To support the global restart of elective surgery, data from an international prospective cohort study of 8492 patients (69 countries) was analysed using artificial intelligence (machine learning techniques) to develop a predictive score for mortality in surgical patients with SARS-CoV-2. We found that patient rather than operation factors were the best predictors and used these to create the COVIDsurg Mortality Score (https://covidsurgrisk.app). Our data demonstrates that it is safe to restart a wide range of surgical services for selected patients.

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The lack of clinical response to the alkylating agent temozolomide (TMZ) in pediatric diffuse midline/intrinsic pontine glioma (DIPG) has been associated with O 6 -methylguanine-DNA-methyltransferase (MGMT) expression and mismatch repair deficiency. Hence, a potent N(3)propargyl analogue (N3P) was derived, which not only evades MGMT but also remains effective in mismatch repair deficient cells. Due to the poor pharmacokinetic profile of N3P (t 1/2 < 1 h) and to bypass the blood−brain barrier, we proposed convection enhanced delivery (CED) as a method of administration to decrease dose and systemic toxicity. Moreover, to enhance N3P solubility, stability, and sustained distribution in vivo, either it was incorporated into an apoferritin (AFt) nanocage or its sulfobutyl ether β-cyclodextrin complex was loaded into nanoliposomes (Lip). The resultant AFt-N3P and Lip-N3P nanoparticles (NPs) had hydrodynamic diameters of 14 vs 93 nm, icosahedral vs spherical morphology, negative surface charge (−17 vs −34 mV), and encapsulating ∼630 vs ∼21000 N3P molecules per NP, respectively. Both NPs showed a sustained release profile and instant uptake within 1 h incubation in vitro. In comparison to the naked drug, N3P NPs demonstrated stronger anticancer efficacy against 2D TMZ-resistant DIPG cell cultures [IC 50 = 14.6 (Lip-N3P) vs 32.8 μM (N3P); DIPG-IV) and (IC 50 = 101.8 (AFt-N3P) vs 111.9 μM (N3P); DIPG-VI)]. Likewise, both N3P-NPs significantly (P < 0.01) inhibited 3D spheroid growth compared to the native N3P in MGMT + DIPG-VI (100 μM) and mismatch repair deficient DIPG-XIX (50 μM) cultures. Interestingly, the potency of TMZ was remarkably enhanced when encapsulated in AFt NPs against DIPG-IV, -VI, and -XIX spheroid cultures. Dynamic PET scans of CED-administered zirconium-89 ( 89 Zr)-labeled AFt-NPs in rats also demonstrated substantial enhancement over free 89 Zr radionuclide in terms of localized distribution kinetics and retention within the brain parenchyma. Overall, both NP formulations of N3P represent promising approaches for treatment of TMZ-resistant DIPG and merit the next phase of preclinical evaluation.

Treatment failure in DIPG is in part due to poor CNS penetration of systemic chemotherapy at non-toxic doses. Convection-enhanced delivery (CED) of carboplatin to the paediatric brainstem through surgically placed microcatheters overcomes the limitations of systemic treatment. Carboplatin is cytotoxic to ex-vivo patient derived DIPG cells in vitro in a dose-dependant manner, with calculated area under the concentration/time curve values (AUC-50) of 4.18 -58.9 mg/ml x min after a 360 minute drug exposure. This AUC can be achieved with direct intra-tumoural infusion of drug, but would be toxic at corresponding systemic doses. 8 children (ages 4-12 years) have been treated in a compassionate treatment program of carboplatin CED for radiological or biopsy proven DIPG using a multi-catheter intermittent regime of carboplatin CED via a bone anchored transcutaneous port. All children underwent robot-assisted stereotactic MRI guided implantation of 4 recessed step catheters using trans-frontal and trans-cerebellar trajectories. Carboplatin at a concentration of 0.18mg/ml was infused on two consecutive days for up to 9 cycles in an intermittent regime. Infusions were well tolerated. Neurological side effects due to the infusion and drug were seen most commonly during the first cycle of treatment and resolved before further infusions. Survival has exceeded 15 months from diagnosis in 3 patients. 7 of the 8 children treated remain alive and 6 continue to receive therapy. CED of carboplatin to the paediatric brainstem is well tolerated and could potentially represent a paradigm shift in the treatment of DIPG. A phase II clinical trial is planned.