Search

Letter to the EditorCoronavirus disease COVID-19 has deeply modified national health services with a profound impact on hospital and in particular emergency and intensive care units (ICU) activities. As recently reported in Italy pediatric emergency accesses substantially decreased likely due to the instructions to prevent overcrowding in emergency rooms and spread of SARS-CoV-2 infection and to fear of the infection.1 At the Santobono-Pausilipon Hospital (Neaples), pediatric emergency accesses in March 2020 were only one fifth of those registered in 2019 in the same period. Likewhise a marked reduction of consultations occurred also in family pediatricians clinics.2We report here 3 children who arrived at hospital in life-threatening conditions at the onset of Acute Lymphoblastic Leukemia (ALL) between March 14 and April 10, 2020.First case: a 2-year-old-child arrived at the emergency department with a 15 days history of fatigue, pallor and dyspnea, in a comatose state, with severe anemia, respiratory distress, hematemesis and metabolic acidosis. Chest X-ray showed interstitial pneumonia. Blood tests showed: hemoglobin 2.7 gr/dL, WBC count 185.000/μl, platelets (PTL) 10.000/μl, LDH 3609 U/L. Peripheral blood was diagnostic for CD10, CD19 and CD58 positive ALL (B-lineage ALL). The patient, admitted at the ICU, intubated, transfused with RBC, PTL and plasma, died 12 hours after arrival at the hospital due to progressive worsening of clinical conditions. The nasal swab was negative for SARS-CoV-2 and positive for adenovirus.Second case: a 5-year-old-child arrived at the emergency department with a one month history of respiratory distress. Imaging showed a mediastinal mass compressing the brachiocephalic vein, the aorta, the pulmonary trunk and the left pulmonary artery, tracheal deviation, compression of the left main bronchus, left lung atelectasis and pleural effusion. Blood tests showed: hemoglobin 14.5 gr/dL, WBC count 37.000/μl, PTL 294.000/μl, LDH 6153 U/L, creatinine 1.9 mg/dl. Peripheral blood was diagnostic for CD5, CD7, CyCD3 and CD8 positive ALL (T-ALL). Steroid treatment was started. Clinical conditions deteriorated rapidly with cardiac and renal failure. The patient, admitted to ICU 2 hours after arrival at the hospital and intubated, died 24h later. The nasal swab was negative for SARS-CoV-2.Third Case: a 4-year-old child arrived at the hospital with one month history of fever, cough and shortness of breath treated at home with antibiotics and steroids without improvement. Imaging showed a mediastinal mass compressing the left brachiocephalic, azygos and superior cava veins, and right pulmonary artery and vein; mild tracheal deviation, compression of the left main bronchus; pericardial and pleural effusion; nephro-hepato-splenomegaly and ascites. Due to signs of cardiac tamponade, pericardiac and pleural drainage were placed and the patient was admitted at ICU and intubated. Blood tests showed: normal hemoglobin, WBC and PTL counts; LDH 2732 U/L, creatinine 2.98 mg/dl, K 8 mEq/L, Ca 5.4 mEq/L. Bone marrow was diagnostic for CD2, CD5, CD7, CD99 and CyCD3 positive ALL (T-ALL). Treatment with steroids was started. Due to progressive renal failure hemodialysis was performed for 9 days. Clinical conditions improved with rapid shrinking of mediastinal masses and resolution of pericardial and pleural effusion. The patient was thus extubated and treatment for ALL was instituted with good response to induction therapy. The nasal swab was negative for SARS-CoV-2.The 3 cases of ALL here described, 2 of them fatal, arrived at the hospital in critical conditions, most likely as a consequence of fear of COVID-19. Delay in diagnosis of neoplastic disease is a well-known problem in low-middle income countries (LMIC), but is quite rare in high-income countries (HIC). Actually, this combination of events never occurred in the past at the Santobono-Pausilipon Hospital, where, at the time of writing, no SARS-CoV-2 positive cases have been identified among children treated for cancer.Considering low prevalence of virus spreading in children and that SARS-CoV-2 positive children are generally asymptomatic or have a very mild course of the disease there is a substantial risk that collateral effects of COVID-19 pandemic, i.e. delays in diagnosis, chemotherapeutic treatments and treatment of chemotherapy complications, may be worse than those posed by the disease itself.3,4,7 Recently the major pediatric cancer scientific associations have expressed great concern on the risk that fear to access to medical care raised by Covid-19 may cause these delays not only in LMIC but also in HIC with dramatic consequences we are not used to face.5-6 Our experience confirms the occurrence of these collateral effects, indicating that there is a need of awareness of this risk and careful medical attention to assure timely diagnoses and adequate treatment adherence in childhood cancer.

BACKGROUND: Rowell syndrome is a rare disease characterized by a combination of lupus erythematosus (LE) and erythema multiforme (EM)-like lesions and a characteristic immunologic pattern, including speckled pattern of antinuclear antibody (ANA), positive anti-Ro/SSA or anti-La/SSB, and positive rheumatoid factor (RF). This disease was first described in 1963, and to date, about 95 cases of EM-like lesions associated with LE have been described in the literature, with the majority of cases being reported in adult female patients. Here, we describe the case of a 17-year-old male patient exhibiting both systemic LE and EM lesions together with ANA and anti-Ro/SSA positivity who was successfully treated with systemic corticosteroids and hydroxychloroquine.

Simple Summary Blinatumomab, a bispecific T-cell engager, binding T-cell CD3 and B-cell CD19 antigens, has remarkably enlarged the treatment options for patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL). The aim of our study was to retrospectively assess the safety and efficacy profile of blinatumomab in 39 r/r ALL children treated in seven AIEOP centers in a compassionate or off-label program. This report is among the largest multicentric real-life retrospective analyses on blinatumomab in pediatric r/r BCP ALL. Blinatumomab showed a tolerable safety profile (34.8% of adverse events ≥grade 3, no cytokine release syndrome and no associated toxic deaths) and proved to be very effective (complete remission rate 46% in the 13 patients with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with

The prevalence of celiac disease (CD) has increased significantly in recent years, and risk prediction and early diagnosis have become imperative especially in at-risk families. In a previous study, we identified individuals with CD based on the expression profile of a set of candidate genes in peripheral blood monocytes. Here we evaluated the expression of a panel of CD candidate genes in peripheral blood mononuclear cells from at-risk infants long time before any symptom or production of antibodies.We analyzed the gene expression of a set of 9 candidate genes, associated with CD, in 22 human leukocyte antigen predisposed children from at-risk families for CD, studied from birth to 6 years of age. Nine of them developed CD (patients) and 13 did not (controls). We analyzed gene expression at 3 different time points (age matched in the 2 groups): 4-19 months before diagnosis, at the time of CD diagnosis, and after at least 1 year of a gluten-free diet. At similar age points, controls were also evaluated.Three genes (KIAA, TAGAP [T-cell Activation GTPase Activating Protein], and SH2B3 [SH2B Adaptor Protein 3]) were overexpressed in patients, compared with controls, at least 9 months before CD diagnosis. At a stepwise discriminant analysis, 4 genes (RGS1 [Regulator of G-protein signaling 1], TAGAP, TNFSF14 [Tumor Necrosis Factor (Ligand) Superfamily member 14], and SH2B3) differentiate patients from controls before serum antibodies production and clinical symptoms. Multivariate equation correctly classified CD from non-CD children in 95.5% of patients.The expression of a small set of candidate genes in peripheral blood mononuclear cells can predict CD at least 9 months before the appearance of any clinical and serological signs of the disease.

IntroductionGrowth impairment has often been described in children who develop coeliac disease (CD). Based on data from the multicentre, longitudinal PreventCD study, we analysed the growth patterns of infants at genetic risk of CD, comparing those who developed CD by 6 years of age (CD ‘cases’, 113 infants) versus those who did not develop CD by 6 years (no CD ‘controls’, 831 infants).MethodsWeight and length/height were measured using a longitudinal protocol. Raw measurements were standardised, computing z-scores for length/height and weight; a linear mixed model was fitted to the data in order to compare the rate of growth in the two cohorts.ResultsNeither cases nor controls had significant growth failure. However, when the mean z-scores for weight and height were analysed, there was a difference between the two groups starting at fourth month of life. When the growth pattern in the first year was analysed longitudinally using mixed models, it emerged that children who develop CD had a significantly lower growth rate in weight z-score (−0.028/month; 95% CI −0.038 to −0.017; pConclusionThe growth of children at risk of CD rarely fell below ‘clinical standards’. However, growth rate was significantly lower in cases than in controls. Our data suggest that peculiar pathways of growth are present in children who develop CD, long before any clinical or serological signs of the disease appear.

Recently, a novel subgroup of B Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL), called Philadelphia-like (Ph-like) ALL, has been described. This high-risk group, despite the absence of BCR-ABL1 rearrangement, shows genomic abnormalities that result in aberrant expression of cytokine receptors genes or tyrosine-kinase-activating signaling. These patients are poor responder to conventional chemotherapy but potentially sensitive to Tyrosine-Kinase Inhibitors (TKIs). Herein we report the case of a 10 year-old girl who received diagnosis of precursor B-ALL on February 2018. She started therapy according to observational protocol ALL 2017 of the Italian Association of Pediatric Hemato-Oncology (AIEOP). After pre-phase, the patient resulted prednisone poor responder and continued induction therapy, including daunorubicin, vincristine, PEG-L-Asparaginase, prednisone and intrathecal methotrexate. Bone marrow evaluation showed persistence of disease on day 15 (88% of lymphoblasts) and 33 (60% of blasts) in flow cytometry. At the end of IA induction phase, Minimal Residual Disease (MRD) in RT-PCR showed high positivity (marker 1 = 7.2x10-1, marker 2= 8.11x10-1). At this time, further molecular studies, using RNA targeted next generation sequencing (PanCancer, Illumina), revealed the presence of EBF1-PDGFRβ gene fusion. Since the patient was resistant to conventional therapy and literature's evidences demonstrated potential sensitivity of EBF1-PDGFRβ to TKIs therapy, we decided to add dasatinib, a second generation TKI, to IB induction, with cyclophosphamide, cytarabine and 6-mercapthopurine. After one week of therapy, clinical course was complicated by Klebsiella Pneumoniae sepsis, followed by digestive hemorrhage. Since we retained that the hemorrhagic event could be related to dasatinib, the drug was temporarily discontinued. However, bone marrow evaluation, after only 10 days of dasatinib administration, showed hematologic remission (3% of lymphoblast) and MRD reduction >1 logarithm (markers 1=1-10-2 e markers 2= 9.9 x 10-3). Given the resistance to chemotherapy alone and the excellent response to dasatinib but its related toxicity in combination, we decided to start immunotherapy with blinatumomab, a bi-specific CD3-CD19 monoclonal antibody, alternated to dasatinib, in order to achieve MRD negativity before to proceed with allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling. The patient received 2 courses of blinatumomab for 28 days continuous infusion (15 mcg/mq days 1-28), interspersed by 15 days of dasatinib (60 mg/mq/day). After the first cycle the patient achieved complete hematological remission and MRD negativity. MRD negativity was confirmed after first course of dasatinib, second course of blinatumomab and second course of dasatinib. Dasatinib, given alone, was well tolerated and no serious adverse event were reported. Actually, the patient is undergoing HSCT by HLA-identical sister. To our knowledge, only few cases of EBF1-PDGFRβ ALL, treated with TKIs, are described in literature and this is the first in which MRD negativity was obtained with a sequential combination of dasatinib and blinatumumomab, a chemo-free approach, showing efficacy and good tolerability. This case highlights also that screening for targetable lesions at diagnosis or in case of resistance to induction phase is mandatory to identify patients who might benefit from alternative therapies as TKIs, immunotherapy or their combination. A longer follow-up is required to definitively establish the long-term efficacy of this biological approach in our patient. Nevertheless, it is interesting to speculate that alternative treatment with TKIs or immunotherapy could avoid, in the future, an intensive chemotherapy, or probably a transplant approach in selected patients, in order to achieve a durable cure in these Ph-like patients. Disclosures Locatelli: Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Parasole:Baxalta: Membership on an entity's Board of Directors or advisory committees; behring: Consultancy; jazz: Honoraria, Speakers Bureau.

AIM To verify the precision and accuracy of transglutaminase antibodies (TGA) assays across Mediterranean countries. METHODS This study involved 8 referral centres for celiac disease (CD) in 7 Mediterranean countries. A central laboratory prepared 8 kits of 7 blinded and randomized serum samples, with a titrated amount of Human TGA IgA. Each sample was analysed three times on three different days, with each centre running a total of 21 tests. The results were included in a blindly coded report form, which was sent to the coordinator centre. The coordinator estimated the mean coefficient of Variation (CoVar = σ/μ), the mean accuracy (Accur = Vobserved - Vreal) and the mean percent variation (Var% = [(Vobserved - Vreal)/Vreal] × 100). RESULTS The analysis showed that 79.17% of the mean variation fell between -25% and +25% of the expected value, with the accuracy and precision progressively increasing with higher titres of TGA. From values 1.25 times greater than the normal cut-off, the measurements were highly reliable. CONCLUSION TGA estimation is a crucial step for the diagnosis of CD; given its accuracy and precision, clinicians could be confident in establishing a diagnosis.