Search

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies, inducing notable and durable clinical responses. However, for solid tumors, including but not limited to pediatric tumors, several peculiar biological features posed substantial challenges for achieving comparable results. Despite sound pre-clinical evidence of the ability of CAR T cells to eradicate solid malignancies, their activity remains suboptimal when facing the in vivo complexity of solid tumors, characterized by antigen heterogeneity, scarce T-cell infiltration, and an immunosuppressive microenvironment. Neuroblastoma was amongst the first tumors to be evaluated as a potential candidate for GD2-targeting CAR T cells, which recently documented promising results in high-risk, heavily pre-treated patients. Moreover, innovative engineering strategies for generating more potent and persistent CAR T cells suggest the possibility to reproduce, and potentially improve, these promising results on a larger scale. In the next years, harnessing the full therapeutic potential of CAR T cells and other immunotherapeutic strategies may open new possibilities for effectively treating the most aggressive forms of pediatric tumors., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: To evaluate and describe the diagnostic process, medical, nutritional, and surgical approach, and neurological outcome, we report data from a large Italian cohort of patients with congenital hyperinsulinism (CHI)., Methods: We retrospectively analyzed 154 CHI patients admitted to Ospedale Pediatrico Bambino Gesù from 1985 to 2022., Results: Hypoglycemia occurred within the first year of life in 85.5% of patients, median time to diagnosis was 1 day (IQR 14 days). Ninety-two percent of patients were treated with diazoxide: 66.9% were responsive. Octreotide was administered to 28.6% of patients: 61.4% were responsive. Forty percent of patients were off-therapy, mostly from diazoxide. Thirty-four percent of patients carried mutations in ABCC8, 12.6% were syndromic, and 9.2% were transient CHI. Surgery was performed in 23/47 diazoxide-unresponsive and 2/95 diazoxide-responsive patients: 64.0% were focal at histology. Combining data from genetics, pancreatic venous sampling, 18F-DOPA PET/CT, and histology, 80.6% resulted diffuse, 16.7% focal, and 2.8% atypical CHI. Post-surgical diabetes developed in 6 patients. Neurocognitive evaluation revealed developmental delay or intellectual disability in 15.7% of 70 patients, mostly of a mild degree. Epilepsy was documented in 13.7% of 139 patients., Conclusion: Our diagnostic and therapeutic results are mainly consistent with the international indications and the CHI Global Registry data, with relatively low rates of neurological outcomes. Good outcomes were likely associated with early diagnosis and prompt management of patients because the majority of patients were diagnosed within 2 weeks. Remarkably, it is of utmost importance to spread the knowledge and refer CHI patients to multidisciplinary expert centers., (© 2024 S. Karger AG, Basel.)

Sickle cell disease (SCD) is an inherited blood disorder, due to a single point mutation in the β-globin gene ( HBB ) leading to multisystemic manifestations and it affects millions of people worldwide. The monogenic nature of the disease and the availability of autologous hematopoietic stem cells (HSCs) make this disorder an ideal candidate for gene modification strategies. Notably, significant advances in the field of gene therapy and genome editing that took place in the last decade enabled the possibility to develop several strategies for the treatment of SCD. These curative approaches were firstly based on the correction of disease-causing mutations holding the promise for a specific, effective and safe option for patients. Specifically, gene-editing approaches exploiting the homology directed repair pathway were investigated, but soon their limited efficacy in quiescent HSC has curbed their wider development. On the other hand, a number of studies on globin gene regulation, led to the development of several genome editing strategies based on the reactivation of the fetal γ-globin gene ( HBG ) by nuclease-mediated targeting of HBG -repressor elements. Although the efficiency of these strategies seems to be confirmed in preclinical and clinical studies, very little is known about the long-term consequences of these modifications. Moreover, the potential genotoxicity of these nuclease-based strategies must be taken into account, especially when associated with high targeting rates. The recent introduction of nuclease-free genome editing technologies brought along the potential for safer strategies for SCD gene correction, which may also harbor significant advantages over HBG -reactivating ones. In this Review, we discuss the recent advances in genome editing strategies for the correction of SCD-causing mutations trying to recapitulate the promising strategies currently available and their relative strengths and weaknesses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Ceglie, Lecis, Canciani, Algeri and Frati.)

High-Grade Gliomas (HGG) are among the deadliest malignant tumors of central nervous system (CNS) in pediatrics. Despite aggressive multimodal treatment - including surgical resection, radiotherapy and chemotherapy - long-term prognosis of patients remains dismal with a 5-year survival rate less than 20%. Increased understanding of genetic and epigenetic features of pediatric HGGs (pHGGs) revealed important differences with adult gliomas, which need to be considered in order to identify innovative and more effective therapeutic approaches. Immunotherapy is based on different techniques aimed to redirect the patient own immune system to fight specifically cancer cells. In particular, T-lymphocytes can be genetically modified to express chimeric proteins, known as chimeric antigen receptors (CARs), targeting selected tumor-associated antigens (TAA). Disialoganglioside GD2 (GD-2) and B7-H3 are highly expressed on pHGGs and have been evaluated as possible targets in pediatric clinical trials, in addition to the antigens common to adult glioblastoma - such as interleukin-13 receptor alpha 2 (IL-13α2), human epidermal growth factor receptor 2 (HER-2) and erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2). CAR-T therapy has shown promise in preclinical model of pHGGs but failed to achieve the same success obtained for hematological malignancies. Several limitations, including the immunosuppressive tumor microenvironment (TME), the heterogeneity in target antigen expression and the difficulty of accessing the tumor site, impair the efficacy of T-cells. pHGGs display an immunologically cold TME with poor T-cell infiltration and scarce immune surveillance. The secretion of immunosuppressive cytokines (TGF-β, IL-10) and the presence of immune-suppressive cells - like tumor-associated macrophages/microglia (TAMs) and myeloid-derived suppressor cells (MDSCs) - limit the effectiveness of immune system to eradicate tumor cells. Innovative immunotherapeutic strategies are necessary to overcome these hurdles and improve ability of T-cells to eradicate tumor. In this review we describe the distinguishing features of HGGs of the pediatric population and of their TME, with a focus on the most promising CAR-T therapies overcoming these hurdles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Antonucci, Canciani, Mastronuzzi, Carai, Del Baldo and Del Bufalo.)

Background . Cirrhosis is associated with abnormal autonomic function and regulation of cardiac rhythm. Measurement of heart rate variability (HRV) provides an accurate and non-invasive measurement of autonomic function as well as liver disease severity currently calculated using the MELD, UKELD, or Child-Pugh scores. This review assesses the methods employed for the measurement of HRV, and evaluates the alteration of HRV indices in cirrhosis, as well as their value in prognosis. Method. We undertook a systematic review using Medline, Embase and Pubmed databases in July 2020. Data were extracted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The risk of bias of the included studies was assessed by a modified version of the Newcastle-Ottawa Scale. The descriptive studies were analysed and the standardized mean differences of HRV indices were pooled. Results. Of the 247 studies generated from our search, 14 studies were included. One of the 14 studies was excluded from meta-analysis because it reported only the median of HRV indices. The studies included have a low risk of bias and include 583 patients with cirrhosis and 349 healthy controls. The HRV time and frequency domains were significantly lower in cirrhotic patients. Between-studies heterogeneity was high in most of the pooled studies ( P  < 0.05). Further, HRV indices predict survival independent of the severity of liver disease as assessed by MELD. Conclusion. HRV is decreased in patients with cirrhosis compared with healthy matched controls. HRV correlated with severity of liver disease and independently predicted survival. There was considerable variation in the methods used for HRV analysis, and this impedes interpretation and clinical applicability. Based on the data analysed, the standard deviation of inter-beat intervals (SDNN) and SDNN corrected for basal heart rate (cSDNN) are the most suitable indices for prognosis in patients with cirrhosis., (Creative Commons Attribution license.)

Controlled Potential Coulometry (CPC) is generally regarded as one of the most accurate analytical methods available for the quantification of plutonium (Pu) in acidic aqueous solutions. With a growing use of mixed oxide nuclear fuel, there has been an interest in the technique's applicability to the analysis of Pu in the presence of uranium (U). Expanding on previous studies, the work presented herein demonstrates the highly accurate CPC analysis of Pu in mixed solutions (Pu + U) containing large quantities of U (U:Pu up to 100:1) as well as establishing the role played by sulfate anions during the analyses. By combining experimental results with speciation simulations, it is shown that the introduction of U in mixed Pu + U solutions is accompanied by increases in sulfate ions in the nitric acid medium which complex unequally with the different Pu cations in solution. The anions' stronger affinity of for Pu(IV) rather than Pu(III) causes a decrease in the formal potential of the Pu(IV)/Pu(III) redox couple, directly affecting the degree of completion of the electrochemical reactions performed during CPC. A correction factor, f, is applied to account for the degree of completion of the analysis' electrochemical steps and compensate for the effects of complexation. Thereby, a level of accuracy comparable to that achieved during the analysis of pure Pu solutions, is attained. Ultimately, a series of recommendations are put forward such that it becomes possible to maintain CPC's good analytical performance for the measurement of Pu content in mixed Pu + U solutions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Reduced heart rate variability (HRV) is an independent predictor of mortality in patients with cirrhosis. However, conventional HRV indices can only be interpreted in individuals with normal sinus rhythm. In patients with recurrent premature ventricular complexes (PVCs), the predictive capacity of conventional HRV indices is compromised. Heart Rate Turbulence (HRT) represents the biphasic change of the heart rate after PVCs. This study was aimed to define whether HRT parameters could predict mortality in cirrhotic patients., Materials and Methods: 24 h electrocardiogram recordings were collected from 40 cirrhotic patients. Turbulence Onset was calculated as HRT indices. The enrolled patients were followed up for 12 months after the recruitment in relation to survival and/or transplantation., Results: During the follow-up period, 21 patients (52.5%) survived, 12 patients (30%) died and 7 patients (17.5%) had liver transplantation. Turbulence Onset was found to be strongly linked with mortality on Cox regression (Hazard ratio = 1.351, p < 0.05). Moreover, Turbulence Onset predicted mortality independently of MELD and Child-Pugh's Score., Conclusion: This study provides further evidence of autonomic dysfunction in cirrhosis and suggests that HRT is reliable alternative to HRV in patients with PVCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Oyelade, Canciani, Bottaro, Zaccaria, Formentin, Moore, Montagnese and Mani.)

Pancreatic neuroendocrine tumours (pNETs) are a heterogeneous group of epithelial tumours with neuroendocrine differentiation. Although rare (incidence of <1 in 100,000), they are the second most common group of pancreatic neoplasms after pancreatic ductal adenocarcinoma (PDAC). pNET incidence is however on the rise and patient outcomes, although variable, have been linked with 5-year survival rates as low as 40%. Improvement of diagnostic and treatment modalities strongly relies on disease models that reconstruct the disease ex vivo. A key constraint in pNET research, however, is the absence of human pNET models that accurately capture the original tumour phenotype. In attempts to more closely mimic the disease in its native environment, three-dimensional culture models as well as in vivo models, such as genetically engineered mouse models (GEMMs), have been developed. Despite adding significant contributions to our understanding of more complex biological processes associated with the development and progression of pNETs, factors such as ethical considerations and low rates of clinical translatability limit their use. Furthermore, a role for the site-specific extracellular matrix (ECM) in disease development and progression has become clear. Advances in tissue engineering have enabled the use of tissue constructs that are designed to establish disease ex vivo within a close to native ECM that can recapitulate tumour-associated tissue remodelling. Yet, such advanced models for studying pNETs remain underdeveloped. This review summarises the most clinically relevant disease models of pNETs currently used, as well as future directions for improved modelling of the disease.

The mortality and severity in COVID-19 is increased in patients with comorbidities. The aim of this study was to evaluate the severity and mortality in COVID-19 patients with underlying kidney and liver diseases. We retrieved data on the clinical features and primary composite end point of COVID-19 patients from Medline and Embase which had been released from inception by the April 16, 2020. The data on two comorbidities, liver diseases and chronic kidney disease, were pooled and statistically analysed to explain the associated severity and mortality rate. One hundred and forty-two abstracts were screened, and 41 full articles were then read. In total, 22 studies including 5595 COVID-19 patients were included in this study with case fatality rate of 16%. The prevalence of liver diseases and chronic kidney disease (CKD) were 3% (95% CI; 2-3%) and 1% (95% CI; 1-2%), respectively. In patients with COVID-19 and underlying liver diseases, 57.33% (43/75) of cases were severe, with 17.65% mortality, while in CKD patients, 83.93% (47/56) of cases were severe and 53.33% (8/15) mortality was reported. This study found an increased risk of severity and mortality in COVID-19 patients with liver diseases or CKD. This will lead to better clinical management and inform the process of implementing more stringent preventative measures for this group of patients.

Information on species thermal physiology is extremely important to understand species responses to environmental heterogeneity and changes. Thermography is an emerging technology that allows high resolution and accurate measurement of body temperature, but until now it has not been used to study thermal physiology of amphibians in the wild. Hydromantes terrestrial salamanders are strongly depending on ambient temperature for their activity and gas exchanges, but information on their body temperature is extremely limited. In this study we tested if Hydromantes salamanders are thermoconform, we assessed whether there are temperature differences among body regions, and evaluated the time required to reach the thermal equilibrium. During summers of 2014 and 2015 we analysed 56 salamanders (Hydromantes ambrosii and Hydromantes italicus) using infrared thermocamera. We photographed salamanders at the moment in which we found them and 1, 2, 3, 4, 5 and 15min after having kept them in the hands. Body temperature was equal to air temperature; salamanders attained the equilibrium with air temperature in about 8min, the time required to reach equilibrium was longer in individuals with large body size. We detected small temperature differences between body parts, the head being slightly warmer than the body and the tail (mean difference: 0.05°C). These salamanders quickly reach the equilibrium with the environment, thus microhabitat measurement allows obtaining accurate information on their tolerance limits., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Temporary observation is a very short stay in Emergency Department, widely carried out in adult patients in our Country. No experience in childhood has been reported. In our emergency department children under 16 with acute diseases are admitted for 24-48 hours. From 1991 we carried out also temporary observation. Its effectiveness has been evaluated by studying our activity in 1992 (14.574 emergency room visits, with 664 admissions to our Department and 274 temporary observation) and 1993 (12820 emergency room visits, 573 admissions, 428 temporary observation). Compared to 1992, in 1993 there was a decrease of both emergency room visits (higher than expected from demographic lowering and in part due to payment for emergency room visits) and hospital admissions, and an increase of temporary observation. The stay in hospital was less than 6 hours in 94.2% of temporary observation patients. 18.2% of them were evaluated on clinical basis, 57% also by diagnostic examinations, 24.8% had some treatment. The 89% of the children were sent home following temporary observation, the others were admitted. Criteria for temporary observation were fairly similar to those for hospital admission, but not far as Central Nervous System and Renal Disease are concerned. Our study confirms the usefulness of temporary observation in childhood to reduce both the number of hospital admissions and the discomfort of the patient and his family. Nevertheless there is a need of criteria of appropriateness. Therefore we have elaborated guide lines for temporary observation and admission to our Department.

Utilization of the pediatric Emergency Room has been evaluated during the year 1991, by a questionnaire study on 694 children. By comparison with a previous research in 1981 it was possible to identify a further decrease of urgent and appropriate visits with increase of those inappropriate. Visits were more frequently urgent of appropriate in case of acute health problems, inappropriate if related to recurrent problems. Without considering true emergencies, three main causes for ER consultation have been identified: family custom, inappropriate relationships with the practitioner, dependence on the hospital. In the first group of children most of the visits proved inappropriate. The study points out a further increase of inappropriate utilization of ER, due mainly to inappropriate relationships between the family and the practitioner. This has to be corrected to reduce costs and improve child care.

Costs and benefits of the repair in Emergency Room of skin lacerations by tissue adhesive in children are reported. In 1987-88 2150 children under 16 were referred to our Institute because of lacerations. About one of three of them needed repair by subcutaneous suture; in the others, sutures or sterile stripes or adhesive tissue could be employed. Adhesive tissue use increased significantly during 1988 because of its advantages: no need of local anesthesia, syringes, sterile suture instruments and dressing materials; no further dressing; no suffering of children during the treatment; good aesthetic results. Now it is the first choice treatment of the lacerations in which subcutaneous suture is not necessary. Moreover this technique is cheap, and reduced significantly 1988 costs for laceration repair in our department.

The authors describe the application of a technique called Patient Flow Analysis aimed at the improvement of Clinic Personnel efficiency and reduction of patient waiting time. Results were satisfactory and encourage further experiences.

Four infants with congenital heart disease showed in their first months of life poor weight gain in spite of the absence of cardiac failure; a diagnosis of intolerance to cow's milk proteins was made on the basis of laboratory findings and subsequently confirmed by the success of the avoidance diet and the positivity of the challenge tests; all four children had previously received nasogastric feeding, and this may represent a favouring factor for sensitization. Intolerance to cow's milk proteins should be considered as a possible cofactor for failure to thrive in infants with congenital heart disease.