Ex-vivo gene therapy (GT) with hematopoietic stem and progenitor cells (HSPCs) engineered with integrating vectors is a promising treatment for monogenic diseases, but lack of centralized databases ...is hampering an overall outcomes assessment. Here we aim to provide a comprehensive assessment of the short and long term safety of HSPC-GT from trials using different vector platforms. We review systematically the literature on HSPC-GT to describe survival, genotoxicity and engraftment of gene corrected cells. From 1995 to 2020, 55 trials for 14 diseases met inclusion criteria and 406 patients with primary immunodeficiencies (55.2%), metabolic diseases (17.0%), haemoglobinopathies (24.4%) and bone marrow failures (3.4%) were treated with gammaretroviral vector (γRV) (29.1%), self-inactivating γRV (2.2%) or lentiviral vectors (LV) (68.7%). The pooled overall incidence rate of death is 0.9 per 100 person-years of observation (PYO) (95% CI = 0.37-2.17). There are 21 genotoxic events out of 1504.02 PYO, which occurred in γRV trials (0.99 events per 100 PYO, 95% CI = 0.18-5.43) for primary immunodeficiencies. Pooled rate of engraftment is 86.7% (95% CI = 67.1-95.5%) for γRV and 98.7% (95% CI = 94.5-99.7%) for LV HSPC-GT (p = 0.005). Our analyses show stable reconstitution of haematopoiesis in most recipients with superior engraftment and safer profile in patients receiving LV-transduced HSPCs.
Neurological manifestations of COVID-19 have been described in both single case reports and retrospective scanty case series. They may be linked to the potential neurotropism of the SARS-COV-2 virus, ...as previously demonstrated for other coronaviruses. We report here the description of a multicenter retrospective-prospective observational study promoted by the Italian Society of Neurology (SIN), involving the Italian Neurological Departments, who will consecutively recruit patients with neurological symptoms and/or signs, occurred at the onset or as a complication of COVID-19. Hospitalized patients will be recruited either in neurological wards or in COVID wards; in the latter cases, they will be referred from other specialists to participant neurologists. Outpatients with clinical signs of COVID and neurological manifestations will be also referred to participating neurologists from primary care physicians. A comprehensive data collection, in the form of electronic case report form (eCRF), will register all possible neurological manifestations involving central nervous systems, peripheral nerves, and muscles, together with clinical, laboratory (including cerebrospinal fluid, if available), imaging, neurological, neurophysiological, and neuropsychological data. A follow-up at hospital discharge (in hospitalized patients), and for all patients after 3 and 6 months, is also planned. We believe that this study may help to intercept the full spectrum of neurological manifestations of COVID-19 and, given the large diffusion at national level, can provide a large cohort of patients available for future more focused investigations. Similar observational studies might also be proposed at international level to better define the neurological involvement of COVID-19.
During the Coronavirus disease 2019 (COVID-19) pandemic, advanced health systems have come under pressure by the unprecedented high volume of patients needing urgent care. The impact on mortality of ...this "patients' burden" has not been determined.
Through retrieval of administrative data from a large referral hospital of Northern Italy, we determined Aalen-Johansen cumulative incidence curves to describe the in-hospital mortality, stratified by fixed covariates. Age- and sex-adjusted Cox models were used to quantify the effect on mortality of variables deemed to reflect the stress on the hospital system, namely the time-dependent number of daily admissions and of total hospitalized patients, and the calendar period. Of the 1225 subjects hospitalized for COVID-19 between February 20 and May 13, 283 died (30-day mortality rate 24%) after a median follow-up of 14 days (interquartile range 5-19). Hospitalizations increased progressively until a peak of 465 subjects on March 26, then declined. The risk of death, adjusted for age and sex, increased for a higher number of daily admissions (adjusted hazard ratio AHR per an incremental daily admission of 10 patients: 1.13, 95% Confidence Intervals CI 1.05-1.22, p = 0.0014), and for a higher total number of hospitalized patients (AHR per an increase of 50 patients in the total number of hospitalized subjects: 1.11, 95%CI 1.04-1.17, p = 0.0004), while was lower for the calendar period after the peak (AHR 0.56, 95%CI 0.43-0.72, p<0.0001). A validation was conducted on a dataset from another hospital where 500 subjects were hospitalized for COVID-19 in the same period. Figures were consistent in terms of impact of daily admissions, daily census, and calendar period on in-hospital mortality.
The pressure of a high volume of severely ill patients suffering from COVID-19 has a measurable independent impact on in-hospital mortality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Eight patients with Hurler syndrome who lacked suitable allogeneic donors received autologous hematopoietic stem and progenitor cells transduced ex vivo with an α-
L
-iduronidase–encoding lentiviral ...vector. This therapy resulted in extensive metabolic correction in peripheral tissues and the central nervous system.
Long-term pulmonary sequelae following hospitalization for SARS-CoV-2 pneumonia is largely unclear. The aim of this study was to identify and characterise pulmonary sequelae caused by SARS-CoV-2 ...pneumonia at 12-month from discharge.
In this multicentre, prospective, observational study, patients hospitalised for SARS-CoV-2 pneumonia and without prior diagnosis of structural lung diseases were stratified by maximum ventilatory support ("oxygen only", "continuous positive airway pressure (CPAP)" and "invasive mechanical ventilation (IMV)") and followed up at 12 months from discharge. Pulmonary function tests and diffusion capacity for carbon monoxide (DLCO), 6 min walking test, high resolution CT (HRCT) scan, and modified Medical Research Council (mMRC) dyspnea scale were collected.
Out of 287 patients hospitalized with SARS-CoV-2 pneumonia and followed up at 1 year, DLCO impairment, mainly of mild entity and improved with respect to the 6-month follow-up, was observed more frequently in the "oxygen only" and "IMV" group (53% and 49% of patients, respectively), compared to 29% in the "CPAP" group. Abnormalities at chest HRCT were found in 46%, 65% and 80% of cases in the "oxygen only", "CPAP" and "IMV" group, respectively. Non-fibrotic interstitial lung abnormalities, in particular reticulations and ground-glass attenuation, were the main finding, while honeycombing was found only in 1% of cases. Older patients and those requiring IMV were at higher risk of developing radiological pulmonary sequelae. Dyspnea evaluated through mMRC scale was reported by 35% of patients with no differences between groups, compared to 29% at 6-month follow-up.
DLCO alteration and non-fibrotic interstitial lung abnormalities are common after 1 year from hospitalization due to SARS-CoV-2 pneumonia, particularly in older patients requiring higher ventilatory support. Studies with longer follow-ups are needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned ...exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pediatric Wiskott-Aldrich syndrome patients treated with autologous lentiviral-vector transduced hematopoietic stem/progenitor cells derived from mobilized peripheral blood (n = 7), bone marrow (n = 5) or the combination of the two sources (n = 1). 8 out of 13 gene therapy patients were enrolled in an open-label, non-randomized, phase 1/2 clinical study (NCT01515462) and the remaining 5 patients were treated under expanded access programs. Although mobilized peripheral blood- and bone marrow- hematopoietic stem/progenitor cells display similar capability of being gene-corrected, maintaining the engineered grafts up to 3 years after gene therapy, mobilized peripheral blood-gene therapy group shows faster neutrophil and platelet recovery, higher number of engrafted clones and increased gene correction in the myeloid lineage which correlate with higher amount of primitive and myeloid progenitors contained in hematopoietic stem/progenitor cells derived from mobilized peripheral blood. In vitro differentiation and transplantation studies in mice confirm that primitive hematopoietic stem/progenitor cells from both sources have comparable engraftment and multilineage differentiation potential. Altogether, our analyses reveal that the differential behavior after gene therapy of hematopoietic stem/progenitor cells derived from either bone marrow or mobilized peripheral blood is mainly due to the distinct cell composition rather than functional differences of the infused cell products, providing new frames of references for clinical interpretation of hematopoietic stem/progenitor cell transplantation outcome.
Fine needle aspiration (FNA) is the reference standard for the diagnosis of thyroid nodules. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has been successfully ...used to discriminate the proteomic profiles of benign and malignant thyroid FNAs within the scope of providing support to pathologists for the classification of morphologically borderline cases. However,
real
FNAs provide a limited amount of material due to sample collection restrictions. Ex vivo FNAs could represent a valuable alternative, increasing sample size and the power of statistical conclusions. In this study, we compared the
real
and ex vivo MALDI-MSI proteomic profiles, extracted from thyrocyte containing regions of interest, of 13 patients in order to verify their similarity. Statistical analysis demonstrated the mass spectra similarity of the proteomic profiles by performing intra-patient comparison, using statistical similarity systems. In conclusion, these results show that post-surgical FNAs represent a possible alternative source of material for MALDI-MSI proteomic investigations in instances where pre-surgical samples are unavailable or the number of cells is scarce.
Abstract Purpose To evaluate the diagnostic performance of quantitative apparent diffusion coefficient (ADC) measurements, in the assessment of the therapeutic response to chemo-radiation therapy ...(CRT) in patients with locally advanced rectal cancer, by analyzing post CRT values of ADC, in relation to tumor regression grade (TRG) obtained by histopathologic evaluation of the rectal specimen. Methods This prospective study was approved by an Institutional Review Board, and informed consent was obtained from all patients. Thirty-one patients with locally advanced rectal cancer underwent pre and post CRT MR imaging at 1.5 T. ADC values were measured in regions of interest (ROIs) drawn independently by two radiologists, blinded to the pathology results, on three slices of the pre and post CRT DW-MR image sets with the corresponding T2 weighted images (T2WI) available for anatomic reference. The two readers’ measurements were compared for differences in ADC values, inter-observer variability (measured as the intraclass correlation coefficient; ICC) and the ADC distributions of responders vs non-responders. The diagnostic performance of ADC in the prediction of the response to CRT was evaluated by calculating the area under the ROC curve (AUC) and the optimal cut-off values. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed. Results The two readers showed an overall strong agreement in measuring ADC values. For both readers, no differences in ADC pre-treatment measurements were observed between responders and non-responders. For reader 1, the post-CRT ADC and the ΔADC presented the higher AUC (0.823 and 0.803, respectively), while Δ%ADC provided the lower AUC value (0.682). The optimal cutoff point was 1.294 s/mm2 for post-CRT measures (sensitivity = 86.4%, specificity = 66.7%, PPV = 86.4%, NPV = 66.7%), 0.500 for ΔADC (sensitivity = 81.8%, specificity = 66.7%, PPV = 85.7%, NPV = 60.0%) and 59.3% for Δ%ADC (sensitivity = 63.4%, specificity = 66.7, PPV = 82.4%, NPV = 42.9%). Similar results were observed for reader 2, with better performance obtained with the ADC post-CRT (AUC of 0.833) and an optimal cut off of 1.277 × 10−3 s/mm2. Conclusion Post-CRT ADC measurements are reliable and reproducible and may be used as a non-invasive tool to evaluate response to therapy as post-CRT ADC values and ΔADC presented good diagnostic performance to select responder patients.
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