Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKTand PI3K and exhibit activation of mammalian Target of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type. Nanomolar levels of the mTORC1/2 inhibitor TAK228 reduced expression of p-AKTS473 and p-S6S240/244 and suppressed the growth of DIPG lines JHH-DIPG1, SF7761, and SU-DIPG-XIII. TAK228 induced apoptosis in DIPG cells and cooperated with radiation to further block proliferation and enhance apoptosis. TAK228 monotherapy inhibited the tumorigenicity of a murine orthotopic model of DIPG, more than doubling median survival (p=0.0017) versus vehicle. We conclude that dual mTOR inhibition is a promising potential candidate for DIPG treatment.

Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate different aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess GBM invasiveness based on detecting tumor-specific anti-luciferase staining in brain slices, we found that U251-RedFLuc cells are more invasive than U87-luc2 cells. Lastly, we determined expression levels of ABC transporters in both models. Our findings indicate that U87-luc2 and U251-RedFLuc GBM models recapitulate different aspects of GBM heterogeneity that need to be considered in preclinical research.

BackgroundVillage Health and Nutrition Days (VHNDs) are a cornerstone of the Government of India’s strategy to provide first-contact primary health care to rural areas. Recent government programmes such as the Janani Suraksha Yojana (JSY) and Mission Indradhanush (MI) have catalysed important changes impacting VHNDs. To learn how VHNDs are currently being delivered, we assessed the fidelity of services provided as compared to government norms in a priority district of Uttar Pradesh.MethodsWe fielded a cross-sectional study of VHNDs to provide a snapshot of health services functioning. Process evaluation data were collected via administrative sources, non-participant observation using a standardised form, and structured questionnaires. Questionnaires were designed using a framework to assess implementation fidelity. Key respondents were VHND participants, front-line workers involved in VHND delivery, and VHND non-participants (pregnant women due for antenatal care or children due for vaccination as per administrative records). Results were summarised as counts, frequencies, and proportions.ResultsIn the 30 villages randomly selected for inclusion, 36 VHNDs were scheduled but four (11.1%) were cancelled and one VHND was not surveyed. Vaccination and antenatal care were offered at 96.8% (30/31) and child weighing at 83.9% (26/31) of VHNDs. Other normed services were infrequently provided or completely absent. Health education and promotion were particularly weak; institutional delivery was the only topic discussed in a majority of VHNDs. The true proportion of any serious problem impeding vaccine delivery was 47.2% (17/36), comprising 4 VHND cancellations and 13 VHNDs experiencing vaccine shortages. Of the 13 incidents of vaccine shortage, 11 related to an unexpected global shortage of injectable polio vaccine (IPV). Over the 31 VHNDs, 37.8% (171 of the 452 scheduled beneficiaries) did not participate. Analysis of missed opportunities for vaccination highlighted inaccuracies in beneficiary identification and tracking and demand side-factors.ConclusionsThe transformative potential of VHNDs to improve population health is only partially being met. A core subset of high-priority services for antenatal care, institutional delivery, and vaccination associated with high-priority government programmes (JSY, MI) is now being provided quite successfully. Other basic health promotion and prevention services are largely not provided, constituting a critical missed opportunity.

The blood-brain barrier (BBB) limits entry of most chemotherapeutic agents into the CNS, resulting in inadequate exposure within CNS tumor tissue. Intranasal administration is a proposed means of delivery that can bypass the BBB, potentially resulting in more effective chemotherapeutic exposure at the tumor site. The objective of this study was to evaluate the feasibility and pharmacokinetics (plasma and CSF) of intranasal delivery using select chemotherapeutic agents in a non-human primate (NHP) model. Three chemotherapeutic agents with known differences in CNS penetration were selected for intranasal administration in a NHP model to determine proof of principle of CNS delivery, assess tolerability and feasibility, and to evaluate whether certain drug characteristics were associated with increased CNS exposure. Intravenous (IV) temozolomide (TMZ), oral (PO) valproic acid, and PO perifosine were administered to adult male rhesus macaques. The animals received a single dose of each agent systemically and intranasally in separate experiments, with each animal acting as his own control. The dose of the agents administered systemically was the human equivalent of a clinically appropriate dose, while the intranasal dose was the maximum achievable dose based on the volume limitation of 1 mL. Multiple serial paired plasma and CSF samples were collected and quantified using a validated uHPLC/tandem mass spectrometry assay after each drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis. CSF penetration was calculated from the ratio of areas under the concentration-time curves for CSF and plasma (AUC). Intranasal administration was feasible and tolerable for all agents with no significant toxicities observed. For TMZ, the degrees of CSF drug penetration after intranasal and IV administration were 36 (32-57) and 22 (20-41)%, respectively. Although maximum TMZ drug concentration in the CSF (C) was lower after intranasal delivery compared to IV administration due to the lower dose administered, clinically significant exposure was achieved in the CSF after intranasal administration with the lower doses. This was associated with lower systemic exposure, suggesting increased efficiency and potentially lower toxicities of TMZ after intranasal delivery. For valproic acid and perifosine, CSF penetration after intranasal delivery was similar to systemic administration. Although this study demonstrates feasibility and safety of intranasal drug administration, further agent-specific studies are necessary to optimize agent selection and dosing to achieve clinically-relevant CSF exposures.

Simulations predicted lower steady-state peak/trough olaparib exposure through 24-36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.

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Purpose-Diffuse intrinsic pontine glioma (DIPG) is one of the deadliest forms of childhood cancers. To date, no effective treatment options have been developed. Recent drug screening studies identified the HDAC inhibitor panobinostat as an active agent against DIPG cells lines and animal models. To guide in the clinical development of panobinostat, we evaluated the CNS pharmacokinetics of panobinostat using CSF as a surrogate to CNS tissue penetration in a pre-clinical nonhuman primate (NHP) model after oral administration.Methods-Panobinostat was administered orally to NHP (n = 3) at doses 1.0, 1.8, 2.4, and 3.0 mg/kg (human equivalent dose: 20, 36, 48, 60 mg/m 2 , respectively). The subjects served as their own controls where possible. Serial, paired CSF and plasma samples were collected for 0-48 h. Panobinostat was quantified via a validated uHPLC-MS/MS method. Pharmacokinetic (PK) parameters were calculated using non-compartmental methods.Results-CSF penetration of panobinostat after systemic delivery was low, with levels detectable in only two subjects. Conclusion-The CSF penetration of panobinostat was low following oral administration in this pre-clinical NHP model predictive of human PK.

Introduction Autologous fat grafting (AFG) is a popular and effective method of breast reconstruction after mastectomy; however, the oncological safety of AFG remains in question. The aim of this study was to determine whether AFG increases the risk of cancer recurrence in the reconstructed breast. Methods A matched, case-control study was conducted from 2000 to 2017 at the senior author's institution. Inclusion was limited to female patients who underwent mastectomy and breast reconstruction with or without AFG. Data were further subdivided at the breast level. χ2 analyses were used to test the association between AFG status and oncologic recurrence. A Cox proportional-hazards model was constructed to assess for possible differences in time to oncologic recurrence. The probability of recurrence was determined by Kaplan-Meier analyses and confirmed with log-rank testing. Results Overall, 428 breasts met study criteria. Of those, 116 breasts (27.1%) received AFG, whereas 312 (72.9%) did not. No differences in the rates of oncologic recurrence were found between the groups (8.2% vs 9.0%, P < 1.000). Unadjusted (hazard ratio = 1.03, confidence interval = 0.41–2.60, P < 0.957) and adjusted hazard models showed no statistically significant increase in time to oncologic recurrence when comparing AFG to non-AFG. In addition, no statistical differences in disease-free survival were found (P = 0.96 by log rank test). Conclusion Autologous fat grafting for breast reconstruction is oncologically safe and does not increase the likelihood of oncologic recurrence. Larger studies (eg, meta analyses) with longer follow-up are needed to further elucidate the long-term safety of AFG as a reconstructive adjunct.