Objectives: Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during “off-label use”. Methods: We performed a retrospective, multicenter chart review for SAEs during “off-label” sirolimus therapy for vascular anomalies and analyzed these cases by a pre-designed workflow. Results: We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n=4), Gorham-Stout disease (n=2), central conducting lymphatic anomaly (n=1), lymphatic malformation (n=4), tufted angioma (n=1), kaposiform hemangioendothelioma (n=1), and venous malformation in a CLOVES syndrome (n=1). Three patients presented two SAEs. The age at initiation of sirolimus therapy was under the age of 2 years (5x), 2 to 6 years (5x) and older than 12 years (4x). SAEs occurred during the first 3 months of sirolimus therapy (7x), between 3 and 12 months (7x) and after one year of therapy (3x). The most frequent SAE was viral pneumonia (8x) resulting in death due to a metapneumovirus infection in a 3 months old and generalized adenovirus infection in a 28 months old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis during sirolimus therapy. Conclusions: Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence risk factors, i.e. underlying vascular anomaly or immune status, may contribute to the risk of SAEs.

Sickle cell disease (SCD) is a hematologic disorder defined by presence of sickle-shaped red blood cells that can occlude blood vessels and cause tissue ischemia and pain. Treating SCD pain adequately and safely is difficult given today’s opioid climate. Buprenorphine-naloxone has been described as an alternative option to treat chronic pain in the adult literature, however, it historically has required discontinuation of full-agonist opioids before initiation, resulting in opioid withdrawal symptoms. Here we present two adolescents with SCD who successfully weaned off large doses of full-agonist opioids by using a micro-dose induction of buprenorphine-naloxone in clinic without patients experiencing withdrawal symptoms. Ambulatory micro-dose induction may remove hurdles that otherwise would discourage patients from trying this regimen while still controlling pain safely.

Bright IDEAS Problem-Solving Skills Training (BI) is an evidence-based behavioral intervention that has been utilized extensively with caregivers of children recently diagnosed with cancer. Considerable evidence has shown that BI is acceptable to caregivers and improvements in problem-solving skills mediate reduced symptoms of distress; and it is most effective with single, minority caregivers. A slightly modified version of BI was offered to caregivers of children with sickle cell disease (SCD) in a two-site pilot feasibility trial. BI was modified to reduce barriers to care, logistical challenges, and stigma associated with receiving behavioral health services. Our goal was to establish high rates of recruitment and retention amongst caregivers of children with SCD. Recruitment was acceptable (94%; N = 72) and retention reasonable (48.6%) across both sites with 35 caregivers successfully completing the BI program. Results showed that caregivers of children with SCD, who successfully completed the BI program reported, significant improvements in problem-solving skills immediately and three months post-intervention completion. Interestingly, initial levels of distress were low with few caregivers reporting clinically significant levels of distress; distress remained low over time. Findings are discussed in the context of psychosocial screening and assumptions regarding caregivers of children with SCD.

Background The diagnostic delay in children and adolescents with cancer is a public health problem in Peru leading to high rates of advanced disease and mortality. We aimed to evaluate the implementation and utility of ONCOpeds, a mobile application that provides consultations, in reducing the latency to diagnosis (LD) and referral time (RT) in children and adolescents diagnosed with cancer in Peru. Material and methods A multicenter pilot study was conducted in the region of Callao between November 2017 and April 2018. Attending primary care physicians were trained in the use of ONCOpeds in 5 educational sessions. Patients younger than 18 years living in Callao and diagnosed with cancer from all the pediatric cancer units were analyzed in two groups: referred by the mobile application or by the conventional referral. Results ONCOpeds was successfully installed in the smartphone devices of 78 attending physicians of Callao. During this period, 23 new cases of cancer in children and adolescents from Callao were collected. Ten patients were referred through the application and 13 in a conventional manner. The LD and RT were reduced in the group referred by ONCOpeds by 66% and 68%, respectively; however, only the RT reached statistical significance (p = 0.02). Conclusions The implementation of the use of ONCOpeds was feasible in this pilot study, having a potential utility in improving the diagnosis and referral in children and adolescents with suspected cancer. A larger study at the national level is required to demonstrate the effectiveness of this telemedicine tool.

Background and aims: Oral mucositis (OM) is common and distressing toxicity in children on chemotherapy. There is limited number of safe and effective therapeutic options available for OM. Ketamine oral rinse has shown promising results in few studies in adults. This randomized, double-blind placebo-controlled trial aimed to test the efficacy of ketamine mouthwash in reducing chemotherapy-induced severe OM pain in children. Methods: Children aged 8-18 years with severe OM were randomized to a single dose of ketamine mouthwash (4 mg/ml solution; dose 1 mg/kg) or a placebo. A sample size of 44 patients was determined. Pain score (6-point faces scale) was noted at baseline and 15, 30, 45, 60, 120, 180, and 240 min. The outcome variables were a reduction in pain score, need for rescue medications, and adverse events. Results: The baseline characteristics were comparable in the two groups. The mean OM pain at 60 min decreased by 1.64 points (CI 1.13-2.14) in the ketamine group and 1.32 points (CI 0.76-1.87) in the placebo group (p=0.425), with a group difference of 0.32 points. Rescue pain medication (at 60 min) was required in 13.6% in the ketamine group and 18.2% in the placebo group (p=1.000). There were no significant adverse events observed. Conclusions: Among children on cancer chemotherapy with severe OM, ketamine mouthwash at a dose of 1 mg/kg did not significantly reduce OM pain. It did not decrease the need for rescue pain medications. Further research is warranted to test higher doses of ketamine for a clinically significant effect.

Abstract Background: Effectiveness of hydroxyurea (HU) in SCD is well established. Unanswered questions persist about use in African children in terms of acceptability and monitoring. We determined real-life user-barriers, safety and effects of therapy among children using HU in Nigeria. Methods: We retrieved and reviewed case notes of children on hydroxyurea (10-15mg/kg/day followed by dose escalation) from January 2017 to June 2019, checked for adherence to drugs, clinics and laboratory tests; starting dose, toxicity and benefits (hematologic, clinical, parental satisfaction). A questionnaire complemented case note findings. Results 116 patients received hydroxyurea (mean dose of 18 mg/kg/ day). Improvement in general well-being was 91.25%, reduction in bone pain 83.3%, hospital admissions 71.9%, abdominal pain 62.3%, blood transfusion 56.1%. Sixteen percent voluntarily stopped HU because of cost and side effects. Sixty-seven percent of parents complained about daily drug use, frequency and cost of monitoring. Adherence to daily HU was 88.8%, doctor’s appointments 22.8%, hematology tests 17.5%, organ function 32.5%. Five patients had mild neutropenia. No significant hepatic or renal toxicity occurred. Common side effects were abdominal pain (18.4%) and headache (13.2%). Significant increase in hemoglobin, fetal hemoglobin, MCV and reduction in absolute neutrophil counts occurred. Conclusion: Hydroxyurea at 10-15mg/kg/day is safe, effective and acceptable to parents. Monitoring is challenging. Care-giver education, support services, staff training, HU clinics may improve utilization. HU protocols that reduce monitoring and yet provide good clinical and laboratory benefits are necessary. This study adds to the implementation science strategies that is needed to increase HU use in Nigeria.

Background: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically-annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy. Methods: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next generation sequencing (NGS) library preparation using a custom 124 gene hybridization capture panel and the 75 gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq. Results: Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n=6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n=8), NTRK3 (n=4), and BRAF. Mutually-exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with both DNA and RNA analyzed. Fusion positive PTC was associated with multifocal disease, higher tumor staging, and higher American Thyroid Association (ATA) risk levels. Both BRAF V600E mutations and gene fusions were correlated with the presence of cervical metastases. Conclusions: Targetable alterations were identified in 75% of pediatric PTC cases with both DNA and RNA evaluated. Inclusion of RNA sequencing for detection of fusion genes is critical for evaluation of these tumors. Patients with fusion positive tumors were more likely to have features of high-risk disease.

The covid-19 pandemic has forced citizens worldwide to rely on social distancing measures as the main tools to prevent the rapid spreading of the virus (1). In pediatric oncology, there were important initial concerns for immunocompromised patients who were considered to be at higher risk of developing severe form of the disease (2,3). Consequently, potential challenges (2) have been identified and advice given by the principal child cancer organizations (3). Although more experience from countries that have been facing the pandemic are being published, results are inconsistent so far ranging from reassuring in Milano (4), Madrid (5) or New York (6) to worrying in France where 4 out of 33 Covid-19 positive patients required intensive care and 1 death at last follow up (7).Over the last weeks, despite the pandemic we were able to maintain “normal“ care for pediatric cancer patients in our institution, including high-dose chemotherapy followed by peripheral stem cells transplantations, or recruitment in early phase clinical trials. Only follow-up visits have been re-scheduled or switched to remote consultations. After almost 2 months of lock-down and still ongoing social distancing measures, an unexpected challenge has emerged. Inddeed, during that period, as usual we had to break bad news: for diagnosis, for relapse or palliative care. Initially, when breaking bad news, I had the feeling something was going wrong, or at least was not going as usual. Was I doing something wrong? Was stress induced by a high level of anxiety due to the lack of specific information on the real risk for adolescents/children with cancer both among the medical team and or parents affecting the “breaking bad news” process?Why didn’t I take that teenagers in my arms after disclosing her a metastatic relapse and she looked in such a distress?Social distancing!Masks to start with. They are of course a barrier to saliva droplets potentially containing covid-19, but most importantly they are also a barrier to adequately transmit and discriminate emotions just relying on eyes expression, looks…beyond tears. Silent communication with long looks without words can sometimes be enough and better that long talks but do parents and children feel the same when half of the face is covered. I asked about it to one of my patients and he answered“I think can read your eyes” . By increasing the physical space between people to avoid virus spreading, but here again, for physicians and some parents/patients, holding hands, holding shoulders, hugging are important non-verbal elements of communications and help showing compassion.We might break social distancing to break bad news, but if not pre-agreed by the patient or its parents, is it acceptable? Couldn’t it be perceived as an additional threat, contribute to alter intuitive communication which is characterized by broad, shared goals and mutual respect?Breaking bad news while trying to maintain social distancing is an unexpected new challenge associated with Covid-19. We will very likely learn to better communicate, read & share our respective emotions even with masks and physical distancing and sometimes allow ourselves exceptions to social distancing. Meanwhile, this impact shall be further evaluated among all stakeholders: patients, their parents, and physicians and adapted strategies to better cope with it developed.

The pandemic of the novel coronavirus disease, COVID-19 is having a serious impact on pediatric patients with cancer. Social distancing, self-quarantining and nationwide lockdown have resulted in restricted movements of patients and families across the country. This has made the optimum management of children with cancer difficult. In this clinical perspective, we discuss the issues related to COVID-19 and pediatric cancer and how we have attempted to optimize the treatment for our patients using telemedicine, reorganizing the day care services, triaging our patients and modifying their treatment plans, partnered with the NGOs and local medical centres to provide care to our patients.

Background: Socioeconomic and health care coverage disparities are established as poor prognostic markers in adults with sarcoma, but few studies examine these differences among pediatric, adolescent and young adults (AYA). This study examines the association between socioeconomic status (SES), insurance status, and disease presentation among children and AYA patients with sarcoma. Methods: This is a retrospective cohort study of patients aged 0-25 years with bone or soft tissue sarcoma from the National Cancer Database. SES assignments were based on estimated median income and education-level. Patient demographics and clinical factors were compared by SES and insurance status. Multivariate logistic regression models were fitted to determine adjusted odds ratios of SES and insurance status on metastatic disease or tumor size ≥5cm at time of presentation. Results: In a cohort of 9112 patients, 2932 (32.1%) had low, 2084 (22.8%) middle, and 4096 (44.9%) high SES. For insurance status, 5864 (64.3%) had private, 2737 (30.0%) public, and 511 (5.6%) were uninsured. Compared to high SES, patients with low SES were more likely to have metastatic disease (OR=1.16, p=0.03) and tumors ≥5cm (OR=1.29, p<0.01). Compared to private insurance, public and no insurance were associated with metastatic disease (OR=1.35, p<0.01 and OR=1.32, p=0.02) and increased tumors ≥5cm (OR=1.28, p<0.01 and OR=1.67, p<0.01). Conclusions: SES disparities exist among children and AYA patients with sarcoma. Low SES and public or no insurance are associated with advanced disease at presentation. Further studies are needed to identify interventions to improve earlier detection of sarcomas in at-risk children and young adults.

Expanding Clinical Spectrum of Female X-linked Lymphoproliferative Syndrome 2Shruthi Suryaprakash, MD1, Mohammad El-Baba2, MD, Kelly J. Walkovich, MD3, Süreyya Savaşan, MD41Children’s Hospital of Michigan2Division of Gastroenterology, Children’s Hospital of Michigan3Division of Hematology/Oncology, Immuno-Hematology Comprehensive Program, C.S. Mott Children’s Hospital, University of Michigan4Division of Hematology/Oncology and Blood and Marrow Transplant Program, Children’s Hospital of Michigan, Carman and Ann Adams Department of Pediatrics, Barbara Ann Karmanos Cancer Center, Central Michigan University College of MedicineCorrespondence: Süreyya Savaşan, MD3901 Beaubien Blvd.Division of Hematology/OncologyBlood and Marrow Transplant ProgramChildren’s Hospital of MichiganDetroit, Michigan 48201E-mail: [email protected]: 313-745-5516 Fax: 313-745-5237Text word count: 495Reference count: 4Tables and figures: 1Short running title: Spectrum of Symptomatic Female XLP2Key words: Female XLP2, EBV reactivation, Vitamin B12 deficiency, B-cell lymphopenia, clonal T-LGL proliferationDear Editor:X-linked lymphoproliferative syndrome type 2 (XLP2) due to pathogenic variants in the X-linked inhibitor of apoptosis (XIAP) gene is a rare cause of primary immunodeficiency. Symptomatic patients, primarily males, present with hemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD) and/or transient hypogammaglobinaemia.1 However, XLP2 in female patients is complicated with the rarity of symptomatic cases and clinical heterogeneity.2 We report a female affected by XLP2 with previously unreported findings.A currently 18-year-old female presented with fever, abdominal pain, diffuse lymphadenopathy, splenomegaly, and pancytopenia three years ago. She was diagnosed with HLH, treated with steroids and found to have low B-cells and borderline hypogammaglobinemia. Additionally, a single pathogenic variant in XIAP (c.389_392delACAG [p.Asp130Glyfs*11]) was identified. Further workup showed presence of EBV IgG, and normal expression of XIAP protein in only 8-19% of various white blood cell types by flow cytometry indicating skewed X chromosome inactivation. She had intermittent infections, one resulting in an additional HLH flare with elevated IL-18 and CXCL9 levels that was treated with steroids and intravenous immunoglobulin (IVIG). Repeated EBV PCR testing had been negative.However, she was found to have EBV reactivation with positive EBV VCA-IgM, high titer VCA-IgG and EA-IgG levels while EBV-PCR was negative when she presented to our clinic with diarrhea. There was ongoing history of headaches, abdominal pain, joint pain, and ADHD at that time. Later, she underwent work up for recurrent abdominal pain, diarrhea, urgency and elevated fecal calprotectin. MRI-enterography and capsule endoscopy were negative. Endoscopy was remarkable for chronic active proctitis. She was prescribed mesalamine with significant improvement in abdominal pain and resolution of mucuosy stools.Due to persistent knee/ankle pain, she was investigated for peripheral neuropathy and was found to have low vitamin B12 levels (112-145pg/mL; N:180-914) without dietary restrictions, absent anti-intrinsic factor antibodies and negative family history. Her pain improved significantly on vitamin B12 injections and gabapentin with normalization of vitamin B12 levels.She continued to have fluctuating and borderline low levels of serum immunoglobulins with persistently low B-cells. She was given IVIG supplementation when serum IgG levels were low. No additional HLH flares have occurred. Mild increase in CD5-dim T-cells (9%) representing T-large granular lymphocytes (T-LGL) and clonal T-cell receptor (TCR) rearrangement pattern were identified in peripheral blood. She continues to have migraine episodes and very high EA-IgG at >150U/mL (N <9).Female carriers are at risk for extra hematopoietic manifestations, if they have an extremely skewed X chromosome inactivation.3 She was EBV-PCR negative, but EBV VCA-IgM positive repeatedly suggesting a recent reactivation at presentation to our institution. Persistent high EBV EA-IgG titers is suggestive of ongoing EBV challenge due to immune deficiency and emphasizes the significance of EBV serology testing. Clonal T-LGL expansion may be related to EBV and/or immune deficiency.4 Low vitamin B12 raises the possibility of impairment in absorption; the presence of proctitis raises possible subclinical inflammation in the distal ileum. Observed conditions in this case add to the spectrum of this rare entity (Table1).

COVID-19 PANDEMIC: A CHALLENGE TO A CHILD WITH CANCER Dear Editor,People of all ages can be infected by the new coronavirus (2019-nCoV). Older people, and people with pre-existing medical conditions (such as asthma, diabetes, heart disease) are more vulnerable to becoming severely ill with the virus. There is a widespread anxiety among families of children with cancer due to risk of exposure to SARS-CoV-2, either in the hospital or community setting. [1]Recently Ogimi et al [2] reported that infants and younger children (i.e., ≤5 years) are more likely to develop severe clinical manifestations than older children, maybe due to immaturity of the immune system. Sullivan et al [3] reported that the COVID-19 pandemic was one of the most serious global challenge to delivering affordable and equitable treatment to children with cancer. They have provided some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures to be taken to contain it (e.g. extreme social distancing) and how to prepare for the anticipated recovery period.The Government and administrative measures such as lockdown has further compounded these challenges. Lack of state transport, closure of district borders, non-availability of medications has put these children at risk of rapid growth of disease, delay in treatment and poor outcome. A four and half year-old child, a known case of synchronous bilateral Wilms tumour, having undergone bilateral nephron sparing surgery was on adjuvant chemotherapy. The COVID-19 pandemic brought about an interruption in his chemotherapy schedule in January 2020. When he presented in early May, he had a small swelling of 1.5 cm diameter below the left subcostal margin (Figure 1a). Ultra sonography revealed a hypoechoic lesion below the skin measuring 1.5 cm in diameter (Figure 1b). Fine needle aspiration cytology was done which revealed sheets of cells with high nuclear/cytoplasm ratio (Figure 1c). The features were highly suspicious of a malignant lesion. The lesion was excised and histo-pathological examination revealed a metastasis from WILMS tumour (Figure 1d). The child has been resumed on further chemotherapy.Most childhood cancers behave aggressively and need immediate treatment, often requiring prolonged periods of intensive multiagent chemotherapy. Postponement of treatment such as surgery, radiation and chemotherapy is not a safe option in children. There is an urgent need amongst health professionals and families for informed guidance on the range of reasonable and safe adaptations to their services and cancer treatment during the pandemic.Conflict of Interest: None.Compliance with Ethical Standards.

Primary bone composite sarcoma is a very rare entity that primarily affects adolescent and young adult patients. It usually combines areas of liposarcoma and osteosarcoma and up to 60% of cases have metastatic disease at diagnosis. It is a highly aggressive pathology with intrinsic resistance to conventional treatment schemes for bone sarcomas. The prognosis is poor, with long term survival rates that do not exceed 30%. We present the case of an adolescent female diagnosed with a primary agressive bone composite sarcoma with rhabdomyosarcoma foci and loco-regional lymph node involvement.

Appropriate high-dose chemotherapy (HDC) for high-risk neuroblastoma has not yet been established. In Japan, a unique HDC regimen (called double-conditioning regimen) comprising two cycles of total 800 mg/m2 of thiotepa and total 280 mg/m2 of melphalan is widely used. To re-evaluate the safety and the efficacy of this regimen for high-risk neuroblastoma, the medical records of 41 patients with high-risk neuroblastoma who underwent the double-conditioning regimen followed by autologous peripheral blood stem cell rescue between 2002 and 2012 were reviewed. MYCN-amplified high-risk neuroblastomas were observed in 23 patients. All patients underwent intensive multidrug induction chemotherapy, but none underwent anti-GD2 antibody immunotherapy. The primary tumor was resected at the adequate time point. The median follow-up duration for living patients was 9.2 years (range = 5.5–14.0 years). The 5-year event-free survival (EFS) and overall survival (OS) rates from treatment initiation were 41.5% ± 7.7% and 56.1% ± 7.8%, respectively. The 5-year EFS of MYCN-amplified high-risk neuroblastoma patients was 60.9% ± 10.2%, which was significantly superior compared to MYCN-non-amplified high-risk neuroblastoma patients (16.7% ± 8.8%; P < 0.001). MYCN amplification was the most favorable prognostic factor for EFS (hazard ratio = 0.29; 95% confidence interval = 0.12–0.66). Of the 41 patients, 3 died because of regimen-related toxicity (infection, n = 2; microangiopathy, n = 1). The double-conditioning regimen with thiotepa and melphalan is effective for high-risk neuroblastoma, especially in patients with MYCN amplification. However, the double-conditioning regimen is toxic and warrants special attention in clinical practice.

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.

We report a case of a 34-month-old girl who has been followed up for 12 months after ingesting 105mg/kg of hydroxyurea (HU) and showed only transient mild bone marrow suppression. With anticipated increase in HU use among children with SCD in sub-Saharan Africa, the possibility of accidental ingestion should be envisaged and appropriate user-education and management guidelines established. Toxicity from accidental HU overdosage is generally mild and transient and should not constitute a barrier to its use in Nigerian children with SCD.

Abbreviations Full term COVID-19 coronavirus disease 2019 SARS-CoV-2 Severe acute respiratory syndrome corona virus 2

CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) is a rare entity recently described. Thirteen CNS HGNET-MN1 patients were identified using genome wide methylation arrays/RT-PCR across 7 institutions and were correlated with treatment and outcome. All patients had surgery (GTR:9/STR:4) as initial management followed by radiotherapy (focal:5/craniospinal:2/CyberKnife:1) and systemic chemotherapy in 3 patients. Seven patients relapsed; 5 local and 2 metastatic despite complete resection and radiotherapy. Three patients died due to their tumor relapse after 24 months despite upfront radiotherapy. Treatment of CNS HGNET-MN1 remains a major challenge with multiple failures, despite aggressive surgical resections and upfront radiotherapy.