venetoclax treatment also demonstrated positive outcomes in terms of response rates, duration of response, and overall survival. The safety profile of venetoclax remained consistent throughout the trial, with no new safety signals identified. The study emphasizes the importance of considering patient-centric factors, such as HRQoL, in CLL treatment decisions, especially in the context of evolving treatment options and long-term outcomes. [Extracted from the article]

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Thromboinflammation/immunothrombosis plays a role in several diseases including thrombotic thrombocytopenic purpura (TTP) and COVID-19. Unlike the extensive research that has been conducted on COVID-19 cytokine storms, the baseline and acute phase cytokine profiles of TTP are poorly characterized. Moreover, we compared the cytokine profiles of TTP and COVID-19 to identify the disease-specific/general characteristics of thromboinflammation/immunothrombosis. Plasma concentrations of 33 soluble mediators (SMs: cytokines, chemokines, soluble receptors, and growth factors) were measured by multiplex bead-based LEGENDplex™ immunoassay from 32 COVID-19 patients (32 non-vaccinated patients in three severity groups), 32 TTP patients (remission/acute phase pairs of 16 patients), and 15 control samples. Mainly, the levels of innate immunity-related SMs changed in both diseases. In TTP, ten SMs decreased in both remission and acute phases compared to the control, one decreased, and two increased only in the acute phase compared to remission, indicating mostly anti-inflammatory changes. In COVID-19, ten pro-inflammatory SMs increased, whereas one decreased with increasing severity compared to the control. In severe COVID-19, sixteen SMs exceeded acute TTP levels, with only one higher in TTP. PCA identified CXCL10, IL-1RA, and VEGF as the main discriminators among their cytokine profiles. The innate immune response is altered in both diseases. The cytokine profile of TTP suggests a distinct pathomechanism from COVID-19 and supports referring to TTP as thromboinflammatory rather than immunothrombotic, emphasizing thrombosis over inflammation as the driving force of the acute phase. [ABSTRACT FROM AUTHOR]

IntroductionWilson's disease may lead to cirrhosis, but timely medical treatment could slow down its progression. Clinical markers helping early diagnosis are essential. Decreased fetuin-A concentration has been reported in cirrhosis of different etiologies. The aim of this study was to investigate whether decreased serum fetuin-A concentration could identify patients with Wilson's disease who developed cirrhosis.Materials and methodsIn this cross-sectional study we determined the serum fetuin-A concentration of 50 patients with Wilson's disease. We analyzed the data of patients with liver involvement, comparing cirrhotic and non-cirrhotic patients.ResultsAmong patients with liver involvement those with cirrhosis had significantly lower fetuin-A and albumin level, white blood cell and platelet count. Fetuin-A negatively correlated with disease duration, bilirubin level, positively with total protein and albumin concentration, but not with copper and ceruloplasmin concentrations or markers of systemic inflammation. In multivariate analysis with fetuin-A and the Nazer score or its parameters only fetuin-A was a significant determinant of having cirrhosis. In receiver operator curve analysis among patients with liver involvement the fetuin-A level of 523 μg/ml was associated with cirrhosis with 82% sensitivity and 87% specificity. The presence of the H1069Q mutation was not associated with alteration in fetuin-A concentration.ConclusionsThe serum concentration of fetuin-A is a sensitive marker of liver cirrhosis in Wilson's disease, independently of the H1069Q mutation, ceruloplasmin concentration or systemic inflammation.

The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10−4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.

Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.

BackgroundPericarditis is rare in Coronavirus disease 2019 (Covid-19) infection and only a few cases were reported in children.Case presentationWe present the case of a 15-year-old boy with symptoms of high fever and worsening chest pain during COVID-19 infection. Chest computer tomography (CT) and echocardiography confirmed pericardial tamponade requiring urgent drainage. Despite antiviral drug treatment, after 18 days severe attack developed requiring repeated pericardiocentesis. High dose ibuprofen, colchicin and the interleukin-1 antagonist, anakinra were given. Clinical symptoms and laboratory parameters improved after seven days of treatment. Autoinflammatory diseases were also suspected in the background the severe pericarditis, but genetic analysis ruled out any mutations.ConclusionPericarditis associated with COVID-19 infection may present in the acute phase or later as MIS-C. Though pericardial tamponade related to ongoing Covid-19 infection is rare in children, even biological treatment with interleukin-1 antagonist may be needed to control the inflammation.

Background: Ibrutinib is widely known as an effective and well-tolerated therapeutical choice of the chronic lymphocytic leukaemia (CLL). However, acquired resistance may occur during the treatment, causing relapse. Early detection of ibrutinib resistance is an important issue, therefore we aimed to find phenotypic markers on CLL cells the expression of which may correlate with the appearance of ibrutinib resistance.Methods: We examined 28 patients’ peripheral blood (PB) samples (treatment naïve, ibrutinib sensitive, clinically ibrutinib resistant). The surface markers’ expression (CD27, CD69, CD86, CD184, CD185) were measured by flow cytometry. Furthermore, the BTKC481S resistance mutation was assessed by digital droplet PCR. Moreover, the CLL cells’ phenotype of a patient with acquired ibrutinib resistance was observed during the ibrutinib treatment.Results: The expression of CD27 (p = 0.030) and CD86 (p = 0.031) became higher in the clinically resistant cohort than in the ibrutinib sensitive cohort. Besides, we found that high CD86 and CD27 expressions were accompanied by BTKC481S mutation. Our prospective study showed that the increase of the expression of CD27, CD69 and CD86 was noticed ahead of the clinical resistance with 3 months.Conclusion: Our study suggests that the changes of the expression of these markers could indicate ibrutinib resistance and the examination of these phenotypic changes may become a part of the patients’ follow-up in the future.

Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by seizures, neuropsychiatric disorders, and tumors of the heart, brain, skin, lungs, and kidneys. We present a three-year follow-up of a patient with TSC-associated rhabdomyoma detected in utero. Genetic examination of the fetus and the parents revealed a de novo variant in the TSC2 gene (c.3037delG, p.Asp1013IlefsTer3). Oral everolimus was initiated in the pregnant mother to regress the fetal tumor, which was successful. To the best of our knowledge, there is very little information regarding the use of everolimus therapy during pregnancy. West-syndrome was diagnosed when the proband was four months old. The symptoms were well-manageable, however temporarily. Therapy-resistant focal seizures were frequent. The patient had good vitals and was under regular cardiological control, showed a balanced circulation, and did not require any medication. Subependymal giant cell astrocytoma (SEGA) identified by regular neuroimaging examinations remained unchanged, which may be a consequence of early intrauterine treatment. Early detection of the pathogenic TSC2 variant, followed by in utero administration of everolimus and early vigabatrin therapy, allowed the detection of a milder developmental delay of the proband. Our study emphasizes how early genetic testing and management of epilepsy are pivotal for proper neurodevelopmental impacts and therapeutic strategies.

Background: Vitamin D deficiency (VDD) may be considered an independent cardiovascular (CV) risk factor, and it is well known that CV risk is higher in males. Our goal was to investigate the pharmacological reactivity and receptor expression of intramural coronary artery segments of male rats in cases of different vitamin D supply. Methods: Four-week-old male Wistar rats were divided into a control group (n = 11) with optimal vitamin D supply (300 IU/kgbw/day) and a VDD group (n = 11, 2 (TXA2)-agonist induced reduced vasoconstriction, testosterone (T) and 17-β-estradiol (E2) relaxations were significantly decreased, a significant decrease in thromboxane receptor (TP) expression was shown, and the reduction in estrogen receptor-α (ERα) expression was on the border of significance in the VDD group. Conclusions: VD-deficient male coronary arteries showed deteriorated pharmacological reactivity to TXA2 and sexual steroids (E2, T). Insufficient vasoconstrictor capacity was accompanied by decreased TP receptor expression, and vasodilator impairments were mainly functional. The decrease in vasoconstrictor and vasodilator responses results in narrowed adaptational range of coronaries, causing inadequate coronary perfusion that might contribute to the increased CV risk in VDD.

BackgroundDysregulation of complement system is thought to be a major player in development of multi-organ damage and adverse outcomes in patients with coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement system activity and development of severe acute kidney injury (AKI) among hospitalized COVID-19 patients.Materials and MethodsIn this multicenter, international study, complement as well as inflammatory and thrombotic parameters were analyzed in COVID-19 patients requiring hospitalization at one US and two Hungarian centers. The primary endpoint was development of severe AKI defined by KDIGO stage 2+3 criteria, while the secondary endpoint was need for renal replacement therapy (RRT). Complement markers with significant associations with endpoints were then correlated with a panel of inflammatory and thrombotic biomarkers and assessed for independent association with outcome measures using logistic regression.ResultsA total of 131 hospitalized COVID-19 patients (median age 66 [IQR, 54–75] years; 54.2% males) were enrolled, 33 from the US, and 98 from Hungary. There was a greater prevalence of complement over-activation and consumption in those who developed severe AKI and need for RRT during hospitalization. C3a/C3 ratio was increased in groups developing severe AKI (3.29 vs. 1.71; p < 0.001) and requiring RRT (3.42 vs. 1.79; p < 0.001) in each cohort. Decrease in alternative and classical pathway activity, and consumption of C4 below reference range, as well as elevation of complement activation marker C3a above the normal was more common in patients progressing to severe AKI. In the Hungarian cohort, each standard deviation increase in C3a (SD = 210.1) was independently associated with 89.7% increased odds of developing severe AKI (95% CI, 7.6–234.5%). Complement was extensively correlated with an array of inflammatory biomarkers and a prothrombotic state.ConclusionConsumption and dysregulation of complement system is associated with development of severe AKI in COVID-19 patients and could represent a promising therapeutic target for reducing thrombotic microangiopathy in SARS-CoV-2 infection.