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Approximately 80% of amputations are complicated by neuromas. Methods for neuroma management include nerve translocation into bone and implantation into skeletal muscle grafts, which have also facilitated the development of regenerative neural interfaces to enable fixation of prosthetics with motor and sensory feedback. However, molecular-level differences between nerves in these environments have not been investigated. This study aimed to elucidate the physiology of regenerating nerves in different settings by assessing gene expression.New Zealand white rabbits underwent transfemoral amputation with sciatic nerve transposition into the femur or tacked to skeletal muscle. At 5 wk, ribonucleic acid (RNA) sequencing of samples of distal nerve terminating in bone or muscle and nerve of the contralateral limb (control) identified differentially expressed genes (DEGs) and biochemical pathways (α = 0.05).Three samples of nerve housed in bone, four of nerve tacked to muscle, and seven naïve controls were analyzed. Relative to controls, nerve housed in bone had little within-group variation and 13,028 DEGs, and nerve tacked to muscle had dramatic within-group variation and 12,811 DEGs. These samples upregulated the following pathways: lysosome, phagosome, antigen processing/presentation, and cell adhesion molecule. Relative to nerve housed in bone, nerve tacked to muscle had 12,526 DEGs, demonstrating upregulation of pathways of B-cell receptor signaling, focal adhesion, natural killer-cell mediated cytotoxicity, leukocyte transendothelial migration, and extracellular matrix-receptor interactions.Nerve housed in bone has a more predictable molecular profile than does nerve tacked to muscle. Thus, the intramedullary canal may provide a more reliable setting for neuroma prevention and neural interfacing.

The precise mechanism through which excessive tension confers poor outcomes in nerve gap repair is yet to be elucidated. Furthermore, the effect of tension on gene expression in regenerating nerves has not been characterized. This study investigated differential gene expression in transected nerves repaired under high and minimal tension.Male Lewis rats underwent right sciatic nerve transection with either minimal-tension or high-tension repair. Fourteen weeks postoperatively, segments of the right sciatic nerves were harvested along with equal-length segments from the contralateral, healthy nerve to serve as internal controls (naïve nerve). Differentially expressed genes (DEGs) and differentially regulated biochemical pathways between the samples were identified.Seventeen animals were studied. The gene expression profiles of naïve nerve and minimal-tension repair demonstrated minimal within-group variation, whereas that of high-tension repair demonstrated heterogeneity. Relative to naïve nerve, high-tension repair samples had 4276 DEGs (1941 upregulated and 2335 downregulated) and minimal-tension repair samples had 3305 DEGs (1479 upregulated and 1826 downregulated). High-tension repair samples had 360 DEGs relative to minimal-tension repair samples (68 upregulated and 292 downregulated). Upregulated biological pathways in all repaired nerves included steroid biosynthesis, extracellular matrix-receptor interaction, and ferroptosis. Finally, upregulated pathways in high-tension repair samples relative to minimal-tension repair samples included tumor necrosis factor signaling, interleukin-17 signaling, cytokine-cytokine receptor interaction, and mitogen-activated protein kinase signaling.The improved outcomes achieved with minimal-tension nerve repair may take root in a favorable gene expression profile. Future elucidation of biochemical pathways in nerve regeneration may identify potential therapeutic targets to optimize primary nerve repair outcomes.

Publication in peer-reviewed journals is a duty and privilege. It is essential to the advancement of evidence-based medicine and often used as a proxy for academic achievement, contributing to decisions around promotion in academia. Within plastic surgery, authors have historically been male surgeons affiliated with academic institutions, lacking representation of women, private practice, medical students, and international collaboration. This study analyzes differences in authors' gender, practice affiliation, degree of education, and international collaboration in articles published in Plastic and Reconstructive Surgery, which was chosen as the representative journal given its high impact factor (3.946) and consistent ranking as the number one journal in plastic surgery worldwide.A list of Breast, Cosmetic, and Hand/Peripheral Nerve articles published between 2006 and 2019 was compiled from the online archive of Plastic and Reconstructive Surgery. Demographic author characteristics were recorded, and statistical analyses were performed to identify trends over time.A total of 2688 articles were analyzed. The proportion of articles written by female authors in the Breast category, authors in private practice with academic affiliation in the Cosmetic section, and U.S. collaboration with other countries increased over time (p = 0.038, p = 0.029, p0.001, respectively). First authors with bachelor's, master's, and doctorate degrees have also been contributing increasingly.This analysis revealed increasing demographic heterogeneity of authors in Plastic and Reconstructive Surgery over time, with increasing contributions from women, surgeons in private practice with academic affiliation, medical students, and international collaborations. The Journal is capturing contributions from an increasingly diverse authorship, consistent with the changing demographics of plastic surgeons.

Relapse following CD19-directed chimeric antigen receptor T-cells (CAR-T) for relapsed/refractory large B-cell lymphoma (r/r LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multi-antigen targeting and PD-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in r/r LBCL as inpatient or outpatient therapy (NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455). Endpoints include toxicity (primary) and response rates (secondary). AUTO3 was manufactured for 62 patients using autologous leukapheresis, modified with a bicistronic transgene. 52 patients received AUTO3 (7/52,50x106; 45/52,150-450x106) and 48/52 received pembrolizumab. Median age was 59 years (range,27-83) and 46/52 had stage III/IV disease. Median follow-up was 21.6 months (range,15.1-51.3) at last data cut (Feb 28, 2022). AUTO3 was safe: grade 1-2 and grade 3 CRS affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), HLH affected 2 patients, and no Pembrolizumab-associated autoimmune sequalae were observed. On this basis, outpatient administration was tested in 20 patients, saving a median of 14 hospital days/patient. AUTO3 was effective: overall response rates were 66% (48.9%, CR; 17%, PR). For patients with CR, median DOR was not reached, with 54.4% (CI: 32.8, 71.7) projected to remain progression-free beyond 12 months after onset of remission. DOR for all responding patients was 8.3 months (95% CI: 3.0, NE) with 42.6% projected to remain progression-free beyond 12 months after onset of remission. Overall, AUTO3 +/- pembrolizumab for r/r LBCL was safe, lending itself to outpatient administration, and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion/persistence in vivo, and selection of CAR binders active at low antigen densities.

Approval of the first generic 0.05% cyclosporine ophthalmic emulsion (COE) in the U.S. represents a milestone achievement of the science and research program in the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research (CDER). COE is a locally acting complex drug product indicated to increase tear production in patients whose production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. The path to approval required overcoming numerous scientific challenges to determining therapeutic equivalence to the reference listed drug. Researchers in CDER’s Office of Pharmaceutical Quality and Office of Generic Drugs developed a quality by design approach to understand the effects of process and formulation variables on the product’s critical quality attributes, including globule size distribution (GSD), turbidity, viscosity, zeta potential, surface tension, and osmolality. CDER researchers explored multiple techniques to perform physicochemical characterization and analyze the GSD including laser diffraction, nanoparticle tracking analysis, cryogenic transmission electron microscopy, dynamic light scattering, asymmetric field flow fractionation, and two-dimensional diffusion ordered spectroscopy nuclear magnetic resonance. Biphasic models to study drug transfer kinetics demonstrated that COEs with qualitative and quantitative sameness and comparable GSDs, analyzed using earth mover’s distance, can be therapeutic equivalents. This body of research facilitated the review and approval of the first U.S. generic COE. In addition, the methods and fundamental understanding developed from this research may support the development and assessment of other complex generics. The approval of a generic COE should improve the availability of this complex drug product to U.S. patients. Graphical Abstract

PURPOSE Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 ( NCT02935257 ) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease–negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4%-84.4%) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL.

A neuropsychiatric diagnosis (ND) has the potential to affect patient satisfaction after breast reconstruction. However, literature regarding the interplay between neuropsychiatric diagnoses and revision operations after reconstruction remains sparse. In this study, we aim to determine whether neuropsychiatric diagnoses result in increased revision operations and healthcare utilization of plastic surgery resources after alloplastic and autologous breast reconstruction.We retrospectively reviewed 200 patients from 2010 to 2019 who underwent postmastectomy alloplastic or autologous breast reconstruction by a single surgeon at our institution. We evaluated for the presence of neuropsychiatric diagnoses, type of neuropsychiatric diagnoses, number of revisions, and number of postreconstruction plastic surgery appointments. Continuous variables were compared using independent samples t tests, and categorical variables were compared using χ 2 tests.Of the 196 patients who met inclusion criteria, the majority underwent at least one revision (65.3%). The presence of an ND did not predict a higher number of revision operations ( P = 0.512) nor was the timing of the diagnosis (preoperative vs postoperative) significantly associated with the number of revision procedures ( P = 0.156). The patients who had a ND at any point during the reconstructive process had a significantly higher number of plastic surgery appointments and a longer duration of follow-up compared with the patients without any neuropsychiatric diagnoses ( P = 0.009 and P = 0.040, respectively). Complications did not impact the number of revision operations ( P = 0.780).Neuropsychiatric diagnoses do not significantly influence the number of revision operations after breast reconstruction. However, neuropsychiatric diagnoses result in increased healthcare utilization of plastic surgery resources that may lead to increased healthcare costs.

BACKGROUND In selecting breast implants for breast reconstruction, current preoperative planning largely relies on 2-dimensional measurements, which are often limited in suboptimal accuracy and objectivity. Although the introduction of 3-dimensional imaging modalities has further improved preoperative planning, they require in-depth analysis of accuracy if they are to be considered as a standardized part of preoperative planning. Thus, the present study analyzes the reliability of the Vectra 3D Imaging System in predicting breast mass and explores potential confounding variables that may limit its accuracy. METHODS A retrospective review of 202 breasts that received direct-to-implant reconstruction by a single surgeon between February 2015 and February 2019 was conducted. Variables recorded included Vectra predicted mass (VPM; in grams), mastectomy mass (MM; in grams), ptosis grade, and body mass index (BMI). Body mass index was classified as follows: underweight (BMI < 20 kg/m), normal (20 kg/m ≤ BMI < 25 kg/m), overweight (25 kg/m ≤ BMI < 30 kg/m), and obese (BMI ≥ 30 kg/m). Cup size was approximated as follows: A and smaller (MM ≤250 g), B (250 g < MM ≤ 450 g), C (450 g < MM ≤ 600 g), and D and larger (MM ≥ 600 g). Correlation between MM and VPM was evaluated using 2-tailed Pearson correlation coefficients (r), and associated formula was derived from a linear model. Equality of variances was assessed with the Bartlett test. Correlation coefficients calculated for ptosis and BMI categories were then compared with the overall correlation coefficient. Significance was set at α = 0.05, and analyses were conducted in R 3.6.0, version 1.70. RESULTS There was a strong correlation between MM and VPM (R = 0.90, P < 0.0001). The following equation was derived to predict MM: [MM] = 0.8 × [VPM] + 32 (adjusted r = 0.81). The Bartlett test indicated that VPM varies significantly across cup sizes (P < 0.0001). Comparison of correlation coefficients for ptosis and BMI categories revealed a significantly reduced correlation coefficient for pseudoptosis (0.90 vs 0.75, P = 0.0425). CONCLUSIONS The present study suggests that the reliability of Vectra in predicting breast mass varies across cup sizes and that there exists a significantly decreased association between VPM and MM among pseudoptotic breasts. These are important considerations when using this technology in surgical planning.

An international sampling study yielded 69 samples of extended-release prescription pharmaceuticals for legal sale in the U.S. Samples included 29 lots of innovator and 40 lots of generic solid oral extended-release drugs manufactured at 16 different facilities and containing 6 different active ingredients. Dosage unit uniformity and dissolution were tested for each lot. All samples met the relevant testing criteria for dosage unit uniformity and dissolution. There were no indications that manufacturer or region impacted a product's acceptability for use by patients. The variability of attributes was used to calculate a process performance index (Ppk) for each facility. Higher Ppk values suggest less variability relative to specification limits. Only two manufacturers fell below a 4-sigma manufacturing benchmark Ppk of 1.33 for dosage unit uniformity: a European manufacturer of a brand drug and an Asian manufacturer of a generic drug. Conversely, all but four manufacturers fell below a 4-sigma benchmark for the minimum Ppk across their product's dissolution timepoints: generic drug manufacturers in India (two), the U.S., and Canada. Compared to the immediate-release products of a previous study, Ppks were generally lower for extended-release products. A retrospective analysis found that manufacturers performing below median Ppks submitted more Field Alert Reports after the end of the sampling period.

Introduction While surgical interventions for temporomandibular joint (TMJ) ankylosis are well-documented, there is lack of consensus regarding the ideal approach in pediatric patients. Surgical interventions include gap arthroplasty, interpositional arthroplasty, or total joint reconstruction. Methods A systematic review of PubMed (Jan 1, 1990-Jan 1, 2017) and Scopus (Jan 1, 1990-Jan 1, 2017) was performed and included studies in English with at least one patient under the age of 18 diagnosed with TMJ ankylosis who underwent surgical correction. Primary outcomes of interest included surgical modality, preoperative maximum interincisal opening (MIO) (MIOpreop), postoperative MIO (MIOpostop), ΔMIO (ΔMIO = MIOpostop - MIOpreop), and complications. Results Twenty-four case series/reports with 176 patients and 227 joints were included. By independent sample t tests MIOpostop (mm) was greater for gap arthroplasty (30.18) compared to reconstruction (27.47) (t = 4.9, P = 0.043), interpositional arthroplasty (32.87) compared to reconstruction (t = 3.25, P = 0.002), but not for gap compared to interpositional (t = -1.9, P = 0.054). ΔMIO (mm) was greater for gap arthroplasty (28.67) compared to reconstruction (22.24) (t = 4.2, P = 0.001), interpositional arthroplasty (28.33) compared to reconstruction (t = 3.27, P = 0.002), but not for interpositional compared to gap (t = 0.29, P = 0.33). Weighted-average follow-up time was 28.37 months (N = 164). 4 of 176 (2.27%) patients reported development of re-ankylosis. There was no significant difference in occurrence of re-ankylosis between interventions. Conclusions Given the technical ease of gap arthroplasty and nonsignificant differences in ΔMIO, MIOpostop, or occurrence of re-ankylosis between gap and interpositional arthroplasty, gap arthroplasty should be considered for primary ankylosis repair in pediatric patients, with emphasis on postoperative physiotherapy to prevent recurrent-ankylosis.

Breast cancer is the most common cancer in women in Wisconsin. Evidence demonstrates that non-White racial minorities in the United States exhibit a higher mortality rate and more advanced or aggressive presentations of the disease than their White counterparts. Postmastectomy breast reconstruction remains essential to the treatment and recovery of these patients; however, racial disparities in the receipt of reconstruction are evident. This study evaluates the presence of racial disparities in postoperative outcomes of breast reconstruction at a single institution in Wisconsin.An institutional review board-exempt retrospective study of postoperative outcomes was performed using a single institution's National Surgical Quality Improvement Program Registry to identify patients who underwent autologous or prosthesis-based breast reconstruction following mastectomy. Patient demographic, preoperative, operative, and postoperative variables were recorded. Postoperative outcomes in relation to self-reported race were evaluated using univariate analysis and propensity score matching.A total of 1,140 patients were included (1,092 White vs 48 non-White), with fewer non-White patients undergoing reconstruction. Patients of non-White race demonstrated a higher incidence of morbid obesity (4.4% White vs 12.5% non-White,This study did not reveal racial disparities in postoperative outcomes of breast reconstruction at a single institution in Wisconsin; however, non-White patients were less likely to undergo reconstruction. Further research into the underlying causes of unequal access to care, influence of insurance, effect of structural racism, and impact of physician- and patient-associated factors is warranted.

Background: Acellular dermal matrices (ADMs) were first incorporated into direct-to-implant (DTI) breast reconstruction by the senior author in 2001 and have since become foundational to implant-based reconstruction. ADM composition has evolved recently and now includes perforated types, which some speculate decrease the likelihood of seroma. The authors performed a retrospective review of perforated (P-ADM) and nonperforated (NP-ADM) ADM-assisted direct-to-implant breast reconstruction patients to evaluate differences in complication rates. Methods: Retrospective review of direct-to-implant breast reconstruction patients operated on by a single surgeon (CAS) from 2011 to 2018 was conducted. Patient and operative characteristics, including ADM type, were recorded. A propensity score matching algorithm accounting for potentially confounding variables was developed, followed by univariate analysis to evaluate the association between ADM perforation and postoperative complications. Results: The review began with 409 patients (761 breasts). Following exclusion of patients with missing demographic information, lack of ADM in their reconstruction, and follow-up times of less than 4 weeks, 364 patients (680 breasts) were included for analysis. A total of 530 (77.94%) and 150 (22.06%) breasts received NP-ADM and P-ADM, respectively. After propensity score matching, there were 294 breasts, composed of equal numbers of P-ADM and NP-ADM recipients. Univariate analysis showed no association between ADM type and any postoperative complication. Conclusions: The complication profile of direct-to-implant breast reconstruction appears to be unaffected by the use of P-ADM or NP-ADM. Current understanding of the association between ADM type and clinical outcomes would benefit from multi-institution, prospective, randomized trials.

It is presently considered the standard of care to perform many routine intra-abdominal operations using a minimally invasive approach. The authors recently identified a racial disparity in access to a laparoscopic approach to inguinal hernia repair, cholecystectomy, appendectomy, and colectomy. The present study further evaluates this patient cohort to assess the relationship between the race and postoperative complications and test the mediating effect of the selected surgical approach.After institutional review board approval, patients in the American College of Surgeons National Surgical Quality Improvement Program database who underwent inguinal hernia repair, cholecystectomy, appendectomy, or colectomy in 2016 were identified. Patient demographics, including the self-reported race and ethnicity, as well as clinical, operative, and postoperative variables were recorded. After the exclusion of cases associated with diagnoses of cancer, a 4:1 propensity score matching algorithm generated a clinically balanced cohort of patients of white and black self-reported race. The mediating effect of an open approach to surgery on the relationship between black self-reported race and postoperative complications was evaluated via a series of regressions.There were 41,340 unilateral inguinal hernia repairs, 3182 bilateral inguinal hernia repairs, 60,444 cholecystectomies, 50,523 appendectomies, and 58,012 colectomies included in the database in 2017. Exclusion of cases associated with cancer and subsequent propensity score matching returned 17,540 unilateral hernia repairs, 890 bilateral hernia repairs, 23,865 cholecystectomies, 11,660 appendectomies, and 12,320 colectomies. On mediation analysis, any complication, severe complication, and death were significant when regressed on black self-reported race (any: odds ratio [OR] = 1.210, 95% confidence interval [CI] = 1.132-1.291, P 0.001; severe: OR = 1.352, 95% CI = 1.245-1.466, P 0.001; death: OR = 1.358, 95% CI = 1.000-1.818, P = 0.044), and open surgery was a significant mediator in the incidence of any complication and severe complication (any: OR = 1.180, 95% CI = 1.105-1.260, P 0.001 and severe: OR = 1.307, 95% CI = 1.203-1.418, P 0.001).These findings underscore the importance of access to a minimally invasive approach to surgery. However, other factors may contribute to racial disparities in postoperative complications after common abdominal operations.

INTRODUCTION We have previously described AUTO1, a CD19 CAR with a fast off-rate CD19 binding domain, designed to reduce CAR-T immune toxicity and improve engraftment. Its clinical activity has been tested in r/r paediatric and adult B-ALL. Cumulatively, this data confirms the intended function of the receptor, with low levels of CRS/ICANS and long-term engraftment of CAR T-cells observed in both patient groups. Recently, CAR-T therapy has been explored in indolent lymphomas such as follicular (FL) and mantle cell lymphoma (MCL), but a high incidence of toxicity including Grade 3-4 ICANS has been reported. We have initiated testing of AUTO1 in the setting of indolent and high-grade B-NHL and CLL (NCT02935257). METHODS Manufacturing: CAR T-cell products were generated using a semi-automated closed process from non-mobilised leukapheresate. Study design: Subjects ≥ 16y underwent lymphodepletion with fludarabine (30mg/m 2 x3) and cyclophosphamide (60mg/kg x1) prior to AUTO1 infusion, with the exception of the DLBCL cohort who additionally received a single dose of pembrolizumab (200mg) on day -1 to potentiate CAR-T expansion. AUTO1 dose varies based on the indication. Split dosing of 230 x10^6 CD19 CAR T-cells at day 0 and day 9 is employed in the CLL cohort. A single dose of 200 x10^6 CD19 CAR T-cells is delivered to patients with B-NHL. Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months. RESULTS As of 17th May 2021, we recruited 13 patients: 7 with FL, 4 with MCL, 1 DLBCL and 1 CLL. Apheresis and product manufacture was successful in all 13 patients and 9 patients were infused: 7 with FL and 2 with MCL. Three patients (1 DLBCL, 1 CLL and 1 MCL) were pending infusion at time of data cut-off and 1 patient (MCL) died due to Covid-19 prior to infusion. Patients treated with AUTO1 had a median age of 56 years (range 39-68y), had received a median of 3 prior lines of treatment (range 2-5) and all patients had stage IV disease at screening. Grade 1 CRS was reported in 4/9 and Grade 2 CRS in 1/9. 1/9 developed MAS which resolved with anakinra/dexamethasone. No ICANS was observed on study. Excellent CAR engraftment was observed and 9/9 patients were in CMR by 18FDG PET-CT post-treatment. At a median of 6.1 months (range 4.0-8.1m), 8/9 patients were disease free at last follow-up. One patient died in CMR at month 5.6 of COVID-19. CONCLUSION AUTO1 has a tolerable safety profile in adult patients with r/r B-NHL despite high disease burden. Early data shows 100% complete remission rates and excellent CAR engraftment/expansion. Additional MCL, CLL and DLBCL patients, updated data and longer follow up will be presented. Disclosures Roddie: Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau. Hartley: Astra Zeneca: Ended employment in the past 24 months; ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Farzaneh: Autolus: Consultancy, Current equity holder in publicly-traded company. Lowdell: Autolus: Consultancy, Current equity holder in publicly-traded company. Linch: Autolus: Consultancy, Current equity holder in publicly-traded company. Pule: Autolus: Current Employment, Current equity holder in publicly-traded company. Peggs: Autolus: Consultancy, Current equity holder in publicly-traded company.

Introduction: Prognosis for adult B-cell Acute Lymphoblastic Leukaemia (B-ALL) is poor and there is currently no licensed CD19 Chimeric Antigen Receptor (CAR) therapeutic. We developed a novel CD19 CAR (CAT-41BBz CAR) with a fast off-rate, designed to result in more physiological T-cell activation, reduce toxicity and improve engraftment. We describe updated data from the Phase I ALLCAR19 (NCT02935257) study of AUTO1 in relapsed/refractory adult B-ALL. Methods: Manufacturing: AUTO1 utilises non-mobilised autologous leukapheresate. The first 6 products were generated using a standard dynabead/WAVE bioreactor process and subsequent products using a semi-automated closed process. Study design: Patients aged >16y underwent lymphodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) followed by split dose CAR T-cell infusion (Day 0: if ≥20% Bone Marrow (BM) blasts, infuse 10 x 106 CAR T-cells; if Results: As of 13 May 2020, 24 patients have been leukapheresed, 23 products manufactured and 19 patients received at least 1 dose of AUTO1. The median age was 43y (range 18-62), 26% had prior blinatumomab, 47% had prior inotuzumab ozogamicin and 63% had prior hematopoietic stem cell transplantation (HSCT). At the time of pre-conditioning, 42% had ≥50% BM blasts. No patients experienced ≥Grade 3 CRS (Lee criteria), 3/19 (16%) experienced Grade 3 ICANS that swiftly resolved with steroids. Of 19 infused patients, 16/19 (84%) achieved Minimal Residual Disease (MRD) negative complete response (CR). Currently 6 patients have died, none related to AUTO1. 11/19 (58%) patients remain on study and continue in MRD negative remission at a median follow up of 12.2 months (range 0.6-24.4m). To date, only 2 patients underwent HSCT whilst in remission. For all treated patients, the event-free survival (EFS) at 6 months was 62% and 76% for those whose products were manufactured using the closed process. Patients exhibited robust CAR expansion (mean peak CAR T levels 716,769 copies/µg DNA). Conclusions: AUTO1 has a tolerable safety profile in adult patients with r/r B-ALL despite high disease burden. Early data shows high remission rates with 84% achieving MRD negative CR. This preliminary data supports the further development of AUTO1 as a standalone treatment in patients with r/r B-ALL. Data from additional patients and longer follow up will be presented. Furthermore, data from extension cohorts of patients with low- and high- grade B-cell Non-Hodgkin's lymphoma and chronic lymphocytic leukaemia will be presented. Figure Disclosures Roddie: Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria. O'Reilly:Gilead: Honoraria; Novartis: Honoraria, Other: Travel support. Hartley:ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding. Linch:Autolus: Consultancy. Pule:UCLB: Patents & Royalties; Mana Therapeutics: Other: entitled to share of revenue from patents filed by UCL; Autolus: Current Employment, Other: owns stock in and receives royalties, Patents & Royalties. Peggs:Autolus: Consultancy.

Background: Sepsis is an uncommon occurrence after appendectomy, but the morbidity and mortality of patients who develop sepsis after appendectomy remains exceedingly high. The purpose of ...

Laparoscopy has become the standard of care for the majority of cases for inguinal hernia repair, cholecystectomy, appendectomy, and colectomy due to the shortened patient recovery time compared to open surgery. This study sought to determine if there exists racial disparity in access to a laparoscopic approach to these common surgeries. This was an IRB-approved retrospective study utilizing data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). Individuals who underwent inguinal hernia repair, cholecystectomy, appendectomy, and colectomy in 2016 were identified. Information on self-reported race and ethnicity and other demographic and pre-operative clinical covariates were recorded. Propensity matching was conducted to evaluate the association between race and a laparoscopic approach to surgery. There were 44,522, 60,444, 50,523, and 58,012 cases of inguinal hernia repair, cholecystectomy, appendectomy, and colectomy identified, respectively. Of these patients, 8.38, 8.76, 6.69, and 9.02% self-identified as black, respectively. Confounding effects of variables other than race were balanced by propensity matching. After propensity matching, there were 7460, 10,574, 10,470, and 6758 cases of hernia repair, cholecystectomy, colectomy, and appendectomy, respectively. On univariate (Chi square) analysis with laparoscopic surgery as the primary outcome, black race was significantly associated with lower likelihood of undergoing a minimally-invasive surgical approach in all four surgical procedures under investigation (33.86% of white patients and 21.69% of black patients, p

Introduction: 2nd generation CD19 CAR T cells show unprecedented efficacy in B-ALL, but several challenges remain: (1) scaling manufacture to meet patient need and (2) feasibility of generating products from lymphopenic patients post allogeneic stem cell transplant (allo-SCT). To overcome these issues we propose: (1) use of the CliniMACS Prodigy (Miltenyi Biotec), a semi-automated cGMP platform that simplifies CAR T cell manufacture and (2) the use of matched donor T cells to overcome the challenge posed by patient lymphopenia, albeit this may come with a heightened risk of graft versus host disease (GvHD). CARD (NCT02893189) is a Phase I study of matched donor derived CD19 CAR T cells generated on the CliniMACS Prodigy in 14 adult patients with relapsed/refractory (r/r) B ALL following allo-SCT. We additionally explore the requirement for lymphodepletion (LD) in the allogeneic CAR T cell setting and report on the incidence of GvHD with this therapy. Methods: Manufacturing: CARD utilises non-mobilised matched donor leucapheresate to manufacture 2nd generation CD19CAR T cells using a closed CliniMACS® Prodigy/ TransACTTM process. Study design: Eligible subjects are aged 16-70y with r/r B ALL following allo SCT. Study endpoints include feasibility of CD19CAR T cell manufacture from allo-SCT donors on the CliniMACS Prodigy and assessments of engraftment and safety including GvHD. To assess the requirement for LD prior to CD19CAR T cells in lymphopenic post-allo-SCT patients, the study is split into Cohort 1 (no LD) and Cohort 2 (fludarabine (30 mg/m2 x3) and cyclophosphamide (300mg/m2 x3)). To mitigate for the potential GvHD risk, cell dosing on study mirrors conventional donor lymphocyte infusion (DLI) schedules and is based on total CD3+ (not CAR T) cell numbers: Dose 1=1x106/kg CD3+ T cells; Dose 2= 3x106/kg CD3+ T cells; Dose 3= 1x107/kg CD3+ T cells. Results: As of 26 July 2019, 17 matched allo SCT donors were leukapheresed and 16 products were successfully manufactured and QP released. Patient demographics are as follows: (1) median patient age was 43y (range 19-64y); (2) 4/17 had prior blinatumomab and 5/17 prior inotuzumab ozogamicin; (3) 7/17 had myeloablative allo SCT and 10/17 reduced intensity allo SCT of which 6/17 were sibling donors and 12/17 were matched unrelated donors. No patients with haploidentical transplant were enrolled. To date, 12/16 patients have received at least 1 dose of CD19CAR T cells: 7/16 on Cohort 1 and 5/16 on Cohort 2 (2/16 are pending infusion on Cohort 2 and 2/16 died of fungal infection prior to infusion). Median follow-up for all 12 patients is 22.9 months (IQR 2.9-25.9; range 0.7 - 25.9). At the time of CAR T cell infusion, 7/12 patients were in morphological relapse with >5% leukemic blasts. Despite this, CD19CAR T cells were administered safely: only 2/12 patients experienced Grade 3 CRS (UPenn criteria), both in Cohort 1, which fully resolved with Tocilizumab and corticosteroids. No patients experienced ≥Grade 3 neurotoxicity and importantly, no patients experienced clinically significant GvHD. In Cohort 1 (7 patients), median peak CAR expansion by flow was 87 CD19CAR/uL blood whereas in Cohort 2 (5 patients to date), median peak CAR expansion was 1309 CD19CAR/uL blood. This difference is likely to reflect the use of LD in Cohort 2. CAR T cell persistence by qPCR in Cohort 1 is short, with demonstrable CAR in only 2/7 treated patients at Month 2. Data for Cohort 2 is immature, but this will also be reported at the meeting in addition to potential mechanisms underlying the short persistence observed in Cohort 1. Of the 10 response evaluable patients (2/12 pending marrow assessment), 9/10 (90%) achieved flow/molecular MRD negative CR at 6 weeks. 2/9 responders experienced CD19 negative relapse (one at M3, one at M5) and 3/9 responders experienced CD19+ relapse (one at M3, one at M9, one at M12). 4/10 (40%) response evaluable patients remain on study and continue in flow/molecular MRD negative remission at a median follow up of 11.9 months (range 2.9-25.9). Conclusions: Donor-derived matched allogeneic CD19 CAR T cells are straightforward to manufacture using the CliniMACS Prodigy and deliver excellent early remission rates, with 90% MRD negative CR observed at Week 6 in the absence of severe CAR associated toxicity or GvHD. Peak CAR expansion appears to be compromised by the absence of LD and this may lead to a higher relapse rate. Updated results from Cohorts 1 and 2 will be presented. Disclosures Roddie: Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. O'Reilly:Kite Gilead: Honoraria. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Qasim:Autolus: Equity Ownership; Orchard Therapeutics: Equity Ownership; UCLB: Other: revenue share eligibility; Servier: Research Funding; Bellicum: Research Funding; CellMedica: Research Funding. Linch:Autolus: Membership on an entity's Board of Directors or advisory committees. Pule:Autolus: Membership on an entity's Board of Directors or advisory committees. Peggs:Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees.

Introduction: In adults, prognosis for B-ALL is poor, patients are more vulnerable to CD19 CAR immunotoxicity and there is currently no CD19 CAR therapeutic with acceptable toxicity and durable efficacy. We have developed a novel second generation CD19CAR (CAT-41BBz CAR), with a faster off-rate but equivalent on rate than the FMC63-41BBz CAR (Kd 116 nM vs 0.9 nM, T1/2 9s vs 4.2 hours) designed to result in more physiological T-cell activation, reduce toxicity and improve engraftment. Preliminary paediatric clinical data of this novel CD19 CAR (AUTO1) supports this assertion. We here describe preliminary data from ALLCAR19 (NCT02935257), a multi-centre, Phase I clinical study of AUTO1 as therapy for r/r adult B-ALL. Methods: Manufacturing: AUTO1 utilises non-mobilised autologous leucapheresate. The first 6 trial products were generated using a standard dynal bead/WAVE Bioreactor process and subsequent products using a semi-automated closed process. Study design: ALLCAR19 is a phase I/II study recruiting subjects 16-65y with r/r B ALL. Lymphodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) is followed by split dose CAR T cell infusion (Day 0: if ≥20% BM blasts, infuse 10 x 106 CAR T cells ; if Results: As of 24 July 2019, 16 patients have been leukaphresed, 14 products manufactured (one failed leukaphresis and one currently in manufacture) and 13 patients have received at least 1 dose of AUTO1. Of the 16 patients, median age was 35.5 (range 18-63), 10/16 (63%) had prior blinatumomab or inotuzumab ozogamicin and 12/16 (75%) had prior HSCT. At the time of pre-conditioning, 9/13 (69%) patients were in morphological relapse with >5% leukemic blasts of which 6/13 (46%) had ≥50% blast. 9/13 patients (69%) received the total target split dose of 410 x 106 CAR T cells while 1/13 patients (8%) received a reduced split total dose of 51.3 x 106 CAR T cells due to manufacturing constraints. 3/13 patients (23%) received only a first dose of 10 x 106 CAR T cells. The dose was administered safely to date: No patients experienced ≥Grade 3 CRS (using Lee criteria) and only 1/13 (8%) experienced Grade 3 neurotoxicity (dysphasia) that resolved swiftly with steroids. All patients had robust CAR expansion (median peak expansion 172 CAR/uL blood). Of the 13 patients dosed (1/13 pending 28 day follow up), 10/12 (83%) achieved MRD negative CR at 1 month and all patients had ongoing CAR T cell persistence at last follow up. Two patients experienced CD19 negative relapse (one at M3, one at M6), 1 patient died on D17 before first response evaluation, 1 died in molecular CR from sepsis, and 1 died from persistent disease. Currently, 7/12 remain on study and continue in flow/molecular MRD negative remission with a median follow up of 9.0 months (range 1.2-14.8). Conclusions: AUTO1 delivers excellent early remission rates with initial data showing 83% MRD negative CR and robust CAR expansion and persistence. Despite high tumour burden, the safety profile compares favourably to other CD19 CARs, with no cases of severe CRS and only one case of Gr3 neurotoxicity. This is consistent with experience in the paediatric cohort. Updated results will be presented. Disclosures Roddie: Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. O'Reilly:Kite Gilead: Honoraria. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Linch:Autolus: Membership on an entity's Board of Directors or advisory committees. Pule:Autolus: Membership on an entity's Board of Directors or advisory committees. Peggs:Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees.

With population growth in Southeastern coastal areas, and impending threats of both gradual and punctuated hazards from climate change, this article examines the effectiveness of one of the most stringent and celebrated state coastal management laws; namely, South Carolina's Beachfront Management Act of 1988 (BMA). The BMA's efficacy is gauged using a comprehensive mixed methodology, including: mandate assessment; plan quality evaluation; external conditions for plan creation and implementation; and post-regulatory conformance-based plan implementation assessment in two barrier island communities, the Towns of Hilton Head Island and Pawleys Island. This unique synthesis of policy analysis approaches reveals that a substantial volume of development has circumvented the BMA's policies, particularly the setback lines based on a forty-year erosion record, and the retreat objective. It exposes a classic challenge of minimal state implementation, prompted by timidity from the specter of Lucas v. South Carolina ...

The Pauma groundwater basin in southern California provides a substantial portion of the irrigation water for agricultural operations in the Pauma Valley. As imported water becomes more scarce and more costly, increasing demands are placed upon this local resource. To better understand the basin and maximize the sustainable use of local groundwater, Yuima Municipal Water District (YMWD) commissioned an integrated geophysical investigation of the valley. The first phase of the geophysical program was a detailed gravity survey to identify the depth to bedrock. Large density contrasts between the igneous and metamorphic bedrock and the overlying sediment make gravimetry a practical tool for this purpose. A gravity-based bedrock model was developed to identify locations with greater accumulations of sediment as potential sites for deeper water supply wells. Preliminary evidence indicates that the Pauma basin is heterogeneous. Heterogeneity in the sediments has been assessed via a resistivity survey to delineate conductive clay units which may form a barrier to groundwater flow. Deep bedrock wells in the region can be highly productive if they encounter significant fractures. A magnetotelluric survey was performed to locate and map conductive fracture zones beneath the sediments.