Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 .

Percutaneous Endoscopic Gastrostomy Placement in Trauma Patients: Early vs Delayed Initiation of Enteral Feeding.

In critically ill trauma patients, adequate nutrition is essential for the body's healing process. Currently, there is no clinical standard for initiating feeds after percutaneous endoscopic gastrostomy (PEG) tube placement. We aimed to demonstrate that early enteral nutrition (EN) is as safe as delayed EN in patients who have undergone PEG tube insertion. We conducted a multi-center, retrospective cohort study of 384 patients from the Prisma Health Trauma Registries who received PEGs. Feeding intolerance was defined as high gastric residuals, nausea, emesis, sustained diarrhea, or ileus. The probability that a patient would experience intolerance was 11.7% in those fed within 6 hours, 5.1% among patients fed between 6 and 12 hours, 6.0% among patients fed between 12 and 24 hours, and 7.6% among patients fed after 24 hours, for which no statistically significant difference was detected. These findings support that early EN after PEG placement is safe in critically ill, trauma patients.

Novel theranostic agent for PET imaging and targeted radiopharmaceutical therapy of tumour-infiltrating immune cells in glioma.

BACKGROUND: Malignant gliomas are deadly tumours with few therapeutic options. Although immunotherapy may be a promising therapeutic strategy for treating gliomas, a significant barrier is the CD11b+ tumour-associated myeloid cells (TAMCs), a heterogeneous glioma infiltrate comprising up to 40% of a glioma's cellular mass that inhibits anti-tumour T-cell function and promotes tumour progression. A theranostic approach uses a single molecule for targeted radiopharmaceutical therapy (TRT) and diagnostic imaging; however, there are few reports of theranostics targeting the tumour microenvironment. METHODS: Utilizing a newly developed bifunctional chelator, Lumi804, an anti-CD11b antibody (αCD11b) was readily labelled with either Zr-89 or Lu-177, yielding functional radiolabelled conjugates for PET, SPECT, and TRT. FINDINGS: 89Zr/177Lu-labeled Lumi804-αCD11b enabled non-invasive imaging of TAMCs in murine gliomas. Additionally, 177Lu-Lumi804-αCD11b treatment reduced TAMC populations in the spleen and tumour and improved the efficacy of checkpoint immunotherapy. INTERPRETATION: 89Zr- and 177Lu-labeled Lumi804-αCD11b may be a promising theranostic pair for monitoring and reducing TAMCs in gliomas to improve immunotherapy responses. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

TIGIT and PD-1 Immune Checkpoint Pathways Are Associated With Patient Outcome and Anti-Tumor Immunity in Glioblastoma.

Glioblastoma (GBM) remains an aggressive brain tumor with a high rate of mortality. Immune checkpoint (IC) molecules are expressed on tumor infiltrating lymphocytes (TILs) and promote T cell exhaustion upon binding to IC ligands expressed by the tumor cells. Interfering with IC pathways with immunotherapy has promoted reactivation of anti-tumor immunity and led to success in several malignancies. However, IC inhibitors have achieved limited success in GBM patients, suggesting that other checkpoint molecules may be involved with suppressing TIL responses. Numerous IC pathways have been described, with current testing of inhibitors underway in multiple clinical trials. Identification of the most promising checkpoint pathways may be useful to guide the future trials for GBM. Here, we analyzed the The Cancer Genome Atlas (TCGA) transcriptomic database and identified PD1 and TIGIT as top putative targets for GBM immunotherapy. Additionally, dual blockade of PD1 and TIGIT improved survival and augmented CD8+ TIL accumulation and functions in a murine GBM model compared with either single agent alone. Furthermore, we demonstrated that this combination immunotherapy affected granulocytic/polymorphonuclear (PMN) myeloid derived suppressor cells (MDSCs) but not monocytic (Mo) MDSCs in in our murine gliomas. Importantly, we showed that suppressive myeloid cells express PD1, PD-L1, and TIGIT-ligands in human GBM tissue, and demonstrated that antigen specific T cell proliferation that is inhibited by immunosuppressive myeloid cells can be restored by TIGIT/PD1 blockade. Our data provide new insights into mechanisms of GBM αPD1/αTIGIT immunotherapy.

Inpatient Antineoplastic Medication Administration And Associated Drug Costs: Institution of a Hospital Policy Limiting Inpatient Administration.

BACKGROUND: Cancer treatment costs are increasing; the global cost of antineoplastic medications rose to $83.7 billion in 2015. As a result, it is imperative for institutions to implement cost-saving strategies and to maximize reimbursement for costly medications such as antineoplastic drugs. OBJECTIVES: Evaluate the necessity and drug costs of administering antineoplastic medications in the inpatient setting and explore savings associated with the 2013 implementation of an institutional policy that defined criteria necessitating inpatient administration of antineoplastic medication. METHODS: We conducted a retrospective chart review of patients receiving inpatient antineoplastic medications during January, April, July, and October of 2010, 2012, 2014, and 2015 at a community teaching hospital. Necessity of chemotherapy administration during the hospital admission was determined based on adherence to institutional policy. RESULTS: Records of 648 patients admitted for chemotherapy were reviewed. The annualized numbers of chemotherapy regimens received during inpatient admission in 2010, 2012, 2014, and 2015 were 537, 618, 369, and 420, respectively. Of all regimens administered in the inpatient setting, 80% in 2010, 78% in 2012, 83% in 2014, and 91% in 2015 met institutional policy criteria for inpatient administration (P = 0.005). The annualized average wholesale price of antineoplastic medications administered to patients that did not meet criteria for inpatient drug administration decreased from $269,049 in 2010 to $105,447 in 2015. A trend in the chemotherapy regimens administered was apparent; only one regimen (carboplatin/paclitaxel), which is relatively inexpensive, was administered to more than 5% of patients in 2015, and all patients receiving monoclonal antibodies in 2015 met criteria for inpatient administration. CONCLUSIONS: Implementation of a policy defining the appropriate criteria necessitating inpatient administration of antineoplastic medications has the potential to decrease the number of inpatient administrations and associated drug costs.

Continuous Intravenous Lidocaine Infusion for the Management of Pain Uncontrolled by Opioid Medications.

Limited data exist describing the outcomes of patients receiving continuous lidocaine infusions. The objective of this study was to evaluate the effect of use of continuous lidocaine infusions for pain management at a community teaching hospital. A retrospective chart review was performed that included adult patients receiving continuous systemic lidocaine infusions for the treatment of pain. Twenty-one patients were included in the analysis. Dosing ranged from 0.25 to 2.8 mg/kg/h, with a median infusion time of 64 hours. Eight patients (38%) experienced a response (≥20% reduction in pain score during the infusion compared with prior to the infusion). Among responding patients, there was a decrease in pain scores at rest after starting lidocaine (compared with prior to lidocaine) (6.5 vs. 3.7, P = .001) that was maintained 24 hours after lidocaine discontinuation. There were no differences in pain scores before, during, or after lidocaine in the entire study sample. A difference in oral morphine equivalent intake was present comparing usage during the infusion vs. day +1 (P = .006) and day +2 (P < .001). Similarly, a difference was present comparing morphine equivalent usage on day -2 with day +2 (P = .008) and day -1 with day +1 (P = .006). Continuous infusions of systemic lidocaine appear to be beneficial in some patients experiencing uncontrolled pain and may improve pain scores while decreasing opioid requirements. Overall beneficial effects of systemic lidocaine may last longer than the infusion itself.