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Growing evidence from observational studies and clinical trials suggests that psychedelics such as lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, and psilocybin may hold treatment potential for alcohol, opioid, tobacco, and other substance use disorders (SUDs). The mechanisms by which psychedelics might exert therapeutic efficacy in these conditions have not been fully elucidated, although the subjective effects of the psychedelic experience appear necessary. Given the often profound nature of psychedelic experiences, they may serve as turning points in the life narratives of users, eliciting lasting behavioral change. To better characterize the extent of psychedelics' therapeutic potential in patients with SUDs, randomized, placebo-controlled trials are needed, with some already underway. However, even if such trials demonstrate compelling evidence of psychedelics' therapeutic potential, these substances may still face considerable challenges to integration into the current SUDs treatment paradigm because of clinician concerns about their addictive potential and philosophical objections from 12-step facilitation programs. [ Psychiatr Ann. 2022;52(9):365–370.]

Background. Clinical trials have demonstrated that subanesthetic intravenous ketamine exerts antidepressant effects lasting a week or longer postinfusion, as well as antisuicidal effects starting approximately 4 hours postinfusion and lasting 72 hours or longer. These findings have generated considerable enthusiasm within psychiatry. However, reports of treatment-emergent suicide attempts and completed suicides in some patients receiving ketamine or the ketamine enantiomer esketamine have begun to emerge. Here, we contribute to the small literature on suicide-related adverse events and ketamine with an unusual case of a patient who died either by suicide or accidental death via autoerotic asphyxiation approximately four days after a ketamine infusion. Case Presentation. The patient was a 28-year-old man with major depressive disorder, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, autism spectrum disorder without intellectual disability, attention deficit hyperactivity disorder, hypothyroidism, low testosterone, and sleep apnea referred for management of treatment resistant depression. His depression briefly remitted with ketamine, and suicidality briefly disappeared. However, these improvements were short-lived. Four days after his seventh and final scheduled ketamine infusion, the patient was found dead, presumably due to autoerotic asphyxiation. Interestingly, ketamine use has been reported in association with autoerotic asphyxiation. However, given our patient’s recent severe suicidality, methods of his past suicide attempts, and family history of suicide, death from suicide seems more likely. Discussion. Here we consider the possibility of whether ketamine may have contributed to the patient’s possible suicide, either via a direct worsening of his suicidality or psychological withdrawal following cessation of treatment, given recent concerns about psychological withdrawal's potential role insuicides following esketamine treatment. Conclusions. Though we are uncertain about the patient’s cause of death, this case provides an opportunity to highlight important gaps in our understanding of the suicide-related risks of subanesthetic intravenous ketamine treatment for mood disorders and suicidality.

Background: HER2 mutations are oncogenic drivers in a subset of metastatic breast cancers (MBC). Neratinib (N) is an oral, irreversible pan-HER tyrosine kinase inhibitor with preclinical and clinical activity against HER2 mutations. Genomic analyses from paired biopsies following N ± fulvestrant (F) suggest that resistance to N may occur via amplification of the mutant allele or by acquisition of secondary HER2 mutations. Addition of trastuzumab (T) to N+F showed encouraging clinical activity with durable responses in the SUMMIT trial in hormone receptor-positive (HR+), HER2-mutant MBC, including patients (pts) who had previously received cyclin-dependent kinase 4 & 6 inhibitors (CDK4/6i) [Jhaveri et al. SABCS 2020]. On the basis of these findings, and in order to better understand the contribution of N to the activity of the N+F+T combination, SUMMIT has recently been expanded to include a randomized Simon 2-stage comparison of N+F+T vs. F+T vs. F in pts with HR+, HER2-mutated, HER2-negative MBC who were exposed to CDK4/6i. Enrollment for stage 1 is now complete (N+F+T, n=7; F+T, n=7; F, n=7), and results will be forthcoming once the data are mature. Here we report updated findings from the breast cancer cohorts of the SUMMIT trial for which data are currently available. Methods: The phase 2 SUMMIT trial (NCT01953926) enrolled pts with HR+, HER2-negative MBC whose tumors harbored activating HER2 mutation(s) identified by genomic sequencing. Prior to starting the randomized portion of the trial, these patients were enrolled in a non-randomized cohort and received N+F+T (oral N 240 mg/d, i.m. F 500 mg d1&15 of cycle 1 then q4w, i.v. T 8 mg/kg initially then 6 mg/kg q3w). Following initiation of the randomized portion of the trial, these pts received N+F+T, F+T or F (1:1:1 ratio; dose schedules as above). Pts with HER2-mutant triple-negative breast cancer (TNBC) were enrolled in a non-randomized cohort and received N+T (dose schedules as above). Loperamide prophylaxis was mandatory during the first 2 treatment cycles. There was no restriction on the number of prior lines of systemic therapy for MBC. Efficacy endpoints: investigator-assessed objective response rate and clinical benefit rate (RECIST v1.1 or other defined criteria); duration of response; best overall response. Results: Prior to enrolling the randomized cohort, 24 pts with HR+, HER2-mutated MBC who had previously received CDK4/6i were enrolled in the non-randomized cohort and received N+F+T, and 17 pts with HER2-mutant TNBC were enrolled and received N+T, as of 18-Jun-2021. Data for randomized pts are not yet mature. HER2 allelic variants across both cohorts (pts may have >1 mutation): kinase domain hotspots (n=26); exon-20 insertion (n=9); extracellular domain hotspot (n=4); exon-19 deletion (n=1); transmembrane domain missense (n=1); kinase domain non-hotspot (n=2). Efficacy findings are reported in the Table. Diarrhea was the most commonly reported adverse event: N+F+T (non-randomized cohort), 96%; N+T (TNBC cohort), 94%. No grade 4 diarrhea was reported. Conclusions: N+F+T is a promising combination for pts with HR+, HER2-mutated MBC with prior exposure to CDK4/6 inhibitors. N+T also showed encouraging activity in HER2-mutated TNBC. The first results from the randomized comparison of N+F+T vs. F+T vs. F in pts with HR+, HER2-mutated MBC (Simon stage 1 analysis) will be presented at the meeting. Table: Efficacy findingsHR+, HER2-mutated, HER2-non-amplified MBCHER2-mutant TNBCN+F+T (n=24)N+T (n=17)Confirmed objective response,a n (%)11 (46)5 (29)CR0 (0)1 (6)PR11 (46)4 (24)ORR, % (95% CI)46 (26–67)29 (10–56)Best overall response, n (%)13 (54)7 (41)CR0 (0)1 (6)PR13 (54)6 (35)Best overall response rate, % (95% CI)54 (33–74)41 (18–67)Medianb DOR, months (95% CI)14.4 (6.4–NR)NRClinical benefit, n (%)14 (58)6 (35)CR or PR11 (46)5 (29)SD ≥24 weeks3 (13)1 (6)CBR,b % (95% CI)58 (37–78)35 (14–62)aORR defined as either a CR or PR confirmed no less than 4 weeks after the response criteria are met; bCBR defined as confirmed CR or PR or SD for ≥24 weeks. Note: Tumor response is based on investigator tumor assessments per RECIST v1.1 for HR+, HER2-mutated cohort, and RECIST v1.1 or modified PERCIST for HER2-mutated TNBC cohort. CBR, clinical benefit rate; CI, confidence interval; CR, complete response; DOR, duration of response; F, fulvestrant; HR+, hormone receptor-positive; MBC, metastatic breast cancer; N, neratinib; NR, not reached; ORR, objective response rate; PERCIST, Positron Emission Tomography Response Criteria in Solid Tumors; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; T, trastuzumab, TNBC, triple-negative breast cancer. Citation Format: Komal Jhaveri, Haeseong Park, James Waisman, Jonathan W Goldman, Angel Guerrero-Zotano, Valentina Boni, Barbara Haley, Ingrid A Mayer, Adam Brufsky, Eddy S Yang, José A García-Sáenz, François-Clement Bidard, John Crown, Bo Zhang, Aimee Frazier, Irmina Diala, Lisa D Eli, Brian Barnett, Hans Wildiers. Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: Latest updates from the SUMMIT trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-10.

We report the case of a 32-year-old male with autism spectrum disorder (ASD) suffering from severe misophonia. After titrating risperidone to 2 mg twice a day, the patient reported a significant reduction in his symptoms and his Amsterdam misophonia scale-revised (AMISOS-R) score dropped by from 31 to 5. Upon discharge, the patient was noted to have decreased irritability and overall improved behavior and effect. This significant symptomatic improvement was likely not explained by inpatient admission alone or other simultaneous pharmacologic treatments, as the effect was seen during an isolated titration of risperidone with other treatments remaining constant. Although, unfortunately, follow-up findings indicated that the treatment was not curative for the patient, risperidone’s potential for treating misophonia may warrant systematic investigation.

Amid a reappraisal of the medicinal and societal worth of psychedelics in many countries, regulatory and financial barriers to conducting clinical research with these compounds appear to be receding. Still, there remains a strong need for a clearer understanding of naturalistic psychedelic use and its associated epidemiology, since this type of psychedelic use, which is growing in many places, will almost certainly always exceed clinical use. Furthermore, psychedelics behave differently depending on the settings in which they are used, meaning many research findings on their effects may significantly differ depending on the contexts in which they are observed. Therefore, improving the collection of data on real-world psychedelic use should be of higher priority for the public health community. Expanding data collection on psychedelic use in the United States National Survey on Drug Use and Health, an already vital tool for researchers examining naturalistic psychedelic use, could address this important public health need, helping ensure the general public, the scientific community, and regulators have access to high-quality information as peoples across the world reevaluate what psychedelics’ place in medicine and society should be.

Objectives A resurgence of research investigating the administration of psychedelic compounds alongside psychotherapy suggests that this treatment is a promising intervention for anxiety, depression, and existential distress in people with cancer. However, psychedelic treatment that induces a mind-altering experience potentially poses barriers to vulnerable cancer patients, and health-care practitioners may have concerns about referring their patients to trials investigating this approach. The aim of the current study was to investigate the perceptions of cancer health-care practitioners based in New Zealand and the USA related to psychedelic-assisted therapy. Methods This study utilized a cross-sectional survey of cancer health-care practitioners in New Zealand and the USA via convenience sampling to identify their perceptions about the concept of conducting psychedelic-assisted therapy with cancer patients. Results Participants perceived that (1) psychedelic-assisted therapy has the potential to provide benefit for cancer patients, (2) research in this area across a variety of domains is important, (3) work should consider spiritual and indigenous perspectives of health, and (4) there was willingness to refer patients to trials in this area, especially patients with advanced disease who were no longer going through curative treatment. Participants in the USA had greater awareness of psychedelics than the New Zealand sample; however, New Zealand participants more strongly believed that spiritual/indigenous factors should be considered in psychedelic-assisted therapy. Significance of results Cancer health-care practitioners in our sample considered research investigating the potential for psychedelic-assisted therapies to be important and may be more open to studies that start in palliative and end-of-life contexts.

Purpose: A key challenge in cancer drug development is optimizing the therapeutic index (TI), a measure of a treatment’s antitumor efficacy and its toxicity, such that the agent is effective in targeting the tumor with an acceptable safety profile. Despite the growing list of emerging treatment modalities, successful translation of a drug candidate into an effective therapeutic agent may be hampered by inability to dose the therapy within the TI. We have developed a novel platform for protein and/or antibody-based therapies by combining protein engineering with biopolymer physics to enhance antitumor mechanisms at lower treatment doses. Our long-term goal is to improve the TI of multiple therapeutic classes. Methods: A drug-engineering platform was developed based on multivalent protein (MVP) conjugates, wherein multiple copies (i.e., valency) of a therapeutic protein, such as monoclonal single-domain antibodies or interleukins, were covalently bound to soluble biopolymers, including heparin and modified celluloses (15 kDa-1.5 MDa). MVP valencies ranging from 2 to 200 protein copies (±10%) per polymer were generated, and the reproducibility of this process was verified by UV analysis and chromatography. The binding affinity of the MVPs to their targets was determined using biolayer interferometry and cell bioassays, and the hydrodynamic radius of the MVPs were measured using dynamic light scattering. Using longitudinal in vitro and in vivo fluorescence measurements of drug signal, the intratumoral (IT) retention, cellular internalization, and systemic distribution of each MVP was compared to that of equimolar unconjugated controls of the corresponding protein. Results: At high valency, the target binding affinity of MVPs was substantially greater than that of the unconjugated protein controls. MVPs with improved cell-receptor engagement could modulate the internalization/processing of antibody-drug conjugates. Multivalent conjugation also increased the hydrodynamic radius of the MVPs to >10-times larger than corresponding unconjugated proteins. This resulted in a high concentration of MVP therapeutics in solid tumors, as demonstrated by an extension of their IT half-lives by >5 times versus unconjugated controls in mouse models of multiple tumor types. Conclusions: An MVP platform can be applied to a wide range of therapeutic mechanisms. Our data demonstrate that MVP therapeutics can be localized within the tumor and potentially enable more potent tumor cell-killing responses compared with equimolar unconjugated protein controls. Thus, the MVP platform represents a compelling new tool for designing protein-based therapies. Further development of our MVP pipeline is continuing, with the aim of identifying a candidate for IND-enabling studies. Citation Format: Amy A. Twite, Adam Barnebey, Livia W. Brier, Brian Barnett, Wesley M. Jackson. A novel platform for protein engineering and modification to expand the therapeutic index of anti-tumor therapeutics [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 1525.

BackgroundThe conditions of diminished ovarian reserve and primary ovarian insufficiency, characterized by poor fertility outcomes, currently comprise a major challenge in reproductive medicine, particularly in vitro fertilization. Currently in the IVF industry, blastocyst developmental success rate per treatment is routinely overlooked when a live birth results from treatment. Limited data are available on this significant and actionable variable of blastocyst development optimization, which contributes to improvement of treatment success Women with elevated basal FSH concentration are reported to still achieve reasonable pregnancy rates, although only a few studies report correlations with blastocysts development. Diagnostic values of AMH/basal FSH concentrations can be useful for determining the optimal stimulation protocol as well as identification of individuals who will not benefit from IVF due to poor prognosis. The objective of this study is to identify actionable clinical and culture characteristics of IVF treatment that influence blastocyst developmental rate, with the goal of acquiring optimal success.Methods and findingsA retrospective observational study was performed, based on 106 women undergoing IVF, regardless of prognosis, over a six-month period from January 1, 2015 to June 31, 2015. Rate of high-quality blastocyst production, which can be used for embryo transfer or vitrification, per normally fertilized oocyte, was evaluated. Treatment was determined successful when outcome was ≥ 40% high-quality blastocysts. The data were initially evaluated with the Evtree algorithm, a statistical computational analysis which is inspired by natural Darwinian evolution incorporating concepts such as mutation and natural selection (see Supplementary Material). The analysis processes all variables simultaneously against the outcome, aiming to maximize discrimination of each variable to then create a "branch" of the tree which can be used as a decision in treatment. The final model results in only those variables which are significant to outcomes. Generalized linear model (GLM) employing logistic regression and survival analysis with R software was used and the final fitting of the model was determined through the use of random forest and evolutionary tree algorithms. Individuals presenting with an [AMH] of >3.15 ng/ml and a good prognosis had a lower success per treatment (n = 11, 0% success) when total gonadotropin doses were greater than 3325 IU. Individuals that presented with an [AMH] of Conclusions[AMH] is a superior indicator of ovarian stimulation response and an actionable variable for stimulation dose management for optimizing blastocyst development in culture. Women whose [AMH] is ≥3.2 mg/ml, having a good prognosis, and developing >12 mature follicles result in

Background: Patients with R/R AML, or intermediate-, high-, and very high-risk MDS have a poor prognosis with, respectively, a 5-year survival of Methods: This is a multicenter, open-label, Phase 1 study of NKX101 (Figure). The study will be conducted in 2 parts: Part 1 (dose finding) to determine the recommended Phase 2 dose (RP2D) of NKX101 utilizing a modified "3+3" enrollment schema. The study will enroll subjects with either R/R primary or secondary AML or R/R higher-risk MDS. Building on existing clinical data referenced above with non-engineered haplomatched NK cells, NKX101 manufactured from NK cells obtained from haplo-identical-related donors (H) will be used in Part 1. Part 2 (dose expansion) will further evaluate safety and tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PDn), and anti-tumor activity of NKX101 from unrelated, HLA-mismatched donors with separate expansion cohorts for patients with AML or MDS. Each dose is defined by the total number of viable CAR NK cells. The starting dose of NKX101 is 1 × 108 viable CAR NK cells where NKX101 will be administered on Days 0, 7, and 14 of a 28-day cycle following standard fludarabine/cyclophosphamide lymphodepletion. Three dose levels are planned (Table). The primary endpoint is incidence of adverse events, dose-limiting toxicities, clinically significant laboratory abnormalities, and determination of the RP2D. Secondary endpoints include evaluation of standard cellular PK parameters, PDn, immunogenicity, and anti-tumor responses. AML patients will be assessed for efficacy using updated ELN criteria (Döhner 2017) including measurable residual disease assessment, and MDS using modified IWG criteria (Cheson 2006). Exploratory endpoints are correlation of various degrees of HLA and KIR ligand match/mismatch between donor and recipient with primary and secondary safety, PK, and efficacy measures. Enrollment across multiple US sites is expected to start in late 2020. Disclosures Bachier: CRISPR: Honoraria; Juno Therapeutics, a Bristol-Myers Squibb Company: Honoraria; AlloVir: Honoraria; Sanofi: Speakers Bureau. Borthakur:Novartis: Research Funding; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Incyte: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Argenx: Consultancy; Abbvie: Research Funding; Jannsen: Research Funding; PTC Therapeutics: Research Funding; GSK: Research Funding; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; BioLine Rx: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; BMS: Research Funding. Hosing:NKARTA Inc.: Consultancy. Blum:Syndax: Membership on an entity's Board of Directors or advisory committees; Celyad: Research Funding; Leukemia and Lymphoma Society: Research Funding; Xencor: Research Funding; Amerisource Bergen: Honoraria. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Ojeras:Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Barnett:Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rajangam:Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Majhail:Mallinckrodt: Honoraria; Anthem, Inc.: Consultancy; Incyte: Honoraria; Nkarta Therapeutics: Honoraria. Nikiforow:Kite/Gilead: Honoraria; Nkarta Therapeutics: Honoraria; Novartis: Honoraria.

Genetically modified (GM) crops have achieved success in the marketplace and their benefits extend beyond the overall increase in harvest yields to include lowered use of insecticides and decreased carbon dioxide emissions. The most widely grown GM crops contain gene/s for targeted insect protection, herbicide tolerance, or both. Plant expression of Bacillus thuringiensis (Bt) crystal (Cry) insecticidal proteins have been the primary way to impart insect resistance in GM crops. Although deemed safe by regulatory agencies globally, previous studies have been the basis for discussions around the potential immuno-adjuvant effects of Cry proteins. These studies had limitations in study design. The studies used animal models with extremely high doses of Cry proteins, which when given using the ig route were co-administered with an adjuvant. Although the presumption exists that Cry proteins may have immunostimulatory activity and therefore an adjuvanticity risk, the evidence shows that Cry proteins are expressed at very low levels in GM crops and are unlikely to function as adjuvants. This conclusion is based on critical review of the published literature on the effects of immunomodulation by Cry proteins, the history of safe use of Cry proteins in foods, safety of the Bt donor organisms, and pre-market weight-of-evidence-based safety assessments for GM crops.

Background: Ado-trastuzumab emtansine (T-DM1) was approved by the FDA (02/2013) for the treatment of HER2+ metastatic breast cancer (mBC). This study assessed the real-world treatment (tx) patterns and medical costs in patients (pts) receiving T-DM1 or other targeted therapy [TT] or chemotherapy [CHT] for the tx of HER2+ mBC in the US. Methods: Adult women with mBC initiated on T-DM1 (index date) covered by their health plan ≥365 days before and ≥30 days after the index date were selected in a large US commercial claims database (Q2 2009–Q2 2014). Pts were observed from the index date to the end of health plan enrollment (study period). Patient characteristics at T-DM1 initiation were reported and tx patterns, including T-DM1 tx duration, discontinuation (no T-DM1 claim for ≥60 days) and switch to a new TT or CHT (among pts who discontinued T-DM1), were analyzed using Kaplan Meier (KM) analyses. In addition, T-DM1 pts were exactly matched to pts treated with another TT or CHT with similar profiles (same line of therapy and metastatic sites) on a 1:1 ratio. Tx change, defined as the initiation of or a switch to a new TT or CHT, and medical costs, measured up to 6 months after index date, were compared between pts receiving T-DM1 vs. other TT or CHT using multivariate Cox and GLM regression models, respectively. Results: A total of 240 T-DM1 pts were selected. Mean age was 54 years and pts had on average 2.9 distinct metastatic sites. Most prevalent sites were bone/bone marrow (69.6%), liver (47.1%), and lung/pleura (40.4%). Median time from mBC diagnosis to index date was 25.0 months. Pts were observed for a median of 5.6 months after index date. 8.3% of pts were initiated on T-DM1 in 1st line therapy, 30.4% in 2nd line, 15.4% in 3rd line, 17.5% in 4th line, and 28.3% in later lines. 9.2% of pts were initiated on T-DM1 concomitantly with hormonal therapy. Pts received a mean of 6.2 doses (median: 5.0) of T-DM1 over the study period. KM median T-DM1 tx duration estimate was 7.4 months. KM rates of T-DM1 discontinuation and switch at 6 months were 18.6% and 23.1%, respectively. Among the matched sample (n=228 in each cohort), T-DM1 pts had a lower risk of tx change (hazard ratio (HR) [95% CI]: 0.61 [0.40; 0.94]) compared to pts treated with other TT or CHT. Among T-DM1 pts, those receiving T-DM1 in 1st or 2nd lines of therapy had a lower risk of tx change than those receiving T-DM1 in later lines (HR [95% CI]: 0.34 [0.14; 0.80]). Once adjusted for potential confounding factors, T-DM1 pts had lower medical costs (adjusted, $1,630 per pt per month [pppm]) compared to pts treated with other TT or CHT (unadjusted, $5,075 vs. $6,204; p Conclusions: In this real-world study of mBC pts treated with T-DM1 shortly after its approval, most pts were initiated on T-DM1 in 2nd and later lines of therapy. When compared to pts with similar profiles initiated on other TT or CHT, T-DM1 pts had a lower risk of tx change and lower medical costs. Citation Format: Cloutier M, Guerin A, Heroux J, Emond B, Wu EQ, Masaquel A, Barnett B. What are the real-world treatment patterns and medical costs in patients with metastatic breast cancer treated with ado-trastuzumab emtansine?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-03.

Background: Ado-trastuzumab emtansine (T-DM1) approved for HER2+ unresectable locally advanced metastatic breast cancer (mBC) has been shown to significantly improve progression-free and overall survival in patients (pts) previously treated with trastuzumab and a taxane. However, little is known about real-world patterns and outcomes of T-DM1. Method: Pt-level data was collected from 90 US oncologists using an online chart extraction tool. Oncologists randomly selected eligible adult mBC pts started on T-DM1 on or after February 22nd 2013. Pts demographics, clinical information, and T-DM1 patterns and responses were described. Among pts whose T-DM1 response was assessed, univariate logistic regression models were used to assess the association between each factor and the probability of achieving complete response (CR). Results: Among the 303 pts, median follow-up after T-DM1 initiation was 5.1 months; 58.4% started T-DM1 in the 2nd half of 2014. Median age was 58 years, most pts were Caucasian (62.0%), median number of metastatic sites was 2, and 65.3% of pts had a mBC diagnosis (dx) within 1 year of the BC dx. Most common metastatic sites were liver (51.5%), lung/pleura (42.6%), and bone/bone marrow (41.6%). Median time from mBC dx to T-DM1 initiation was 7.1 months. 34.0% of pts started T-DM1 in 1st line for mBC, 55.4% in 2nd line, and 10.6% in later lines after mBC dx; most common prior treatments were trastuzumab, pertuzumab, and taxane. Best response achieved while on T-DM1 was CR in 17.5% of pts, partial response (PR) in 46.2%, stable disease in 11.2%, recurrence/progression in 3.6%, and the response was unknown in 21.5% of pts. CR/PR was achieved within a median of 5 months of T-DM1 initiation. At the end of follow-up, 80.2% were still on T-DM1, 3.3% had switched, 12.9% had discontinued without switching, and 3.6% were deceased. 44.9% of pts discontinued/switched after CR/PR and 32.7% after progression. When physicians were surveyed about their practice, 30.0% reported intention to interrupt T-DM1 after CR and 7.8% after an a priori determined number of cycles. Among pts whose response on T-DM1 was assessed (78.5%), race (Asian), initiation of T-DM1 shortly after mBC dx or in 1st line for mBC, ≤ 2 metastatic lesions, single metastatic site, and estrogen (ER)+ /progesterone (PR)+ at T-DM1 initiation were found to be significant predictors of CR, while pts who progressed between mBC dx and T-DM1 were less likely to achieve CR. Table 1. Factors Associated with CR Odds Ratio and 95% Confidence IntervalsAsian (vs non-Asian)2.9 (1.2 - 7.4)T-DM1 ≤ 1 year after mBC dx (vs > 1)3.2 (1.4 - 7.6)T-DM1 in 1st line after mBC dx (vs later lines)3.8 (2.0 - 7.2)≤ 2 metastases (vs>2)3.8 (1.9 - 7.6)1 metastatic site (vs >1)4.4 (2.3 - 8.4)ER+/PR+ (vs other status)4.9 (2.5 - 9.7)Progression between mBC dx and T-DM1 (vs no progression)0.2 (0.1 - 0.4) Conclusions: Most pts started T-DM1 as 1st or 2nd line therapy for mBC and were still treated with T-DM1 at the end of follow-up. CR/PR, assessed by treating oncologists, was achieved in >50% of pts within 5 months of T-DM1 initiation. Citation Format: Gauthier G, Guerin A, Zhdanava M, Wu E, Masaquel A, Barnett B. A chart review of patient characteristics, treatment patterns and response in metastatic breast cancer patients treated with ado-trastuzumab emtansine in first-line therapy and beyond. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-04.

Background: Previous studies found differences in treatment patterns and costs by SOC for first-line chemotherapy treatment for both early stage and metastatic breast cancer (esBC and mBC) in commercial populations. This study extends the research to a predominantly Medicare population comparing chemotherapy treatment patterns, cost and quality of care in physician office (PO) and hospital outpatient (HO) centers. Methods: First-line chemotherapy or biologic therapy for esBC and mBC patients was compared by SOC. Patients initiating infusion therapy in 2008–2012 were identified in Humana medical claims data. First-line length of therapy (LOT) in days and number of infusions (NI) were calculated. SOC cohort (HO vs PO) was based on where the patient received ≥90% of their infusions. Total healthcare costs based on medical and pharmacy claims were assessed. Differences in quality indicators, use of infusions or hospitalizations 30 days prior to death were evaluated. SOC differences were assessed using X2, T-tests and Wilcoxon Rank Sum (Wil) tests. P-values are for X2 and Wil tests. Cost-related results are from generalized linear models adjusted for age, sex, comorbidity and geographic region. LOT and NI are presented as median (IQR). Results: A total of 2,784 esBC patients (73% PO and 27% HO) and 1,602 mBC patients (64% PO and 36% HO) were identified. Most patients (67%) were Medicare beneficiaries. Mean comorbidity index was similar by SOC for esBC patients (PO 4.2, HO 4.1, p=0.3308) but higher in HO for mBC patients (PO 7.5, HO 7.9, p=0.0003). LOT in days for esBC was greater in the PO for anthracycline-based therapy, PO 64(43-72), HO 47(43-64), p=0.0420 and taxane-based therapy, PO 64(64-106), HO 64(64-76), p=0.0005. NI for esBC was greater in the PO for patients on biologic and cytotoxic therapy, PO 21(17-29), HO 18(16-25), p=0.038 and taxane–based therapy PO 4(4-6), HO 4(4-4), p=0.0005. No difference in LOT by SOC was seen for mBC patients; however, patients on taxane-based therapy had a greater NI at the PO 6(4-12) vs HO 5.5(4-9), p=0.0225. Total healthcare costs were higher in the HO vs PO setting for esBC and mBC patients. Costs were 22% higher in the HO $51,191 vs PO $41,943, p There were no statistically significant differences in use of infusions or hospitalizations 30 days prior to death among Medicare patients. Among 223 esBC and 369 mBC Medicare patients who died, use of infusions prior to death was 24% for HO and 16% for PO among esBC, p=0.2357 and 23% for HO and 26% for PO among mBC, p=0.5319. Hospitalizations prior to death were 59% for HO and 59% for PO for esBC, p=0.9940 and 60% for HO and 55% for PO for mBC, p=0.3105. Conclusion: Differences by site of care, particularly in healthcare costs, were found in a mostly Medicare population of esBC and mBC patients. Patients in the HO setting had shorter length of therapy and fewer infusions, but had higher total healthcare costs than those in the PO setting. Quality indicators, infusions and hospitalizations prior to death were similar by site of care. Future research will focus on other quality indicators and patient satisfaction. Citation Format: Masaquel A, Hopson S, Casebeer A, Drzayich-Jankus D, Tao Z, Stemkowski S, Howe A, Patton J, Small A, Barnett B. First-line chemotherapy for breast cancer patients by site of care (SOC): Treatment patterns, cost and quality indicators. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-16-04.

This Review covers a sequence of key discoveries and technical achievements that eventually led to the birth of the lithium-ion battery. In doing so, it not only sheds light on the history with the advantage of contemporary hindsight but also provides insight and inspiration to aid in the ongoing quest for better batteries of the future. A detailed retrospective on ingenious designs, accidental discoveries, intentional breakthroughs, and deceiving misconceptions is given: from the discovery of the element lithium to its electrochemical synthesis; from intercalation host material development to the concept of dual-intercalation electrodes; and from the misunderstanding of intercalation behavior into graphite to the comprehension of interphases. The onerous demands of bringing all critical components (anode, cathode, electrolyte, solid-electrolyte interphases), each of which possess unique chemistries, into a sophisticated electrochemical device reveal that the challenge of interfacing these originally incongruent components often outweighs the individual merits and limits in their own properties. These important lessons are likely to remain true for the more aggressive battery chemistries of future generations, ranging from a revisited Li-metal anode, to conversion-reaction type chemistries such as Li/sulfur, Li/oxygen, and metal fluorides, and to bivalent cation intercalations.

Background Trastuzumab reduces the risk of relapse in women with HER2+ early stage breast cancer. Yet, little information exists on the timing of trastuzumab initiation and its association with relapse and survival outcomes in these patients. The study aimed to investigate the impact of delaying the initiation of adjuvant trastuzumab treatment for >6 months on time to relapse, overall survival, and relapse-free survival among patients with HER2+ early stage breast cancer who did not receive neoadjuvant therapy. Methods Adult women initiating trastuzumab adjuvant therapy within 1 year of breast cancer surgery who did not receive neoadjuvant therapy were selected from the US Department of Defense health claims database from 01/2003 to 12/2012 (N = 2,749). By design, participants had to be alive and relapse-free at the time they initiated adjuvant trastuzumab. Patients were classified into two groups based on the time from breast cancer diagnosis to trastuzumab initiation: ≤6 months and >6 months. An algorithm based on secondary neoplasm ICD9 codes along with treatment gaps and initiations was used to identify relapses. Percent relapses and/or deaths were reported by study groups and compared using χ2 tests. The impact of delaying trastuzumab initiation on time to relapse, overall survival, and relapse-free survival was estimated from Cox regression models adjusted for age, overall comorbidity profile at the time of the BC diagnosis (Charlson index), type of surgery (breast conserving vs. breast removing), and radiotherapy (prior to the initiation of trastuzumab). In all three Cox models the follow-up started at adjuvant trastuzumab initiation. Results Of 2,749 women who met the selection criteria, 79.3% initiated adjuvant trastuzumab ≤6 months of diagnosis and 20.7% initiated adjuvant trastuzumab >6 months after the diagnosis (Table). Patients who delayed the initiation of trastuzumab for >6 months were younger (57.2% aged 6 months after diagnosis had a higher risk of relapse, death, or relapse/death than those who initiated trastuzumab ≤6 months of diagnosis in both unadjusted and adjusted analyses (Table). N events (% events)Hazard Ratio (95% CI) ≤6 months group N = 2,180>6 months group N = 569p-value>6 months group vs ≤6 months groupRelapse outcome333 (15.2%)134 (24.3%)< .0011.40 (1.14 - 1.72)*Death outcome (overall survival)138 (6.3%)64 (11.6%)< .0011.44 (1.06 - 1.96)*Relapse or death outcome (Relapse-free survival)386 (17.6%)148 (26.8%)< .0011.33 (1.09 - 1.61)**p-value < .05 Conclusions The results of this population-based study among patients with HER2+ early stage breast cancer who did not receive neoadjuvant therapy suggest that delays of over 6 months in the initiation of trastuzumab among HER2+ early stage breast cancer patients are associated with a higher risk of relapse and shorter overall survival and relapse-free survival. Disclaimer Research derived from an IRB approved protocol at Naval Medical Center Portsmouth, VA. The views expressed in this abstract are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army, Department of the Navy, Department of Defense or the United States Government. Dr. C.G. and Dr. K.M. are members of the U.S. military. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that 'Copyright protection under this title is not available for any work of the United States Government.' Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person's official duties. Citation Format: Christopher M Gallagher, Kenneth More, Anthony Masaquel, Tripthi Kamath, Annie Guerin, Raluca Ionescu-Ittu, Marjolaine Gauthier-Loiselle, Roy Nitulescu, Nicholas Sicignano, Brian Barnett, Eric Wu. Delay in trastuzumab initiation leads to decreased overall survival in patients with HER2+ early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-21-03.

Purpose The NSABP Trial B-31 and NCCTG Trial N9831 (B-31/N9831 trials, Romond et al. in N Engl J Med 353:1673–84, 2005. doi:10.1056/NEJMoa052122; Perez et al. in J Clin Oncol 32:3744–52, 2014. doi:10.1200/JCO.2014.55.5730) established the efficacy of adjuvant trastuzumab for patients with HER2-positive early stage breast cancer. We aimed to estimate the overall survival (OS) and relapse-free survival (RFS) of HER2-positive non-metastatic breast cancer patients treated with adjuvant trastuzumab in a clinical practice setting in the United States. Methods Adult women initiating adjuvant trastuzumab within 1 year of breast cancer surgery were identified in the health claims database of the US Department of Defense (01/2003–12/2012). OS and RFS unadjusted rates at 4 and 6 years after the first trastuzumab treatment following the breast cancer diagnosis were estimated from Kaplan–Meier analyses. Results The study sample included 3188 women followed for a median of 3.3 years after trastuzumab initiation and treated continuously with trastuzumab for a median of 12 months. The OS rates (95 % confidence intervals) at 4 and 6 years were 90.0 % (88.6–91.2) and 87.1 (85.3–88.6), respectively. The corresponding RFS rates were 75.8 % (74.0–77.5) and 72.7 (70.7–74.7), respectively. The OS and RFS rates at 6 years reported in the B-31/N9831 trials were 89.8 and 81.4 %, respectively. Conclusions OS rates estimated in this study were in range with those estimated in the B-31/N9831 trials, while RFS rates were lower. However, patients in the B-31/N9831 trials were younger and possibly had fewer comorbidities than patients in the current study; these differences were not adjusted for in the crude OS and RFS analyses. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-2008-9) contains supplementary material, which is available to authorized users.

Objective: This retrospective study compared the real-world incidence and costs of systemic treatment-related adverse events (AEs) in patients with metastatic breast cancer in a Medicaid population. Methods: Insurance claims data for adult women who received biologic or chemotherapy (± hormonal therapy) for metastatic breast cancer between 2006–2013 were extracted from the Truven Health MarketScan® Multi-State Medicaid database. Incidence of AEs (per 100 person years) and average monthly AE-related healthcare costs (per-patient-per-month) during each line of therapy (first or later lines) were estimated. The association between AEs and total all-cause healthcare costs was estimated using multivariable regression. Results: A total of 729 metastatic breast cancer patients were analyzed. Hematological (202.3 per 100 person years) and constitutional AEs (289.6 per 100 person years) were the most common class of AEs reported. Unadjusted per-patient-per-month AE-related expenditure by class were highest for hematological AEs ($1524), followed by gastrointestinal ($839) and constitutional AEs ($795), with anemia ($942), nausea/vomiting ($699), and leukopenia/neutropenia ($550) having incurred the highest total AE-related costs. Adjusted total all-cause monthly costs increased with the number of AEs ($19,701 for >7 AEs, $16,264 for 4 − 6 AEs, and $13,731 for 1 − 3 AEs) compared to no AEs ($5908) (all p Conclusions: Among metastatic breast cancer patients treated with systemic therapy in a Medicaid population, AEs were associated with significant increases in costs, which increased with the number of AEs experienced. Therapies associated with a lower incidence of AEs may reduce cost burden and improve patient outcomes.

Purpose The antibody-drug conjugate trastuzumab emtansine (T-DM1) has improved outcomes in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), as demonstrated in phase III studies. Few data approximating its use in routine clinical practice are available. Methods The T-DM1 Patient Access Study was an expanded-access, multicenter study of T-DM1 in US patients with pretreated HER2-positive locally advanced breast cancer or MBC. The primary endpoint was safety. The secondary endpoint was investigator-assessed objective response rate among patients with measurable disease at baseline. Data are presented for the first 215 enrolled patients. Results The median number of prior systemic MBC agents was 8 (range, 3-23). At baseline, median left ventricular ejection fraction was 60%, and 52.6% of patients had nonclinically significant cardiovascular disease. Median T-DM1 treatment duration was 5.0 months (range, 0-29 months; median follow-up, 5.9 months), with 18.6% having received more than 18 cycles. The most common any-grade adverse events were fatigue (50.7%) and nausea (38.1%). Adverse events of grade 3 or greater were reported in 46.5%, most commonly thrombocytopenia and platelet count decrease (10.2%). Bleeding of grade 3 or greater was reported in 4 patients (1.9%). Cardiac dysfunction (primarily asymptomatic left ventricular ejection fraction decreases) was reported in 14 patients (6.5%). Among those with measurable disease at baseline (n = 172), objective response rate was 25.6% (95% confidence interval, 19.2%-32.8%). Discussion The safety profile of T-DM1 in this real-world setting of heterogeneous, HER2-positive, pretreated, locally advanced breast cancer or MBC was comparable with that reported in phases II and III studies of similar patient populations. T-DM1 was efficacious with no new safety signals.

Background: More than 20 million echocardiograms are performed every year in the United States at an average cost of approximately five hundred dollars per study. Despite this large expense, these studies can provide significant information that influences patient care. In the fast growing segment of nonagenarians, we sought to determine if echocardiograms have been appropriately obtained according to current Appropriate Use Criteria (AUC). Methods: Over a one-year period at Baylor Scott and White Memorial Hospital, the following characteristics of echocardiography cases performed for elderly patients (90 years and older) were summarized according to Appropriate Use Criteria class: age, gender, patient origin (inpatient/outpatient), type of study (TTE/TEE), and clinical service. Each characteristic was compared among 3 AUC classes (appropriate, inappropriate, and undetermined). ANOVA or Kruskal-Wallis test was used for continuous variable comparisons and Chi-square test or Fisher’s exact test was used for categorical variable comparisons. Proportion (95% confidence interval (CI)) of cases that received echocardiography due to appropriate reasons was estimated for entire group. A p-value of less than 0.05 indicated a statistical significance. Results: Four hundred eighty cases that met inclusion criteria were included in the analysis. Among 480 cases, 91% (435 cases, 95% CI (88-93%)) were conducted due to appropriate reasons. Four percent (21 cases, 95% CI (3-7%)) were performed due to inappropriate reasons and 5% (24 cases, 95% CI (3-7%)) were done due to undetermined reasons. There were no significant differences among the three AUC classes by age, gender, or type of study. However, there are significant differences (P Conclusions: 9% of echocardiograms performed in this demographic, including 26% of outpatient studies, were not appropriate according to current AUC. There was significant variance between referring service and by site of origin. Investigation in larger groups of patients may provide enhanced awareness of and improved adherence to AUC.

Li-ion technology enabled a revolution in consumer electronics by offering the highest energy density among rechargeable battery chemistries resulting in dramatically improved runtimes in a variety of devices. Given its unique combination of energy, power capability and life, lithium-ion technology is poised to revolutionize several emerging applications such as automotive, electric bikes, robotics, and air-borne drones for consumer and business applications. Cells used for each of these applications, which have markedly discharge rates and duty cycles, and must be optimized for energy density and specific energy. For example, the typical consumer electronics application has discharge rates of C/10, battery electric vehicles (BEVs) C/3, plug-in hybrid electric vehicles (PHEVs) 4C, hybrid electric vehicles (HEVs) 10 C, and drones 5C to 10 C. Designing a Li-ion cell with optimum energy density for each of these duty cycles requires not only selection of suitable active materials, but also suitable electrolytes and separators, and electrode designs that can support the specific duty cycles. At CAMX Power, we have been designing Li-ion cells for a wide range of applications including vehicles, electronics applications, lead-acid replacement batteries, and drone applications. Our work has revealed surprising impact of inactive materials on the energy and power capability of Li-ion cells. An important finding has been the role of the separator in determining the rate/power capability, and even energy density of Li-ion cells. Figure 1 shows the discharge rate performance of a high-nickel cathode material as a function of discharge rate for three different electrode loadings. The rate capability appears independent of loading for rates less than 1 C. However, at rates higher than 2C, the rate capability appears to depend strongly on the loading. From these data, it is tempting to conclude that this result is a consequence of ion-diffusion limitations in the thicker electrode – essentially the thickness of the electrode at the loading of 27.1 mg/cm2 is almost twice the thickness of the electrode at a loading of 15.6 mg/cm2. However, a different conclusion emerges if these same data are plotted as a function of areal current density instead of C-rate (Figure 2). The discharge capacities appear independent of the electrode loading, but depend strongly on the areal current density. Essentially, the ionic limitations are not in the electrode, but elsewhere in the cell. These studies have shown that the primary ionic limitation under these conditions occurs in the separator. Data presented in Figure 3 demonstrate this effect. Essentially, by changing only the separator the discharge capacity at a current density of 16 mA/cm2 (corresponding to 5 C) can be increased by a factor of four. We have used this improved understanding of the factors that control the rate and power capability of Li-ion cells to design and fabricate high energy Li-ion cells that can be discharged at very high rates. Figure 4 shows measured performance data of a 1.1 Ah CAM-7/silicon-anode based cell that can support > 270 Wh/kg at a 5C rate. A photograph of the cell is shown in Figure 5. In this presentation, we will further discuss the role of inactive components and cell designs on the rate and power capability of Li-ion cells. Using data comparing the rate capability of different cathode active materials, we will discuss the implications of our findings for research aimed at understanding the power and rate capability of active materials. We will show how judicious selection of test conditions can prevent erroneous conclusions of active material rate capability. We will provide coin cell design guidelines for measuring the rate capabilities of active materials. Finally, we will describe the key design details of the CAM-7/silicon cells that enable achieving this very high specific energy at 5C discharge rate. Figure 1

Despite the obvious success of Li-ion technology over the last 20 years, safety concerns remain. Under suitable triggers, Li-ion cells can experience thermal runaway, i.e., a rapid increase in cell temperature accompanied by venting of combustible vapors, smoke, vent-with-flame, ejection of cell parts, fire and explosion. Safety failures of lithium-ion cells can result from a variety of triggers; examples of which include overheating, overcharging, crushing, mechanical impact, external shorting and development of internal shorts. The underlying physics for these different failure mechanisms can be quite different, with different reaction kinetics and timing to failure, post trigger. The internal short circuit trigger is the least studied but most dangerous trigger because it can result in violent cell failure with little warning and with the appearance that cell operation is "normal". Most Li-ion safety failures that occur in the field take place due to the slow and rare development of such "grown-in" internal short circuits that mature to the point that they result in thermal runaway. An adequate safety test for grown-in internal short development, that replicates the conditions by which such failures occur in the field, has not previously been available and would be a significant improvement in battery safety both at the component level and the system level. In pursuit of better understanding of these types of failures, we investigated the mechanism by which grown-in internal shorts develop from manufacturing defects, specifically, from the presence in cells of small foreign metal particles. In parallel, we employed a finite element analysis (FEA) model to develop an enhanced understanding of how such shorts result in thermal runaway. In this work, supported by the US Department of Energy, we successfully developed methods to implant metal particles in cells, without perturbing cell performance, in order to subsequently reproduce failures “similar” to those that occur in the field. Following metal particle implantation, charge-discharge cycling of cells leads to shorting and/or thermal runaway. Extensive cell post-mortems were carried out to confirm the mechanism of shorting. Factors investigated include the influence of specific metallic contaminant, the electrochemical environment in which the short initiates and develops, chemical and physical characteristics of the surface of the metallic contaminant, and the electrical environment governing current flow to the area of the short. Different metal contaminants clearly exhibit different electrochemical characteristics including different dissolution, plating, and short-formation behaviors. For example, a cell prepared with a single small nickel particle on the cathode developed an internal short circuit during charge-discharge cycling. A post-mortem clearly showed nickel deposition on the anode with additional nickel deposits in/on the separator. Based on insights gained from these investigations we have successfully developed technologies to manage internal short circuits in Li-ion. CAMX Power (a wholly owned subsidiary of TIAX LLC) has developed two distinct, non-invasive and chemistry-agnostic technologies for sensitive early detection of internal shorts in Li-ion batteries before they pose a thermal runaway threat. The technologies are non-invasive and easily implemented in Li-ion battery packs. Detection of developing shorts using these technologies occurs at levels far below the point at which a thermal runaway occurs and, in the best cases, many charge-discharge cycles prior to thermal runaway, as will be illustrated using test data such as are captured in the attached Figure. One of these technologies will be demonstrated "live" during the presentation. Prototype test systems have been supplied to major automakers and are now in advanced stages of demonstration for automotive applications. Reliable early detection provides multiple opportunities for productive intervention. Subsequently we employed a variety of experimental methods in pursuit of a better understanding of the contrast in physics and mechanism between grown-in failures (described above) and failures caused by "hard" shorts that result from crash/crush/penetration events that often result in instantaneous thermal events. Our experiments included development of custom equipment to create instantaneous "hard" shorts, as well as use of high speed data acquisition and high speed photography to monitor processes following instantaneous creation of a hard short. This work revealed fundamental new findings regarding how hard shorts result in thermal runaway in contrast to "soft" shorts. Use of widely considered safety technologies such as ceramic separators and non-flammable electrolytes were investigated using this approach. The findings clearly illustrate that the underlying physics for grown-in shorts versus hard shorts are quite different, with different reaction kinetics and timing to failure, post trigger. Examples of high speed photographic resolution of thermal runaway processes will be shown and recommendations for safe Li-ion batteries will be summarized. Figure 1

Safety of lithium-ion batteries is a critical topic that has not received adequate attention in the past, largely due to the fact that data regarding safety failures have been severely restricted. As a result, there are numerous misunderstandings in a field that has not received the same degree of scientific and technical rigor as other areas of lithium-ion battery technology development. However, safety of lithium-ion batteries will become even more important as lithium-ion technology enters transportation markets. Under suitable triggers, Li-ion cells can experience thermal runaway, i.e., the rapid increase in cell temperature accompanied by venting, vent-with-flame, ejection of cell parts, fire, and explosion. Safety failures of lithium-ion cells can result from a variety of triggers including overcharging, overheating, crushing, mechanical impact, and external short circuits. Safety tests have been devised for all these abuses, with varying degrees of fidelity. However, most safety incidents that have taken place with lithium-ion batteries occur due to the slow and rare development in cells of internal short circuits that mature to the point that they result in thermal runaway. Most safety tests carried out in the laboratory or factory do not replicate the conditions by which safety incidents actually occur in the field. These issues are characterized in detail, and an improved overall framework for considering lithium-ion battery safety is suggested.

TIAX is developing laminated prismatic lithium-ion (Li-ion) cells capable of rapid charging at low temperature (to -50 deg C) to replace current lead-acid vehicle batteries. The novel cells are based on TIAX?s high energy, high power CAM-7 cathode material, high rate capability lithium titanate (LTO) anode material, and a nitrile-cosolvent electrolyte formulation, and target cell-level energy content greater than 90 Wh/kg and 250 Wh/l.

Viruses of the family Coronaviridae have recently emerged through zoonotic transmission to become serious human pathogens. The pathogenic agent responsible for severe acute respiratory syndrome (SARS), the SARS coronavirus (SARS-CoV), is a member of this large family of positive-strand RNA viruses that cause a spectrum of disease in humans, other mammals, and birds. Since the publicized outbreaks of SARS in China and Canada in 2002-2003, significant efforts successfully identified the causative agent, host cell receptor(s), and many of the pathogenic mechanisms underlying SARS. With this greater understanding of SARS-CoV biology, many researchers have sought to identify agents for the treatment of SARS. Here we report the utility of the potent antiviral protein griffithsin (GRFT) in the prevention of SARS-CoV infection both in vitro and in vivo . We also show that GRFT specifically binds to the SARS-CoV spike glycoprotein and inhibits viral entry. In addition, we report the activity of GRFT against a variety of additional coronaviruses that infect humans, other mammals, and birds. Finally, we show that GRFT treatment has a positive effect on morbidity and mortality in a lethal infection model using a mouse-adapted SARS-CoV and also specifically inhibits deleterious aspects of the host immunological response to SARS infection in mammals.

e17670 Background: First line chemotherapy regimens for a variety of cancer types have been found to differ by site of care. This is the first study to explore differences in treatment patterns bet...

e17798 Background: Existing treatments for breast cancer (BC) are effective; however, patients often experience adverse events (AEs). The healthcare cost related to AEs in a Medicaid population is relatively unknown. Methods: A retrospective cohort study using a multi-state Medicaid insurance claims database (2006-2013) was conducted in women with a BC diagnosis treated with biologic or chemotherapy. Data were stratified by disease status (metastatic or non-metastatic) and by line of therapy (first or prior exposure). Incidence and average monthly AE-related health care costs of AEs during a line of therapy were calculated. Multivariable models were fit to estimate adjusted total healthcare costs. Results: A sample of 3,861 BC patients met inclusion criteria; mean follow-up range: 149-229 days. The most common AE types were hematological (non-metastatic 50%; metastatic 66%), constitutional (non-metastatic 50%; metastatic 78%) and gastrointestinal (non-metastatic 39%; metastatic 59%). Hematological AEs inc...

Many applications require Li-ion cells that can support high rates and/or high-power pulses. In order to effectively design such cells, it is important to understand the factors that control the rate and/or power capability of Li-ion cells. Work done at TIAX has shown a surprising impact of the separator employed in the cell on the rate/power capability of Li-ion cells. Figure 1 shows the rate capability of a high-nickel cathode material as a function of discharge rate for three different electrode loadings. The rate capability appears independent of loading for rates less than 1 C. However, at rates higher than 2C, the rate capability appears to depend strongly on the loading. From these data it is tempting to conclude that this result is a consequence of increased ion diffusion limitation in the thicker electrode – essentially the thickness of the electrode at the loading of 27.1mg/cm2 is almost twice the thickness of the electrode at a loading of 15.6mg/cm2. However, a different conclusion emerges if these same data are plotted as a function of areal current density instead of C-rate (Figure 2). The discharge capacities appear independent of the electrode loading, but depend strongly on the areal current density. Essentially, the ionic limitations are not in the electrode, but elsewhere in the cell. Studies at TIAX have shown that the primary ionic limitation under these conditions occurs in the separator. Data presented in Figure 3 demonstrate this effect. Essentially, by changing only the separator the discharge capacity at a current density of 16 mA/cm2(corresponding to 5 C) can be increased by a factor of four. These combined results discussed above show that the ionic transport limitations in the separator play a major role in determining the rate capability of Li-ion cells. In this paper, we will present rate data using separators with a wide range of physical properties, and demonstrate a correlation between the rate capability and separator properties. Using data comparing the rate capability of different cathode active materials, we will discuss the implications of our findings for research aimed at understanding the power and rate capability of active materials. Finally, we will provide coin cell design guidelines for measuring the rate capabilities of active materials.

e11601 Background: Adjuvant trastuzumab (T) reduces the risk of relapse in women with HER2+ early stage breast cancer (EBC). This study assessed the impact of relapse on overall survival (OS) in wo...

Denileukin diftitox (DT) depletes regulatory T cells (Treg) that correlates with immune and clinical benefits in metastatic human melanoma and improved clinical outcomes in a renal cancer vaccine trial. We tested immune and clinical effects of Treg depletion using DT in a phase 0/I cancer trial and a phase II ovarian cancer trial. In our phase 0/I trial, we noted reductions in blood Treg prevalence and concentration (median ~18% and ~50%, respectively) 3-7 days after one intravenous DT infusion at 9 or 12 μg/kg, in 6 of 7 evaluable patients with breast, lung, and ovarian cancers, and melanoma, and increased blood IFN-γ+ and Ki-67+ T cells. Weekly DT significantly reduced metastatic tumors in one ovarian cancer patient prompting a small phase II trial in epithelial ovarian cancers. 28 patients received DT once every 3-4 weeks which significantly depleted functional Tregs from blood and the tumor microenvironment, but with variable immune outcomes and no significant clinical efficacy. Weekly DT eventually reduced effector T cells. In mouse ovarian cancer models we found that: i) DT efficacy depended on adaptive immunity, ii) its IL-2 moiety did not mediate clinical effects, and iii) its treatment mechanism appeared distinct from anti-CD25 antibody, which depleted Tregs in a human breast cancer trial. DT depletes Tregs in various carcinomas but requires more dosing and schedule studies. Treg-specific agents and combination treatments could also improve Treg depletion efficacy.

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Lunasin is a peptide derived from the soybean 2S albumin seed protein that has both anticancer and anti-inflammatory activities. Large-scale animal studies and human clinical trials to determine the efficacy of lunasin in vivo have been hampered by the cost of synthetic lunasin and the lack of a method for obtaining gram quantities of highly purified lunasin from plant sources. The goal of this study was to develop a large-scale method to generate highly purified lunasin from defatted soy flour. A scalable method was developed that utilizes the sequential application of anion-exchange chromatography, ultrafiltration, and reversed-phase chromatography. This method generates lunasin preparations of >99% purity with a yield of 442 mg/kg defatted soy flour. Mass spectrometry of the purified lunasin revealed that the peptide is 44 amino acids in length and represents the original published sequence of lunasin with an additional C-terminal asparagine residue. Histone-binding assays demonstrated that the biological activity of the purified lunasin was similar to that of synthetic lunasin. This study provides a robust method for purifying commercial-scale quantities of biologically-active lunasin and clearly identifies the predominant form of lunasin in soy flour. This method will greatly facilitate the development of lunasin as a potential nutraceutical or therapeutic anticancer agent.