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Abstract Background Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. Methods We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. Results Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. Conclusions We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. Trial registration NCT05338931; Date: 2022–04-01.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Abstract Background This article investigates the hospital costs related to the management of COVID-19 positive patients, requiring a hospitalization (from the positivity confirmation to discharge, including rehabilitation activities). Methods A time-driven activity-based costing analysis, grounding on administrative and accounting flows provided by the management control, was implemented to define costs related to the hospital management of COVID-19 positive patients, according to real-word data, derived from six public Italian Hospitals, in 2020. Results Results reported that the higher the complexity of care, the higher the hospitalization cost per day (low-complexity = €475.86; medium-complexity = €700.20; high-complexity = €1,401.65). Focusing on the entire clinical pathway, the overall resources absorption, with the inclusion of rehabilitation costs, ranged from 6,198.02€ to 32,141.20€, dependent from the patient’s clinical condition. Conclusions Data could represent the baseline cost for COVID-19 hospital management, thus being useful for the further development of proper reimbursement tariffs devoted to hospitalized infected patients.

Immunotherapy has revolutionized the treatment of cancer. In particular, immune checkpoint blockade, bispecific antibodies, and adoptive T-cell transfer have yielded unprecedented clinical results in hematological malignancies and solid cancers. While T cell-based immunotherapies have multiple mechanisms of action, their ultimate goal is achieving apoptosis of cancer cells. Unsurprisingly, apoptosis evasion is a key feature of cancer biology. Therefore, enhancing cancer cells’ sensitivity to apoptosis represents a key strategy to improve clinical outcomes in cancer immunotherapy. Indeed, cancer cells are characterized by several intrinsic mechanisms to resist apoptosis, in addition to features to promote apoptosis in T cells and evade therapy. However, apoptosis is double-faced: when it occurs in T cells, it represents a critical mechanism of failure for immunotherapies. This review will summarize the recent efforts to enhance T cell-based immunotherapies by increasing apoptosis susceptibility in cancer cells and discuss the role of apoptosis in modulating the survival of cytotoxic T lymphocytes in the tumor microenvironment and potential strategies to overcome this issue.

Abstract Background To evaluate the potential benefits of the Magnetic Resonance-guided high intensity Focused Ultrasound (MRgFUS) introduction in the clinical practice, for the treatment of uterine fibroids, in comparison with the standard “conservative” procedures, devoted to women who wish to preserve their uterus or enhance fertility: myomectomy and uterine artery embolization (UAE). Methods A Health Technology Assessment was conducted, assuming the payer’s perspective (Italian National Healthcare Service). The nine EUnetHTA Core Model dimensions were deeply investigated, by means of i) a literature review; ii) the implementation of health economics tools (useful for uterine fibroids patients’ clinical pathway economic evaluation, and budget impact analysis), to define MRgFUS economic and organizational sustainability, and iii) administration of specific questionnaires filled by uterine fibroids’ experts, to gather their perceptions on the three possible conservative approaches (MRgFUS, UAE and myomectomy). Results Literature revealed that MRgFUS would generate several benefits, from a safety and an efficacy profile, with significant improvement in symptoms relief. Advantages emerged concerning the patients’ perspective, thus leading to a decrease both in the length of hospital stay (p-value

Mutations in the ARID1B subunit of the BAF chromatin remodeling complex are associated with the neurodevelopmental Coffin-Siris syndrome. Here the authors reveal that there is a transition from ARID1A-containing complexes to ARID1B during cranial neural crest cell differentiation that is impaired in Coffin-Siris patient-derived cells, which is important for exit from pluripotency.

Primary care represents an answer to the growing demand of an ageing population for healthcare services outside the hospital. As a support mechanism of primary care, the distribution of health technologies to chronic patients plays an important role, but it has been investigated from the operational viewpoint only, ignoring the patient's perspective. We explored patient's satisfaction in relation to the distribution processes of incontinence health technologies, investigating its antecedents and isolating the factors driving the satisfaction of patients – which could be leveraged to design better distribution processes for better primary care services. We performed a survey study on 650 patients in primary care services affected by incontinence in Italy, building on the ServQual and Kano models. Partial Least Square Structural Equation Modelling (PLS-SEM) with Multi-Group Analysis (MGA) was adopted to analyse the data. Results show that interaction of patients with the personnel delivering the service is the key driver of patient satisfaction: this is an element more important than the operational features of distribution services (such as punctuality/reliability of the service or its flexibility).

Lucrezia Ferrario,1 Fabrizio Schettini,1 Elisabetta Garagiola,1 Adriana Cecchi,2 Lucia Lugoboni,3 Paolo Serra,4 Emanuele Porazzi,1 Emanuela Foglia1 1Carlo Cattaneo – LIUC University and LIUC Business School, Castellanza, Italy; 2ARCS – Azienda Regionale di Coordinamento per la Salute, Udine, Italy; 3Bee Care, Lugano, Switzerland; 4Brotzu Hospital, Cagliari, ItalyCorrespondence: Lucrezia FerrarioCarlo Cattaneo – LIUC University and LIUC Business School, Corso Matteotti 22, Castellanza, VA 21053, ItalyTel +39 033 1572504Fax +39 033 1572513Email lferrario@liuc.itPurpose: To evaluate the incremental benefits concerning the implementation of closed-system medical devices for the preparation and administration of chemotherapy agents (integrated or not with traceable workflow), within an Italian clinical practice, in which the use of such technologies is not standardized.Methodology: Four Scenarios, implying different levels of technologies introduction, were analyzed, based on the presence and/or absence of closed systems and traceable workflow, in the preparation and in the administration phase. A literature review was conducted, in order to retrieve efficacy and safety measures. Economic and organizational benefits, assuming a hospitals perspective, were assessed by means of health-economics tools, considering 27,660 (± 695.86) drugs on average prepared, on an annual basis, by 12 hospitals involved. The typology of medical devices and other devices/equipment used, the human resources involved, and the time spent for the preparation and administration phases were collected.Results: Literature stated that the introduction of advanced technologies (CSTDs in the preparation phase, closed-system in the administration phase, both integrated by a traceable workflow) could: i) decrease surface contamination (12.24% vs 26.39%, P< 0.001) and ii) improve the capability to identify dosage errors (7% vs 0.096%, P< 0.05). The above technologies presented the best trade-off between cost sustained and efficacy gained. Despite marginal investments (ranging from +1% to +6%) being required for their acquisition, an organizational saving equal to more than 1,000 working hours emerged, which could be spent on other hospital activities.Conclusion: The implementation of closed systems, integrated with a traceable workflow grounding on gravimetric control, may be considered a valid technological alternative within the investigated setting. The marginal incremental costs could be absorbed already in the first year after their introduction, in particular, because of the potential time saving in using closed systems in both the preparation and administration phases, demonstrating the sustainability and feasibility of such advanced technologies.Keywords: closed-system medical device, chemotherapy agents, safety, economic evaluation, HTA, organisational benefits

IFN-β has been the treatment for multiple sclerosis (MS) for almost three decades, but understanding the mechanisms underlying its beneficial effects remains incomplete. We have shown that MS patients have increased numbers of GM-CSF+ Th cells in circulation, and that IFN-β therapy reduces their numbers. GM-CSF expression by myelin-specific Th cells is essential for the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These findings suggested that IFN-β therapy may function via suppression of GM-CSF production by Th cells. In the current study, we elucidated a feedback loop between monocytes and Th cells that amplifies autoimmune neuroinflammation, and found that IFN-β therapy ameliorates central nervous system (CNS) autoimmunity by inhibiting this proinflammatory loop. IFN-β suppressed GM-CSF production in Th cells indirectly by acting on monocytes, and IFN-β signaling in monocytes was required for EAE suppression. IFN-β increased IL-10 expression by monocytes, and IL-10 was required for the suppressive effects of IFN-β. IFN-β treatment suppressed IL-1β expression by monocytes in the CNS of mice with EAE. GM-CSF from Th cells induced IL-1β production by monocytes, and, in a positive feedback loop, IL-1β augmented GM-CSF production by Th cells. In addition to GM-CSF, TNF and FASL expression by Th cells was also necessary for IL-1β production by monocyte. IFN-β inhibited GM-CSF, TNF, and FASL expression by Th cells to suppress IL-1β secretion by monocytes. Overall, our study describes a positive feedback loop involving several Th cell- and monocyte-derived molecules, and IFN-β actions on monocytes disrupting this proinflammatory loop.

Tiziana Galli,1 Paolo Mirata,2 Emanuela Foglia,3 Davide Croce,3,4 Emanuele Porazzi,3 Lucrezia Ferrario,3 Elena Ricci,5 Elisabetta Garagiola,3 Roberta Pagani,3 Giuseppe Banfi6,7 1Department of Functional Recovery and Re-education, Hospital of Saronno, Hospital Authority “ASST Valle Olona”, Saronno, Italy; 2Department of Functional Recovery and Re-education, Hospital of Busto Arsizio, Hospital Authority “ASST Valle Olona”, Busto Arsizio, Italy; 3Centre for Research on Health Economics Social and Health Care Management (CREMS), LIUC - Università Cattaneo, Castellanza, Italy; 4School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 5Department of Infectious Diseases, Fatebenefratelli Sacco Hospital, Milan, Italy; 6Orthopaedics Institute, IRCCS Galeazzi, Milan, Italy; 7San Raffaele Scientific Institute, Milan, Italy Purpose: The aim of the present study was to compare 2 clinical assessment tools, the Modified Barthel Index (currently administered to patients admitted into inpatient rehabilitation units after elective hip or knee arthroplasty) with the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 scale, in order to identify which tool is more suitable for assessing the disability and the “recovery rate”.Patients and methods: A perspective multicenter observational study was developed, involving 2 hospital authorities in Italy. Eighty consecutive cases of inpatients were enrolled. Patient’s disability was evaluated using both of the aforementioned tools, before and after the rehabilitation program.Results: The WHODAS 2.0 score was, on average, 12.21% higher than the Modified Barthel Index, before the surgical intervention. Modified Barthel Index measures could be considered as a determinant and a predictor of length of stay.Conclusion: The Modified Barthel Index is limited, since it does not consider a patient’s perspective. The WHODAS 2.0 scale fully considers a patient’s perception of disability. Therefore, both assessment scales should be administered in clinical practice, in order to provide integration of clinical information with a patient’s reported outcome measures. Keywords: disability, Modified Barthel Index, WHODAS 2.0, orthopedics, rehabilitation

Abstract Objective Lumbar arthrodesis is a common surgical technique that consists of the fixation of one or more motion segments with pedicle screws and rods. However, spinal surgery using these techniques is expensive and has a significant impact on the budgets of hospitals and Healthcare Systems. While reusable and disposable instruments for laparoscopic interventions have been studied in literature, no specific information exists regarding instrument kits for lumbar arthrodesis. The aim of the present study was to perform a complete health technology assessment comparing a disposable instrument kit for lumbar arthrodesis (innovative device) with the standard reusable instrument. Methods A prospective and observational study was implemented, by means of investigation of administrative records of patients undergoing a lumbar arthrodesis surgical procedure. The evaluation was conducted in 2013, over a 12- month time horizon, considering all the procedures carried out using the two technologies. A complete health technology assessment and a multi-criteria decision analysis approach were implemented in order to compare the two alternative technologies. Economic impact (with the implementation of an activity based costing approach), social, ethical, organisational, and technology-related aspects were taken into account. Results Although the cost analysis produced similar results in the comparison of the two technologies (total cost equal to € 4,279.1 and € 4,242.6 for reusable instrument kit and the disposable one respectively), a significant difference between the two instrument kits was noted, in particular concerning the organisational impact and the patient safety. Conclusions The replacement of a reusable instrument kit for lumbar arthrodesis, with a disposable one, could improve the management of this kind of devices in hospital settings.

Summary: The role of chromatin structure in lineage commitment of multipotent hematopoietic progenitors (HPCs) is presently unclear. We show here that CD34+ HPCs possess a post-replicative chromatin globally devoid of the repressive histone mark H3K27me3. This H3K27-unmodified chromatin is required for recruitment of lineage-determining transcription factors (TFs) C/EBPα, PU.1, and GATA-1 to DNA just after DNA replication upon cytokine-induced myeloid or erythroid commitment. Blocking DNA replication or increasing H3K27me3 levels prevents recruitment of these TFs to DNA and suppresses cytokine-induced erythroid or myeloid differentiation. However, H3K27me3 is rapidly associated with nascent DNA in more primitive human and murine HPCs. Treatment of these cells with instructive cytokines leads to a significant delay in accumulation of H3K27me3 in nascent chromatin due to activity of the H3K27me3 demethylase UTX. Thus, HPCs utilize special mechanisms of chromatin modification for recruitment of specific TFs to DNA during early stages of lineage specification. : Petruk et al. find that hematopoietic progenitor cells possess a state of post-replicative chromatin globally devoid of the repressive histone mark H3K27me3. This de-condensed chromatin is required for recruitment of lineage-determining transcription factors to DNA just after replication in early stages of cytokine-induced myeloid or erythroid lineage specification. Keywords: DNA replication, nascent DNA, nascent chromatin, H3K27me3, KDMs, HMTs, hematopoietic progenitors, myeloid and erythroid differentiation, transcription factors

Giuliano Rizzardini,1 Umberto Restelli,2 Paolo Bonfanti,3 Emanuele Porazzi,2 Elena Ricci,1 Emanuela Foglia,2 Laura Carenzi,1 Davide Croce21First Infectious Diseases Department, "Luigi Sacco" Hospital, Milan; 2Centre for Research on Health Economics, Social, and Health Care Management, Università Carlo Cattaneo, Castellanza; 3Infectious Diseases Department, "Alessandro Manzoni" Hospital, Lecco, ItalyBackground: In recent years, the increased efficacy and effectiveness of antiretroviral treatment has led to longer survival of patients infected with human immunodeficiency virus (HIV), but has also raised the question of what happens to consumption of resources. Early highly active antiretroviral treatment (HAART), management of hepatitis C virus (HCV) coinfection, and expensive newly marketed drugs may affect the economic sustainability of treatment from the point of view of the National Healthcare Services. The present study aimed to provide information on the economic burden of HIV-positive patients resident in the Lombardy region using a three-year time horizon.Methods: This was a retrospective, observational, budget impact study, based on information collected for the period 2007–2009, including hospitalizations, outpatient services, and HAART and non-HAART drug utilization. Patients with confirmed HIV infection, aged ≥ 18 years, resident in the Lombardy region, and followed at the "L Sacco" Hospital in Milan from 2007 to 2009 were eligible.Results: A total of 483 patients (mean age 44.1 years) were included in the study. The mean CD4+ cell count increased over the study period from 462 ± 242 cells/mm3 in 2007, to 513 ± 267 cells/mm3 in 2008, to 547 ± 262 cells/mm3 in 2009. In total, 162 subjects (33.5%) were coinfected with HCV. Hospitalizations and HAART costs increased from 2007 to 2009, whereas outpatient visits and non-HAART drug costs decreased slightly over time. The total cost increase was also significant when limiting the analysis to experienced patients, HCV-negative patients, and experienced HCV-negative patients.Conclusion: CD4+ cell count, a major predictor of costs, increased over the study period. However, immunological improvement was achieved by greater expense in the short term. Whether this may be compensated by a long-term decrease in opportunistic infections and in the costs of management of HIV-related events is an area still to be investigated.Keywords: health care costs, human immunodeficiency virus infection, risk factors, retrospective study

RESENHA: PETRINI, Carlo. Slow Food: princípios da nova gastronomia. Trad. de Renata Lúcia Botina. São Paulo: Editora Senac, 2009. 245 p.

Os hábitos alimentares de escolares têm apresentado tendências ao consumo de lanches rápidos, co-responsáveis pela obesidade infanto-juvenil e pelo risco de doenças associadas. A merenda escolar visa contribuir para hábitos alimentares saudáveis, porém, muitas vezes, os escolares optam por alimentos de questionável valor nutricional para seus lanches. O presente estudo busca identificar as preferências alimentares e o consumo de crianças e adolescentes no período escolar, visando futuras ações de educação em nutrição. A pesquisa, transversal e exploratória, identificou 266 alunos que costumam consumir lanche escolar e indicaram preferência ao consumo de lanches rápidos, com elevado valor calórico e reduzida qualidade nutricional, refletindo o hábito regional, porém o consumo regular da refeição “merenda escolar” foi apontada por 46% destes alunos. A alimentação das crianças na fase escolar deve propiciar seu desenvolvimento integral e assegurar saúde no decorrer da vida e, para tanto, as ações educativas em nutrição devem promover orientações para atitudes alimentares saudáveis e influenciar na seleção dos alimentos consumidos pelos escolares. A participação consciente da escola e da família no processo formativo das pessoas da sociedade deve ser grande aliada aos princípios da ciência da Nutrição, em prol da saúde geral da população.

ObjectiveTo estimate the lifetime cost utility of two antiretroviral regimens (once-daily atazanavir plus ritonavir [ATV+r] versus twice-daily lopinavir/ritonavir [LPV/r]) in Italian human immunodeficiency virus (HIV)-infected patients naïve to treatment.DesignWith this observational retrospective study we collected the clinical data of a cohort of HIV-infected patients receiving first-line treatment with LPV/r or ATV+r.MethodologyA Markov microsimulation model including direct costs and health outcomes of first- and second-line highly active retroviral therapy was developed from a third-party (Italian National Healthcare Service) payer's perspective. Health and monetary outcomes associated with the long-term use of ATV+r and LPV/r regimens were evaluated on the basis of eight health states, incidence of diarrhoea and hyperbilirubinemia, AIDS events, opportunistic infections, coronary heart disease events and, for the first time in an economic evaluation, chronic kidney disease (CKD) events. In order to account for possible deviations between real-life data and randomised controlled trial results, a second control arm (ATV+r 2) was created with differential transition probabilities taken from the literature.ResultsThe average survival was 24.061 years for patients receiving LPV/r, 24.081 and 24.084 for those receiving ATV+r 1 and 2 respectively. The mean quality-adjusted life-years (QALYs) were higher for the patients receiving LPV/r than those receiving ATV+r (13.322 vs. 13.060 and 13.261 for ATV+r 1 and 2). The cost-utility values were 15,310.56 for LPV/r, 15,902.99 and 15,524.85 for ATV+r 1 and 2.ConclusionsUsing real-life data, the model produced significantly different results compared with other studies. With the innovative addition of an evaluation of CKD events, the model showed a cost-utility value advantage for twice-daily LPV/r over once-daily ATV+r, thus providing evidence for its continued use in the treatment of HIV.

B Introduction: b Despite recent successes with CAR T-cell therapy against CD19 in patients with B-celllymphomas, only ~30%-40% of DLBCL and FL patients maintain a durable complete long-term remission, and over half of the patients will ultimately relapse. To investigate CAR T-cell-mediated tumor killing in human cells in combination with EZH2i tazemetostat, we used the GCB-DLBCL cell lines SUDHL4 (EZH2 SP Y641F sp ), OCI-Ly18 and Toledo (WT EZH2). [Extracted from the article]