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Background The primary objective of the study is to describe the cellular characteristics of bronchoalveolar lavage fluid (BALF) of COVID-19 patients requiring invasive mechanical ventilation; the secondary outcome is to describe BALF findings between survivors vs non-survivors. Materials and methods Patients positive for SARS-CoV-2 RT PCR, admitted to ICU between March and April 2020 were enrolled. At ICU admission, BALF were analyzed by flow cytometry. Univariate, multivariate and Spearman correlation analyses were performed. Results Sixty-four patients were enrolled, median age of 64 years (IQR 58–69). The majority cells in the BALF were neutrophils (70%, IQR 37.5–90.5) and macrophages (27%, IQR 7–49) while a minority were lymphocytes, 1%, TCD3+ 92% (IQR 82–95). The ICU mortality was 32.8%. Non-survivors had a significantly older age ( p  = 0.033) and peripheral lymphocytes ( p  = 0.012) were lower compared to the survivors. At multivariate analysis the percentage of macrophages in the BALF correlated with poor outcome (OR 1.336, CI95% 1.014–1.759, p  = 0.039). Conclusions In critically ill patients, BALF cellularity is mainly composed of neutrophils and macrophages. The macrophages percentage in the BALF at ICU admittance correlated with higher ICU mortality. The lack of lymphocytes in BALF could partly explain a reduced anti-viral response.

CAR− CD4+ T cell lymphopenia is an emerging issue following CAR‐T cell therapy. We analyzed the determinants of CD4+ T cell recovery and a possible association with survival in 31 consecutive patients treated with commercial CAR‐T for diffuse large B‐cell (DLBCL) or mantle cell lymphoma. Circulating immune subpopulations were characterized through multiparametric‐flow cytometry. Six‐month cumulative incidence of CAR− CD4+ T cell recovery (≥200 cells/μL) was 0.43 (95% confidence interval [CI]: 0.28–0.65). Among possible determinants of CD4+ T cell recovery, we recognized infusion of a 4‐1BB product (tisagenlecleucel, TSA) in comparison with a CD28 (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [HR] [95% CI]: 5.79 [1.16–24.12] p = 0.016). Higher CD4+ T cell counts resulted with TSA at month‐1, ‐2 and ‐3. Moderate‐to‐severe infections were registered with prolonged CD4+ T cell lymphopenia. Early, month‐1 CD4+ T cell recovery was associated with a worse outcome in the DLBCL cohort, upheld in a multivariate regression model for overall survival (HR: 4.46 [95% CI: 1.12–17.71], p = 0.03). We conclude that a faster CAR− CD4+ T cell recovery is associated with TSA as compared to AXI/BRX. Month‐1 CAR− CD4+ T cell subset recovery could represent a “red flag” for CAR‐T cell therapy failure in DLBCL patients.

Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after autologous stem cell transplantation (ASCT), although only 20% complete response (CR) rate was observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI). Twelve patients with relapse/refractory (R/R) HL (median age 28.5 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 9 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 3 responding patients received ALI alone, as a control cohort. No severe adverse events were recorded. HL-treated patients achieved negative PET scan CR and 8 are alive and disease-free after a median follow-up of 28 months. Four patients underwent subsequent allogeneic SCT. Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients. Our data show anti-tumor activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favor the expansion of the “adaptive” NK cell compartment in patients with HCMV seropositivity, in the absence of HCMV reactivation.

Skeletal erosion has been found to represent an independent prognostic indicator in patients with advanced stages of chronic lymphocytic leukaemia (CLL). Whether this phenomenon also occurs in early CLL phases and its underlying mechanisms have yet to be fully elucidated. In this study, we prospectively enrolled 36 consecutive treatment-naïve patients to analyse skeletal structure and bone marrow distribution using a computational approach to PET/CT images. This evaluation was combined with the analysis of RANK/RANKL loop activation in the leukemic clone, given recent reports on its role in CLL progression. Bone erosion was particularly evident in long bone shafts, progressively increased from Binet stage A to Binet stage C, and was correlated with both local expansion of metabolically active bone marrow documented by FDG uptake and with the number of RANKL + cells present in the circulating blood. In immune-deficient NOD/Shi-scid, γcnull (NSG) mice, administration of CLL cells caused an appreciable compact bone erosion that was prevented by Denosumab. CLL cell proliferation in vitro correlated with RANK expression and was impaired by Denosumab-mediated disruption of the RANK/RANKL loop. This study suggests an interaction between CLL cells and stromal elements able to simultaneously impair bone structure and increase proliferating potential of leukemic clone.

In this study, we aimed at disclosing the main features of paroxysmal nocturnal hemoglobinuria (PNH) clones, their association with presentation syndromes, and their changes during follow-up. A large-scale, cooperative collection (583 clones from 529 patients) of flow cytometric and clinical data was entered into a national repository. Reason for testing guidelines were provided to the 41 participating laboratories, which followed the 2010 technical recommendations for PNH testing by Borowitz. Subsequently, the 30 second-level laboratories adopted the 2012 guidelines for high-resolution PNH testing, both upon order by the local clinicians and as an independent laboratory initiative in selected cases. Type3 and Type2 PNH clones (total and partial absence of glycosyl-phosphatidyl-inositol-anchor, respectively) were simultaneously present in 54 patients. In these patients, Type3 component was sevenfold larger than Type2 (p < 0.001). Frequency distribution analysis of solitary Type3 clone size (N = 442) evidenced two discrete patterns: small (20% of peripheral neutrophils) and large (> 70%) clones. The first pattern was significantly associated with bone marrow failure and myelodysplastic syndromes, the second one with hemolysis, hemoglobinuria, and thrombosis. Pediatric patients (N = 34) showed significant preponderance of small clones and bone marrow failure. The majority of PNH clones involved neutrophils, monocytes, and erythrocytes. Nevertheless, we found clones made exclusively by white cells (N = 13) or erythrocytes (N = 3). Rare cases showed clonal white cells restricted only to monocytes (6 cases) or neutrophils (3 cases). Retesting over 1-year follow-up in 151 cases showed a marked clone size increase in 4 cases and a decrease in 13, demonstrating that early breaking-down of PNH clones is not a rare event (8.6% of cases). This collaborative nationwide study demonstrates a clear-cut difference in size between Type2 and Type3 clones, emphasizes the existence of just two classes of PNH presentations based on Type3 clone size, depicts an asymmetric cellular composition of PNH clones, and documents the possible occurrence of changes in clone size during the follow-up.

Background Available criteria for cognitive phenotypes in multiple sclerosis (MS) do not consider the severity of impairment. Objectives To identify cognitive phenotypes with varying degrees of impairment in MS patients and describe their demographic, clinical and MRI characteristics. Methods Two hundred and forty-three MS patients and 158 healthy controls underwent neuropsychological tests to assess memory, attention, and executive function. For each domain, mild impairment was defined as performing 1.5 standard deviations below the normative mean on two tests, while the threshold for significant impairment was 2 standard deviations. Patients were classified into cognitive phenotypes based on severity of the impairment (mild/significant) and number of domains affected (one/more). Results Five cognitive phenotypes emerged: Preserved cognition (PC; 56%), Mild Single-Domain Impairment (MSD; 15%), Mild Multi-Domain Impairment (MMD; 9%), Significant Single-Domain Impairment (SSD; 12%), Significant Multi-Domain Impairment (SMD; 8%). Compared with PC, MSD patients were older, had longer disease duration (DD) and higher T2-hyperintense lesion volume (LV; all p ≤ 0.02); MMD patients were older, had longer DD, higher disability, higher T2 LV and lower thalamic volume (all p ≤ 0.01); SSD patients had longer DD and lower gray matter cortical volume, thalamic, caudate, putamen and accumbens volumes (all p ≤ 0.04); and SMD patients were older, had longer DD, higher disability and more extensive structural damage in all brain regions explored (all p ≤ 0.03), except white matter and amygdala volumes. Conclusions We identified five cognitive phenotypes with graded levels of impairment. These phenotypes were characterized by distinct demographic, clinical and MRI features, indicating potential variations in the neural substrates of dysfunction throughout disease stages.

In this study, we investigated whether regional distribution of white matter (WM) lesions, normal-appearing [NA] WM microstructural abnormalities and gray matter (GM) atrophy may differently contribute to cognitive performance in multiple sclerosis (MS) patients according to sex. Using the same scanner, brain 3.0T MRI was acquired for 287 MS patients (females = 173; mean age = 42.1 [standard deviation, SD = 12.7] years; relapsing-remitting = 196, progressive = 91; median Expanded Disability Status Scale = 2.5 [interquartile range, IQR = 1.5–5.0]; median disease duration = 12.1 [IQR = 6.3–19.0] years; treatment: none = 70, first-line = 130, second-line = 87) and 172 healthy controls (HC) (females = 92; mean age = 39.3 [SD = 14.8] years). MS patients underwent also Rao’s neuropsychological battery. Using voxel-wise analyses, we investigated in patients sex-related differences in the association of cognitive performances with WM lesions, NAWM fractional anisotropy (FA) and GM volumes ( p  < 0.01, family-wise error [FWE]). Sixty-six female (38%) and 48 male (42%) MS patients were cognitively impaired, with no significant between-group difference ( p  = 0.704). However, verbal memory performance was worse in males ( p  = 0.001), whereas verbal fluency performance was worse in females ( p  = 0.004). In both sexes, a higher T2-hyperintense lesion prevalence in cognitively-relevant WM tracts was significantly associated with worse cognitive performance ( p  ≤ 0.006), with stronger associations in females than males in global cognition ( p  ≤ 0.004). Compared to sex-matched HC, male and female MS patients had widespread lower NAWM FA and GM volume ( p  < 0.01). In both sexes, worse cognitive performance was associated with widespread reduced NAWM FA ( p  < 0.01), with stronger associations in females than males in global cognition and verbal memory ( p  ≤ 0.009). Worse cognitive performance was significantly associated with clusters of cortical GM atrophy in males ( p  ≤ 0.007) and mainly with deep GM atrophy in females ( p  ≤ 0.006). In this study, only limited differences in cognitive performances were found between male and female MS patients. A disconnection syndrome due to focal WM lesions and diffuse NAWM microstructural abnormalities seems to be more relevant in female MS patients to explain cognitive impairment.

Background Heterogeneous processes may contribute to cognitive impairment in multiple sclerosis (MS). Objective To apply a longitudinal multiparametric MRI approach to identify mechanisms associated with cognitive worsening in MS patients. Methods 3 T brain functional and structural MRI scans were acquired at baseline and after a median follow-up of 3.4 years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening (reliable change index score < − 1.25 at the Rao’s battery) and longitudinal changes in regional T2-hyperintense white matter (WM) lesions, diffusion tensor microstructural WM damage, gray matter (GM) atrophy and resting state (RS) functional connectivity (FC) were explored. Results At follow-up, HC showed no clusters of significant microstructural WM damage progression, GM atrophy or changes in RS FC. At follow-up, 10 MS patients (29%) showed cognitive worsening. Compared to cognitively stable, cognitively worsened MS patients showed more severe GM atrophy of the right anterior cingulate cortex and bilateral supplementary motor area ( p  < 0.001). Cognitively worsened vs cognitively stable MS patients showed also decreased RS FC in the right hippocampus of the right working memory network and in the right insula of the default mode network. Increased RS FC in the left insula of the executive control network was found in the opposite comparison ( p  < 0.001). No significant regional accumulation of focal WM lesions nor microstructural WM abnormalities occurred in both patients’ groups. Conclusions GM atrophy progression in cognitively relevant brain regions combined with functional impoverishment in networks involved in cognitive functions may represent the substrates underlying cognitive worsening in MS.

Background Cognitive impairment is a common clinical manifestation in people with multiple sclerosis (PwMS) and significantly impacts patients' quality life. Cognitive assessment is crucial for treatment decisions and understanding disease progression. Several neuropsychological batteries are used in MS, including the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), Minimal Assessment of Cognitive Function in MS (MACFIMS), and Brief International Cognitive Assessment for MS (BICAMS). However, normative data for BRB-N version A in Italy are outdated. Objectives To revise and update normative data for the BRB-N version A in the Italian population. Methods From the Italian Neuroimaging Network Initiative (INNI) database, we retrospectively selected 342 healthy subjects (172 males and 170 females) evaluated at four Italian INNI-affiliated sites (Milan, Siena, Rome, Naples). The subjects underwent neuropsychological assessment using the BRB-N version A. Regression-based method relying on scaled scores was used to calculate demographic correction procedures. Results No significant differences were found in age, education, and sex distribution among the four sites ( p  ≥ 0.055). Regression analysis provided normative data to calculate demographically adjusted z -scores for each BRB-N version A test. Discussion This study provides updated normative data for the BRB-N version A in the Italian population. The use of a regression-based method and scaled scores ensures consistency with other neuropsychological batteries commonly used in Italy, namely MACFIMS and BICAMS. The availability of updated normative data increases reliability of neuropsychological assessment of cognitive function in Italian PwMS and other clinical populations using BRB-N version A, providing valuable insights for both clinical and research applications.

Background Research work has shown that hippocampal subfields are atrophic to varying extents in multiple sclerosis (MS) patients. However, studies examining the functional implications of subfield-specific hippocampal damage in early MS are limited. We aim to gain insights into the relationship between hippocampal atrophy and memory function by investigating the correlation between global and regional hippocampal atrophy and memory performance in early MS patients. Methods From the Italian Neuroimaging Network Initiative (INNI) dataset, we selected 3D-T1-weighted brain MRIs of 219 early relapsing remitting (RR)MS and 246 healthy controls (HC) to identify hippocampal atrophic areas. At the time of MRI, patients underwent Selective-Reminding-Test (SRT) and Spatial-Recall-Test (SPART) and were classified as mildly (MMI-MS: n.110) or severely (SMI-MS: n:109) memory impaired, according to recently proposed cognitive phenotypes. Results Early RRMS showed lower hippocampal volumes compared to HC (p < 0.001), while these did not differ between MMI-MS and SMI-MS. In MMI-MS, lower hippocampal volumes correlated with worse memory tests (r = 0.23–0.37, p ≤ 0.01). Atrophic voxels were diffuse in the hippocampus but more prevalent in cornu ammonis (CA, 79%) than in tail (21%). In MMI-MS, decreased subfield volumes correlated with decreases in memory, particularly in the right CA1 (SRT-recall: r = 0.38; SPART: r = 0.34, p < 0.01). No correlations were found in the SMI-MS group. Conclusion Hippocampal atrophy spreads from CA to tail from early disease stages. Subfield hippocampal atrophy is associated with memory impairment in MMI-MS, while this correlation is lost in SMI-MS. This plays in favor of a limited capacity for an adaptive functional reorganization of the hippocampi in MS patients.