Pediatric acute promyelocytic leukemia and Fanconi anemia: Case report and literature review.

Acute promyelocytic leukemia (APL) represents 5%-10% of childhood acute myeloid leukemia (AML) and is the most curable subtype of AML. Fanconi anemia (FA) is one of the most common inherited bone marrow failure syndromes caused by biallelic pathogenic variants (PV) in specific DNA-repair genes. Biallelic PVs in FANCD1/BRCA2 (FA-D1) account for 3% of FA and are associated with early-onset leukemia and a high risk of solid tumors. We report a 4 year-old boy from non-consanguineous parents diagnosed with standard risk APL. This child had café-au-lait spots and an extra thumb remnant. Genomic sequencing revealed two PV in FANCD1/BRCA2 confirming a diagnosis of FA-D1. Chromosomal breakage studies were compatible with FA. Each parent carried one variant and had no personal history of cancer. Morphological then molecular remissions were achieved with all-trans retinoic acid and Arsenic trioxide. This patient underwent haploidentical stem cell transplant. In addition to our patient, a literature search revealed four additional patients with APL/FA, with a total of three patients with FA-D1. This raises the possibility of an association between such rare disorders. Practical management of APL in the setting of FA-D1 is discussed with an overview of current evidence and knowledge gaps.

Case Report of Renal Calculi in a Child Receiving Imatinib for Acute Lymphoblastic Leukemia.

Rationale: Imatinib is used in the treatment of Philadelphia chromosome positive (Ph+) leukemias and has been reported to have a direct effect on bone physiology. Presentation: To report on a child with Ph+ acute lymphoblastic leukemia who presented with bilateral flank pain and gross hematuria. Diagnosis: She was diagnosed with obstructive kidney stones 101 days after commencing daily oral imatinib. Stone analysis revealed the presence of calcium phosphate. Interventions and outcome: The patient passed the stones spontaneously with medical therapy that included the use of thiazide, allopurinol, and potassium citrate, but she required temporary insertion of a double-J stent to relieve an obstruction. Novel findings: Imatinib inhibits receptor tyrosine kinases and stimulates the flux of calcium from the extracellular fluid into bone, resulting in hypocalcemia with a compensatory rise in parathyroid hormone that may result in phosphaturia and the formation of calcium phosphate stones. Given that kidney stones are rare events in children, we believe that monitoring for kidney stone formation needs to be performed in children receiving imatinib.

Justification: L'imatinib est utilisé dans le traitement des leucémies à chromosome Philadelphie (Ph+) et a été décrit comme ayant un effet direct sur la physiologie osseuse. Présentation du cas: Une enfant atteinte d'une leucémie lymphoblastique aiguë à Ph+ présentant des douleurs lombaires bilatérales et une hématurie macroscopique. Diagnostic: La patiente a reçu un diagnostic de calculs rénaux obstructifs 101 jours après avoir commencé la prise quotidienne d'imatinib par voie orale. L'analyse des calculs a révélé la présence de phosphate de calcium. Interventions et résultats: La patiente a éliminé spontanément ses calculs grâce à un traitement médical qui comprenait un diurétique thiazidique, de l'allopurinol et du citrate de potassium, mais on a dû lui insérer temporairement une endoprothèse double J pour traiter une obstruction. Nouveaux enseignements: L'imatinib inhibe les récepteurs de la tyrosine kinase et favorise le flux du calcium du liquide extracellulaire vers les os, ce qui entraîne une hypocalcémie avec élévation secondaire de l'hormone parathyroïdienne pouvant provoquer une phosphaturie et la formation de calculs de phosphate de calcium. Puisque la formation de calculs rénaux est rare chez les enfants, nous pensons qu'elle devrait faire l'objet d'une surveillance chez les enfants qui reçoivent de l'imatinib.

Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.

BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer. METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668. FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8·6 months (IQR 2·5-16·4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60·0%; 95% CI 32·3-83·7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5·9% (95% CI 2·6-11·3). INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Acquired thrombotic thrombocytopenic purpura with isolated CFHR3/1 deletion-rapid remission following complement blockade.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is caused by the abundance of uncleaved ultralarge von Willebrand factor multimers (ULvWF) due to acquired (autoantibody-mediated) or congenital vWF protease ADAMTS13 deficiency. Current treatment recommendations include plasma exchange therapy and immunosuppression for the acquired form and (fresh) frozen plasma for congenital TTP. CASE-DIAGNOSIS/TREATMENT: A previously healthy, 3-year-old boy presented with acute microangiopathic hemolytic anemia, thrombocytopenia, erythrocyturia and mild proteinuria, but normal renal function, and elevated circulating sC5b-9 levels indicating complement activation. He was diagnosed with atypical hemolytic uremic syndrome and treated with a single dose of eculizumab, followed by prompt resolution of all hematological parameters. However, undetectably low plasma ADAMTS13 activity in the pre-treatment sample, associated with inhibitory ADAMTS13 antibodies, subsequently changed the diagnosis to acquired TTP. vWF protease activity normalized within 15 months without further treatment, and the patient remained in long-term clinical and laboratory remission. Extensive laboratory workup revealed a homozygous deletion of CFHR3/1 negative for anti-CFH antibodies, but no mutations of ADAMTS13, (other) alternative pathway of complement regulators or coagulation factors. CONCLUSIONS: This case, together with a previous report of a boy with congenital TTP (Pecoraro et al. Am J Kidney Dis 66:1067, 2015), strengthens evolving in-vitro and ex-vivo evidence that ULvWF interferes with complement regulation and contributes to the TTP phenotype. Comprehensive, prospective complement studies in patients with TTP may lead to a better pathophysiological understanding and novel treatment approaches for acquired or congenital forms.

Novel 3q27.2-qter deletion in a patient with Diamond-Blackfan anemia and immunodeficiency: Case report and review of literature.

3q27.2-qter deletion syndromes feature an overlapping set of terminal and interstitial deletions with variable congenital malformations. Diamond-Blackfan anemia (DBA) is etiologically heterogeneous disorder in which one cause is dominant mutations of the RPL35A gene on 3q29. We report a child with a 3q27.2-qter deletion that contains the RPL35A gene. She had clinical and laboratory features consistent with DBA and as well, an unexplained immunodeficiency disorder. Given these unusual findings, we reviewed other patients in the literature with overlapping genomic deletions. In addition, we evaluated our patient for the immunodeficiency disorder, RIDDLE syndrome, due to recessive mutations in the RNF168 gene on 3q29. A PubMed search for case reports of 3q27.2-qter overlapping deletions was performed. To determine if RPL35A was in the deletion region, the chromosomal regions reported were mapped to genomic regions using the UCSC Genome Browser. We identified 85 overlapping deletions, of which six included the RPL35A gene and all should be had DBA. Interestingly, none of the reported cases had immunodeficiency. To evaluate RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties), we sequenced the remaining RNF168 gene and examined her fibroblast culture for a DNA double strand break repair deficiency. These results were normal, indicating that the immunodeficiency is unlikely to result from a RNF168 deficiency. We show that RPL35A haploinsufficiency is a cause of DBA and we report a novel case with 3q27.2-qter deletion and immunodeficiency. The etiology for the immunodeficiency remains unsolved and could be caused by an unknown gene effect or consequent to the DBA phenotype.

Procedural pediatric sedation by nurses: available, competent, and safe.

Sedation and/or analgesia are standard of care for pediatric patients during painful intervention or medical imaging requiring immobility. Physician availability is frequently insufficient to allow for all procedural sedation. A nurse-led sedation program was created at the Centre Hospitalier Universitaire de Sherbrooke (CHUS) to address this problem. Objective. To evaluate the effectiveness and the safety of our program. Methods. A retrospective study of all the procedural sedations done over one year was performed. Complications were separated in four categories: (1) major complications (call for help; unexpected admission, aspiration, and code); (2) reportable sedation events (oxygen saturation <90%, bradycardia (more than 2 SD below normal for the age of the child), and hypotension (more than 2 SD below normal for the age of the child); (3) difficult sedation (agitation, inadequate sedation, and failure to perform the procedure), (4) minor complications. Results. 448 patients, 249 boys and 199 girls; received sedation for 555 procedures. Overall, 78% (432) of interventions were successfully accomplished: 0% of major complications, 8% of reportable sedation events; 5% of difficult sedation; 9% of minor complications. Conclusion. Our nurse-led sedation program compares favorably to other similar systems.

Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas.

PURPOSE: Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA. EXPERIMENTAL DESIGN: We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes. RESULTS: Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic ß-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation. CONCLUSIONS: OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients.