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Acute leukemia is the most common pediatric cancer. In most cases, this disease results from the malignant transformation of either the B-cell (B-ALL) or, less frequently, T-cell progenitors (T-ALL). Recently, a marked overexpression of KCTD15, a member of the emerging class of the potassium (K) channel tetramerization domain-containing proteins (KCTDs) has been detected in both patients and continuous cell lines as in vitro model systems. Because there is growing evidence of the key, yet diversified, roles played by KCTDs in cancers, we here report an exhaustive analysis of their expression profiles in both B-ALL and T-ALL patients. Although for most KCTDs, no significant alterations were found in these pathological states, for some members of the family, significant up- and down-regulations were detected in comparison with the values found in healthy subjects in the transcriptome analysis. Among these, particularly relevant is the upregulation of the closely related KCTD1 and KCTD15 in T-ALL patients. Interestingly, KCTD1 is barely expressed in both unaffected controls and B-ALL patients. Therefore, not only does this analysis represent the first study in which the dysregulation of all KCTDs is simultaneously evaluated in specific pathological contexts, but it also provides a promising T-ALL biomarker that could be suitable for clinical applications.

Although children and young adults with Hodgkin's lymphoma usually have a favorable prognosis, patients with primary refractory disease and some subsets of relapsed patients still have a dismal outcome. Brentuximab vedotin (BV) in combination with bendamustine may represent a suitable salvage therapy; data on 32 patients aged less than 25 years were retrospectively analyzed. Patients received up to six cycles of treatment of BV 1.8 mg/kg on day 1 and bendamustine 90-120 mg/m

Reduced bone mineral density (BMD) is a well-known complication in childhood acute lymphoblastic leukemia (ALL) survivors; the optimal method to assess BMD is still debated. We studied BMD by quantitative ultrasound (QUS) in 72 ALL survivors, and evaluated any correlation with cumulative doses of steroids and cytotoxic agents. Mean age at diagnosis was 61±45 months, while mean age at QUS was 318.3±129.6 months; mean period of follow-up was 41.2±37.8 months. Mean amplitude-dependent speed of sound z-score was -1.22±1.19. Ten survivors (13.8%) presented a z-score below -2 SD. A negative correlation was found between amplitude-dependent speed of sound z-score and age at diagnosis (P=0.01). A positive correlation was observed with length of follow-up (P=0.01). No correlation was found with cytotoxic drugs. This study represents the largest cohort of childhood ALL survivors studied by QUS. Our results suggest that QUS for its characteristics of being radiation free may be an effective option to assess BMD in pediatric age. In addition, our data outline the importance to improve the awareness about the specific expression of this complication in the pediatric age, concerning the major determinants of bone impairment, which are the disease itself and the phase of bone growth when the disease occurs.

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.

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

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.

The toxicity and effi cacy of intrathecal liposomal cytarabine (LC) were evaluated in children with central nervous system (CNS) relapsed/refractory acute leukemia/lymphoma. Thirty patients (male:female ratio 21:9; median age 9.4 years) with CNS relapsed/ resistant disease were treated with intrathecal LC at dosages adjusted for age. Twenty-seven (90%) patients simultaneously received systemic chemotherapy, including concurrent highdose cytarabine or methotrexate in 21 (70%) cases. Of 28 patients evaluable for response, 25 patients (89%) achieved CNS complete remission and three (11%) partial remission. The median number of intrathecal LC administrations per patient was 4. The cerebrospinal fl uid was cleared after a median of 3 intrathecal LC administrations. Neurological toxicity ≥ grade 3 occurred in four (13%) patients. No permanent sequelae were observed. The median overall survival was 20.9 months and the 5-year probability of survival was 46%. These encouraging data suggest that intrathecal LC is well tolerated and eff ective in children with relapsed/refractory CNS leukemia/lymphoma.

The advent of more intensive chemotherapy and the improvement of supportive cares have dramatically changed the natural history of childhood acute lymphoblastic leukemia (ALL), with current estimated 5-year overall survival of about 80%. The increased survival rate and the establishment of follow-up survey for long term survivors (LTS) have allowed the identification of late chemo-radiotherapy adverse effects on psychological and general health. We retrospectively evaluate the incidence and type of sequelae and / or late effects in a cohort of 301 childhood ALL LTS, followed in a single pediatric AIEOP center. From June 1986 to June 2013, 301 LTS (154 male and 147 female), aged Mean FU time (time from the stop therapy to the last control) was 6 years (range 1.8-26.8 years). The majority of LTS were teenager or young adults : 35% ranged between 15 and 20 years; 19.7% was more than 21 years old and the 45.3% was less than 14 years old. During FU, 16 late recurrences (5.3%) were identified and 3 secondary malignancies (0.99%) such as one mesenteric paraganglioma and two Acute Myeloid Leukemia in second complete remission ALL LTS. 40 patients (13.3%) received cranial radiotherapy during treatment. 39 LTS (13%) reported at least one sequelae. The most frequent sequelae were neurological and orthopedic (6% and 3% respectively) as summarized in Figure 2 151 LTS (50.17%) presented at least one late effect as showed in Figure 3. In our experience at least one late effect occurred in 50.17% of LTS; these late complications affect negatively the quality of life of survivors. Endocrine-metabolic events are the most frequent late effect (34,5%). 13% of LTS have at least one sequelae mainly neurological and orthopedic. Prevention and/or early identification of complications during follow-up survey of LTS are crucial in order to decrease the long-term health risks associated with curative treatment for childhood ALL. Disclosures: No relevant conflicts of interest to declare.

Hypereosinophilia as first clinical presentation has rarely been reported in paediatric acute lymphoblastic leukaemia. It is commonly associated with specific cytogenetic abnormalities. Although eosinophilia is considered a reactive, non-neoplastic epiphenomenon, it adversely affects patient outcomes, both in children and adults. We describe herewith two paediatric patients who had marked eosinophilia at onset of acute lymphoblastic leukaemia. We point out the importance of a correct differential diagnosis in persistent, unexplained peripheral hypereosinophilia. Clinicians should keep in mind that eosinophilia can be part of the overall pattern of acute leukaemia and therefore needs to be properly investigated. We also provide some recommendations for an appropriate approach to hypereosinophilia - related morbidities.