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Background Letermovir (LMV) is indicated for cytomegalovirus (CMV) prophylaxis in seropositive adults after allogeneic hematopoietic stem cell transplants (alloSCT). LMV is well tolerated compared to its alternatives. Our institution restricts LMV use to high-risk patient groups to maximize the cost/benefit of LMV. Despite these restrictions, LMV was in our institution’s top 50 drug expenditures, prompting a formal evaluation of its use. We describe a real-world experience with LMV at a 576-bed academic transplant center. Methods This was a single center, retrospective, descriptive study of LMV use at a transplant center. Any hospitalized patient who received ≥ 1 dose of LMV between August 2021 and January 2022 was eligible for analysis. Data collection included age, LMV administration data, length of stay, transplant status, Infectious Diseases (ID) consultation, documented rationale for non-criteria uses, and drug cost. The primary outcome was incidence of use not aligning with restriction criteria. The secondary outcome was institutional drug expenditure for non-criteria uses compared to approved uses. Results Over 6 months, 388 doses of LMV were administered to 31 unique patients during 41 admissions. LMV use during 12/41 admissions (31.7%) fell outside the institutional criteria. ID consult occurred in 58.3% (7/12) of cases. 27/31 (87%) were alloSCT patients, including 1 pediatric patient. There was also 1 liver and 1 heart transplant recipient. Reasons for non-criteria use were: primary prophylaxis in the heart transplant patient to avoid ganciclovir toxicity and in 2 alloSCT patients without high risk for CMV, pre-emptive therapy due to CMV reactivation (n=2), and step-down therapy for CMV viremia (n=4). LMV was used for extended periods ( > 100 days from transplant) in 2 cases. Non-criteria use of LMV accounted for $20 414 in drug cost over 6 months, 29% of total expenditure. Conclusion Our data suggest real world use of LMV often differs from the patient types enrolled in the phase 3 trials. Use of LMV as an alternative to available CMV therapies to avoid drug toxicities appears to drive much of this use. In addition, use outside of criteria was frequent and incurred a nontrivial cost. Modification of our criteria, such as requiring an ID consultation for off-label use, should be considered. Disclosures James S. Lewis, PharmD, FIDSA, Cidara: Advisor/Consultant|Merck: Advisor/Consultant|SeLux Diagnostics: Advisor/Consultant.

Background Coagulase-negative Staphylococci (CoNS), including mecA-positive Staphylococcus epidermidis (MRSE), are among the bacteria identified by BioFire blood culture identification (BCID2). After transition to BCID2 on 31 March 2021, our institution began providing a suggested empiric antimicrobial therapy (EAT) comment with rapid diagnostic results, whereas no suggestions were given with the prior platform. Limited data exist on the impact of EAT suggestions on antibiotic use when likely contaminants such as CoNS are identified. Methods This was a single center, observational, pre- and post-intervention study of patients aged ≥ 18 years with CoNS in the blood between 1 April 2020 and 30 September 2021. Patients with compromised immunity, intravenous drug use, polymicrobial cultures, or MRSE-active therapy use for a documented infection were excluded. Primary outcome was the rate of initiation or discontinuation of MRSE-active agent in response to the rapid diagnostic result. Secondary outcome was healthcare resource utilization such as Infectious Diseases consultation and delayed discharge. Results A total of 174 patients were included (pre-BCID2, n=93; post-BCID2, n=81). For all CoNS rapid diagnostic results, no significant difference was noted in MRSE-active agent initiation (33.3% vs. 37.0%, p=.90) and discontinuation (61.3% vs. 48.4%, p=.31). A subgroup analysis of S. epidermidis was performed with 64 and 46 patients in pre- and post-BCID2 groups, respectively; in the latter, BCID2 identified 31/46 (67.4%) as MRSE. In this subgroup, empiric MRSE-active agent was significantly less likely to be discontinued if EAT suggestion was reported with results (68.4% vs. 31.2%, p=.03). This change was not seen if Staphylococcus species were identified as the suggestion was to withhold EAT. There was no difference in healthcare resource utilization. Conclusion Providing EAT suggestion with BCID2 result for S. epidermidis unexpectedly encouraged continuing empiric MRSE-active agent for likely contaminants. In contrast, suggestion to withhold treatment had no impact on EAT use for other CoNS. The reason for this difference is unclear, but may be a result of the highlighted methicillin resistance in the BCID2 result reporting which is specific to S. epidermidis. Disclosures James S. Lewis, PharmD, FIDSA, Cidara: Advisor/Consultant|Merck: Advisor/Consultant|SeLux Diagnostics: Advisor/Consultant.

Osteosarcoma (OS) frequently metastasizes to lung where it greatly contributes to patient mortality. Frustratingly, OS treatment options have remained static due to a paucity of strong pre-clinical evidence to motivate clinical trials. To identify therapeutic targets, we assessed a number of FDA approved therapies for their cytotoxic effects. We found that histone deacetylase (HDAC) inhibitors (panobinostat and romidepsin) limited OS viability at low nM and were highly effective for the treatment of lung metastatic disease in vivo. Although clinically approved, HDAC inhibitors have noted toxicities. Therefore, we next examined the potential mechanisms through which HDAC controlled OS growth. Gene expression analyses on romidepsin treated OS cells revealed key up and downregulated targets. We found that SLC17A7, a vesicular glutamate transporter, was highly and consistently induced in response to romidepsin (greater than 100 fold more than base line) across multiple OS cell lines. Functionally, SLC17A7 traps glutamate in cytoplasmic synaptic vesicles that are then released via exocytosis. Our data show that HDAC inhibition reduces glutamate secretion from OS cells while SLC17A7 overexpression significantly impaired OS viability. Further, we showed that the glutamate export inhibitor, riluzole, significantly impairs the OS growth in vitro and is highly effective for the treatment of lung metastatic OS in vivo. Taken together, we conclude that HDAC1/2 suppression of SLC17A7 ensures high cytoplasmic glutamate levels that can be leveraged for OS growth. We posit that targeting glutamate usage by OS cells using FDA approved inhibitors such as riluzole will be highly effective for the treatment of lung metastatic OS. Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Ryan T. Bishop, Diana Yu, Damon R. Reed, Conor C. Lynch. Delineating the role of vesicular glutamate transporter SLC17A7 in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 276.

Background Patient interview, penicillin skin testing (PST) and/or an oral challenge can be used to evaluate penicillin allergies. Programs favor PST prior to oral challenge, but there is interest in bypassing PST and directly oral challenging for logistical and financial reasons. Data on the safety and efficacy of a direct challenge in the inpatient setting when the index reaction is moderate to severe (e.g. swelling of throat, angioedema, anaphylaxis) is lacking. Methods Adult patients (≥18 years) admitted with a penicillin allergy were evaluated for eligibility between September 2019 and June 2021. Pregnant patients were excluded, while critically ill patients and those on anti-histamine medications were evaluated if clinical need was high. Institutional protocols allowing for patients to be challenged without PST if reaction was more than 10 years ago were used. Data collected included the number of patients challenged and delabeled, number of patients who had moderate to severe index reactions, number of patients who were relabeled without cause, and number of patients who declined further testing. Results Two hundred twenty-five patients were evaluated; 11 patients declined testing. Two hundred four patients were delabeled (95%) among those fully evaluated. One hundred twelve patients were delabeled by interview and chart review alone (52%), 99 by oral challenge (46%), and 2 by PST and oral challenge (1%). Twenty-nine patients with moderate to severe reactions were challenged and 27 were delabeled. Ten patients could not be delabeled due to mild or delayed reactions to challenge or subsequent treatment, including 2 patients with severe index reactions who had mild challenge reactions and required no rescue medications. No patients required epinephrine during challenge. Five patients were relabeled and then delabeled again as no new reaction had occurred. Conclusion Penicillin allergies can be removed with a pharmacy-driven algorithm that prioritizes direct challenges when appropriate even when the index reaction was moderate to severe. Risks of a reaction are low, and reactions tend to be mild. Given well-documented benefits of delabeling patients for the patient and the institution, more hospitals should consider starting such services. Disclosures All Authors: No reported disclosures

Background: Osteosarcoma (OS) frequently metastasizes to lung and the prognosis for these patients is grim with 5-year overall survival rates as low as 30%. There has been little change in the treatment paradigm for this disease and new targeted therapies are an urgent and unmet clinical need. Previously, we showed that the epigenetic regulators, histone deacetylase 1 and 2 (HDAC1 and 2) are key mediators of OS progression and lung metastasis and that the HDAC1/2 selective inhibitor (romidepsin) significantly prevented OS lung metastasis in vivo. Yet, inhibition of HDACs by romidepsin has noted toxicities in humans and here we define the potential mechanisms through which HDAC1/2 mediate their effects in a bid to identify additional therapeutic targets. Methods: Human OS cell lines were treated with vehicle or romidepsin for 24h before undergoing RNA/protein isolation for microarray/proteomics to identify differentially regulated genes. Standard siRNA, proliferation, migration and molecular analyses were preformed to investigate the role of candidate genes in OS malignant behavior. Results: Microarray/proteomics analyses on romidepsin treated OS cells identified neuropilin-1 (NRP1), a membrane bound co-receptor for vascular endothelial growth factor, to be highly downregulated in response to romidepsin; ( Conclusions: HDAC1/2 contributes to OS growth potentially via the upregulation of NRP1, a therapeutically actionable target. Citation Format: Niveditha Nerlakanti, Jeremy Mcguire, Diana Yu, Damon Reed, Conor C. Lynch. Epigenetic upregulation of neuropilin-1 promotes osteosarcoma progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 988.

The sequencing of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) remains a matter of controversy. This cohort study analyzed the overall survival (OS) and progression-free survival (PFS) of afatinib compared with erlotinib and gefitinib first-line. EGFRm+, advanced NSCLC patients treated with either afatinib, erlotinib or gefitinib were retrospectively analyzed. A total of 107 patients were included. There was no statistically significant difference in PFS among the 3 groups. In the ≥ 60 years age group, the afatinib group had longer survival compared to the gefitinib group (p = 0.01). Median OS were 19.1, 22.9, and 35.6 months for gefitinib, erlotinib, and afatinib groups, respectively, with statistical significance between the gefitinib and afatinib groups (p = 0.009). Patients on afatinib also had longer median OS than erlotinib and gefitinib pooled together (35.5 versus 21.4 months; hazard ratio = 0.54, p = 0.016), despite similar median PFS. In conclusion, afatinib is a better choice compared to gefitinib or erlotinib for EGFRm+ patients. The OS obtained with afatinib is just 3 months shorter than osimertinib in the FLAURA trial. Direct comparison studies with osimertinib are still needed to determine optimal sequencing.

Malignant peripheral nerve sheath tumor (MPNST) is a type of soft-tissue sarcoma strongly associated with dysfunction in neurofibromin; an inhibitor of the RAS pathway. We performed high-throughput screening of an array of FDA approved and promising agents in clinical development both alone and in combination at physiologically achievable concentrations against a panel of established MPNST cell line models. We found that drugs targeting a variety of factors in the RAS pathway can effectively lead to cell death in vitro with considerable drug combination synergy in regimens that target MEK or mTOR. We observed that the degree of relative sensitivity to chemotherapeutic agents was associated with the status of neurofibromin in these cell line models. Using a combination of agents that target MEK and mTORC1/2, we effectively silenced RAS/PI3K/MEK/mTOR signaling in vitro. Moreover, we employed RNAi against NF1 to establish that MPNST drug sensitivity is directly proportional to relative level of intracellular neurofibromin. Thus, two-drug combinations that target MEK and mTORC1/2 are most effective in halting the RAS signaling cascade, and the relative success of this and related small molecule interventions in MPNSTs may be predicated upon the molecular status of neurofibromin.

Background Penicillin allergies are reported by approximately 10% of the US population; however, studies reveal that >90% of those patients can tolerate penicillins. Penicillin allergies are associated with negative health outcomes, both clinical and financial, due to reduced efficacy and increased adverse effects of alternative antibiotics. Patient interview, penicillin skin testing (PST) and/or an oral graded challenge can be used to evaluate penicillin allergies. Different facilities use various algorithms for testing. The objective of this project was to determine whether a pharmacist-driven penicillin allergy evaluation and testing protocol which largely bypasses PST could safely de-label patients. Methods Adult patients (≥18 years) admitted with a penicillin allergy were evaluated for eligibility between September 2019 and June 2020. Pregnant patients, critically-ill patients, and patients receiving test-invalidating medication were excluded. Patients were evaluated and tested using institutional protocols, which allowed for the majority of patients to be challenged without PST. Allergies were removed with standardized documentation, and patients were given a pamphlet and counseled to discourage relabeling. Data collected included but were not limited to, the number of patients challenged and de-labeled, number of patients who were relabeled, and number of patients whose change in allergy status resulted in change of therapy. Results Forty-eight patients were interviewed and evaluated. One patient was evaluated by PST and oral graded challenge while 27 patients underwent an oral graded challenge only. Twenty patients were de-labeled as a result of patient interview. One patient failed oral challenge with minor itching that did not require any treatment, while 27 patients passed. Forty-seven allergies were removed or modified. Two patients who were de-labeled were relabeled with no record of a new reaction. Of de-labeled patients, 50% received a penicillin following removal of the allergy. Conclusion Penicillin allergies can be evaluated and removed using a pharmacy-driven algorithm that prioritizes direct challenges when appropriate. Risks of a reaction are low, and removal leads to change in treatment in a significant portion of patients. Disclosures All Authors: No reported disclosures

Background Antibiotic appropriateness is the gold standard for informing antimicrobial stewardship efforts to optimize prescribing. The objectives of this study were to evaluate appropriateness of antibiotics for resistant gram-positive infections in pediatric inpatients and identify factors associated with inappropriate prescribing. Methods We included pediatric inpatients between July 2017 and July 2018 where an antibiotic typically used for resistant Gram-positive infections (per NHSN) was administered. We developed an algorithm based on laboratory data and diagnosis codes to categorize each antibiotic day of therapy as appropriate, inappropriate, or indeterminate. If indeterminate, we reviewed charts to assess appropriateness. We calculated total, appropriate, and inappropriate days of therapy (DOT) overall and per patient-day. We evaluated clinical characteristics and indications as potential predictors of inappropriate DOT using Chi-squared or Kruskal-Wallis tests. Results Among 591 included encounters, we assessed 708 total antibiotic courses. The algorithm allowed for classification of 422 encounters (71%) and the remaining 171 encounters (29%) were classified using manual record review. The most frequent antibiotics were vancomycin (68%) and clindamycin (29%). Patients received a median of 3 days of gram-positive agent therapy per visit, or 5 per every 10 patient-days. Most common indications for gram-positive therapy were surgical prophylaxis (28% of encounters) and empiric therapy (10%) (Figure 1). Of the 1,754 total days of therapy assessed, 94.8% were ruled appropriate. Thirty-one (4.4%) courses were classified as at least partially inappropriate among 27 unique encounters (4.6%). There was a median of 2 inappropriate days among those with any inappropriate therapy. The reason for inappropriate rulings for empiric or prophylaxis indications was most often “longer than necessary duration,” which was the case for 16 of 21 (76%) occurrences. Figure 1. Appropriate and Inappropriate Days of Therapy (DOT) by Indication and Antibiotic Conclusion Inappropriate antibiotic use for Gram-positive infections was low in our patient population for the agents studied. We identified limiting the duration for patients receiving prophylactic or empiric therapy as a potential stewardship intervention target. Disclosures All Authors: No reported disclosures

Background Vancomycin and daptomycin are commonly used in outpatient parenteral antimicrobial therapy (OPAT) for patients requiring lengthy courses of intravenous antimicrobials who are otherwise stable for discharge. Balancing the convenience and cost-savings of OPAT with the potential for adverse effects is challenging, this study compared the rates of complications and antimicrobial interventions for patients receiving vancomycin versus daptomycin across multiple OPAT settings. Methods We performed a retrospective chart review of adult OPAT patients who received >72 hours of vancomycin or daptomycin via home infusion, infusion center, or skilled nursing facility between January 2017 and August 2019. The outcomes evaluated included the rates of adverse drug reactions (ADRs), laboratory results above a defined threshold (vancomycin levels >20 mg/mL in the vancomycin arm and creatinine phosphokinase (CPK) levels >500 units/L in the daptomycin group), line complications, emergency department (ED) visits, and hospital readmissions. Other outcomes included additional phone calls and interventions required to coordinate care (additional labs, assessment of symptoms, additional test or antimicrobial-related dose changes) by the OPAT team. Results 180 patients were included; 130 received vancomycin and 50 received daptomycin. (Table 1) Patients in the vancomycin group had more supratherapeutic vancomycin troughs than elevated CPK for patients in the daptomycin group (rate ratio [RR] 0.16, 95% CI 0.05-0.50, p=0.0018). Rates of interventions (RR 0.37, 95% CI 0.26-0.52, p< 0.0001) and additional phone calls (RR 0.56, 95% CI 0.43-0.72, p< 0.0001) were also higher for patients in the vancomycin group. There were no statistically significant differences between groups in the rates of ADRs, line complications, ED visits, or hospital readmissions. (Table 2) Table 1. Baseline Characteristics Table 2. Outcomes Conclusion Vancomycin-treated patients had significantly more laboratory abnormalities and required significantly more time in patient care coordination by the OPAT team. The difference in healthcare utilization between these groups suggests a potential for significant cost-savings for OPAT patients and the healthcare system. Disclosures All Authors: No reported disclosures

Background For marginally operable stage IIIA non–small-cell lung cancer (NSCLC), surgery might not be done as planned after neoadjuvant concurrent chemoradiotherapy (CCRT) for reasons (unresectable or medically inoperable conditions, or patient refusal). This study aims to investigate the outcomes of a phased CCRT protocol established to maximize the operability of marginally operable stage IIIA NSCLC and to care for reassessed inoperable patients, in comparison with continuous-course definitive CCRT. Materials and Methods Forty-seven patients with marginally operable stage IIIA NSCLC receiving CCRT were included. Twenty-eight patients were treated with our phased CCRT protocol, including neoadjuvant CCRT followed by surgery (group A, n = 16) or, for reassessed inoperable patients, maintenance chemotherapy and split-course CCRT boost (group B, n = 12). The other 19 were treated with continuous-course definitive CCRT (group C). Overall survival (OS) and progression-free survival (PFS) were analyzed. Results Among all, median OS and PFS were 35.6 and 12.8 months, respectively (median follow-up, 22.3 months). The median OS of group A (not reached) was better than that of group B (34.4 months) and group C (15.2 months) ( P = .009). On multivariate analysis, performance status 0 to 1 (hazard ratio [HR], 0.026; P P = .003), and group A (HR, 0.199; P = .033) were independent prognostic factors. The OS of group B (HR, 0.450; 95% confidence interval, 0.118-1.717; P = .243) was not statistically different from that of group C. Conclusions For marginally operable stage IIIA NSCLC, our phased CCRT strategy may optimize survival by maximizing operability and maintain an acceptable survival for reassessed inoperable patients by split-course CCRT boost following maintenance chemotherapy.

Purpose Systemic therapy has improved rhabdomyosarcoma event-free and overall survival; however, approximately 40 % of patients will have progressive or recurrent disease which is difficult to cure and remains a considerable challenge. Minimal progress has been made in improving outcomes for metastatic or relapsed RMS due to a lack of effective therapeutic agents. Targeted therapies are likely to be incorporated into regimens which rely on conventional cytotoxic chemotherapy. A system to evaluate novel combinations of interest is needed. Methods In this study, we explored 8 agents, 5 that are routinely used or similar to agents used in the clinical management of RMS and 3 biologically targeted agents with novel mechanisms of action, the Wee1 inhibitor AZD1775, the tyrosine kinase inhibitor cabozantinib, and the proteasome inhibitor bortezomib. All were tested individually at clinically achievable concentrations for activity in 4 RMS cell lines and then for potential synergy in two-drug combinations. Results We found single-agent activity in five of the agents (or their active metabolites) that constitute the standard of care in RMS and for AZD1775 with mean IC50 values of 207 ng/ml, well below clinically achievable levels. In addition, the combination of individual cytotoxic chemotherapeutics currently used for RMS demonstrated largely synergistic activity with higher, but clinically achievable concentrations of AZD1775 in our assays. Conclusions Prioritization of chemotherapeutics in RMS is possible using an in vitro system that can define novel drug combinations worthy of future investigation. AZD1775 exhibits single-agent activity, as well as synergy with conventional cytotoxic chemotherapy, and is a novel targeted agent that warrants further study in RMS. Electronic supplementary material The online version of this article (doi:10.1007/s00280-016-3077-8) contains supplementary material, which is available to authorized users.

Osteosarcoma is an orphan disease with only 900 patients diagnosed each year in US. Most patients are adolescents with small number of older patients. The 5-survival rates for those with metastatic disease is only 30%. Frustratingly, there has been little change in treatment options (chemotherapy, surgery and radiotherapy) due to the difficulty of conducting clinical trials in this rare but deadly cancer. To address this, strong pre-clinical trial information is required to motivate clinical trial design. In vitro and in vivo, we identified that the pan-HDAC inhibitor, panobinostat is highly effective in limiting osteosarcoma growth and metastasis. Panobinostat is approved for the treatment of other malignancies but has noted toxicities. Therefore, to identify therapeutic targets, we explored the HDACs responsible for driving osteosarcoma metastasis and the specific genes through which those HDACs mediated their effects. Our data shows that HDAC1 and HDAC2 are key for osteosarcoma survival using siRNA approaches. Use of the HDAC1/2 selective inhibitor romidepsin in vitro and in vivo supported this finding. To identify targets being regulated by HDAC1/2, we performed microarray and proteomics analyses on romidepsin treated osteosarcoma cells. We found and validated independently that, SLC17A7, a metabolic vesicular glutamate transporter to be highly induced in response to romidepsin treatment; >100 fold more than base line in multiple osteosarcoma cell lines. Functionally, SLC17A7 allows entry of glutamate into the synaptic vesicles from cytoplasm and releases the glutamate from the cells via exocytosis. In our studies, we have seen that romidepsin treatment leads to reduced glutamate levels in the conditioned media and cell death indicating key roles for SLC17A7 in driving osteosarcoma progression and metastasis. In conclusion, our data shows that HDAC1/2 suppression of SLC17A7 is a novel means of promoting osteosarcoma progression and metastasis. Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Diana Yu, Damon R. Reed, Conor C. Lynch. Epigenetic silencing of SLC17A7 promotes osteosarcoma growth [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-044.

Gliomas are the most common primary central nervous system tumor but the molecular mechanisms responsible for their development and progression are not completely understood. Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II-III glioma and secondary glioblastoma (GBM) but functional validation of this alteration has been hampered by difficulties generating autochthonous mouse models harboring mutant IDH. In this study, we used the RCAS/TVA glioma mouse model to assess the role of IDH1(R132H) in glioma development in the context of clinically-relevant cooperating genetic alterations in vitro and in vivo. Immortal Cdkn2a, Pten, and Atrx-deficient astrocytes expressing IDH1(R132H) exhibited elevated (R)-2-hydroxyglutarate (2-HG) levels, reduced NADPH, increased proliferation, and anchorage-independent growth. Cell proliferation and soft agar growth was significantly enhanced by co-expression of PDGFA. Substitution of IDH1(R132H) with a cell membrane-permeable [tri-fluoromethyl benzyl (TFMB)-esterified] version of (R)-2HG mimicked the phenotype observed in cells expressing IDH1(R132H). Interestingly, addition of TFMB-(R)-2HG further enhanced colony formation in cells expressing IDH1(R132H) while treatment with the mutant IDH1 inhibitor AG-120 reduced anchorage independent growth. These data suggest that the effects of IDH1(R132H) are mediated by 2-HG and not loss of native IDH1 activity. Although not sufficient on its own, IDH1(R132H) cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo. These tumors resembled proneural human mutant IDH1 GBM genetically, histologically, and functionally. Our findings support the hypothesis that IDH1(R132H) promotes glioma development through production of 2-HG. This model validates a role for IDH1(R132H) in glioma development, permits mechanistic studies that further our understanding of oncogenesis in this context, and enables rapid testing of rationale therapeutic strategies designed to combat this deadly disease.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear.A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations.One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005).Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.

Background Antibiotics are commonly overused in the treatment of ventilator-associated tracheitis (VAT). Antimicrobial stewardship programs (ASP) optimize antibiotic prescribing and decrease unnecessary antibiotic use. At our institution, clinicians who have initiated antibiotics for the treatment of tracheitis do not agree with ASP recommendations in 35% of cases. The goal of this study was to compare antibiotic duration and treatment failure in children treated for VAT who did and did not receive an ASP recommendation. Methods We performed a retrospective cohort study to evaluate VAT treatment courses and subsequent treatment failures. For this study, we included all children who were hospitalized from January 2009 to February 2013 and reviewed by ASP for receiving a monitored drug with an indication of VAT. Treatment failure was defined as a patient requiring a repeat course of antibiotics with an indication of VAT within 14 days of completing a previous antibiotic course. Results A total of 220 VAT cases were included. ASP provided recommendations to optimize antibiotics in 44 cases (20%) and stop antibiotics in 53 cases (24%). The shortest duration of treatment (days) was prescribed when ASP recommended stop therapy (median 4.7, IQR 3.0–6.5) when compared with no intervention (6.0, 4.3–7.0; P = 0.01). Treatment failure occurred in 33 (15%) cases. No difference in antibiotic duration was observed between those who did or did not fail (6.3 vs. 5.9, respectively; P = 0.11). Additionally, treatment failure rates did not differ by ASP recommendation status (no recommendation 15%; optimize 18%; stop 11%; ID involved 20%; P = 0.78). Conclusion ASP recommendations for the treatment of pediatric VAT were not associated with an increased likelihood of treatment failure. Further work is needed to standardize the diagnosis and treatment of VAT to avoid unnecessary antibiotic use in these children. Disclosures All authors: No reported disclosures.

Background Regulatory agencies strongly encourage the development of hospital-based antimicrobial stewardship (AS) programs (ASP) to support appropriate antimicrobial prescribing. One component of an ASP is a multidisciplinary team. While the initial conception centered on a physician and a pharmacist, including nurses in AS has been highlighted due to the nurse’s vital role in patient care. There are little data on nurses’ knowledge, attitudes, and practices in AS. The aim of this project was to determine ideas, concerns, and gaps in knowledge of bedside nurses at a local hospital level. Methods This project was conducted at an academic pediatric hospital in an urban setting. A survey was designed to obtain nurses’ attitudes and views of AS and to address their frequency and confidence of various AS activities, including triage/isolation, allergy history, obtainment of appropriate diagnostic studies, interpretation of microbiology results, antibiotic de-/escalation, intravenous-to-oral switches of antibiotics, patient/family education, and identification of antimicrobial-associated adverse events. Respondents were asked to identify barriers to AS participation and to propose educational topics of interest. The survey was sent out to nurses, with 3 weekly reminders. Results 155 of 513 respondents initiated the survey (response rate 30.2%); however, 112 participants completed the entire survey (completion rate 72.3%). Of the respondents, 67% believed that nurses should provide AS but only 32% themselves provided AS; furthermore, 26% of the respondents felt that nurses were equipped to provide AS. The most frequent AS activity reported was patient/family education while the least reported activity was the interpretation of microbiology reports. A correlation was identified between frequency and confidence of performing various AS-related tasks (R2 = 0.95). Barriers identified by respondents included antimicrobial knowledge, other timely priorities, and inclusion of nurses on bedside rounds. Conclusion Although few respondents felt prepared to provide antimicrobial stewardship, the majority (74%) were interested in learning more about how nurses could be involved. We are currently developing a nurse-centric educational curriculum based on the feedback from the survey. Disclosures All authors: No reported disclosures.

Background Assessing appropriateness of hospital antibiotic use is typically a labor-intensive task for antimicrobial stewardship teams and relies heavily on clinician judgement rather than a systematic process. Vancomycin is a frequently used agent that is a common stewardship target. We developed an algorithm to automatically classify the appropriateness of vancomycin days of therapy (DOTs) based upon electronic health record data. Methods We constructed a retrospective cohort of Oregon Health and Science University (OHSU) Hospital and Doernbecher Children’s Hospital patients admitted August 1, 2017 to July 31, 2018 receiving vancomycin. Data were collected on demographic, encounter, pharmacy, microbiology, and surgery data. An electronic algorithm was applied to classify vancomycin DOTs as appropriate, inappropriate, or indeterminate. Inappropriate use was defined as any case in which there was an opportunity for de-escalation as identified using microbiology data, ICD-10 codes, and procedure codes. Results We included 4,231 encounters; 493 (12%) were pediatric patients. Our algorithm automatically classified 59%, 3%, and 38% of encounters as having either appropriate, inappropriate, or indeterminate DOTs, respectively. Forty-four percent of all encounters received no more than a 24-hour course of vancomycin and were considered appropriate empiric therapy; half of these were attributed to surgical prophylaxis. Nine percent of all encounters had vancomycin administered within 3 days of a blood, sputum or tissue culture in which either a methicillin-resistant Staphylococcus species or an ampicillin-resistant, vancomycin-susceptible Enterococcus species was isolated and were classified as appropriate. Six percent of all encounters had cultures in which only Gram-negatives, fungi, or yeast were isolated and were therefore considered appropriate in the empiric period (≤48 hours) but inappropriate thereafter. Conclusion Automated assessments of antibiotic appropriateness could facilitate more informed antimicrobial stewardship initiatives and serve as a valuable stewardship metric. Characterization of indeterminate vancomycin use may inform increased automated classification. Further effort is needed to validate these assessments. Disclosures All authors: No reported disclosures.

Osteosarcoma (OS) is the most common bone malignancy in adolescents. At the time of initial diagnosis, approximately 15% of the patients present with metastatic disease in lungs. Prognosis for this cohort is grim with 5-year overall survival rates at 30%. Frustratingly, these statistics have changed little over the past three decades, in part due to the lack of progress in identifying effective therapies and difficulty in coordinating robust clinical trials in this relatively rare malignancy. To address this, we previously screened 54 FDA approved drugs against 5 different OS cell lines and identified the histone deacetylase inhibitor (HDAC), panobinostat (Pano) as having potent effects in vitro. Here, we explore whether Panobinostat is effective in preventing multiple stages of OS progression in vivo using the K7M2 and SAOS2LM7 pre-clinical models of the disease. Pano prevents the growth of primary OS and lung metastasis. Mice were intratibially inoculated with K7M2-Luc cells and then treated with vehicle (n=11) or panobinostat (n=10; 10 mg/kg for all in vivo studies). Tumor growth was measured by bioluminescence (RLU). The clinical endpoint was 1x106RLU (IVIS-200). Primary OS growth was significantly slower in the panobinostat treated group (p Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Diana Yu, Damon R. Reed, Conor C. Lynch. HDAC inhibition significantly reduces primary and lung metastatic osteosarcoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2016.

Background While antibiotics frequently cause adverse drug reactions (ADR), the rate of antifungal (AF) ADR is unknown. The mechanisms of AF ADR and cross-reactivity among a drug class (i.e., azoles) are poorly understood. Given the use of AF therapy is on the rise, it is important to better understand the prevalence of AF ADR and how these reactions influence prescribing. Methods Thirty-two hospitals participated in a quarterly pediatric point prevalence survey that documented details on all admitted patients 0–17 years receiving any systemic antimicrobials, including drug, dose, and documented history of an antimicrobial ADR between June 2016 and December 2017. Patients who were recorded as receiving at least one systemic AF were included. A comparison of AF prescribing practices between those with and without an AF ADR was performed. Results Among 13,179 total patients, 2,213 AF were prescribed to 2,101 unique patients. The most common indications for AF included prophylaxis (64%), fever with neutropenia (4%), neonatal sepsis (3%), and catheter-related bloodstream infection (3%). The prevalence of patients with any documented AF ADR was 2.9%. Amphotericin was most commonly associated with an ADR. Fluconazole was the most commonly prescribed AF in those with no ADR (49%) when compared with those with an AF ADR (13%; P < .05). Patients with an amphotericin ADR were more likely to receive voriconazole (29%) when compared with those without (15%; P < .05). Interestingly, posaconazole use was highest in those with an azole ADR (22%) when compared with those with no azole ADR (4%; P < .05). Echinocandin ADR were infrequent, and those with a reported ADR still received an echinocandin 62% of the time. Conclusion Significant differences in antifungal prescribing exists based on ADR status. More work is needed to be able to effectively classify AF ADR, determine safe prescribing practices in those with an AF ADR, and evaluate outcomes associated with AF ADR status. Disclosures All authors: No reported disclosures.

Background The clinical impact of antimicrobial stewardship programs (ASP) on children admitted to the intensive care units (ICU) or oncology wards is unknown. The objective of this study was to determine whether following ASP recommendations improved clinical outcomes in pediatric ICU and oncology patients. Methods We performed a retrospective cohort study to evaluate the relationship between ASP recommendation(s) agreement and patient outcomes (hospital length of stay [LOS], 30-day mortality, hospital readmission within 30 days, and hospital-onset Clostridium difficile infection [HO-CDI]) in a high-risk (HR) population. For this study, we included all children admitted to the neonatal ICU (NICU), pediatric ICU (PICU), or oncology (Onc) ward from March 2008 to March 2017 who underwent an ASP review. Unadjusted differences in LOS, mortality, readmissions, and HO-CDI were compared between cases of ASP agreement and disagreement. Generalized linear mixed models were used to control for potential confounders and account for patients with >1 ASP review. Results ASP performed 11,545 antimicrobial reviews (PICU 3,628; NICU 2,824; Onc 5,093) on 7,329 unique patients. ASP provided 2,088 recommendations. Stop antibiotics was the most common recommendation (N = 1,045; 50%) followed by narrow antibiotics (N = 474; 23%), and obtain an infectious disease consultation (N = 334; 16%). Agreement with ASP by the prescribing clinician occurred in 70% of cases. Overall, 356 (5%) patients died, 87 (1%) had HO-CDI, and 2,608 (36%) were readmitted. Agreeing with an ASP recommendation was not associated with increased odds of mortality or readmission. Agreement with an ASP recommendation was not associated with decreased odds of acquiring HO-CDI (adjusted OR 1.58, 95% CI: 0.35, 7.26). Among HR patients with a single ASP review, the median LOS was significantly shorter for clinicians who agreed with recommendations vs. disagreed (10.3 days vs. 12.5 days, respectively, P = 0.02). Conclusion Agreement with an ASP recommendation was associated with a shorter LOS and no increase in readmissions or mortality. Further stewardship strategies are needed to optimize antimicrobial use in this HR pediatric population. Disclosures All authors: No reported disclosures.

Systemic therapy has improved osteosarcoma event-free and overall survival, but 30–50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. We found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of two-drug combinations to define synergistic combinations by Chou and Talalay analysis. We then evaluated order of addition to choose the combinations that may be best to translate to the clinic. We conclude that the repurposing of chemotherapeutics in osteosarcoma by using an in vitro system may define novel drug combinations with significant in vivo activity. In particular, combinations of proteasome inhibitors with histone deacetylase inhibitors and ixabepilone and MK1775 demonstrated excellent activity in our assays.

The use of complementary and alternative medicine (CAM) amongst oncology patients is widespread. There is little data regarding the sources of clinical information on CAM that oncology practitioners utilise. The aim of this study was to investigate the sources of clinical information on CAM utilised by Australian oncology practitioners. A structured self-administered questionnaire was sent to Australian oncology practitioners, defined as oncologists, oncology pharmacists and pharmacists at drug information centres (DICs). Key information was sought on their level of satisfaction with the accessibility, reliability and usefulness of this information and the frequency of, and initiating factors for, seeking this information. A substantial proportion of oncologists (57.1%) reported having never sought information on CAM, compared to 27.3% of oncology pharmacists, and 18.8% of DIC pharmacists. Oncologists most commonly reported seeking information on CAM one to three times per year compared to four to ten times per year for oncology pharmacists. Databases were the most common information source used by oncologists (48.1%) and oncology pharmacists (91.7%) and the second most common information source used by DICs (92.3%). There was wide variation in the source of clinical information on CAM used by the three different professional groups. Oncology practitioners often seek information on CAM; however the frequency, nature and sources of information utilised varied widely. The usefulness and reliability of the sources utilised were inconsistent.

Activating mutations in BRAF have been identified in a significant number of human cancers including both pediatric and adult gliomas of varying grades. Specifically, the BRAFV600E mutation, which is the most common mutational variant, has been found in ~27% of pediatric anaplastic astrocytoma (WHO grade III), ~12% of pediatric glioblastomas (GBM, WHO grade IV), and ~5% of adult GBMs. Using the RCAS/TVA glioma mouse model system, we previously demonstrated that activated BRAF induces GBM formation in vivo when combined with Ink4a/Arf loss and Akt activation (Robinson et al, Oncogene, 2010). In this study, we used the modified inducible RCAN/TVA glioma mouse model, which allows for temporal regulation of BRAFV600E expression in vivo, to determine the dependence of these gliomas on continued MAPK signaling in the context of Pten and Ink4a/Arf loss. Viral delivery of BRAFV600E, Tet-off, and Cre into Nestin::TVA;Ptenlox/lox;Ink4a/Arflox/lox mice produced gliomas in 80% (20/25) of the animals. Of these tumors, 65% (13/20) resembled highly invasive GBM with a diffuse growth pattern, aberrant angiogenesis, and psuedopalisading necrosis. Histological characterization revealed pleomorphic tumors displaying a spectrum of cellular morphologies ranging from small round cells to spindle cells and giant cells. Administration of doxycycline (DOX) allowed for suppression of BRAFV600E expression, which resulted in tumor regression, as verified by MRI, and a significant increase in survival. Interestingly, more than half of the DOX treated animals experienced disease progression while on DOX. With recent reports of mixed clinical outcomes in patients treated with mutant BRAF inhibitors, this model may allow for the identification of resistance mechanisms and novel therapeutic strategies to improve the outcome for patients with BRAFV600E glioma.

Background: Malignant Peripheral Nerve Sheath Tumor (MPNST) is a malignant sarcoma that derives from a peripheral nerve or plexiform neurofibroma. Neurofibromatosis type 1 (NF-1) patients are particularly susceptible, with a higher risk, earlier onset, and worse prognosis. The major factor associated with MPNST and NF-1 is Neurofibromin 1, coded by the NF1 gene. NF1 mutation results in RAS hyperactivation. Chemotherapy for MPNST is currently limited, with poor prognosis for metastatic or unresectable tumors. Thus, the development of promising treatment solutions for MPNST to translate to clinical trials is required. Methods: Here, we seek to identify efficacious chemotherapeutic treatments for MPNST with a combination of drug screening and biological pathway analysis. We used our previously established preclinical system to test FDA approved or promising developmental agents against five cell line models for MPNST. We screened sixty agents with diverse mechanisms of action below published maximum plasma concentrations, and measured effects with a CellTiter-Glo viability assay. Promising agents were then tested in two-drug combinations, allowing for determination of synergism. We then examined the molecular effects of the top candidates with use of antibody arrays that permit detection of a series of phosphorylated proteins. Results: The group of most efficacious drugs was enriched with agents that target factors downstream of RAS, including MEK, mTOR, and PI3K inhibitors, with microtubule inhibitors, genotoxics, and HDAC inhibitors also demonstrating good results. Strong synergism was observed across our cell line models particularly in combinations containing the dual mTORC1/2 inhibitor INK128. Interestingly, drug sensitivity varied greatly between cell lines, correlating with relative NF1 protein and RAS-GTP levels. We analyzed the activation of the RAS pathway in response to drug treatment with antibody arrays and found that, following treatment, relative phosphorylation signal was more decreased compared to controls in cell lines with lower relative NF1 protein levels. Doxorubicin was able to reduce phosphorylation signal compared to controls to a level near comparable to targeted inhibitors, which could contribute to doxorubicin’s current usefulness against MPNSTs. Importantly, we identified combination treatments that were able to greatly reduce the relative phosphorylation signal of RAS pathway members versus control. Combinations containing INK128 resulted in the most pathway shutdown. These findings suggest that MPNSTs may be susceptible to combination treatments targeting RAS pathway members. Moreover, it may be possible to use pathway analysis as a diagnostic tool to predict drug tolerance. Citation Format: Elliot Kahen, Darcy Welch, Diana Yu, Christopher Cubitt, Jae Lee, Andrew Brohl, Damon R. Reed. RAS pathway activation and sensitivity to therapeutic agents is correlated with NF1 residual activity in malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1340. doi:10.1158/1538-7445.AM2017-1340

Background: Sarcomas are a heterogeneous group of mesenchymal malignant tumors that make up approximately 15% of all childhood tumors and represent the fourth most common group of malignancies in children, remaining common in young adults with cancer as well. While over 35 agents have been FDA approved for adult carcinomas in the past 3 years, little progress has been made in incorporating new agents into the chemotherapy plans for pediatric sarcomas in the past few decades. A system to rapidly evaluate many agents and combinations of agents which can immediately be translated into clinical trials in a clinically relevant manner is needed. Methods: Here, we seek to examine the therapeutic activity of single agent and combinations of FDA approved chemotherapy agents using high-throughput screening platforms, based on well-established childhood cancer cell line models for most prevalent forms of pediatric bone sarcomas (osteosarcoma and Ewing sarcoma). Taking into consideration past lessons learned from in vitro experiments, we designed stringent screening conditions that assess the candidate compounds at clinically-relevant concentrations and time of exposures that mimic the in vivo pharmacokinetics in an effort to maximize the translational potential of these results to the clinical setting. Fifty-four agents, mainly FDA approved but also including agents with promising mechanism of action or preclinical data were screened across 5 cell lines for each histology. Caspace glo and cell titer glo assays were used to determine apoptosis and cell viability at the maximal achievable serum concentration from phase I studies and at two lower concentrations. Promising agents were then studied in 2 drug combinations to evaluate for synergy with careful attention to metabolism pathways, existing clinical data for combinations, and non-overlapping toxicities. Combinations of FDA approved agents with promising therapeutic efficacy and predicated non-overlapping toxicities will be translated to the clinic using the established Sunshine Project network. Results: Our screening results indicate that a number of FDA approved chemotherapy agents, evaluated at clinically relevant concentrations and exposure times, significantly reduced cell viability and induced up regulation of caspase3/7 activities across all cell lines. These findings suggest promising opportunities for developing combinational approach to treating childhood bone sarcomas and can be utilized to explore other pediatric tumors with existing cell lines. Citation Format: Diana Yu, Christopher Cubitt, Daniel Sullivan, Damon Reed. Assessing combinations of FDA approved chemotherapy in childhood sarcoma cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 812. doi:10.1158/1538-7445.AM2014-812