Case report: EBV-related eye orbits and sinuses lymphohistiocytic infiltration responsive to rituximab in a patient with X lymphoproliferative syndrome type 1.

Background and aims: X lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity due to mutations of SH2D1A, encoding for slam-associated protein (SAP). The clinical phenotype includes severe mononucleosis, hemophagocytic lymphohistiocytosis (HLH), and B-cell lymphomas. Methods: We report the case of a child affected with XLP1 who presented with an incomplete HLH, triggered by Epstein-Barr virus (EBV) and treated with rituximab, involving orbits and paranasal sinuses. Results: The lesion was indistinguishable from lymphoma, complicating diagnosis and treatment. In addition, considering the high incidence of lymphoma in patients with XLP1, histology helped define its nature, driving therapeutic choices. Conclusion: We described an unusual presentation of incomplete HLH in a patient affected with XLP1: an EBV-driven infiltration of the orbits and paranasal sinuses. This led us to a challenging differential diagnosis of lymphoma-associated hemophagocytic syndrome, which can be frequently observed in patients with XLP1. Considering the extremely poor prognosis of this clinical finding, we sought for a prompt diagnosis and managed to obtain it and to immediately establish the right treatment on the basis of the pathological finding.

Healthcare migration in Italian paediatric haematology-oncology centres belonging to AIEOP.

BACKGROUND: In Italy, there is a network of centres headed by the Italian Association of Pediatric Hematology and Oncology (AIEOP) for the diagnosis and treatment of paediatric cancers on almost the entire national territory. Nevertheless, migration of patients in a hospital located in a region different from that of residence is a widespread habit, sometimes motivated by several reasons. The aim of this paper is to assess the impact of migration of children with cancer to AIEOP centres in order to verify their optimal distribution throughout the national territory. METHODS: To this purpose, we used information on 41,205 registered cancer cases in the database of Mod.1.01 Registry from AIEOP centres, with age of less than 20 years old at diagnosis, diagnosed from 1988 to 2017. Patients' characteristics were analysed and compared using the X2 or Fisher's exact test or Mann-Whitney test, when appropriate. Survival distributions were estimated using the method of Kaplan and Meier, and the log-rank test was used to examine differences among subgroups. RESULTS: Extra-regional migration involved overall 19.5% of cases, ranging from 23.3% (1988-1997) to 16.4% (2008-2017) (p < 0.001). In leukaemias and lymphomas we observed a mean migration of 8.8% overall, lower in the North (1.2%) and Centre (7.8%) compared to the South & Isles (32.3%). In the case of solid tumours, overall migration was 25.7%, with 4.2% in the North, 17.2% in the Centre and 59.6% in the South & Isles. For regions with overall levels of migration higher than the national average, most migration cases opted for AIEOP centres of close or even neighbouring regions. Overall survival at 10 years from diagnosis results 69.9% in migrants vs 78.3% in no migrants (p < 0.001). CONCLUSIONS: There is still a certain amount of domestic migration, the causes of which can be easily identified: migration motivated by a search for high specialization, migration due to lack of local facilities, or regions in which no AIEOP centres are present, which makes migration obligatory. Better coordination between AIEOP centres could help to reduce so-called avoidable migration, but technical and political choices will have to be considered, with the active participation of sector technicians.

miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1S expression.

Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor GATA-1 that result in exclusive production of its shorter isoform (GATA-1S). Given the common hallmark of altered miRNA expression profiles in haematological malignancies and the pro-leukaemic role of GATA-1S, we aimed to search for miRNAs potentially able to modulate the expression of GATA-1 isoforms. Starting from an in silico prediction of miRNA binding sites in the GATA-1 transcript, miR-1202 came into our sight as potential regulator of GATA-1 expression. Expression studies in K562 cells revealed that miR-1202 directly targets GATA-1, negatively regulates its expression, impairs GATA-1S production, reduces cell proliferation, and increases apoptosis sensitivity. Furthermore, data from TAM and myeloid leukaemia patients provided substantial support to our study by showing that miR-1202 down-modulation is accompanied by increased GATA-1 levels, with more marked effects on GATA-1S. These findings indicate that miR-1202 acts as an anti-oncomiR in myeloid cells and may impact leukaemogenesis at least in part by down-modulating GATA-1S levels.

Safety and effectiveness of subcutaneously anchored securement for tunneled central catheters in oncological pediatric patients: A retrospective study.

BACKGROUND: Proper securement of central venous catheters plays an important role in onco-hematological pediatric patients. A new subcutaneously anchored securement device has been recently introduced in the clinical practice, and it has been extensively used in children. METHOD: In our study, we have retrospectively investigated the safety and the effectiveness of such device, reviewing the experience of three Italian pediatric oncological units. We have considered only tunneled catheters (cuffed or non-cuffed) inserted in children with malignancy; all types of tunneled central catheters were included in the analysis (both centrally and peripherally inserted) as long as they were secured with a subcutaneously anchored device. We investigated the incidence of dislodgment and of other catheter-related complications, with special attention to local adverse effects potentially related to the securement device. RESULTS: We collected data from 311 tunneled catheters of different caliber: 80.4% were centrally inserted central catheters (CICC), 15.4% were peripherally inserted (PICC), and 4.2% were femorally inserted. Approximately half of the catheters (51%) were non-cuffed. Incidence of dislodgment was very low (2.6%) and the incidence of local pain or inflammation potentially related to the securement device was minimal (1.9%). Catheter related bacteremias were below 1 episode/1000 catheter days. No symptomatic catheter related thrombosis was reported. There was no significant difference in complications comparing cuffed versus non-cuffed catheters, or CICCs versus PICCs, or hematologic tumors versus solid tumors. CONCLUSION: In our retrospective analysis of a vast population of oncological pediatric patients with tunneled central catheters, the subcutaneously anchored securement device was tolerated very well, and it was highly effective in preventing dislodgment, both in cuffed and non-cuffed catheters.

High-Risk Acute Myeloid Leukemia: A Pediatric Prospective.

Pediatric acute myeloid leukemia is a clonal disorder characterized by malignant transformation of the hematopoietic stem cell. The incidence and the outcome remain inferior when compared to pediatric ALL, although prognosis has improved in the last decades, with 80% overall survival rate reported in some studies. The standard therapeutic approach is a combined cytarabine and anthracycline-based regimen followed by consolidation with allogeneic stem cell transplantation (allo-SCT) for high-risk AML and allo-SCT for non-high-risk patients only in second complete remission after relapse. In the last decade, several drugs have been used in clinical trials to improve outcomes in pediatric AML treatment.

Diagnosis and management of neutropenia in children: The approach of the Study Group on Neutropenia and Marrow Failure Syndromes of the Pediatric Italian Hemato-Oncology Association (Associazione Italiana Emato-Oncologia Pediatrica - AIEOP).

Neutropenia refers to a group of diseases characterized by a reduction in neutrophil levels below the recommended age threshold. The present study aimed to review the diagnosis and management of neutropenia, including a diagnostic toolkit and candidate underlying genes. This study also aimed to review the progress toward the definition of autoimmune and idiopathic neutropenia rising in infancy or in late childhood but without remission, and provide suggestions for efficient diagnostics, including indications for the bone marrow and genetic testing. The management and treatment protocols for common and unique presentations are also reviewed, providing evidence tailored to a single patient.

Blinatumomab in Children and Adolescents with Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia: A Real-Life Multicenter Retrospective Study in Seven AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) Centers.

Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80-85%. However, 15-20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0-21 years old with r/r BCP-ALL were treated with blinatumomab with the aim of inducing remission (n = 13) or reducing MRD levels (n = 26) in the frame of different multiagent chemotherapy schedules, in seven AIEOP centers. Patients were treated in compassionate and/or off-label settings and were not enrolled in any controlled clinical trials. Treatment was well tolerated; 22 (56.4%) patients reported adverse events (AE) on a total of 46 events registered, of which 27 (58.7%) were ≤2 grade according to CTCAE. Neurological AEs were 18 (39.1%); only two patients required transient blinatumomab discontinuation. Complete remission (CR) rate was 46% for the 13 patients treated with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with blasts < 5%. Median relapse-free survival was 33.4 months (95% CI; 7.5-59.3); median overall survival was not reached over a mean follow-up of 16 months. In our study, as in other real-life experiences, blinatumomab proved to be effective and well-tolerated, able to induce a high rate of CR and MRD negativity.

KCTD15 deregulation is associated with alterations of the NF-κB signaling in both pathological and physiological model systems.

Like other KCTD proteins, KCTD15 is involved in important albeit distinct biological processes as cancer, neural crest formation, and obesity. Here, we characterized the role of KCTD15 in different physiological/pathological states to gain insights into its diversified function(s). The silencing of KCTD15 in MLL-rearranged leukemia models induced attenuation of the NF-κB pathway associated with a downregulation of pIKK-ß and pIKB-α. Conversely, the activation of peripheral blood T cells upon PMA/ionomycin stimulation remarkably upregulated KCTD15 and, simultaneously, pIKK-ß and pIKB-α. Moreover, a significant upregulation of KCTD15 was also observed in CD34 hematopoietic stem/progenitor cells where the NF-κB pathway is physiologically activated. The association between KCTD15 upregulation and increased NF-κB signaling was confirmed by luciferase assay as well as KCTD15 and IKK-ß proximity ligation and immunoprecipitation experiments. The observed upregulation of IKK-ß by KCTD15 provides a novel and intriguing interpretative key for understanding the protein function in a wide class of physiological/pathological conditions ranging from neuronal development to cancer and obesity/diabetes.

The lncRNA TEX41 is upregulated in pediatric B-Cells Acute Lymphoblastic Leukemia and it is necessary for leukemic cell growth.

BACKGROUND: Long non-coding RNAs (lncRNAs) represent a diverse class of RNAs involved in the regulation of various physiological and pathological cellular processes, including transcription, intracellular trafficking, and chromosome remodeling. LncRNAs deregulation was linked to the development and progression of various cancer types, such as acute leukemias. In this context, lncRNAs were also evaluated as a novel class of biomarkers for cancer diagnosis and prognosis. Here, we analyzed TEX41 in childhood B cell acute lymphoid leukemia (B-ALL). METHODS: Total RNA was extracted from pediatric B-ALL patients (at diagnosis and after induction of therapy) and from healthy subjects. Total RNA was also extracted from different leukemia cell line models. The expression level of TEX41 was evaluated by q-RT-PCR. Also, the dataset deposited by St. Jude Children's Research Hospital was consulted. Furthermore, the silencing of TEX41 in RS4;11 cell line was obtained by 2'-Deoxy, 2'Fluroarabino Nucleic Acids (2'F-ANAs) Oligonucleotides, and the effect on cell proliferation was evaluated. Cell cycle progression and its regulators were analyzed by flow cytometry and immunoblotting. RESULTS: We exploited the St Jude Cloud database and found that TEX41 is a lncRNA primarily expressed in the case of B-ALL (n = 79) while its expression levels are low/absent for T-cell ALL (n = 25) and acute myeloid leukemia (n = 38). The association of TEX41 with B-ALL was confirmed by real-time PCR assays. TEX41 disclosed increased expression levels in bone marrow from patients with B-ALL at diagnosis, while its expression levels became low or absent when retested in Bone Marrow cells of the same patient after 1 month of induction therapy. Also, silencing experiments performed on RS4;11 cells showed that TEX41 downregulation impaired in vitro leukemic cell growth determining their arrest in the G2-M phase and the deregulation of cell cycle proteins. CONCLUSIONS: Our findings highlight that TEX41 is an upregulated lncRNA in the case of B-ALL and this feature makes it a novel potential biomarker for the diagnosis of this leukemia subtype in pediatric patients. Finally, TEX41 expression seems to be critical for leukemic proliferation, indeed, silencing experiments targeting TEX41 mRNA in the RS4;11 cell line hampered in vitro cell growth and cell cycle progression, by inducing G2-M arrest as confirmed propidium iodide staining and by the upregulation of p53 and p21 proteins.

Antibiotic Resistant Bloodstream Infections in Pediatric Patients Receiving Chemotherapy or Hematopoietic Stem Cell Transplant: Factors Associated with Development of Resistance, Intensive Care Admission and Mortality.

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium. Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.

Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis.

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, a relevant number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34+ cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34+ cells have a cellular composition that resembles bone marrow, supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPCs). To overcome the limit of bone marrow harvest/ HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex-vivo expansion of HSPCs coupled with lentiviral gene transfer. Circulating CD34+ cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector (LV) expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NSG recipients. Moreover, when CD34+ cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPCs coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by bone marrow fibrosis.

The HLA Variant rs6903608 Is Associated with Disease Onset and Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Caucasians.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (ß -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

A Prospective Study of Hematologic Complications and Long-Term Survival of Italian Patients Affected by Shwachman-Diamond Syndrome.

OBJECTIVE: To describe the hematologic outcome and long-term survival of patients enrolled in the Shwachman-Diamond syndrome Italian Registry. STUDY DESIGN: A retrospective and prospective study of patients recorded in the Shwachman-Diamond syndrome Italian Registry. RESULTS: The study population included 121 patients, 69 males and 52 females, diagnosed between 1999 and 2018. All patients had the clinical diagnosis confirmed by mutational analysis on the SBDS gene. During the study period, the incidence of SDS was 1 in 153 000 births. The median age of patients with SDS at diagnosis was 1.3 years (range, 0-35.6 years). At the first hematologic assessment, severe neutropenia was present in 25.8%, thrombocytopenia in 25.5%, and anemia in 4.6% of patients. A normal karyotype was found in 40 of 79 patients, assessed whereas the most frequent cytogenetic abnormalities were isochromosome 7 and interstitial deletion of the long arm of chromosome 20. The cumulative incidence of severe neutropenia, thrombocytopenia, and anemia at 30 years of age were 59.9%, 66.8%, and 20.2%, respectively. The 20-year cumulative incidence of myelodysplastic syndrome/leukemia and of bone marrow failure/severe cytopenia was 9.8% and 9.9%, respectively. Fifteen of 121 patients (12.4%) underwent allogeneic stem cell transplantation. Fifteen patients (12.4%) died; the probability of overall survival at 10 and 20 years was 95.7% and 87.4%, respectively. CONCLUSIONS: Despite an improvement in survival, hematologic complications still cause death in patients with SDS. Further studies are needed to optimize type and modality of hematopoietic stem cell transplantation and to assess the long-term outcome in nontransplanted patients.

Successful management plan of COVID-19 in a pediatric hemato-oncology department: a single-centre experience.

COVID-19 pandemic raised concern about management of patients with paediatric cancer. We present the operating system that the Hemato-Oncology Department of the Santobono-Pausilipon Hospital applied. We divided our department in three zones: surveillance and screening; quarantine and COVID free, in order to screen admitted patients and to reduce the risk of cross infection. From 3 April until 29 May 2020 (56 days), 662 patients and caregivers underwent rapid serological tests for a total of 1397 assays. No patient or parent with SARS-CoV2 infection was found, demonstrating the effectiveness of COVID-19 screening process.

GATA-1 isoforms differently contribute to the production and compartmentation of reactive oxygen species in the myeloid leukemia cell line K562.

Maintenance of a balanced expression of the two isoforms of the transcription factor GATA-1, the full-length protein (GATA-1FL ) and a shorter isoform (GATA-1 S ), contributes to control hematopoiesis, whereas their dysregulation can alter the differentiation/proliferation potential of hematopoietic precursors thereby eventually leading to a variety of hematopoietic disorders. Although it is well established that these isoforms play opposite roles in these remarkable processes, most of the molecular pathways involved remain unknown. Here, we demonstrate that GATA-1FL and GATA-1S are able to differently influence intracellular redox states and reactive oxygen species (ROS) compartmentation in the erythroleukemic K562 cell line, thus shedding novel mechanistic insights into the processes of cell proliferation and apoptosis resistance in myeloid precursors. Furthermore, given the role played by ROS signaling as a strategy to escape apoptosis and evade cell-mediated immunity in myeloid cells, this study highlights a mechanism through which aberrant expression of GATA-1 isoforms could play a role in the leukemogenic process.

Single center experience on efficacy and safety of Aprepitant for preventing chemotherapy-induced nausea and vomiting (CINV) in pediatric Hodgkin Lymphoma.

Chemotherapy-induced nausea and vomiting (CINV) is a distressing treatment side-effect that could negatively affect children's quality of life (QoL). Different scoring systems for CINV were applied and different antiemetic drugs were used; however, few studies have been performed in children undergoing chemotherapy with Aprepitant. Herein, we report a pediatric experience on efficacy and safety of Aprepitant as part of triple antiemetic prophylaxis, in a cohort of thirty-two children and adolescents with Hodgkin Lymphoma (HL), treated with moderate/highly emetogenic chemotherapy (MEC/HEC) regimens in a single Hemato-Oncology Institution. The triple therapy was compared to standard antiemetic therapy in a cohort of twenty-three HL patients (control group). Aprepitant therapy was associated to a significant decrease of chemotherapy-induced vomiting (p = 0.0001), while no impact on the reduction of nausea was observed; these observations were also confirmed by multivariate analysis (p = 0.0040). Aprepitant was well tolerated and the most commonly reported adverse events were neutropenia and hypertransaminasemia. No significant differences on the toxicity were observed between the two compared groups. Our experience on Aprepitant efficacy and safety, associated with feasibility of orally administration, suggests a possible widespread use of the drug to prevent pediatric CINV.

Cortical route for facelike pattern processing in human newborns.

Humans are endowed with an exceptional ability for detecting faces, a competence that, in adults, is supported by a set of face-specific cortical patches. Human newborns, already shortly after birth, preferentially orient to faces, even when they are presented in the form of highly schematic geometrical patterns vs. perceptually equivalent nonfacelike stimuli. The neural substrates underlying this early preference are still largely unexplored. Is the adult face-specific cortical circuit already active at birth, or does its specialization develop slowly as a function of experience and/or maturation? We measured EEG responses in 1- to 4-day-old awake, attentive human newborns to schematic facelike patterns and nonfacelike control stimuli, visually presented with slow oscillatory "peekaboo" dynamics (0.8 Hz) in a frequency-tagging design. Despite the limited duration of newborns' attention, reliable frequency-tagged responses could be estimated for each stimulus from the peak of the EEG power spectrum at the stimulation frequency. Upright facelike stimuli elicited a significantly stronger frequency-tagged response than inverted facelike controls in a large set of electrodes. Source reconstruction of the underlying cortical activity revealed the recruitment of a partially right-lateralized network comprising lateral occipitotemporal and medial parietal areas overlapping with the adult face-processing circuit. This result suggests that the cortical route specialized in face processing is already functional at birth.