Inhibition of Wee1 is emerging as a novel therapeutic strategy for cancer, and some data suggest that cells with dysfunctional p53 are more sensitive to Wee1 inhibition combined with conventional chemotherapy than those with functional p53. We and others found that Wee1 inhibition sensitizes leukemia cells to cytarabine. Thus, we sought to determine whether chemosensitization by Wee1 inhibition is dependent on p53 dysfunction and whether combining Wee1 inhibition is tolerable and effective in vivo. Synergistic inhibition of proliferation with a Wee1 inhibitor in clinical development, MK1775, and cytarabine was observed in all acute myeloid leukemia (AML) cell lines tested, regardless of p53 functionality. Mechanistic studies indicate that inhibition of Wee1 abrogates the S-phase checkpoint and augments apoptosis induced by cytarabine. In AML and lung cancer cell lines, genetic disruption of p53 did not alter the cells' enhanced sensitivity to antimetabolites with Wee1 inhibition. Lastly, mice with AML were treated with cytarabine and/or MK1775. The combination of MK1775 and cytarabine was well-tolerated in mice and enhanced the anti-leukemia effects of cytarabine, including survival. Thus, inhibition of Wee1 sensitizes hematologic and solid tumor cell lines to antimetabolite chemotherapeutics, whether p53 is functional or not, suggesting that the use of p53 mutation as a predictive biomarker for response to Wee1 inhibition may be restricted to certain cancers and/or chemotherapeutics. These data provide preclinical justification for testing MK1775 and cytarabine in patients with leukemia.

While some children with acute lymphoblastic leukemia (ALL) have excellent prognoses, the prognosis for adults and children with T cell ALL is more guarded. Treatment for T-ALL is heavily dependent upon antimetabolite chemotherapeutics, including cytarabine. Targeted inhibition of WEE1 with AZD1775 has emerged as a strategy to sensitize cancer cells to cytarabine and other chemotherapeutics. We sought to determine if this strategy would be effective for T-ALL with clinically relevant anti-leukemia agents. We found that AZD1775 sensitizes T-ALL cells to several traditional anti-leukemia agents, acting synergistically with cytarabine by enhancing DNA damage and apoptosis. In addition to increased phosphorylation of H2AX at serine 139 (γH2AX), AZD1775 led to increased phosphorylation of H2AX at tyrosine 142, a signaling event associated with promotion of apoptosis over DNA repair. In a xenograft model of T-ALL, the addition of AZD1775 to cytarabine slowed leukemia progression and prolonged survival. Inhibition of WEE1 with AZD1775 sensitizes T-ALL to several anti-leukemia agents, particularly cytarabine. Mechanistically, AZD1775 promotes apoptosis over DNA repair in cells treated with cytarabine. These data support the development of clinical trials including AZD1775 in combination with conventional chemotherapy for acute leukemia.

Objective: To evaluate the impact of early disseminated intravascular coagulation (DIC) on illness severity in children using a database of ED encounters for children with suspected sepsis, in view of similar associations in adults.Study design: Laboratory and clinical data were extracted from a registry of Emergency Department (ED) encounters of children with suspected sepsis between April 01, 2012 and June 26, 2017. International Society of Thrombosis and Hemostasis DIC scores were calculated from laboratory values obtained within 24 hours of ED admission. Univariate logistic regression, multivariable logistic regression, and Cox regression were used to assess the influence of DIC scores on vasopressor use (primary outcome), mortality, ventilator requirement, pediatric intensive care unit admission, and hospital duration (secondary outcomes). The optimal DIC score cutoff for outcome prediction was determined.Results: Of 1,653 eligible patients, 284 had DIC scores within 24 hours, including 92 who required vasopressors and 23 who died within one year. An initial DIC score≥3 was the most sensitive and specific DIC score for predicting adverse outcomes. Those with a DIC score ≥3 vs.

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of posttransplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatmentrelated mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/ LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide,

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.

Rab GTPases are critical regulators of protein trafficking in the cell. To ensure proper cellular localization and function, Rab proteins must undergo a posttranslational modification, termed geranylgeranylation. In the isoprenoid biosynthesis pathway, the enzyme geranylgeranyl diphosphate synthase (GGDPS) generates the 20-carbon isoprenoid donor (geranylgeranyl pyrophosphate [GGPP]), which

We describe a Caucasian family with asymptomatic, nonconsanguineous parents, and a daughter with unexplained microcytic anemia diagnosed on routine hemoglobin screening at her 12-month well child check. After failed response to oral and parental iron supplementation, iron refractory iron deficiency anemia was suspected. The family underwent genetic testing and the proband was found to be a compound heterozygote for 2 previously unreported TMPRSS6 variants.

Background Post solid organ transplant Burkitt lymphoma (PSOT-BL) is a rare form of monomorphic post-transplant lymphoproliferative disease (M-PTLD). Outcome data in pediatric patients are limited and guidelines on optimal treatment in PSOT-BL are lacking. Methods Retrospective study and analysis of clinical characteristics, treatment, and outcome data from patients diagnosed with PSOT-BL at age ≤ 21 years (y) in 11 US pediatric transplant centers. Results We identified 28 patients transplanted between 1993-2016 who developed PSOT-BL. Median age at organ transplantation and at diagnosis of PSOT-BL was 2.9y (range, 0.1-14) and 7.5y (range, 7-17), respectively, with median interval from transplant to PSOT-BL diagnosis of 3.8y (range 2-7). Heart and liver were the most frequently transplanted organs (n=14, 11), while bowel, kidney, and lung were each transplanted in one patient. Immunosuppressive therapy at the time of PSOT-BL diagnosis was tacrolimus alone (n=9), or in combination with mycophenolate (n=7), azathioprine (n=6), cyclosporin (n=3), or prednisone (n=3). None were receiving an mTOR inhibitor at time of PSOT-BL diagnosis. Six, twelve, and ten patients corresponded to Murphy stages II, III, and IV, respectively. Lactate dehydrogenase was elevated in 23 patients (82%) and was > 2x upper limit of normal in 14 (50%). All tumors were pathologically consistent with BL; MYC FISH testing was positive in 10/10 tumors tested, while 21/23 tumors (90%) had detectable Epstein Barr Virus. Rituximab-containing regimens were given to 25/28 patients (93%). These treatment regimens were as follows: rituximab alone (n=2), low dose cyclophosphamide, prednisone, and rituximab (CPR) (n=10), Burkitt lymphoma specific therapy: (FAB/LMB chemotherapy (n=3) or FAB/LMB therapy with rituximab (n=8)), reduced dose FAB/LMB (n=2), diffuse large B-cell lymphoma (DLBCL) regimens including EPOCH-R (n=2) and R-CHOP (n=1). Treatment modifications/reductions were infrequent. Methotrexate dose modification and/or omission were required in four patients due to renal dysfunction (n=3) and ascites (n=1). Doxorubicin was electively eliminated in one cardiac transplant recipient due to concern for cardiotoxicity and dose-reduced in another due to prolonged myelosuppression. There was no treatment related mortality. There were two episodes of rejection, one was a liver rejection that was successfully treated without graft loss, the other occurred after achieving partial response (PR) to 3 cycles of CPR, required intensive immune suppression, and was followed by PTLD/DLBCL and death from PTLD progression. There were two additional cases of a second PTLD/DLBCL. One died of PTLD progression nine months after developing a second PTLD and the other is alive in complete remission (CR) 17 months after diagnosis of a second PTLD. Of the two patients treated with rituximab alone, one had no response and the other relapsed. Both were subsequently treated with BL chemotherapy and are alive in CR 15- and 7-years following BL diagnosis, respectively. For all study patients over a median of 6.8y follow-up (range, 0.5-17), 3-year event-free survival (EFS) was 73.5% and 3-year overall survival (OS) was 92.6%, see figure. Three patients died of Burkitt lymphoma (all had been treated with CPR, experienced treatment failure and required treatment escalation to intensive BL chemoimmunotherapy but died of progressive disease). Of the 11 patients who received Burkitt lymphoma intensive therapy, all are alive in CR. One had progressed on treatment but achieved CR with further treatment intensification. Another developed a second PTLD/DLBCL, with subsequent CR. Conclusion This collaborative study represents the largest pediatric series of PSOT-BL reported to date. In this study patients with PSOT-BL treated with intensive BL directed therapy appear to have comparable outcome to immunocompetent pediatric patients with BL. Figure 1 Figure 1. Disclosures Orjuela: ATARA Pharmaceuticals: Other: Scientific Advisory Board.