Pilot Safety Research Articles

Targeting TRPV1 activity via high-dose capsaicin in patients with sickle cell disease.

Evidence suggests neuropathic pain (NP) develops over time in sickle cell disease (SCD), contributing to a complex, difficult‐to‐treat phenotype, with management based on scant evidence. One characteristic of NP found is hyperalgesia caused by nervous system sensitization, but risk factors for this have not been identified within the SCD population, as exact mechanisms leading to its development are not well defined. The SPICE (Sickle cell Pain: Intervention with Capsaicin Exposure) trial was a pilot safety and feasibility trial of high‐dose (8%) topical capsaicin for patients with SCD and recurrent/chronic pain with neuropathic features, aimed at exploring capsaicin's utility as a mechanistic probe and adjunctive pain treatment for this population. Ten participants identifying “target” sites of pain with NP‐type qualities consented to treatment. The primary endpoint was safety/tolerability. The novel Localized Peripheral Hypersensitivity Relief score (LPHR) was developed to determine improvement in sensitivity attributable to TRPV1 neutralization. There were no severe treatment‐related adverse events. Higher baseline pain sensitivity at a given body site was associated with self‐reported history of more frequent localized vaso‐occlusive pain episodes at that site. There was a statistically significant improvement in the mean LPHR, evidencing TRPV1's importance to the development of hypersensitivity and a potential therapeutic benefit of capsaicin for SCD.

Robust unsupervised learning of temporal dynamic vehicle-to-vehicle interactions

Robust unsupervised learning of temporal dynamic interactions is an important problem in robotic learning in general and automated unsupervised learning in particular. Temporal dynamic interactions can be described by (multiple) geometric trajectories in a suitable space over which unsupervised learning techniques may be applied to extract useful features from raw and high-dimensional data measurements. Taking a geometric approach to robust unsupervised learning for temporal dynamic interactions, it is necessary to develop suitable metrics and a systematic methodology for comparison and for assessing the stability of an unsupervised learning method concerning its tuning parameters. Such metrics must account for (geometric) constraints in the physical world as well as uncertainties associated with the learned patterns. In this paper, we introduce a model-free metric based on the Procrustes distance for robust learning of dynamic vehicle interactions, and an optimal transport-based distance metric for comparing between distributions of interaction patterns. These distance metrics can serve as an objective for assessing the stability of an interaction learning algorithm. They are also used for comparing the outcomes produced by different algorithms. Moreover, they may also be adopted as an objective function to obtain clusters and representative interaction primitives. These concepts and techniques will be introduced, along with mathematical properties, while their usefulness will be demonstrated in unsupervised learning of vehicle-to-vehicle interactions extracted from the Safety Pilot database, one of the world’s largest databases for connected vehicles. Results reveal that the proposed methods outperform existing techniques under several well-founded notions of clustering efficiencies.

An Open-Label, Single-Arm, Pilot Intervention Study to Assess the Efficacy and Safety of Apixaban in Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a serious adverse drug reaction due to its related risk of life- and limb-threatening thrombosis. Apixaban is a direct factor Xa inhibitor that may be intended as an ideal alternative for the management of HIT. In this open-label, single-arm, pilot intervention study, the efficacy and safety of apixaban were evaluated in 30 patients aged >18 years with clinically suspected HIT (4Ts score ≥4 points). Patients with mechanical heart valves, chronic kidney disease, hepatic impairment, and active bleeding were excluded. In all patients with inclusion criteria, heparin or enoxaparin was discontinued and apixaban was started. The dose of apixaban for HIT suspected patients was defined on the basis of the reason for anticoagulant therapy. End points included confirmed thrombosis, mortality, and adverse treatment-related events. After apixaban therapy, platelet counts normalized in all patients; none of the 30 subjects developed new, progressive, or recurrent thrombosis; and only 1 of 30 patients developed a hemorrhagic event. Five patients (16.7%) died, but the reason for death was not linked to thrombosis, hemorrhage, or adverse effects of apixaban. Along with the available emerging data, our results propose that apixaban could be a safe and effective drug for the management of suspected HIT in clinically stable patients.

Abstract 4234: ONM-501: A polyvalent STING agonist for oncology immunotherapy

Abstract Background: The stimulator of interferon genes (STING) plays a central role in innate immune response against infection and cancer. Several cyclic di-nucleotide (CDN) and non-CDN small molecule STING agonists have demonstrated effectiveness against cancer in preclinical animal models, however their clinical trials showed limited therapeutic efficacy. ONM-501, a dual-activating STING agonist employs PC7A, a synthetic polymer that induces polyvalent STING condensation and prolongs innate immune activation has been recently developed. ONM-501 encapsulates the endogenous STING agonist cGAMP with the PC7A micelles offering dual ‘burst’ and ‘sustained’ STING activation. The mechanism and effectiveness of intratumorally delivered ONM-501 as an immunotherapy against solid tumors has been demonstrated in preclinical models. Methods: ONM-501 was recently evaluated for STING activation across different species: STING related IFNB1 and CXCL10 gene expression after ONM-501 treatment was measured by RT-qPCR in PBMCs from rat, cynomolgus monkey, and human. ONM-501 antitumor efficacy was evaluated in murine syngeneic tumor models. Abscopal effect was demonstrated by studying antitumor efficacy using both a primary/distal model and a lung metastatic model. STING knockout mice and STING knockout cancer cells were used to clarify the dependence of STING status to the ONM-501 antitumor immunity. Immune cell dependence was further elucidated by depletion of specific immune cell populations. Pilot safety studies including major organ function and systemic cytokine levels were performed in immunocompetent mice. Results: STING activation was observed across different species by measuring IFNB1 and CXCL10 mRNA in PBMCs from rat, cynomolgus monkey, and human after ONM-501 treatment. Antitumor efficacy was demonstrated both as a monotherapy and in combination with anti-PD1 in six different syngeneic tumor models. ONM-501 also induced an abscopal effect - tumor inhibition was observed in both primary and distal MC38 tumors in the same animal. Reduction of lung metastasis in an immune “cold” triple negative orthotopic breast cancer 4T1 model further confirmed the systemic antitumor immunity. Knocking out host STING (i.e. STING KO mice) rather than cancer cell STING KO resulted in abrogation of tumor inhibition suggesting that the host STING status is responsible for ONM-501-mediated anti-tumor immunity. Immune cell depletion studies further clarified that the antitumor immunity is dependent on CD8+ T cell and dendritic cells (DCs). No alteration of main organ function or systemic cytokine storm were observed in the pilot safety study. Conclusions: ONM-501 demonstrated marked anti-tumor efficacy in a panel of syngeneic tumor models. The anti-tumor effect was mediated by host STING and dependent on CD8+ T cells and DCs. These results support further evaluation of ONM-501 as a clinical candidate for the potential treatment of solid tumors. Citation Format: Suxin Li, Jian Wang, Jonathan Wilhelm, Qingtai Su, Gaurav Bharadwaj, Jason Miller, Wei Li, Katy Torres, Ruolan Han, Tian Zhao, Jinming Gao. ONM-501: A polyvalent STING agonist for oncology immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4234.

A Randomized Trial of Topical Fibrinogen-Depleted Human Platelet Lysate Treatment of Dry Eye Secondary to Chronic Graft-versus-Host Disease.

PurposeThe purpose of the study was to evaluate, as a pilot trial, safety and tolerability of CAM-101 10% and 30% topical ophthalmic fibrinogen-depleted human platelet lysate (FD hPL) solution in patients with dry eye disease (DED) secondary to graft-versus-host disease (GvHD) after 6 weeks of treatment.DesignA phase I/II, pilot, prospective, multicenter, randomized, double-masked clinical trial.ParticipantsPatients with DED secondary to GvHD.MethodsSixty-four adult patients were stratified by “symptom severity” (Ocular Surface Disease Index [OSDI], ocular discomfort Visual Analog Scale (VAS), ocular symptom frequency, and use of artificial tears) and then randomized 1:1:1 to CAM-101 (FD hPL) at 10% or 30% concentration or an electrolyte (Plasma-Lyte A) vehicle control, 1 drop in both eyes, 4 times daily, for 42 days. After 42 days, control patients were offered 42 days of open-label treatment with 30% FD hPL.Main Outcome MeasuresPrimary outcome safety measures were ocular and systemic adverse events and the number of patients in each group with clinically significant change from normal to abnormal in any ocular findings. Secondary outcomes were changes from baseline to day 42 in ocular discomfort, OSDI, fluorescein corneal staining, and lissamine green conjunctival staining relative to the vehicle control. The ocular symptom frequency was assessed on a 100-point VAS.ResultsFD hPL 10% and 30% were safe and well tolerated. Relative to the vehicle control, significant decreases from baseline to day 42 were seen in the FD hPL 30% group with regard to ocular discomfort (mean decrease = −18.04; P = 0.018), frequency of burning/stinging (−20.23; P = 0.022), eye discomfort (−32.97; P < 0.001), eye dryness (−21.61; P = 0.020), pain (−15.12; P = 0.044), photophobia (−24.33; P = 0.0125), and grittiness (−20.08; P = 0.0185). Decreases were also seen for itching and foreign body sensation, though not statistically significant. Improvements were seen in tear breakup time (mean increase = 1.30 seconds; P = 0.082) and the investigator’s global evaluation 4-point scale (mean decrease = −0.86; P = 0.026). Corneal fluorescein staining was not improved. The OSDI had a mean decrease of −8.88 compared to the vehicle, although not statistically significant.ConclusionsFibrinogen-depleted human platelet lysate appears to be well tolerated, with no significant toxicity at concentrations of 10% and 30%. These initial data suggest some efficacy, especially for subjective outcome measures relative to baseline assessments and treatment with the vehicle, but larger studies are needed to confirm these effects.

Open label safety and efficacy pilot to study mitigation of equine recurrent uveitis through topical suppressor of cytokine signaling-1 mimetic peptide

Equine recurrent uveitis (ERU) is a painful and debilitating autoimmune disease and represents the only spontaneous model of human recurrent uveitis (RU). Despite the efficacy of existing treatments, RU remains a leading cause of visual handicap in horses and humans. Cytokines, which utilize Janus kinase 2 (Jak2) for signaling, drive the inflammatory processes in ERU that promote blindness. Notably, suppressor of cytokine signaling 1 (SOCS1), which naturally limits the activation of Jak2 through binding interactions, is often deficient in autoimmune disease patients. Significantly, we previously showed that topical administration of a SOCS1 peptide mimic (SOCS1-KIR) mitigated induced rodent uveitis. In this pilot study, we test the potential to translate the therapeutic efficacy observed in experimental rodent uveitis to equine patient disease. Through bioinformatics and peptide binding assays we demonstrate putative binding of the SOCS1-KIR peptide to equine Jak2. We also show that topical, or intravitreal injection of SOCS1-KIR was well tolerated within the equine eye through physical and ophthalmic examinations. Finally, we show that topical SOCS1-KIR administration was associated with significant clinical ERU improvement. Together, these results provide a scientific rationale, and supporting experimental evidence for the therapeutic use of a SOCS1 mimetic peptide in RU.

MO1020: Alkaline Phosphatase to Prevent Ischemia Reperfusion Injury in Living Kidney Transplantation—A Safety Pilot Study

Abstract BACKGROUND AND AIMS Ischemia-reperfusion injury (IRI) during kidney transplant procedures can induce acute kidney injury (AKI) [1]. Extracellular ATP is a key player of pro-inflammatory processes during IRI in the kidney [2], whereas conversion of ATP into adenosine has protective effects to the kidney. Alkaline phosphatase (AP) is the only enzyme that converts ATP directly into adenosine by dephosphorylation[3]. In earlier clinical trials of AP in sepsis-associated AKI (SA-AKI), it was suggested that AP has a protective effect on endogenous creatinine clearance and mortality [4]. With the pathophysiologic similarity between SA-AKI and IRI, we aimed to evaluate the effect and feasibility of periprocedural AP to improve kidney function in living donor kidney transplantation. METHOD We conducted a pilot, phase II, double-blinded and randomized controlled trial comparing medicinal AP (tradename: `bRESCAP’, courtesy Alloksys Life Sciences) and placebo. All consecutive recipients of living donor kidneys were asked for informed consent. After randomization, intravenous AP (bolus 1000IU and 9000IU continuously) or placebo was administered at the start of the procedure and continued for the following 24 h. Graft function was measured with measured GFR (using an iohexol distribution curve) after 12 months. Plasma creatinine and a panel of novel injury biomarkers and systemic inflammation markers were measured in both urine and serum during the 7 days after the procedure. Drug reactions and adverse events (AEs) were monitored in the first 7 days. Secondary outcomes included all-cause mortality and dialysis dependency. RESULTS Between June 2019 and October 2019, 11 patients were enrolled. Patients did not differ between groups, bRESCAP (n = 5) and placebo (n = 6) at baseline: 36% were male; the median age was 58 [interquartile range (IQR) 40–65] years; and the median eGFR 12 (10–15) mL/min/1.73 m2. After 1 year, median measured GFR was similar in the bRESCAP group [52.2 (40.5–61.4)] and placebo group [52.4 (37.6–66.1)] (P = 1.000). Mixed model analysis showed no difference in the fall of plasma creatinine or cystatin-C over the first 7 days after the procedure. There were no adverse events observed in the bRESCAP group. CONCLUSION These pilot data indicate that bRESCAP can be administered safely but offers no benefits to recipients of kidneys from living donors. This study opens the way to study recipients of kidneys from deceased donors, where IRI plays a much more prominent role and frequently leads to delayed graft function.

The relationship between sense of calling and safety behavior among airline pilots: The role of harmonious safety passion and safety climate

Pilot safety behavior plays a crucial role in airlines safety performance and aviation safety, so it is vital to identify factors that may enhance pilot safety behavior and explore their mechanisms. Drawing upon self-determination theory, this study examines whether, how, and when the sense of calling influences pilot safety behavior from the perspective of occupational psychology. Using a sample of 321 Chinese commercial airline pilots, we tested a moderated mediation model in which the relationship between sense of calling and pilot safety behavior was mediated by harmonious safety passion and moderated by safety climate. The results indicated that the sense of calling had a positive direct effect on pilot safety behavior and that this relationship was partially mediated by harmonious safety passion. Moreover, safety climate negatively moderates the positive relationship between sense of calling and harmonious safety passion as well as the indirect effect of sense of calling on safety behavior via harmonious safety passion. In particular, sense of calling had a stronger effect on harmonious safety passion and a stronger indirect effect on safety behavior when the safety climate was lower. Theoretical contributions and practical implications for aviation safety managementpractices are discussed.

Immunosafe(r)-by-design nanoparticles: Molecular targets and cell signaling pathways in a next-generation model proxy for humans.

Nanotechnology research covers a wide field of studies pointing to design and shape complex matter in a scale between 1 and 100nm, with unique size-depending properties and applications. The value and potential of engineered nanoparticles in human diagnostics and therapies essentially relay on their safety and biocompatibility. Entering a cell, in fact, these particles take complex interactions with the surrounding biological environment, dramatically changing their own identity. The formation of a custom-made protein corona is the first signal of their interplay with the cell defensive mechanisms, and a major issue in their application in medicine. Preliminary in-depth studies in model organisms have been developed to assess immunological safety and competence in facing the host immune system and its defensive response. New affordable animal models are emerging in pilot nano-response and safety studies. Sea urchins, benthic marine Echinoderms, have a wide and very efficient immune system working with innate defense mechanisms and are widely used in immune studies. Nano-safety studies have been showing that the sea urchin Paracentrotus lividus displays an excellent sensing system and high defensive capability, joined to the availability of easily accessible immune cells. As in mammals, nanoparticle recognition and interaction activate specific signaling pathways, metabolic rewiring and homeostasis maintenance. In this chapter, we point to the value of planning new research and developing nano-immune studies using an easy nonmammalian next-generation model, able to unravel new specific response mechanisms to nanoparticles.

Sensor Data Based Anomaly Detection in Autonomous Vehicles using Modified Convolutional Neural Network

Automated Vehicles (AVs) reform the automotive industry by enabling real-time and efficient data exchange between the vehicles. While connectivity and automation of the vehicles deliver a slew of benefits, they may also introduce new safety, security, and privacy risks. Further, AVs rely entirely on the sensor data and the data from other vehicles too. On the other hand, the sensor data is susceptible to anomalies caused by cyber-attacks, errors, and faults, resulting in accidents and fatalities. Hence, it is essential to create techniques for detecting anomalies and identifying their sources before the wide adoption of AVs. This paper proposes an anomaly detection model using a Modified-Convolutional Neural Network (M-CNN) with Safety Pilot Model Deployment (SPMD) dataset. The M-CNN model comprises specifically trained layers involving the ReLU activation function for feature extraction and detection of AV anomalies. Furthermore, the Adam is used as the optimization algorithm to train the model. The detection accuracy of the proposed model is compared with Isolation Forest (IF) and Support Vector Machine (SVM). The experimental result reveals that the proposed model outperforms the other models with an accuracy of 99.40% in AV anomaly detection.

Low-Concentration Norepinephrine Infusion for Major Surgery: A Safety and Feasibility Pilot Randomized Controlled Trial

Prevention of hypotension during the intra- and postoperative period is an important goal. Peripheral administration of low-concentration norepinephrine may be a safe and effective strategy to reduce the risk of hypotension. We conducted a 2-center, randomized pilot feasibility trial, with a target of 60 adult patients undergoing major noncardiac surgery. We randomized patients to receive a peripheral low-concentration (10 µg/mL) norepinephrine or placebo (saline 0.9%) infusion. The study drug infusion was titrated to achieve a minimum systolic blood pressure target, preselected within 10% of baseline value and within the range limit 100 to 120 mm Hg during surgery and for up to 4 or 24 hours postoperatively. We achieved a high consent rate (84%), successful study drug administration throughout surgery (98% of patients) and absence of unblinding. There were no important study drug-related adverse events. The average intraoperative systolic blood pressure was 120 ± 12.6 mm Hg in the norepinephrine group and 115 ± 14.9 mm Hg in the placebo group. The mean difference between the intraoperative systolic blood pressure achieved less the preselected minimum systolic blood pressure target was 10.0 ± 12.7 mm Hg in the norepinephrine group and 2.9 ± 14.7 mm Hg in the placebo group; difference in means, 7.1 (95% confidence interval, 0.2-14.0) mm Hg. A future large trial evaluating the effectiveness and safety of peripheral administration of low-concentration norepinephrine during the perioperative period is feasible, and likely to achieve a minimum systolic blood pressure threshold.

Driving behavior at midblock crosswalks with Rectangular Rapid Flashing Beacons: Hidden Markov model approach using naturalistic data

Pedestrian fatalities have increased in the U.S. with the largest increase being observed on urban arterials and away from intersections. Rectangular Rapid Flashing Beacon (RRFB) has been widely implemented as a safety countermeasure to improve driver awareness and visibility of pedestrians, especially for midblock crosswalks. Studies show that drivers are more likely to yield to pedestrians at crosswalks with an RRFB. These studies are often based on a binary outcome of whether or not drivers yield to pedestrians. Nevertheless, it is also important to consider the drivers’ deceleration behavior as a dynamic process at these crosswalks and the impact of pedestrians being present or not. Understanding this dynamic behavior and the related circumstances can provide information on the design of alerting systems that help drivers make more appropriate decisions at these crosswalks to avoid a vehicle–pedestrian crash. This study examined this research topic using Hidden Markov Models (HMMs) and data from a naturalistic study. More specifically, four HMMs were applied to the naturalistic brake and jerk data from the Safety Pilot Model Deployment (SPMD) program given drivers’ intention to slow down, the RRFB activation status, and the presence of pedestrians. The time-based data sequence was converted to distance-based through a moving window to enhance result comparison and interpretation. Grid-search was used to select the best moving window parameters and the optimal number of hidden states. This study confirmed the high compliance at an activated RRFB when pedestrians were present. Even without pedestrians, one in five traversals showed drivers slowing down to less than 8.94 m/s (20 mph) within 35 m of the crosswalk. Model results further indicate that drivers started braking as far back as 180 m before the crosswalk and stopped braking from 70 m before the crosswalk at an activated RRFB without pedestrians. When there were pedestrians, drivers would start braking 20 to 30 m later but would brake more firmly and for longer. Finally, drivers were not likely to brake or decelerate when RRFB was off and no pedestrians were present.

Feasibility of early waking cardiac arrest patients whilst receiving therapeutic hypothermia: The therapeutic hypothermia and early waking (THAW) trial

AimTo determine the safety and feasibility of an early (12 h) waking and extubation protocol for out-of-hospital cardiac arrest (OHCA) patients receiving targeted temperature management (TTM). MethodsThis was a single-centre, prospective, non-randomised, observational, safety and feasibility pilot study which included successfully resuscitated OHCA patients, of presumed cardiac cause. Inclusion criteria were: OHCA patients aged over 18 years with a return of spontaneous circulation, who were going to receive TTM33 (TTM at 33 °C for 24 h and prevention of hyperthermia for 72 h) as part of their post cardiac arrest care. Clinical stability was measured against physiological and neurological parameters as well as clinical assessment. Results50 consecutive patients were included (median age 65.5 years, 82% male) in the study. Four (8%) patients died within the first twelve hours and were excluded from the final cohort (n = 46). Twenty-three patients (46%) were considered clinically stable and suitable for early waking based on the intention to treat analysis; 12 patients were extubated early based on a variety of clinical factors (21.4 ± 8.6 h) whilst continuing to receive TTM33 with a mean core temperature of 34.2 °C when extubated. Of these, five patients were discharged from the intensive care unit (ICU) <48 h after admission with a mean ICU length of stay 1.8 ± 0.4 days. Twenty-eight patients (56%) were discharged from the ICU with a modified Rankin Score of 0–2. The overall intra-hospital mortality was 50% (n = 25). ConclusionsIt is safe and feasible to wake selected comatose OHCA patients at 12 h, allowing for earlier positive neuro-prognostication and reduced ICU stay.

Public health and work safety pilot study: Inspection of job risks, burn out syndrome and job satisfaction of public health inspectors in Greece

This is a cross-sectional, nationwide pilot study conducted in the first quarter of 2021 in Greece. The aim of this study was to report the job risks of public health inspectors in Greece and investigate possible relationships with burnout and job satisfaction. An online survey was created, and the web link was distributed to respondents by email, through the National Public Health Inspectorate Administration, while anonymity was retained. A total number of 78 Public Health Inspectors were contacted and 46 responses were collected (response rate 58.97%). The study found that biological, ergonomic, and psychosocial risks are perceived as most severe in public health inspection. Higher levels of emotional exhaustion were associated with more prevalent ergonomic and psychosocial risks. Job satisfaction was associated with ergonomic risks, but it was most strongly predicted by demographic variables. Perceived quality of job training was found to be negatively related to psychosocial risks. It was concluded that Public Health Inspectors in Greece face a variety of job risks the severity of which contribute to burnout and more specifically to emotional exhaustion. These findings are among the first to address occupational health and safety of Public Health Inspectors in Greece and worldwide and can contribute significantly to the development of the appropriate framework to reduce job risks and emotional exhaustion among employees of Public Health Inspection.

Treatment of Fistulizing Perianal Crohn's Disease by Autologous Microfat Enriched With Adipose-Derived Regenerative Cells.

In this pilot study, short-term efficacy and safety of fat graft enriched with Adipose-Derived Regenerative Cells (ADRC) in the treatment of Crohn’s high anal fistula was evaluated. Clinical fistula healing was achievable in 75% of cases, by a single treatment.

A Single-Arm, Open-Label, Pilot Trial of Autologous CD7-CAR-T Cells for CD7 Positive Relapsed and Refractory T-Lymphoblastic Leukemia/Lymphoma

Introduction:T lymphoblastic leukemia/lymphoma (T-ALL/LBL) is highly aggressive. Although intensive chemotherapies such as ALL-type regimens are commonly used, about half patients eventually relapse and die of T-ALL/LBL.Chimeric antigen receptor (CAR) T cells have given rise to breakthroughs in treating B cell hematological malignancies. However, there are few clinical studies of CAR-T on T cell malignant tumors. CD7, overexpressed in up to 100% of relapsed/refractory T-ALL/LBL, is an attractive therapeutic target for T-lymphoblastic leukemia/lymphoma (T-ALL/LBL). Although several healthy donor derived CD7-CAR-T trials have been reported, autologous CD7-CAR-T cell therapy represents another promising strategy. In current study, a nanobody derived autologous CD7-CAR-T with a highly optimized structure and a clinically feasible strategy to overcome CAR-T cell fratricide and exclude abnormal T cell contamination have been developed.MethodThis is a single-arm, open label, safety and efficacy pilot study (NCT04004637). Study participants will receive Flu/Cy pre-treatment before CAR-T infusion. CD7 CAR-T was then administered at a single dose of 1.0x10 6 (N=5) or 1.5x10 6 (N=1; Pt#1) or 2x10 6 (N=3; Pt#7, 8,) CAR-T cells/kg. Adverse events were categorized by NCI-CTCAE V5.0. Tumor responses were assessed based on the 2014 Lugano Evaluation Criteria for Lymphoma and 2016 Chinese Guideline for Diagnosis and Treatment of Acute Lymphoblastic Leukemia.Results:Total of 8 patients including 5 r/r T-ALL/LBL and 3 r/r ETP-ALL/LBL (case 4, 5, 6) were assigned to receive CD7 CAR-T cell and completed the efficacy assessment. Overall response rate at 1 month was 100%. In patients followed up for ≥ 3 months, complete remission (CR) rate at 3 month was 75%. Case 1-6 was administered at 1.0×10 6 CAR-T/Kg except for case 1 (1.0×10 6 CAR-T/Kg). Bone marrow (BM) tumor burden of case 1 decreased from 70.03% to 19.51% and case 1 has an OS for nearly two years. Case 2 died due to abdominal infection at 3 month although he was still in MRD- status then. Case 3 had sustained MRD- for 7 months but appeared MRD+ in BM at 8 month, so second CD7 CAR-T infusion had been performed and achieved CR at 14th day again. Case 4 has been achieving CR 12 months. Case 5 and 6 had a DOR (Duration of response) of about 3 and 2 months respectively. In case 1-6, despite case1-2 appeared grade 2 CRS, all other cases only had grade 1. Therefore, in order to further explore the best effective dose, case 7-8 had received dose of 2.0×10 6 CAR-T/Kg. Case 8 are still in complete remission.Unfortunately, case 7 relapsed at 6 month due to CD7 negative blasts. The absence of CD7 on the cell surface enables the tumor to evade CAR T cell-mediated recognition and clearance, despite continued persistence of CAR-T cells.Conclusions:Autologous CD7 CAR-T represents a promising immunotherapy for r/r T-ALL/LBL and exhibited encouraging clinical efficacy and safety in treating r/r T-ALL/LBL and ETP-ALL/LBL. DisclosuresNo relevant conflicts of interest to declare.

In Africa, a High Proportion of Adults with HbSC Meet American Society of Hematology's Eligibility Criteria for Severe Sickle Cell Disease and Starting Hydroxyurea Therapy in a Clinical Trial Setting

▪Introduction: Sickle cell disease (SCD), HbSC, is the second most frequent hemoglobinopathy after HbSS. Worldwide, an estimated 54,736 babies are delivered annually with HbSC disease, with the highest HbC gene frequency in West Africa (Piel et al.2013). A retrospective study at the Ghana Institute of Clinical Genetics [(GICG), a sickle cell clinic] reported that 40% of the 3,000 SCD patients attending the clinic yearly are HbSC (Asare et al.2018). HbSC disease usually results in a comparatively milder form of SCD. However, rates of maternal-fetal morbidity, retinopathy, avascular necrosis (AVN) of the hip, priapism, and chronic kidney disease are increased (Powars et al.2002; Oppong et al.2018). While microalbuminuria is lower in HbSC than HbSS, it still occurs in >23% of adults (Drawz et al.2016). In addition, thrombosis, silent cerebral infarction, sensorineural hearing loss, and pulmonary hypertension may be higher than previously suspected (Sathi et al.2019). Unlike HbSS, hydroxyurea is not routinely recommended for HbSC patients because they are all perceived to have a milder phenotype, with improved life expectancy. Thus, HbSC individuals are often excluded from randomized controlled trials in children and adults with SCD (Luchtman-Jones et al.2016).Given the high proportion of adults with HbSC in Ghana, who may benefit from hydroxyurea therapy, we tested the hypothesis that at least 5% of adults with HbSC will meet the ASH criteria for severe disease and treatment. Data indicating that a significant proportion of adults with HbSC are eligible for hydroxyurea could potentially support pilot safety trials to determine the optimal hydroxyurea dose to ameliorate symptoms while limiting toxicity. Data can also facilitate government health policy decisions to subsidize hydroxyurea costs.Methodology: We conducted a medical chart review of all adults with HbSC disease (total: 639; 18-45years) who attended the SCD clinic, GICG (January 1, 2019, to December 31, 2019). We identified a comparison group of 639 adults with HbSS, age, and gender-matched to the HbSC patients from the same clinic. Severe complications were defined as a history of ≥3 sickle cell-associated moderate to severe pain episodes/year, a history of severe acute chest syndrome (ACS), and severe symptomatic chronic anemia that interferes with daily activities or quality of life (Hydroxyurea and Transfusion Therapy for the Treatment of Sickle Cell Disease.2014). We defined acute pain episode as new onset of pain that lasts at least 4 hours, for which there is no explanation other than vaso-occlusion, which requires therapy with parenteral opioids in a medical setting (Ballas et al.2010). Severe symptomatic chronic anemia was defined as a drop in hemoglobin by ≥2g/dL below the steady state. Data were analyzed using SPSS version 23 and summarized as simple descriptive statistics. Study endpoints were the proportion of individuals with SCD who met the definition of severe disease and were eligible for hydroxyurea. We also calculated the pain and ACS incidence rates.Results: The 639 HbSC participants had a mean age of 30.8years during the one-year study period, which was identical to that of the HbSS group. At least 8.5% of HbSC adults had ≥three acute pain episodes/ year, while 1.6% had ACS. No HbSC patient had severe symptomatic chronic anemia . In total, 10.0%(64/639) of patients with HbSC disease met the eligibility criteria for hydroxyurea therapy, compared to 24.1%(154/639) of patients with HbSS, p=<0.001. The pain and ACS incidence rates for the HbSC and HbSS individuals were [74.6; 95% CI(67.9-81.3) and 2.3; 95% CI(1.2-3.5)] events per 100 patient-years vs. [123.0; 95% CI(114.4-131.6) and 5.6; 95% CI(3.8-7.5)] events per 100 patient-years respectively. Also, 1.1%(7/639), 7.7%(49/639), 0.5%(4/639), and 4.4%(11/252) of patients with HbSC had papillary necrosis, AVN, stroke, and priapism, respectively while 8.5%(54/639) of patients with HbSS had proteinuria, Table 1. Only 0.9%(HbSC) and 2.3%(HbSS) took hydroxyurea during the study period.Conclusion: Based on ASH's evidence-based guidelines, in a large SCD clinic at an academic medical center in Ghana, 10.0% of HbSC adults meet the criteria for shared decision-making to consider starting hydroxyurea therapy in a clinical trial setting. The optimal dose of hydroxyurea that maximizes benefit and minimizes toxicity in adults with HbSC is yet to be determined. [Display omitted] DisclosuresAsare: ASH Global Research Award: Research Funding.

Protocol for a pilot feasibility, safety and efficacy study of artificially introducing an air-pleura interface for detection of pleural nodules by computed tomography: the AIR study

Abstract Background: Pleural effusions are common and can arise from many causes including primary or metastatic malignancies. Computed tomography (CT) is part of the routine workup for pleural effusions especially if pleural fluid analysis fails to show an underlying cause. CT can help detect pleural abnormalities such as thickening or nodules and allow imaging guided percutaneous biopsies. Otherwise surgical procedures are often required to obtain histological specimens but have inherent risks. The presence of air in the pleural cavity (eg with trapped lung) has been shown in a case series to enhance CT detection of pleural abnormalities. The AIR study is a prospective, pilot, proof-of-concept study to assess the feasibility and safety of instilling air intrapleurally to create an air-pleura interface during CT imaging, and the efficacy of this artificial pneumothorax in aiding CT detection of pleural abnormalities. Methods: This study will recruit 40 patients with suspected or proven malignant pleural effusions that have a chest tube (including indwelling pleural catheter) in-situ and no pre-existing radiological evidence of advanced pleural abnormalities. A standard CT scan with pleural phase contrast enhancement will be performed. Air will be instilled via the chest tube to introduce an artificial air-pleura interface and a second (non-contrast) CT chest scan will be performed in the prone position. The air will be immediately aspirated after the procedure. The aims of this study are to determine 1) the feasibility and safety of introducing an air-pleura interface using a pre-defined protocol and 2) its effectiveness in detecting additional pleural abnormalities. Discussion: The AIR study is the first study to evaluate the feasibility, safety and efficacy of creating an artificial air-pleura interface to enhance detection of pleural abnormalities by CT. Improvements in detection may inform imaging-guided tissue sampling, avoid more invasive tissue acquisition procedures, and add to the assessment of pleural disease burden.

The Effect of Aerobic Exercise on Concussion Recovery: A Pilot Clinical Trial.

The purpose of this study was to pilot safety and tolerability of a 1-week aerobic exercise program during the post-acute phase of concussion (14-25 days post-injury) by examining adherence, symptom response, and key functional outcomes (e.g., cognition, mood, sleep, postural stability, and neurocognitive performance) in young adults. A randomized, non-blinded pilot clinical trial was performed to compare the effects of aerobic versus non-aerobic exercise (placebo) in concussion patients. The study enrolled three groups: 1) patients with concussion/mild traumatic brain injury (mTBI) randomized to an aerobic exercise intervention performed daily for 1-week, 2) patients with concussion/mTBI randomized to a non-aerobic (stretching and calisthenics) exercise program performed daily for 1-week, and 3) non-injured, no intervention reference group. Mixed-model analysis of variance results indicated a significant decrease in symptom severity scores from pre- to post-intervention (mean difference = -7.44, 95% CI [-12.37, -2.20]) for both concussion groups. However, the pre- to post-change was not different between groups. Secondary outcomes all showed improvements by post-intervention, but no differences in trajectory between the groups. By three months post-injury, all outcomes in the concussion groups were within ranges of the non-injured reference group. Results from this study indicate that the feasibility and tolerability of administering aerobic exercise via stationary cycling in the post-acute time frame following post-concussion (14-25 days) period are tentatively favorable. Aerobic exercise does not appear to negatively impact recovery trajectories of neurobehavioral outcomes; however, tolerability may be poorer for patients with high symptom burden.

Dropless penetrating keratoplasty using a subconjunctival dexamethasone implant: safety pilot study

Background/aimRejection is the main cause of graft failure after penetrating keratoplasty (PK). Its prevention by repeated instillation of steroid eye-drops has not evolved in decades. Poor adherence and discontinuous nature...