Search

Inpatient medication order verification is an important skill for pharmacy students to learn for patient safety. This article describes a systematic approach to order verification that enables students to apply didactic knowledge and determine the presence of drug therapy problems during verification decisions.At two different colleges of pharmacy, an order verification module for second-year pharmacy students introduced a checklist for reviewing medication orders in a patient chart and identifying the presence of drug therapy problems. Students had to make a "verify or not" decision for each non-verified order and document their decision in both the chart and on a game-based learning platform.Over four academic years, 756 students participated in the module. With the checklist approach to order verification, students were able to identify the drug therapy problems of "dose too high" and "no drug therapy problem present" but were challenged by "wrong drug," "dose too low/renal dosing," and "duplication of therapy."The order verification checklist was a beneficial tool for teaching a systematic approach to inpatient medication order verification.

This study determined the safety and Recommended Phase 2 Dose (RP2D) of the multi-kinase inhibitor cabozantinib in combination with trifluridine/tipiracil (TFT/TPI) in refractory metastatic colorectal carcinoma (mCRC). Single institution investigator-initiated phase 1 study using 3 + 3 design. Eligible mCRC patients had received prior standard regimens. Cabozantinib was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1–28, and FTD/TPI p.o. at 35 mg/m2 on days 1–5 and 8–12 every 28 days. Fifteen patients were enrolled. Median age 56 years (31–80), male (12/15), ECOG 0/1 = 9/6. Three patients were treated at DL 0 and another nine were treated at DL 1, none exhibiting a DLT. Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%) and rash (25%). G3-4 TRAE were neutropenia (25%) and thrombocytopenia, hypokalemia, weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS was 3.8 months (95% CI 1.9–6.8) and disease control rate was 86.7%. The combination of cabozantinib and TFT/TPI is feasible and tolerable at standard doses and showed encouraging clinical activity in refractory mCRC. ClinicalTrials.Gov: NCT04868773

PDF - 140K, Characteristics of Placebo. In this section, estimates are given for the molar concentrations of certain compounds in BBIC and the Masa Harina placebo in the mouth and in the body of the oral leukoplakia patients.

PDF - 59K, Analysis of Sample Size if Placebo was 30 percent. Point one: formerly studies were powered anticipating a response rate in the placebo of about 10%. Power estimates for our Phase IIB study were performed by the dose-response observed in our preceding, single-arm, Phase IIA trial(4) In the IIA study response rate (PR+CR) at the lowest dose (200CIU) was 12.5 percent (1 out of 8 participants).

PDF - 54K, Stability of Drug Potency over Time. An interim, blinded analysis on the relative percent change in total lesion area, performed when roughly half of the desired subjects were accrued and presented to an independent board, had shown some promise of a positive final result.

PDF - 53K, Clinical Impression from Photographs. Across study arms, 91 participants had evaluable photo pairs: 45 in the drug arm and 46 in the placebo arm

PDF - 56K, Lipid Analysis in Study Patients. Cholesterol, Lipids, AML, and Triglycerides Summary of Levels Pre and Post Treatment for Those with Readings at Both Times

PDF - 59K, Summary of Adverse Events. There were 322 case-report forms on adverse events from the 132 randomized patients. Of these 322, 147 were blank or listed only "None," "Not Applicable," "No Complaints" and the like. These were set aside, as were a further 37 reports dated before the subject was randomized. The number of adverse-event reports from the 132 randomized subjects dated on or after randomization was 138.

Background Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival. Methods Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration. Results Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%. Conclusions AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted. Trial registration NCT, NCT03400917, Registered 10 January 2018

Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival.Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration.Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%.AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted.NCT, NCT03400917 , Registered 10 January 2018.

Current guidelines recommend neoadjuvant (NAC) and/or adjuvant chemotherapy for locally advanced gastric cancers (LAGCs). However, the choice and duration of NAC regimen is standardized, rather than personalized to biologic response, despite the availability of several different classes of agents for the treatment of gastric cancer (GC). The current trial will use a tumor-informed ctDNA assay (Signatera™) and monitor response to NAC. Based on ctDNA kinetics, the treatment regimen is modified. This is a prospective single center, single-arm, open-label study in clinical stage IB-III GC. ctDNA is measured at baseline and repeated every 8 weeks. Imaging is performed at the same intervals. The primary end point is the feasibility of this approach, defined as percentage of patients completing gastrectomy.

BackgroundGlioblastoma (GBM) is the most common primary, malignant brain tumor in adults and has a poor prognosis. The median progression-free survival (mPFS) of newly diagnosed GBM is approximately 6 months. The recurrence rate approaches 100%, and the case-fatality ratio approaches one. Half the patients die within 8 months of recurrence, and 5-year survival is less than 10%. Advances in treatment options are urgently needed. We report on the efficacy and safety of a therapeutic vaccine (SITOIGANAP: Epitopoietic Research Corporation) administered to 21 patients with recurrent GBM (rGBM) under a Right-to-Try/Expanded Access program. SITOIGANAP is composed of both autologous and allogeneic tumor cells and lysates.MethodsTwenty-one patients with rGBM received SITOIGANAP on 28-day cycles in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), cyclophosphamide, bevacizumab, and an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody (either nivolumab or pembrolizumab).ResultsThe mPFS was 9.14 months, and the median overall survival (mOS) was 19.63 months from protocol entry. Currently, 14 patients (67%) are at least 6 months past their first SITOIGANAP cycle; 10 patients (48%) have received at least six cycles and have a mOS of 30.64 months and 1-year survival of 90%. The enrollment and end-of-study CD3+/CD4+ T-lymphocyte counts strongly correlate with OS.ConclusionsThe addition of SITOIGANAP/GM-CSF/cyclophosphamide to bevacizumab and an anti-PD-1 monoclonal antibody resulted in a significant survival benefit compared to historic control values in rGBM with minimal toxicity compared to current therapy.

TAS-102 is approved for treatment of refractory metastatic gastroesophageal carcinoma (mGEC). This study sought to determine whether the combination of TAS-102 with irinotecan (TASIRI) was safe and effective in previously treated mGEC. This was a single-arm phase 1b study for patients (pts) with mGEC previously treated with at least one line of fluoropyrimidine and platinum-containing regimen. TAS-102 was given at 25mg/m2 twice daily on days 1 to 5 with irinotecan 180mg/m2 on day 1 of a 14-day cycle. The primary endpoint was progression-free survival at 6months ≥ 35% (PFS-6). 20 Pts were enrolled. The study met its primary endpoint. PFS-6 is 40% (95% CI 19.3-60.0). Median PFS and overall survival are 5.3months and not reached, respectively. 17 of 20 pts had measurable disease by RECIST criteria. Of the 17, 13 had stable disease and 4 had progressive disease as best response (8 pts had tumor shrinkage 5% of pts were anemia (20%) and neutropenia (10%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls.

Asthma self-management can improve symptom control, but adherence to established self-management behaviors is often poor. With adult asthma uncontrolled in over 60% of U.S. cases, there is a need for scalable, cost-effective tools to improve asthma outcomes. Here we describe a protocol for the Asthma Digital Study, a 24-month, decentralized, pragmatic, open-label, randomized controlled trial investigating the impact of a digital asthma self-management (DASM) program on asthma outcomes in adults. The program leverages consumer-grade devices with a smartphone app to provide "smart nudges," symptom logging, trigger tracking, and other features. Participants are recruited (target N = 900) from throughout the U.S., and randomized to a DASM or control arm (1:1). Co-primary outcomes at one year are a) asthma-associated costs for acute care and b) change from baseline in Asthma Control Test™ scores. Findings may inform decisions around adoption of digital tools for asthma self-management. Trial registration:clinicaltrials.gov identifier: NCT04609644. Registered: Oct 30, 2020.

After potentially curative treatment, colorectal cancer (CRC) patients remain at high risk for recurrence, second primary CRC, and high-risk adenomas. In combination with existing data, our previous findings provide a rationale for reducing tissue polyamines as tertiary prevention in non-metastatic CRC patients. The goal of this study was to demonstrate rectal tissue polyamine reduction in optimally treated stage I-III CRC patients after intervention with daily oral aspirin + dietary arginine restriction. A single-institution phase IIa clinical trial was conducted. Patients were treated with aspirin 325 mg/day and an individualized dietary regimen designed to reduce arginine intake by ≥30% over a 12-week study period. Dietary intake, endoscopy with rectal biopsies, and phlebotomy were performed pre- and post-intervention. The primary endpoint was to demonstrate ≥50% decrease in rectal tissue putrescine levels from baseline as a measure of polyamine reduction in the target tissue. Twenty eligible patients completed the study. After study intervention, mean dietary arginine intake decreased from 3.7 g/day ± 1.3 SD to 2.6 g/day ± 1.2 SD (29.7% decrease, p < 0.02 by Sign test). Mean plasma arginine levels decreased from 46.0 ng/mL ± 31.5 SD at baseline to 35 ng/mL ± 21.7 SD (p < 0.001). Rectal tissue putrescine levels were 0.90 nMol/mg-protein pre-intervention and 0.99 nMol/mg-protein post-intervention (p < 0.64, NS). No significant differences were observed for the other tissue polyamines investigated: spermidine (p < 0.13), spermine (p < 0.21), spermidine:spermine ratio (p < 0.71). Among CRC survivors, treatment with daily oral aspirin and an individualized dietary arginine restriction intervention resulted in lower calculated dietary arginine intake and plasma arginine levels but did not affect rectal tissue polyamine levels.

345 Background: Most mGEA patients (pt) progress on therapy including ICI, with about 5% progression-free at 6mo (PFS-6) with single agent ICI in later lines of therapy. Alternative therapeutic approaches are needed. Cabo is a multi-tyrosine kinase inhibitor which might modulate immunosuppression in the tumor microenvironment. This study reports on safety and efficacy of the combination of Cabo+Pembro in mGEA refractory to ICI. Methods: Investigator-initiated, single‐arm, two-stage, single institution, phase 2 study in pts with mGEA after ≥1L of fluoropyrimidine and platinum-containing regimens. Additionally, pts with a PD-L1 CPS score ≥10% had also progressed on ICI. Cabo dose was 40mg p.o. daily on days 1 through 21 of a 21‐day cycle, with Pembro 200 mg i.v. on day 1. The primary endpoint was PFS-6, with H0=5%, Ha≥20%. Stage one results (n=19) exceeded the futility threshold. The complete design requires 27 evaluable pts and n≥4 pts with PFS-6 to reject H0 in favor of Ha. Results: 25 pts are currently enrolled. Because stage one did not signal futility, enrollment continues. Median age 58 years (24-75), female (n=13), ECOG 0/1= 13/12, GC/GEJ= 14/11, Caucasian/Hispanic/Asian/other = 7/7/8/3. After a median follow-up of 5.1mo (1.2-24.6), the median PFS and OS are 2.9mo (95% CI 2.1-4.6) and 9.5mo (95% CI 3.1-14.6), respectively. 11/25 had disease progression on or before the first imaging timepoint at 8 weeks, i.e. the clinical benefit rate is 56% (14/25). 13/20 pts had measurable disease by RECISTv1.1: PR 1(7.7%), SD 7(41.2%), PD 5(38.5%). The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (28%), fatigue (20%), and hypertension (16%). G3-4 TRAE were seen in n=3 pts (Hypertension, Thromboembolic event, esophageal perforation; each n=1). No G5 were reported. Conclusions: In this interim analysis of this ongoing study, the combination of Cabo+Pembro shows promising clinical benefit with an estimated OS of 9.5mo in mGEA pts resistant to prior ICI. Follow-up of the primary endpoint is ongoing. The regimen appears tolerable with no new safety signals. More mature data including the primary endpoint and correlative studies will be presented at the meeting. Clinical trial information: NCT04164979 .

98 Background: Salvage treatments for refractory mCRC are an unmet need. This study determined the safety and Recommended Phase 2 Dose (RP2D) of the multi-kinase inhibitor Cabo in combination with FDT/TPI in mCRC. Methods: Single institution investigator-initiated phase 1 study using 3+3 design. Patients (pts) with mCRC previously treated with a fluoropyrimidine, oxaliplatin, irinotecan and appropriate biologics were eligible. Cabo was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth factors were allowed. The primary endpoint was Dose Limiting Toxicity (DLT) at 28 days. Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate and CEA response. Results: 12 pts were enrolled. Median age 57 years (31-80), male (9/12), ECOG 0/1 = 7/5, Caucasian/Hispanic/Asian = 7/4/1. 3 pts were treated at DL 0 with no observed DLT. Another 9 pts (n = 6 pts to determine RPD2 and additional n = 3 pts in expansion) were treated at DL 1, none exhibiting a DLT. The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%) and rash (25%). G3-4 TRAE in > 5% of patients were neutropenia (25%) and thrombocytopenia, hypokalemia, weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS and OS were 4.1 (95% CI 1.9-6.8) and 6.7 (95% CI 2.2-not evaluable) months, respectively. The disease control rate was 75%. 5/12 (42%) pts had a CEA decline > 30%. Conclusions: The combination of Cabo and FTD/TPI is feasible and tolerable and showed encouraging clinical activity in refractory mCRC. Additional pts are being enrolled at DL 1 and will be presented at the meeting. Clinical trial information: NCT04868773 .

In primary glioblastoma (GBM), overall survival (OS) is poor despite standard aggressive therapy. Adjunctive AV-GBM-1 vaccine immunotherapy may improve OS. In this multi-institutional phase II trial, key eligibility criteria for intent-to-treat (ITT) enrollment were: (1) primary GBM, (2) age < 70 years when GBM was resected, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, (5) KPS > 70 post-surgery, and (6) plan to treat with concurrent RT/TMZ. Dendritic cells (DC) were differentiated from monocytes by culturing in IL-4 and granulocyte-macrophage colony stimulating factor (GM-CSF). AV-GBM-1 consisted of autologous DC incubated with autologous tumor antigens contained in the lysate of irradiated cultured GBM cells. After recovery from RT/TMZ, doses were admixed with 500 mcg GM-CSF; up to 8 doses were injected subcutaneously over 6 months. Patients were not excluded by apparent progression or pseudo-progression post RT/TMZ. OS and progression-free-survival (PFS) were calculated from ITT enrollment. The success rate was 97% for both GBM cell cultures and collection of monocytes; 60/60 vaccines were successfully manufactured. Median age was 59 years. 57 patients received 392 injections. After two weekly injections there were significant increases in plasma lipocalin-2 and angiopoietin-1, and decreases in thrombospondin-5, angiotensinogen, and beta-fibroblast growth factor. The most common adverse events attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). With follow up from 15.2 to 32 months, median PFS and OS were 10.3 (8.5,11.6 95% CI) and 16.0 (13.0,21.3 95% CI) months respectively. OS was better in the 25 patients who had methylguanine-methyltransferase (MGMT) methylation and/or isocitrate dehydrogenase (IDH) mutation. Age was not independently correlated with survival. From date of first injection, OS was not increased in 14 patients who were treated with alternating electrical tumor-treating fields. CONCLUSION: feasibility, safety, and PFS were encouraging. A phase III trial is in development. Clinicaltrials.gov NCT03400917.

BackgroundStandard therapy of glioblastoma (GBM), which includes maximum safe resection, concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ) followed by maintenance TMZ, is associated with poor overall survival (OS). Adding treatment with AV-GBM-1, a vaccine consisting of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA) may improve OS. A multi-center phase II clinical trial was conducted to determine feasibility, safety, and efficacy of AV-GBM-1.MethodsKey eligibility criteria for tumor collection were clinical suspicion of newly diagnosed GBM and age 18 to 70 years at the time of surgery. Prior to starting RT/TMZ, key eligibility criteria for intent-to-treat-with-AV-GBM-1 enrollment were: (1) primary GBM confirmed, (2) successful GBM cell culture, (3) collection of sufficient numbers of monocytes (MC) by leukapheresis, (4) Karnofsky Performance Status 70 or greater and (5) plan to treat with concurrent RT/TMZ. AV-GBM-1 was manufactured during RT/TMZ. Interleukin-4 and granulocyte-macrophage colony stimulating factor (GM-CSF) were used to differentiate MC into DC. AV-GBM-1 consists of autologous DC incubated with ATA from the lysate of irradiated GBM cells grown in serum-free media with factors that favor the survival and proliferation of stem cells and early progenitor cells. After recovery from RT/TMZ, over six months patients received up to 8 subcutaneous injections of AV-GBM-1 admixed with 500 μg GM-CSF. The primary objective was to determine if OS was 75% or higher 14.6 months from ITT enrollment, which ended January 2020. The minimum follow-up at the time of analysis was 15.2 months. Secondary endpoints included progression-free survival (PDS) from ITT enrollment and from the first injection.ResultsSuccess rates for cell cultures and sufficient monocyte collections were both 97%. AV-GBM-1 was manufactured for 60/60 (100%). 57 patients received 392 injections; 68% received all 8. The primary adverse events (AE) attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Progression-free survival (PFS) from ITT enrollment is 10.3 months, about 50% longer than reported in four randomized trials with comparable standard therapy arms. PFS from the first injection is 8.3 months, which is 51% and 107% longer than reported in two randomized trials with comparable standard therapy arms. OS was 72% at 12 months, but dropped to 54% at 14.6 months; median OS is 16.0 months.ConclusionsPatent-specific AV-GBM-1 was reliably manufactured and distributed for administration. AV-GBM-1 produced minimal toxicity. PFS was very encouraging but did not translate into OS, perhaps because of discontinuation of treatment after 8 months.Trial Registration[Clinicaltrials.gov NCT03400917]Ethics ApprovalWestern IRB, approval number 20182582Consent n/a

BackgroundStandard aggressive therapy of glioblastoma (GBM), which includes maximum safe resection, concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ) followed by maintenance TMZ, is associated with a 25% 2-year overall survival (OS). Adding treatment with AV-GBM-1, a vaccine consisting of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA) may improve OS by inducing and/or enhancing the host anti-GBM immune response. Methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter, and mutation of the gene for isocitrate dehydrogenase (IDH) are favorable prognostic markers in newly diagnosed GBM. An objective of a multi-center phase II clinical trial was to determine whether these markers were still prognostic for OS in patients treated with adjunctive AV-GBM-1.MethodsKey eligibility criteria for intent-to-treat (ITT) enrollment were: (1) confirmation of primary GBM, (2) successful GBM cell culture, (3) collection of sufficient numbers of monocytes (MC) by leukapheresis, (4) Karnofsky Performance Status 70 or greater after recovery from surgery, and (5) plan to treat with concurrent RT/TMZ. AV-GBM-1 was manufactured while patients were being treated with RT/TMZ. Interleukin-4 and granulocyte-macrophage colony stimulating factor (GM-CSF) were used to differentiate DC from MC. Each vaccine consisted of autologous DC incubated with ATA from the lysate of irradiated cultured GBM cells grown in serum-free media with factors that favor survival and proliferation of stem cells and early progenitor cells (tumor-initiating cells). After recovery from RT/TMZ, intent was to vaccinate for up to six months with cryopreserved AV-GBM-1 admixed with 500 mg GM-CSF. All patients had testing for MGMT-methylation and IDH-mutation. OS was calculated from date of ITT enrollment.Results60 patients were enrolled during August 2018 to January 2020. MGMT promoter methylation was detected in 21 (35%), mutated IDH in 7 (12%), and one or both in 25 (42%). At a minimum follow-up of 15 months, median OS had not been reached for patients with a methylated MGMT promotor, IDH mutation, or one or both, compared to 14.6 months for 38 with unmethylated MGMT promotor (p=0.026), 14.7 months for 53 with IDH wild-type (p=0.044), and 14.6 months for 35 who had neither (p=0.017). 18-month OS rates were 59% vs 35% for MGMT promotor methylation, 71% vs 40% for IDH mutation and 58% vs 32% for either.ConclusionsBoth MGMT promotor methylation and IDH mutation were associated with a substantial and similar survival benefit in primary GBM patients treated with AV-GBM-1 in addition to standard aggressive therapy.Trial RegistrationClinicaltrialsgov NCT03400917Ethics ApprovalThis study was approved by the Western IRB, approval number 20182582; all participants gave written informed consent before taking part

Earlier detection of lung cancer is possible, but difficult and costly to achieve. Screening with Low Dose Computed Tomography (LDCT)scanning has been shown to reduce mortality by 20-25% over the past decade but uptake amongst those most likely to suffer the disease has been slow. Resource constraints and a high false positive rate have also limited adoption of LDCT in many health systems. Targeted screening of people most likely to benefit using a range of biomarkers may be one way to improve the yield and reduce the resource requirements of LDCT. Autoantibodies, which amplify the signal produced by cancer derived proteins, are present in the blood of people mounting an immune response to cancer are a potential way to select those at highest risk. We have followed up 12 208 people enrolled in the ECLS trial for three years and shown that the specificity for early stage (I &II) disease is 90.3% throughout that period. More cancers were detected in the control than the intervention arm of the trial (101V 83). Sensitivity was 77.8% after 6 months and dropped to 46.4% after 3 years. At the end of three years the hazard ratios (95%CI) for All Cause, Cancer Specific and Lung Cancer Mortality was 0.82(0.67-1.01), 0.72(0.54-0.97) and 0.70(0.46-1.08) respectively for those randomised to Early CDT testing. As a range of treatment modalities become increasingly more effective it is even more important to target LDCT on those most likely to have early stage disease. Autoantibody testing may be one method of targeting early detection on those most likely to benefit.

Importance and objective The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. Design Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. Setting 5 VA Medical Centers. Participants Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. Interventions Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. Main outcomes and measures The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. Results Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. Conclusions and relevance This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. Trial registration Clinicaltrials.gov—NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.

Background Risk assessment of patients with acute COVID-19 in a telemedicine context is not well described. In settings of large numbers of patients, a risk assessment tool may guide resource allocation not only for patient care but also for maximum health care and public health benefit. Objective The goal of this study was to determine whether a COVID-19 telemedicine risk assessment tool accurately predicts hospitalizations. Methods We conducted a retrospective study of a COVID-19 telemedicine home monitoring program serving health care workers and the community in Atlanta, Georgia, with enrollment from March 24 to May 26, 2020; the final call range was from March 27 to June 19, 2020. All patients were assessed by medical providers using an institutional COVID-19 risk assessment tool designating patients as Tier 1 (low risk for hospitalization), Tier 2 (intermediate risk for hospitalization), or Tier 3 (high risk for hospitalization). Patients were followed with regular telephone calls to an endpoint of improvement or hospitalization. Using survival analysis by Cox regression with days to hospitalization as the metric, we analyzed the performance of the risk tiers and explored individual patient factors associated with risk of hospitalization. Results Providers using the risk assessment rubric assigned 496 outpatients to tiers: Tier 1, 237 out of 496 (47.8%); Tier 2, 185 out of 496 (37.3%); and Tier 3, 74 out of 496 (14.9%). Subsequent hospitalizations numbered 3 out of 237 (1.3%) for Tier 1, 15 out of 185 (8.1%) for Tier 2, and 17 out of 74 (23%) for Tier 3. From a Cox regression model with age of 60 years or older, gender, and reported obesity as covariates, the adjusted hazard ratios for hospitalization using Tier 1 as reference were 3.74 (95% CI 1.06-13.27; P=.04) for Tier 2 and 10.87 (95% CI 3.09-38.27; P Conclusions A telemedicine risk assessment tool prospectively applied to an outpatient population with COVID-19 identified populations with low, intermediate, and high risk of hospitalization.

Introduction Many patients with mild coronavirus disease 2019 (COVID-19) have symptoms requiring acute and follow-up care. The aims of this study were to assess (1) provider-reported use of medications and their perceived effectiveness and (2) degree of difficulty managing specific symptoms at episodic COVID-19 care sites and in a longitudinal monitoring program. Methods We sent an online survey to physicians, advanced practice providers, and registered nurses redeployed to COVID-19 care sites at an academic medical center from March to May 2020. We asked about the use of medications and perceived effectiveness of medications to treat symptoms of COVID-19 and the perceived challenge of symptom management. Comparison was made by provider type (episodic or longitudinal site of care). Results Responses from 64 providers were included. The most frequently used medications were acetaminophen (87.1% of respondents), benzonatate (83.9%), and albuterol metered dose inhalers (MDI) (80.6%). Therapies for lower respiratory tract symptoms were reported as more commonly used by longitudinal follow-up providers compared to episodic providers including guaifenesin (90.6% vs 60.0%, p = 0.007), benzonatate (93.8% vs 73.3%, p = 0.04), nebulized albuterol for patients with asthma (75.0% vs 43.3%, p = 0.019), and albuterol MDIs for patients without asthma (90.6% vs 66.7%, p = 0.029). Medications found to have the highest perceived efficacy by respondents using the therapy (> 80% reporting “very efficacious”) included albuterol, acetaminophen for fever, non-sedating antihistamines, nasal steroid spray, and non-steroidal anti-inflammatory drugs (NSAIDs) for myalgia, arthralgia, or headache. Lower respiratory symptoms and anxiety were rated as the most challenging symptoms to manage. Conclusions Providers reported that clinical care of mild COVID-19 with medications in common use for other respiratory infections is effective, both at episodic care and longitudinal sites of care, but that specific symptoms are still challenging to manage. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00432-8.

Author(s): Bota, Daniela; Taylor, Thomas; Kong, Xiao-Tang; Fu, Beverly; Hsu, Frank; Strik, Ankie; Schijns, Virgil; Stathopoulos, Apostolos | Abstract: Abstract ERC1671 is an allogeneic/autologous therapeutic vaccine – composed of whole, inactivated tumor cells mixed with tumor- cell lysates. The hypothesized action of ERC1671 is to potentiate the patients’ immune system against the tumor. Goals of this ongoing, phase 2 study are to determine the safety and effectiveness (overall survival) of ERC1671 in combination with GM-CSF and cyclophosphamide as an add-on treatment to bevacizumab at the time of GBM recurrence. To date 22 recurrent bevacizumab-naive rGBM patients have been randomized to ERC1671/GM-CSF/Cyclophosphamide + Bevacizumab or Placebo + Bevacizumab. Median age is 56.5 (33–74), 7 patients (32%) are female, and average KPS is 82.3 (70–100). Of the 22, two discontinued before completing one cycle of therapy and two remain on blinded treatment. Currently 18 patients are unblinded due to further progression: 8 were on vaccine and 10 on placebo. Five of those on placebo crossed to vaccine at progression. All but one of the 18 are now deceased. Median overall survival of unblinded patients randomized to ERC1671 + Bevacizumab (n = 8) is 264.5 days from the start of study treatment, compared to 182 days for those randomized to placebo + Bevacizumab who did not cross over (n = 5). Median overall survival of unblinded patients on vaccine at randomization or crossover is 328 days after first study treatment (n = 13). While sparse, the data to date suggest pre-treatment and maximal CD4+T lymphocyte count in the peripheral blood correlate with OS more strongly in the ERC1671 group than in the placebo group. First clinical results for toxicity show no difference in the distribution of AEs between the Vaccine and Placebo groups, with no Gr4/Gr5 AEs in either group. This phase 2 randomized, double-blinded study is ongoing, with the addition of one more site.

Author(s): Bota, Daniela; Piccioni, David; LaRocca, R; Duma, Christopher; Kesari, Santosh; Carrillo, Jose; O’Donnell, Robert T; Aiken, Robert; Hsu, Frank; Kong, Xiao-Tang; Hsieh, Candace; Langford, Chris; Carta, Krystal; Wang, Adrienne; Langford, James; Taylor, Thomas; Nistor, Gabriel; Dillman, Robert | Abstract: Abstract GBM standard treatment is associated with poor survival. Adjunctive therapy with patient-specific vaccines may improve outcomes by enhancing anti-GBM immune responses. A multi-institutional phase II clinical trial was designed with a primary objective of 75% survival 15 months after intent-to-treat enrollment. IL-4 and GM-CSF were used to generate dendritic cells (DC) from monocytes. DC were incubated with autologous tumor antigens (ATA) from the lysate of cultured GBM cells to produce each patient-specific DC-ATA vaccine. Each dose was admixed with 500 mcg GM-CSF at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Enrollment has been completed in April 2020 (n=60). Three patients withdrew from the study prior to starting treatment leaving 57 patients for whom data is available. So far 57 patients have received 344 doses; 27 have completed all 8 doses, 11 received fewer than 8 doses at the time they discontinued treatment, 19 are currently in treatment. No patient has discontinued treatment because of toxicity. 9 pt had died and the preliminary 12 months overall survival is 74%. In a preliminary serologic analysis 12 of 16 patients (75%) had an increase in markers associated with Th1/NK, Th2/immunoglobulins, and Th2 hypersensitivity (eotaxins, IgE and IL17F) by week-3; 9 of 15 (60%) had a decrease in angiogenesis factors, growth factors, and tumor markers by week-8. Immunologic data for all 55 patients who received at least two injections will be available November 2020. This patient-specific DC-ATA immunotherapy approach is feasible, is associated with changes in serologic markers, and may be increasing intratumor inflammation that may be associated with on-target toxicity and efficacy. A interim survival analysis will be conducted in mid-October 2020, 15 months after the 28th patient was enrolled; results will be available November 2020 [Clinicaltrials.gov NCT03400917].

Background Primary glioblastoma (GBM) is associated with poor survival. Adjunctive vaccines may improve survival by inducing or enhancing anti-GBM immune responses. Methods A multi-institutional phase II clinical trial was conducted with a primary objective of 75% survival 15 months after intent-to-treat enrollment. Key eligibility criteria were: (1) primary GBM diagnosis, (2) age 70 after surgical recovery. Dendritic cells (DC) were differentiated from autologous monocytes, then incubated with autologous tumor antigens (ATA) from the GBM cell line-lysate to produce each patient-specific DC-ATA vaccine. Doses were suspended in 500 mcg granulocyte-macrophage colony-stimulating factor (GM-CSF) at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Patients were enrolled just prior to starting standard concurrent temozolomide (TMZ) and radiation therapy (RT) for the intent-to-treat after recovery from RT/TMZ. Results Tumors were collected August 2018-January 2020. Cell line success rate was 71/73 (97%); monocyte collection success rate was 63/65 (97%), but 10 patients required a second leukapheresis. Patients were enrolled for in-to-treat October 2018-February 2020. The 60 patients included 42 men and 18 women with median age of 59 years (range of 27–70). Racial make-up was 43 White, 10 Hispanic, 2 Black, 1 Asian and 3 Other. KPS was 100 in 4, 90 in 25, 80 in 17 and 70 in 14 (mean 83.2). MGMT methylation was present in 13, absent in 31, and unknown in 16; IDH mutation was present in 7, absent in 50, and unknown in 3. 57 patients had received 380 doses with 9 still under treatment at time of abstract submission. 32 had completed all 8 doses; 16 had received fewer than 8 doses when they discontinued treatment. No patient discontinued treatment because of toxicity, but 28 have been hospitalized for 53 treatment-emergent central nervous system-related serious adverse events including seizures (15 episodes), falls and/or increased focal weakness (13 episodes), or severe headaches or visual changes (3 episodes). Conclusions This patient-specific DC-ATA approach is feasible and may be increasing intratumor inflammation that is associated with on-target efficacy and/or toxicity. An interim survival analysis will be conducted in October 2020, 15 months after the median patient was enrolled; results will be available November 2020 as will immunologic data for 55 patients who received at least two injections. Trial Registration Clinicaltrials. gov NCT03400917. Ethics Approval The study was approved by UCI IRB, approval number 2018-4148.

BACKGROUND Risk assessment of patients with acute COVID-19 in a telemedicine context is not well described. In settings of large numbers of patients, a risk assessment tool may guide resource allocation not only for patient care but also for maximum health care and public health benefit. OBJECTIVE The goal of this study was to determine whether a COVID-19 telemedicine risk assessment tool accurately predicts hospitalizations. METHODS We conducted a retrospective study of a COVID-19 telemedicine home monitoring program serving health care workers and the community in Atlanta, Georgia, with enrollment from March 24 to May 26, 2020; the final call range was from March 27 to June 19, 2020. All patients were assessed by medical providers using an institutional COVID-19 risk assessment tool designating patients as Tier 1 (low risk for hospitalization), Tier 2 (intermediate risk for hospitalization), or Tier 3 (high risk for hospitalization). Patients were followed with regular telephone calls to an endpoint of improvement or hospitalization. Using survival analysis by Cox regression with days to hospitalization as the metric, we analyzed the performance of the risk tiers and explored individual patient factors associated with risk of hospitalization. RESULTS Providers using the risk assessment rubric assigned 496 outpatients to tiers: Tier 1, 237 out of 496 (47.8%); Tier 2, 185 out of 496 (37.3%); and Tier 3, 74 out of 496 (14.9%). Subsequent hospitalizations numbered 3 out of 237 (1.3%) for Tier 1, 15 out of 185 (8.1%) for Tier 2, and 17 out of 74 (23%) for Tier 3. From a Cox regression model with age of 60 years or older, gender, and reported obesity as covariates, the adjusted hazard ratios for hospitalization using Tier 1 as reference were 3.74 (95% CI 1.06-13.27; P=.04) for Tier 2 and 10.87 (95% CI 3.09-38.27; P CONCLUSIONS A telemedicine risk assessment tool prospectively applied to an outpatient population with COVID-19 identified populations with low, intermediate, and high risk of hospitalization.

TitleInitial Experience in Validation of a Telemedicine Risk Assessment Tool for Hospitalization of Patients with COVID-19ImportanceRisk assessment of patients with acute coronavirus disease 2019 (COVID-19) in a telemedicine context is not well described. In the setting of large numbers of patients, a risk assessment tool may guide resource allocation not only for patient care but also for maximum healthcare and public health benefit.ObjectiveTo determine whether a risk prediction tool developed and implemented in March 2020 (“COVID-19 Telemedicine Risk Tier Assessment”) accurately predicts subsequent hospitalizations.DesignRetrospective cohort study, enrollment from March 24 to May 26, 2020 with follow-up calls until hospitalization or clinical improvement (final call date range March 27 to June 19, 2020)SettingSingle center “Virtual Outpatient Management Clinic” (VOMC) assessing and managing outpatients from a large quaternary medical system in Atlanta, GeorgiaParticipants496 patients with COVID-19 confirmed by nasopharyngeal sampling in isolation at home at the time of diagnosis. Exclusion criteria included: (1) hospitalization prior to VOMC enrollment, (2) immediate discharge from VOMC with no follow-up calls due to resolution.ExposureAcute COVID-19 illnessMain Outcome and MeasuresHospitalization was the outcome. Days to hospitalization was the metric. Survival analysis using Cox regression was used to determine factors associated with hospitalization.ResultsThe risk-assessment rubric assigned 496 outpatients to tiers as follows: Tier 1, 237 (47.8%); Tier 2, 185 (37.3%); Tier 3, 74 (14.9%). Subsequent hospitalizations numbered 3 (1%), 15 (7%), and 17 (23%) and for Tiers 1-3, respectively. From a Cox regression model with age ≥ 60, gender, and self-reported obesity as covariates, the adjusted hazard ratios using Tier 1 as reference were: Tier 2 HR=3.74 (95% CI, 1.06-13.27; P=0.041); Tier 3 HR=10.87 (95% CI, 3.09-38.27; PConclusions and RelevanceA telemedicine risk assessment tool prospectively applied to an outpatient population with COVID-19 identified both low-risk (Tier 1) and high-risk (Tier 3) patients with better performance than individual risk factors alone. This approach may be appropriate for optimum allocation of resources.

Background: Meningiomas are the most common adult primary intracranial tumors in the United States. Despite high recurrence rate of atypical and malignant subtypes, there is no approved drug indicated specifically for meningioma. Since the majority of meningiomas exhibit high density of somatostatin receptors subtypes, somatostatin analogs have been under close investigation. The aim of this study was to evaluate efficacy and safety of Sandostatin LAR (octreotide) in patients with progressive, and/or recurrent meningioma, and identify subset of patients who were more likely to benefit from this treatment. Methods: A total of 43 patients ≥ 18 years old were included in the retrospective chart review. The patients underwent treatment with Sandostatin LAR (octreotide) from 01.01.2010 to 06.01.2017 at the University of California, Irvine after confirmation of the diagnosis. Six months progression free survival (PFS6) was defined as a primary endpoint, and the overall survival (OS), safety, and toxicity were identified as secondary endpoints. Results: The OS for 6 months, 1, and 3 years for all WHO grades was 94.8, 88.1, and 67.0%, respectively. The PFS6 for WHO I, II, III, and all was 89.4, 89, 33.3, and 80% respectively. For patients with no prior surgeries, chemotherapy or radiation, the PFS6 was 88.9, 84.8, and 94.8%, respectively. Interestingly, the PFS6 was 90.5% for skull-based and 80% for 3-6 cm tumors. Patients with tumors in parasagittal location had PFS6 of 83.3% compared to PFS6 of 50.0% for patients with convexity tumors. Evaluation of PFS6 based on the effect of estrogen and progesterone on meningioma identified that ER-PR+ tumors had PFS6 of 87.8% while patients with ER-PR- meningiomas had PFS6 of 62.5%. Median TTP for WHO grade I, II, and III was 3.1, 2.40, and 0.26 years, respectively. Subgroup analysis showed that median TTP was 3.1 years for

Objectives To evaluate the effectiveness of practices used to support appropriate clinical laboratory test utilization. Methods This review followed the Centers for Disease Control and Prevention (CDC) Laboratory Medicine Best Practices A6 cycle method. Eligible studies assessed one of the following practices for effect on outcomes relating to over- or underutilization: computerized provider order entry (CPOE), clinical decision support systems/tools (CDSS/CDST), education, feedback, test review, reflex testing, laboratory test utilization (LTU) teams, and any combination of these practices. Eligible outcomes included intermediate, systems outcomes (eg, number of tests ordered/performed and cost of tests), as well as patient-related outcomes (eg, length of hospital stay, readmission rates, morbidity, and mortality). Results Eighty-three studies met inclusion criteria. Fifty-one of these studies could be meta-analyzed. Strength of evidence ratings for each practice ranged from high to insufficient. Conclusion Practice recommendations are made for CPOE (specifically, modifications to existing CPOE), reflex testing, and combined practices. No recommendation for or against could be made for CDSS/CDST, education, feedback, test review, and LTU. Findings from this review serve to inform guidance for future studies.

Background The aim of this pragmatic, embedded adaptive trial was to measure the effectiveness of subcutaneous sarilumab in addition to an evolving standard of care for clinical management of inpatients with moderate to severe COVID-19 disease (NCT04359901). The study is also a real-world demonstration of the realization of a prospective learning healthcare system. Methods Two-arm, randomized, open-label controlled 5-center trial comparing standard care alone to standard care (SOC), which evolved over time, with addition of subcutaneous sarilumab (200 mg or 400 mg anti-IL6R) among hospitalized patients with moderate to severe COVID-19 not requiring mechanical ventilation. The primary outcome was 14-day incidence of intubation or death. The trial used a randomized play-the-winner design and was fully embedded within the EHR system, including the adaptive randomization process. Results Among 417 patients screened, 162 were eligible based on chart review, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death ( >30% of eligible patients enrolled) (Figure 1). After the second interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. Figure 1. Key Study Milestones, Outcomes, and Adaptations Conclusion This randomized trial of patients hospitalized with COVID-19 and requiring supplemental oxygen but not mechanical ventilation found no evidence of benefit from subcutaneous sarilumab in addition to an evolving standard-of-care. The numbers of patients and events were too low to allow independent conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6 inhibition in the treatment of patients hospitalized with COVID-19. The major innovation of this trial was the advancement of embedded, point-of-care clinical trials for FDA-approved drugs; this represents a realization of the learning healthcare system. Methods developed and piloted during the conduct of this trial can be used in future investigations to speed the advancement of clinical science. Disclosures Nishant Shah, MD, General Electric (Shareholder)Pfizer, Inc. (Research Grant or Support) Karen Visnaw, RN, Liquidia (Shareholder) Paul Monach, MD,PhD, Celgene (Consultant)ChemoCentryx (Consultant)Kiniksa (Advisor or Review Panel member)

BackgroundDespite standard aggressive therapy (maximum safe surgical resection, concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ), then maintenance TMZ), 2-year survival is only about 25% for patients with newly diagnosed primary glioblastoma (GBM). Adding AV-GBM-1, a vaccine consisting of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA) may improve survival. One objective of a multi-center phase II clinical trial was to determine the feasibility of collecting fresh GBM and establishing short-term cell cultures of GBM tumor-initiating cells (TIC) to serve as ATA source.MethodsKey eligibility criteria for tumor collection were (1) clinical suspicion of new primary GBM, (2) age 18 to 70 years (3) tentative agreement to undergo a leukapheresis procedure after recovery from surgery, and (4) tentative plans for RT/TMZ. Fresh tumor was placed in media and shipped in a transport kit by overnight courier to AIVITA where a cell suspension was placed in culture and incubated in serum-free medium with factors that favor survival and proliferation of TICS (stem cells and early progenitor cells). The intent was to produce a patient-specific DC-ATA vaccine by incubating a lysate of irradiated TICs with autologous DC for subsequent subcutaneous injection.ResultsPatients were enrolled from five sites in California, one in Kentucky and one in New Jersey. Tumors were collected between August 2018 and January 2020. 106 patients consented for tumor collection, but 15 were not GBM, 4 had insufficient tissue to send, 2 patients withdrew consent, 4 were ineligible because of age, and 1 was ineligible because of autoimmune disease. Of the 80 GBM tumors that were placed into culture, 7 were discontinued because of patient withdrawal. 71/73 (97%) resulted in a successful cell culture; two were unsuccessful because of contamination. 60/71 subsequently consented for intent-to-treat ; 46/60 (77%) had cells in culture for 28 days or less, 11 were in culture for 30 to 35 days, and the remaining 3 were cultured 46, 54, and 55 days. The average number of cells per culture at the time of irradiation was 14.0 million (range 0.78 to 63.3 million). 58/60 (97%) yielded more than 1 million TICs for irradiation for the tumor cell lysate; 36/60 (60%) had more than 10 million cells irradiated. 57 patients were subsequently treated with AV-GBM-1 after recovery from RT/TMZ.ConclusionsSelf-renewing GBM TIC cultures can be reliably and rapidly established for use as the antigen source for personal DC-ATA vaccines.Trial RegistrationClinicaltrialsgov NCT03400917Ethics ApprovalThis study was approved by the Western IRB, approval number 20182582; all participants gave written informed consent before taking part

The impact of infiltrating chloride salts on the electrochemical behavior of lanthanum strontium manganite-yttria stabilized zirconia (LSM-YSZ) cathodes was investigated under solid oxide fuel cell operation. Infiltrating a lanthanum chloride solution resulted in the formation of a lanthanum oxychloride (LaOCl) phase. A LaOCl phase also formed by infiltrating an ammonium chloride solution; however, lanthanum was scavenged from the LSM phase to form LaOCl. The third infiltrating solution, a combination of zirconium chloride and yttrium nitrate, formed LaOCl by scavenging lanthanum from LSM and produced YSZ nanoparticles. Electrochemical impedance spectroscopy results suggest that LaOCl improves oxygen adsorption kinetics compared to a baseline LSM-YSZ cathode, reducing the low frequency impedance by 30%. In addition, scavenging lanthanum from LSM improved oxygen ion diffusion polarization as indicated by the observed 40% reduction in high frequency impedance and improved serial ohmic resistance by 19%. Finally, YSZ nanoparticles further reduced the high frequency impedance and ohmic resistance by 45% and 23%, respectively. The findings reveal new strategies for lowering the impedance of LSM-YSZ cathodes.

BackgroundFor patients with newly diagnosed primary glioblastoma (GBM), maximum safe surgical resection, concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ) followed by maintenance TMZ results in a 2-year survival of only 25%. Adding treatment with AV-GBM-1, a personal vaccine consisting of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA), may improve survival. One objective of a multi-center phase II clinical trial was to determine the feasibility of collecting sufficient monocytes (MC) from which to generate DC for pulsing with ATA from GBM tumor-initiating cells (TIC).MethodsPeripheral blood mononuclear cells were collected by leukapheresis per local standard operating procedures, then shipped by overnight courier to the AIVITA laboratory in Irvine, CA. The product was enriched for MC using the Elutra® Cell Separation System (Terumo, Lakewood, CO.). If fewer than 450 million MC were collected, an additional leukapheresis was allowed. MC were cryopreserved in liquid nitrogen and subsequently thawed and incubated in media containing granulocyte-macrophage colony-stimulating factor and interleukin-4 to differentiate MC into DC. Batches of patient-specific AV-GBM-1 were produced by incubating autologous DC with a lysate of irradiated TICs and aliquoted into individual doses.ResultsPatients enrolled from five sites in California, one in Kentucky and one in New Jersey. 65 patients underwent 77 leukapheresis procedures between September 2018 and February 2020; 54 underwent a single pheresis, 10 two phereses, and 1 three (all unsuccessful). The average time from surgical resection to first pheresis was 26 days (range 6 to 90; 64/65 within 51 days). 63/65 (97%) had sufficient MC collected, 53/65 (82%) from a single leukapheresis; 10 required a second procedure. The interval from surgery to first pheresis was the same for those for whom MC collections were satisfactory after one pheresis compared to those who required more than one. The success rate for MC collection for East-coast sites was 14/15 versus 52/62 for West-coast sites (p=0.68); so, longer shipping distance was not an issue. 60 patients who enrolled with intent-to-treat had an average of 1.7 billion monocytes cryopreserved, which were subsequently thawed and differentiated into DC. An average of 750 million DC were incubated with ATA for the final DC-ATA product.ConclusionsLeukapheresis procedures reliably resulted in collection of sufficient numbers of monocytes to generate DC and large batches of personal AV-GBM-1 vaccines. Success after a single leukapheresis was not related to the interval from surgery to pheresis procedure, or distance from the processing site.Trial RegistrationClinicaltrialsgov NCT03400917Ethics ApprovalThis study was approved by the Western IRB, approval number 20182582; all participants gave written informed consent before taking part

BackgroundDespite standard aggressive therapy, including maximum safe surgical resection, concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ) followed by maintenance TMZ, survival is still extremely poor for patients with newly diagnosed primary glioblastoma (GBM). Adding treatment with AV-GBM-1, a personal vaccine consisting of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA) may improve survival. One objective of a multi-center phase II clinical trial was to determine changes in blood proteomics before and after injections of AV-GBM-1.MethodsAV-GBM-1 consists of autologous DC incubated with ATA from a lysate of irradiated autologous GBM cells that had been placed in culture and incubated in serum-free medium with factors that favor the survival and proliferation of stem cells and early progenitor cells. After recovery from RT/TMZ, GBM patients were injected subcutaneously with AV-GBM-1 admixed in granulocyte-macrophage colony-stimulating factor (GM-CSF) at weeks 1, 2, 3, 8, 12, 16, 20, and 24. Blood samples obtained at baseline (week-0), just prior to the third injection (week-2) and just prior to the fourth injection (week-8), were cryopreserved and subsequently analyzed for 448 proteomic markers using quantitative, multiplex enzyme-linked immunosorbent assays (Raybiotech, Inc., Norcross, GA.). In this preliminary analysis the averages of paired samples for each time point were determined and compared using the student T-Test with a focus on differences of pResultsPatients were enrolled from five sites in California, and one each in Kentucky and New Jersey. 57 patients were treated during November 2018 to October 2020. Paired samples from all three time points were available for 49 patients. After two weekly injections there were increases in thymus-and activation-regulated chemokine (TARC, CCL17), the chemotactic protein chemerin, lipocalin-2, (expressed by macrophages and epithelium in response to inflammation) and angiopoietin-1 (suppressor of vascular inflammation), and decreases in thrombospondin-5 (possibly involved in synaptogenesis in brain repair), angiotensinogen (a precursor of all angiotensin peptides), and beta-fibroblast growth factor (important in tissue repair). The increase in TARC (pConclusionsIf there were humoral changes in proteins associated with Th1 and Th2 responses, these were no longer present after two weekly vaccinations. More sophisticated analyses of this data set, such as principal component analysis, may be needed to understand the effects of AV-GBM-1.Trial RegistrationClinicaltrialsgov NCT03400917Ethics ApprovalThis study was approved by the Western IRB, approval number 20182582; all participants gave written informed consent before taking part

Background Specimen labeling errors have long plagued the laboratory industry, putting patients at risk of transfusion-related death, medication errors, misdiagnosis, and patient mismanagement. Many interventions have been implemented and deemed to be effective in reducing specimen error rates. The objective of this review was to identify and evaluate the effectiveness of laboratory practices and interventions to develop evidence-based recommendations for the best laboratory practices to reduce labeling errors. Content The standardized Laboratory Medicine Best Practices InitiativeTM A-6 methods were used to conduct this systematic review. Total evidence included 12 studies published from 1990 to September 2015. Combined data from 7 studies found that the interventions developed from improved communication and collaboration between the laboratory and clinical staff resulted in substantial decreases in specimen labeling errors [median relative percent change in labeling errors: −75.86; interquartile interval (IQI): −84.77, −58.00]. Further data from the subset of 4 studies showed a significant decrease in specimen labeling errors after the institution of the standardized specimen labeling protocols (median relative percent decrease in specimen labeling errors: −72.45; IQI: −83.25, −46.50). Summary Based on the evidence included in this review, interventions that enhance communication and collaboration between laboratory and healthcare professionals can decrease the number of specimen identification errors in healthcare settings. However, more research is needed to make any conclusion on the effectiveness of other evaluated practices in this review, including training and education of the specimen collection staff, audit and feedback of labeling errors, and implementation of new technology (other than barcoding).

Newly-diagnosed glioblastoma (GBM) patients have a limited survival (18–24 months). In the last decade immunotherapy has improved survival for patients with other malignancies, but not GBM. Herein we present the design and initial enrollment results for the AV-GBM-1 single-arm phase 2 trial. The study enrolls patients with primary GBM who have undergone craniotomy, have a tumor cell culture established, and complete satisfactory leukapheresis prior to planned concurrent chemotherapy and radiation. Patients are scheduled to receive up to 8 vaccine injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Blood samples are collected just prior to each injection. The primary endpoint is overall survival from date of enrollment for intent-to-treat with AV-GBM-1. The study has fully enrolled 26 of planned 55 patients. The cell line success rate is 30/32, with 6 in progress; successful completion of leukapheresis is 28/29. Two patients have completed all 8 doses, two discontinued after dose 3 and dose 6 because of progressive disease; 15 are currently in treatment, and 6 are about to start treatment. There have been seven SAE, all for hospitalizations related to GBM. For the first 8 treated patients, plasma samples from baseline and weeks 2, 3, and 8 have been analyzed for immune markers by RayBiotech Life Inc. using quantitative multiplex ELISA array. Markers reflecting Th1, Th2, Th17 pathways and B-cells, natural killer cells and cytotoxic T-lymphocytes increased in 7/8 patients. Principal component analysis demonstrates correlative marker groupings with early dominance of Th1/Th17 (weeks 1 and 2) followed by Th2/immunoglobulins at week 8. These findings show that these patient-specific dendritic cell vaccines are inducing pro-inflammatory responses similar to what was observed in a previous trial in melanoma. The study is progressing efficiently. Full enrollment data may be available for presentation at the time of the annual meeting.

OBJECTIVE: This study was conducted to evaluate the responses of 3,265 health professionals who took a continuing education (CE) activity during June 2009 - April 2012 for a comprehensive set of good laboratory practice recommendations for molecular genetic testing. DESIGN: Participants completed an evaluation questionnaire as part of the CE activity. Responses were summarized to assess the participants’ learning outcomes and commitment to applying the knowledge gained. PARTICIPANTS: Participants included nurses (47%), laboratory professionals (18%), physicians (14%), health educators (4%), public health professionals (2%), office staff (1%), and other health professionals (10%). RESULTS: Only 32% of all participants correctly answered all 12 open-book knowledge-check questions, ranging from 4 to 42% among the different professional groups (P

e16006 Background: FTD/TPI, an antimetabolite, is approved for treatment of refractory mGEC. This study sought to determine whether the combination of FTD/TPI with IRI (“TASIRI”) was safe and effective in mGEC previously treated with FP. Methods: This investigator‐initiated, multicenter, open‐label, single-dose level, single‐arm phase 1b study enrolled pts with mGEC previously treated with at least one line of FP containing regimen. FTD/TPI was given at 25 mg/m2 twice daily on days 1 to 5 with 180 mg/m2 IRI on day 1 of a 14‐day cycle. The primary endpoint was progression-free survival at six months (mo) (PFS-6). The aim was to show an improvement of PFS-6 from 15% to at least 30% based on historical controls. Results: At the time of data-cutoff (03Feb2021), 23 pts were screened and ultimately 20 pts were treated. The study met its primary endpoint. With a median follow-up of 9.8 mo (range 0.7 – 17), 8 pts are still on treatment and 4 pts have died. PFS-6 is 53.9% (lower limit of 95% CI: 28%). Median PFS and overall survival are 6.9 mo and not reached, respectively. At the time of data-cutoff, data were available for 13 pts with measurable disease by RECIST criteria and at least 1 on-treatment scan. Of those, 11 had stable disease and 2 had progressive disease as best response (5 pts had tumor shrinkage < 30%), therefore the disease control rate was 84.6%. The most common any grade (G) treatment related adverse events (TRAE) were nausea (n = 14, 70%), diarrhea (n = 9, 45%), and fatigue (n = 8, 40%). G3-4 TRAE in > 5% of pts were anemia (17%) and neutropenia (9%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. Conclusions: The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls. TASIRI was well tolerated and no new safety signals were seen. TASIRI warrants further investigation for patients with refractory mGEC and limited treatment options. Updated results with longer follow-up will be presented at the meeting. Clinical trial information: NCT04074343.

The thermochemical stability of lanthanum strontium cobalt ferrite (LSCF) processed between 1000 °C–1200 °C via the in situ carbon templating method was studied. This method generates high surface area ceramics at traditional solid oxide fuel cell (SOFC) sintering temperatures by generating a carbon template in situ and subsequently removing the template by oxidation at 700 °C. Argon processed samples produced an amorphous carbon template, whereas nitrogen tended to form graphitic carbon. Prior to the oxidation step, nitrogen samples comprised larger La2O3 crystallites (22–40 nm) compared to argon (9–17 nm). Upon oxidation, argon samples resulted in a pure LSCF phase with surface areas in the 21–29 m2·g−1 range, whereas nitrogen samples contained significant impurities. This demonstrates that the size of La2O3 crystallites formed during inert processing limited the ability to produce a pure LSCF phase. Symmetrical cells comprising nano-LSCF electrodes generated by the templating method were compared to cells sintered directly in air. Impedance results suggest that nano-LSCF cells and cells processed in air were dominated by interfacial charge transfer resistance and gas diffusion, respectively. The results map out conditions for preparing and integrating high surface area, nanostructured LSCF into SOFC electrodes at traditional sintering temperatures. Strategies for improving the interfacial resistance of nano-LSCF electrodes are discussed.

TPS253 Background: GEC is the third leading cause of cancer mortality and the fifth most common malignancy worldwide. Fluoropyrimidine and platinum-based combinations are the most commonly used 1L treatment regimens. There are few standard treatment options after 1st line regimens. In the 3L+ GEC Keynote-059 trial, objective response rate (ORR) with Pembro was 15.5% in PD-L1(+) vs. 6.4% in PD-L1(-) tumors. While the responses were durable, the 6-months PFS (6-PFS) was only 14.1% and the median PFS was 2.0 mo. This highlights the remaining unmet need for the majority of patients who either are refractory or develop disease progression following treatment with PD-1 inhibitors in GEC. Cabo plus checkpoint inhibitors have shown clinical benefit in various cancers including hepatocellular, renal cell (RCC), urothelial and castration-resistant prostate cancers. In the CheckMate-9ER trial, Cabo+Nivolumab improved both OS and PFS vs sunitinib in 1L RCC. In patients with RCC who had progression on anti-PD1 inhibitor treatment, Cabo showed promising activity with an ORR of 33% and DCR of 79% (ESMO 2018, abstract 3793). Hypothesis: Based on preclinical and clinical observations, Cabo might contribute to overcoming primary or secondary resistance to PD-1 blockade in GEC. Methods: Prospective, open label, non-randomized phase 2 trial. Eligibility: Diagnosis of GEC, 2+ line of treatment including previous fluoropyrimidine/platinum, ECOG 0-2, adequate organ function, prior checkpoint inhibitor if tumor PD-L1 CPS≥10%. Treatment: Cabozantinib 40mg PO daily, Pembrolizumab 200 mg IV on day 1 of 21d cycle. Primary objective: Feasibility of the combination and estimate of efficacy. Primary endpoint:PFS-6. Secondary objectives: OS, ORR, adverse events. Total number of patients to be enrolled N = 27. Current enrollment (Sep 2020) N = 10. Statistics: If the PFS-6 is > 25%, the study would be regarded as positive, in which case it is planned to expand patient enrollment into a larger single arm phase 2 trial with additional sites to establish the efficacy of the regimen. Clinical trial information: NCT04164979.

Standard treatment of primary glioblastoma (GBM) is associated with poor survival. Adjunctive therapy with patient-specific vaccines may improve outcomes by inducing or enhancing each patient's anti-GBM immune response. A multi-institutional phase II clinical trial was designed with a primary objective of 75% survival 15 months after intent-to-treat enrollment. Key eligibility criteria were: (1) primary GBM diagnosis, (2) age < 70 years at time of tumor resection, (3) successful cell culture of GBM cells in serum-free media, (4) successful monocyte collection by leukapheresis, and (5) KPS > 70 after recovery from surgery. IL-4 and GM-CSF were used to generate dendritic cells (DC) from monocytes. DC were incubated with autologous tumor antigens (ATA) from the lysate of cultured GBM cells to produce each patient-specific DC-ATA vaccine. Each dose was admixed with GM-CSF at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. At the time of this analysis, cell line success rate is 61/63 (97%); monocyte collection success rate is 53/55 (96%), but 10 patients required a second apheresis. 50 of a planned 55 patients have enrolled after recovery from surgery, just prior to starting standard concurrent radiation therapy (RT) and temozolomide (TMZ), with intent-to-treat after recovery from RT/TMZ. The 50 patients include 36 men and 14 women; median age is 58 years with a range of 27 to 70. Average KPS is 82.8. MGMT methylation has been documented in 22% of patients and IDH mutation in 14%. 37 patients have started treatment and received 231 doses. 16 have completed all 8 doses, 7 received fewer than 8 doses, and 14 are currently undergoing treatment. No patient has discontinued treatment because of toxicity, but 20 patients have experienced 35 treatment-emergent serious adverse events including hospitalizations for falls and/or increased focal weakness (12 episodes), seizures (10 episodes), or severe headaches or visual changes (3 episodes). 6-month actual survival rate is 96% for the 28 patients at risk 6 months or longer from enrollment. Serologic analyses show that 12 of 16 patients (75%) had an increase in markers associated with Th1/NK, Th2/immunoglobulins, and Th2 hypersensitivity (eotaxins, IgE and IL17F) by week-3; 9 of 15 (60%) had a decrease in angiogenesis factors, growth factors, and tumor markers by week-8. On serial MRI scans, 7 of 13 patients (54%) have exhibited an increase in T2 (tumor) and flare (edema) for several weeks after starting DC-ATA, followed by a slow gradual decrease in both. This patient-specific DC-ATA immunotherapy approach is feasible, is associated with changes in serologic markers, and may be increasing intratumor inflammation that may be associated with on-target toxicity and efficacy. Longer follow up is needed before the survival objective can be assessed. [Clinicaltrials.gov NCT03400917] Citation Format: Daniella A. Bota, Christopher M. Duma, Santosh Kesari, David E. Piccioni, Renato V. LaRocca, Robert T. O'Donnell, Robert D. Aiken, Jose A. Carrillo, Candace Hsieh, Chris J. Langford, Krystal Carta, Adrienne M. Wang, James A. Langford, Thomas H. Taylor, Gabriel I. Nistor, Robert O. Dillman. Adjunctive treatment of primary glioblastoma with patient-specific dendritic cell vaccines pulsed with antigens from self-renewing autologous tumor cells: A phase II trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT182.

Background Discrimination is a major driver of health disparities among minority groups and can impede the reach of public health programs. In the Dominican Republic, residents of bateyes, or agricultural ‘company towns,’ often face barriers to health care. This study examined the extent of perceived discrimination among batey populations and places the findings within the context of disease elimination efforts. Methods In March—April 2016, a stratified, multi-stage cluster survey that included the 9-item Everyday Discrimination Scale (EDS) was conducted among residents (n = 768) of bateyes across the Dominican Republic. Exploratory factor analysis, differential item functioning, and linear and logistic regression were used to assess associations between EDS scores, ethnic group status, reasons for discrimination, and healthcare-seeking behavior. Results Three ethnic groups were identified in the population: Haitian-born persons (42.5%), Dominican-born persons with Haitian descent (25.5%), and Dominican-born persons without Haitian descent (32.0%). Mean EDS scores (range 0–45) were highest among persons born in Haiti (18.2, 95% confidence interval [CI] = 16.4–20.1), followed by persons with Haitian descent (16.5, 95% CI = 14.9–18.0), and those without Haitian descent (13.3, 95% CI = 12.1–14.5). Higher EDS scores were significantly associated with Haitian birth (β = 6.8, 95% CI = 4.2—9.4; p p = 0.278). Conclusion Perceived discrimination is common among batey residents of all backgrounds but highest among Haitian-born people. Discrimination did not appear to be a primary barrier to care-seeking, suggesting other explanations for reduced care-seeking among Haitian populations. Public health community engagement strategies should avoid exacerbating stigma, build active participation in programs, and work towards community ownership of disease control and elimination goals.

Objective Hyperuricemia has been epidemiologically associated with multiple comorbidities including chronic renal failure and cardiovascular disease. Cause and effect are difficult to address, given comorbidities associated with and prevalence of metabolic syndrome. One impediment to achieving serum uric acid (sUa) levels less than or equal to 6.0 mg/DL is the concept that allopurinol might be nephrotoxic. We examined the relation of sUa less than or equal to 6.0 mg/dL to renal function over time. Methods This is a medical records review study of 348 hyperuricemia patients identified in 2015, as having been followed with serial uric acid measurements. After 1 year of serial urate levels, to allow for treatment, patient cohorts were defined: sUa less than or equal to 6.0 mg/dL and sUa greater than 6.0 mg/dL. A repeated measure model was used to test for an association between uric acid level and serum creatinine, while adjusting for covariates. Results There was a significant difference in the least square means of serum creatinine comparing those who achieved an sUa less than or equal to 6.0 mg/dL versus sUa greater than 6.0 mg/dL (1.39 mg/dL [95% confidence interval, 1.30-1.48] vs 1.57 mg/dL [95% confidence interval, 1.46-1.69]; p = 0.0015). This is a between-group difference in creatinine of 0.18 mg/dL. If a change in serum creatinine of 0.2 is considered significant, this short-term between-group progression of renal failure approaches clinical significance. Conclusions Given that most serial measures were within the first few years of follow-up, and change in renal function occurs slowly over time, the between group difference of sUa of 0.18 mg/dL is close to a clinically significant creatinine difference of 0.2 mg/dL.