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Background: Treatment of Ewing sarcoma is associated with severe toxicities including chemotherapy-induced mucositis. Here we investigated the role of circulating biomarkers and genetic factors in predicting mucositis severity in Ewing sarcoma. Methods: Blood samples were collected from 111 Ewing sarcoma patients during treatment. Circulating total CK18 and FLT3 ligand concentrations were measured in plasma. Germline DNA was used to investigate associations between genetic variants and mucositis severity. Results: An increase in median tCK18 levels was observed during cycle 1, from 189 (86−736) U/L at cycle 1 day 1 pre-chemotherapy to 311 (141–1138) U/L on cycle 1 day 2–5 (p = 0.0001). Patients experiencing a ≥ 1.3-fold increase in tCK18 at 48–120 hours after administration of the first cycle had a higher likelihood of developing grade 3 mucositis in any cycle (p = 0.044). Genetic analysis revealed an association between a gene set associated with chemotherapy induced severe mucositis and differentially expressed genes set for minor salivary gland (p = 4.12 ×10−4) and esophageal mucosa (p = 1.55 ×10−5). Discussion: Early increases in circulating CK18 levels correlated with grade 3 mucositis. Genome-wide association analysis highlighted genes that may be associated with mucositis pathology, offering insights into biological mechanisms underlying susceptibility.

Abstract: The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies.

Infants and young children represent an important but much understudied childhood cancer patient population. The pharmacokinetics and pharmacogenetics of the widely used anticancer prodrug cyclophosphamide were investigated in children 2 (5–75 mg/kg), with various infusion times as determined by the standard treatment regimen that each patient was receiving. Polymorphisms in genes including CYP2B6 and CYP2C19 were investigated. Data generated for cyclophosphamide were analysed using a previously published population pharmacokinetic model. Cyclophosphamide pharmacokinetics was assessed in 111 samples obtained from 25 patients ranging from 4–23 months of age. The average cyclophosphamide clearance for the patients was 46.6 mL/min/m2 (ranging from 9.4–153 mL/min/m2), with marked inter-patient variability observed (CV 41%). No significant differences in cyclophosphamide clearance or exposure (AUC) were observed between patient groups as separated by age or body weight. However, marked differences in drug clearance and metabolism were noted between the current data in children

Introduction UNAIDS “90‐90‐90” strategy calls for 90% of HIV‐infected individuals to be diagnosed by 2020, 90% of whom will be on anti‐retroviral therapy (ART) and 90% of whom will achieve sustained virologic suppression. Reaching these targets by 2020 will reduce the HIV epidemic to a low‐level endemic disease by 2030. However, moving the global response towards this universal test and treat model will pose huge challenges to public health systems in resource‐limited settings, including global and local supply chain systems. These challenges are especially acute in Africa, which accounts for over 70% of the persons affected by HIV. Discussion From a supply chain perspective, each of the “90's” has possible complications and roadblocks towards realizing the promise envisioned by 90‐90‐90. For instance, ensuring that 90% of HIV‐infected persons know their status will require a large increase in access to HIV tests compared with what is currently available. To ensure that there are enough anti‐retrovirals available to treat the nearly 25 million people that will require them by 2020 represents a near doubling of the ARV supplied to treat the 13 million currently on treatment. Similarly, to monitor those on treatment means an unprecedented scale‐up of viral load testing throughout Africa. Conclusions Larger issues include whether the capacity exists at the local level to handle these commodities when they arrive in the most severely affected countries, including considerations of the human resources and costs needed to make this strategy effective. We believe that such “real world” analysis of proposed strategies and policies is essential to ensure their most effective implementation.