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OBJECTIVES: Our aim was to describe the frequency and severity of infectious complications after chimeric antigen receptor (CAR) T-cell therapy in patients with large B-cell lymphoma (LBCL). METHODS: We retrospectively reviewed clinical records of LBCL patients treated with CD19-targeted CAR T-cell therapy from July/2018 to December/2021 at our institution, and identified all infectious episodes from CAR T-cell infusion until disease progression, death or last follow-up. RESULTS: Overall, 137 patients were included. Thirty six percent had received ≥3 previous lines of therapy and 26% an autologous hematopoietic cell transplantation (auto-HCT). Cytokine release syndrome occurred in 87 (64%) patients. Antibacterial prophylaxis was not used in any patient; only 38% received antifungal prophylaxis. Sixty three infectious events were observed in 41 (30%) patients. Fifty two (83%) of the infectious events had at least one pathogen identified (bacteria [n = 38], virus [n = 11], and fungi [n = 3]). Most of the infectious events occurred during hospitalization for CAR-T treatment. Infection-related mortality was observed in two patients. Independent risk factors for infection included male gender, previous auto-HCT, ≥3 lines of treatment and pre-lymphodepletion neutropenia. CONCLUSIONS: Infections after CAR T-cell therapy in patients with lymphoma are frequent but generally not severe. A conservative and tailored antimicrobial prophylaxis seems to be a safe approach.
Subject(s)
Antifungal Agents , Immunotherapy, Adoptive , Humans , Male , Female , Immunotherapy, Adoptive/methods , Immunotherapy, Adoptive/adverse effects , Middle Aged , Aged , Antifungal Agents/therapeutic use , Adult , Retrospective Studies , Antibiotic Prophylaxis/methods , Lymphoma, B-Cell/therapy , Lymphoma, B-Cell/immunology , Neoplasm Staging , Receptors, Chimeric Antigen , Hematopoietic Stem Cell Transplantation/adverse effects , Lymphoma, Large B-Cell, Diffuse/therapy , Anti-Bacterial Agents/therapeutic use , Mycoses/prevention & control , Mycoses/etiology , Risk FactorsABSTRACT
For the development of nanofilters and nanosensors, we wish to know the impact of size on their geometric, electronic, and thermal stabilities. Using the semiempirical tight binding method as implemented in the xTB program, we characterized Möbius boron-nitride and carbon-based nanobelts with different sizes and compared them to each other and to normal nanobelts. The calculated properties include the infrared spectra, the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), the energy gap, the chemical potential, and the molecular hardness. The agreement between the peak positions from theoretical infrared spectra compared with experimental ones for all systems validates the methodology that we used. Our findings show that for the boron-nitride-based nanobelts, the calculated properties have an opposite monotonic relationship with the size of the systems, whereas for the carbon-based nanobelts, the properties show the same monotonic relationship for both types of nanobelts. Also, the torsion presented on the Möbius nanobelts, in the case of boron-nitride, induced an inhomogeneous surface distribution for the HOMO orbitals. High-temperature molecular dynamics also allowed us to contrast carbon-based systems with boron-nitride systems at various temperatures. In all cases, the properties vary with the increase in size of the nanobelts, indicating that it is possible to choose the desired values by changing the size and type of the systems. This work has many implications for future studies, for example our results show that carbon-based nanobelts did not break as we increased the temperature, whereas boron-nitride nanobelts had a rupture temperature that varied with their size; this is a meaningful result that can be tested when the use of more accurate simulation methods become practical for such systems in the future.
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CONTEXT: The interaction between carbon nanostructures and heavy metal clusters is of great interest due to their potential applications as sensors and filters to remove the former from environment. In this work, we investigated the interaction between two types of carbon nanobelts (Möbius-type nanobelt and simple nanobelt) and nickel, cadmium, and lead nanoclusters. Our aim was to determine how both systems interact which would shed light on the potential applications of the carbon nanostructures as pollutant removal and detecting devices. METHODS: To investigate the interaction between carbon nanostructures and heavy metal nanoclusters, we utilized the semiempirical tight binding framework provided by xTB software with the GFN2-xTB Hamiltonian. We performed calculations to determine the best interaction site, lowest energy geometries, complexes stability (using molecular dynamics at 298K), binding energy, and electronic properties. We also carried out a topological study to investigate the nature and intensity of the bonds formed between the metal nanoclusters and the nanobelts. Our results demonstrate that heavy metal nanoclusters have a favorable binding affinity towards both nanobelts, with the Möbius-type nanobelt having a stronger interaction. Additionally, our calculations reveal that the nickel nanocluster has the lowest binding energy, displaying the greatest charge transfer with the nanobelts, which was nearly twice that of the cadmium and lead nanoclusters. Our combined results lead to the conclusion that the nickel nanoclusters are chemisorbed, whereas cadmium and lead nanoclusters are physisorbed in both nanobelts. These findings have significant implications for the development of sensor and filtering devices based on carbon and heavy metal nanoclusters.
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The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.
Subject(s)
Antineoplastic Agents , Hematologic Neoplasms , Humans , Antifungal Agents/adverse effects , Voriconazole , Azoles/therapeutic use , Antineoplastic Agents/adverse effects , Hematologic Neoplasms/complications , Hematologic Neoplasms/drug therapyABSTRACT
A total 302 teeth (148 molars and 154 premolars) corresponding to 152 patients aged ≥18 years were evaluated for caries using the ICDAS (International Caries Detection and Assessment System), fluorescence (DD, DIAGNOdent) and electrical impedance (IMS, CarieScan PRO) systems. Fissurotomy and intraoral radiographs were used as the gold standard. Accordingly, 27.5% (n=84) of the teeth were classified as sound, while 26.9% (n=81) had enamel involvement and 45.6% (n=138) presented carious lesions reaching the dentin. Sensitivity (Se), specificity (Sp), and the area under the curve (AUC) were, respectively, 90.7%, 87.8%, and 0.954 (IMS); 92.4%, 92.7%, and 0.954 (DD); and 79.0%, 72.3%, and 0.756 (ICDAS). With regard to Se and Sp, there were significant differences between ICDAS and DD (p<0.001) and between ICDAS and IMS (p=0.01), but not between IMS and DD (p=0.07). In relation to AUC, there were significant differences between ICDAS and DD (p<0.001), and between ICDAS and IMS (p<0.001), but not between IMS and DD (p>0.05). The correlations between fissurotomy and each method were 88.7% (IMS), 89.7% (DD), and 77.1% (ICDAS). Within the limitations of this study, clinically, the electrical system is not useful for differentiating between sound teeth and truly incipient caries lesions by itself. The fluorescence or electrical systems are recommended with the ICDAS to detect carious lesions in their early stages.
Subject(s)
Dental Caries , Dielectric Spectroscopy , Adolescent , Adult , Dental Caries/diagnosis , Dental Caries/pathology , Dental Enamel/pathology , Fluorescence , Humans , Molar/pathology , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
To describe and compare the characteristics of necrotizing fasciitis (NF) in patients with and without haematological malignancy. All adult patients diagnosed with NF and treated at our hospital were included (January 2010-March 2019). Diagnosis was based on intraoperative findings or consistent clinical/radiological characteristics, and patients were classified as group A (with haematological malignancy) or group B (without haematological malignancy). Student's t (quantitative), Fisher's exact (qualitative), and Kaplan-Meyer tests were used for the statistical analysis. The study included 29 patients: 8 in group A and 21 in group B. All haematological patients had severe neutropenia (0.2 [0.02-0.5] ×109 cells/L; p < 0.001) and positive blood cultures (100% vs. 61.9%; p = 0.04) at diagnosis. Gram-negative bacilli NF was more common in group A (87.5% vs. 9.5%; p = 0.001), predominantly due to Escherichia coli (50% vs. 9.5%; p = 0.056). Surgical treatment was less common in haematological patients (5 [62.5%] vs. 21 [100%]; p = 0.015). Overall, 9 (31%) patients died: 4 (50%) in group A and 5 (23.8%) in group B (p = 0.17). The univariate analysis showed that mortality tended to be higher (OR 3.2; 95%CI 0.57-17.7; p = 0.17) and to occur earlier (2.2 ± 2.6 vs. 14.2 ± 19.9 days; p = 0.13) in haematological patients. The LRINEC index > 6 did not predict mortality in either group. In our study, NF in patients with haematological malignancies was mainly due to Gram-negative bacilli, associated to high and early mortality rates. In our experience, the LRINEC scale was not useful for predicting mortality.
Subject(s)
Escherichia coli Infections/mortality , Escherichia coli , Fasciitis, Necrotizing/mortality , Hematologic Neoplasms/mortality , Neutropenia , Adult , Aged , Disease-Free Survival , Escherichia coli Infections/therapy , Fasciitis, Necrotizing/microbiology , Fasciitis, Necrotizing/therapy , Female , Hematologic Neoplasms/microbiology , Hematologic Neoplasms/therapy , Humans , Male , Middle Aged , Neutropenia/microbiology , Neutropenia/therapy , Retrospective Studies , Spain/epidemiology , Survival RateABSTRACT
We aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to P. aeruginosa conducted across 34 centers in 12 countries from January 2006 to May 2018. A mixed logistic regression model was used to estimate a model to predict the multidrug resistance of the causative pathogens. Of a total of 1,217 episodes of BSI due to P. aeruginosa, 309 episodes (25.4%) were caused by MDR strains. The rate of multidrug resistance increased significantly over the study period (P = 0.033). Predictors of MDR P. aeruginosa BSI were prior therapy with piperacillin-tazobactam (odds ratio [OR], 3.48; 95% confidence interval [CI], 2.29 to 5.30), prior antipseudomonal carbapenem use (OR, 2.53; 95% CI, 1.65 to 3.87), fluoroquinolone prophylaxis (OR, 2.99; 95% CI, 1.92 to 4.64), underlying hematological disease (OR, 2.09; 95% CI, 1.26 to 3.44), and the presence of a urinary catheter (OR, 2.54; 95% CI, 1.65 to 3.91), whereas older age (OR, 0.98; 95% CI, 0.97 to 0.99) was found to be protective. Our prediction model achieves good discrimination and calibration, thereby identifying neutropenic patients at higher risk of BSI due to MDR P. aeruginosa The application of this model using a web-based calculator may be a simple strategy to identify high-risk patients who may benefit from the early administration of broad-spectrum antibiotic coverage against MDR strains according to the local susceptibility patterns, thus avoiding the use of broad-spectrum antibiotics in patients at a low risk of resistance development.
Subject(s)
Bacteremia/microbiology , Drug Resistance, Multiple, Bacterial , Neoplasms/microbiology , Neutropenia/microbiology , Pseudomonas Infections/microbiology , Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Female , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Models, Biological , Neoplasms/complications , Neutropenia/complications , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , ROC Curve , Retrospective Studies , Risk Factors , Treatment OutcomeABSTRACT
Background: Nance-Horan syndrome (NHS) is an X-linked rare congenital disorder caused by mutations in the NHS gene. Clinical manifestations include congenital cataracts, facial and dental dysmorphism and, in some cases, intellectual disability. The aim of the present work was to identify the genetic cause of this disease in two unrelated Spanish NHS families and to determine the relative involvement of this gene in the pathogenesis.Materials and methods: Four members of a two-generation family, three males and one female (Family 1), and seven members of a three-generation family, two males and five females (Family 2) were recruited and their index cases were screened for mutations in the NHS gene and 26 genes related with ocular congenital anomalies by NGS (Next Generation Sequencing).Results: Two pathogenic variants were found in the NHS gene: a nonsense mutation (p.Arg373X) and a frameshift mutation (p.His669ProfsX5). These mutations were found in the two unrelated NHS families with different clinical manifestations.Conclusions: In the present study, we identified two truncation mutations (one of them novel) in the NHS gene, associated with NHS. Given the wide clinical variability of this syndrome, NHS may be difficult to detect in individuals with subtle clinical manifestations or when congenital cataracts are the primary clinical manifestation which makes us suspect that it can be underdiagnosed. Combination of genetic studies and clinical examinations are essential for the clinical diagnosis optimization.
Subject(s)
Cataract/congenital , Genetic Diseases, X-Linked/etiology , Membrane Proteins/genetics , Mutation , Tooth Abnormalities/etiology , Adult , Cataract/etiology , Cataract/pathology , Child , Female , Genetic Diseases, X-Linked/pathology , Humans , Infant , Infant, Newborn , Male , Middle Aged , Pedigree , Prognosis , Tooth Abnormalities/pathologySubject(s)
Demography , Physicians/supply & distribution , Adult , Age Distribution , Aged , Aged, 80 and over , Economics , Education, Medical/trends , Female , Forecasting , Foreign Medical Graduates/statistics & numerical data , Health Planning , Health Services Needs and Demand , Humans , Male , Middle Aged , Retirement/statistics & numerical data , Social Determinants of Health , Spain/epidemiology , Urban HealthABSTRACT
In this work, we made use of fragment-based drug design (FBDD) and de novo design to obtain more powerful acetylcholinesterase (AChE) inhibitors. AChE is associated with Alzheimer's disease (AD). It was found that the cholinergic pathways in the cerebral cortex are compromised in AD and the accompanying cholinergic deficiency contributes to the cognitive deterioration of AD patients. In the FBDD approach, fragments are docked into the active site of the protein. As fragments are molecular groups with a low number of atoms, it is possible to study their interaction with localized amino acids. Once the interactions are measured, the fragments are organized by affinity and then linked together to form new molecules with a high degree of interaction with the active site. In the other approach, we used the de novo design technique starting from reference drugs used in the AD treatment. These drugs were broken into fragments (seeds). In the growing strategy, fragments were added to each seed, growing new molecules. In the linking strategy, two or more separated seeds were linked with different fragments. Both strategies combined produced a library of more than 2 million compounds. This library was filtered using absorption, distribution, metabolism, and excretion properties. The resulting library with around six thousand compounds was filtered again. In this case, structures with Tanimoto coefficients >.85 were discarded. The final library with 1500 compounds was submitted to docking studies. As a result, 10 compounds with better interaction energy than the reference drugs were obtained.
Subject(s)
Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Databases, Pharmaceutical , Drug Development , High-Throughput Screening Assays/methods , Molecular Docking Simulation , Molecular Dynamics Simulation , Alzheimer Disease , Catalytic Domain , Drug Design , Humans , Ligands , Quantitative Structure-Activity RelationshipABSTRACT
We present a study of a novel vacuum arc deposition system composed of a water-cooled aluminum cathode and a hot refractory anode. The plasma of the arc system was diagnosed using a cylindrical electrostatic probe. It was found that the mean electron temperature was â¼2 eV, the plasma density could be varied in the range of 0.5-6 × 1016 m-3, and the ion flux was between 0.06 and 0.35 A m-2. Optical emission spectroscopy measurements showed the presence of emission lines corresponding to Al i and Al ii. The characterization of the coatings showed that the deposition rate varied from 0.8 to 4 nm/s and the surface roughness (Ra) of the films was as low as 25 nm. We demonstrated that it was possible to deposit films with low macroparticle densities, overcoming the principal disadvantage of the vacuum arc process. Measurements of the arc voltage and current were performed as a function of time and the applied magnetic field. The anode temperature was measured using a pyrometer through a ZnS window as a function of time and arc current, and the maximum value was 1800 °C with heating rates of up to 110 °C/s.
ABSTRACT
To choose the most relevant ten papers constitutes a challenge in several ways. We have elaborated this selection based on the papers we find to be most useful and ground-breaking for the clinician faced daily by the infectious problems in onco-hematological patients. The selection has been structured in four parts: bacterial infections, viral infections, fungal infections and infections related with new drugs in onco-hematological patients.
Subject(s)
Hematologic Neoplasms/complications , Hematologic Neoplasms/drug therapy , Infections/complications , Infections/drug therapy , Humans , Infections/microbiology , Infections/virologyABSTRACT
PURPOSE: To describe the anatomical and functional results of intravitreal antiangiogenic treatment in optic nerve head drusen associated with choroidal neovascularisation. CASE REPORT: An 8 year-old male patient with a diagnosis of neovascular membrane in the right eye associated with bilateral optic nerve head drusen. Best-corrected visual acuity (BCVA) was by counting fingers in the right eye and improved to 0.4 after antiangiogenic treatment. A complete consolidation of the lesion was observed with no associated complications arising from the treatment. DISCUSSION/CONCLUSIONS: Antiangiogenic treatment is an effective option, and no side-effects have been observed in treatment of neovascular tissue associated with optic disc drusen in children.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Choroidal Neovascularization/drug therapy , Optic Disk Drusen/complications , Child , Choroidal Neovascularization/etiology , Fibrosis , Humans , Intravitreal Injections , Male , Papilledema/etiology , Remission Induction , Retinal Hemorrhage/etiology , Subretinal Fluid , Tomography, Optical CoherenceABSTRACT
The resistive switching properties of silicon-aluminium oxynitride (SiAlON) based devices have been studied. Electrical transport mechanisms in both resistance states were determined, exhibiting an ohmic behaviour at low resistance and a defect-related Poole-Frenkel mechanism at high resistance. Nevertheless, some features of the Al top-electrode are generated during the initial electroforming, suggesting some material modifications. An in-depth microscopic study at the nanoscale has been performed after the electroforming process, by acquiring scanning electron microscopy and transmission electron microscopy images. The direct observation of the devices confirmed features on the top electrode with bubble-like appearance, as well as some precipitates within the SiAlON. Chemical analysis by electron energy loss spectroscopy has demonstrated that there is an out-diffusion of oxygen and nitrogen ions from the SiAlON layer towards the electrode, thus forming silicon-rich paths within the dielectric layer and indicating vacancy change to be the main mechanism in the resistive switching.
ABSTRACT
BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biologic therapies. AIMS: To review, from an infectious diseases perspective, the safety profile of therapies targeting cell surface receptors and associated signaling pathways among cancer patients and to suggest preventive recommendations. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Vascular endothelial growth factor (VEGF)-targeted agents (bevacizumab and aflibercept) are associated with a meaningful increase in the risk of infection, likely due to drug-induced neutropaenia, although no clear benefit is expected from the universal use of anti-infective prophylaxis. VEGF tyrosine kinase inhibitors (i.e. sorafenib or sunitinib) do not seem to significantly affect host's susceptibility to infection, and universal anti-infective prophylaxis is not recommended either. Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) induce neutropaenia and secondary skin and soft tissue infection in cases of severe papulopustular rash. Systemic antibiotics (doxycycline or minocycline) should be administered to prevent the latter complication, whereas no recommendation can be established on the benefit from antiviral, antifungal or anti-Pneumocystis prophylaxis. A lower risk of infection is reported for anti-ErbB2/HER2 monoclonal antibodies (trastuzumab and pertuzumab) and ErbB receptor tyrosine kinase inhibitors (including dual-EGFR/ErbB2 inhibitors such as lapatinib or neratinib) compared to conventional chemotherapy, presumably as a result of the decreased occurrence of drug-induced neutropaenia. IMPLICATIONS: With the exception of VEGF-targeted agents, the overall risk of infection associated with the reviewed therapies seems to be low.
Subject(s)
Biological Therapy/adverse effects , Communicable Diseases/therapy , Molecular Targeted Therapy/adverse effects , Signal Transduction/drug effects , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Biological Therapy/methods , Clinical Trials as Topic , Communicable Disease Control , Consensus , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/therapeutic use , Humans , Immunocompromised Host , Molecular Targeted Therapy/methods , Receptors, Cell Surface/antagonists & inhibitors , Vascular Endothelial Growth Factor A/drug effectsABSTRACT
Dysthyroid optic neuropathy (DON) is one of the complications that can affect Graves' orbitopathy (GO) patients. Its prevalence is estimated at less than 5%. It is usually treated with intravenous steroids, radiotherapy or orbital decompression. Tocilizumab has been proposed as a treatment option in cases of GO refractory to steroid treatment, with good clinical results. Our aim is to report the case of a patient with optic neuropathy secondary to GO treated with tocilizumab as primary treatment option.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Graves Ophthalmopathy/complications , Optic Nerve Diseases/drug therapy , Humans , Male , Middle Aged , Optic Nerve Diseases/diagnosis , Optic Nerve Diseases/etiology , Tomography, Optical Coherence , Visual Acuity/physiology , Visual Fields/physiologyABSTRACT
OBJECTIVE: Type 2 idiopathic macular telangiectasia (MacTel2) is a rare retinal disease that has still not been well-defined. The aim of the present manuscript is to describe the clinical features by multimodal retinal imaging, to present the functional characteristics, and to estimate the prevalence of the disease. METHODS: A retrospective study was conducted on the 12 eyes of 6 patients with MacTel2. Fundus colour photographs, fundus autofluorescence, fluorescein angiography, optical coherence tomography (OCT), and OCT-angiography were performed and subsequently analysed. Visual acuity (VA) was prospectively recorded. The prevalence was established based on the patients referred to a specialised macular diseases unit. Minimum follow-up period was 18 months. RESULTS: Prevalence of MacTel 2 in our study was 0.12%. Clinical features were presented using multimodal retinal imaging. VA remained stable during follow-up. Three patients developed choroidal neovascularisation (CNV), requiring intravitreal treatment with antiangiogenic agents. CONCLUSIONS: The prevalence of the disease found was 0.12%. The study using multimodal imaging allows a more accurate diagnosis and follow-up of this pathology. The VA is maintained during the 18-month follow-up (P=.492). Patients who develop CNV and are treated with antiangiogenic agents appear to respond adequately to them. More studies are needed to establish these conclusions.
Subject(s)
Retinal Telangiectasis , Aged , Diagnostic Techniques, Ophthalmological , Female , Humans , Middle Aged , Phenotype , Prevalence , Retinal Telangiectasis/classification , Retinal Telangiectasis/diagnostic imaging , Retinal Telangiectasis/epidemiology , Retinal Telangiectasis/genetics , Retrospective StudiesABSTRACT
Given the growing incidence of invasive candidiasis in critically ill and haemato-oncological patients and its poor outcomes, an early diagnosis and treatment are need for get a better prognosis. This document reviews the current ap-proaches that help in diagnosis of invasive candidiasis based on culture-independent microbiological tests. The combination of clinical prediction scores with fungal serological markers could facilitate the approach in antifungal therapy, optimiz-ing it. This article also reviews the epidemiology and primary risk factors for invasive candidiasis in these patients, updating the therapeutic approach algorithms in both clinical contexts based on the main evidence and international guidelines.