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Alcohol Use Disorder (AUD) poses global health challenges, and causes hematological alterations such as macrocytosis and oxidative stress. Disruption of protein structures by alcohol and/or its metabolites may exacerbate AUDs; proteomics can elucidate the underlying biological mechanisms. This study examined the proteins differentially expressed in the cytosol and membrane fractions of erythrocytes obtained from 30 male patients with AUD, comparing them to samples from 15 age- and BMI-matched social drinkers (SDs) and 15 non-drinkers (control). The analysis aimed to identify the molecular differences related to alcohol consumption. The AUD patient subgrouping was based on mean corpuscular volume (MCV), with 16 individuals classified as having a normal MCV and 14 having a high MCV. Proteins were separated via two-dimensional(2D)-gel electrophoresis, digested with trypsin, and identified via Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (TOF) mass spectrometry (MALDI-TOF/TOF). Additionally, levels of malondialdehyde and 4-hydroxyalkenals (MDA + HAE), reduced glutathione (GSH), oxidized glutathione (GSSG), serum carbohydrate-deficient transferrin (%CDT), disialotransferrin (%DST), and sialic acid (SA) were analyzed. The results showed increased MDA + HAE and decreased total thiols in AUD patients, with GSSG elevated and the GSH/GSSG ratio reduced in the AUD MCV-high subgroup. Serum %CDT, %DST, and SA were significantly higher in AUD. Compared to the control profiles, the AUD group exhibited differential protein expression. Few proteins, such as bisphosphoglycerate mutase, were downregulated in AUD versus control and SD, as well as in the MCV-high AUD subgroup. Conversely, endoplasmin and gelsolin were upregulated in AUD relative to control. Cytoskeletal proteins, including spectrin-alpha chain, actin cytoplasmic 2, were overexpressed in the AUD group and MCV-high AUD subgroup. Several proteins, such as 14-3-3 isoforms, alpha-synuclein, translation initiation factors, heat shock proteins, and others, were upregulated in the MCV-high AUD subgroup. Under-expressed proteins in this subgroup include band 3 anion transport protein, bisphosphoglycerate mutase, tropomyosin alpha-3 chain, uroporphyrinogen decarboxylase, and WD repeat-containing protein 1. Our findings highlight the specific changes in protein expression associated with oxidative stress, cytoskeletal alterations, and metabolic dysregulation, specifically in AUD patients with an elevated MCV. Understanding these mechanisms is crucial for developing targeted interventions and identifying biomarkers of alcohol-induced cellular damage. The complex interplay between oxidative stress, membrane composition, and cellular function illustrates how chronic alcohol exposure affects cellular physiology. Full article

Background: Multiple myeloma (MM) is an incurable plasma cell dyscrasia with particularly adverse prognosis in relapsed, multi-drug refractory settings. The management of those patients is challenging as treatment options are limited. In this context, bispecific antibodies (BsAbs) have recently emerged as promising therapeutic agents, and several have gained regulatory approval. To better understand their impact in MM landscape, we performed a systematic review and meta-analysis assessing their efficacy and safety in patients with relapsed/refractory MM (RRMM). Methods: A systematic search was conducted in the PubMed, ScienceDirect, Scopus and ClinicalTrials.gov databases for clinical trials investigating BsAbs for RRMM. Pooled estimates in terms of proportions along with 95% confidence intervals were calculated with random-effects models. The present meta-analysis was performed following PRISMA guidelines and was registered in PROSPERO (ID: CRD420251028553). Results: Based on data from six clinical trials involving 850 patients, the pooled overall response and complete response or better rates were 69% and 42%, respectively, whereas the pooled rate of duration of response for at least one year was 71%. The estimated one-year progression-free survival and overall survival were 56% and 72%, respectively. Neutropenia was the most frequently observed severe hematological toxicity, with a pooled incidence of 46%. Grade ≥3 infections occurred in 29%, while any-grade CRS occurred in 69%, as per pooled analysis. Finally, an exploratory minimal residual disease (MRD) analysis in four of the six studies yielded a pooled MRD-negativity rate of 24%. Conclusions: BsAbs demonstrated commendable efficacy in heavily pretreated RRMM patients, in terms of response rates and survival outcomes. However, notable rates of hematologic toxicity, infections, and CRS were recorded. These findings support the clinical utility of BsAbs in RRMM, while highlighting the need for comprehensive toxicity management. Full article

Background/Objectives: This study was designed to investigate the relationship between peripheral hematological inflammation markers, namely, neutrophil/lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), systemic immune inflammation index (SII), and systemic inflammatory response index (SIRI) and high-grade cervical lesions (CIN2+). Methods: A retrospective cohort analysis was conducted on 358 patients who underwent cervical excision procedures. Patients were divided into two groups: <CIN2 and CIN2+. Preoperative complete blood count data were used to calculate the inflammation indices. HPV genotypes were also recorded. Logistic regression and ROC analyses were performed to evaluate the predictive performance. Results: CIN2+ lesions were detected in 69.6% of participants. In the univariate analysis, only age and HPV 16 positivity (p < 0.005) showed a significant association with the presence of CIN2+. NLR, PLR, MLR, SII, and SIRI values did not show significant differences between groups (all p > 0.05). In the multivariate analysis, increasing age was independently associated with a decrease in the risk of CIN2+ (OR = 0.96, 95% CI: 0.94–0.99), while HPV 16 positivity was associated with an increase in risk (OR = 2.44, 95% CI: 1.43–4.18). ROC analysis showed that combining age and HPV 16 status improved the specificity (85.1%) of predicting CIN2+ compared to using age alone (42.2%). Conclusions: Peripheral haematological inflammation markers (NLR, PLR, MLR, SII, and SIRI) did not show predictive value in predicting CIN2+ lesions. However, age and HPV 16 infection were found to be independent predictors. These findings suggest that haematological indices may reflect systemic inflammatory responses but are not sufficient on their own for the detection of CIN2+. HPV genotyping is of critical importance for the early detection of high-grade lesions. Full article

Background and Clinical Significance: Acute megakaryoblastic leukemia (AMKL) is a rare and aggressive hematologic malignancy. The presence of genetic abnormalities often increases the complexity of AMKL. Among these, patients with monosomy 7 constitute a high-risk group associated with a poorer prognosis and greater chemoresistance. We report the case of a 10-year-old boy who had AMKL along with monosomy 7 and familial GATA2 deficiency. The case highlights the diagnostic and therapeutic challenges faced, as well as the critical importance of early genetic screening and timely hematopoietic stem cell transplantation (HSCT). Case Presentation: A 10-year-old boy presented with easy bruising and pancytopenia. AMKL was diagnosed with the help of a bone marrow biopsy and immunophenotyping. Genetic testing showed a GATA2 mutation and monosomy 7. Two induction cycles with daunorubicin and cytarabine were administered but failed to eliminate residual disease. The patient also developed pneumonia of a fungal origin. HSCT was delayed due to liver toxicity and elevated minimal residual disease (MRD). Azacitidine and venetoclax stabilized the disease, thereby allowing for successful haploidentical HSCT. The patient achieved complete remission with full donor chimerism. Conclusions: This case emphasizes the importance of early molecular diagnostics in pediatric AMKL. Identifying GATA2 mutations and monosomy 7 early can help guide risk stratification and the timing of HSCT. Multimodal therapy, which includes the use of infection control and targeted agents, is important for improving the outcomes in high-risk patients. Full article

Background/Objectives: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting for 80% of leukemias in this group and about 25% of all cancers. The 5-year survival rate is now over 90%. Achieving such a good outcome is made possible by the introduction of intensive, high-dose chemotherapy. However, it is associated with numerous complications, affecting up to 80% of patients. Among the most common of these are infections and intestinal, hepatic, hematological or neurological complications. For their effective treatment and prevention, it is necessary to develop predictors. High hopes in this aspect are placed on miRNAs. The aim of the following paper is to present the role of miRNAs as predictors of chemotherapy complications in children with ALL. Methods: A systematic review of the available literature in the PubMed, Scopus, Embase and Google Scholar scientific databases was conducted. Fourteen publications were included in the analysis. Results: Changes in miRNA expression and single-nucleotide polymorphisms in miRNAs are associated with complications of ALL therapy. Among the most notable are miR-1206 (in mucositis and myelotoxicity), miR-2053 (in neurotoxicity and mucositis), miR-938 and miR-3117 (in gastrointestinal toxicity and neurotoxicity), miR-1307 (in gastrointestinal toxicity and mucositis) and miR-323b (in gastrointestinal toxicity and myelotoxicity). In addition, miR-155, miR-3117 and miR-4268 may be potential therapeutic targets in complications of ALL therapy. Conclusions: miRNAs are good potential predictors of ALL chemotherapy toxicity and may be therapeutic targets in these complications. Full article

Background: Adenocarcinoma arising from the ampulla of Vater is an extremely rare neoplasm, and there are limited data regarding frontline therapy for metastatic disease. We investigated the outcomes of first-line treatment with FOLFIRINOX by comparing it with other treatments in patients with advanced ampullary adenocarcinoma. Methods: We included 123 patients with advanced ampullary adenocarcinoma who were treated with frontline FOLFIRINOX (n = 32), fluorouracil (FU)-based chemotherapy (n = 20), and gemcitabine-based chemotherapy (n = 65) between August 2007 and January 2024 in this retrospective study. The median progression-free survival (mPFS) and overall survival (mOS) according to treatment and clinicopathological features were calculated using the Kaplan–Meier method. Results: The median age of the patients was 62 years (range, 36–78), and 75,6% of the patients had an ECOG performance status of 0–1. The mOS were 13 months (95% CI, 10.6–14.4), 11 months (95% CI, 10.6–14.4), and 12 months (95% CI, 10.6–14.4), respectively [p = 0.865]. There were no significant differences in OS among the chemotherapeutic agents according to histological subtypes. However, FOLFIRINOX and FU-based treatments appeared more effective in the intestinal subtype, while gemcitabine-based therapies were less effective. In the pancreaticobiliary subtype, FU-based therapies yielded a shorter outcome compared to FOLFIRINOX and gemcitabine-based therapies. Grade 3 or 4 hematologic toxicities were higher in patients treated with FOLFIRINOX. Conclusions: In advanced ampullary adenocarcinoma, despite higher toxicity, frontline FOLFIRINOX showed a trend toward an OS benefit in the intestinal subtype while providing a similar outcome in the pancreaticobiliary subtype. Full article

Background: High-risk chromosomal abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH) have a well-established adverse prognostic impact in multiple myeloma (MM). It is increasingly recognized that the coexistence of two or more HRCAs identifies a particularly poor-risk subgroup, often referred to as double- or multiple-hit MM. However, there is currently no consensus on its definition. Methods: We retrospectively analyzed a multicenter cohort of 1122 newly diagnosed MM patients from 2008 to 2019. Double-hit MM was defined as the coexistence of at least two of the following four HRCAs: t(14;16), gain(1q), del(17p), and del(1p). Based on this definition, we constructed a novel prognostic model, the HBDH (Institute of Hematology & Blood Diseases Hospital) double-hit model, and assessed its prognostic value for progression-free survival (PFS) and overall survival (OS). Results: According to the HBDH model, double-hit patients showed significantly inferior outcomes compared to non-double-hit patients, with median PFS of 20.6 vs. 53.3 months (p < 0.001) and median OS of 40.2 vs. 84.2 months (p < 0.001). The addition of del(13q), t(4;14), or t(11;14) did not improve the prognostic performance of the model. Importantly, the HBDH model was independent of the International Staging System (ISS), elevated LDH, and advanced age. Conclusions: The HBDH double-hit model identifies a subset of ultra-high-risk MM patients carrying at least two major HRCAs, providing a simple and robust framework for prognostic stratification and a potential reference for future biologically driven treatment approaches. Full article

The deformability of red blood cells (RBCs) is critical for microvascular circulation and is impaired in hematological disorders such as thalassemia, a prevalent public health concern in Guangdong, China. While microfluidics enable high-precision deformability assessment, current studies lack standardization in deformation metrics and rarely investigate post-deformation recovery dynamics. This study introduces an automated microfluidic platform for systematically evaluating RBC deformability in healthy and thalassemic individuals. A biomimetic chip featuring 4 µm, 8 µm, and 16 µm wide channels (7 µm in height) was designed to simulate capillary dimensions, with COMSOL CFD numerical modeling validating shear stress profiles. RBC suspensions (10⁷ cells/mL in DPBS) were hydrodynamically focused through constrictions while high-speed imaging (15,000 fps) captured deformation–recovery dynamics. Custom-built algorithms with deep-learning networks automated cell tracking, contour analysis, and multi-parametric quantification. Validation confirmed significantly reduced deformability in Paraformaldehyde (PFA)-treated RBCs compared to normal controls. Narrower channels and higher flow velocities amplified shear-induced deformations, with more deformable cells exhibiting faster post-constriction shape recovery. Crucially, the platform distinguished thalassemia patient-derived RBCs from healthy samples, revealing significantly lower deformability in diseased cells, particularly in 4 µm channels. These results establish a standardized, high-throughput framework for RBC mechanical characterization, uncovering previously unreported recovery dynamics and clinically relevant differences in deformability in thalassemia. The method’s diagnostic sensitivity highlights its translational potential for screening hematological disorders. Full article

Autologous stem cell transplantation (ASCT) after high-dose chemo-therapy (HDCT) is an option of consolidation therapy in patients with AML, lymphoma, or myeloma. Clonal hematopoiesis (CH) is a premalignant state, associated with an increased risk of hematological cancer. The incidence of CH in patients with AML, myeloma, and lymphoma and its effect on the outcome after HDCT/ASCT remain poorly studied. Here we screened 142 patients treated with HDCT/ASCT between 2002 and 2021 at Bern University Hospital for somatic gene mutations in ASXL1, DNMT3A, JAK2, TET2, and TP53. CH-associated somatic gene mutations were detected in 14/31 AML patients (45%), 13/64 myeloma patients (20%), and 9/47 lymphoma patients (19%). Clinical characteristics, treatment modalities, and responses to treatment were similar in patients with and without CH. Patients with CH-associated gene mutations had higher relapse rates and reduced progression free survival, most evident in lymphoma patients (p = 0.007). Overall survival tended to be shorter in lymphoma patients with CH-associated mutations (p = 0.078), whereas this was not observed in AML and myeloma patients. Survival in lymphoma patients with CH was inferior, which may have an impact on post-transplant surveillance strategies in the future. In contrast, survival outcomes were not associated significantly with CH in AML and myeloma patients in our study. Longer follow-ups and larger cohorts will be needed to validate our observations. Full article

VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still’s disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease. Full article

Purpose: Evaluate long-term immunogenicity and its association with the number of vaccines and breakthrough infections in patients with hematologic malignancies compared to a healthy cohort. Methods: This study is an amendment of a multicenter study (DRKS00027372) which described the upsurge of anti-spike-IgGs on day 120 from a blunted day-35 response in patients with hematologic neoplasms. In this amendment, 191 individuals from the original study (patients with myeloid and lymphoid neoplasms and controls) were followed beyond month 12 after first SARS-CoV-2-vaccination. The long-term humoral and cellular responses and their correlation with the number of vaccines were studied. Results: After a median follow-up of 18 months, a median of three vaccinations (range 1–5) were given. Antibody levels did not correlate with the number of vaccinations (≤2 versus ≥3) (p = 0.3). With a median of 5274 U/mL anti-spike-IgGs, the inferior day-120 antibody response in patients with lymphoid neoplasms was no longer detected. Breakthrough SARS-CoV-2-infections, mostly mild, occurred in 67% of controls and 46% of patients. Patients with lymphoid neoplasms with two vaccinations did not have more infections compared to patients with more doses (p = 0.4). There was a significant decline in the spike-specific T-cell response for CovCD4⁺ and CovCD8⁺ (p < 0.001). On last assessment, 33% of individuals lost their day-120 CovCD4⁺-positive response (p < 0.001). There was no correlation between the number of vaccinations and cellular immune response in patients and controls (p = 0.3). Conclusions: In this study, breakthrough infections were high despite repeated boosting, which by itself does not lead to an upsurge in the cellular immune response in the majority of patients. Full article

This report presents the case of a seven-year-old West Highland White Terrier diagnosed with relapsed and refractory multiple myeloma (MM), managed using multiple treatment approaches, including conventional chemotherapy (melphalan, vincristine, doxorubicin, and dexamethasone), radiation therapy (RT), and novel agents such as the selective inhibitor of nuclear export (verdinexor), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), and tyrosine kinase inhibitors (TKIs; toceranib and sorafenib). Treatment response was monitored using serum globulin concentration and imaging studies. Verdinexor achieved the longest period of stable remission with minimal toxicity post-RT. Bortezomib + dexamethasone was effective in controlling hyperglobulinemia at doses ≥ 1.45 mg/m², although cumulative hematologic and gastrointestinal toxicity limited its prolonged use. Second-line proteasome inhibitors and TKIs demonstrated limited efficacy. Despite initial therapeutic response, the patient’s condition deteriorated due to persistent hyperglobulinemia and hyperviscosity syndrome. The absence of advanced supportive options, including plasmapheresis, contributed to a fatal outcome. This case highlights the potential utility of novel therapies such as verdinexor and bortezomib in managing refractory canine MM. Timely intervention, individualized dosing, and supportive care are essential for optimizing treatment outcomes. Further research is required to define effective combinations and integrate advanced care options, including stem cell transplantation and targeted antibody therapies, in veterinary MM. Full article

Background/Objectives: Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are widely performed procedures often associated with significant blood loss, leading to the need for allogeneic blood transfusion. Transfusions carry inherent risks and increase healthcare costs, making the identification of transfusion predictors crucial. This study aimed to assess preoperative predictors associated with transfusion requirement in patients undergoing THA or TKA. Methods: This single-center, retrospective analysis included 742 patients who underwent primary TKA or THA between 2016 and 2023. Preoperative variables such as hemoglobin, red blood cell count (RBC), INR, APTT, and use of tranexamic acid (TXA) were collected. Univariable and multivariable logistic regression analyses were conducted to identify independent predictors of transfusion. Results: Transfusions were required in 12.0% of patients. Multivariable analysis revealed that lower preoperative HGB and RBC levels, absence of TXA use, higher INR, and undergoing THA (versus TKA) were independently associated with increased transfusion risk. INR was not significant in univariable analysis but reached significance in the adjusted model. The final multivariable model demonstrated good predictive performance, with an area under the ROC curve (AUC) of 0.79. Conclusions: Lower hemoglobin and RBC levels, elevated INR, absence of TXA use, and THA surgery were independent predictors of transfusion. These findings may guide the use of routine preoperative hematologic and coagulation assessments to guide perioperative management and reduce transfusion rates in joint arthroplasty. Full article

Background: Atrial fibrillation (AF) is common complication of heart failure with preserved ejection fraction (HFpEF) that sufficiently intervenes in the prognosis. The aim of the study is a) to investigate the possible discriminative value of adropin for newly onset AF in patients with HFpEF without a previous history of AF and who are being treated in accordance with conventional guideline and b) to compare it with predictive potencies of conventionally used predictors. Methods: A total of 953 patients with HFpEF who had sinus rhythm on ECG were enrolled in the study. The course of the observation was 3 years. Echocardiography and assessment of conventional hematological, biochemical parameters and biomarker assay including N-terminal brain natriuretic pro-peptide (NT-proBNP), high-sensitivity cardiac troponin T, tumor necrosis factor-alpha, high-sensitivity C-reactive protein (hs-CRP), galectin-3, interleukin-6, soluble suppressor tumorigenisity-2 (sST2) and adropin, were performed at baseline. Results: Incident atrial fibrillation was found in 172 patients with HFpEF, whereas 781 had sinus rhythm. In unadjusted rough Cox regression model, age ≥ 75 years, type 2 diabetes mellitus, chronic kidney disease (CKD) stages 1–3, left atrial volume index (LAVI) ≥ 40 mL/m², NT-proBNP ≥ 1440 pmol/mL, hs-CRP ≥ 5.40 mg/L, adropin ≤ 2.95 ng/mL, sST2 ≥ 15.5 ng/mL were identified as the predictors for new onset AF in HFpEF patients. After adjusting for age ≥ 75 years, a presence of type 2 diabetes mellitus and CKD stages 1–3, the levels of NT-proBNP ≥ 1440 pmol/mL and adropin ≤ 2.95 ng/mL were independent predictors of new onset AF in patients HFpEF. We also found that discriminative value of adropin was superior to NT-proBNP, while adding adropin to NT-proBNP did not improve predictive information of adropin alone. Conclusions: adropin ≤ 2.95 ng/mL presented more predictive information than NT-proBNP ≥ 1440 pmol/mL alone for new cases of AF in symptomatic patients with HFpEF, whereas the combination of both biomarkers did not improve the predictive ability of adropin alone. Full article

Pulmonary carcinoids (PCs) are rare neoplasms involving typical and atypical carcinoids (TCs and ACs), defined histologically by absent or focal necrosis and mitotic counts (<2/mm² vs. 2–10/mm²), respectively. Although uncommon overall, TCs and ACs represent the most frequent non-hematologic malignancies in the pediatric population. However, significantly less is known about PC in AYAs, a population often overlooked or analyzed within pediatric or adult cohorts. In this critical review, we analyzed existing literature on PCs in the AYA population using a question-and-answer format, emphasizing the substantial gap in current knowledge in this field and the urgent unmet clinical need for future scientific proposals. First, we analyzed epidemiology and the data availability about the association between PCs in AYA patients and genetic syndromes that typically reach the maximal diagnostic incidence within this age group. We then reviewed the available literature about the pathologic characteristics, clinical presentation, and treatment strategies for localized and metastatic disease in PC AYA patients. According to our findings, a significant lack of age-specific evidence and the need for international collaboration and prospective, AYA-focused clinical studies were underscored. Advancing research in this area is essential to improve understanding and develop tailored, evidence-based therapeutic approaches for this peculiar population. Full article