Polyethylene Glycol Epirubicin-Loaded Transcatheter Arterial Chemoembolization Procedures Utilizing a Combined Approach with 100 and 200 μm Microspheres: A Promising Alternative to Current Standards

PURPOSE:To report clinical effectiveness, toxicity profile, and prognostic factors of combined 100 μm ± 25 and 200 μm ± 50 epirubicin-loaded polyethylene glycol (PEG) microsphere drug-eluting embolic transcatheter arterial chemoembolization protocol in patients with hepatocellular carcinoma. MATERIALS AND METHODS: In this prospective, single-center, single-arm study with 18 months of follow-up, 36 consecutive patients (mean age 69.9 y ± 10.8; 26 men, 10 women; 54 naïve lesions) were treated. Embolization was initiated with 100 μm ± 25 microspheres, and if stasis (10 heart beats) was not achieved, 200 μm ± 50 microspheres were administered. Each syringe (2 mL) of PEG microsphere was loaded with 50 mg of epirubicin. Results were evaluated using Modified Response Evaluation Criteria In Solid Tumors with multidetector computed tomography/magnetic resonance imaging at 1, 3-6, 9-12, and 15-18 months. Toxicity profile was assessed by laboratory testing before and after the procedure. Complications were recorded. Postembolization syndrome (PES) was defined as onset of fever/nausea/pain after the procedure. Patient/lesion characteristics and treatment results were correlated with predicted outcome using regression analysis. Child-Pugh score was A in 86.1% of patients (31/36) and B in 13.9% (5/36). RESULTS: In 10 of 21 lesions, < 2 cm in diameter (47.5%) stasis was achieved with 100 μm ± 25 microspheres only, whereas all other lesions required adjunctive treatment with 200 μm ± 50 microspheres. Reported adverse events were grade 1 acute liver bile duct injury (3/39 cases, 7.7%) and PES (grade 2; 3/39 cases, 7.7%). Complete response (CR) at 1, 3-6, 9-12, and 15-18 months was 61.1%, 65.5%, 63.63%, and 62.5%. Objective response (CR + partial response) at 1, 3-6, 9-12, and 15-18 months was 83.3%, 65.85%, 63.63%, and 62.5%. No single factor (laboratory testing, etiology, patient status, hepatic status, tumor characteristics, administration protocol) predicted outcomes except for albumin level at baseline for CR (P < .05, odds ratio = 1.09). CONCLUSIONS: The combined microsphere sizing strategy was technically feasible and yielded promising results in terms of effectiveness and toxicity

A model of hyphal tip growth involving microtubule-based transport

We propose a simple model for mass transport within a fungal hypha and its subsequent growth. Inspired by the role of microtubule-transported vesicles, we embody the internal dynamics of mass inside a hypha with mutually excluding particles progressing stochastically along a growing one-dimensional lattice. The connection between long range transport of materials for growth, and the resulting extension of the hyphal tip has not previously been addressed in the modelling literature. We derive and analyse mean-field equations for the model and present a phase diagram of its steady state behaviour, which we compare to simulations. We discuss our results in the context of the filamentous fungus, Neurospora crassa.Comment: 5 pages, 5 figure

Management of post-intubation tracheal stenoses using the endoscopic approach

Background and Aim. Tracheal stenosis is a common complication of intubation with or without subsequent tracheotomy whose management remains poorly defined. Over 600 post-intubation tracheal stenoses have been treated in our centre since 1982: the aim of this study was to determine the safety and efficacy of our endoscopic approach. Methods. This retrospective study includes 113 new cases treated between 1998 and 2001. We chose this period to have a standardised technique and a significant number of cases with a sufficiently long follow up (28-78 months). Forty patients who did not meet the criteria for “true stenosis” (granulomas, pseudoglottic stenosis, etc.) were excluded from the study. Results. 73 patients (50±21 years) entered the study: 13 (18%) web-like and 60 (82%) complex stenoses. Most web-like stenoses were successfully treated with Laser Assisted Mechanical Dilation (LAMD) alone; among complex stenoses LAMD was sufficient to treat 13 patients (22%), whereas 47 patients (78%) required stent placement: 22 had their stent removed after one year and did not require any further therapy, 13 inoperable patients required permanent stent and 12 were referred to surgery after failure of multiple endoscopic treatments. No permanent complications secondary to endoscopic treatment were observed. 48 patients (66%) obtained a stable, good result with the endoscopic procedure, 13 (18%) required a permanent stent while 12 patients (16%) were referred to surgery. Conclusions. Our results indicate that the endoscopic treatment of post-intubation tracheal stenoses performed in an expert setting can be considered a safe first-line therapy, leaving some selected cases and the relapsing stenoses, for surgical resection

Surgical resection is superior to TACE in the treatment of HCC in a well selected cohort of BCLC-B elderly patients—A retrospective observational study

Simple Summary Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Liver transplantation (LT) and surgical resection (SR) are currently the primary treatments with curative intent. Nevertheless, more than two-thirds of patients are elderly and, therefore, excluded from LT; while, according to the Barcelona Clinic Liver Cancer (BCLC) system, SR should only be offered to a small group of patients with early stage HCC. The identification in stage B of an intermediate subgroup of patients that fulfill the criteria for surgery may play an important role in the implementation of potentially curative treatments. Hepatocellular carcinoma (HCC) usually develops in cirrhotic liver, with high recurrence rates. However, considering its increasing detection in non-cirrhotic liver, the choice of treatment assumes particular relevance. This study aimed to investigate outcomes of patients among BCLC stages and enrolled for surgical resection (SR) according to a more complex evaluation, to establish its safety and efficacy. A total of 186 selected HCC patients (median age 73.2 yrs), submitted to SR between January 2005 and January 2021, were retrospectively analyzed. Of which, 166 were staged 0, A, B according to the BCLC system, while 20 with a single large tumor (>5 cm) were classified as stage AB. No perioperative mortality was recorded; complications occurred in 48 (25.80%) patients, and all but two were Clavien-Dindo grade I-II. Median follow-up was 9.2 years. Subsequently, 162 recurrent patients (87,1%) were selected for new treatments. Comparable overall survival rates (OS) were observed at 1, 3, 5, and 10 years in 0, A, B and AB stages (p = 0.2). Eventually, the BCLC-B group was matched to 40 BCLC-B patients treated (2015-2021) with TACE. Significant differences in baseline characteristics (p <0.0001) and in OS were observed at 1 and 3 years (p <0.0001); a significant difference was also observed in oncological outcomes, in terms of the absence, residual, or relapse of disease (p <0.05). Surgery might be a valid treatment in HCC for patients affected by chronic liver disease in a condition of compensation, up to BCLC-B stage. Surgical indication for liver resection in case of HCC should be extensively revised

Impact of infectious comorbidity and overall time of hospitalization in total outpatient management of acute myeloid leukemia patients following venetoclax and hypomethylating agents

Venetoclax (VEN) and hypomethylating agent (HMAs) regimens are emerging as the standard of care for unfit for chemotherapy acute myeloid leukemia (AML) patients, but the safety and feasibility of a total outpatient management have not been fully investigated. Fifty-nine AML patients with active disease received VEN and HMAs. Nineteen out of 59 (32.2%) patients received the first cycle as inpatients, whereas 40/59 (67.8%) patients were treated in the outpatient setting. No significant differences were observed with regard to incidence of adverse events (AEs), including tumor lysis syndrome (TLS), and the 30-day and 60-day mortality was comparable. Notably, an infectious prophylaxis inspired to that adopted during intensive chemotherapy resulted in a low infection rate with a reduced bacterial infections incidence in out- versus hospitalized patients (p <.0001). The overall time of hospitalization was significantly shorter in patients who received a total outpatient treatment as compared to those who received the first cycle as inpatients (5.9 vs. 39.7 days, p <.0001). Despite the adopted differences in treatment management, the efficacy was similar. These data indicate that a total outpatient management of VEN and HMAs is feasible in AML patients without negatively impacting on treatment efficacy and may yield pharmacoeconomic and quality-of-life benefits

A Mathematical model for Astrocytes mediated LTP at Single Hippocampal Synapses

Many contemporary studies have shown that astrocytes play a significant role in modulating both short and long form of synaptic plasticity. There are very few experimental models which elucidate the role of astrocyte over Long-term Potentiation (LTP). Recently, Perea & Araque (2007) demonstrated a role of astrocytes in induction of LTP at single hippocampal synapses. They suggested a purely pre-synaptic basis for induction of this N-methyl-D- Aspartate (NMDA) Receptor-independent LTP. Also, the mechanisms underlying this pre-synaptic induction were not investigated. Here, in this article, we propose a mathematical model for astrocyte modulated LTP which successfully emulates the experimental findings of Perea & Araque (2007). Our study suggests the role of retrograde messengers, possibly Nitric Oxide (NO), for this pre-synaptically modulated LTP.Comment: 51 pages, 15 figures, Journal of Computational Neuroscience (to appear

Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments

Astrocytes orchestrate neural development by powerfully coordinating synapse formation and function and, as such, may be critically involved in the pathogenesis of neurodevelopmental abnormalities and cognitive deficits commonly observed in psychiatric disorders. Here, we report the identification of a subset of cortical astrocytes that are competent for regulating dopamine (DA) homeostasis during postnatal development of the prefrontal cortex (PFC), allowing for optimal DA-mediated maturation of excitatory circuits. Such control of DA homeostasis occurs through the coordinated activity of astroglial vesicular monoamine transporter 2 (VMAT2) together with organic cation transporter 3 and monoamine oxidase type B, two key proteins for DA uptake and metabolism. Conditional deletion of VMAT2 in astrocytes postnatally produces loss of PFC DA homeostasis, leading to defective synaptic transmission and plasticity as well as impaired executive functions. Our findings show a novel role for PFC astrocytes in the DA modulation of cognitive performances with relevance to psychiatric disorders

Evaluation of a large set of patients with Autoimmune Polyglandular Syndrome from a single reference centre in context of different classifications

Purpose: To characterize patients with APS and to propose a new approach for their follow-up. Query ID="Q1" Text="Please check the given names and familynames." Methods: Monocentric observational retrospective study enrolling patients referred to the Outpatients clinic of the Units of Endocrinology, Diabetology, Gastroenterology, Rheumatology and Clinical Immunology of our Hospital for Autoimmune diseases. Results: Among 9852 patients, 1174 (11.9%) [869 (73.9%) female] were diagnosed with APS. In 254 subjects, the diagnosis was made at first clinical evaluation (Group 1), all the other patients were diagnosed with a mean latency of 11.3 ± 10.6 years (Group 2). Group 1 and 2 were comparable for age at diagnosis (35.7 ± 16.3 vs. 40.4 ± 16.6 yrs, p =.698), but different in male/female ratio (81/173 vs 226/696, p =.019). In Group 2, 50% of patients developed the syndrome within 8 years of follow-up. A significant difference was found after subdividing the first clinical manifestation into the different outpatient clinic to which they referred (8.7 ± 8.0 vs. 13.4 ± 11.6 vs. 19.8 ± 8.7 vs. 7.4 ± 8.1 for endocrine, diabetic, rheumatologic, and gastroenterological diseases, respectively, p <.001). Conclusions: We described a large series of patients affected by APS according to splitters and lumpers. We propose a flowchart tailored for each specialist outpatient clinic taking care of the patients. Finally, we recommend regular reproductive system assessment due to the non-negligible risk of developing premature ovarian failure

Prostaglandin E2 Regulates AMPA Receptor Phosphorylation and Promotes Membrane Insertion in Preoptic Area Neurons and Glia during Sexual Differentiation

Sexual differentiation of the rodent brain is dependent upon the organizing actions of the steroid hormone, estradiol. In the preoptic area, a brain region critical for the expression of adult reproductive behavior, there are twice as many dendritic spine synapses per unit length on newborn male neurons compared to female neurons and this sex difference correlates with the expression of adult male copulatory behavior. The sex difference in the POA is achieved via estradiol's upregulation of the membrane-derived lipid signaling molecule prostaglandin E2 (PGE2); PGE2 is necessary and sufficient to masculinize both dendritic spine density and adult sexual behavior in rats. We have previously shown that PGE2 activates EP2 and EP4 receptors which increases protein kinase A (PKA) activity and that masculinized dendritic spine density and sex behavior are both dependent upon PKA as well as activation of AMPA type glutamate receptors. In the current experiments, we build upon this signaling cascade by determining that PGE2 induces phosphorylation of the AMPA receptor subunit, GluR1, which leads to increased AMPA receptor insertion at the membrane. Treating female pups on the day of birth with PGE2 induced the phosphorylation of GluR1 at the PKA-sensitive site within 2 hours of treatment, an effect that was blocked by co-administration of the PKA/AKAP inhibitor, HT31 with PGE2. Brief treatment of mixed neuronal/glial POA cultures with PGE2 or the cAMP/PKA stimulator, forskolin, increased membrane associated GluR1 in both neurons and glia. We speculate that PGE2 induced increases in AMPA receptor associated with the membrane underlies our previously observed increase in dendritic spine density and is a critical component in the masculinization of rodent sex behavior

SHANK3 controls maturation of social reward circuits in the VTA.

Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy