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B Introduction: b Axi-cel and tisa-cel are reimbursed for the treatment of LBCL relapsed/refractory (R/R) after at least two treatments; brexu -cel for R/R MCL failing a BTK inhibitor. In the whole population, all grade CRS was observed in 355/426 (83%) patients, with 47 (11%) severe (grade 3-4); ICANS in 103 (24%) patients, with 39 (9%) severe (grade 3-4). The Italian CART-SIE real life multicenter observational study on Chimeric Antigen Receptor T-cell (CAR-T) therapy for large B-cell (LBCL) and mantle cell (MCL) lymphomas. [Extracted from the article]

All grades CRS was observed in 49/57 (86%) PMBCL and 118/135 (87%) LBCL patients, with 9 (16%) and 12 (9%) severe (grade 3-4) CRS, respectively; all grades ICANS were reported in 25 (44%) PMBCL patients and in 46 (34%) LBCL, with 12 (21%) and 14 (10%) severe (grade 3-4) ICANS, respectively. CART-SIE REAL LIFE STUDY: PRIMARY MEDIASTINAL B-CELL LYMPHOMA (PMBCL) HAVE A SUPERIOR OUTCOME COMPARED TO LARGE B-CELL LYMPHOMA (LBCL) TREATED WITH AXICABTAGENE CILOLEUCEL B Introduction: b In Italy, axicabtagene ciloleucel (axi-cel) is commercially available for the treatment of LBCL, including diffuse large B-cell lymphoma (DLBCL-NOS), high grade B-cell lymphoma (HGBCL), transformed follicular lymphoma (tFL), and PMBCL patients, relapsed/refractory ( I R i / I R i ) after at least two prior treatments. [Extracted from the article]

ABSTRACT Isotope variations were studied in necropolises of the early (6th to 7th century CE) and central (10th to 11th century CE) medieval period located in Fruili-Venezia Giulia (Northeastern Italy). The two periods each shortly followed two great barbarian invasions that changed the politics and economy of Italy: the arrivals of Langobards in 578 CE and the Hungarian incursions from the end of the 9th to the first half of the 10th century. These events had a tragic effect on the economy of Friuli-Venezia Giulia: severe depopulation and the partial abandonment of the countryside with fall of agricultural production. Am J Phys Anthropol 154:561-574, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Anti-ganglioside antibody production and dysfunction of blood-cerebrospinal fluid (CSF) barrier (BCB) are frequent findings in dysimmune neuropathy patients, whereas intrathecal synthesis of immunoglobulins is still a matter of debate. We examined the CSF, immunological and electrophysiological characteristics from a cohort of patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), and from patients with other neurological diseases as control. Thirty-eight percent of GBS patients and 28% of CIDP patients had detectable serum titers of anti-ganglioside antibodies, which were associated with a high incidence of motor conduction block and increased F wave latencies. In GBS patients, but not in CIDP or control patients, there was an association between anti-ganglioside antibodies and increased CSF immunoglobulin-G (IgG) levels as determined by the IgG index. However, none of the GBS patients had CSF oligoclonal bands (OBs) or indications of intrathecal anti-ganglioside antibody synthesis. The possibility of an abnormal CSF concentration of immunoglobulins from serum through dysfunctional BCB or damaged nerve roots, and the role of serum anti-ganglioside reactivity in this process are discussed. [ABSTRACT FROM AUTHOR]

At the present time genito-urinary tuberculosis is encountered infrequently in urological practice. 20 new cases of urinary tuberculosis were reported from the special unit at Wrightington Hospital in 1974, several of these being examples of advanced disease (O'Boyle and Cow, 1975). The low ureteric stricture is a common problem in the management of this infection. The use of effective chemotherapy and improved radiology services have reduced the necessity for open wrgical intervention, particularly in early cases. Consequently few urologists have the opportunity to evaluate the different surgical techniques of reimplantation of the ureter following excision of the tuberculous stricture. The series reported here covers a 25-year period in the evolution of the operative treatment of lower ureteric stricture. [ABSTRACT FROM AUTHOR]

Concanavalin-A-activated T cells and their crude supernatants were assayed for suppressive activity on an IgE-producing U-266 cell line. Detectable and comparable degrees of suppression were obtained with the co-culture and the supernatant protocols. Separation of the effector population into T4+ and T8+ subsets showed the most effective cells in the IS' fraction. Control experiments demonstrated that the IgE down-regulation was selective, since parallel measurement of β2-microglobulin synthesis showed no effect of T-cells or T-cell-derived supernatants. In addition, several human T-cell lymphoma-leukaemia virus I-transformed T-cell lines were explored for their capacity to produce factor(s) able to suppress IgE synthesis in the U-266 cell line, and four out of 25 cell lines could be shown to do this in a constitutive manner. Kinetic studies suggested that the inhibition occurred at a transcriptional level. The results indicate that the T-cell-myeloma system is an interesting model to define better the regulation of IgE in the human. [ABSTRACT FROM AUTHOR]

Focuses on the beta glucuronidase immunotherapy in allergic rhinoconjunctivitis and its possible effects on the differentiation and maturation of dendritic cells (DC). Cytokine produced by mature DC; Design followed by the study; assessment of the DC surface phenotype.

Disease burden is a critical determinant of outcomes in CAR-T therapy for B-cell lymphomas, and one of the most widely used techniques for its assessment is Total Metabolic Tumor Volume (TMTV) measured via [ 18 F]FDG PET/CT. Biological parameters may further refine the risk profile. We analyzed baseline [ 18 F]FDG PET/CT scans from 40 patients treated with CAR-T, using an AI-based automated segmentation algorithm to determine TMTV. Our analysis identified that a baseline TMTV greater than 48.4 cm³ and elevated LDH independently predicted progression-free survival (PFS) after CAR-T therapy (HR 4.28, p = 0.007, and HR 8.20, p < 0.001, respectively). We then proposed a 0-to-2 risk score, assigning one point each for elevated TMTV and elevated LDH. All patients with a score of two experienced a PFS of less than 90 days following CAR-T infusion. Among the remaining patients, those with 0 points versus 1 point demonstrated a 3-month PFS of 100% versus 85%, a 6-month PFS of 92% versus 53%, and a 12-month PFS of 83% versus 53%, respectively. Importantly, patients with high baseline TMTV who achieved a TMTV reduction to less than 1.99 cm³ by day 30 had a PFS of 66%, significantly better compared to those who did not achieve this reduction. AI-guided TMTV assessment, combined with LDH levels, provides a rapid and sensitive method for risk stratification at the bedside, which could help optimize patient management prior to CAR-T therapy., (© 2024 The Author(s). Hematological Oncology published by John Wiley & Sons Ltd.)

Despite Peng and colleagues providing an extensive review of the clinical and laboratory aspects of CAR-T-associated coagulopathy, the current literature often lacks specificity in nomenclature and gradings, and the clinical implications of coagulopathy may remain unclear. Clear recommendations on stratification and prophylaxis are still required to standardize the clinical approach to this topic. Commentary on: Peng et al. Coagulation abnormalities associated with CAR-T therapy in hematological malignancies: A review. Br J Haematol 2024;205:420-428., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

CD4 + and CD8 + chimeric antigen receptor T cells (CAR-T) play different roles in the in vivo anti-tumour response, but the role of the CD4 + /CD8 + ratio among infused CAR-T has not been clearly defined yet. We analysed leftovers from infused anti-CD19 CAR-T bags of 31 patients with aggressive B-cell lymphomas. The median ratio was 1.44, lower for brexu-cel compared to tisa-cel and axi-cel. The CAR+CD4 + /CD8 + ratio was influenced by lactate dehydrogenase levels at apheresis, not by age, previous treatments or the CD4 + /CD8 + ratio in peripheral blood. Patients with a response at 3 months after CAR-T (M3) had a lower CAR+CD4 + /CD8 + ratio in the infused products compared to non-responders (ratio 0.74 vs. 2.47, p = 0.011). A CAR+CD4 + /CD8 + ratio higher than the cut point of 1.12 was associated with an increased risk of treatment failure at M3 (OR 23.3, p = 0.012) and M6 (OR 10, p = 0.028). The median 6-month PFS was 76% for patients with a ratio lower than 1.12% vs. 31% for the others. The prognostic role of the CAR+CD4 + /CD8 + ratio was independent of the costimulatory domain (CD28 vs. 4-1BB) of the product (OR 16.41, p = 0.041). Our data indicate a crucial role for CD8 + CAR-T and the CAR+CD4 + /CD8 + ratio in predicting CAR-T efficacy., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Aim: we sought to test the inter-center reproducibility of 16 echo laboratories involved in the EACVI-Afib Echo Europe., Methods: This was done on a dedicated setting of 10 patients with sinus rhythm (SR) and 10 with persistent atrial fibrillation (AF), collected by the Principal Investigator. Images and loops of echo-exams were stored and made available for labs. The tested measurements included main echo-Doppler parameters, global longitudinal strain (GLS) and peak atrial longitudinal strain (PALS)., Results: Single measures interclass correlation coefficients (ICCs) of left ventricular mass and ejection fraction were suboptimal in both patients with SR and AF. Among diastolic parameters, ICCs of deceleration time were poor, in particular in AF (=.50). ICCs of left atrial size and function, besides optimal in AF, showed an acceptable despite moderate concordance in SR. ICC of GLS was .81 and .78 in SR and AF respectively. ICCs of PALS were suitable but lower in 4-chamber than in 2-chamber view. By depicting the boxplot of the 16 laboratories, GLS distribution was completely homogeneous in SR, whereas GLS of AF and PALS of both SR and AF presented a limited number of outliers. GLS mean ± SE of the 16 labs was 19.7 ± .36 (95% CI: 18.8-20.4) in SR and 16.5 ± .29 (95% CI: 15.9-17.1) in AF, whereas PALS mean ± SE was 43.8 ± .70 (95% CI: 42.3-45.3) and 10.2 ± .32 (95% CI: 9.5-10.9) respectively., Conclusion: While the utilization of some standard-echo variables should be discouraged in registries, the application of GLS and PALS could be largely promoted because their superior reproducibility, even in AF., (© 2023 The Authors. Echocardiography published by Wiley Periodicals LLC.)

Cytokine release syndrome (CRS) and consumptive coagulopathy can complicate the treatment with chimeric antigen receptor T (CAR-T) cells. The modified version of the Endothelial Activation and Stress Index (mEASIX), a score derived from haematopoietic stem cell transplantation, combines platelets, C-reactive protein (CRP), and lactate dehydrogenase (LDH) and has been correlated with CRS and endothelial biomarkers. In 38 consecutive patients with aggressive lymphoproliferative disease we measured a coagulative laboratory panel at baseline and early after infusion of anti-CD19 CAR-T. The panel was investigated also in the presence of CRS graded 2 or higher, or immune effector cell-associated neurotoxicity syndrome (ICANS). Moreover, we examined the relationship between mEASIX, coagulation biomarkers, and toxicities of CAR-T cells. During CRS grade 2 or higher, we found increased prothrombin time (PT) and activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, factor VIII (FVIII), and von Willebrand factor (vWF) antigen levels, and decreased platelet count and antithrombin levels. The occurrence of immune effector cell-associated neurotoxicity syndrome was associated with higher PT values, D-dimer, FVIII, and vWF levels, and decreased fibrinogen levels and platelet count. A higher mEASIX score correlated with increased aPTT values, fibrinogen, D-dimer, FVIII and vWF levels, and decreased antithrombin levels. Baseline mEASIX was predictive for consumptive coagulopathy and CRS graded 2 or higher, and for progression-free survival and overall survival., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The clinical management of older adult patients with Hodgkin lymphoma (HL) remains a major challenge. The aim of this study was to evaluate the impact of comorbidity assessment according to a standardized approach, the Cumulative Illness Rating Scale (CIRS), on prognosis in patients with classical HL aged 60 years and older. We studied 76 consecutive older adult patients with HL (median age 69 y, range 60-84) who had been treated in our institution between 1999 and 2018. Comorbidity was assessed at diagnosis according to CIRS. Anthracycline-containing chemotherapy with curative intent was administered in 59 (78%) patients. We identified 41 (54%) patients with at least one severe comorbidity rated on CIRS grade ≥ 3. Patients with severe comorbidity were more likely to have advanced-stage disease (P = .003), to have an International Prognostic Score (IPS) > 3 (P = .03), and to not receive anthracycline-containing chemotherapy (P = .008). The probability of overall survival (OS) at 3 years was 88% (95% CI, 71%-95%) in patients without severe comorbidities, while it was only 46% (95% CI, 29%-62%) in patients with a comorbidity CIRS grade ≥ 3 (P = .0001). The impact of comorbidity on prognosis was also evident when restricting the analysis to patients treated with anthracycline-containing therapy. The 3-year OS was 93% (95% CI, 76%-98%) (P = .004) in patients without severe comorbidity and 72% (95% CI, 47%-87%) in patients with severe comorbidity (P = .004). In a multivariate analysis, presence of comorbidity, but not age, was a significant factor for OS. Therefore, we conclude that a significant proportion of older adult patients with HL has severe comorbidity on the CIRS scale, which impacts more importantly than age on prognosis., (© 2020 John Wiley & Sons Ltd.)

Background: Treatment strategy for low-gradient (LG) aortic stenosis (AS) remains an unresolved issue. The presence of a low aortic gradient and preserved left ventricular ejection fraction (LVEF) might lead toward the underestimation of aortic stenosis severity and a more conservative management. We sought (a) to describe the nature and timing of intervention according to flow/gradient subgroups in patibents with LG-AS, (2) to determine the factors associated with the decision to intervene, and (c) to describe prognosis., Methods and Results: One hundred and ten patients prospectively included in this study underwent a standardized clinical and imaging evaluation at inclusion and at 1-year follow-up. According to aortic flow, gradient and LVEF, patients were divided into 4 groups: LG-normal flow [n = 27], LG-low flow-low LVEF [n = 27], LG-low flow-normal LVEF [n = 16], and high gradient (HG) [n = 40]). 73% of patients underwent AVR 86 ± 59 days after the initial assessment. The HG subgroup had significantly higher intervention rates (P < .001). In multivariable analysis, four parameters were associated with the AVR: aortic gradient (HR 1.52 [1.10-2.11], P = .012), LVEF (HR 0.58 [0.40-0.85], P = .006), atrial fibrillation (HR 0.43 [0.021-0.87], P = .019), and NT-proBNP (HR 0.92[0.86-0.98), P = .008]. Patients operated earlier had better outcomes than those having a delayed AVR (P = .042). LG-AS patients had worse outcomes than HG-AS patients (P < .001)., Conclusion: Compared to HG-AS, LG-AS is less likely to benefit from an AVR and had a significantly worse outcome. Further interventional studies are needed to investigate the timing of AVR in these patients., (© 2019 Wiley Periodicals, Inc.)

Aims: Functional mitral regurgitation (FMR) is associated with poor outcome in systolic heart failure (HF) patients. Percutaneous edge-to-edge mitral valve repair (PMVR) in Mitra-Fr study failed to prove any beneficial effect over optimal medical treatment (OMT) but win in COAPT study. Nevertheless, little is known about the effect of PMVR on LV performance and mechanics in HF patients with severe secondary MR., Method and Results: Thirty-seven patients with severe FMR undergoing PMVR were included and compared (according to indices of LV myocardial function and the relationship between LV-size and the degree of regurgitation) to nineteen patients with FMR treated by OMT. Both groups were clinically comparable. At 6-month follow-up, cardiac index such as LV global constructive work (GCW) improved significantly in both groups (1.86 vs 2.13 L/min/m 2 , P = .02, 1.73 vs 2.28 L/min/m 2 P = .002 and 977 vs 1101 mm Hg.%, P = .003, 967 vs 1110 mm Hg.%, P = .002 for PMVR and OMT groups, respectively) whereas left ventricular (LV) end-systolic volume index, LV ejection fraction, and global longitudinal strain were not different. Receiver operating characteristics in PMVR with LVEF ≤ 35% subgroup analysis demonstrated that global work index (GWI) had the best ability to identify patients with worse evolution (AUC = 0.882; P = .009), confirmed by univariable logistic regression, particularly for patients with GWI < 482 mm Hg.%., Conclusion: Echocardiographic characteristics at 6-month follow-up are not different when compare PMVR and OMT for HF patients with severe FMR. A low global work index might be a tool for discouraging the implantation of clips for this indication., (© 2019 Wiley Periodicals, Inc.)

Background: Myocardial work (MW) estimation by pressure-strain loops (PSL) allows the non-invasive assessment of myocardial performance. Aim of this study is to provide the reference values for global myocardial work index (WI), constructive work (CW), wasted work (WW), and work efficiency (WE) in a group of healthy volunteers accounting for age and gender., Methods and Results: 2D standard and speckle-tracking echocardiography were performed in 115 healthy volunteers (median age 36.3 [18-69] years, males: 67%). PSLs were used to assess MW. Mean ± standard deviation or median and inter-quartile range, 5° and 95° percentile values for global myocardial WI, CW, WW, and WE in the whole population were 1926 ± 247 mm Hg, (1534-2356); 2224 ± 229 mm Hg, (1894-2647); 90 (61-123) mm Hg%, (38-195); and 96 (94-97)%, (91-98), respectively. Global WI (2031 ± 247 vs 1874 ± 232 mm Hg%, P = .001) and global CW (2289 ± 261 vs 2194 ± 207 mm Hg%, P = .04) were higher in women than in men. Age did not affect MW parameters. The segmental analysis showed that myocardial WI, CW, and WE were lower in the left ventricular basal segments than in the apex. The apex-to-base gradient was inverted for WW (all P < .0001)., Conclusions: The assessment of MW is feasible in normal subjects. The presented referral ranges of global myocardial WI, CW, WW, and WE were not affected by age. An apex-to-base gradient was observed for all MW parameters. Nevertheless, the wide variability of MW parameters prevents for the moment the application of this technique in the routine clinical setting., (© 2019 Wiley Periodicals, Inc.)

Background: The estimation of myocardial work by pressure strain loops (PSLs) is a totally new non-invasive approach to assess myocardial performance, and its role in patients with hypertrophic cardiomyopathy is unknown. The aims of the present study are therefore: (a) to compare myocardial work in patients with non-obstructive hypertrophic cardiomyopathy (HCM) and in a subset of age-matched healthy controls and (b) to assess the correlation between myocardial work and left ventricular (LV) fibrosis., Design: Eighty-two patients with non-obstructive HCM (58 ± 14 years) and 20 age-matched healthy subjects (58 ± 7 years, P = 0.99) underwent standard and speckle-tracking echocardiography to assess myocardial dimensions and deformation parameters. PSLs analysis was used to estimate global myocardial constructive work (GCW) and wasted work (GWW). LV fibrosis was estimated at cardiac magnetic resonance (CMR) by qualitative assessment of late gadolinium enhancement (LGE), and significant fibrosis was defined as LGE in ≥2 LV segments., Results: Global constructive work (1599 ± 423 vs 2248 ± 249 mm Hg%, P < 0.0001) was significantly reduced in HCM compared to the control group. No difference was observed in GWW (141 ± 125 vs 101 ± 88 mm Hg%, P = 0.18) and LV ejection fraction (LVEF) (63 ± 13 vs 66 ± 4% P = 0.17) between the two groups. In HCM, GCW was the only predictor of LV fibrosis at multivariable analysis (OR 1.01, 95% CI: 0.99-1.08, P = 0.04). A cutoff value of 1623 mm Hg% (AUC 0.80, 95% CI: 0.66-0.93, P < 0.0001) was able to predict myocardial fibrosis with a good sensitivity and fair specificity (82% and 67%, respectively)., Conclusions: Global constructive work is significantly reduced in HCM despite normal LVEF and is associated with the LV fibrosis as assessed by LGE., (© 2018 Wiley Periodicals, Inc.)

Background: In aortic stenosis (AS), the left ventricle (LV) should face an increased afterload that is due to both the stenotic aortic valve and the peripheral vascular resistance (PVR). Valvulo-arterial impedance (ZV a ) is a recently introduced parameter, which permits the evaluation of global LV afterload in AS. Aim of this study was to assess the influence of increasing ZV a on the longitudinal, circumferential, and radial components of LV mechanics., Methods: A total of 126 patients (mean age: 80.1±12.0 years, males: 47%) with severe AS (aortic surface <1 cm 2 or <0.6 cm 2 /m 2 ) underwent standard echocardiography to characterize aortic valve gradients, LV function, and ZV a . 2D speckle tracking echocardiography was used to estimate global longitudinal (GLS), circumferential (GCS), and radial (GRS) LV strain., Results: The population was divided into four groups according to ZV a quartiles: Q1 (ZV a ≤3.43 mm Hg/mL/m 2 ), Q2 (3.43a ≤4.1 mm Hg/mL/m 2 ), Q3 (4.1a ≤5.1 mm Hg/mL/m 2 ), ad Q4 (ZV a >5.1 mm Hg/mL/m 2 ). ZV a increase from Q1 to Q4 was associated with a progressive reduction in GLS and GCS (ANOVA, both P<.0001). GRS was relatively insensitive to ZV a increase, a significant reduction of GRS appearing only in Q4 patients with respect to Q1 (29.7±16.4 vs 20.7±13.2%, P=.01)., Conclusions: Left ventricle myocardial fibers show a different response to afterload increase. Subendocardial fibers function is impaired earlier, whereas mid-wall circumferential fibers remain substantially unaffected, providing interesting insights into the mechanisms of LV dysfunction in AS., (© 2016, Wiley Periodicals, Inc.)

The idea that a mechanism of autoimmunity could play a role in the pathogenesis of atopic dermatitis gained support from the observation that patients with atopic dermatitis display IgE reactivity to a variety of human protein antigens, several of which have been characterized at molecular level. A broad spectrum of at least 140 IgE-binding self-antigens associated with atopic dermatitis has been demonstrated; they might promote, perpetuate, or both, skin inflammation by binding IgE antibodies or activating specific T cells. Even if the presence of autoreactivity seems to be associated with the severity of the disease and may be used as a parameter reflecting chronic tissue damage, at the state of art the role of autoimmunity in atopic dermatitis is far from clear. Data from the literature show that the use of autoantibodies as biomarkers of atopic dermatitis are still limited by the evidence that the epiphenomenon of autoreactivity is detectable only in a percentage of patients and that the involved self-allergens often are not the same; further longitudinal case-control studies are needed to investigate and to clarify the pathogenethic role of autoimmunity in the course of atopic dermatitis., (© 2014 Japanese Dermatological Association.)