Journal articles on the topic 'Organ Jacobsona'

Many animals use their vomeronasal organs to gain direct and specific contact with chemical cues released by congeners and in biological fluids. These cues provide information about the physiological status of the emitter and facilitate or regulate social interactions such as sexual relationships. The present review gives a short description of the discovery of the vomeronasal organ and the pivotal findings of Jacobson. The distribution of the organ and its anatomy in some vertebrates are described. The mechanisms for stimulus entry and egress are discussed, and the findings that led to the appreciation of the vomeronasal organ in mammals as a main chemosensory organ for pheromones mediating reproductive status and inducing sexual behaviour are reported. The anatomical, biochemical and functional properties of the receptor neurones are described.

AbstractAn analysis of the interaction between the tongue and Jacobson's organ was conducted using x-ray cinematography and two experimental procedures. The results failed to support the traditional hypothesis of a direct linkage between the tongue and Jacobson's organ since the tongue was never observed to enter the lumen of Jacobson's organ. Conversely, the results presented provide strong support for the role of elevation of the anterior lingual processes as the mechanism for stimulus transfer.

Abstract The montpellier snake, Malpolon monspessulana, used in the current work in order to study the nervi terminalis and vomeronasalis. The vomeronasal organ or Jacobson’s organ is a part of the olfactory apparatus. This organ is innervated by the terminal and vomeronasal nerves. These nerves emerge from the sensory epithelium of Jacobson’s organ simultaneously. The bundles of the terminal and vomeronasal nerves traverse together the cavity of the nasal capsule in their way to the brain. These nerves bear scattered ganglionic cells which represent the ganglion terminale. They leave the capsule through the foramen olfactorium advehens. The terminal and vomeronasal nerves are connected with the olfactory nerve and enter the olfactory formation of the forebrain.

The vomeronasal organ (VNO) or Jacobson's organ is responsible in terrestrial vertebrates for the sensory perception of pheromones, chemicals that elicit stereotyped behaviors among individuals of the same species. Pheromone-induced behaviors and a functional VNO have been described in a number of mammals, but the existence of this sensory system in human is still debated. Recently, two nonhomologous gene families, V1R and V2R, encoding pheromone receptors have been identified in rat. These receptors belong to the seven-transmembrane domain G-protein-coupled receptor superfamily. We sought to characterize V1R-like genes in the human genome. We have identified seven different human sequences by PCR and library screening with rodent sequences. These human sequences exhibit characteristic features of V1R receptors and show 52%–59% of amino acid sequence identity with the rat sequences. Using PCR on a monochromosomal somatic cell hybrid panel and/or FISH, we demonstrate that these V1R-like sequences are distributed on chromosomes 7, 16, 20, 13, 14, 15, 21, and 22 and possibly on additional chromosomes. One sequence hybridizes to pericentromeric locations on all the acrocentric chromosomes (13, 14, 15, 21, and 22). All of the seven V1R-like sequences analyzed show interrupted reading frames, indicating that they represent nonfunctional pseudogenes. The preponderence of pseudogenes among human V1R sequences and the striking anatomical differences between rodent and human VNO raise the possibility that humans may have lost the V1R/VNO-mediated sensory functions of rodents.[Sequence data from this article have been deposited with the DDBJ/EMBL/GenBank Data Libraries under accession nos. U73852–73853 andAF253312–253316.]

The article attempts to evaluate the balance of United Nations accomplishments in the field of peace and security since 1945. The first part deals with the elements one has to take into consideration to properly evaluate such performance. These are what the Organization ought to do (its objectives), what it could do (its means) and what it has done (the kinds of activities). In the second part, each one of these elements is examined. About the objectives, the article distinguishes between manifest and latent objectives and it argues that the first ones have not changed when the second ones have much changed. About the means, the article analyzes the powers given the UN and the way its principal organs exercise them. It traces the evolution of the roles of the Security Council, the General Assembly, the Secretary general and the International Court of Justice. Concerning the kinds of activities, the article uses a typology developed by H.K. Jacobson to argue that the main function of the UN is a "verbal" or informational one, that the normative function especially in its collective legitimization aspect is the second most important, that the rule supervisory function accounts or few activities, and, that the operational function is more developed than it may appear. The article concludes that the balance is a positive one pointing to the flexibility, the adaptability and the continued usefulness of the UN.

Heavy birth weight, increased calving difficulty, heart function defects, increased perinatal mortality and organ immaturity have been reported for calves produced from IVP embryos compared to those produced from MOET or AI (van Wagtendonk AM et al., 2000 Theriogenology 53, 575–597; Jacobsen H et al., 2002 Anim Reprod Sci 70, 1–11). In this study we examined birth weight (BWT), and blood chemistry at 1 day of age, gestation length and heart function at 7 days, and response to an ACTH challenge at 21 days of calves derived from IVP in a ‘semi-defined’ IVC system (Thompson JG et al., 2000 J. Reprod. Fertil. 118, 47–55) and of contemporary MOET or AI calves. Holstein Friesian (HF) 2- and 3-year-old recipients carrying single HF calves (101×IVP and 21×MOET) were monitored in this study. Within 1 day of birth the calves were weighed and a blood sample taken for analysis. At 7d, ultrasound measurement of the left ventricle diastolic diameter (LVEDd) and % ejection fraction (EF%) was determined. Each calf was then transported to a rearing unit. At 3 weeks of age, 30 IVP and 30 control AI calves of the same age were injected i.v. with Synacthen (synthetic ACTH, Ciba Corporation, 0.1μgkg−1 body weight). Blood samples were collected at −30, 0, 30, 60 and 90min (0min=time of injection) for cortisol measurements. There was no difference in BWT for MOET or IVP calves (40.9±4.7 v. 35.6±4.8kg, respectively). Moreover, gestation lengths (279 days v. 281 days) and calving assistance scores (1.3 v. 1.6) did not differ. Calf mortality at birth was higher for IVP calves (16%) than for MOET calves (5%). All but 7 surviving calves (6×IVP and 1×MOET) had high GGT levels at 1 day. Blood chemistry revealed no differences between the calf types, all measures being within normal ranges. For all calves, heart function analysis revealed no abnormalities with mean LVEDd=4.1±0.6cm and mean EF%=78.5±8.4%. All calves exhibited elevated cortisol following ACTH challenge. There was no difference between control and IVP calves for mean cortisol concentration at any time point (0min, 13.8±5.2; 30min, 46.6±9.8; 60min, 42.8±9.9; 90min, 28.1±8.9ngmL−1). These data suggest that, unlike calves produced in less defined culture systems, calves produced by IVP in a semi-defined culture system have birth weight and gestation lengths similar to those of MOET calves. Moreover, no abnormalities in organ (heart, adrenal) function were detected. However, of concern was the high number of unexplained deaths for IVP calves. This may be due to an overall lack of vigour in IVP calves that, in an unsupervised calving, results in calf death. More vigilence at calving may be needed to ensure calf survival. The authors thank Juliet Jensen, Waikato Hospital, for ultrasound measurements and David Stewart, Morrinsville Veterinary Services, for calf care. This study was funded by Vialactia Biosciences and FRST.

We have used in situ hybridisation to establish the temporal and spatial expression patterns of the mouse homeobox-containing gene; Hox-7, in the developing embryonic cranium and nervous system of the mouse between embryonic days 9.5 (E9.5) and E15.5. Hox-7 has previously been associated with areas of mesenchymal-epithelial interaction and cell migration especially in neural crest ectomesenchymal cells. Aside from the expression patterns seen in the facial anlage at E9.5, Hox-7 transcripts were also detected in the neuroepithelium including cells of the dorsal midline of the neural tube. This expression pattern persisted throughout the embryonic time span studied. At E11.5, expression of Hox-7 became obvious in the neuroepithelium of the forming tela choroida and the telencephelii in areas destined to form the choroid plexus before any atrophy of the neuroepithelium took place. High expression of Hox-7 was also present in the mesenchyme cells invading the pouch formed by the involuting choroid plexus neuroepithelium. A second major site where Hox-7 was expressed was the anlage of the anterior pituitary; the Rathke's pouch. Expression became obvious at E10.5 throughout the pouch but by E12.5 became more regionalised in areas of the pouch destined to form the pars distalis. Hox-7 was also expressed in the forming meninges and skull bone precursors from E10.5 onwards. Expression of the Hox-7 gene is also seen in the external ear, the forming eye, the nasal pits and forming Jacobson's organs. When these expression patterns are considered together with characterised human and mouse retinoic acid embryopathies and the congenital malformations seen in human children associated with deletion of chromosome 4p16.1 (Wolf-Hirschhorn syndrome), Hox-7 may be a good candidate as one of the genes involved in the initiation of the choroid plexus phenotype and its subsequent formation, the formation of the outer ear, formation of the dentition and the differentiation of the cell types of the anterior pituitary. The expression pattern of Hox-7 in the dorsal midline of the neural tube further suggests that it may also be involved in the specification of the dorsal-ventral axis of the developing nervous system.

Abstract Introduction: A common initial treatment approach for PTLD includes reduction of immunosuppression (RIS) and single-agent rituximab, followed by sequential chemoimmunotherapy for non-responding patients (pts). However, in relapsed disease, there is less consensus on optimum therapy. Moreover, there are very limited data regarding the use of chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory SOT-related PTLD, despite its documented efficacy and tolerability in large B-cell lymphoma (LBCL). Methods: We conducted a multicenter, retrospective, RWE analysis of adults who had SOT-associated PTLD. We obtained baseline clinical features at diagnosis of PTLD including prior organ transplant, immunosuppression usage, international prognostic index (IPI), EBV status, treatment course, response to therapy, and clinical course with CD19 CAR-T. Post-CAR-T survival analyses were performed using Kaplan-Meier with comparison by response using log rank. Results: A total of 20 pts across 8 U.S. academic centers were included in the analysis. Pathology was monomorphic B-cell PTLD in all cases; most pts had diffuse LBCL NOS, with 3 high-grade BCL NOS cases. Prior SOT included 15 kidney transplants (75%), 3 liver (15%), 1 intestinal (5%), and 1 heart transplant (5%). Median time from SOT to PTLD diagnosis was 107 months (mos) (5-379). The median age at time of CART was 55 years (31-75 years) with 4 pts (22.2%) aged >70 years (see Table). The tumor EBV status was negative in 16 pts (80%), positive in 1 (5%), and unavailable in 3 pts (15%). The IPI score upon relapse prior to CAR-T therapy was 3-5 among 14 pts (70%) and 0-2 for the other 6 pts (30%). Most of the pts had stage III-IV disease (95%), and elevated LDH (80%) prior to CAR-T. There were also 5 pts (25%) with >1 site of extranodal involvement, and 1 pt (5%) had secondary central nervous system involvement. For initial therapy of PTLD, 4 pts (20%) received rituximab alone, 12 (60%) had R-CHOP, and 4 (20%) received dose-adjusted R-EPOCH. The median number of prior therapies prior to CAR-T was 2 (1-4); bridging therapy prior to CAR-T are listed in the Table. Immunosuppression was stopped completely prior to CAR-T infusion in 15 (75%) pts, with prednisone alone continued for 3. For CAR-T therapy, 13 pts (65%) received tisagenlecleucel and 7 pts (35%) axicabtagene ciloleucel; 18 received commercial product and 2 were treated on a clinical trial. For tolerability, 16 (80%) pts experienced cytokine release syndrome (CRS): 9 (45%) grade (G) 1, 5 (25%) G2, and 1 (5%) each for G3 and G4. The immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 14 (70%) pts: 2 (10%) G1, 5 (25%) G2, 5 (25%) G3, and 2 (10%) G4. There were 2 (10%) pts with treatment-related mortality (TRM) at 1.5 and 4.5 mos post-CAR-T (1 pneumonia/sepsis and 1 encephalopathy). The overall response rate was 65%, with 50% complete remission (CR) and 20% stable disease. 13 of 15 pts resumed immunosuppression post-CAR-T after a median of 2.2 mos (1-14). Of these pts, 8 were started on steroids; 2 on tacrolimus, 1 both steroid and tacrolimus; 1 everolimus; and 1 on sirolimus. 3 pts (15%) experienced allograft rejection after CAR-T, all of which were kidney SOTs occurring at 1, 4, and 14.6 mos after CAR-T infusion; 1 pt died due to disease progression (1.5 mos) and the 2 other pts required hemodialysis. CRS and ICANS scoring for these 3 pts were 0, 0, 2, and 1, 3, 1, respectively, and all were off immunosuppression at time of rejection. Overall, at a median follow-up of 25 mos (5-112), 13 pts (65%) had progression of disease or TRM, and 7 pts (35%) remained in remission (Figure A/B). Additionally, as highlighted in Figure C/D, all non-relapsing pts had achieved CR with CAR-T therapy (7/10 CR remain in remission), which was strongly associated with outcomes (PFS HR 0.03 (95% CI 0.00-0.29), P=0.002; and OS HR 0.06 (95% CI 0.01-0.57), P=0.014). Conclusions: This RWE provides the largest analysis to date of CD19 CAR-T therapy in relapsed/refractory SOT-related LBCL PTLD. We found that rates of CAR-T-related CRS and neurologic events appeared comparable with previous non-PTLD CAR-T data. Furthermore, 50% of SOT-PTLD pts obtained a CR, with approximately one-third of pts sustaining long-term remission, and achievement of CR was a critical factor associated with survival. Finally, with abrogation of immunosuppression prior to CAR-T, and careful resumption post-therapy, organ preservation was achieved in most pts. Figure 1 Figure 1. Disclosures Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Lazaryan: Kadmon: Consultancy; Avrobio: Membership on an entity's Board of Directors or advisory committees; Humanigen: Membership on an entity's Board of Directors or advisory committees. Jacobson: Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Nastoupil: TG Therapeutics: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Denovo Pharma: Other: DSMC; Epizyme: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; IGM Biosciences: Research Funding; Caribou Biosciences: Research Funding; Bayer: Honoraria; MorphoSys: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ahmed: Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen: Research Funding; Merck: Research Funding; Xencor: Research Funding.

Background:A disease model of systemic lupus erythematosus (SLE) that predicts short-term outcomes (disease activity and prednisone use) and links them to long-term outcomes (accrual of organ damage and mortality) was previously developed in a single center SLE cohort (Johns Hopkins [JH]) to support health economic analyses (Watson 2015), which has not been comprehensively replicated in other cohorts or contexts.Objectives:As part of an effort to develop and refine this existing disease model, the aim of this study was to replicate the previously estimated network of risk equations for short- and long-term outcomes in the SLICC Inception Cohort, an international cohort of patients (33 centers,11 countries).Methods:The SLICC Inception Cohort enrolled patients fulfilling ACR Classification Criteria for SLE within 15 months of diagnosis from 1999-2011 with annual follow-up through April 2020. The network of risk equations included two linear random effects models to predict (1) change in annual average Systemic Lupus Disease Activity Index (SLEDAI) score based on patient characteristics and the presence of renal, hematological, and immunological involvement in the prior year and (2) average annual prednisone dose based on SLEDAI score in the same year. These equations were then linked to parametric survival models that predicted time to the occurrence of organ damage (system-specific based on the ACR/SLICC Damage Index) and mortality. We compared model performance between the SLICC Cohort and the original analysis from the JH Cohort.Results:In comparison to the JH cohort (N=1354), the SLICC cohort (N=1697) had a smaller fraction of patients of African descent (39% vs 17%) and shorter disease duration at entry (4.8 vs 0.5 years). In the first equation predicting change in annual SLEDAI score, predictors were generally aligned with the same direction and significance, with the exception of renal involvement in the prior period, which had a positive association with change in SLEDAI in the SLICC cohort but was negatively associated in the JH cohort (Table 1). The second equation predicting prednisone dose was also consistent with the original analysis showing a significant positive association between higher disease activity and prednisone use. In all of the parametric survival analyses (individual organ damage and mortality models), coefficients were generally in the same direction and magnitude, though some were no longer significant in the SLICC cohort.Conclusion:The relationships identified in the original analysis were broadly replicated in the SLICC Inception Cohort. Observed differences may reflect differences in the patient populations, structure of the two cohorts (prevalent vs inception), and frequency of visits (quarterly visits in the JH cohort vs annual visits with the SLICC cohort may more closely capture a decrease in SLEDAI associated with treatment specifically related to renal involvement). Additional analyses relaxing the requirement to completely align with the original structure are underway to further assess the predictive accuracy of these models.References:[1]Watson P, et al. Rheumatology (Oxford). 2015;54(4):623-32.JH Cohort(N=1354)SLICC Cohort(N=1697)Female, %92.988.8African descent, %38.816.7Disease duration at entry, mean (SD), years4.8 (6.3)0.5 (0.3)SLEDAI at first visit, mean (SD)3.7 (4.1)5.4 (5.4)Change in average annual SLEDAICoefficientCoefficientConstant1.491*5.762*Annual average SLEDAI in prior period−0.460*−0.755*Male gender−0.080−0.207Log transformation of age−0.241*−1.134*Renal involvement in prior period−0.301*0.627*African descent0.383*0.126Increased DNA binding in prior period0.276*0.939*Low complement in prior period0.484*0.775*Hematological involvement in prior period0.104−0.025Anemia in prior period0.152**0.144Associated annual average prednisone dose (mg/day)Constant3.475*2.738*SLEDAI in same period0.777*0.648**p<0.001; **p<0.05Acknowledgements:We acknowledge the support on this abstract of the following investigators of the Systemic Lupus International Collaborating Clinics:John Hanly - john.hanly@nshealth.caCaroline Gordon - p.c.gordon@bham.ac.ukSang-Cheol Bae - scbae@hanyang.ac.krJuanita Romero-Diaz - juanita.romerodiaz@gmail.comJorge Sanchez-Guerrero - jorge.sanchez-guerrero@uhn.caSasha Bernatsky - sasha.bernatsky@mcgill.caAnn Clarke - aeclarke@ucalgary.caDaniel Wallace - dwallace@ucla.edu/danielwallac@gmail.comDavid Isenberg - d.isenberg@ucl.ac.ukAnisur Rahman - anisur.rahman@ucl.ac.ukJoan Merril - JTMmail@aol.comPaul Fortin - paul.fortin@crchudequebec.ulaval.caDafna Gladman - dafna.gladman@utoronto.caMurray Urowitz - m.urowitz@utoronto.caIan Bruce - ian.bruce@manchester.ac.ukMichelle Petri - mpetri@jhmi.eduEllen Ginzler - ellen.ginzler@downstate.eduMA Dooley - Mary_Dooley@med.unc.eduRosalind Ramsey-Godman - rgramsey@northwestern.eduSusan Manzi - susan.manzi@ahn.org; Susanmanzi@gmail.comAndreas Jonsen - andreas.jonsen@med.lu.seGraciela Alarcon - galarcon@uab.eduRonald van Vollenhoven - r.vanvollenhoven@amsterdamumc.nlCynthia Aranow - CAranow@Northwell.eduMeggan Mackay – mmackay@northwell.eduGuillermo Ruiz-Irastorza - r.irastorza@outlook.esSam Lim - sslim@emory.eduMurat Inanc - drinanc@istanbul.edu.tr; minanc2008@gmail.comKenneth Kalunian - kkalunian@ucsd.eduSoren Jacobsen - sj@dadlnet.dkChristine Peschken - christine.peschken@umanitoba.caDiane Kamen - kamend@musc.eduAnca Askanase - ada20@columbia.eduDisclosure of Interests:Ann E Clarke Consultant of: BMS, AstraZeneca, GSK, and Exagen Diagnostics., Yvan St-Pierre: None declared, Victoria Paly: None declared, Ian N. Bruce Speakers bureau: GSK, UCB, Consultant of: BMS, Eli Lilly, GSK, Astra Zeneca, Merck Serono; UCB, ILTOO, Aurinia, Grant/research support from: Genzyme/Sanofi, GSK, Roche, UCB, Chiara Malmberg: None declared, Andrew Briggs Speakers bureau: Alexion, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Gilead, GSK, Kite, Merck, Novartis, Rhythm, Roche, Sanofi, Takeda, Consultant of: Alexion, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Gilead, GSK, Kite, Merck, Novartis, Rhythm, Roche, Sanofi, Takeda, Yuanhui Zhang Shareholder of: Bristol Myers Squibb., Employee of: Bristol Myers Squibb., Jiyoon Choi Shareholder of: JNJ., Employee of: BMS, Alan Brennan Consultant of: Alan Brennan is a paid consultant on advisory boards regarding cost-effectiveness modelling., Grant/research support from: Alan Brennan received research grants.

Abstract Background and Rationale: Axi-cel is a standard-of-care treatment for relapsed or refractory LBCL after 2 or more lines of systemic therapy. Some patients who would have been ineligible for ZUMA-1 criteria due to comorbidities have been treated with axi-cel in the real-world setting. We interrogated a large registry of patients treated with standard-of-care axi-cel for a definitive report on the impact of age or certain comorbidities on safety and efficacy outcomes after axi-cel infusion. Methods: From October 2017 to August 2020, 1500 patients were enrolled in the postapproval safety observational study of axi-cel treated at 79 centers. Patients eligible for the protocol and followed up for at least 6 months with complete data entry by the time of analyses were included. One patient rescinded consent and 1 was deemed ineligible. Patients previously treated with immune effector cell therapy (n=31), with incomplete follow-up reporting (n=92), or alive but last contacted &lt;180 days postinfusion (n=32) were excluded from analysis. Main efficacy outcomes included complete and objective response rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS). Safety endpoints of interest included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Outcomes were assessed and compared by age and preselected coexisting disease or organ impairment within 3 months prior to the infusion included in the hematopoietic cell transplantation comorbidity index. Multivariate logistic and Cox regression models were used to assess the impact of age or coexistent organ dysfunction on outcomes via odds ratio (OR) or hazard ratio (HR) and their 95% CIs. Results A total of 1343 patients were included in the analysis with a median 25.1 months (range, 10.3-42.7 months) for potential follow-up, defined from infusion to data cutoff date, and a median 11.8 months (range, 0.1-38.8 months) for actual follow-up time, defined from infusion to date of death or last contact. Of these, 38% were 65 years or older (median 62 years), 4% had a performance score ≥2, 13% had cardiac comorbidities, 16% had a prior cancer, 9% were obese, 2% had moderate to severe hepatic comorbidities, and 2% had renal comorbidities. Transformed lymphoma, double or triple-hit by fluorescence in situ hybridization, prior autologous transplant and refractory disease were present in 28%, 15%, 27% and 66%, respectively. Bridging therapy was administered in 21% of patients. Overall, ORR was 74%, (CR 56%), and probabilities of DOR, PFS, and OS at 18 months were 61% (95% CI, 57-65%), 42% (95% CI, 39-45%) and 52% (95% CI, 49-55%), respectively. Overall rates of CRS and ICANS were 83% and 55%, respectively. ORR was 78% (CR 62%, median OS 17.5 [95% CI, 16.0-not evaluated (NE)] months) for patients ≥65 years, ORR 57% (CR 29%; median OS 4.3 [95% CI, 2.5-8.3] months) for patients with hepatic dysfunction, ORR 70% (CR 43%; median OS 8.9 [95% CI, 3.8-NE] months) for patients with renal dysfunction; and ORR 47% (CR 20%, median OS 4 [95% CI, 2.6-6.9] months) for patients with Eastern Cooperative Oncology Group (ECOG) 2 or 3. Multivariate analyses indicated that advanced age (≥65 years vs &lt;65 years; OR 1.38; 95% CI, 1.05-1.83), moderate to severe pulmonary disease (yes vs no; OR 0.74; 95% CI, 0.55-0.98), and ECOG (2-3 vs 0-1; OR 0.31, 95% CI, 0.18-0.53) impacted ORR (Table). Age ≥65 years did not have an impact on survival (HR 1.05, 95% CI, 0.88-1.26), although it was associated with CRS (OR 1.42, 95% CI, 1.03-1.96) and ICANS (OR 1.78, 95% CI, 1.39-2.28). Coexistent cardiac disease (HR 1.44, 95% CI, 1.12-1.83), renal disease (HR 2.13, 95% CI, 1.32-3.46) and hepatic dysfunction (HR 2.65, 95% CI, 1.69-4.14) had an impact on OS, but not on response, CRS, and ICANS. ECOG significantly impacted all efficacy outcomes. None of the other comorbidities tested significantly impacted outcomes. Conclusion: Advanced age (≥65 years) was not associated with worse efficacy outcomes after axi-cel, despite higher rates of CRS and ICANS, which require closer monitoring. Performance status rather than age should be accounted for in patient selection and treatment decisions with axi-cel. Most coexistent organ dysfunctions have no clinically significant impact on axi-cel objective response and safety outcomes. Figure 1 Figure 1. Disclosures Locke: Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Amgen: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Wugen: Consultancy, Other; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cowen: Consultancy; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Legend Biotech: Consultancy, Other; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role. Jacobson: Axis: Speakers Bureau; Nkarta: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Ma: Kite, a Gilead Company: Current Employment. Dong: Kite, a Gilead Company: Current Employment. Hu: Kite, a Gilead Company: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Siddiqi: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncternal: Research Funding; Janssen: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: 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; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Ghobadi: Atara: Consultancy; Wugen: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Miklos: 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; 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. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Legend: Consultancy; Vineti: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Merck: Research Funding; Takeda: Research Funding. Perales: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Nektar Therapeutics: Honoraria, Other; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; NexImmune: Honoraria; Sellas Life Sciences: Honoraria; Cidara: Honoraria; Merck: Honoraria; Omeros: Honoraria; Servier: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Other; Kite/Gilead: Honoraria, Other; Incyte: Honoraria, Other; Medigene: Honoraria; Karyopharm: Honoraria; Equilium: Honoraria. Lunning: Daiichi-Sankyo: Consultancy; TG Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy; ADC Therapeutics: Consultancy; Spectrum: Consultancy; Beigene: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Legend: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; Novartis: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Acrotech: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy. Hill: Gentenech: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Xu: Gilead Sciences: Other: stock or other ownership ; Kite, A Gilead Company: Current Employment. Pasquini: Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding.

Background:Lymphoma was one of the most severe complications of primary Sjögren’s syndrome (pSS). Lymphomas often developed in organs where pSS is active, such as salivary glands. The enlargement of salivary glands is considered a predictive factor in previous studies. It is clarified that salivary gland ultrasound can visually and clearly demonstrate the parenchyma structure, which is a feasible method for SS diagnosis. However, there are no specific ultrasound features of salivary gland lymphoma and no early ultrasonic alarming system have been reported.Objectives:To descript the characteristic ultrasound features and assess ultrasonic alarming value of salivary gland lymphoma in patients with pSS.Methods:We followed a cohort of 63 patients with pSS from March 2017 to September 2019 and salivary gland ultrasound was performed every three months. All patients were examined by grey-scale and color Doppler ultrasound (US). The size, echostructure and vascularity of salivary glands were analyzed. US-guided core-needle biopsy (US-CNB) was used for the diagnosis of salivary gland lymphoma.Results:In 63 patients with pSS, parotid enlargement occurred in 11 patients and none of them had submandibular gland enlargement. During the follow-up, 2 patients with parotid enlargement demonstrated recovery of size and echostructure improved. The remaining 9 patients had permanent parotid swelling and echostructure unchanged. US-CNB was performed in these 9 patients and histological and immunohistochemical findings of the cores suggested parotid lymphoma. Compared with other patients, these 9 patients revealed marked, permanent parotid enlargement of the unilateral or bilateral or asymmetric parotid. The parotid lymphoma ultrasonography was characterized by multiple, relatively large, well-demarcated hypoechoic (>6mm) with increased vascularity.Conclusion:Ultrasonographic assessment of salivary gland helped to alarm the occurrence of lymphoma in pSS patients. Marked, permanent and asymmetric parotid enlargement with multiple, relatively large, well-demarcated hypoechoic in echostructure seemed to be characteristic for parotid lymphoma in pSS patients.References:[1]Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R, Jacobsson LT. Lymphoma and other malignancies in primary Sjögren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65(6):796-803.[2]Nocturne G, Mariette X. Sjögren’s Syndrome-associated lymphomas: an update on pathogenesis and management. Br J Haematol. 2015;168(3):317-27.[3]Alunno A, Leone MC, Giacomelli R, Gerli R, Carubbi F. Lymphoma and lymphomagenesis in primary Sjögren’s syndrome. Front Med (Lausanne). 2018;5:102.[4]Orita Y, Sato Y, Kimura N, Marunaka H, Tachibana T, Yamashita Y, et al. Characteristic ultrasound features of mucosa-associated lymphoid tissue lymphoma of the salivary and thyroid gland. Acta Otolaryngol. 2014;134(1):93-9.Disclosure of Interests:None declared

Abstract Introduction B-cell post-transplant lymphoproliferative disorders (B-PTLD) represent a spectrum of lymphoid neoplasms arising as a consequence of impaired T-cell surveillance secondary to immunosuppressive medications. Epstein-Barr Virus (EBV) has been implicated in the development of B-PTLD. B-PTLDs diagnosed within one year post-transplant are more likely to be associated with EBV whereas B-PTLD diagnosed after a year are more likely to be EBV-negative and are associated with worse prognosis. Studies have shown that EBV up-regulates CD30 expression, a member of the TNF-receptor superfamily (Haque et al 2011). Novel agents are now available that target cells expressing CD30. Hence, knowledge of the expression profiles and the clinical characteristics of CD30+ neoplasms is warranted. In this study, we evaluated CD30 expression in 59 cases of B-PTLD and correlated CD30 and EBV status with clinical characteristics. Methods Consecutive cases of B-PTLD diagnosed between 1997 and 2013 were retrieved from our archives. Immunohistochemistry (ISH) for CD30 was performed on formalin-fixed, paraffin embedded biopsies using the BerH2 monoclonal antibody (BioSB, Santa Barbara, CA) according to standard methods. Positive expression was pre-defined as CD30 expression by ≥20% of the lesional cells (Figure 1). Log-rank and Fischer's Exact 2-sided Test were performed in STATA 11, as appropriate. Results The 59 B-PTLDs occurred in 54 patients. Three patients had two different sites biopsied during the diagnostic workup. Two other patients had recurrent B-PTLD. The median age at diagnosis was 22.8 years old (range 1.2 to 75.9 years); 65% were male. The median time from transplant to diagnosis was 2.6 years (range 6 weeks to 15.9 years, mean 4.2 years). Eighteen cases (35%) were diagnosed within the first year of transplantation. The organs transplanted are detailed in Table 1 with the percentage of CD30+ cases noted. Prior to transplantation, only 25/44 (57%) patients were EBV IgG seropositive, likely reflecting the number of children who were younger than age ten when transplanted (21/52; 40%). (Orjuela et al 2011). Serum EBV Polymerase Chain Reaction (PCR) was positive in 18/27 (67%) cases analyzed. Pathological data are summarized in Table 2. In total, 39 of 59 cases (66%) showed 20% or more CD30 expression. Positive EBV ISH was significantly associated with CD30 expression (r=0.38, p< 0.01). Of 59 tumors informative for CD30 and EBV (by ISH), 32/41 of EBV-positive tumors were CD30 positive (78%) while 7 of 18 tumors that were EBV negative were CD30 positive (39%) (r=0.38 for the association of EBV and CD30 status, p=0.01). Detectable serum viremia was associated with CD30 status (r=0.49, p=0.02). There was no association found between CD20 status and CD30 status. There was no significant association between CD30 status and ki67 index or c-myc expression either (data not shown). Conclusion We observed a high frequency of CD30 expression in patients with B-PTLD. Expression of CD30 correlates with ISH evidence of EBV infection in B-PTLD. In addition, positive serum EBV PCR was associated with CD30 expression. These two findings further support the link between EBV infection and CD30 expression. CD30 positivity was still found in 39% of EBER – negative cases, suggesting that CD30 ISH should be considered on all cases of B-PTLD. A monoclonal antibody conjugated to the cytotoxic agent MMAE,Brentuximab Vedotin (SGN-35), has shown activity in clinical trials against CD30 positive lymphomas (Jacobson et al 2012). Considering the relatively common prevalence of CD30+ expression in PTLD, brentuximab vedotin could be considered for study in combination with traditional front-line therapies or as an alternative therapy for relapsed/refractory disease. A prospective clinical trial (NCT 01805037) at Northwestern University is ongoing. Disclosures: Schecter: Seattle Genetics: Research Funding, Speakers Bureau. O'Connor:Seattle Genetics: Research Funding.

Background: Adoptive engineered autologous cellular immunotherapy has had a significant impact on the lives of some patients with advanced hematologic malignancies. However, the use of these therapies on a larger proportion of patients has been limited by variability of the final cell product, feasibility concerns, cost, and toxicity. Off-the-shelf allogeneic (allo) products offer the opportunity to address some of these concerns. Allo products have their own theoretical limitations, including the potential for graft-versus-host disease (GvHD) causing additional toxicity and host-versus-graft rejection limiting efficacy. PBCAR0191, an anti-CD19 allogeneic CAR T cell, was designed to limit the risk of GvHD by specifically inserting a CD19 specific CAR into the TRAC (T cell receptor alpha constant) locus in cells harvested from healthy donors. Those cells are then expanded, a CD3 elimination step is performed, followed by another expansion, and then PBCAR0191 is vialed and frozen for shipment then thawing, dilution, and infusion at the treatment site. To reduce the risk of PBCAR0191 rejection and increase the chances of cell expansion, lymphodepletion prior to dosing is required. This phase 1 3+3 dose escalation study is designed to identify an optimal dose of PBCAR0191 for efficacy evaluation. Methods: In each of 3 dose levels (3 x 105, 1 x 106, and 3 x 106 CAR-T+ cells/kg), up to 6 patients may be enrolled in each of 2 cohorts (Non-Hodgkin Lymphoma (NHL) and Acute Lymphoblastic Leukemia (ALL)). Eligibility requirements include adequate organ function, confirmed diagnosis to fit one of the cohorts, evaluable disease, at least 2 prior standard treatment regimens, no immunodeficiencies, no CNS disease, no active infections or other major medical issues requiring intervention, and no active GvHD. Eligible patients may have received allogeneic stem cell transplant or another CAR-T therapy. Lymphodepletion was administered on day -5 to day -3 using fludarabine 30mg/m2/day and cyclophosphamide 500mg/m2/day. Cells were administered on day 0. Correlative serum and PBMC samples were taken, while patients remained on study, on days 0, 1, 3, 7, 10, 14, 28, 42, 60 and every 30 days until 180 and then every 90 days until day 360. Assessment of response compared to baseline was performed on day 14 (optional for NHL only), and days 28, 60, 90, 180, 270, and 360, until progression. Results: Three patients with advanced NHL were enrolled and treated in DL1 between April 25, 2019 and May 24, 2019. Two males (one MCL, one DLBCL) and 1 female (DLBCL) ages 34 - 64 (median 64) years were treated. Two screen failures occurred, both patients with ALL, due to non-compliance (1) and loss of CD19 surface expression (1). One patient enrolled post disease progression after treatment with Axicabtagene ciloleucel. No significant toxicity was observed, including no serious adverse events and no dose-limiting toxicities with all patients having a minimum follow-up of 28 days (median 60 days). Two of the three patients experienced objective tumor response by Lugano criteria, at day 14 and day 28, respectively. Both patients progressed due to new lesions (on day 28 and day 60, respectively). The third patient has not met the definition of response, but has had evidence of central necrosis, decreased tumor size, and decreased PET-avidity at day 28, in the context of post-infusion tumor site pain and mild CRS symptoms. Peripheral blood analysis for CAR-T expansion has identified preliminary evidence of cell expansion with a low absolute numbers quantified, likely due to the low dose level at which treatment was initiated. Peripheral blood serum analysis for IFN-gamma, IL-6, and IL-15 indicate preliminary evidence of cell expansion, though not definitive. Conclusions: Further enrollment of patients into DL2 is ongoing. Data from DL2 entered by early October will be included in a presentation in the meeting. Findings to date indicate preliminary evidence of short-lived cell-mediated anti-tumor effect and preliminary evidence of cell expansion in vivo, which will be evaluated more fully at DL2 and DL3. Disclosures Jacobson: Bayer: Consultancy, Other: Travel Expenses; Humanigen: Consultancy, Other: Travel Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel Expenses. Herrera:Adaptive Biotechnologies: Consultancy; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Budde:F. Hoffmann-La Roche Ltd: Consultancy. DeAngelo:Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy; Novartis: Consultancy, Research Funding; Glycomimetics: Research Funding; Abbvie: Research Funding; Blueprint: Consultancy, Research Funding. Heery:Precision BioSciences: Employment. Stein:Amgen: Consultancy, Speakers Bureau; Stemline: Speakers Bureau; Celgene: Speakers Bureau. Jain:Kite/Gilead: Consultancy. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria.

Background:Remission, LDA and LDAS have been proposed as treatment goals for SLE. However, the independent impact of these states on damage accrual has not been fully evaluated.Objectives:To determine the independent impact of remission (both off & on treatment), LDA, and LLDAS on damage accrual.Methods:We studied a long-term longitudinal multinational SLE cohort, including patients completing at least two annual assessments. Remission off-treatment was defined as a SLEDAI (excluding serology) =0, without prednisone and immunosuppressive (IS) drugs. Remission on-treatment was defined as a SLEDAI (excluding serology) =0, prednisone daily dose<=5 mg/d and maintenance IS drugs. LDA was defined as a SLEDAI (excluding serology) <=2, without prednisone or IS drugs. LLDAS was defined as a SLEDAI <=4 with no activity in major organ systems, with no new features of lupus disease activity compared to the previous assessment, prednisone daily dose<=7.5 mg/d and maintenance IS drugs. Antimalarials were allowed in all groups. Damage accrual was ascertained with the SLICC/ACR damage index (SDI). Univariable and multivariable generalized estimated equation (GEE) negative binomial regression models were used. To create mutually exclusive groups, disease activity was divided into five states: remission off-treatment, remission on-treatment (minus remission off treatment), LDA (minus remission), LLDAS (minus remission and LDA) and not-optimally controlled. The proportion of the time that patients were in the specific state at each visit since cohort entry was determined. Possible effect modifiers and confounders adjusted for included sex, age at diagnosis, race/ethnicity, education, baseline disease duration, follow-up time, the highest-ever glucocorticoid dose prior to cohort entry, antimalarials and SDI. Time-dependent covariates were determined at the same annual visit as disease activity state; the outcome was the increase in the SDI and it was assessed at the subsequent visit.Results:There were 1,652 patients, 1464 (88.6%) were female, mean age at diagnosis was 34.6 (SD 13.4) years and mean baseline disease duration was 5.5 (SD 4.1) months. Patients had a mean follow-up of 6.5 (SD 4.3) years, 11686 visits were included. 763 patients (46.2%) had an increase in SDI score ≥1 during follow-up. 2483 (21.2%) of the visits were classified as remission off-treatment, 2276 (19.5%) as remission on-treatment, 544 (4.7%) as LDA, 657 (5.6%) as LLDAS and 5726 (49.0%) as not-optimally controlled. Being in remission off-treatment, remission on-treatment, LDA and LLDAS were predictive of a lower probability of damage accrual [remission off-treatment IRR=0.403, 95% CI 0.301-0.541); remission on-treatment IRR=0.313 (95% CI 0.218-0.451) LDA: IRR=0.469 (CI 95% CI 0.272-0.809); LLDAS IRR=0.440 (95% CI 0.241-0.803)]. The multivariable model is summarized in Table 1.Table 1.Multivariable GEE model of the impact of disease activity states on damage accrual.Incidence Rate Ratio95% CIDisease activity stateRemission off treatment0.4030.301-0.541Remission on treatment0.3130.218-0.451LDA0.4690.272-0.809LLDAS0.4400.241-0.803Gender, male1.2741.086-1.495Age at diagnosis1.0241.020-1.029EthnicityCaucasian USRef.Caucasian other1.0170.849-1.217African1.4671.211-1.776Asian0.8630.693-1.075Hispanic1.2661.034-1.550Other1.1210.759-1.656Educational level, years0.9770.957-0.996Disease duration at baseline0.9600.801-1.150Follow-up time0.9420.923-0.960Antimalarial use0.7860.681-0.908Highest prednisone dose before baseline1.0021.001-1.007SDI before1.1001.050-1.1152LLDAS: Low lupus disease activity state LDA: Low disease activity SDI: SLICC/ACR Damage IndexConclusion:Remission on- and off-treatment, LDA and LLDAS were associated with less damage accrual, even adjusting for possible confounders and effect modifiers. This highlights the importance of treating to target in SLE.Disclosure of Interests:Manuel F. Ugarte-Gil Grant/research support from: Pfizer, Janssen, John Hanly: None declared, Murray B Urowitz: None declared, Caroline Gordon Speakers bureau: UCB, Consultant of: Center for Disease Control, Astra-Zeneca, MFP, Sanofi, UCB, Sang-Cheol Bae: None declared, Juanita Romero-Diaz: None declared, Jorge Sanchez-Guerrero: None declared, Sasha Bernatsky: None declared, Ann E Clarke Consultant of: AstraZeneca, BristolMyersSquibb, GlaxoSmithKline, and Exagen Diagnostics, Daniel J Wallace Grant/research support from: Exagen, David Isenberg: None declared, Anisur Rahman: None declared, Joan T Merrill: None declared, Paul Fortin: None declared, Dafna D Gladman Consultant of: Abbvie, Janssen, Pfizer, Novartis, Amgen, Grant/research support from: Abbvie, Janssen, Pfizer, Novartis, Amgen, Ian N. Bruce: None declared, Michelle A Petri: None declared, Ellen M Ginzler Grant/research support from: Aurinia pharmaceutical, M.A. Dooley: None declared, Rosalind Ramsey-Goldman: None declared, Susan Manzi: None declared, Andreas Jonsen: None declared, Ronald van Vollenhoven Speakers bureau: AbbVie, Galapagos, GSK, Janssen, Pfizer, UCB, Consultant of: Abbvie, AstraZeneca, Biogen, Biotest, Celgen, Galapagos, Gilead, Janssen, Pfizer, Sanofie, Servier, UCB, Vielabo, Grant/research support from: BMS, GSK, Lilly, UCB, Cynthia Aranow: None declared, Meggan Mackay: None declared, Guillermo Ruiz-Irastorza: None declared, S. Sam Lim: None declared, Murat Inanc: None declared, Kenneth C Kalunian Consultant of: Roche, Biogen, Janssen, AstraZeneca, Eli Lilly, Genetech, Gilead, ILTOO, Nektar, Viela, Equillium, Bristol-Meyers Squibb, Soren Jacobsen Grant/research support from: BMS, Christine Peschken: None declared, Diane L Kamen: None declared, Anca Askanase Consultant of: Abbvie, Grant/research support from: Glaxo Smith Kline, Astra Zeneca, Janssen, Eli Lilly and Company, Mallinckrodt, Pfizer, Bernardo Pons-Estel Consultant of: GSK, Janssen, Graciela S Alarcon: None declared.

Abstract Introduction Axicabtagene citoleucel (axi-cel) is a recently approved, highly effective treatment for relapsed and refractory aggressive B cell lymphomas. It is complicated by the occurrence of cytokine release syndrome (CRS) in > 90% of patients (Neelapu, Locke et al. 2017). CRS is characterized by high fevers and elevation in inflammatory markers such as C-reactive protein (CRP) and ferritin. It can progress to hypotension and end-organ damage. The clinical distinction between CRS and bacterial infections is virtually impossible. Procalcitonin (PCT) is FDA approved to aid in antibiotic management and stopping antibiotics in sepsis. It has been shown in several studies and meta-analyses to reduce antibiotic exposure without affecting mortality, including patients with cancer (Bouadma, Luyt et al. 2010, Schuetz, Chiappa et al. 2011, Sedef, Kose et al. 2015). Methods We sought to evaluate the utility of PCT as an infectious biomarker in patients undergoing commercial treatment with axi-cel. Patient data was collected retrospectively from two institutions and analyzed for clinical and laboratory characteristics, presence of documented infections, and presence and severity of cytokine release syndrome. PCT levels were drawn per the treating team's discretion based on clinical changes (new onset fever, new onset hypotension, requirement of vasopressors, change in level of care). Results A total of 30 patients received axi-cel for relapsed and refractory aggressive B-cell lymphoma and had PCT levels checked during their admission (Table 1). Median age was 61.5 years. Median baseline CRP and ferritin on day of infusion were 22.9 mg/L and 654 ng/mL, respectively. All patients had febrile episodes and evidence of at least grade I CRS by Lee criteria. Median duration of CRS was 6 days. Twenty-two patients (73.3%) had grade 2 or higher CRS. Median maximal temperature was 39.5 0C with a median duration of 5 days. Median number of days till first fever was 1 and median neutrophil count on day of first fever (> 38 0C) was 1475/mm3. Twenty-seven (90%) of the patients were on levofloxacin prophylaxis. Eight patients (26.7%) had an absolute neutrophil count (ANC) of less than 500/mm3 on the day of first fever. All but one patient (97%) were started on intravenous antibiotics during their admission. None of the patients had positive blood cultures. One patient had C. difficile infection and one patient had invasive sinusitis with mucormycosis. The timing of these infections did not correspond to the diagnosis of these infections. Median PCT was 0.86 ng/mL. Twelve patients (40%) had values below the cut-off for bacterial infections. Two of these patients required vasopressors. Three patients expired (10%). Two had progressive disease and one had an invasive fungal infection. Figure 1 shows one patient (panel A) who had normal PCT during their CRS episode and another who had abnormal ones. Discussion Axi-cel is a novel and promising therapy for treatment of relapsed and refractory aggressive B-cell lymphomas. Therapy is complicated by occurrence of CRS in 94% of patients, which can be fatal if not properly identified and managed. CRS can mimic sepsis and patients are frequently placed on broad-spectrum intravenous antibiotics, inducing risk for multi-drug resistant organisms and C. difficile infections. Unlike ferritin and CRP, PCT is typically only elevated in settings of bacterial infections, trauma and surgery and is FDA approved to be utilized in a treatment algorithm for earlier discontinuation of antibiotics in septic patients. It has not been studied in CRS. PCT was checked per the treating team's discretion and the trend was not followed for most of these patients. We herein hypothesize that PCT does not follow the same kinetics of other inflammatory markers frequently interrogated and may serve as a way to distinguish infection from CRS in this population, where 100% of patients experienced CRS and fevers, but 40% had normal PCT levels. The utility of PCT in antibiotic stewardship and the cut-off of 0.5 ng/mL should be further explored to guide antibiotic use in this population. Disclosures Jacobson: Pfizer: Consultancy; Kite: Consultancy; Humanigen: Consultancy; Novartis: Consultancy; Precision Bioscience: Consultancy; Bayer: Consultancy. Abramson:Merck: Consultancy; Juno Therapeutics: Consultancy; Celgene: Consultancy; Humanigen: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Karyopharm: Consultancy; Verastem: Consultancy. Kline:Merck: Honoraria, Research Funding; iTeos: Research Funding. Cohen:BioInvent: Consultancy; Janssen: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Gopal:Teva: Research Funding; Asana: Consultancy; Brim: Consultancy; Aptevo: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Incyte: Consultancy. Acharya:Teva: Honoraria; Juno Therapeutics: Research Funding. Jaglowski:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Juno: Consultancy; Kite Pharma: Consultancy, Research Funding.

Abstract Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy that provides high rates of durable response, with a manageable safety profile, in adult patients with R/R diffuse large B-cell lymphoma (DLBCL). An overall response (OR) rate of 53% and progression-free survival (PFS) rate of ~35% at 12 months were observed in the pivotal Phase II trial, JULIET (NCT02445248) [Jaeger et al. Blood 2020; Schuster et al. NEJM 2019]. Early data from the CIBMTR registry indicate similar efficacy and a more favorable safety profile in the commercial setting [Pasquini et al. Blood Adv 2020]. Outcomes are reported here for a larger group of patients with aBNHL who received commercial tisagenlecleucel with longer follow-up, including those considered ineligible for JULIET. Methods: This non-interventional prospective study used data from the CIBMTR registry and included adult patients with R/R aBNHL in the USA and Canada. Patients who received commercial tisagenlecleucel after August 30, 2017 were included, stratified by eligibility for JULIET based on patient characteristics reported in the registry (eg disease histology, treatment history, ECOG performance status, organ function). The safety and efficacy sets included those with completed Day 100 safety and efficacy forms, respectively, with ≥6 months' follow-up. Patients who died or discontinued prior to data cut-off were also included. Center-reported efficacy outcomes included OR rate, complete response (CR) rate, partial response (PR) rate, PFS, duration of response (DOR) and overall survival (OS). Adverse events of interest, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), were reported using the ASTCT grading criteria. Results: As of October 30, 2020, data were collected from 405 patients who received commercial tisagenlecleucel ≥6 months prior to data cut-off, with 365 patients included in the safety set and 362 in the efficacy set. In the full cohort, DLBCL was the histologic subtype in 79.5% of patients. Median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25-33). At infusion, median age was 66 years, with 54.3% of patients aged ≥65 years. Patients had received a median of 3 (range: 0-11) prior lines of therapy and 34.3% had primary refractory disease. ECOG performance status at screening was &lt;2 in 80.2% of patients. Based on the above criteria, 263 patients (64.9%) were considered JULIET-ineligible. In the efficacy set (median follow-up 15.8 months), the OR rate was 59.4% (95% CI 54.1-64.5), and 39.5% achieved a CR. Six patients with a 100-day best overall response of PR converted to CR. The 12-month PFS rate was 33.5% (95% CI 27.9-39.3), 12-month OS rate was 60.3% (95% CI 53.7-66.2) and median DOR was not reached. Overall, efficacy outcomes in the JULIET-ineligible subgroup reflected those of the wider study population (Table 1). In the safety set, any-grade CRS within 100 days of infusion was observed in 47.7% (n=174) patients, with Grade ≥3 CRS in 4.9% (n=18). Median time to CRS onset from infusion was 4 days (range: 1-15) and median duration was 5 days (95% CI 5-6). Any-grade ICANS within 100 days of infusion was observed in 17.0% (n=62) patients, with Grade ≥3 in 6.0% (n=22). Median time to onset from infusion was 7 days (range: 1-33) and median duration was 9 days (95% CI 6-12). The safety profile of tisagenlecleucel in the JULIET-ineligible subgroup reflected that of the wider study population (Table 1). Conclusions: Updated registry data confirm that aBNHL patients receiving commercial tisagenlecleucel experience similar efficacy outcomes and more favorable safety outcomes than those enrolled in JULIET, even though approximately two-thirds of patients did not appear to meet JULIET eligibility criteria. The CIBMTR registry remains an important source of safety and efficacy outcomes for a large population of aBNHL patients treated with commercial tisagenlecleucel. Updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Landsburg: Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Triphase: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Morphosys: Membership on an entity's Board of Directors or advisory committees. Frigault: BMS: Consultancy; Editas: Consultancy; Takeda: Consultancy; Iovance: Consultancy; Arcellx: Consultancy; Kite: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Jaglowski: Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy; Novartis: Consultancy, Research Funding. Locke: Legend Biotech: Consultancy, Other; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Wugen: Consultancy, Other; Umoja: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role; Cowen: Consultancy; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Calibr: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Perales: Nektar Therapeutics: Honoraria, Other; MorphoSys: Honoraria; Miltenyi Biotec: Honoraria, Other; Merck: Honoraria; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; Cidara: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria. Jacobson: Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Hill: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZenica: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Foley: Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria. Riedell: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding; Xencor: Research Funding; Tessa Therapeutics: Research Funding; MorphoSys: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy. Tiwari: Novartis Healthcare private limited: Current Employment. Masood: Novartis: Current Employment, Current holder of stock options in a privately-held company. Lim: Novartis Pharmaceuticals Corporation: Current Employment. Majdan: Novartis: Current Employment. Pasquini: Kite Pharma: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Turtle: Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; T-CURX: Other: Scientific Advisory Board; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Nektar Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; Asher Bio: Consultancy; Amgen: Consultancy; PACT Pharma: Consultancy; TCR2 Therapeutics: Research Funding; Allogene: Consultancy.

Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is approved for treatment of adult pts with R/R LBCL after ≥ 2 lines of systemic therapy. In the pivotal ZUMA-1 study, axi-cel demonstrated durable responses and a largely manageable safety profile (Locke FL, et al. Lancet Oncol. 2019). ZUMA-9 (NCT03153462), a multicenter, open-label study, provided pts with R/R LBCL with expanded access to axi-cel until commercial availability (Cohort 1 [C1]) and later, if commercially manufactured product did not meet commercial release specification(s) (Cohort 2 [C2]). Safety and efficacy of axi-cel (C1 and C2) and translational analyses (C2) are presented. Methods: Eligible adults had histologically confirmed R/R LBCL, ECOG ≤ 1, and received prior CD20-targeting and an anthracycline-containing regimen. C2 pts must have had commercial OOS product. Pts underwent leukaphersis and conditioning chemotherapy (cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day) for 3 days followed by a single axi-cel infusion (target dose, 2 × 106 CAR T cells/kg). C1 and C2 pts with high disease burden could receive bridging therapy before conditioning at investigator's discretion. Endpoints included frequency of adverse events (AEs), objective response rate (ORR) per standard-of-care imaging assessment, overall survival (OS) for C1 and C2, and blood CAR T cells levels and serum cytokines for C2 only. Outcomes were contextualized with the primary analysis of ZUMA-1 C1+2 (n = 101; ≥ 6 mo of follow-up; Neelapu SS, et al. NEJM. 2017). Results: As of 11/29/2019 (C1) and 3/15/2020 (C2), 25 C1 pts and 36 C2 pts received axi-cel with a median follow-up of 27.1 mo (range, 23.6 - 29.6) and 13.2 mo (range, 0.4 - 25.7), respectively. In C1, median age was 56 y (range, 28 - 76), 60% were male, 80% had DLBCL, 48%/0% had ECOG1/≥2, 44% had IPI ≥3, and 64% had ≥ 3 prior lines of therapy. In C2, median age was 61 y (range, 24 - 81), 75% were male, 78% had DLBCL, 58%/17% had ECOG 1/≥2, 56% had IPI ≥3, and 69% had ≥ 3 prior lines of therapy. In C2, 50% of pts had OOS product with low viability, 28% had high IFN-γ, 14% had low IFN-γ, 14% received a low dose, and 6% had high transduction ratio. The ORR was 76% (64% complete response [CR]) for C1, 53% (36% CR) for C2, and 82% (54% CR) for ZUMA-1 C1+2. Median OS was 23.8 mo (95% CI, 13.5 - NE) for C1 and not reached (95% CI, 3.4 - NE) for C2, respectively. ORR and OS were consistent in C2 OOS subgroups (Table). Grade ≥ 3 AEs were reported in 88% and 89% of C1 and C2 pts, respectively. Grade ≥ 3 CRS (Lee et al, Blood. 2014) was not observed in C1 but was reported in 3% of C2 pts (13% in ZUMA-1 C1+2). Grade ≥ 3 neurologic events (NEs) occurred in 36% and 19% of pts in C1 and C2, respectively, and 28% of pts in ZUMA-1 C1+2. No Grade 5 CRS or NEs occurred in C1 or C2. All CRS and NEs resolved in C1, and most CRS (29/30) and NEs (19/24) resolved in C2 as of the data cutoff. Of 3 Grade 5 AEs in C1, 2 were unrelated to axi-cel (clostridial sepsis [on Day (D) 6] and respiratory failure [on D212]) and 1 was related to conditioning (myelodysplastic syndrome [on D563]). Of 3 Grade 5 AEs in C2, 2 were unrelated to axi-cel (multiple organ dysfunction syndrome [on D6] and cardiac arrest [on D482]) and 1 was related to axi-cel (systemic mycosis [on D30]). Median peak CAR T cell levels and median CAR T cell expansion (area under the curve in the first 28 days) were lower in ZUMA-9 C2 (n = 32/36; 12 cells/µL [range, 0 - 442] and 112 cells/µL × days [range, 0 - 3413]) vs ZUMA-1 C1+2 (n = 96/101; 42 cells/µL [range, 1 - 1514] and 462 cells/µL × days [range, 5 - 14,329]). Serum IFN-γ levels peaked within 8 days after axi-cel infusion (median, 170 pg/mL [range, 8 - 1876]) and were lower vs ZUMA-1 C1+2 (median, 477 pg/mL [range, 8 - 8209]). Axi-cel in ZUMA-9 C2 contained fewer, less differentiated CCR7+ naïve and central memory T cells, and a greater proportion of more differentiated CCR7- effector memory and effector T cells vs ZUMA-1 C1+2. No cases of replication-competent retroviruses were reported in C1 or C2. Conclusion: Axi-cel treatment demonstrated a manageable safety profile and meaningful clinical benefit in this expanded access and OOS product study. While CAR T cell therapy showed clinical benefit in C2 (OOS product), the lower CR rate was corroborated by lower CAR T cell expansion and a more differentiated product vs ZUMA-1 C1+2, warranting further investigation. ZUMA-9 C2 is enrolling pts and evaluation is ongoing. Disclosures Jacobson: Precision Biosciences: Consultancy, Honoraria, Other: travel support; Celgene/BMS: Consultancy, Honoraria, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; AXIS: Speakers Bureau; Nkarta: Consultancy, Honoraria, Other: travel support; Clinical Care Options: Speakers Bureau; Pfizer: Research Funding; Lonza: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Locke:Calibr: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Wugen: Consultancy; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; Allogene: Consultancy. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Miltenyi Biotec: Research Funding; Janssen: Consultancy, Other: Travel support; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Vose:Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Karyopharm Therapeutics: Consultancy, Honoraria; Allogene: Honoraria; Loxo: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Miltenyi Biotec: Honoraria; Janssen: Honoraria; Epizyme: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Wugen: Honoraria; Celgene: Honoraria; Roche/Genetech: Consultancy, Honoraria, Other. Lin:Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Vineti: Consultancy; Gamida Cells: Consultancy; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding. Budde:Roche: Consultancy; Merck: Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Consultancy; Gilead Sciences: Consultancy; Mustang Therapeutics: Research Funding; AstraZeneca: Research Funding. Maloney:Celgene: Consultancy, Honoraria, Research Funding; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Gilead Sciences: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Bioline Rx: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Jaglowski:Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR: Consultancy; Novartis: Consultancy, Research Funding. Riedell:MorphoSys: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Karyopharm Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Perales:Celgene: Honoraria; MolMed: Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Research Funding; Miltenyi Biotec: Research Funding; Merck: Consultancy, Honoraria; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Research Funding. Kim:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Kawashima:Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership . Yang:Kite, a Gilead Company: Current Employment. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Goyal:Kite, a Gilead Company: Current Employment. Neelapu:Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding; Adicet Bio: Other; 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; Precision Biosciences: Other: personal fees, Research Funding; Poseida: Research Funding; Calibr: Other; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Karus Therapeutics: Research Funding; Cellectis: Research Funding; N/A: Other.

The adenosine A2A receptor (A2AAR) is a prototypical member of the class A subfamily of G-protein-coupled receptors (GPCRs) that is widely distributed in various tissues and organs of the human body, and participates in many important signal-regulation processes. We have previously summarized a common activation pathway of class A GPCRs in which a series of conserved residues/motifs undergo conformational change during extracellular agonist binding and finally induce the coupling of intracellular G protein. Through this mechanism we have successfully predicted several novel constitutive active or inactive mutations for A2AAR. To reveal the molecular mechanism of mutation-induced constitutive activity, we determined the structure of a typical mutant I92N complexed with the agonist UK-432097. The mutated I92N forms a hydrophilic interaction network with nearby residues including Trp6.48 of the CWxP motif, which is absent in wild-type A2AAR. Although the mutant structure is similar overall to the previously determined intermediate-state A2AAR structure (PDB ID 3qak) [Xu, Wu, Katritch, Han, Jacobson, Gao, Cherezov & Stevens (2011). Science, 332, 322–327], molecular dynamics simulations suggest that the I92N mutant stabilizes the metastable intermediate state through the hydrophilic interaction network and favors the conformational transition of the receptor towards the active state. This research provides a structural template towards the special pharmacological outcome triggered by conformational mutation and sheds light on future structural or pharmacological studies among class A GPCRs.

Introduction: Hypoplastic left heart syndrome (HLHS) is a genetically heterogenous, severe form of congenital heart disease. Hypothesis: Patients with reported genetic abnormalities will have worse outcomes than those without reported genetic abnormalities. Methods: This was a retrospective review of patients enrolled in the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) phase I registry. Registry enrollment occurred at discharge following stage 1 palliation. Patients were placed into one of three groups: major syndromes (Turner, Down, CHARGE, DiGeorge, Jacobsen, VATER, heterotaxy), other genetic abnormality, or no reported genetic abnormality. Demographic and clinical variables were compared using Pearson Chi-square, one-way ANOVA, or Kruskal-Wallis test. Tukey post-hoc test was applied to adjust p-values for pairwise group comparisons. Outcomes of length of stay, death, and combined outcomes of death, not a candidate for stage 2 palliation and transplant were compared among the groups. Results: Of the 2182 patients, major syndromes were reported in 110 (5%), other genetic abnormalities in 126 (5.8%) and no abnormalities in 1946 (89.2%). Those with major syndromes weighed less at birth and the time of stage I palliation, were more likely to be female and have a primary cardiac diagnosis of unbalanced AVC. Those with major syndromes or other genetic abnormalities were more likely to have moderate to severe AV valve regurgitation, moderate to severe ventricular dysfunction, arrhythmia requiring therapy, and major anomalies of other organ systems compared to those with no abnormalities. Patients with no reported genetic abnormalities reached full oral feeds sooner after the Norwood (19 vs 24 days), were more likely to be discharged on all oral feeds (75% vs 59% and 62%) and were discharged earlier (35 vs 45 and 43 days). For the outcome of death, there was no significant difference among the groups. The combined outcome of death, not a candidate for stage 2 palliation, and heart transplant was more likely in those with a major syndrome after adjusting for covariates. Conclusions: Patients with HLHS and major syndromes or other genetic abnormalities experience greater morbidity and mortality during the interstage period.

IntroductionFor both consumers and creators, Web series have been viewed for some time as an appealing alternative to television series. As Alice explains, creating content for the Web was once seen as “a last resort” for projects that were unable to secure funding for television production (59). However, the Web has, in recent years, become a “legitimized” space, allowing Web series to be considered a media platform capable of presenting narratives of various genres (Alice 59). Moreover, due to the lack of restrictions and overheads placed on Web producers, it is argued that there is more capacity to take risks in Web series and thus depict “a broader array of stories” (Christian, “The Web” 352). Nevertheless, television still remains the traditional mode of storytelling, and for many producers, it is still an “object of desire” (Christian, “The Web” 352). Emerging producers still see television as the ultimate “end goal”, leaving the Web as a sufficient platform that will allow them to create something. Alternatively, for many established creators, the Web is understood to be a stage upon which they can tell stories television would perhaps never consider. Regardless of why creators are attracted to the Web, the platform has indeed cemented its place as an alternative in the television media landscape. For Abbi Jacobson and Ilana Glazer, the Web, or more specifically, YouTube, provided an unbridled space for their creativity when nowhere else would. The two comediennes co-wrote and starred in their Web series, Broad City, back in 2009, and it has since been picked up by Comedy Central and successfully turned into a television series. The fourth season is set to air in August 2017. Both versions of the series follow two twenty-something women, Abbi Abrams and Ilana Wexler (played by Jacobson and Glazer respectively), as they explore themselves, and New York City. Broad City is one of the few Web series to be picked up as a television series and maintain its success; an impressive accomplishment, no matter how legitimate Web series have become. However, the unwavering devotion maintained by the television series to continue depicting millennial women in the same fashion as the Web series is, arguably, more impressive. With a focus on Broad City’s depiction of its two eccentric protagonists, this article explores how the transitions from Web to television are negotiated. In the case of Broad City, I contend that its unconventional start as a web series is what allows the television series to continue depicting contemporary womanhood honestly. Taking the Alternate Path: YouTubeDefined as “scripted, episodic and experimental videos made for the internet”, Web episodes (or Webisodes) hold many advantages to the traditional television medium (Kornblum; Peirce 317). Aware of these advantages and struggling to be noticed naturally for their work in the sketch comedy group, Upright Citizens Brigade (UCB), Glazer and Jacobson took to the Internet to write and create their own series, Broad City. This trend arose in 2007 during the difficult phase American television when the Writers Guild of America began its fifteen-month strike (De Moraes). During this time, Peirce states that producing a new program for television proved “almost impossible” (315). There was a level of uncertainty plaguing the future of prime-time television, and with budgets being refashioned, reality programs were filling television line-ups more than any other genre of show (Peirce 315). Within this climate, it is unsurprising that the Google-owned video-sharing website, YouTube, quickly became the frontrunner in online video (Christian, “The Web” 351). YouTube is argued to be responsible for opening the doors to the next wave of entertainment media, after pledging to give users their own personal video network. Suddenly, amateurs, independents and corporations alike were, for the first time, able to compete against each other in shaping this post-network era of television (Christian, “The Web” 351). Moreover, the premise of “anyone can upload” meant that this era allowed for a new variety of television, in a range of genres and storytelling modes that were once considered untouchable to television networks (Christian, “The Web” 351). Evidently, such freedom is appealing to all kinds of online content creators, no matter their status. Established actor, comedian, and writer Louis C.K. most recently joined the Web series movement with his creation Horace and Pete (2016-). The dark comedy is written, directed, and produced entirely by C.K. and he plays the main protagonist, Horace. However, the appeal was not so much the control he would potentially have over the product, but more how the viewers could access it. Upon the release of the pilot episode, C.K. released a statement clarifying why he made a series outside of the television studio system. He explains that he was intrigued by the idea of providing viewers with the newly made show “directly and immediately”, with each episode being posted onto his Website as soon as it is shot. Additionally, C.K. also sought to create a show “without the usual promotion” that, he states, tells the viewer “what the show feels and looks like before you get to see it yourself” (C.K.). It is clear that the unique nature of the modern medium provides benefits to creators at all levels. For the Broad City duo, who unlike C.K., had yet to be noticed, YouTube was appealing because it provided them with an outlet through which they could control the product themselves. Jacobson states, “After a while, we thought, ‘why are we trying to be on something that someone else controls?’” (Paumgarten). The Web series commenced in late 2009 and ran until 2011, with each episode ranging anywhere between one and eight minutes. In the thirty-three episodes created, Abbi and Ilana consistently find themselves in awkward and comedic situations while they try to navigate their lives in New York City. These awkward situations vary in their complexity. One episode simply looks at the two protagonists trying to survive riding the subway, while another looks at the issue of being catcalled and objectified by strangers. There is no narrative arc in either season, the storylines are simply extracted from the lives of the creators. Glazer and Jacobson have discussed this in various interviews, explaining that these characters are essentially exaggerations of themselves and the show is a “heightened version” of their dynamic (Amy Poehler’s Smart Girls, 2014; Justin; Matthews). As such, Broad City contributes to a well-established trend of comedians impersonating younger, lazier, and poorer versions of themselves. However, since the Web series’ thematic relies so heavily on the experiences and personality traits of the writers, Glazer and Jacobson are more like the characters they portray than the likes of Tina Fey’s Liz Lemon (30 Rock, 2007-2013) or Lena Dunham’s Hannah Horvath (Girls, 2012-), for example. A result is that the Web series does not seek to provide its viewers with neat conclusions, or have the protagonists grow and evolve over the span of a season. This freedom is only designated to the Web series format, as television viewers – despite not always getting it – yearn for a heartier resolution (DeFino 99). Another attribute of video-sharing sites like YouTube is that they allow anyone to share anything they create, regardless of the budget. The two seasons of Broad City, the Web series, are written, created, and produced by Glazer and Jacobson primarily. As they were still undiscovered, both women were working on the series with very limited funds, and were therefore only able to have friends or family assist them in the production. This results in a series which feels authentically home-made in its aesthetic; features which eventually become characteristics essential to the transferral from Web to television. Glazer and Jacobson resolved to make the Web series from a more professional standpoint by the second season by following a production schedule and choosing to treat the vignettes as if they were real television shorts. As Glazer states, the pair “just had a new attitude”, and suddenly the aim shifted from producing webisodes as a creative outlet, to pitching the show in Los Angeles (Kameir). By the time the final episode was set to go into production, the two creators believed that the chances of having the series picked up by a network would increase if the episode featured a guest star. Because of their involvement in the UCB, Glazer and Jacobson approached one of the founders of the sketch group, Amy Poehler, to make a brief cameo. The Web series as a whole had garnered half a million hits, but the finale in which Poehler plays herself, received almost seventy-five thousand (Paumgarten). Poehler agreed to work with the Broad City duo following her appearance in the finale, and signed on to be Executive Producer should the show ever be made into a television series. The star power held by Poehler is undoubtedly a lead contributor to the success in Broad City’s transfer between the media. Poehler states that she felt a kinship towards the project because of her work in translating UCB sketches to television. In a roundtable interview, she says “Feeling very protective about the material, but wanting to bring it to a bigger audience…I related to that and understood it” (The Paley Centre for Media). On the difficult business of bringing Web series to television, Poehler compares it to that of an organ transplant, explaining “You have to move fast. You have to keep it on ice and be careful not to harm it in any way. A lot of things can go wrong. Sometimes the best way to get a heart or a kidney to a recipient is to get people to move out of the way” (Paumgarten). With Poehler’s assistance, the concept of Broad City as a television series was introduced to various networks before being successfully picked up by Comedy Central. From January of 2014, the network aired Broad City’s first season, comprised of ten, twenty-two-minute-long episodes. Averaging 1.2 million viewers per episode, season one of Broad City became one of Comedy Central’s highest rated shows since 2012 (Ng). From Web to TV: Alternative Ideas of Millennial Women in Broad CityThe factors behind why certain texts effectively transfer from Web to television and others fail continues to be debated within academic and popular culture circles. Series such as Quarterlife (2007), The CollegeHumor Show (2009), and the more recent Haters Back Off (2016-) - all texts which were originally made for online consumption only - were each met with criticism when translated for television (Peirce 317; Lowry; Christian, “How” ). This does not necessarily mean that a Web series is undeserving of a place in commercial or network television. Obviously, it comes down to multiple factors, but often it is because the television series comes across as out of touch, compared to its online version. As Alice points out, with the speed of online release, and the “virality” that accompanies this kind of media, writers have the ability to be “guided by and to capitalise on what and how the viewer public feels” (60). Television series are often seen commenting on outside criticism within episodes, but there is extensive lagging due to the time it takes to produce a season. Broad City was set to have an easier time on television, what with its impressive following, and “Celebrity Shepherd”, Amy Poehler - Poehler presented as a necessity when making the jump from Web to TV, according to Christian (“The Web”). But there appears to be a fine line when shifting between the platforms: in staying too close to the original, a series could come off as unoriginal and therefore unnecessary. Or, alternatively, a series could add too many other storylines in order to fill the time slot, and ruin the simplicity of the premise. Adaptation theorist, Linda Hutcheon, contends that a successful translation occurs when a text remains loyal to the original, but brings creativity to the reimagining (21). If investigating the transferral within the realm of adaptation theory, Broad City’s success as a television series is arguably due to it following this formula. Hutcheon writes that to adapt is not to slavishly copy, but rather, is the process of reclaiming the adapted material. “What one does with the text” is where the novelty is found (21). In looking at what Broad City, the television series, has done with Broad City, the Web series, there is clear loyalty shown to the original. This is seen most significantly in the treatment of the same two protagonists, and the dynamic of their friendship. In both versions of Broad City, Abbi is the older of the two and the more responsible one, to a degree. While she still enjoys smoking marijuana with Ilana, Abbi is also constantly striving to reach traditional goals in her life such as having a career she enjoys, or maintaining a healthy relationship. Ilana, on the other hand, is a proud marijuana enthusiast who occasionally shows up for her job, but cares more for smoking weed, enjoying casual sex, and being with her friends (primarily Abbi). Neither the Web series nor the television series explicitly states how the two characters met, but it is implied that they have built a strong, sister-like relationship with one another. Often Ilana comments on her sexual attraction to Abbi, but it is always seen as comedic rather than as a hint towards a possible coupling in future episodes. In the Web series’ second season, the episode Valentine’s Day, introduces this satirical take on female friendships for the first time. The three-minute episode shows brief cuts of Abbi and Ilana doing various activities in the city, all of which are stereotypically featured in films of the romantic comedy genre. As they play in the snow, ride a ferry, and watch couples ice-skate at the Rockefeller Centre, the clarinet music playing over the sequence builds momentum. However, the scene is suddenly halted as Ilana goes in to kiss Abbi and, unlike in said romantic film montages, Abbi quickly jolts back and cries “Ilana, what the fuck? How many times do I have to fucking tell you?” This is the first line of audible dialogue in the scene thus far, to which a frustrated Ilana responds, “I’m trying to seal the night with a kiss.” Following this is a heated debate regarding how each character viewed the intention of the day, with Ilana thinking it was a really “romantic day”, despite knowing that Abbi is decidedly heterosexual. This kind of satirical angle taken towards the trope of female friendship is carried over to the television series and made just as prominent, with almost every single episode making a joke at Ilana’s romantic desire for Abbi. Alongside the sexual attraction, the closeness of the two female leads remains unchanged between the two media. In the television series, for example, jokes about Ilana’s love for Abbi are scattered throughout, and as in the original series, they remain brief and inconsequential. In the television pilot, What a Wonderful World, the episode opens to a typical scene of the two characters having a V-chat (a nod to a favoured motif in the Web series). While chatting to Abbi, it initially appears as though Ilana is bopping up and down to the music of Lil Wayne. However, it is quickly revealed when Ilana shifts her laptop screen down, that she is actually having sex with her casual partner, Lincoln (Hannibal Buress). The sequence cuts to Abbi looking outraged at her laptop, asking “Oh my god, is that Lincoln?”. Lincoln then replies, “Yep”, just before the camera cuts to him lying on the bed, with Ilana’s laptop on his stomach. When Abbi asks if they are having sex, Ilana casually replies “I’m just keeping it warm”, forcing Abbi to once again have a discussion about boundaries. Once they close the V-chat, the scene stays on a low angle shot of Ilana as she says to Lincoln, “That was like a threesome”, reassuring the audience that she has learned nothing. This is a strong opening scene as it reinforces the understanding that the relationship between the two characters is unchanged. Furthermore, it proves to audiences that although Broad City has moved into a television landscape, it will not be tamed. The result of refusing to be tamed in its new environment is that Broad City can continue representing female friendship in more honest ways, as well as offer new ideas of what it is to be a millennial woman today.Conclusion In an interview, Glazer explains how television has a history of never being honest in its representation of women, arguing, “Nothing’s real on TV” (Miller). Jacobson follows on from this, stating “When we write for these characters… I think the thing we talk about the most is like, well, what would we really do? It’s just real” (Miller). In abiding by this sentiment throughout the web series and the television series, Broad City effectively offers the idea that depicting diversity is possible on both platforms. With various Web series still unable to successfully make the jump to television today, it becomes more obvious that Broad City’s decision to continue showcasing bold female narratives is what allows it to maintain its popularity. Starting in such an uninhibited environment has proven a burden for other texts when it comes to transferring creativity to the more traditional medium of television. For Broad City, however, the alternative storytelling platform allowed the show to create its strong foundation and dedicated fan base. One that has willingly followed Broad City across the platforms, but will only stay tuned if it stays true to representing millennial women honestly, regardless of whether mainstream television is ready.ReferencesAlice, Jessica. “Clicking with Audiences: Web Series and Diverse Representations.” Metro Magazine: Media and Education 187 (2016): 58-63.Angelo, Megan. “The Sneak Attack Feminism of Broad City.” Wall Street Journal, 2011. 17 Dec. 2016 <http://blogs.wsj.com/speakeasy/2011/02/14/the-sneak-attack-feminism-of-broad-city/>. 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