Treg/Tcon Immunotherapy and High Dose Marrow Irradiation Ensure Full Control of Leukemia Relapse in Haploidentical Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most powerful therapy for patients with high risk of relapse. In spite of that, no matter the donor source or conditioning regimen used, leukemia relapse is still the leading cause of HSCT failure. In HLA-haploidentical HSCT, we recently applied a clinical protocol consisting of total body irradiation (TBI)-based conditioning regimen and a peripheral blood CD34+ cell graft combined with the adoptive transfer of naturally occurring regulatory T cells (Tregs) and conventional T cells (Tcons). No post-transplant pharmacologic GvHD prophylaxis was given. Such protocol was associated with low GvHD and relapse rate (Martelli et al., Blood 2014). To further reduce leukemia relapse in Treg/Tcon-based haploidentical HSCT (Treg/Tcon haplo-HSCT) we used high dose hyper-fractionated TBI (HF-TBI) in the conditioning regimen. We also extended Treg/Tcon haplo-HSCT to patients that are unfit (because of previous comorbidities) and/or too old to withstand high intensity regimens. In these patients the extra-hematologic toxicity of irradiation was reduced with the use of targeted total marrow and lymph node irradiation (TMLI). 40 patients with high risk acute leukemia (36 AML, 4 ALL) received Treg/Tcon haplo-HSCT. All but 3 patients were transplanted in complete remission. 12 younger patients (median age: 28, range: 20-43) received HF-TBI, while 28 older or unfit patients (59, 40-70) received TMLI in the conditioning regimen. HF-TBI (14.4 Gy) was administered in 12 fractions, 3 times a day for 4 days. TMLI was administered by means of Helical Tomotherapy HI-ART (9 fractions, 2 times a day for 4.5 days). Irradiation was followed by chemotherapy with Thiotepa, Fludarabine, and Cyclophosphamide. 2 × 106/kg freshly isolated CD4+CD25+FOXP3+ Tregs were transferred 4 days before the infusion of 1 × 106/kg Tcons and a mega-dose of CD34+ hematopoietic stem cells. No post-transplant pharmacologic GvHD prophylaxis was given. 38/40 patients engrafted. 12 (31%) developed aGvHD grade ³2 (10 are alive and off-therapy). 6 (16%) died because of transplant related complications (2 because of aGvHD, 2 infections, 1 veno-occlusive disease, 1 intracranial hemorrhage). Strikingly, despite the high risk diseases, no patient relapsed after a median follow up of 13 months (range 1-36, Fig. A). Further, only 1 patient developed cGvHD. Thus, cGvHD/Leukemia-free survival was 82% (Fig. B). Treg adoptive transfer allows for the safe infusion of an otherwise lethal dose of donor alloreactive Tcons in the absence of any other form of immune suppression. Our results demonstrate that the potent graft versus leukemia effect of Treg/Tcon adoptive transfer was boosted by high dose marrow irradiation. Thus, this study proves that the right combination of haploidentical Treg/Tcon immunotherapy plus a powerful conditioning regimen can fully eradicate leukemia

Reliability assessment of ultrasound muscle echogenicity in patients with rheumatic diseases: Results of a multicenter international web-based study

ObjectivesTo investigate the inter/intra-reliability of ultrasound (US) muscle echogenicity in patients with rheumatic diseases.MethodsForty-two rheumatologists and 2 radiologists from 13 countries were asked to assess US muscle echogenicity of quadriceps muscle in 80 static images and 20 clips from 64 patients with different rheumatic diseases and 8 healthy subjects. Two visual scales were evaluated, a visual semi-quantitative scale (0–3) and a continuous quantitative measurement (“VAS echogenicity,” 0–100). The same assessment was repeated to calculate intra-observer reliability. US muscle echogenicity was also calculated by an independent research assistant using a software for the analysis of scientific images (ImageJ). Inter and intra reliabilities were assessed by means of prevalence-adjusted bias-adjusted Kappa (PABAK), intraclass correlation coefficient (ICC) and correlations through Kendall’s Tau and Pearson’s Rho coefficients.ResultsThe semi-quantitative scale showed a moderate inter-reliability [PABAK = 0.58 (0.57–0.59)] and a substantial intra-reliability [PABAK = 0.71 (0.68–0.73)]. The lowest inter and intra-reliability results were obtained for the intermediate grades (i.e., grade 1 and 2) of the semi-quantitative scale. “VAS echogenicity” showed a high reliability both in the inter-observer [ICC = 0.80 (0.75–0.85)] and intra-observer [ICC = 0.88 (0.88–0.89)] evaluations. A substantial association was found between the participants assessment of the semi-quantitative scale and “VAS echogenicity” [ICC = 0.52 (0.50–0.54)]. The correlation between these two visual scales and ImageJ analysis was high (tau = 0.76 and rho = 0.89, respectively).ConclusionThe results of this large, multicenter study highlighted the overall good inter and intra-reliability of the US assessment of muscle echogenicity in patients with different rheumatic diseases

Third-generation iterative reconstruction on a dual-source, high-pitch, low-dose chest CT protocol with tin filter for spectral shaping at 100 kV: a study on a small series of COVID-19 patients

Objectives To investigate the role of third-generation iterative reconstruction (ADMIRE) in dual-source, high-pitch chest CT protocol with spectral shaping at 100 kVp in Coronavirus disease 2019 (COVID-19). Methods Confirmed COVID-19 inpatients undergoing to unenhanced chest CT were scanned with a dual-energy acquisition (DECT, 90/150Sn kV) and a dual-source, high-pitch acquisition with tin-filtered 100 kVp (LDCT). On the DECT with ADMIRE 3 (DECT3) were evaluated the pulmonary findings and their extension (25-point score). Two radiologists in consensus evaluated with 5-point scales the overall image quality, the anatomical structures, and the elementary findings on LDCT reconstructed with filtered backprojection (LDCT0), with ADMIRE 3 (LDCT3) and 5 (LDCT5), and on DECT3. The signal-to-noise ratio (SNR), the body mass index, the exposure times, and the radiation doses were recorded. Results Seventy-five patients (57 M/18F; median age: 63 y.o.) were included, with median pulmonary extension of 13/25 points. The imaging findings were detected in proportion comparable to the available literature. The ADMIRE significantly improved the SNR in LDCT (p < 0.00001) with almost no significant differences in overweight patients. The LDCT had median effective dose of 0.39 mSv and acquisition time of 0.71 s with significantly less motion artifacts than DECT (p < 0.00001). The DECT3 and LDCT3 provided the best image quality and depiction of pulmonary anatomy and imaging findings, with significant differences among all the series (p < 0.00001). Conclusion The LDCT with spectral shaping and ADMIRE3 provided acceptable image quality in the evaluation of patients with COVID-19, with significantly reduced radiation dose and motion artifacts

New advances in CT imaging of pancreas diseases: a narrative review

Computed tomography (CT) plays a pivotal role as a diagnostic tool in many diagnostic and diffuse pancreatic diseases. One of the major limits of CT is related to the radiation exposure of young patients undergoing repeated examinations. Besides the standard CT protocol, the most recent technological advances, such as low-voltage acquisitions with high performance X-ray tubes and iterative reconstructions, allow for significant optimization of the protocol with dose reduction. The variety of CT tools are further expanded by the introduction of dual energy: the production of energy-selective images (i.e., virtual monochromatic images) improves the image contrast and lesion detection while the material-selective images (e.g., iodine maps or virtual unenhanced images) are valuable for lesion detection and dose reduction. The perfusion techniques provide diagnostic and prognostic information lesion and parenchymal vascularization and interstitium. Both dual energy and perfusion CT have the potential for pushing the limits of conventional CT from morphological evaluation to quantitative imaging applied to inflammatory and oncological diseases. Advances in post-processing of CT images, such as pancreatic volumetry, texture analysis and radiomics provide relevant information for pancreatic function but also for the diagnosis, management and prognosis of pancreatic neoplasms. Artificial intelligence is promising for optimization of the workflow in qualitative and quantitative analyses. Finally, basic concepts on the role of imaging on screening of pancreatic diseases will be provided

New Frontiers in Oncological Imaging With Computed Tomography: From Morphology to Function

: The latest evolutions in Computed Tomography (CT) technology have several applications in oncological imaging. The innovations in hardware and software allow for the optimization of the oncological protocol. Low-kV acquisitions are possible thanks to the new powerful tubes. Iterative reconstruction algorithms and artificial intelligence are helpful for the management of image noise during image reconstruction. Functional information is provided by spectral CT (dual-energy and photon counting CT) and perfusion CT

Synthesis and Evaluation of Bithiazole Derivatives As Potential α-Sarcoglycan Correctors

4′-Methyl-4,5′-bithiazoles were previously identified as cystic fibrosis transmembrane regulator (CFTR) correctors, thus being able to correct folding defective mutants of the channel regulating chloride transport through the membrane. Additionally, bithiazole derivative C17 was reported to recover α-sarcoglycan in vitro and in vivo. We report here the synthesis of two new derivatives of C17, in which the two sides of the bithiazole scaffold were modified. The synthesized compounds and the corresponding precursors were tested in myogenic cells to evaluate the expression of α-sarcoglycan. The results highlighted that both substitutions of the bithiazole scaffold are important to achieve the maximum recovery of the α-sarcoglycan mutant. Nonetheless, partial preservation of the activity was observed. Accordingly, this paves the way to further derivatizations/optimization and target fishing studies, which were preliminarily performed in this study as a proof of concept, allowing the investigation of the molecular mechanisms leading to the α-sarcoglycan correction

Pulmonary atresia with intact ventricular septum and systemic-pulmonary collateral arteries

Pulmonary atresia with intact ventricular septum and major systemic-pulmonary collateral arteries is a very rare congenital heart lesion with dismal natural history. Herein we report on a case of pulmonary atresia with intact ventricular septum with hypoplastic right ventricle, very small confluent pulmonary arteries, absent arterial duct, and pulmonary blood flow exclusively provided by bronchial-type systemic-pulmonary collateral arteries that was successfully treated at our institution. (C) 2002 by The Society of Thoracic Surgeons

Chest CT features of coronavirus disease 2019 (COVID-19) pneumonia: key points for radiologists

COVID-19 is an emerging infection caused by a novel coronavirus that is moving so rapidly that on 30 January 2020 the World Health Organization declared the outbreak a Public Health Emergency of International Concern and on 11 March 2020 as a pandemic. An early diagnosis of COVID-19 is crucial for disease treatment and control of the disease spread. Real-time reverse-transcription polymerase chain reaction (RT-PCR) demonstrated a low sensibility; therefore chest computed tomography (CT) plays a pivotal role not only in the early detection and diagnosis, especially for false negative RT-PCR tests, but also in monitoring the clinical course and in evaluating the disease severity. This paper reports the CT findings with some hints on the temporal changes over the course of the disease: the CT hallmarks of COVID-19 are bilateral distribution of ground glass opacities with or without consolidation in the posterior and peripheral lung, but the predominant findings in later phases include consolidations, linear opacities, "crazy-paving" pattern, "reversed halo" sign and vascular enlargement. The CT findings of COVID-19 overlap with the CT findings of other diseases, in particular the viral pneumonia including influenza viruses, parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus, human metapneumovirus, etc. There are differences as well as similarities in the CT features of COVID-19 compared with those of the severe acute respiratory syndrome. The aim of this article is to review the typical and atypical CT findings in COVID-19 patients in order to help radiologists and clinicians to become more familiar with the disease

The role of a chest computed tomography severity score in coronavirus disease 2019 pneumonia

The chest computed tomography (CT) characteristics of coronavirus disease 2019 (COVID-19) are important for diagnostic and prognostic purposes. The aim of this study was to investigate chest CT findings in COVID-19 patients in order to determine the optimal cut-off value of a CT severity score that can be considered a potential prognostic indicator of a severe/critical outcome.The CT findings were evaluated by means of a severity score that included the extent (0-4 grading scale) and nature (0-4 grading scale) of CT abnormalities. The images were evaluated at 3 levels bilaterally. A receiver operating characteristics (ROC) curve was used to identify the optimal score (Youden's index) predicting severe/critical COVID-19.The study involved 165 COVID-19 patients (131 men [79.4%] and 34 women [20.6%] with a mean age of 61.5 ± 12.5 years), of whom 30 (18.2%) had severe/critical disease and 135 (81.8%) mild/typical disease. The most frequent CT finding was bilateral predominantly subpleural and basilar airspace changes, with more extensive ground-glass opacities than consolidation. CT findings of consolidation, a crazy-paving pattern, linear opacities, air bronchogram, and extrapulmonary lesions correlated with severe/critical COVID-19. The mean CT severity score was 63.95 in the severe/critical group, and 35.62 in the mild/typical group (P < .001). ROC curve analysis showed that a CT severity score of 38 predicted the development of severe/critical symptoms.A CT severity score can help the risk stratification of COVID-19 patients

''Designed'' grafts for HLA-haploidentical stem cell transplantation

Today human leukocyte antigen-haploidentical transplantation is a feasible option for patients with high-risk acute leukemia who do not have matched donors. Whether it is T-cell replete or T-cell depleted, it is still, however, associated with issues of transplant-related mortality and posttrans-plant leukemia relapse. After reports that adoptive immunotherapy with T-regulatory cells controls the alloreactivityof conventional T lymphocytes in animal models, tomorrow’s world of haploidentical transplantation will focus on new “designed” grafts. They will contain an appropriate ratio of conventional T lymphocytes and T-regulatory cells, natural killer cells, gd T cells, and other accessory cells. Preliminary results of ongoing clinical trials show the approach is feasible. It is associated with better immune reconstitution and a quite powerful graft-versus-leukemia effect with a low incidence of graft-versus-host disease and no need for posttransplant pharmacological prophylaxis. Future strategies will focus on enhancing the clinical benefit of T-regulatory cells by increasing their number and strengthening their function