A narrative review of central nervous system involvement in acute leukemias.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadAcute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although asymptomatic or with unspecific symptoms, CNS leukemia should be assessed in both AML/ALL patients, through a combination of flow cytometry and cytological analysis of CSF. Intrathecal therapy (ITT) is a preventive measure for CNS involvement in AML and ALL, still much research is needed in finding the appropriate target that would dramatically lower CNS involvement in acute leukemia. Keywords: Acute leukemias; central nervous system involvement (CNS involvement); clinical management; pathophysiology.Iuliu Hatieganu University-School of Doctoral Studies (PCD 2019-2021) Romanian Government Ion Chiricuta Oncology Institute Cluj Napoca European Economic Spac

Outcomes of CAR-T Cell Therapy Recipients Admitted to the ICU: In Search for a Standard of Care—A Brief Overview and Meta-Analysis of Proportions

Objective: Our primary objective was to describe the baseline characteristics, main reasons for intensive care unit (ICU) admission, and interventions required in the ICU across patients who received CAR-T cell immunotherapy. The secondary objectives were to evaluate different outcomes (ICU mortality) across patients admitted to the ICU after having received CAR-T cell therapy. Materials and Methods. We performed a medical literature review, which included MEDLINE, Embase, and Cochrane Library, of studies published from the inception of the databases until 2022. We conducted a systematic review with meta-analyses of proportions of several studies, including CAR-T cell-treated patients who required ICU admission. Outcomes in the meta-analysis were evaluated using the random-effects model. Results: We included four studies and analyzed several outcomes, including baseline characteristics and ICU-related findings. CAR-T cell recipients admitted to the ICU are predominantly males (62% CI-95% (57–66)). Of the total CAR-T cell recipients, 4% CI-95% (3–5) die in the hospital, and 6% CI-95% (4–9) of those admitted to the ICU subsequently die. One of the main reasons for ICU admission is acute kidney injury (AKI) in 15% CI-95% (10–19) of cases and acute respiratory failure in 10% CI-95% (6–13) of cases. Regarding the interventions initiated in the ICU, 18% CI-95% (13–22) of the CAR-T recipients required invasive mechanical ventilation during their ICU stay, 23% CI-95% (16–30) required infusion of vasoactive drugs, and 1% CI-95% (0.1–3) required renal replacement therapy (RRT). 18% CI-95% (13–22) of the initially discharged patients were readmitted to the ICU within 30 days, and the mean length of hospital stay is 22 days CI-95% (19–25). The results paint a current state of matter in CAR-T cell recipients admitted to the ICU. Conclusions: To better understand immunotherapy-related complications from an ICU standpoint, acknowledge the deteriorating patient on the ward, reduce the ICU admission rate, advance ICU care, and improve the outcomes of these patients, a standard of care and research regarding CAR-T cell-based immunotherapies should be created. Studies that are looking from the perspective of intensive care are highly warranted because the available literature regarding this area is scarce

The role of adatoms in chloride-activated colloidal silver nanoparticles for surface-enhanced Raman scattering enhancement

Chloride-capped silver nanoparticles (Cl-AgNPs) allow for high-intensity surface-enhanced Raman scattering (SERS) spectra of cationic molecules to be obtained (even at nanomolar concentration) and may also play a key role in understanding some fundamental principles behind SERS. In this study, we describe a fast (<10 min) and simple protocol for obtaining highly SERS-active colloidal silver nanoparticles (AgNPs) with a mean diameter of 36 nm by photoconversion from AgCl precursor microparticles in the absence of any organic reducing or capping agent. The resulting AgNPs are already SERS-activated by the Cl− ions chemisorbed onto the metal surface where the chloride concentration in the colloidal solution is 10−2 M. Consequently, the enhanced SERS spectra of cationic dyes (e.g., crystal violet or 9-aminoacridine) demonstrate the advantages of Cl-AgNPs compared to the as-synthesized AgNPs obtained by standard Ag+ reduction with hydroxylamine (hya-AgNPS) or citrate (cit-AgNPs). The results of SERS experiments on anionic and cationic test molecules comparing Cl-AgNPs, hya-AgNPs and cit-AgNPs colloids activated with different amounts of Cl− and/or cations such as Ag+, Mg2+ or Ca2+ can be explained within the understanding of the adatom model – the chemisorption of cationic analytes onto the metal surface is mediated by the Cl− ions, whereas ions like Ag+, Mg2+ or Ca2+ mediate the electronic coupling of anionic species to the silver metal surface. Moreover, the SERS effect is switched on only after the electronic coupling of the adsorbate to the silver surface at SERS-active sites. The experiments presented in this study highlight the SERS-activating role played by ions such as Cl−, Ag+, Mg2+ or Ca2+, which is a process that seems to prevail over the Raman enhancement due to nanoparticle aggregation

‘De Novo’ Brain AVMs—Hypotheses for Development and a Systematic Review of Reported Cases

Background and Objectives: Brain arteriovenous malformations AVMs have been consistently regarded as congenital malformations of the cerebral vasculature. However, recent case reports describing “de novo AVMs” have sparked a growing debate on the nature of these lesions. Materials and Methods: We have performed a systematic review of the literature concerning de novo AVMs utilizing the PubMed and Google Academic databases. Termes used in the search were “AVM,” “arteriovenous,” “de novo,” and “acquired,” in all possible combinations. Results: 53 articles including a total of 58 patients harboring allegedly acquired AVMs were identified by researching the literature. Of these, 32 were male (55.17%), and 25 were female (43.10%). Mean age at de novo AVM diagnosis was 27.833 years (standard deviation (SD) of 21.215 years and a 95% confidence interval (CI) of 22.3 to 33.3). Most de novo AVMs were managed via microsurgical resection (20 out of 58, 34.48%), followed by radiosurgery and conservative treatment for 11 patients (18.97%) each, endovascular embolization combined with resection for five patients (8.62%), and embolization alone for three (5.17%), the remaining eight cases (13.79%) having an unspecified therapy. Conclusions: Increasing evidence suggests that some of the AVMs discovered develop some time after birth. We are still a long way from finally elucidating their true nature, though there is reason to believe that they can also appear after birth. Thus, we reason that the de novo AVMs are the result of a ‘second hit’ of a variable type, such as a previous intracranial hemorrhage or vascular pathology. The congenital or acquired characteristic of AVMs may have a tremendous impact on prognosis, risk of hemorrhage, and short and long-term management

A Holistic Perspective: Exosomes Shuttle between Nerves and Immune Cells in the Tumor Microenvironment

One of the limitations of cancer research has been the restricted focus on tumor cells and the omission of other non-malignant cells that are constitutive elements of this systemic disease. Current research is focused on the bidirectional communication between tumor cells and other components of the tumor microenvironment (TME), such as immune and endothelial cells, and nerves. A major success of this bidirectional approach has been the development of immunotherapy. Recently, a more complex landscape involving a multi-lateral communication between the non-malignant components of the TME started to emerge. A prime example is the interplay between immune and endothelial cells, which led to the approval of anti-vascular endothelial growth factor-therapy combined with immune checkpoint inhibitors and classical chemotherapy in non-small cell lung cancer. Hence, a paradigm shift approach is to characterize the crosstalk between different non-malignant components of the TME and understand their role in tumorigenesis. In this perspective, we discuss the interplay between nerves and immune cells within the TME. In particular, we focus on exosomes and microRNAs as a systemic, rapid and dynamic communication channel between tumor cells, nerves and immune cells contributing to cancer progression. Finally, we discuss how combinatorial therapies blocking this tumorigenic cross-talk could lead to improved outcomes for cancer patients

Spatial immune profiling of glioblastoma identifies an inflammatory, perivascular phenotype associated with longer survival

ISSN:0001-6322ISSN:1432-053

Chimeric Antigen Receptor T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia

Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects