Search Results (112)

Introduction: Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers, with a subset progressing to locally advanced (laSCC) or metastatic (mSCC) stages. The introduction of anti-PD1 immunotherapy has transformed treatment, but real-world data remain limited, particularly in immunosuppressed patients. Methods: This single-centre, retrospective study included 189 patients with advanced cSCC treated between 2012 and 2022. Demographic, clinical, and treatment data were analyzed to assess clinical management and outcomes before and after the introduction of anti-PD1. Results: Among the 189 patients, 72.5% were male, with a median age of 79 years. Overall, 86 patients presented with laSCC and 103 with mSCC. In 100 patients, a preceding primary cSCC was documented, and its complete resection (R0) was associated with significantly better overall survival (OS) after diagnosis of advanced disease (p < 0.001). Immunosuppressed patients, including organ transplant recipients and those with chronic lymphocytic leukemia (CLL), had significantly reduced OS (p = 0.017 and p = 0.0059, respectively). First-line treatment prior to 2018 predominantly involved surgery and radiotherapy. Following the introduction of anti-PD1 therapy, its use increased rapidly in both first- and second-line settings. From 2018 onward, the number of advanced cSCC cases discussed at the multidisciplinary tumorboard increased approximately threefold. Median OS was significantly longer for mSCC patients treated in the post-2018 era (p = 0.025), while the survival disadvantage of CLL patients compared to non-CLL patients widened, suggesting limited benefit from advances in systemic therapy in this subgroup. Best overall response to first-line anti-PD1 correlated significantly with OS, with complete responders achieving a 1-year progression-free survival of 83.3%. Conclusions: The introduction of anti-PD1 has demonstrated improved survival outcomes in advanced cSCC, though significant challenges remain for immunosuppressed patients, particularly those with CLL and solid organ transplant recipients. Future research should focus on optimizing treatment for these high-risk groups, therapeutic sequencing, and the role of perioperative (neoadjuvant and adjuvant) immunotherapy strategies. Full article

Background/Objectives: Covalent Bruton’s tyrosine kinase inhibitors (cBTKis) and the BCL-2 inhibitor venetoclax (VEN) have largely replaced traditional chemotherapy in clinical guidelines for frontline treatment of chronic lymphocytic leukemia (CLL). However, real-world evidence comparing these therapies on key outcomes remains limited. This study examined overall survival (OS) and time to next treatment (TTNT) among U.S. Medicare beneficiaries initiating frontline CLL therapy. Methods: In this retrospective study using 2016–2023 national 100% Medicare fee-for-service claims, we identified 10,949 patients aged ≥65 who initiated CLL treatment between June 2019 and December 2022. Patients received VEN-based regimens (n = 1503), cBTKi-based regimens (n = 5956), or other regimens (n = 3490). Results: Kaplan-Meier analyses showed superior OS for VEN-based regimens compared with cBTKi-based regimens and other regimens; three-year survival was 77% for VEN, 67% for cBTKis, and 62% for other regimens. In Cox regression models, cBTKis (hazard ratio [HR] 1.48, 95% CI 1.31–1.67) and other therapies (HR 1.66, 95% CI 1.47–1.89) were associated with worse OS relative to VEN. TTNT results also favored VEN; the percentage of patients with no evidence of second-line treatment at 3-years higher for VEN-based regimens (86%) compared to cBTKi-based regimens (69%) and other regimens (52%), despite similar follow-up times (median [months] VEN = 26.6, cBTKis = 26.2, Other = 21.8). cBTKis (HR 2.69, 95% CI 2.23–3.26) and other regimens (HR 6.47, 95% CI 5.32–7.86) were associated with a greater hazard for subsequent treatment relative to VEN. Conclusions: Our study demonstrates better survival and reduced need for subsequent treatment with VEN in patients with CLL treated in the frontline setting. Full article

The long-term effects of agricultural management systems (AMS) on soil physical properties and water infiltration in tropical Ferralsols remain incompletely understood. We assessed steady-state infiltration rates and soil physical properties in a Ferralsol after 20 years under five AMS in a Cerrado–Atlantic Forest transition area in Brazil: no-tillage (NT), conventional tillage (CT), integrated crop–livestock in crop (CL-C) and livestock (CL-L) phases, and permanent pasture (PP). Soil samples were collected at four depths, and infiltration was measured using the InfiAsper simulator at 60 mm h⁻¹. Integrated systems showed the best topsoil (0–0.05 m) physical condition, with higher macroporosity, aggregate stability, and organic carbon than NT and CT. Surface bulk density under PP was similar to integrated systems; higher bulk density values were observed under NT and CT at 0.10–0.20 m. Steady-state infiltration rates ranged from 26.40 mm h⁻¹ (PP) to 54.32 mm h⁻¹ (NT), with integrated systems averaging 59% higher than PP. Total SOC stocks (0–0.40 m) were significantly greater under CL-L (92.7 Mg C ha⁻¹) and CL-C (88.1 Mg C ha⁻¹) than PP (73.5 Mg C ha⁻¹; p = 0.004), driven by higher subsoil SOC concentrations under integrated systems; the lower subsoil bulk density under PP partially attenuated its calculated stock. These results demonstrate that integrated crop–livestock systems simultaneously improve soil physical condition, water infiltration, and carbon accumulation per unit land area, supporting sustainable intensification in the Brazilian Cerrado and Atlantic Forest biomes. Full article

This work contains the results of the research carried out on the framework of the design of the resonant power module of DAB. The peculiarity of this device is that it is supposed to be used as part of the basic element of a scalable power storage system, the load of which is an industrial three-phase network. The paper proposes a method of designing such devices based on preliminary analytical calculations and the development of numerical models. This method includes three stages. In the first iteration, the parameters of the resonant CLLC converter. In the second iteration, in the course of performing more accurate calculations and development of numerical models, the output parameters and the adjustment characteristic of the converter are determined, taking into account the specifics of the load. At the third stage, a numerical model of a high-frequency transformer is developed to determine the number of losses in the core and estimate the values of magnetic induction. Full article

This paper introduces a novel switching method called copolar switching, designed to maintain high power efficiency in CLLC bidirectional chargers across different modes of operation. The proposed method sets the switching frequency close to the resonance of the LC tank within the CLLC circuit, ensuring efficient power conversion in both the forward (charging) and reverse (discharging) modes. Using Fourier series analysis and circuit theory, the necessary duty cycle for achieving the target efficiency is derived and applied to the full bridge on the high-voltage side in reverse mode. Copolar switching ensures that the entire CLLC circuit operates at a single resonant frequency, addressing the conventional issue of unbalanced efficiency between forward and reverse power conversions. A prototype circuit was designed for power conversion between 400 V and 48 V. Experimental results demonstrate 1 kW power conversion with 97% efficiency in forward mode and 800 W conversion with the same efficiency in reverse mode. Additionally, the copolar switching method shows potential for applications requiring voltage output adjustments, such as converting between 400 V and 50 V. Full article

Background: Artificial intelligence (AI) shows promising results in lymphoma detection, prediction, and classification. However, translating these findings into practice requires a rigorous assessment of potential biases, clinical utility, and further validation of research models. Objective: The goal of this study was to summarize existing studies on artificial intelligence models for the histopathological detection of lymphoma. Design: This study adhered to the PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines. A systematic search was conducted across three major databases (Scopus, PubMed, Web of Science) for English-language articles and reviews published between 2016 and 2025. Seven precise search queries were applied to identify relevant publications, accounting for variations in study modality, algorithmic architectures, and disease-specific terminology. Results: The search identified 612 records, of which 36 articles met the inclusion criteria. These studies presented 36 AI models, comprising 30 diagnostic and six prognostic applications, with Convolutional Neural Networks (CNNs) being the predominant architecture. Regarding data sources, 83% (30/36) of datasets utilized Hematoxylin and Eosin (H&E)-stained images, while the remainder relied on diverse modalities, including IHC-stained slides, bone marrow smears, and other tissue preparations. Studies predominantly utilized retrospective, private cohorts with sample sizes typically ranging from 50 to 400 patients; only a minority leveraged open-access repositories (e.g., Kaggle, TCGA). The primary application was slide-level multi-class classification, distinguishing between specific lymphoma subtypes and non-neoplastic controls. Beyond diagnosis, a subset of studies explored advanced prognostic tasks, such as predicting chemotherapy response and disease progression (e.g., in CLL), as well as automated biomarker quantification (c-MYC, BCL2, PD-L1). Reported diagnostic performance was generally high, with accuracy ranging from 60% to 100% (clustering around 90%) and AUC values spanning 0.70 to 0.99 (predominantly >0.90). Conclusions: While AI models demonstrate high diagnostic accuracy, their translation into practice is limited by unstandardized protocols, morphological complexity, and the “black box” nature of algorithms. Critical issues regarding data provenance, image noise, and lack of representativeness raise risks of systematic bias, hence the need for rigorous validation in diverse clinical environments. Full article

In conventional CLLC topologies, CC/CV charging is typically implemented using closed-loop control strategies based on phase shift modulation. This not only increases control complexity but also requires additional voltage and current sensing circuits, thereby raising the overall system cost. To address these issues, this paper proposes a novel CC/CV charging strategy. By analyzing the inherent characteristics of the coupled network, the switching frequencies corresponding to the CC and CV operating points are derived. By jointly applying frequency modulation and phase shift control to the CLLC converter, the system not only realizes CC/CV charging, but also enables the regulation of both the magnitude and the direction of power flow. Furthermore, to improve the system’s efficiency, a fine frequency tuning method is introduced to ensure operation under the critical zero-voltage switching (ZVS) condition. Finally, a 500 W prototype is constructed to validate the effectiveness of the proposed control strategy. Full article

Introduction: This review specifically focuses on interventional clinical trials in leukemias and myelodysplastic syndromes (MDS), summarizing how patient-reported outcome measures (PROMs) have been implemented to evaluate treatment effects rather than to directly influence clinical outcomes. Objective: Clinical outcomes of interest typically include response rates, disease-free survival (DFS), and overall survival (OS). Patient-reported outcome measures (PROMs) are standardized questionnaires that collect information regarding health outcomes directly from the patient and are used to evaluate new treatments and healthcare quality. In addition, the use of PROMs in cancer care has been shown to improve patient-provider communication and patient satisfaction. Material and Methods: This is a qualitative, narrative synthesis and review structured around PROMs focused on six critical themes: symptoms/symptom burden, physical, emotional, social/role, and functional status, and global health status measurement. Results: PROMs that are assessed in oncologic research include the EORTC QLQ-C30, FACT-Leu, QLQ-CLL16, and EQ-5D. PROs are associated with clinical outcomes such as DFS and OS, and the FACT-Leu scales, HRQOL and physical functioning scores were independent prognosticators of OS in patients with AML. Conclusions: Through our review, notable trends were identified that further highlight the importance of greater incorporation of PRO measures in future clinical trials, particularly in the understudied realm of hematologic malignancies, in order to better delineate the link between survival and HRQOL. Full article

Background: A strikingly unusual pattern with a possible up-field shift in Hemoglobin A1c (HbA1c) and A0 (HbA0) peaks and an unexplained hemoglobin F (HbF) peak with capillary electrophoretic shift in the HbA1c chromatograms of a leukemia patient were found while performing a HbA1c screen. Methods: A review of the patient’s history with an exhaustive search of the literature ruled out medications as interfering factors or contributing to the abnormal findings. Other than hyperleukocytosis, the patient did not have the aberrant HbF peak noted previously in the electrophoresis or contributing factors. We hypothesized that the irregular chromatographic pattern and wrong location of the HbA1c peak, hereafter referred to as the downfield shift in the electrophoretic species, was due to various glycation or fructosamine adducts and derivatives within the HbA1c and A0 protein. Results: A literature search offered little guidance. However, the instrument troubleshooting measures suggested a hemoglobin variant or exogenous transfusion as a putative source for the HbF peak, while the downfield shift in the chromatogram remained unexplained. Full article

BTK (Bruton’s tyrosine kinase) has become a key therapeutic target across several hematologic diseases, beginning with its original use in CLL/SLL. As a central mediator of B-cell receptor signaling and microenvironment interactions, BTK supports survival, proliferation, and trafficking in multiple mature B-cell malignancies (mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and other indolent/aggressive lymphomas) and in selected immune-mediated conditions such as chronic graft-versus-host disease. Covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) irreversibly bind the C481 residue and have produced high response rates and durable disease control, often replacing chemoimmunotherapy in the relapsed setting and, for some entities, even in the first line. Differences in kinase selectivity lead to different safety profiles: second-generation covalent agents generally maintain efficacy while reducing significant off-target toxicities, especially atrial fibrillation and hypertension. Resistance to covalent BTK inhibitors most commonly develops through BTK C481 substitutions and activating PLCG2 mutations, with other kinase-domain variants increasingly recognized. Non-covalent BTK inhibitors (e.g., pirtobrutinib) bind BTK independently of C481, can overcome classic C481-mediated resistance, and extend BTK pathway targeting into later lines of therapy. Overall, BTK inhibition has evolved into a versatile platform enabling long-term, often chemo-free management strategies. Full article

The growing market penetration of Electric Vehicles (EVs) requires very efficient bidirectional on-board chargers. These converters must allow the power transfer from the grid to the battery of the vehicle and vice versa, since Vehicle to Grid (V2G) applications enable a mitigation of the peak demand and help regulate both the voltage and the frequency of the grid. In this paper, an innovative double asymmetric modulation was studied and applied to a resonant Dual Active Bridge (DAB), CLLC resonant filter configuration. The results of the study showed a significant efficiency boost and an easier controllability of the converter with respect to more traditional modulations or variable frequency techniques, maintaining Zero-Voltage Switching (ZVS) conditions for all the switches in a wide operating range, from 28 to 100% of the maximum power (4–14 kW). A map of optimum points, where converter losses are minimized, is calculated offline through an algorithm in MATLAB R2024a and a proper interpolation between these points allows any output power for each possible voltage level of the battery to be achieved: from 250 V up to 400 V. The modulations are compared and evaluated through simulations carried out in PLECS, both offline and using hardware-in-the-loop (HIL), as well as through experimental tests. Full article

Over the past decade, chronic lymphocytic leukaemia (CLL) treatment has shifted from chemoimmunotherapy to targeted oral agents, predominantly Bruton’s tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax. These therapies have significantly improved outcomes and are now established as first-line treatment options. However, CLL remains incurable, and resistance or intolerance to both drug classes (double-refractory disease) is an emerging challenge. This has driven the development of novel therapeutic strategies, including non-covalent BTKis such as pirtobrutinib and nemtabrutinib, which retain activity in BTK C481-mutated disease. Next-generation BCL-2 inhibitors (sonrotoclax, lisaftoclax) and BTK degraders are promising in early clinical trials. Immunotherapeutic approaches, such as bispecific T-cell engagers, CD20/CD3 antibodies, and CAR-T cell therapies, provide additional options for high-risk patients. Although PI3K inhibitors remain under investigation, their role is yet to be defined due to safety concerns. Minimal residual disease (MRD)-guided, fixed-duration regimens represent a significant paradigm shift toward personalised treatment and potentially deeper remissions. Ongoing clinical studies are expected to introduce new effective therapies that may further transform the management of CLL in the coming years. Full article

Gallium nitride (GaN) devices are gaining rapid adoption in electric vehicle (EV) power electronics because of their high switching speed, efficiency, and passive size reduction. The remaining gaps concern reliability across real drive cycles, integration with vehicle-level thermal subsystems, and scalability to high-voltage platforms. This review addresses these gaps by synthesizing experimental reports and automotive case studies from 2019 to 2025. We examine reliability through junction stress and derating maps derived from urban/highway duty profiles and temperature extremes, and we link device hot-spots to thermal pathways (TIMs, spreaders, liquid/air cooling) within the EV thermal budget. We then compare GaN-based onboard chargers (OBCs), DC–DC stages (LLC/CLLC/DAB), traction inverters, and EMI strategies against Si/SiC baselines. Results indicate OBC efficiencies of 96–98% at 100–500 kHz, with 30–60% passive reduction; inverter efficiencies > 98% on 400 V platforms; and strong potential for GaN paired with Vienna or T-type rectifiers in 800 V charging, while >900 V traction remains largely SiC-led. We conclude with a topology-selection framework that balances switching and conduction losses, gate-driver complexity, and EMI, plus a roadmap toward EMI-compliant MHz operation and data-driven reliability evaluation. Full article

Background/Objectives: Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by uncontrolled accumulation of B lymphocytes. A key feature of CLL is the presence of genetic aberrations, particularly alterations of chromosome 17, such as deletion of 17q and/or mutations in the TP53 gene. Since these abnormalities are highly relevant for therapeutic decision-making, assessment of TP53 mutational status is strongly recommended in routine diagnostics. This study aimed to evaluate the reliability of TP53 sequencing results depending on the type of DNA sample analyzed. Methods: DNA was isolated from two different sample types of the same patient: mononuclear cells (CLL1) and purified CD19+ cells (CLL2). The entire coding region of TP53 (exons 2–11), including splice sites (+/− 10 bp), was analyzed using capture-based next-generation sequencing (NGS). Reads were aligned to the GRCh37/hg19 reference genome, and variants were interpreted using DRAGEN Enrichment (Illumina) and Franklin (QIAGEN). Results: In sample CLL1, the NM_000546.6:c.626_627del mutation (Tier I) was identified with a variant allele frequency (VAF) of 57.06%. The same mutation was confirmed in CLL2, but with a higher VAF of 94.78%. Importantly, an additional Tier I mutation (NM_000546.6:c.825_826del) was detected exclusively in CLL2 at a VAF of 1.59%. Both findings met the required sequencing depth as well as coverage per sample, confirming their validity. Conclusions: The study demonstrates that inadequate starting material for DNA isolation may mask low-frequency TP53 mutations, resulting in false-negative results. Accurate detection requires ensuring sufficient CD19+ cell content, which is critical for reliable diagnostics and supports personalized treatment approaches in CLL. Full article

The cause of nephrotic–nephritic syndrome and elevated blood pressure values was investigated by renal biopsy in a 72-year-old Caucasian male with B-cell chronic lymphocytic leukemia (B-CLL) and a low level of IgG/lambda paraprotein. Double-contoured glomerular capillaries, glomerular thrombi, interstitial B-CLL infiltrates, and normal-looking arteries and arterioles were observed histologically. The glomerular capillaries displayed nonspecific entrapment of IgM and C3 and pseudolinear C4d positivity immunohistochemically. With electron microscopy, diffusely effaced foot processes, widened and duplicated glomerular basement membrane (BM), mesangial cell interposition, and thickened, non-fenestrated, and serrated endothelial cells located on subendothelial BM layer(s) were seen. The peritubular capillaries lacked any significant BM multilayering. Chronic glomerular thrombotic microangiopathy (TMA) was diagnosed; the C4d positivity result indicated structural remodeling of glomerular capillary walls. Laboratory features of microangiopathic hemolytic anemia were absent. The functional complement assay found selective classical pathway activation and the consumption of early complement components. The components of the alternative pathway were not consumed. A disease-causing variant in the coding region of the complement C2 gene was screened, with negative results. The kidney function gradually deteriorated to stage 4 chronic kidney disease over a period of six months. Second-line treatment with ibrutinib markedly decreased the leukemic symptoms, stopped the production of paraprotein, and eliminated the nephrotic syndrome; the kidney function improved. The decreased activity of the classical pathway remained unchanged. The culprit of glomerular anomalies seemed to be the paraprotein, which acted as a nephrotoxic mediator and triggered glomerular TMA. A hypothetical pathophysiologic explanation of TMA is presented. The paraneoplastic classical pathway activation of complement did not play any role in the development of glomerular TMA. Full article