Concomitant variants in NF1, LZTR1 and GNAZ genes probably contribute to the aggressiveness of plexiform neurofibroma and warrant treatment with MEK inhibitor.

Neurofibromatosis 1 (NF1) is caused by germline mutations in the NF1 gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of NF1. In this study, we investigated a life-threatening plexiform neurofibroma in a 9-month-old female infant with NF1. Germline mutations in two RASopathy-associated genes were identified using whole-exome sequencing-a de novo pathogenic variant in the NF1 gene, and a known pathogenic variant in the LZTR1 gene. Somatic analysis of the plexiform neurofibroma revealed NF1 loss of heterozygosity and a variant in GNAZ, a gene encoding a G protein-coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1/2 activation compared to those expressing wild-type GNAZ. Taken together, we suggest the variants in NF1, LZRT1 and GNAZ act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non-NF1 variants affecting the NF1 clinical phenotype and supports use of personalized, targeted therapy.

Renal function in ß-thalassemia major patients treated with two different iron-chelation regimes.

BACKGROUND: Renal injury in transfusion dependent ß thalassemia patients (TDT) has been attributed to iron overload, chronic anemia and iron-chelation therapy (ICT) toxicity. We studied renal function in TDT patients treated with two different ICT regimes. PATIENTS AND METHODS: We studied 36 TDT patients: 26 received deferasirox (DFX) and 10 were treated with deferoxamine (DFO) +/- deferiprone (DFP). RESULTS: Increased uNAG was found in 30% of the DFX group vs. 10% of the DFO+/-DFP group, the mean uNAG level in the DFX group was significantly higher than in the DFO+/-DFP group, (P < 0.05). A moderate negative correlation was found between uNAG levels and mean serum ferritin for the prior 10 years (P = 0.03), more pronounced for the DFO+/-DFP group. Twenty nine patients had had their renal function evaluated 10 years earlier; eGFR significantly declined in patients switched to DFX (P = 0.0093) but not in patients who continued DFO+/-DFP. CONCLUSIONS: A high prevalence of renal tubular damage was observed in our TDT patients, particularly those treated with DFX; uNAG was negatively associated with mean 10-year serum ferritin, suggesting ICT's involvement in tubular injury. A significant decline in eGFR compared to a decade earlier was observed only in patients currently treated with DFX. Strict follow-up of renal function in TDT patients is warranted.

Immune Thrombocytopenia Secondary to Hodgkin's Lymphoma in Children

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disorder of variable origin that results in bleeding and decreased platelet count. Autoimmune abnormalities have been described in patients with malignancies including non-Hodgkin's lymphoma but are rarely described in patients with Hodgkin's lymphoma. OBJECTIVES: To describe an unusual presentation of Hodgkin's lymphoma in an unusual age and alarm pediatricians of the challenging diagnosis. METHODS: We present two cases that highlight an unusual clinical presentation of childhood Hodgkin's lymphoma occurring at an atypical age. RESULTS: Over a 4-year period, two children aged 5 and 6 years were admitted for suspected ITP, both had cervical lymphadenopathy. Bone marrow examination showed no evidence of tumor or fibrosis. Biopsy of the lymph node was possible only after administration of intravenous immunoglobulins and normalization of the platelet count. Platelet counts increased after initiation of chemotherapy. CONCLUSIONS: The identification of the clinical presentation of ITP as a possible presentation of Hodgkin's lymphoma is important to facilitate timely diagnosis and management.

Doxorubicin-Eluting Intra-Arterial Therapy for Pediatric Extra-Abdominal Desmoid Fibromatoses: A Promising Approach for a Perplexing Disease.

Systemic doxorubicin is effective for desmoid fibromatosis (DF), but its use is limited by dose-dependent cardiotoxicity. A protocol of selective intra-arterial doxorubicin drug-eluting embolization (DEE) was designed to maximize target tissue efficacy of doxorubicin, while minimizing systemic exposure. Four children with recurrent or refractory DF were treated between 2014 and 2017. Tumor volumes were reduced by 54%-97% over a follow-up interval of 6-32 months. A single patient experienced transient lower extremity paresthesia (Common Terminology Criteria for Adverse Events grade I). Further investigation is needed to better establish these promising results for doxorubicin DEE in DF treatment.

STAT3 gain-of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds.

Autoimmune lymphoproliferative syndrome (ALPS) is typically caused by mutations in genes of the extrinsic FAS mediated apoptotic pathway, but for about 30% of ALPS-like patients the genetic diagnosis is lacking. We analyzed 30 children with ALPS-like disease of unknown cause and identified two dominant gain-of-function mutations of the Signal Transducer And Activator Of Transcription 3 (STAT3, p.R278H, p.M394T) leading to increased transcriptional activity. Hyperactivity of STAT3, a known repressor of FAS, was associated with decreased FAS-mediated apoptosis, mimicking ALPS caused by FAS mutations. Expression of BCL2 family proteins, further targets of STAT3 and regulators of the intrinsic apoptotic pathway, was disturbed. Cells with hyperactive STAT3 were consequently more resistant to intrinsic apoptotic stimuli and STAT3 inhibition alleviated this effect. Importantly, STAT3-mutant cells were more sensitive to death induced by the BCL2-inhibitor ABT-737 indicating a dependence on anti-apoptotic BCL2 proteins and potential novel therapeutic options.

Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study.

AIMS: Cytarabine is a pyrimidine analogue used to treat a variety of haematological malignancies. There are few data regarding the pharmacodynamics of cytarabine. The only publications regarding this issue cite a biphasic pattern of decline in white blood cell (WBC) counts following low and intermediate doses, in patients with various malignancies, most of them non-haematological. Our purpose was to establish the pharmacodynamics of cytarabine induced leucopenia in acute myeloid leukaemia (AML) patients treated with contemporary cytarabine containing protocols. METHODS: We conducted a retrospective cohort study, including 56 patients with AML in complete remission who had received 89 cycles of intermediate or high dose cytarabine. Daily counts for WBCs and neutrophils (ANC) were collected during the first 15 days after the initiation of cytarabine administration and pharmacodynamics were analyzed. Further analysis was carried out to correlate between WBC and ANC pharmacodynamics and different cytarabine protocols [high dose cytarabine (HiDAC) vs. intermediate dose cytarabine (IDAC)]. RESULTS: Analysis of blood counts demonstrated a monophasic decline of WBCs and ANCs, unlike a previous depiction of a biphasic pattern. HiDAC was associated with a significantly sharper decline of WBCs than IDAC. CONCLUSIONS: Our data support a monophasic decline pattern of WBCs and ANCs following contemporary cytarabine protocols. The decline rate is steeper for patients receiving HiDAC than for those receiving IDAC. These results might help form evidence based guidelines regarding patient monitoring intensity, timing of prophylactic antibacterial and antifungal treatment as well as growth factors' support following cytarabine based consolidation for AML.

Sporadic desmoid tumors in the pediatric population: A single center experience and review of the literature.

BACKGROUND/PURPOSE: We present our long experience with desmoid tumors in children. METHODS: Data were retrospectively collected from 17 children/adolescents treated for sporadic desmoid tumors at a tertiary pediatric hospital in 1988-2016. There were 10 girls and 7 boys aged 1-17years. Tumor sites included head and neck, trunk, extremity, and groin. Eight patients underwent radical resection, with complete remission in 7 and local relapse in one which was treated with chemotherapy. Four patients underwent incomplete surgical resection, three with adjuvant chemotherapy. Five patients underwent biopsy only and chemotherapy. Two of the 9 chemotherapy-treated patients also had intraarterial chemoembolization. Chemotherapy usually consisted of vincristine and actinomycin-D with or without cyclophosphamide or low-dose vinblastine and methotrexate. Two patients also received tamoxifen. RESULTS: After a median follow-up of 3.3years, 10 patients were alive in complete remission, 5 had stable disease, and 2 had reduced tumor size. Five-year overall survival was 100%, and event-free survival, 87.5%. Ten were screened for CTNNB1 mutations. CTNNB1 gene sequencing yielded mutations in 5/10 samples tested: 3 T41A, 2 S45F. There was no association of CTNNB1 mutation with clinical outcome or prognosis. CONCLUSION: Pediatric desmoid tumors are rare, with variable biologic behavior and morbidity. Treatment requires a multidisciplinary approach. LEVEL OF EVIDENCE: LEVEL IV, treatment study.

An 8-Year-Old Child with Malignant Deciduoid Mesothelioma of the Abdomen: Report of a Case and Review of the Literature.

Malignant mesothelioma is an uncommon tumor that usually arises in the pleural cavity of adults with a history of asbestos exposure. Less frequently, it appears in the peritoneum or other mesothelial surfaces. Deciduoid mesothelioma is a rare subtype that has been found at both sites. Of the 3 reported cases in children, 2 originated in the mesenterium and 1 in the pleura. We describe a 4th case of pediatric, malignant, deciduoid mesothelioma and a third case in the mesenteric cavity. The patient was an 8-year-old girl who presented with abdominal pain and fullness. Workup revealed extensive involvement of the abdomen by a serosa-based tumor. The clinical and pathologic findings are described, and the pertinent literature is reviewed.