Journal articles on the topic 'SURROGATE CURBS'

The paper presents a microsimulation approach for assessing the safety performance of turbo-roundabouts where Cooperative Autonomous Vehicles “CAVs” have been introduced into the traffic mix alongside conventional vehicles “CVs”. Based on the analysis of vehicle trajectories from VISSIM and subsequent analysis of traffic conflicts through the Surrogate Safety Assessment Model (SSAM), the research aims to evaluate the safety benefits of turbo-roundabouts where the lanes are physically separated by raised curbs, compared to roundabouts without such curbs. The paper will then describe the methodological path followed to build VISSIM models of turbo-roundabouts with and without raised curbs in order to calibrate the simulation models and estimate the potential conflicts when a higher percentage of CAVs are introduced into the traffic mix. A criterion has been also proposed for setting properly the principal SSAM filters. The results confirmed both higher safety levels for turbo-roundabouts equipped with raised lane dividers compared to turbo-roundabout solutions without curbs, and better safety conditions under the traffic mix of CVs and CAVs. Therefore, it follows that, in absence of crash data including CAVs, the surrogate measures of safety are the only approach in which the safety performance of any roundabout or road entity can be evaluated.

The word surrogacy has its origin among the Latin term “surrogatus” which suggests a lady acts as a substitute for a pregnant woman. Surrogacy has been in practice form last thirty years. The surrogacy regulated by business can be classified as then, altruistic surrogacy and commercial surrogacy. The paper aim to conduct systematic review on surrogacy. The literature review was conducted using PubMed and alternative search engines. Further, additional information concerning the constitutional articles was collected from search engines like legal service of India, prsinndia.org, icmr.nic.in, Press Information Bureau, Wikipedia, IJCM and Indiankanoon. In India, surrogacy is legally recognised since 2002. This paper looks into various aspects of surrogacy. Factors faced by the surrogate mother such as exploitation, psychological conditions, human rights, dignity and respect, feminism and religious issues are explored. The paper discuss the economic benefit is mostly enjoyed by the medical practitioners. The Indian government tried to curb the problems by updating the law to overcome the challenges but with time government introduce the surrogacy bill in 2016 which addressed many issues and still in 2020 it address various aspects of surrogacy to prevent the exploitation.

Abstract If globalisation has led to a greater mobility of people specific issues have emerged with the current coronavirus pandemic. Consequently, extreme measures have been taken worldwide to flatten the curb of the virus. From lockdowns to several levels of isolation these measures have worked undoubtedly for some situations. Nonetheless, these same measures have sown chaos in other situations. One good example is surrogacy especially when this practice is undergone overseas, revealing the legal insecurity of the use of surrogacy whether for the intended parents, the surrogate born child or the surrogate mother for whom the risks have heightened.

In 2011, the United Nations Road Safety Collaboration (UNRSC) developed a Global Plan for the Decade of Action for Road Safety 2011–2020. Among the categories or “pillars” of activities, is the improvement of road safety for infrastructures. Furthermore, this plan is aligned by the UN Sustainable Development Goals that included even traffic safety. In this regard, this study estimates safety improvements achieved by converting a standard roundabout into an egg turbo roundabout. In particular, turbo roundabouts have become very popular in Northern Europe for both their safety and their capacity. Many studies have shown these advantages thanks to their features: preventive separation of entering flows, limited lane changing and low speeds due to curbs. Given the absence of existing turbo roundabouts in Italy, this research studied and compared a “virtual” roundabout with spiraling circular carriageways to an existing multi-lane roundabout in order to assess its significant reduction in terms of potential collisions. This study relied on traffic conflicts in micro-simulation by using VISSIM software and then Surrogate Safety Assessment Model (SSAM). The research is based on the traffic process observed at a standard roundabout in Cosenza (Italy) marked by a high level of congestion and safety problems. Speeds, critical gaps, queue lengths, and floating car data, obtained from video observations, have been used as input data for the calibration procedure of the first scenario (case study roundabout). Then, the turbo roundabout solution was built and simulated by using the previously derived parameters. Finally, the two roundabout scenarios were compared in terms of spatial distribution of the potential conflicts determined by SSAM. The results could help to measure the performance and safety impact of these two roundabout configurations.

Zimbabwe has experienced an economic meltdown dating back to 2000, which created perennial economic woes such as a liquidity crisis that continued haunting the country to date. Various possible solutions were explored but did not yield the desired results. Amongst the explored solutions was an introduction of surrogate currency specifically to curb the liquidity crisis. This paper sought to explore the effects of using "surrogate currency" to address the liquidity crisis in Zimbabwe by employing a desk review. Currently, there is a dearth of literature on using surrogate currency in African countries. Hence this study contributes to the existing literature on the use of such currency. The review established that the surrogate currency led to the emergence of bad money as propounded by Gresham’s law of currency systems. Moreover, the surrogate currency rapidly lost its value, whereas the introduction of the surrogate currency failed to address the liquidity crisis, leading to other socio-economic challenges. Finally, financial reporting under the surrogate currency became a challenge as well. This study recommends the withdrawal of the surrogate currency and the use of multicurrency along with the promotion of products for export to attract more foreign currency into the economy.

In this paper, a multi-disciplinary optimization frame considering weld fatigue constraints is constructed based on kriging surrogate model in order to improve the fatigue reliability of vehicle structures. Under this frame, kriging surrogate model is used to construct weight, strength, stiffness, frequency, fatigue life responses for optimization, which improves effectively the computing efficiency. For weld fatigue analysis, master S-N curve method in AMSE criterion is used for reliable fatigue life. The curb girders of a high-speed train are taken as an example, a light-weight optimization model considering static strengthen and weld fatigue constrains is constructed and solved by use of submodelling technology under the proposed optimization frame. After optimization, the weight of the curb girders is reduced about 33% from 1.73 ton to 1.16 ton. These results show the proposed optimization method is effective, and provide the preference for the light-weight design of high-speed trains.

Returning orphan bear cubs to the wild can benefit bear welfare and conservation but is hindered in Asia by the scarcity of documented experience. We experimented with rehabilitation of two Asiatic Black Bear cubs in Thailand using the assisted method of soft-release. We raised the 5-month old cubs for 11 months with minimal human contact in a remote enclosure in high quality habitat, letting cubs out periodically to walk with caretakers in the forest. The caretakers acted as surrogate mothers, allowing cubs to safely acquire foraging skills and familiarity with the forest. Supplementary feeding resulted in the cubs’ rapid weight gain (average 157g/day), faster than would occur in the wild. Faster growth allowed the cubs to be released sooner, reducing the likelihood of long-term habituation. After three months of rehabilitation, the bear cubs started showing signs of being wary of the caretakers (e.g., cautious when we approached their enclosure) and their focus during walks switched from play to foraging. After seven months they began to spend nights away from their enclosure, thus declining the supplemental food. This sequence and timing of increasing separation and independence from people matched other assisted soft releases in the region. The cubs went missing in month 12, shortly before planned collaring and release. They were seen together 2.5 months later on a fruiting tree and ran away when approached. Assisted soft releases might be a promising option for bear rehabilitation in Asia but more data are needed to evaluate their effectiveness relative to other methods. This method affords direct observations of bears in the wild that can augment our knowledge of bear behavior and ecology.

Abstract Background: Overall survival (OS) remains the definitive primary efficacy endpoint to evaluate previously untreated acute myeloid leukemia (AML) therapies, but it requires prolonged follow-up. An earlier endpoint assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate event-free survival (EFS) as a surrogate endpoint for OS in untreated AML. Methods: Individual patient data were analyzed from 2,475 patients (pts) from 4 multicenter, randomized controlled phase III trials of active treatment in previously untreated AML using anthracycline and cytarabine induction chemotherapy as the concurrent control (CALGB 10201, n=506, enrollment period 2003-2006, age 60-88 years (y); CALGB 10603, n=717, enrollment period 2008-2015, age 18-60 y, FLT3-mutated pts only; SWOG 0106, n=595, enrollment period 2004-2009, age 18-60 y; ECOG-ACRIN 1900, n=657, enrollment period 2002-2008, age 17-60 y). Individual patient-level surrogacy examines the association between the individual patients' EFS and OS time after adjusting for treatment effect, and was assessed using the copula bivariate survival model (Kendall's tau). Trial-level surrogacy measures how precisely the treatment effect on OS can be predicted on the basis of observed treatment effect on EFS, and was evaluated using both linear regression (R2WLS) weighted by trial size and Copula bivariate (R2Copula) models. Pre-specified criteria for surrogacy required either R2WLS or R2Copula ≥0.80, neither below 0.7, with either lower bound 95% Confidence Interval (CI) >0.60. Sensitivity analyses were conducted using different EFS definitions (Table 1). Results: With a median follow-up of 50.2 months for the 896 patients still alive, the median OS and EFS across all four trials were 20.9 months (95% CI: 19.0-22.7) and 5.6 months (95% CI: 4.5-6.4), respectively. Trial-level surrogacy for EFS was strong (R2WLS=0.79; R2Copula=0.89), indicating a high correlation of treatment effect between EFS and OS. At the individual patient-level, however, EFS showed weak association with OS (tau= 0.52), compared to the strength of trial-level surrogacy. The discrepancy between patient-level EFS and OS was greatest among patients who did not achieve a CR, followed by those who achieved a CR but relapsed (Figure 1). Sensitivity analysis on alternative EFS definitions showed that the trial-level surrogacy was similar, but individual patient-level surrogacy varied across different EFS definitions (Table 1). This is consistent with what we previously reported (ASH 2016): EFS estimates differed considerably based on the definition of induction failure (IF) in a single arm setting, but this had minimal impact on the estimation of the treatment effect using EFS in randomized trials. In addition, when considering only relapse and death as events (definition 4), both individual patient- and trial-level correlations were high. Conclusions: Correlation between EFS and OS was impacted by patients not achieving CR during induction. Despite the lack of patient-level correlation, a strong correlation between hazard ratios for treatment effects was observed between EFS and OS on the trial level. Hence, it remains debatable whether EFS represents a clinical benefit in itself for patient with untreated AML considering the strong correlation in treatment effects. Further validation is needed due to the small number of trials included and the heterogeneity across trials. Acknowledgment: We gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf, SWOG S0106 Study Chair. Support: U10CA180821, U10CA180882, U10CA180794, U10CA180820, U10CA180888; Clinicaltrials.gov Identifiers: NCT00085124 (10201), NCT00651261 (10603), NCT01253070 (11001), NCT00085709 (SWOG S0106), and NCT00049517 (ECOG-ACRIN E1900) Disclosures Uy: Curis: Consultancy; GlycoMimetics: Consultancy. Larson:Pfizer: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding.

The appropriateness of test vehicles specified in NCHRP Report 350 was assessed, including ( a) whether the 2000-kg, three-quarter-ton pickup truck should continue to be used as a test vehicle, and if not, what replacement vehicle would be appropriate; ( b) whether the 820-kg passenger car should continue to be used as a test vehicle, and if not, what replacement vehicle would be appropriate; and ( c) whether another test vehicle should be added to the matrix—for example, an intermediate-sized passenger car. From the analysis, the following conclusions and recommendations were drawn: ( a) The three-quarter-ton pickup truck appears to be a good surrogate for the light truck subclasses. The recommendation is to keep the 2000-kg, three-quarter-ton pickup truck as one of the design test vehicles in the update of the guidelines for NCHRP Report 350. ( b) A potential problem is the availability of three-quarter-ton pickup trucks with standard cabs. An alternative design test vehicle may be an intermediate-sized sport utility vehicle, ( c) The availability of the 820-kg passenger car design test vehicle will be a problem within the next few years. The recommendation is to keep the current test vehicle as long as it is still readily available, or until the NCHRP Report 350 guidelines are updated, and to increase the curb weight to a level consistent with the curb weights of the two smallest passenger cars with reasonably high sales volume. ( d) The addition of a third design vehicle—for example, a 1500-kg intermediate-sized passenger car—to ensure that a roadside feature performs satisfactorily across the entire vehicle spectrum is highly desirable but cost-prohibitive. The addition of an intermediate-sized design test vehicle is therefore not recommended except in situations in which there is a perceived concern that the device may not function properly when impacted by an intermediate-sized vehicle.

Decoding stem cell metabolism has implicated a tight linkage between energy metabolism and cell fate regulation, a dynamic interplay vital in the execution of developmental and differentiation programs. The inherent plasticity in energy metabolism enables prioritisation of metabolic pathways in support of stage-specific demands. Beyond traditional support of energetic needs, intermediate metabolism may also dictate cell fate choices through regulation of cellular signalling and epigenetic regulation of gene expression. The notion of a ‘metabolism-centric’ control of stem cell differentiation has been informed by developmental embryogenesis based upon an on-demand paradigm paramount in defining diverse developmental behaviours, from a post-fertilisation nascent zygote to complex organogenesis leading to adequate tissue formation and maturation. Monitored through natural or bioengineered stem cell surrogates, nutrient-responsive metabolites are identified as mediators of cross-talk between metabolic flux, cell signalling and epigenetic regulation charting, collectively, whether a cell will self-renew to maintain progenitor pools, lineage specify to ensure tissue (re)generation or remain quiescent to curb stress damage. Thus, bioenergetics are increasingly recognised as integral in governing stemness and associated organogenic decisions, paving the way for metabolism-defined targets in control of embryology, stem cell biology and tissue regeneration.

SummaryPassive acoustic monitoring is rapidly gaining recognition as a practical, affordable and robust tool for measuring gun hunting levels within protected areas, and consequently for its potential to evaluate anti-poaching patrols’ effectiveness based on outcome (i.e., change in hunting pressure) rather than effort (e.g., kilometres patrolled) or output (e.g., arrests). However, there has been no report to date of a protected area successfully using an acoustic grid to explore baseline levels of gun hunting activity, adapting its patrols in response to the evidence extracted from the acoustic data and then evaluating the effectiveness of the new patrol strategy. We report here such a case in Cameroon’s Korup National Park, where anti-poaching patrol effort was markedly increased in the 2015–2016 Christmas/New Year holiday season to curb the annual peak in gunshots recorded by a 12-sensor acoustic grid in the same period during the previous 2 years. Despite a three- to five-fold increase in patrol days, distance and area covered, the desired outcome – lower gun hunting activity – was not achieved under the new patrol scheme. The findings emphasize the need for adaptive wildlife law enforcement and how passive acoustic monitoring can help attain this goal, and they warn about the risks of using effort-based metrics of anti-poaching strategies as a surrogate for desired outcomes. We propose ways of increasing protected areas’ capacity to adopt acoustic grids as a law enforcement monitoring tool.

BackgroundCheckpoint inhibitor antibodies have improved survival in a variety of cancers, however, a great unmet need remains since only a small fraction of patients responds. Reasons for lack of efficacy are believed to include lack of tumor infiltrating immune cells, a notion supported by improved efficacy observed following combined checkpoint blockade with tumor oncolytic virotherapy which promotes intratumoral T cell infiltration. Oncolytic vaccinia viruses (oVV) also allow genetic encoding of transgenes. This is of special interest for therapeutic proteins exhibiting toxicological limitation or pharmacokinetic issues. Here, BioInvent and Transgene present a potentially safe and more efficacious strategy to combine checkpoint inhibition in the context of oncolytic virotherapy.MethodsUsing the F.I.R.S.T™ discovery platform we have isolated a human recombinant Treg-depleting antibody that has been vectorized alongside GM-CSF into the Invir.IO® oVV. This product named BT-001 consists of a Copenhagen double deleted vaccinia virus encoding the human CTLA4-specific antibody 4-E03 IgG1, which shows improved Treg-depletion compared with ipilimumab in a human PBMC-based NOG/SCID-transfer model. BT-001 also encodes GM-CSF, the cytokine expressed in clinically approved products. A surrogate murine mAb was vectorized into the same oVV (mBT-1) allowing for functional and mechanistic in vivo studies.ResultsOur studies demonstrate that 4-E03 and GM-CSF were expressed as functional molecules after infection by BT-001 of human tumor cell lines in vitro. Moreover, following intratumoral administration in immune competent and immune deficient mice transplanted with mouse or human tumors, transgene expression was sustained at levels associated with receptor saturation for days to weeks. In contrast, and supporting the tumor-selective nature of oVV, blood concentrations of anti-CTLA4 mAb were lower compared to those observed following i.v. administration of therapeutic doses of mAb. The in vivo anti-tumor activity of mBT-1 was assessed in multiple syngeneic mouse tumor models including CT26, EMT6, A20 and C38. Murine surrogate mBT-1 conferred cures in the majority of challenged mice irrespective of tumor origin. The excellent anti-tumoral profile depends on anti-CTLA4 expression and could be boosted by co-administration of anti-PD-1 mAb. Intratumoral treatment with mBT-1 also induces abscopal anti-tumor responses and protects against tumor rechallenge demonstrating a long-lasting systemic anti-tumor activity.ConclusionsA clinical batch of BT-001 has been produced and toxicological evaluation is ongoing. Transgene and BioInvent have applied for a clinical trial targeting injectable superficial tumors. Here, the tumor-localized delivery of anti-CTLA4 may allow a better tolerated and more effective combination therapy with antibodies targeting the PD-1/PDL1 axis.

ABSTRACT Aim To present an overview of the current Artificial Reproductive Techniques (ART) guidelines focussing on grey zones Introduction Infertility is a major health and social concern in modern day India. Due to the great diversity in management protocols and absence of standard operating procedures, there is a necessity to develop country-specific guidelines for assisted reproduction. Also, there is need to curb unethical practices. Guidelines in this regard have undergone several changes over the years. It is important that adequate care is taken before the bill becomes a law so that both patients and health workers mutually benefit from ART Overview The present article gives an insight into the development of guidelines over the years with elaboration of the salient features of the current ART Bill under specific chapter headings, ten chapters in total. Also discussed is the recent Surrogacy Bill. In each context, critical analysis is provided that underscores the grey areas that need to be addressed. At the end of the article, certain recommendations have been put forward to aid the successful implementation of current guidelines Clinical significance It is imperative that all ART practitioners be well versed with the current ART guidelines as ignorance cannot be cited as an excuse under any circumstance. Also, practitioners can give valuable inputs before the bill finally becomes a law. The law must ensure that physicians are not unnecessarily persecuted in the name of patient rights, as this will lead to fearful practice, which in turn will hamper patient management. How to cite this article Sharma PJ, Mittal M. Critical Analysis of the Current Assisted Reproductive Technology Guidelines. Int J Infertil Fetal Med 2017;8(3):113-119.

Abstract Background: IRAK4 kinase activity is required for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in a variety of myeloid and lymphoid cell types. Recruitment of IRAK4 to these receptors and its subsequent activation is facilitated by the MYD88 adaptor protein. The MYD88-L265P activating mutation is prevalent in DLBCL (~30% in ABC subtype) and WM (>90%). MYD88- L265P leads to constitutive activation of NF-κB signaling that is associated with worse prognosis. In MCL, dysregulation of B-cell receptor (BCR) and TLR pathway components correlate with constitutive NF-κB signaling. CA-4948 is a small molecule inhibitor of IRAK4 kinase that modulates the TLR and IL-1R signaling cascades. CA-4948 is being developed as a novel agent for the treatment of hematologic cancers with dysregulated IRAK4 signaling and is currently in a Ph1 trial for R/R NHL (clinicaltrials.gov NCT03328078). In preclinical studies, CA-4948 demonstrates pharmacodynamic and antitumor activity in in vitro and in vivo models with MYD88 alterations, and was previously shown to have a synergistic anti-tumor activity when combined with venetoclax in vivo. To further guide CA-4948's clinical development in NHL, we report here nonclinical studies exploring a twice-daily dosing schedule in DLBCL xenograft models. We also investigated the use of an ex-vivo whole-blood TLR-stimulation assay as a surrogate PD response biomarker. Additionally, we tested the efficacy of CA-4948 alone or in combination with the BTK inhibitor ibrutinib in DLBCL and MCL tumor models. Furthermore, preliminary PK and PD data from the first-in-human Ph1 trial are presented. Methods: Mice bearing DLBCL PDX tumors were orally administered CA-4948 twice-daily (BID) with 37.5 or 75 mg/kg doses and once-daily (QD) with 75 or 150 mg/kg doses. The ex-vivo whole blood assay involved TLR-stimulation of blood isolated at various time-points after CA-4948 administration. For the drug combination studies, mice bearing subcutaneous tumors of a MYD88-L265P DLBCL cell line or six MCL cell lines were treated. Results: (1) CA-4948 exhibited dose-dependent tumor growth inhibition in two DLBCL PDX xenograft tumor models with BID dosing showing equal or enhanced efficacy as compared to the equivalent total daily QD dose. The BID schedule was well tolerated with only a slight body weight loss as compared to the equivalent total QD dose schedule. (2) Overall, in mouse, the ex-vivo blood assay showed a time and exposure dependent relationship with the level of cytokine production after TLR-stimulation. A similar CA-4948 dose-dependent inhibition of TLR-stimulated cytokine production was observed in healthy human whole blood samples in which CA-4948 was spiked into the blood sample. Based on these findings, CA-4948 exposure levels capable of inhibiting TLR-stimulation are anticipated to be readily achievable in clinical studies. This was also supported by preliminary clinical PD data showing post treatment, on-target, reduced release of NF-κB-associated cytokines in 2 of 4 patients treated so far. (3) In xenograft efficacy studies using MCL models, single agent CA-4948 and ibrutinib exhibited anti-tumor activity and showed an additive effect when combined in the majority of the models known to have BCR-driven constitutive canonical NF-kB signaling (REC-1, MINO, and JeKo-1). Interestingly, neither CA-4948, ibrutinib, nor the combination had anti-tumor activity in Z-138 and GRANTA-591 xenograft models, consistent with these cell lines having activated NF-κB through the alternative NIK signaling pathway. (4) The human QD PK data (n=4) demonstrated that CA-4948: was rapidly absorbed, Tmax 1-3 hr, and t1/2 of 3.6 -6.8 hr. The bioavailability and exposure, as assessed by Cmax and AUC, is within the expected range compared to non-clinical PK and did not show any evidence of accumulation after QD dosing for 15 consecutive days. Conclusion: These results provide a rationale for CA-4948 BID dosing and incorporating the use of an ex-vivo whole-blood TLR-stimulation assay as a surrogate PD response biomarker, the former of which will be evaluated in the current Ph1 dose escalation soon and the latter of which is currently being implemented in the Ph1 trial for patients with advanced NHL. The murine xenograft results further support exploration of CA-4948 as monotherapy and in combination with canonical and alternative NF-κB pathway-targeted agents in DLBCL and MCL. Disclosures Booher: Curis, Inc: Employment, Equity Ownership. Patel:Juno Therapeutics: Consultancy; Pharmacyclics/Janssen: Speakers Bureau; Genentech: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Sunesis Pharmaceuticals: Consultancy. Lunning:Celgene: Consultancy; AbbVie: Consultancy; Astra-Zeneca: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Genzyme: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Juno: Consultancy; Kite: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Samson:Curis, Inc: Employment, Equity Ownership. Atoyan:Curis, Inc: Employment, Equity Ownership. Ma:Curis, Inc: Employment, Equity Ownership. Xu:Curis, Inc: Employment, Equity Ownership. Dellarocca:Curis, Inc: Employment, Equity Ownership. Modafferi:Curis, Inc: Employment, Equity Ownership. Borek:Curis, Inc: Employment, Equity Ownership. Zhang:Curis, Inc: Employment, Equity Ownership. Parker:Curis, Inc: Employment, Equity Ownership. Whitney:Curis, Inc: Employment, Equity Ownership. Wang:Curis, Inc: Employment, Equity Ownership. Tuck:Curis, Inc: Employment, Equity Ownership. Younes:Merck: Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Abbvie: Honoraria; Seattle Genetics: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Incyte: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; J&J: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding; Curis: Research Funding.

Abstract Therapeutic antibodies have improved survival of both hematologic and solid cancer patients, inducing long-lasting responses and even cures. Clinically successful antibodies exert antitumor activity by targeting tumor cells directly (e.g. anti-HER2 mAb in HER2+ breast cancer, anti-CD20 mAb in B cell cancer) or by targeting and activating immune cells that seek and destroy cancer cells in the tumor microenvironment (immune checkpoint blocking antibodies; ICB). Still, many patients fail to respond or acquire resistance to these therapies. Understanding mechanisms and overcoming resistance to distinct classes of antibody drugs, is therefore clearly warranted and has the potential to further improve cancer outcomes. The inhibitory Fc gamma receptor (FcγR) IIB imbues resistance to cancer immunotherapy by several mechanisms, acting both on tumor and immune effector cells. We previously developed an FcγRIIB blocking antibody (BI-1206) which is currently being explored in clinical trials (NCT03571568, NCT04219254, and NCT02933320). BI-1206 was found to have cytolytic activity against malignant B cells and the ability to block rituximab internalization from tumor cells, as well as enhance rituximab therapeutic activity in mice humanized for CD20 and FcγRIIB or bearing relapsed/refractory CLL in vivo. Emerging data demonstrate that FcγRs modulate the therapeutic activity of many therapeutic antibodies among them HER2 targeting antibodies such as Trastuzumab. Trastuzumab alone or in combination with chemotherapy significantly improves overall survival of HER2+ breast cancer patients. However, many patients remain uncured and develop Trastuzumab resistance resulting in relapse of the disease. Means of improving anti-HER2 therapy and overcoming resistance are therefore highly desirable. We report the generation of a fully human FcγRIIB-blocking antibody (BI-1607) engineered to eliminate Fc-mediated FcγR binding and function (Fc-null anti-FcγRIIB). Using a mechanism-of-action-matched surrogate antibody, we demonstrate that Fc-null anti-FcγRIIB enhances therapeutic efficacy, both in tumor growth and overall survival of anti-HER2 in the syngeneic immune competent TUBO mouse model. This enhanced therapeutic efficacy is associated with increased tumor influx of myeloid and NK-cells. Collectively our results provide proof-of-concept for Fc-null anti-FcγRIIB to enhance anti-HER2 in the treatment of cancer. Citation Format: Linda Mårtensson, Robert Oldham, Marie Borggren, Mathilda Kovacek, Therese Blidberg, Ulla-Carin Tornberg, Ingrid Karlsson, Steve Beers, Mark Cragg, Ingrid Teige, Björn Frendeus. A novel FcγRIIB-blocking antibody to enhance FcγR-dependent antitumor immunity with anti-HER2 therapy [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 3423.

Introduction: The use of PET-CR as a surrogate endpoint would expedite the development of novel therapies and enable better estimates of sample size based on early outcomes of a trial. Previous studies have reported an association between end-of-therapy (EOT) PET results and long-term progression-free (PFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) patients receiving standard first-line chemoimmunotherapy. We have also previously shown that the overall predictability of PET-CR for PFS and OS in these trials is similar to that in 18 literature-based studies. (15-ICML 2019, P195). To assess the potential for PET-CR as a surrogate endpoint in registration trials, we conducted a prospectively designed individual patient-level-data meta-analysis of available clinical trials. Methods: We synthesized patient-level data from three prospective phase II and III trials (GOYA [NCT01287741], GATHER [NCT01414855], MAYO [NCT00670358]) conducted in previously untreated DLBCL patients, using a Bayesian hierarchical model. We considered the two treatment arms in GOYA (GOYA-R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] and GOYA-G-CHOP [obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone]) separate; hence a total of four arms, excluding patients without baseline PET scans. We investigated the relationship between PET-CR and long-term survival outcomes overall and within patient subgroups. We used Kaplan-Meier plots to compare survival endpoints by PET-CR status. We considered hypothetical RCTs that have PET-CR and PFS as endpoints to show how our model of the relationship between PET-CR and PFS can be used to predict the trial outcome. Results: We included 1496 patients (GOYA-R, GOYA-G, GATHER, MAYO, respectively: 665, 669, 100, 62). EOT PET-CR status was determined by the Lugano criteria in GOYA and by IHP in the other two studies. The overall rate of PET-CR was 72%; respectively 72%, 73%, 62% and 74% per arm. Panel A of the Figure shows Kaplan-Meier plots of PFS by PET-CR status. The Bayesian modeled hazard ratio (HR) comparing PET-CR versus nonCR was 0.13 (95% CI: 0.10, 0.15). The model can be used in planning a clinical trial as follows. Suppose a new therapy improves the PET-CR rate from 70% to 85%. Based on our model the expected HR for PFS treatment effect would be 0.71 (95% CI: 0.58, 0.84). The trial sample size required to demonstrate such an improvement with 90% power is about 650 patients, assuming an accrual rate of 50 patients per month and a minimum follow-up time of 12 months. Panel B of the Figure shows the model-based PFS HR and its CI (shaded) as it depends on the PET-CR rate of the new therapy. This plot also shows the estimated total trial sample size (in red), again assuming the relationship between PET-CR and PFS in our model. However, our model may not apply for the new therapy; and the trial could have an adaptive design with final sample size tailored to the accruing information about PET-CR and PFS and their relationship for the therapies in the trial. Conclusions: Achieving an EOT PET-CR in newly diagnosed DLBCL is highly predictive of favorable outcome in the populations we considered. The estimated HR is 0.13 for PFS, PET-CR versus nonCR, and it is 0.10 for OS. Based on our model, a treatment that improves PET-CR rate could be reasonably expected to have a benefit on PFS and OS, for the populations we considered. Whether a new therapy, with a different mechanism of action, that improves PET-CR rate will extend PFS in a clinical trial is less clear. An adaptive trial could be initiated based on our model as a hypothesis. This hypothesis can be verified or updated using accruing information in the trial itself. Our model can also help in planning clinical trials for re-estimating sample size during the trial and considering early stopping for futility. Further work should investigate the applicability of PET-CR in predicting PFS and/or OS for treatments that have different mechanisms of action and for other populations of patients. Acknowledgements: This work was funded by Genentech/Roche. Disclosures Berry: Berry Consultants, LLC: Consultancy, Employment, Equity Ownership, Other: Berry Consultants, LLC is a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia. Broglio:Berry Consultants LLC: Employment. Ward:Hoffmann La Roche: Employment, Equity Ownership. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. McGlothlin:Berry Consultants, LLC: Consultancy, Employment. Elliott:Berry Consultants, LLC: Employment. Sehn:Lundbeck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Trněný:Abbvie: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Vitolo:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding.

Abstract Introduction Patients (pts) with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART), but more than half of recipients will experience treatment failure. High pretreatment tumor burden by elevated LDH, metabolic tumor volume, or circulating tumor DNA (ctDNA) levels by clonotype sequencing are associated with inferior outcomes. Low pass whole genome sequencing (lpWGS) is a highly simplified assay capable of identifying copy number alterations (CNA) from cell free DNA (cfDNA) in blood and requires less time, cost, and sample volume to perform vs. other cfDNA sequencing methods; it may be an efficient and precise proxy for tumor burden to identify pts at high risk of progression after CART. Here, we performed lpWGS on pretreatment plasma samples from pts who received CART for rrLBCL and incorporated it into a prognostic risk model. Methods Pts with rrLBCL treated with standard-of-care CART between 5/2018 and 2/2021 at MDACC with plasma samples from time of apheresis were retrospectively identified. cfDNA was extracted from plasma, DNA libraries constructed, and lpWGS performed with a mean coverage of 1.3X. CNA segmentation was generated by CopyWriteR and CNApp (Franch-Expósito et al. Elife 2020) was used to compute scores for focal (FCS, <50% chromosome arm affected), broad (BCS, ≥50%), and relative global (GCS) CNA burdens. Baseline pt characteristics were recorded at time of apheresis. Co-primary endpoints were progression free survival (PFS) from CART infusion and rate of durable response, defined as achieving a complete or partial response without a PFS event with ≥ 3-month follow up. A regularized cox regression model and recursive partitioning analysis tested all covariates against PFS and durable response rate, respectively. Results A total of 135 pts had available plasma collected from the apheresis timepoint, of which 131 (97%) were successfully sequenced and included in the analysis. A total of 122 (93%) pts received their CART product and 9 (7%) died before infusion. Median follow up was 20.7 mo (range 0.5-36) with data cutoff 6/15/2021. Pt characteristics at time of apheresis are described in Table 1. A total of 83 (68%) treated pts progressed and 68 (56%) died. Median PFS and OS were 4.5 and 13.5 mo, respectively, with 1-year PFS and OS rates of 36% and 57%. ECOG PS > 1 was the only covariate associated with death before infusion (p<0.0001). A total of 38 of 121 (31%) evaluable pts (excluding 9 who died before CART and 1 lost to follow up early) were durable responders. Associations between covariates and PFS by univariable analysis are shown in Table 1. Multivariable selection for PFS determined that the 3 independent covariates that comprised the best model were > 1 extranodal (EN) site of disease, LDH > upper limit normal (ULN), and FCS > 52 (median). FCS > 52 was associated with inferior PFS (p=0.0029, HR 1.93 95% CI 1.24-2.99, Fig. 1A), durable response rate (44 v 18%, p=0.0031), and OS (p=0.0027, HR 2.09 95% CI 1.28-3.41, Fig. 1B). Representative genome-wide CNA profiles of 2 pts with FCS of 40 (Fig. 2A) and 203 (Fig. 2B) are included. We created a risk score from 0-3 where pts received 1 point for each negative prognostic feature met (> 1 EN site, LDH > ULN, and FCS > 52), then stratified pts by low (0), intermediate (1-2), or high risk (3). PFS (p<0.0001, Fig. 3A), durable response rate (75 v 32 v 10%, p<0.0001) and OS (p<0.0001, Fig. 3B) were significantly different when comparing low, intermediate, and high-risk pts. Discussion This retrospective analysis is the first to incorporate lpWGS of pretreatment cfDNA to determine CNA burden and associate it with outcomes after CART therapy. The FCS score is associated with survival and is likely a surrogate for ctDNA and tumor burden due to variability in tumor purity. Having > 1 EN site of disease and LDH > ULN were also independently associated. A simple risk model using the 3 variables can reliably risk stratify CART pts prior to therapy, should be validated in an independent/prospective dataset, and could achieve the goal of identifying high-risk pts for interventional studies. lpWGS may therefore represent a more time-, cost-, and sample-efficient method of utilizing pt plasma vs. alternative sequencing methods. Figure 1 Figure 1. Disclosures Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Parmar: Cellenkos Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Ahmed: Merck: Research Funding; Seagen: Research Funding; Xencor: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Steiner: Seattle Genetics: Research Funding; Rafael Pharmaceuticals: Research Funding; BMS: Research Funding. Samaniego: Imbrium: Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding. Nastoupil: MorphoSys: Honoraria; Pfizer: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Janssen: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; ADC Therapeutics: Honoraria; TG Therapeutics: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; IGM Biosciences: Research Funding; Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Epizyme: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding. Neelapu: Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Westin: Curis: Research Funding; Umoja: Consultancy; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding.

Background: Diffuse large B-cell lymphomas (DLBCL) are a heterogeneous group of aggressive B-cell non-Hodgkin lymphomas (NHL). Primary mediastinal B-cell lymphoma (PMBCL) is often grouped and managed as DLBCL, yet PMBCL is biologically and clinically different. Although about two-third of patients are cured with initial therapy, those who are refractory or progress within the first two years do poorly and will die from their disease. There is an unmet need for effective therapeutic approaches in this patient population. Evasion of the host immune responses is an important mechanism for inducing resistance to cancer therapy. Strategies to block molecular and cellular mediators of cancer induced immunosuppression such as programmed death -1 receptor (PD-1) have been explored. Targeting PD-1 immune checkpoints has the potential to play a major role in cancer therapy by reversing tumor immune escape. Trials using PD-1 blockers in advanced hematological malignancies demonstrated remarkable activity in Hodgkin lymphoma. Unfortunately, results in the DLBCL cohort with nivolumab were marginal and short lived. A phase 1b trial in heavily pre-treated relapsed/refractory (RR) PMBCL using pembrolizumab (a PD-1 blocker) showed that it was safe and active with an ORR of 41%. In recent years, several signaling pathways implicated in DLBCL pathogenesis have been targeted, including the PI3K-AKT-mTOR pathway. Copanlisib, a pan-PI3K inhibitor, with particularly potent PI3K-α/PI3K-δ inhibition, showed activity in both indolent and aggressive NHL, with a safer toxicity profile than the FDA-approved agent idelalisib. In a preclinical DLBCL mouse model, treatment with copanlisib resulted in effective down regulation of tumor‐infiltrating T-regulatory cells (Tregs). In the same model, copanlisib, when combined with a surrogate anti‐mouse PD‐1, showed in vivo responses in 75% vs 0% in the monotherapy groups. These data support the rational for the combination of copanlisib and checkpoint blockade in DLBCL. We developed a phase 2 prospective study with two RR cohorts (DLBCL and PMBCL), treated with the combination of copanlisib and nivolumab. Study Design: copanlisib hydrochloride 60 mg is given IV on days 1, 8 and 15 of cycles 1-8 and days 1 and 15 of subsequent cycles. Nivolumab 240 mg IV is given on days 1 and 15 of cycles 1-8 and 480 mg on day 1 of subsequent cycles. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Copanlisib dose will be determined using a safety cohort in 6 patients. The primary outcome is to assess ORR defined as complete and partial responses (CR+PR). Secondary outcomes are to evaluate safety of the combination; to assess progression free survival (PFS), duration of response (DOR), CR rate, and overall survival (OS). Exploratory objectives are to characterize the effects of the copanlisib and nivolumab combination regimen on tumor cells, tumor microenvironment and the immune response in RR DLBCL and PMBCL. We will also do Lymph3CX assay as an integrated biomarker to distinguish between DLBCL and PMBCL. Key inclusion criteria: adult patients with RR DLBCL and PMBCL who have measurable disease with at least one lesion that is >15mm in the longest diameter on cross-sectional imaging; After failure of ASCT or after failure of frontline therapy in subjects who declined or are not ASCT candidates; and have appropriate organ function. Key exclusion criteria: High grade B-cell lymphomas; Active, known or suspected autoimmune disease or patients on any prohibited therapies; History of active CNS involvement or leptomeningeal involvement This study is expected to enroll a maximum of 96 (6 safety cohort, 44 DLBCL and 46 PMBCL) evaluable patients. We anticipate accruing 10 additional patients to account for ineligibility, cancellation, or other reasons. Therefore, the study is expected to accrue a maximum of 106 patients. The largest success proportion where the proposed treatment regimen would be considered ineffective in DLBCL is 25% and 30% in PMBCL. The smallest success proportion that would warrant subsequent studies with the proposed regimen is 45% in DLBCL and 50% in PMBCL. This design has a 90% power with a 1-sided 10% level test. This study is conducted through NCI-CTEP (NCI Protocol #10193; NCT03484819) and is funded by Bayer. The study is to open in fall of 2019 at 11 ECTCN sites, and is available to interested sites to join in. Figure. Disclosures Bennani: Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board. Nowakowski:Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Ansell:Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding.

Introduction. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common adverse effects of chimeric antigen receptor (CAR) T-cell therapy. Elevated biomarkers, such as ferritin and LDH, have been shown to correlate with more severe toxicity. The endothelial activation and stress index (EASIX) is a surrogate of endothelial activation, and correlates to other biomarkers of endothelial dysfunction. In allogeneic hematopoietic cell transplantation (HCT), it is predictive of toxicity such as fluid overload, which is correlative with endothelial dysfunction, as well as sinusoidal obstruction syndrome, non relapse mortality and overall survival (Luft et al, BMT 2019, Varma et al, BBMT, 2020, Jiang et al, Haematologica, 2020). In this study we describe the correlation of EASIX to CAR T cell related CRS and ICANS. Methods. Retrospective data from consecutive patients treated with standard of care axi-cel for non-Hodgkin's lymphoma at MD Anderson Cancer Center between January 2018 and April 2020 were included in the study. CRS and ICANS were graded according to CARTOX criteria (Neelapu et al, Nat Rev Clin Oncol, 2018), and after 5/2019, according to the ASTCT criteria (Lee et al, BBMT, 2019). EASIX parameters were recorded prior to lymphodepletion (the latest value on days -12 to -6) and were available for all 171 patients. The score was defined as lactate dehydrogenase (U/L) × creatinine (mg/dL)/ thrombocytes (10^9 cells per L), with LDH adjusted to the upper limit of normal. Predictors of toxicity were evaluated using Fine and Grey regression analysis considering death before grade 2-4 toxicity as a competing risk. Results. 171 consecutive patients treated with commercial axi-cel for diffuse large B cell lymphoma (n=133), transformed follicular lymphoma (n=28) and primary mediastinal lymphoma (n=10) were included in the study. Median age was 59 years (range, 18-85), and 120 (70%) were male. 151 patients had an ECOG performance status ≤1, 45 patients (26%) had a previous autologous HCT, and 3 (1.8%) had a previous allogeneic HCT. Prior to lymphodepletion, 96 (56%) patients had a high IPI score (≥3) and 134 (78%) were refractory to the previous line of treatment. With a median follow-up of 259 days (range: 25-800) since infusion, ICANS of any grade was noted in 109 (64%) patients, with 84 (49%) having grades 2-4. CRS of any grade was observed in 160 (93%) patients, with 81 (47%) having grades 2-4 CRS. A total of 56 (33%) patients were diagnosed with grade 2-4 ICANS and CRS. The median EASIX score for the entire cohort was 2.1 (range: 0.3-283; inter-quartiles: 1.1 and 4.6). On univariate analysis, EASIX levels above the median were associated with higher cumulative incidence (CI) of grade 2-4 ICANS (% CI: 61 vs 31%; HR=2.4, p<0.001); and levels above the upper quartile were associated with grade 2-4 CRS (% CI: 71 vs 38%; HR=2.2, p=0.02), (Figure 1,2). Additional predictors of grade 2-4 toxicity included IPI score ≥3 (HR=1.6, p=0.03) and female gender (HR=1.7, p=0.05) for ICANS; and IPI score ≥ 3 (HR=1.6, p=0.04) and lack of prior autologous transplant (HR=2, p=0.02) for CRS. Multivariate analysis showed EASIX score to be an independent predictor of grade 2-4 ICANS (HR=2.3, p=0.001) or CRS (HR=2.3, p=0.001); female gender of ICANS (HR=1.7, p=0.03) and lack of prior autologous transplant of CRS (HR=1.9, p=0.02). The impact of IPI did not reach statistical significance for either ICANS (HR=1.3, p=0.3) or CRS (HR=1.2, p=0.4). Further multivariate analysis for other biomarkers and their incorporation into a revised biomarker score will be presented at the meeting. Conclusions. Our results suggest that the EASIX score prior to lymphodepletion predicts higher grade CRS and ICANS in patients receiving axi-cel. These results of routinely available clinical variables require further prospective studies for validation, however our study shows that this score may better stratify patient risk of toxicity, and possibly inform clinical decisions and prevention strategies for patients at higher risk. Disclosures Nieto: Secura Bio: Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Affimed: Consultancy, Other: Grant Support. Hosing:NKARTA Inc.: Consultancy. Westin:47: Research Funding; Amgen: Consultancy; Morphosys: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Lee:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Guidepoint Blogal: Consultancy; Aptitude Health: Speakers Bureau; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding. Nastoupil:Celgene: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Gamida Cell: Honoraria; Gilead/KITE: Honoraria; Novartis: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Wang:Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; OncLive: Honoraria; InnoCare: Consultancy; Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding. Flowers:AbbVie: Consultancy, Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Bayer: Consultancy; National Cancer Institute: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy. Hawkins:Kite: Membership on an entity's Board of Directors or advisory committees. Rezvani:GemoAb: Membership on an entity's Board of Directors or advisory committees; Affimed: Other: Educational grant; Adicet Bio: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: Educational grant; Virogen: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing agreement; Formula Pharma: Membership on an entity's Board of Directors or advisory committees. Champlin:Takeda: Patents & Royalties; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Actinium: Consultancy; Johnson and Johnson: Consultancy; Omeros: Consultancy; Cytonus: Consultancy. Shpall:Magenta: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees. Neelapu:Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Adicet Bio: Other; Calibr: Other; Unum Therapeutics: Other, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; N/A: Other. Kebriaei:Jazz: Consultancy; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board; Ziopharm: Other: Research Support; Pfizer: Other: Served on advisory board; Amgen: Other: Research Support.

Abstract Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is approved for the treatment of pts with relapsed/refractory LBCL with ≥ 2 prior systemic therapies. In the 2-year analysis of ZUMA-1 (NCT02348216), the multicenter, single-arm phase 1/2 study evaluating axi-cel in pts with refractory LBCL, the objective response rate (ORR) was 83%, including a complete response (CR) rate of 58%; 39% of pts had ongoing response with a median follow-up of 27.1 months (Locke et al. Lancet Oncol. 2019). EFS is emerging as a robust surrogate endpoint for OS in hematologic malignancies. A recent systematic analysis demonstrated a linear correlation between EFS and OS in pts with diffuse LBCL after first-line immunochemotherapy (Zhu et al. Leukemia. 2020). Here, we report updated survival findings from the phase 2 portion of ZUMA-1 after 4 years of follow-up, including an evaluation of the association of OS with EFS. Methods: Eligible pts had refractory LBCL (diffuse LBCL, primary mediastinal B cell lymphoma, transformed follicular lymphoma). After leukapheresis at enrollment, pts received low-dose conditioning chemotherapy (fludarabine and cyclophosphamide) followed by a target dose of 2×10 6 anti-CD19 CAR T cells/kg (Neelapu et al. N Engl J Med. 2017). The primary endpoint was ORR, with the first response assessment occurring 4 weeks following infusion. Additional endpoints included safety and translational evaluations. An exploratory analysis of OS by EFS at 12 and 24 months was performed. EFS was defined as the time from axi-cel infusion until disease progression, initiation of new lymphoma therapy (excluding stem cell transplant), or death from any cause. Comparisons of OS by EFS outcomes were analyzed via Kaplan-Meier estimates. Results: Of 111 enrolled pts, axi-cel was administered to 101 pts. As of August 11, 2020, median follow-up was 51.1 months. With over 4 years of follow-up, median OS was 25.8 months, and the 4-year OS rate was 44%. Median EFS in pts treated with axi-cel was 5.7 months, with a 12-month EFS rate of 43% (95% CI, 33-52) and a 24-month EFS rate of 38% (95% CI, 28-47). In pts with an EFS event by Month 12 (EFS12; n=57) vs those without EFS12 (n=44), 4-year OS rates were 7% (95% CI, 2-16) vs 91% (95% CI, 78-97), respectively. Among the 17 pts with EFS12 who were alive at Month 12, 13 (76%) died by Month 48, while among the 44 pts alive at Month 12 without EFS12, 4 (9%) died by Month 48. In pts with an EFS event by Month 24 (EFS24; n=62) vs those without EFS24 (n=39), 4-year OS rates were 13% (95% CI, 6-23) vs 92% (95% CI, 78-98), respectively. Among the 12 pts with EFS24 who were alive at Month 24, 4 (33%) died by Month 48, while among the 39 pts alive at Month 24 without EFS24, 3 (8%) died by Month 48. Since the 2-year analysis (Locke et al. Lancet Oncol. 2019), there have been no new safety signals reported, including no new serious adverse events, no axi-cel-related secondary malignancy, and no confirmed cases of replication-competent retrovirus. Overall, 26 pts received subsequent anti-cancer therapy; median time to next therapy was 8.7 months (range, 0.3 - 53.8). Immunoglobulin therapy was administered to 38 (38%) pts. Two pts in axi-cel-induced remission received allogeneic stem cell transplant; 1 pt was in CR and 1 pt was in partial response. Among treated pts, 58 (57%) have died, primarily due to progressive disease (46%; n=46), followed by other reasons (7%; n=7), adverse events (4%; n=4), and secondary malignancy (myelodysplastic syndrome, with onset on Day 574) unrelated to axi-cel (1%; n=1). Among pts without EFS12 and without EFS24, 1 pt each (2% and 3%, respectively) died due to disease progression >24 months following axi-cel infusion; >36 months, 2 pts each (5% for both) died due to disease progression (1 pt each [2% and 3%]) and other reasons (1 pt each [2% and 3%]. One pt (2%) without EFS12 died due to disease progression between 12 and 24 months. Updated findings with ≥5 years of follow-up, including translational correlations, will be presented. Conclusion: In this long-term survival analysis of ZUMA-1 with ≥4 years of follow-up, axi-cel demonstrated longer OS in pts without EFS events at Month 12 and Month 24 vs pts with events at these timepoints. These data support the use of EFS as a surrogate endpoint for long-term OS in refractory LBCL, and the relationship between EFS and 5-year OS will be presented. Disclosures Jacobson: Nkarta: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Clinical Care Options: Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support. Locke: Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Janssen: Consultancy, Other: Scientific Advisory Role; Gerson Lehrman Group: Consultancy; Novartis: Consultancy, Other, Research Funding; Legend Biotech: Consultancy, Other; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Emerging Therapy Solutions: Consultancy; Takeda: Consultancy, Other; Wugen: Consultancy, Other; EcoR1: Consultancy; Umoja: Consultancy, Other; Cowen: Consultancy; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Miklos: Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Patents & Royalties; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy. Oluwole: Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy; Curio Science: Consultancy. Lin: Gamida Cell: Consultancy; Legend: Consultancy; Juno: Consultancy; Takeda: Research Funding; Merck: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Vineti: Consultancy; Sorrento: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Epizyme: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Timmerman: Spectrum Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Corvus: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Merck: Research Funding; TG Therapeutics: Current equity holder in publicly-traded company. Deol: Kite, a Gilead Company: Consultancy. Reagan: Seagen: Research Funding; Kite, a Gilead Company: Consultancy; Genentech: Research Funding; Curis: Consultancy. Stiff: Karyopharm: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; Kite, a Gilead Company: Research Funding; Amgen: Research Funding; Macrogenics: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Research Funding; Gamida Cell: Research Funding; Seagen: Research Funding; Cellectar: Research Funding; Incyte: Research Funding; BioLineRX: Research Funding; Cellectar: Research Funding; Actinium: Research Funding; MorphoSys: Consultancy, Honoraria. Flinn: Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Farooq: Kite, a Gilead Company: Honoraria. Goy: MorphoSys: Honoraria, Other; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Michael J Hennessey Associates INC: Consultancy; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Medscape: Consultancy; Xcenda: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech/Hoffman la Roche: Research Funding; Infinity/Verastem: Research Funding; Janssen: Research Funding; Rosewell Park: Consultancy; LLC(Targeted Oncology): Consultancy; Hoffman la Roche: Consultancy; Xcenda: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Karyopharm: Research Funding; Phamacyclics: Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Muñoz: Bayer, Kite, a Gilead Company, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seagen, and Janssen, Millennium: Research Funding; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics, Janssen, Seagen, Acrotech, Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/Bristol Myers Squibb, Genentech, and Roche: Speakers Bureau; Pharmacyclics, Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa, Alexion, Beigene, Fosun Kite, Innovent, Seagen, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, and Servier: Consultancy; Targeted Oncology, OncView, Kyowa, Physicians' Education Resource, and Seagen: Honoraria; OncView: Honoraria; Kyowa Kirin: Honoraria; Physicians' Education Resource: Honoraria. Siddiqi: Oncternal: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding. Shen: Atara: Current Employment, Current equity holder in publicly-traded company, Other: Leadership role, Patents & Royalties; Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Other: Leadership role, Patents & Royalties. Bot: Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support. Dong: GliaCure/Tufts: Consultancy, Patents & Royalties; Gilead: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Singh: Kite, a Gilead Company: Current Employment. Spooner: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company. Karalliyadda: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company. Kim: Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Zheng: Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding.

Following a comprehensive and coordinated effort between CBER and CDER, FDA established a table of acceptable surrogate endpoints (SEs) to support drug marketing applications. The publicly accessible SE Table was first published in 2018 as a response to the 21st Century Cures Act legislation and is updated every 6 months to reflect current FDA thinking. The criteria for the table headings and content were chosen to foster succinctness and consistency, while reflecting the degree of scientific understanding for each listed SE. Prior to the publication of the SE table there was the misconception that FDA only approved drugs based on a limited number of SEs. Contrary to this viewpoint, the SE table demonstrates that FDA frequently uses SEs as they are used in over 100 disease/use and patient population combinations. This article describes the considerations and approach taken when establishing the SE table as well as a discussion of the benefits and limitations of the SE table when used by various stakeholders.

Abstract Background Hepatitis C nucleic acid testing to confirm sustained virological response (SVR) after antiviral treatment is technical and expensive, hampering scale-up and decentralisation of care in resource-poor settings. Serial liver function testing may offer a cheaper means of screening for treatment failure. Methods In an HCV treatment shortening study in Vietnam (n=51), we analysed whether a change in ALT or AST from EOT to EOT+ 12 weeks (ΔALT; ΔAST) was a sensitive surrogate for HCV RNA in detecting treatment failure. We compared ΔALT and ΔAST between cures (38) and failures (13), and assessed sensitivity, specificity and area under receiver-operator curves (AUROC) vs gold standard HCV RNA. We validated our findings in a second, larger study population from a UK treatment shortening study (n=202). Both study populations had mild liver disease, and all participants were treated with 4-8 weeks direct acting antiviral therapy. Results In Vietnam, among 46 HCV genotype 1 or 6-infected individuals who supressed ALT on therapy, 11 failed to achieve SVR. Median ΔALT was -1 IU/L in cures vs +24 IU/L in treatment failures (p< 0.001). Increase in ALT (ΔALT > 0) after end-of-treatment was 100% (95% C.I. [66.4 – 100]) sensitive and 48% [26.8 – 69.4] specific vs HCV RNA in identifying failures (AUROC = 0.99). These results were validated among 193 genotype 1 or 4-infected individuals who supressed ALT on treatment in a UK study (in which 60 failed to achieve SVR). Median ΔALT was +1 IU/L in cures vs +45 IU/L in treatment failures (p< 0.001). ΔALT > 0 was 100% sensitive (95% C.I. [94.6 – 100]) and 47% [38.3-56.3] specific (AUC = 0.98). ΔAST performed similarly. Figure 1Change in ALT from EOT to EOT+12 in cures and from EOT to start of retreatment (EOT+6 to 24) in treatment failures in a) Vietnam study b) UK study Conclusion ΔALT from EOT to EOT+12 is a highly sensitive screen for identifying DAA treatment failures. Using this strategy, only around half of treated individuals require HCV RNA testing 12 weeks after end of treatment, offering substantial benefits in terms of cost reductions and decentralisation of care. Disclosures All Authors: No reported disclosures.

The 21st Century Cures Act requires FDA to expand its use of real-world evidence (RWE) to support approval of previously approved drugs for new disease indications and post-marketing study requirements. To address this need in neonates, the FDA and the Critical Path Institute (C-Path) established the International Neonatal Consortium (INC) to advance regulatory science and expedite neonatal drug development. FDA recently provided funding for INC to generate RWE to support regulatory decision making in neonatal drug development. One study is focused on developing a validated definition of bronchopulmonary dysplasia (BPD) in neonates. BPD is difficult to diagnose with diverse disease trajectories and few viable treatment options. Despite intense research efforts, limited understanding of the underlying disease pathobiology and disease projection continues in the context of a computable phenotype. It will be important to determine if: 1) a large, multisource aggregation of real-world data (RWD) will allow identification of validated risk factors and surrogate endpoints for BPD, and 2) the inclusion of these simulations will identify risk factors and surrogate endpoints for studies to prevent or treat BPD and its related long-term complications. The overall goal is to develop qualified, fit-for-purpose disease progression models which facilitate credible trial simulations while quantitatively capturing mechanistic relationships relevant for disease progression and the development of future treatments. The extent to which neonatal RWD can inform these models is unknown and its appropriateness cannot be guaranteed. A component of this approach is the critical evaluation of the various RWD sources for context-of use (COU)-driven models. The present manuscript defines a landscape of the data including targeted literature searches and solicitation of neonatal RWD sources from international stakeholders; analysis plans to develop a family of models of BPD in neonates, leveraging previous clinical trial experience and real-world patient data is also described.

Importance: There is increasing emphasis on getting medical devices to market more quickly by use of priority review pathways, promoted in recent US Food & Drug Administration (FDA) guidance documents and the 21 st Century Cures Act of 2016. Objective: To evaluate the impact of priority review pathways for high-risk cardiovascular devices by analyzing the quality and characteristics of premarket clinical studies in support of their approval and the frequency of postmarket recalls. Design and Setting: Descriptive study of premarket clinical studies supporting all high-risk cardiovascular devices approved via the priority review premarket approval (PMA) pathway between January 1, 2005 and June 15, 2017. Exposure: Priority Review PMA Main Outcome(s) and Measure(s): For all clinical studies which supported priority review PMAs we analyzed: number of patients enrolled, number of patients analyzed for each primary endpoint, demographic information, randomization, blinding, use and type of controls, use of training patients, number and location of study sites, and time of FDA review to approval. We also determined if a post hoc analysis was conducted. We counted all Class 1 and Class 2 recalls and examined FDA expert device panel recommendations. Results: There were 16 priority review cardiovascular devices approved, with mean 1.4 (SD 0.6, range 1-3) pivotal studies per device. Eleven of 16 (69%) were approved based on a single pivotal study. Of 23 pivotal studies, ten (43%) were randomized, 3 (13%) were single-blinded, and none were double-blinded. Twelve (52%) used a noninferiority primary endpoint hypothesis for at least one endpoint and 18 (78%) used a surrogate endpoint. Of the 11 votes on device effectiveness by FDA expert panels, 6 (55%) voted devices were effective. There were a total of 18 Class 1 and 2 recalls for 7 of these devices. Conclusions and Relevance: Most priority review pathway high-risk cardiovascular devices are approved without a randomized or blinded trial. Noninferiority design and use of surrogate endpoints are common. These devices are frequently subject to recalls.

Although many studies have been carried out on pedestrian crossing safety, comprehensive research evaluating vehicle–pedestrian conflict in areas with zebra crossing (AWZCs) versus areas without zebra crossing (AWOZCs) is still neglected. In the present study, through a naturalistic driving study (NDS), drivers’ behavior was recorded in AWZCs and AWOZCs. Vehicle–pedestrian conflicts were evaluated by examining the evasive maneuver behavior of drivers and pedestrians based on surrogate measures of safety (SMoS). The severity of conflicts was categorized by a K-means clustering method into three specific groups based on the critical thresholds of SMoS. The evasive maneuvers performed by pedestrians and drivers were classified into three levels: normal, slight, and serious. In conflicts resulting in normal and serious maneuvers, drivers would attempt to prevent collisions by changing the speed and direction of the vehicle. Moreover, a pedestrian at the slight level of conflict was the determinative factor in reducing the possibility of collisions by performing actions such as returning to the curb of the street or increasing walking speed. Also, the results showed that pedestrians were more likely to cross with a smaller margin of safety in AWOZCs than in AWZCs. This study explains how both pedestrians and drivers play a crucial role in preventing collisions during different levels of conflict. Given this finding, conducting future research to evaluate the interaction between drivers and pedestrians may lead to establishing a basic framework for designing an algorithm to detect the possibility of a pedestrian collision.

Objectives: A successful weaning prediction score could be a useful tool to predict non-airway extubation failure. However, it may carry some challenges without considering the effect of the physiological reserve on the sustainability of extubation. This study investigated the possible correlation between the physiological reserve surrogate characteristics including acute, baseline, and biochemical patients’ factors and non-airway extubation failure in patients with pneumonia. Methods: A retrospective cohort study at two academic teaching hospitals was conducted between January 2019 and January 2020 with patients with pneumonia requiring invasive mechanical ventilation and with Burns Wean Assessment Program (BWAP) scores equal to or exceeding 50. Acute clinical, biochemical, and baseline characteristics were collected for both successful and failed non-airway extubation patients. Results: Among 313 patients, the mean age was 63.63 ± 10.44 years and most of the patients were males (60.7%). The median invasive mechanical duration was 7 days [Interquartile range (IQR): 5–12], the median length of ICU stay was 12 [IQR: 6–23] and the in-hospital mortality was 16.9%. Among this cohort of patients with pneumonia, 37.7% had non-airway extubation failure. Multivariate logistic regression analyses showed that higher CURB-65 score, longer duration of invasive mechanical ventilation, hemodynamic instability, healthcare-associated pneumonia, older men, history of diabetes mellitus, history of cardiac disease, hypophosphatemia, hypocalcemia, and higher admission serum sodium were associated with increased risk of non-airway extubation failure in patients with pneumonia with high BWAP score. Conclusion: A distinct successful weaning score for patients with pneumonia that considers patients’ acute clinical, biochemical, and baseline characteristics may be effective, and these factors could be reflective of the underlying physiological reserve. Sustainability score from IMV rather than weaning score is needed and may be more predictive for the extubation outcome.

Abstract The search for new strategies to curb the spread of the SARS-CoV-2 coronavirus, which causes COVID-19, has become a global priority. Various nanomaterials have been proposed as ideal candidates to inactivate the virus; however, because of the high level of biosecurity required for their use, alternative models should be determined. This study aimed to compare the effects of two types of nanomaterials—gold (AuNPs) and silver nanoparticles (AgNPs), recognized for their antiviral activity and affinity with the coronavirus spike protein—using PhiX174 and enveloped Phi6 bacteriophages as models. To reduce the nanoparticles' toxicity, a species known for its intermediate antiviral activity, Solanum mammosum L. (Sm), was used. NPs prepared with sodium borohydride (NaBH4) functioned as the control. Antiviral activity against PhiX174 and Phi6 was analyzed using its seed, fruit, leaves, and essential oil; the leaves were the most effective on Phi6. Using the aqueous extract of the leaves, AuNPs-Sm of 5.34 ± 2.25 nm and AgNPs-Sm of 15.92 ± 8.03 nm, measured by transmission electron microscopy (TEM), were obtained. When comparing NPs with precursors, both gold(III) acetate and silver nitrate were more toxic than their respective NPs (99.99% at 1 mg/mL). The AuNPs-Sm were less toxic, reaching 99.30% viral inactivation at 1 mg/mL, unlike the AgNPs-Sm, which reached 99.94% at 0.01 mg/mL. Gallic acid was the main component identified in the leaf extract using high performance liquid chromatography with diode array detection (HPLC-DAD). The FT-IR spectra showed the presence of a large proportion of polyphenolic compounds, and the antioxidant analysis confirmed the antiradical activity. The control NPs showed less antiviral activity than the AuNPs-Sm and AgNPs-Sm, which was statistically significant; this demonstrates that both the S. mammosum extract and its corresponding NPs have a greater antiviral effect on the surrogate Phi bacteriophage, which is an appropriate model for studying SARS-CoV-2.

This article presents an overview of the dynamics of the human heart and the main goal is the discussion of its fluid mechanic features. We will see, however, that the flow in the heart can not be fully described without considering its electrophysiology and elastomechanics as well as the interaction with the systemic and pulmonary circulations with which it is strongly connected. Biologically, the human heart is similar to that of all warm-blooded mammals and it satisfies the same allometric laws. Since the Paleolithic Age, however, humans have improved their living conditions, have modified the environment to satisfy their needs and, more recently, have developed advanced medical knowledge which has allowed triple the number of heartbeats with respect to other mammals. In the last century, effective diagnostic tools, reliable surgical procedures and prosthetic devices have been developed and refined leading to substantial progress in cardiology and heart surgery with routine clinical practice which nowadays cures many disorders, once lethal. Pulse duplicators have been built to reproduce the pulsatile flow and ‘blood analogues’, have been realized. Heart phantoms, can attain deformations similar to the real heart although the active contraction and the tissue anisotropy still can not be replicated. Numerical models have also become a viable alternative for cardiovascular research: they do not suffer from limitations of material properties and device technologies, thus making possible the realization of truly digital twins. Unfortunately, a high-fidelity model for the whole heart consists of a system of coupled, nonlinear partial differential equations with a number of degrees of freedom of the order of a billion and computational costs become the bottleneck. An additional challenge comes from the inherent human variability and the uncertainty of the heart parameters whose statistical assessment requires a campaign of simulations rather than a single deterministic calculation; reduced and surrogate models can be employed to alleviate the huge computational burden and all possibilities are currently being pursued. In the era of big data and artificial intelligence, cardiovascular research is also advancing by exploiting the latest technologies: equation-based augmented reality, virtual surgery and computational prediction of disease progression are just a few examples among many that will become standard practice in the forthcoming years.

This article presents an overview of the dynamics of the human heart and the main goal is the discussion of its fluid mechanic features. We will see, however, that the flow in the heart can not be fully described without considering its electrophysiology and elastomechanics as well as the interaction with the systemic and pulmonary circulations with which it is strongly connected. Biologically, the human heart is similar to that of all warm-blooded mammals and it satisfies the same allometric laws. Since the Paleolithic Age, however, humans have improved their living conditions, have modified the environment to satisfy their needs and, more recently, have developed advanced medical knowledge which has allowed triple the number of heartbeats with respect to other mammals. In the last century, effective diagnostic tools, reliable surgical procedures and prosthetic devices have been developed and refined leading to substantial progress in cardiology and heart surgery with routine clinical practice which nowadays cures many disorders, once lethal. Pulse duplicators have been built to reproduce the pulsatile flow and ‘blood analogues’, have been realized. Heart phantoms, can attain deformations similar to the real heart although the active contraction and the tissue anisotropy still can not be replicated. Numerical models have also become a viable alternative for cardiovascular research: they do not suffer from limitations of material properties and device technologies, thus making possible the realization of truly digital twins. Unfortunately, a high-fidelity model for the whole heart consists of a system of coupled, nonlinear partial differential equations with a number of degrees of freedom of the order of a billion and computational costs become the bottleneck. An additional challenge comes from the inherent human variability and the uncertainty of the heart parameters whose statistical assessment requires a campaign of simulations rather than a single deterministic calculation; reduced and surrogate models can be employed to alleviate the huge computational burden and all possibilities are currently being pursued. In the era of big data and artificial intelligence, cardiovascular research is also advancing by exploiting the latest technologies: equation-based augmented reality, virtual surgery and computational prediction of disease progression are just a few examples among many that will become standard practice in the forthcoming years.

Abstract Background Heart failure (HF) is highly associated with systemic iron deficiency (ID) yet its association with myocardial iron depletion (MID) remains barely unveiled. Similarly, it has been unclear whether and how MID deteriorates the progression to advanced HF. Furthermore, neither the underlying pathophysiology nor the negative impact of unmet iron availability to the failing heart, at the molecular level, is elucidated. Purpose We aim to integrate clinical information and experimental data from human explanted heart tissues: 1) to establish the defining criterion of MID in advanced HF population; 2) to recapitulate the pathophysiological role MID plays in the progression of HF; and 3) to identify novel HF molecular signatures or potential cures to correct MID status underestimated in the failing hearts. Methods Adult failing hearts (N=143), including dilated (n=76) and ischemic (n=67) cardiomyopathies, and non-failing control hearts (NFC, N=46) were collected per Human Explanted Heart Program. Iron levels were measured directly from both ventricles, which were re-evaluated by cardiac magnetic resonance imaging (CMR) mapping sequences (e.g. T1, T2*, etc.). Mitochondrial metabolic, reactive oxygen species (ROS) and ROS-scavenging profiles were assessed spectrophotometrically. Tissue remodeling and ultrastructure characteristics were captured by confocal and electron microscopies respectively. Meanwhile, the patients' clinical profiles were integrated into the analysis of molecular regulatory mechanism. Results Myocardial iron content in LV was significantly lower in HF versus NFC [121.4 (88.1–150.3) vs. 137.4 (109.2–165.9) μg/g dry weight, p<0.05], while both RVs showed no difference. With a cutoff of 86.1 μg/g iron level in LV, it screened ∼23% HF patients with MID (HF-MID). Compared with non-MID HF patients, depleted iron store weakly correlated with systemic hemoglobin concentration (r=−0.27, p=0.13) but highly with T2* and magnetic susceptibility proving CMR as an exceptional surrogate for non-invasive diagnosis. And it was noted that MID independently predicted ominous endpoints as NYHA grade increased and LV dysfunctions worsened (all p<0.05). Cardiac respiratory chain enzymatic activities from complex I to V (except for COX III) were further suppressed in the iron-deficient failing hearts, indicating altered myocardial metabolism and excessive ROS production. Moreover, the whole anti-ROS defense were severely impaired, consistent with remarkably inverse tissue remodeling and ultrastructure disintegrity in HF-MID. Mechanistically, two iron-regulatory proteins (IRP-1/2) and following iron trafficking pathways were inactivated possibly determine the restricted iron availability to advanced failing hearts. Conclusions MID worsens HF progression primarily mediated by mitochondrial dysfunction and collapsed oxidative protection in LV, independently predicting an inferior prognosis. CMR demonstrates clinical potential to monitor MID. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Canadian Institutes for Health Research (CIHR); Heart & Stroke Foundation (HSF)

Cookbooks can be interpreted as sites of exchange and transformation. This is not only due to their practical use as written instructions that assist in turning ingredients into dishes, but also to their significance as interconnecting mediums between teacher and student, perceiver and perceived, past and present. Hinging on inescapable notions of apprenticeship, occasion, and the passing of time—and being at once familiar and unfamiliar to both the reader and the writer—the recipe “as text” renders a specific brand of culinary uncanny. In outlining the function of cookbooks as chronicles of the everyday, Janet Theophano points out that they “are one of a variety of written forms, such as diaries and journals, that [people] have adapted to recount and enrich their lives […] blending raw ingredients into a new configuration” (122). The cookbook unveils the peculiar ability of the ephemeral “text” to find permanence and materiality through the embodied framework action and repetition. In view of its propensity to be read, evaluated, and reconfigured, the cookbook can be read as a manifestation of voice, a site of interpretation and communication between writer and reader which is defined not by static assessment, but by dynamic and often incongruous exchanges of emotions, mysteries, and riddles. Taking the in-between status of the cookbook as point of departure, this paper analyses the cookbook as a “living dead” entity, a revenant text bridging the gap between the ephemerality of the word and the tangibility of the physical action. Using Joanne Harris’s fictional treatment of the trans-generational cookbook in Five Quarters of the Orange (2001) as an evocative example, the cookbook is read as a site of “memory, mourning and melancholia” which is also inevitably connected—in its aesthetic, political and intellectual contexts—to the concept of “return.” The “dead” voice in the cookbook is resurrected through practice. Re-enacting instructions brings with it a sense of transformative exchange that, in both its conceptual and factual dimensions, recalls those uncanny structural principles that are the definitive characteristic of the Gothic. These find particular resonance, at least as far as cookbooks are concerned, in “a sense of the unspeakable” and a “correspondence between dreams, language, writing” (Castricano 13). Understanding the cookbook as a “Gothic text” unveils one of the most intriguing aspects of the recipe as a vault of knowledge and memory that, in an appropriately mysterious twist, can be connected to the literary framework of the uncanny through the theme of “live burial.” As an example of the written word, a cookbook is a text that “calls” to the reader; that call is not only sited in interpretation—as it can be arguably claimed for the majority of written texts—but it is also strongly linked to a sense of lived experience on the writer’s part. This connection between “presences” is particularly evident in examples of cookbooks belonging to what is known as “autobiographical cookbooks”, a specific genre of culinary writing where “recipes play an integral part in the revelation of the personal history” (Kelly 258). Known examples from this category include Alice B. Toklas’s famous Cook Book (1954) and, more recently, Nigel Slater’s Toast (2003). In the autobiographical cookbook, the food recipes are fully intertwined with the writer’s memories and experiences, so that the two things, as Kelly suggests, “could not be separated” (258). The writer of this type of cookbook is, one might venture to argue, always present, always “alive”, indistinguishable and indivisible from the experience of any recipe that is read and re-enacted. The culinary phantom—understood here as the “voice” of the writer and how it re-lives through the re-enacted recipe—functions as a literary revenant through the culturally prescribed readability of the recipes as a “transtextual” (Rashkin 45) piece. The term, put forward by Esther Rashkin, suggests a close relationship between written and “lived” narratives that is reliant on encrypted messages of haunting, memory, and spectrality (45). This fundamental concept—essential to grasp the status of cookbooks as a haunted text—helps us to understand the writer and instructor of recipes as “being there” without necessarily being present. The writers of cookbooks are phantomised in that their presence—recalling the materiality of action and motion—is buried alive in the pages of the cookbook. It remains tacit and unheard until it is resurrected through reading and recreating the recipe. Although this idea of “coming alive” finds resonance in virtually all forms of textual exchange, the phantomatic nature of the relationship between writer and reader finds its most tangible expression in the cookbook precisely because of the practical and “lived in” nature of the text itself. While all texts, Jacques Derrida suggests, call to us to inherit their knowledge through “secrecy” and choice, cookbooks are specifically bound to a dynamic injunction of response, where the reader transforms the written word into action, and, in so doing, revives the embodied nature of the recipe as much as it resurrects the ghostly presence of its writer (Spectres of Marx 158). As a textual medium housing kitchen phantoms, cookbooks designate “a place” that, as Derrida puts it, draws attention to the culinary manuscript’s ability to communicate a legacy that, although not “natural, transparent and univocal”, still calls for an “interpretation” whose textual choices form the basis of enigma, inhabitation, and haunting (Spectres of Marx 16). It is this mystery that animates the interaction between memory, ghostly figures and recipes in Five Quarters of the Orange. Whilst evoking Derrida’s understanding of the written texts as a site of secrecy, exchange and (one may argue) haunting, Harris simultaneously illustrates Kelly’s contention that the cookbook breaks the barriers between the seemingly common everyday and personal narratives. In the story, Framboise Dartigen—a mysterious woman in her sixties—returns to the village of her childhood in the Loire region of France. Here she rescues the old family farm from fifty years of abandonment and under the acquired identity of the veuve Simone, opens a local crêperie, serving simple, traditional dishes. Harris stresses how, upon her return to the village, Framboise brings with her resentment, shameful family secrets and, most importantly, her mother Mirabelle’s “album”: a strange hybrid of recipe book and diary, written during the German occupation of the Loire region in World War II. The recipe album was left to Framboise as an inheritance after her mother’s death: “She gave me the album, valueless, then, except for the thoughts and insights jotted in the margins alongside recipes and newspaper cuttings and herbal cures. Not a diary, precisely; there are no dates in the album, no precise order” (Harris 14). It soon becomes clear that Mirabelle had an extraordinary relationship with her recipe album, keeping it as a life transcript in which food preparation figures as a main focus of attention: “My mother marked the events in her life with recipes, dishes of her own invention or interpretations of old favourites. Food was her nostalgia, her celebration, its nurture and preparation the sole outlet for her creativity” (14). The album is described by Framboise as her mother’s only confidant, its pages the sole means of expression of events, thoughts and preoccupations. In this sense, the recipes contain knowledge of the past and, at the same time, come to represent a trans-temporal coordinate from which to begin understanding Mirabelle’s life and the social situations she experienced while writing the album. As the cookery album acts as a medium of self-representation for Mirabelle, Harris also gestures towards the idea that recipes offer an insight into a person that history may have otherwise forgotten. The culinary album in Five Quarters of the Orange establishes itself as a bonding element and a trans-temporal gateway through which an exchange ensues between mother and daughter. The etymological origin of the word “recipe” offers a further insight into the nature of the exchange. The word finds its root in the Latin word reciperere, meaning simultaneously “to give and to receive” (Floyd and Forster 6). Mirabelle’s recipes are not only the textual representation of the patterns and behaviours on which her life was based but, most importantly, position themselves in a process of an uncanny exchange. Acting as the surrogate of the long-passed Mirabelle, the album’s existence as a haunted culinary document ushers in the possibility of secrets and revelations, contradictions, and concealment. On numerous occasions, Framboise confesses that the translation of the recipe book was a task with which she did not want to engage. Forcing herself, she describes the reading as a personal “struggle” (276). Fearing what the book could reveal—literally, the recipes of a lifetime—she suspects that the album will demand a deep involvement with her mother’s existence: “I had avoided looking at the album, feeling absurdly at fault, a voyeuse, as if my mother might come in at any time and see me reading her strange secrets. Truth is, I didn’t want to know her secrets” (30). On the one hand, Framboise’s fear could be interpreted as apprehension at the prospect of unveiling unpleasant truths. On the other, she is reluctant to re-live her mother’s emotions, passions and anxieties, feeling they may actually be “sublimated into her recipes” (270). Framboise’s initial resistance to the secrets of the recipe book is quickly followed by an almost obsessive quest to “translate” the text: “I read through the album little by little during those lengthening nights. I deciphered the code [and] wrote down and cross-referenced everything by means of small cards, trying to put everything in sequence” (225). As Harris exposes Framboise’s personal struggle in unravelling Mirabelle’s individual history, the daughter’s hermeneutic excavation into the past is problematised by her mother’s strange style: “The language […] in which much of the album was written was alien to me, and after a few abortive attempts to decipher it, I abandoned the idea […] the mad scrawlings, poems, drawings and accounts […] were written with no apparent logic, no order that I could discover” (31). Only after a period of careful interpretation does Framboise understand the confused organisation of her mother’s culinary thoughts. Once the daughter has decoded the recipes, she is able to use them: “I began to make cakes [...] the brioche and pain d’épices of the region, as well as some [...] Breton specialties, packets of crêpes dentelle, fruit tarts and packs de sablés, biscuits, nutbread, cinnamon snaps [...] I used my mother’s old recipes” (22). As Framboise engages with her mother’s album, Mirabelle’s memory is celebrated in the act of reading, deciphering, and recreating the recipes. As a metaphorically buried collection waiting to be interpreted, the cookbook is the catalyst through which the memory of Mirabelle can be passed to her daughter and live on. Discussing the haunted nature of texts, Derrida suggests that once one interprets a text written by another, that text “comes back” and “lives on” (‘Roundtable on Translation’ 158). In this framework of return and exchange, the replication of the Mirabelle’s recipes, by her daughter Framboise, is the tangible expression of the mother’s life. As the collective history of wartime France and the memory of Mirabelle’s life are reaffirmed in the cookbook, the recipes allow Framboise to understand what is “staring [her] in the face”, and finally see “the reason for her [mother’s] actions and the terrible repercussions on [her] own” life (268). As the process of culinary translating takes place, it becomes clear that her deceased mother’s album conceals a legacy that goes beyond material possessions. Mirabelle “returns” through the cookbook and that return, in Jodey Castricano’s words, “acts as inheritance.” In the hauntingly autobiographical context of the culinary album, the mother’s phantom and the recipes become “inseparable” (29). Within the resistant and at times contradictory framework of the Gothic text, legacy is always passed on through a process of haunting which must be accepted in order to understand and decode the writing. This exchange becomes even more significant when cookbooks are concerned, since the intended engagement with the recipes is one of acceptance and response. When the cookbook “calls”, the reader is asked “to respond to an injunction” (Castricano 17). In this framework, Mirabelle’s album in Five Quarters of the Orange becomes the haunted channel through which the reader can communicate with her “ghost” or, to be more specific, her “spectral signature.” In these terms, the cookbook is a vector for reincarnation and haunting, while recipes themselves function as the vehicle for the parallel consciousness of culinary phantoms to find a status of reincarnated identification through their connection to a series of repeated gestures. The concept of “phantom” here is particularly useful in the understanding put forward by Nicholas Abraham and Maria Torok—and later developed by Derrida and Castricano—as “the buried speech of another”, the shadow of perception and experience that returns through the subject’s text (Castricano 11). In the framework of the culinary, the phantom returns in the cookbook through an interaction between the explicit or implied “I” of the recipe’s instructions, and the physical and psychological dimension of the “you” that finds lodging in the reader as re-enactor. In the cookbook, the intertextual relationship between the reader’s present and the writer’s past can be identified, as Rashkin claims, “in narratives organised by phantoms” (45). Indeed, as Framboise’s relationship with the recipe book is troubled by her mother’s spectral presence, it becomes apparent that even the writing of the text was a mysterious process. Mirabelle’s album, in places, offers “cryptic references” (14): moments that are impenetrable, indecipherable, enigmatic. This is a text written “with ghosts”: “the first page is given to my father’s death—the ribbon of his Légion d’Honneur pasted thickly to the paper beneath a blurry photograph and a neat recipe for buck-wheat pancakes—and carries a kind of gruesome humour. Under the picture my mother has pencilled 'Remember—dig up Jerusalem artichokes. Ha! Ha! Ha!'” (14). The writing of the recipe book is initiated by the death of Mirabelle’s husband, Yannick, and his passing is marked by her wish to eradicate from the garden the Jerusalem artichokes which, as it is revealed later, were his favourite food. According to culinary folklore, Jerusalem artichokes are meant to be highly “spermatogenic”, so their consumption can make men fertile (Amato 3). Their uprooting from Mirabelle’s garden, after the husband’s death, signifies the loss of male presence and reproductive function, as if Mirabelle herself were rejecting the symbol of Yannick’s control of the house. Her bittersweet, mocking comments at this disappearance—the insensitive “Ha! Ha! Ha!”—are indicative of Mirabelle’s desire to detach herself from the restraints of married life. Considering women’s traditional function as family cooks, her happiness at the lack of marital duties extends to the kitchen as much as to the bedroom. The destruction of Yannick’s artichokes is juxtaposed with a recipe for black-wheat pancakes which the family then “ate with everything” (15). It is at this point that Framboise recalls suddenly and with a sense of shock that her mother never mentioned her father after his death. It is as if a mixture of grief and trauma animate Mirabelle’s feeling towards her deceased husband. The only confirmation of Yannick’s existence persists in the pages of the cookbook through Mirabelle’s occasional use of the undecipherable “bilini-enverlini”, a language of “inverted syllables, reversed words, nonsense prefixes and suffices”: “Ini tnawini inoti plainexini [...] Minini toni nierus niohwbi inoti” (42). The cryptic language was, we are told, “invented” by Yannick, who used to “speak it all the time” (42). Yannick’s presence thus is inscribed in the album, which is thereby transformed into an evocative historical document. Although he disappears from his wife’s everyday life, Yannick’s ghost—to which the recipe book is almost dedicated on the initial page—remains and haunts the pages. The cryptic cookbook is thus also a “crypt.” In their recent, quasi-Gothic revision of classical psychoanalysis, Nicholas Abraham and Maria Torok write about the trauma of loss in relation to psychic crypts. In mourning a loved one, they argue, the individual can slip into melancholia by erecting what they call an “inner crypt.” In the psychological crypt, the dead—or, more precisely, the memory of the dead—can be hidden or introjectively “devoured”, metaphorically speaking, as a way of denying its demise. This form of introjection—understood here in clear connection to the Freudian concept of literally “consuming” one’s enemy—is interpreted as the “normal” progression through which the subject accepts the death of a loved one and slowly removes its memory from consciousness. However, when this process of detachment encounters resistance, a “crypt” is formed. The crypt maps, as Abraham and Torok claim, the psychological topography of “the untold and unsayable secret, the feeling unfelt, the pain denied” (21). In its locus of mystery and concealment, the crypt is haunted by the memory of the dead which, paradoxically, inhabits it as a “living-dead.” Through the crypt, the dead can “return” to disturb consciousness. In Five Quarters of the Orange, the encoded nature of Mirabelle’s recipes—emerging as such on multiple levels of interpretation—enables the memory of Yannick to “return” within the writing itself. In his preface to Abraham and Torok’s The Wolf-Man’s Magic Word, Derrida argues that the psychological crypt houses “the ghost that comes haunting out the Unconscious of the other” (‘Fors’ xxi). Mirabelle’s cookbook might therefore be read as an encrypted reincarnation of her husband’s ghostly memory. The recipe book functions as the encrypted passageway through which the dead re-join the living in a responsive cycle of exchange and experience. Writing, in this sense, re-creates the subject through the culinary framework and transforms the cookbook into a revenant text colonised by the living-dead. Abraham and Torok suggest that “reconstituted from the memories of words, scenes and affects, the objective correlative of loss is buried alive in the crypt” (130). With this idea in mind, it is possible to suggest that, among Mirabelle’s recipes, the Gothicised Yannick inhabits a culinary crypt. It is through his associations with both the written and the practical dimension food that he remains, to borrow Derrida’s words, a haunting presence that Mirabelle is “perfectly willing to keep alive” within the bounds of the culinary vault (‘Fors’ xxi). As far as the mourning crypt is concerned, the exchange of consciousness that is embedded in the text takes place by producing a level of experiential concealment, based on the overarching effect of Gothicised interiority. Derrida remarks that “the crypt from which the ghost comes back belongs to someone else” (‘Fors’ 119). This suggestion throws into sharp relief the ability of the cookbook as a haunted text to draw the reader into a process of consciousness transmission and reception that is always and necessarily a form of “living-dead” exchange. In these terms, the recipe itself—especially in its embodiment as instructed actions—needs to be understood as a vector for establishing the uncanny barriers of signification erected by the bounds of the cookbook itself as a haunted site of death, enchantment, and revenant signs. In this way, eating, a vital and animated activity, is “disturbingly blended with death, decomposition and the corpse” (Piatti-Farnell 146). And far from simply providing nourishment for the living, Mirabelle’s encrypted recipes continue to feed the dead through cycles of mourning and melancholia. Mirabelle’s cookbook, therefore, becomes a textual example of “cryptomimeses”, a writing practice that, echoing the convention of the Gothic framework, generates its ghostly effects through embodying the structures of remembrance and the dynamics of autobiographic deconstructive writing (Castricano 8). As heimliche and unheimliche collide in practices of culinary reading and writing, the cookbook acts as quasi-mystical, haunted space through which the uncanny frameworks of language and experience can become actualised. ReferencesAbraham, Nicolas, and Maria Torok, The Shell and the Kernel: Renewals of Psychoanalysis. Chicago: U of Chicago P, 1994. Amato, Joseph. The Great Jerusalem Artichoke Circus. Minneapolis: U of Minnesota P, 1993. Castricano, Jodey. Cryptomimesis: The Gothic and Jacques Derrida’s Ghost Writing. London: McGill-Queen’s UP, 2003. Derrida, Jacques. “Fors: the Anglish words of Nicolas Abraham and Maria Torok.” Eds. Nicholas Abraham, and Maria Torok. The Wolf Man’s Magic Word: A Cryptonomy. Minneapolis: U of Minnesota Pr, 1986. xi–xlviii ---. “Roundtable on Translation.” The Ear of the Other: Otobiography, Transference, Translation. London: U of Nebraska P, 1985. 91–161. Floyd, Janet, and Laurel Foster. The Recipe Reader: Narratives–Contexts–Traditions. Aldershot: Ashgate, 2003. Harris, Joanne. Five Quarters of the Orange. Maidenhead: Black Swan, 2002. Kelly, Traci Marie. “‘If I Were a Voodoo Priestess’: Women’s Culinary Autobiographies.” Kitchen Culture in America: Popular Representations of Food, Gender and Race. Ed. Sherrie A. Inness. Philadelphia: U of Pennsylvania P, 2001. 251–70. Piatti-Farnell, Lorna. Food and Culture in Contemporary American Fiction. New York: Routledge, 2011. Rashkin, Esther. Family Secrets and the Psychoanalysis of Narrative. Princeton: Princeton UP, 1992. Slater, Nigel. Toast: The Story of a Boy’s Hunger. London: Harper Perennial, 2004. Theophano, Janet. Eat My Words: Reading Women’s Lives Through The Cookbooks They Wrote. New York: Palgrave, 2002. Toklas, Alice B. The Alice B. Toklas Cook Book. New York: Perennial,1984.

In recent years, the US television landscape has been flooded with reboots, remakes, and revivals of “classic” nineties television series, such as Full/er House (1987-1995, 2016-present), Will & Grace (1998-2006, 2017-present), Roseanne (1988-1977, 2018), and Charmed (1998-2006, 2018-present). The term “reboot” is often used as a catchall for different kinds of revivals and remakes. “Remakes” are derivations or reimaginings of known properties with new characters, cast, and stories (Loock; Lavigne). “Revivals” bring back an existing property in the form of a continuation with the same cast and/or setting. “Revivals” and “remakes” both seek to capitalise on nostalgia for a specific notion of the past and access the (presumed) existing audience of the earlier series (Mittell; Rebecca Williams; Johnson).Reboots operate around two key pleasures. First, there is the pleasure of revisiting and/or reimagining characters that are “known” to audiences. Whether continuations or remakes, reboots are invested in the audience’s desire to see familiar characters. Second, there is the desire to “fix” and/or recuperate an earlier series. Some reboots, such as the Charmed remake attempt to recuperate the whiteness of the original series, whereas others such as Gilmore Girls: A Life in the Year (2017) set out to fix the ending of the original series by giving audiences a new “official” conclusion.The Roseanne reboot is invested in both these pleasures. It reunites the original cast for a short-lived, but impactful nine-episode tenth season. There is pleasure in seeing Roseanne (Roseanne Barr), Dan (John Goodman), Jackie (Laurie Metcalf), Becky (Lecy Goranson [seasons one to six, ten], Sarah Chalke [seasons six to nine]), Darlene (Sara Gilbert), and DJ (Michael Fishman) back in the Conner house with the same well-worn couch and afghan. The (attempted) recuperation is of author-star Barr, whose recent politics are in stark contrast to the working-class second-wave feminist politics of her nineties’ persona. This article is particularly interested in the second pleasure, because both the original series and the reboot situate the voice of Barr as central to the series’ narrative and politics.Despite achieving the highest ratings of any US sitcom in the past three years (O’Connell), on 29 May 2018, ABC announced that it was cancelling the Roseanne reboot. This decision came about in the wake of a racist tweet, where Barr compared a black woman (high-ranking Obama aide Valerie Jarrett) to an ape. Barr’s tweet and the cancellation of Roseanne, highlight the limits of nostalgia and Roseanne/Barr’s particular brand of white feminism. While whiteness and a lack of racial awareness are (and always have been) at the centre of Barr’s performance of feminism, the political landscape has shifted since the 1990s, with the rise of third and fourth-wave feminisms and intersectional activism. As such in the contemporary landscape, there is the expectation that white feminist figures take on and endorse anti-racist stances.This article argues that the reboot’s attempt to capitalise on nineties nostalgia exposes the limits of Roseanne/Barr’s feminism, as well as the limits of nostalgia. The feminist legacy of nineties-era Roseanne cannot and does not recuperate Barr’s star-persona. Also, the reboot and its subsequent cancellation highlight how the feminism of the series is embodied by Barr and her whiteness. This article will situate Roseanne and Barr within a feminist tradition on US television, before exploring how the reboot operates and circulates differently to the original series.From Roseanne (1988-1997) to Roseanne (2018)In its original form, Roseanne holds the distinction of being one of the most highly discussed and canonised feminist-leaning television series of all time, alongside The Mary Tyler Moore Show (1970-1977), Cagney and Lacey (1981-1988), and Buffy the Vampire Slayer (1997-2004). Roseanne also enabled and informed many popular feminist-leaning contemporary series, including Girls (2012-2017), Mom (2013-present), Better Things (2016-present), and Dietland (2018). Although it may seem anachronistic today, Roseanne and Barr helped define what it means to be a feminist and speak feminist politics on US television.Roseanne depicts the lives of the Conner family, headed by parents Roseanne and Dan. They live in the fictional blue-collar town of Lanford, Illinois with their three children Becky, Darlene, and DJ. Both Roseanne and Dan experience precarious employment and embark on numerous (mostly failed) business ventures throughout the series’ run. The reboot catches up with the Conner family in 2018, after Roseanne has experienced a health scare and single mom Darlene has moved into her parents’ house with her two children Harris (Emma Kenney) and Mark (Ames McNamara). In the new season, Roseanne and Dan’s children are experiencing similar working conditions to their parents in the 1990s. Becky works at a Mexican restaurant and is eager to act as surrogate mother to earn $50,000, Darlene is recently unemployed and looking for work, and DJ has just returned from military service.A stated objective of reviving Roseanne was to address the contentious US political landscape after the election of President Donald J. Trump (VanDerWerff). Barr is a vocal supporter of President Trump, as is her character in the reboot. The election plays a key role in the new season’s premise. The first episode of season 10 establishes that the titular Roseanne has not spoken to her sister Jackie (who is a Hillary Clinton supporter) in over a year. In both its nineties and 2018 incarnations, Roseanne makes apparent the extent to which feminist politics are indebted to and spoken through the author-star. The series is based on a character that Barr created and is grounded in her life experience. Barr and her character Roseanne are icons of nineties televisual feminism. While the other members of the Conner family are richly drawn and compelling, Roseanne is the centre of the series. It is her voice and perspective that drives the series and gives it its political resonance. Roseanne’s power in the text is authorised by Barr’s stardom. As Melissa Williams writes: “For nearly a decade, Barr was one of the most powerful women in Hollywood” (180).In the late 1980s and into the 1990s, Roseanne (and Barr) represented a new kind of feminist voice on US television, which at that stage (and still today) was dominated by middle-class women. Unlike Mary Richards (Mary Tyler Moore), Claire Huxtable (Phylicia Rashad), or Murphy Brown (Candice Bergen), Roseanne did not have a stable job and her family’s economic situation was often precarious. Roseanne/Barr adopted and used a feminism of personality popularised on television by Mary Tyler Moore and Lucille Ball. Unlike her foremothers, though, Roseanne/Barr was not slender, feminine, or interested in being likeable to men. Roseanne did not choose to work outside of the home, which marked her as different from many of US television’s other second-wave feminists and/or mothers. As Rachael Horowitz writes: “Roseanne’s feminism was for women who have to work because bills must get paid, who assert their role as head of the house despite the degrading work they often do during the day to pay for their kids’ food and clothes” (9).According to Kathleen Rowe, Barr is part of a long line of “female grotesques” whose defining features are excess and looseness (2-3). Rowe links Barr’s fatness or physical excess with her refusal to shut up and subversive speech. The feminism of Roseanne is contained within and expressed through Barr’s unruly white body (and voice). Barr’s unruliness and her unwillingness to follow the social conventions of politeness and decorum are tied to her (perceived) feminist politics.Understandings of Barr’s stardom, however, have shifted considerably in the years since the publication of Rowe’s analysis. While Barr is still “unruly,” her unruliness is no longer located in her body (which has been transformed to meet more conventional standards of western beauty), but rather in her Twitter presence, which is pro-Israel, pro-Trump, and anti-immigration. As Roxane Gay writes of the reboot: “Whatever charm and intelligence she [Barr] brought to the first nine seasons of her show, a show I very much loved, are absolutely absent in her current persona, particularly as it manifests on Twitter.”Feminist Voice and Stardom on US TVRoseanne performs what Julie D’Acci calls “explicit general feminism,” which is defined by “dialogue and scenes that straightforwardly addressed discrimination against women in both public and private spheres, stories structured around topical feminist causes, and the use of unequivocal feminist language and slogans” (147). However, the feminist politics of Roseanne and Barr are (and never were) straightforward or uncomplicated.Studies of feminism on US television have primarily focused on comedies that feature female television stars who function as advocates for feminism and women’s issues (Spigel; Rabinovitz; D’Acci). Much of the critical discussion of feminist voice in US female-led television identifies the feminist intervention as taking place at the level of performance (Dow; Spigel; Spangler). Comedic series such as I Love Lucy (1951-1957), Murphy Brown (1988-1998, 2018-present), and Grace Under Fire (1993-1998), and dramatic series’, such as Cagney and Lacey and Buffy the Vampire Slayer, privilege the articulation of feminist ideas through performance and character.Roseanne is not a series that derives its comedy from a clash of different perspectives or a series where politics are debated and explored in a nuanced a complex way. Roseanne promotes a distinct singular perspective – that of Roseanne Barr. In seasons one to nine, the character Roseanne is rarely persuaded to think differently about an issue or situation or depicted as “wrong.” The series centres Roseanne’s pain and distress when Becky elopes with Mark (Glenn Quinn), or when Jackie is abused by her boyfriend Fisher (Matt Roth), or when Darlene accidently gets pregnant. Although those storylines are about other characters, Roseanne’s emotions are central. Roseanne/Barr’s perspective (as fictional character and media personality) informs the narrative, sensibility, and tone. Roseanne is not designed to contain multiple perspectives.Roseanne is acutely aware of its place in the history of feminist voice and representations of women on US television. Television is central to the series’ articulation of feminism and feminist voice. In season seven episode “All About Rosey,” the series breaks the fourth wall (as it does many times throughout its run), taking the audience behind the scenes where some of US television’s most well-known (and traditional) mothers are cleaning the Conner’s kitchen. June Cleaver (Barbara Billingsley) from Leave It to Beaver (1957-1963), Joan Nash (Pat Crowley) from Please Don’t Eat the Daisies (1965-1967), Ruth Martin (June Lockhart) from Lassie (1958-1964), Norma Arnold (Alley Mills) from The Wonder Years (1988-1993), and Louise Jefferson (Isabel Sanford) from The Jeffersons (1975-1985) at first sit in judgment of Barr and her character Roseanne, claiming she presents “wrong image” for a TV mother. However, Roseanne/Barr eventually wins over the TV mothers, declaring “the important thing is on my show, I’m the boss and father knows squat” (7.19). It is in contrast to more traditional television mothers that Roseanne/Barr’s feminist voice comes into focus.In the ninth and final season of Roseanne’s initial run, the series (arguably) becomes a parody of its former self. By this point in the series, “Barr was seen as the sole cause of the show’s demise, as a woman who was ‘imploding,’ ‘losing the plot,’ or ‘out of control’” (White 234). White argues that depicting the working-class Conners’ social and economic ascension to upper-class diminishes the distinction between Barr and her character (243). White writes that in the series’ finale, the “line between performer and character is irrevocably blurred; it is unclear whether the voice we are hearing is that of Roseanne Conner or Roseanne Barr” (244). This blurring between Roseanne and Barr becomes particularly contentious in season 10.Rebooting Roseanne: Season 10Season 10 redacts and erases most of the events of season nine, which itself was a fantasy, as revealed in the season nine finale. As such, the reboot is not a simple continuation, because in the season nine finale it is revealed that Dan suffered a fatal heart attack a year earlier. The final monologue (delivered in voice-over by Barr) “reveals” that Roseanne has been writing and editing her experiences into a digestible story. The “Conners winning the lottery” storyline that dominated season nine was imagined by Roseanne as an elaborate coping strategy after Dan’s death. Yet in the season 10 reboot, Dan is revealed to be alive, as is Darlene and David’s (Johnny Galecki) daughter Harris, who was born during the events of season nine.The limits of Roseanne/Barr’s feminism within the contemporary political landscape come into focus around issues of race. This is partly because the incident that incited ABC to cancel the reboot of Roseanne was racially motivated, and partly because Roseanne/Barr’s feminism has always relied on whiteness. Between 1997 and 2018, Barr’s unruliness has become less associated with empowering working-class women and more with railing against minorities and immigrants. In redacting and erasing the events of season nine, the reboot attempts to step back the conflation between Roseanne and Barr with little success.In the first episode of season 10, “Twenty Years to Life”, Roseanne is positioned as the loud-mouthed victim of circumstance and systemic inequality – similar to her nineties-persona. Yet in 2018, Roseanne mocks same things that nineties’ Roseanne took seriously, including collective action, community building, and labour conditions. Roseanne claims: “It is not my fault that I just happen to be a charismatic person that’s right about everything” (10.01). Here, the series attempts to make light of a now-outdated understanding of Barr’s persona, but it comes off as tone-deaf and lacking self-awareness.Roseanne has bigoted tendencies in both the 1990s and in 2018, but the political resonance of those tendencies and their relationships to feminisms and nostalgia differs greatly from the original series to the reboot. This is best illustrated by comparing season seven episode “White Men Can’t Kiss” and season 10 episode “Go Cubs.” In the former, Roseanne is appalled that she may have raised a racist son and insists DJ must kiss his black classmate Geena (Rae’Ven Larrymore Kelly) in the school play. Towards the end of this episode, Geena’s father comes by the restaurant where Roseanne and Jackie are closing up. When the tall black man knocks on the locked door, Roseanne refuses to let him inside. She appears visibly afraid. Once Roseanne knows he is Geena’s father, she lets him in and he confronts her about her racist attitude. Roseanne (and the audience) is forced to sit in the discomfort of having her bigotry exposed. While there are no material consequences for Roseanne or DJ’s racism, within the context of the less intersectional 1990s, this interaction does not call into question Roseanne or Barr’s feminist credentials.In season 10, Roseanne tackles similar issues around race, ignorance, and bigotry, but it plays out very differently. In the reboot’s seventh episode, Roseanne suspects her Muslim refugee neighbours Fatima (Anne Bedian) and Samir (Alain Washnevky) are terrorists. Although Roseanne is proven wrong, she is not forced to reckon with her bigotry. Instead, she is positioned as a “hero” later in the episode, when she berates a supermarket cashier for her racist treatment of Fatima. Given what audiences know about Barr’s off-screen politics, this does not counteract the impression of racism, but compounds it. It also highlights the whiteness of the politics embodied by Roseanne/Barr both on-screen and off. Although these are two very different racial configurations (anti-blackness and Islamophobia), these episodes underline the shifting reception and resonance of the feminism Roseanne/Barr embodies.ConclusionIn June 2018, shortly after the cancellation of the Roseanne reboot, ABC announced that it was developing a spin-off without Barr called The Conners (2018-present). In the spin-off Roseanne is dead and her family is dealing with life after Roseanne/Roseanne (Crucchiola). Here, Roseanne suffers the same fate as Dan in season nine (she dies off-screen), but now it is Barr who is fictionally buried. While The Conners attempts to rewrite the story of the Conner family by rejecting Barr’s racist views and removing her financial and creative stake in their stories, Barr cannot be erased or redacted from Roseanne or the story of the Conner family, because it is her story.The reboot and its cancellation illuminate how Barr and Roseanne’s feminist voice has not evolved past its white second-wave roots. The feminism of Roseanne is embodied by Barr in all her unruliness and whiteness. Roseanne/Barr/Roseanne has not taken on the third and fourth-wave critiques of second-wave feminisms, which emphasise the limits of white feminisms. The failure of the Roseanne reboot reveals that the pleasure and nostalgia of seeing the Conner family back together is not enough. Ultimately, Roseanne is without intersectionality, and thus cannot (and should not) be recognised as feminist in the contemporary political landscape.ReferencesBetter Things. Cr. Pamela Adlon and Louis C.K. 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