IMMU-01. TEM-GBM: AN OPEN-LABEL, PHASE I/IIA DOSE-ESCALATION STUDY EVALUATING THE SAFETY AND EFFICACY OF GENETICALLY MODIFIED TIE-2 EXPRESSING MONOCYTES TO DELIVER IFN-A WITHIN GLIOBLASTOMA TUMOR MICROENVIRONMENT

Abstract Temferon is a macrophage-based treatment relying on ex-vivo transduction of autologous HSPCs to express immune-payloads within the TME. Temferon targets the immune-modulatory molecule IFN-a, to a subset of tumor infiltrating macrophages known as Tie-2 expressing macrophages (TEMs) due to the Tie2 promoter and a post-transcriptional regulation layer represented by miRNA-126 target sequences. As of 31st May 2021, 15-patients received Temferon (D+0) with follow-up of 3 – 693 days. After conditioning neutrophil and platelet engraftment occurred at D+13 and D+13.5, respectively. Temferon-derived differentiated cells, as determined be the number of vector copy per genome, were found within 14 days post treatment and persisted albeit at lower levels up to 18-months. Very low concentrations of IFN-a in the plasma (8.7 pg/ml-D+30) and in the CSF (1.6 pg/ml-D+30) were detected, suggesting tight regulation of transgene expression. Five-deaths occurred at D+322, +340, +402, +478 and +646 due to PD, and one at D+60 due to complications following the conditioning regimen. Eight-patients had progressive disease (range: D-11 to +239) as expected for this tumor type. SAEs include GGT elevation (possibly related to Temferon) and infections, venous thromboembolism, brain abscess, hemiparesis, seizures, anemia and general physical condition deterioration, compatible with ASCT, concomitant medications and PD. Four-patients underwent 2ndsurgery. Recurrent tumors had gene-marked cells and increased expression of ISGs compared to first surgery, indicative of local IFNa release by TEMs. In one patient, a stable lesion had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased ISGs than in the progressing lesion, detected in the same patient. Tumor-associated clones expanded in the periphery. TME characterization by scRNA and TCR-sequencing is ongoing. To date, Temferon is well tolerated, with no DLTs identified. The results provide initial evidence of Temferon potential to activate the immune system of GBM patients, as predicted by preclinical studies

A Deep Learning Model for Preoperative Differentiation of Glioblastoma, Brain Metastasis, and Primary Central Nervous System Lymphoma: An External Validation Study

(1) Background: Neuroimaging differentiation of glioblastoma, primary central nervous system lymphoma (PCNSL) and solitary brain metastasis (BM) represents a diagnostic and therapeutic challenge in neurosurgical practice, expanding the burden of care and exposing patients to additional risks related to further invasive procedures and treatment delays. In addition, atypical cases and overlapping features have not been entirely addressed by modern diagnostic research. The aim of this study was to validate a previously designed and internally validated ResNet101 deep learning model to differentiate glioblastomas, PCNSLs and BMs. (2) Methods: We enrolled 126 patients (glioblastoma: n = 64; PCNSL: n = 27; BM: n = 35) with preoperative T1Gd-MRI scans and histopathological confirmation. Each lesion was segmented, and all regions of interest were exported in a DICOM dataset. A pre-trained ResNet101 deep neural network model implemented in a previous work on 121 patients was externally validated on the current cohort to differentiate glioblastomas, PCNSLs and BMs on T1Gd-MRI scans. (3) Results: The model achieved optimal classification performance in distinguishing PCNSLs (AUC: 0.73; 95%CI: 0.62–0.85), glioblastomas (AUC: 0.78; 95%CI: 0.71–0.87) and moderate to low ability in differentiating BMs (AUC: 0.63; 95%CI: 0.52–0.76). The performance of expert neuro-radiologists on conventional plus advanced MR imaging, assessed by retrospectively reviewing the diagnostic reports of the selected cohort of patients, was found superior in accuracy for BMs (89.69%) and not inferior for PCNSL (82.90%) and glioblastomas (84.09%). (4) Conclusions: We investigated whether the previously published deep learning model was generalizable to an external population recruited at a different institution—this validation confirmed the consistency of the model and laid the groundwork for future clinical applications in brain tumour classification. This artificial intelligence-based model might represent a valuable educational resource and, if largely replicated on prospective data, help physicians differentiate glioblastomas, PCNSL and solitary BMs, especially in settings with limited resources

Cushing’s disease: a prospective case-control study of health-related quality of life and cognitive status before and after surgery

Some studies have highlighted psychological and neuropsychological difficulties and a potential reduction in health-related quality of life (HRQOL) in patients with pituitary tumors, despite hormone deficits or excess. To the authors' knowledge, this study is the first prospective longitudinal case-control study with the aim of simultaneously testing whether HRQOL and psychiatric and neuropsychological disabilities are related to neural dysfunction due to hypercortisolism per se, or tumor mass and/or surgery in patients with Cushing's disease (CD). The authors evaluated a homogeneous cohort of patients with CD and nonfunctioning pituitary adenomas (NFPAs) before and after neurosurgery and compared these patients with healthy controls

Cushing's disease: a prospective case-control study of health-related quality of life and cognitive status before and after surgery

Some studies have highlighted psychological and neuropsychological difficulties and a potential reduction in health-related quality of life (HRQOL) in patients with pituitary tumors, despite hormone deficits or excess. To the authors' knowledge, this study is the first prospective longitudinal case-control study with the aim of simultaneously testing whether HRQOL and psychiatric and neuropsychological disabilities are related to neural dysfunction due to hypercortisolism per se, or tumor mass and/or surgery in patients with Cushing's disease (CD). The authors evaluated a homogeneous cohort of patients with CD and nonfunctioning pituitary adenomas (NFPAs) before and after neurosurgery and compared these patients with healthy controls

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1-6D peptide.

The use of "altered peptide ligands" (APL), epitopes designed for exerting increased immunogenicity as compared with native determinants, represents nowadays one of the most utilized strategies for overcoming immune tolerance to self-antigens and boosting anti-tumor T cell-mediated immune responses. However, the actual ability of APL-primed T cells to cross-recognize natural epitopes expressed by tumor cells remains a crucial concern. In the present study, we show that CAP1-6D, a superagonist analogue of a carcinoembriyonic antigen (CEA)-derived HLA-A*0201-restricted epitope widely used in clinical setting, reproducibly promotes the generation of low-affinity CD8(+) T cells lacking the ability to recognized CEA-expressing colorectal carcinoma (CRC) cells. Short-term T cell cultures, obtained by priming peripheral blood mononuclear cells from HLA-A*0201(+) healthy donors or CRC patients with CAP1-6D, were indeed found to heterogeneously cross-react with saturating concentrations of the native peptide CAP1, but to fail constantly lysing or recognizing through IFN- gamma release CEA(+)CRC cells. Characterization of anti-CAP1-6D T cell avidity, gained through peptide titration, CD8-dependency assay, and staining with mutated tetramers (D227K/T228A), revealed that anti-CAP1-6D T cells exerted a differential interaction with the two CEA epitopes, i.e., displaying high affinity/CD8-independency toward the APL and low affinity/CD8-dependency toward the native CAP1 peptide. Our data demonstrate that the efficient detection of self-antigen expressed by tumors could be a feature of high avidity CD8-independent T cells, and underline the need for extensive analysis of tumor cross-recognition prior to any clinical usage of APL as anti-cancer vaccines

Cardiac Magnetic Resonance for Prophylactic Implantable-Cardioverter Defibrillator Therapy in Ischemic Cardiomyopathy: The DERIVATE-ICM International Registry

Background: Implantable cardioverter-defibrillator (ICD) therapy is the most effective prophylactic strategy against sudden cardiac death (SCD) in patients with ischemic cardiomyopathy (ICM) and left ventricle ejection fraction (LVEF) ≤35% as detected by transthoracic echocardiograpgy (TTE). This approach has been recently questioned because of the low rate of ICD interventions in patients who received implantation and the not-negligible percentage of patients who experienced SCD despite not fulfilling criteria for implantation. Objectives: The DERIVATE (CarDiac MagnEtic Resonance for Primary Prevention Implantable CardioVerter DebrillAtor ThErapy)-ICM registry (NCT03352648) is an international, multicenter, and multivendor study to assess the net reclassification improvement (NRI) for the indication of ICD implantation by the use of cardiac magnetic resonance (CMR) as compared to TTE in patients with ICM. Methods: A total of 861 patients with ICM (mean age 65 ± 11 years, 86% male) with chronic heart failure and TTE-LVEF <50% participated. Major adverse arrhythmic cardiac events (MAACE) were the primary endpoints. Results: During a median follow-up of 1,054 days, MAACE occurred in 88 (10.2%). Left ventricular end-diastolic volume index (HR: 1.007 [95% CI: 1.000-1.011]; P = 0.05), CMR-LVEF (HR: 0.972 [95% CI: 0.945-0.999]; P = 0.045) and late gadolinium enhancement (LGE) mass (HR: 1.010 [95% CI: 1.002-1.018]; P = 0.015) were independent predictors of MAACE. A multiparametric CMR weighted predictive derived score identifies subjects at high risk for MAACE compared with TTE-LVEF cutoff of 35% with a NRI of 31.7% (P = 0.007). Conclusions: The DERIVATE-ICM registry is a large multicenter registry showing the additional value of CMR to stratify the risk for MAACE in a large cohort of patients with ICM compared with standard of care

La conservazione ex situ della biodiversit\ue0 delle specie vegetalispontanee e coltivate in Italia Stato dell\u2019arte, criticit\ue0 e azioni da compiere

Il presente documento riguarda lo stato della conservazione ex situ della biodiversità vegetale in Italia, le criticità riscontrate relativamente alle diverse componenti della flora (specie spontanee autoctone, forestali e coltivate) e le azioni da compiere in via prioritaria per risolvere i problemi piùacuti. Seppure destinati a ”invecchiare”, in molti casi sono stati elaborati i costi di alcune delle azioni da compiere per rendere concreto l’impegno economico che, in taluni casi, la difesa della biodiversità comporta. Sebbene perfettibile, il lavoro tenta di fornire una sintesi, con base rigorosamente scientifica, sulla conservazione ex situ della biodiversità delle specie vegetali ed è perciò un contributo alla Strategia nazionale per la biodiversità