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Programmed cell death protein-1 (PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. We generated PD-1 and T cell receptor (TCR) deficient mesothelin-specific CAR-T (MPTK-CAR-T) cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study. A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion. No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients. The best overall response was stable disease (2/15 patients). Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month. TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion. We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models. Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.

To construct an FDG PET/CT metabolic parameter-based model to predict early recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT). A total of 62 patients with HCC after LT were enrolled with a follow-up period of 1 year. Basic clinical, pathology, and laboratory data, CT features (CPLC), and PET metabolic parameters (CPLCP) were collected for model construction. A CPLC nomogram without metabolic parameters and a CPLCP nomogram with metabolic parameters were established. The net reclassification index (NRI) and integrated discrimination improvement (IDI) of the two models were calculated. The constructed model was compared with Milan criteria and University of California San Francisco (UCSF) criteria. The time-dependent area under the receiver operating characteristic curve (time-AUC) was used to compare the efficiency of the models, and the bootstrap method was used to for verification. Harrell’s concordance index (C-index) was used to evaluate the performance of these models. Decision curve analysis (DCA) was used to evaluate the clinical practicability of each model. Thirty out of 62 patients experienced a recurrence during the 1-year follow-up. BCLC stage (P = 0.009), MVI (P = 0.032), AFP (P = 0.004), CTdmax (P = 0.033), and MTV (P = 0.039) were the independent predictors. The CPLC nomogram and the CPLCP nomogram were established. Compared with the CPLC nomogram, the NRI of the CPLCP nomogram increased by 38.98% (95% CI = −18.77–60.43%) and the IDI increased by 4.40% (95% CI = −1.00–16.62%). The AUC value of the CPLCP nomogram was higher than those of Milan criteria and UCSF criteria in the time-AUC curve. Moreover, the CPLCP nomogram had a higher C-index (0.774) than other models. Finally, the DCA curve showed that clinical practicability of the CPLCP nomogram outperformed the Milan criteria and UCSF criteria. The CPLCP nomogram combining basic clinical data, pathology data, laboratory data, CT features, and PET metabolic parameters showed good efficacy and high clinical practicability in predicting the early recurrence of HCC after LT.

Processing nonconventional luminophores into ultralong room-temperature phosphorescence (RTP) materials with bright emission is extremely difficult but highly desired because of their intrinsic advantages together with the relatively weak spin-orbit coupling and rapid nonradiative decay in comparison to traditional aromatic compounds. Here, a straightforward heat treatment method was developed to promote the intersystem crossing efficiency and to suppress nonradiative pathways. A "dehydration-induced through-space conjugation" mechanism was proposed for explaining the activating of fluorescence and RTP of nonconventional luminophores. RTP materials with a phosphorescence quantum yield of 23.8% and emission lifetime of 1.3 s are developed. In addition, the emission color and lifetimes can be modulated by tuning the structure of ligands, which allows their applications in multilevel information encryption. These results open the door for designing highly efficient ultralong RTP materials, which also provides a clue to clarify the detailed emission profiles of RTP materials.

Lymphovascular invasion (LVI) impairs surgical outcomes in lung adenocarcinoma (LAC) patients. Preoperative prediction of LVI is challenging by using traditional clinical and imaging parameters. The purpose of this study was to investigate the value of the radiomics nomogram integrating clinical factors, CT features, and maximum standardized uptake value (SUVmax) to predict LVI and outcome in LAC and to evaluate the additional value of the SUVmax to the PET/CT-based radiomics nomogram.A total of 272 LAC patients (87 LVI-present LACs and 185 LVI-absent LACs) with PET/CT scans were retrospectively enrolled, and 160 patients with SUVmax ≥ 2.5 of them were used for PET radiomics analysis. Clinical data and CT features were analyzed to select independent LVI predictors. The performance of the independent LVI predictors and SUVmax was evaluated. Two-dimensional (2D) and three-dimensional (3D) CT radiomics signatures (RSs) and PET-RS were constructed with the least absolute shrinkage and selection operator algorithm and radiomics scores (Rad-scores) were calculated. The radiomics nomograms, incorporating Rad-score and independent clinical and CT factors, with SUVmax (RNWS) or without SUVmax (RNWOS) were built. The performance of the models was assessed with respect to calibration, discrimination, and clinical usefulness. All the clinical, PET/CT, pathologic, therapeutic, and radiomics parameters were assessed to identify independent predictors of progression-free survival (PFS).CT morphology was the independent LVI predictor. SUVmax provided better discrimination capability compared with CT morphology in the training set (P 0.001) and test set (P = 0.042). A total of 1409 CT and PET radiomics features were extracted and reduced to 8, 8, and 10 features to build the 2D CT-RS, 3D CT-RS, and the PET-RS, respectively. There was no significant difference in AUC between the 2D-RS and 3D-RS (P 0.05), and 2D CT-RS showed a relatively higher AUC than 3D CT-RS. The CT-RS, the CT-RNWOS, and the CT-RNWS showed good discrimination in the training set (AUC [area under the curve], 0.799, 0.796, and 0.851, respectively) and the test set (AUC, 0.818, 0.822, and 0.838, respectively). There was significant difference in AUC between the CT-RNWS and CT-RNWOS (P = 0.044) in the training set. Decision curve analysis (DCA) demonstrated the CT-RNWS outperformed the CT-RS and the CT-RNWOS in terms of clinical usefulness. Furthermore, DCA showed the PETCT-RNWS provided the highest net benefit compared with the PET-RNWS and CT-RNWS. PFS was significantly different between the pathologic and RNWS-predicted LVI-present and LVI-absent patients (P 0.001). Carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), pathologic LVI, histologic subtype, and SUVmax were independent predictors of PFS in the 244 CT-RNWS-predicted cohort; and CA125, NSE, pathologic LVI, and SUVmax were the independent predictors of PFS in the 141 PETCT-RNWS-predicted cohort.The radiomics nomogram, incorporating Rad-score, clinical and PET/CT parameters, shows favorable predictive efficacy for LVI status in LAC. Pathologic LVI and SUVmax are associated with LAC prognosis.

BACKGROUND To develop a model of malignant risk prediction of solitary pulmonary nodules (SPNs) using metabolic characteristics of lesions. METHODS A total of 362 patients who underwent PET/CT imaging from January 2013 to July 2017 were analyzed. Differences in the clinical and imaging characteristics were analyzed between patients with benign SPNs and those with malignant SPNs. Risk factors were screened by multivariate nonconditional logistic regression analysis. The self-verification of the model was performed by receiver operating characteristic (ROC) curve analysis, and out-of-group verification was performed by k-fold cross-validation. RESULTS There were statistically significant differences in age, maximum standardized uptake value (SUVmax ), size, lobulation, spiculation, pleural traction, vessel connection, calcification, presence of vacuoles, and emphysema between patients with benign nodules and those with malignant nodules (all P

The study describes an unusual case that a patient with previous history of adenocarcinoma of sigmoid colon who has developed chronic suppurative cholecystitis and peritonitis was misdiagnosed as metastasis. This case is presented to illustrate the importance of considering benign etiologies that may mimic metastatic disease when interpreting positron emmision tomography (PET)/CT scans.

PurposeTo develop and validate the radiomics nomogram that combines clinical factors and radiomics features to estimate overall survival (OS) in patients with clear cell renal cell carcinoma (ccRCC), and assess the incremental value of radiomics for OS estimation.Materials and MethodsOne hundred ninety-four ccRCC cases were included in the training cohort and 188 ccRCC patients from another hospital as the test cohort. Three-dimensional region-of-interest segmentation was manually segmented on multiphasic contrast-enhanced abdominal CT images. Radiomics score (Rad-score) was calculated from a formula generated via least absolute shrinkage and selection operator (LASSO) Cox regression, after which the association between the Rad-score and OS was explored. The radiomics nomogram (clinical factors + Rad-score) was developed to demonstrate the incremental value of the Rad-score to the clinical nomogram for individualized OS estimation, which was then evaluated in relation to calibration and discrimination.ResultsRad-score, calculated using a linear combination of the 11 screened features multiplied by their respective LASSO Cox coefficients, was significantly associated with OS. Calibration curves showed good agreement between the OS predicted by the nomograms and observed outcomes. The radiomics nomogram presented higher discrimination capability compared to clinical nomogram in the training (C-index: 0.884; 95% CI: 0.808–0.940 vs. 0.803; 95% CI: 0.705–0.899, P < 0.05) and test cohorts (C-index: 0.859; 95% CI: 0.800–0.921 vs. 0.846; 95% CI: 0.777–0.915, P < 0.05).ConclusionsThe radiomics nomogram may be used for predicting OS in patients with ccRCC, and radiomics is useful to assist quantitative and personalized treatment.

To develop and validate a radiomics nomogram for preoperative differentiating renal angiomyolipoma without visible fat (AML.wovf) from homogeneous clear cell renal cell carcinoma (hm-ccRCC). Ninety-nine patients with AML.wovf (n = 36) and hm-ccRCC (n = 63) were divided into a training set (n = 80) and a validation set (n = 19). Radiomics features were extracted from corticomedullary phase and nephrographic phase CT images. A radiomics signature was constructed and a radiomics score (Rad-score) was calculated. Demographics and CT findings were assessed to build a clinical factors model. Combined with the Rad-score and independent clinical factors, a radiomics nomogram was constructed. Nomogram performance was assessed with respect to calibration, discrimination, and clinical usefulness. Fourteen features were used to build the radiomics signature. The radiomics signature showed good discrimination in the training set (AUC [area under the curve], 0.879; 95%; confidence interval [CI], 0.793–0.966) and the validation set (AUC, 0.846; 95% CI, 0.643–1.000). The radiomics nomogram showed good calibration and discrimination in the training set (AUC, 0.896; 95% CI, 0.810–0.983) and the validation set (AUC, 0.949; 95% CI, 0.856–1.000) and showed better discrimination capability (p

Purpose: The prognostic significance of ypN0 rectal cancer with comparison to pN0 disease still remains poorly defined. This study aimed to compare the prognosis of ypN0 and pN0 rectal cancer.Methods: Eligible patients were identified from the SEER18 registries research database (the latest data up to date was on April 15, 2019). Propensity score (PS) matching was usually performed to reduce the imbalance and potential confounding that were introduced by inherent differences between the groups. The cause-specific survival (CSS) was analyzed to evaluate the prognostic prediction of ypN0 and pN0 groups using the Kaplan–Meier method with the log-rank test. Cox proportional hazard model was also used to identify independent prognostic variables.Results: In total, 26,832 patients diagnosed with pN0 or ypN0 rectal cancer were confirmed as the final cohort, including 7,237 (27.0%) patients with radiation and 19,595 (73.0%) patients without radiation prior to surgery. The median follow-up time was up to 81 months. After adjusting for other prognostic factors, neoadjuvant radiotherapy was not an independent prognostic variable of CSS (HR = 1.100, 95%CI = 0.957–1.265, P = 0.180, using pN0 group as the reference).Conclusions: ypN0 rectal cancer was strongly associated with worse pathological diagnoses compared with pN0 rectal cancer, contributing to worse oncologic outcomes. However, the receipt of neoadjuvant chemoradiotherapy was not an independent prognostic factor of worse prognosis in pathological node-negative patients. Our study could give guidance to the treatment of ypN0 rectal cancer.

Objective We conducted this large population-based study to re-evaluate the survival paradox between stage IIB/C and stage IIIA colon cancer based on the newest staging criteria. Methods Colon cancer patients were recruited from the Surveillance, Epidemiology, and End Results (SEER) database using SEER*Stat software (version 8.3.4) with strict inclusion criteria. We used Chi-square test to compare categorical variables between patients diagnosed with stage IIB/IIC and stage IIIA colon cancer. Survival probabilities were then assessed using the Kaplan-Meier method. Cox proportional hazards models were used to analyze hazard ratios (HRs) and 95% confidence intervals (CIs) of clinicopathologic characteristics in stage IIB/IIC and stage IIIA colon cancer patients. Results In the current study, a total of 9,227 eligible colon cancer patients were collected from the SEER database between 2010 and 2015. It was found that stage IIIA had 66.4% decreased risk of colon cancer-specific mortality compared with stage IIB (HR = 0.336, 95%CI = 0.286-0.394 for stage IIIA, P < 0.001, using stage IIB as the reference) after the adjustment for other known prognostic factors. And T1N2a colon cancer had significantly lower 5-year overall survival (OS) rate compared with T2N1 disease (74.7% vs. 57.1%, P = 0.018). Conclusions Our study confirmed the existence of survival paradox between stage IIB/IIC and stage IIIA colon cancer based on the newest staging criteria. What is more, the subgroup analyses revealed that T1N2a had the least influence on the survival paradox. N2a colon cancer seemed to be associated with worse prognosis than T2 disease, which would give us a better understanding of tumor biology of colon cancer and be conducive to the refinement of individualized treatment regimens in stage III disease.

Smart window is a promising green technology with feature of tunable transparency under external stimuli to manage light transmission and solar energy. However, more functions based on the intelligent management of the solar spectrum need to be integrated into present smart windows. In this work, a dual-function smart window is fabricated by pairing the luminescent switch with the electrochromic window. The dual function is based on a single fluorine doped tin oxide coated glass functionalized with tungsten oxide and copper nanocluster, among which tungsten oxide serves as an electrochromic material and copper nanocluster provides photoinduced luminescence. Along with the regulation of the visible light based on the electrochromism of the window, the luminescence can be finely switched on and off, which establishes a pair of reversible states ("on" and "off") for the dual-function smart window. The contrast between two states reaches 88%. Furthermore, the manipulation of dual-function smart window is highly reversible with a short response time of 12.6 s. This prototype of dual-function smart window paves the way for developing multifunctional smart windows by integrating different functional materials into one smart window based on the rational management of the solar spectrum.

BACKGROUND This study aimed to assess the value of contrast-enhanced ultrasound (CEUS) in the diagnosis and prognosis of lymphoma based on PET-CT. MATERIAL AND METHODS Our study included 88 superficial lymph nodes and 63 patients who underwent ultrasound-guided biopsy or surgery for pathology from October 2015 to March 2017. All lymph nodes were assessed by CEUS and PET-CT. CEUS and PET-CT parameters were recorded, including arrive time (AT), time to peak (TTP), base intensity (BI), peak intensity (PI), ascending slope (AS), descending slope (DS), area under the TIC curve (AUC), maximum standardized uptake value (SUVmax), and mean standardized uptake value (SUVmean). Pearson's correlation was used to assess the associations of CEUS and PET-CT parameters. RESULTS Of the 88 lymph nodes examined,12 were Hodgkin's lymphoma (HL) and76 were non-Hodgkin's lymphoma (NHL). The variations of CEUS dose parameters (ΔI, AUC, and AS) were positively correlated with PET-CT results (SUVmax and TLG). Correlation coefficients were 0.609, 0.518, 0.456, 0.630, 0.593, and 0. 532, respectively. The remaining time values (AT, TP, and ΔT) were negatively associated with PET-CT results. Correlation coefficients were -0.239, -0.272, -0.284and -0.377, -0.391, and -0.320, respectively. CONCLUSIONS Quantitative CEUS data were correlated with PET-CT values, with potential use in the diagnosis of lymphoma.

The battery and the screen are the two components occupying the largest volume in many electronic devices. Integrating them together will eventually engender a great reduction of device size. The current study demonstrates a promising strategy towards ultimate-compact electronic devices. Herein, a photoluminescent microbattery with reasonable light-permeability and hazing ability is developed. This aqueous Zn–MnOx/polypyrrole based microbattery features a flat architecture with interdigitated electrodes and utilizes a photoluminescent gelatin based electrolyte by embedding colloidal CdTe quantum dots. Furthermore, borax is introduced into the electrolyte as an additive, which effectively prevents luminescence quenching of the quantum dots and simultaneously enhances the electrochemical performance of the microbattery. A high device energy density of 21 mW h cm−3 is obtained. One step further, a three-primary-color (red–green–blue, RGB) photoluminescent microbattery array is assembled, endowing the battery with the function of a color filter and realizing a battery-in-screen configuration.

Severe cytokine release syndrome (CRS) and neurotoxicity following chimeric antigen receptor T cell (CAR-T) therapy can be life-threatening in some cases, and management of those toxicities is still a great challenge for physicians. Researchers hope to understand the pathophysiology of CRS and neurotoxicity, and identify predictive biomarkers that can forecast those toxicities in advance. Some risk factors for severe CRS and/or neurotoxicity including patient and treatment characteristics have been identified in multiple clinical trials of CAR-T cell therapy. Moreover, several groups have identified some predictive biomarkers that are able to determine beforehand which patients may suffer severe CRS and/or neurotoxicity during CAR-T cell therapy, facilitating testing of early intervention strategies for those toxicities. However, further studies are needed to better understand the biology and related risk factors for CRS and/or neurotoxicity, and determine if those identified predictors can be extrapolated to other series. Herein, we review the pathophysiology of CRS and neurotoxicity, and summarize the progress of predictive biomarkers to improve CAR-T cell therapy in cancer.

Solar steam generation is a promising application for utilizing exhaustless solar energy for steam generation, desalination, sterilization, and water treatment. Over the past several decades, scientists have made many attempts to design rational structures to promote evaporation efficiency including optimizing optical absorption, photothermal conversion, heat localization, and water transportation. Here, an efficient solar steam generation device was fabricated through decorating a nonstoichiometric W18O49 mesocrystal, as a solar light-to-heat material, onto a hydrophilic PTFE membrane. Nonstoichiometric W18O49 mesocrystals were incorporated into the membrane, and confirmed by the XRD, SEM, TEM, and XPS characterizations, which can transfer light to heat after absorbing sunlight and lead to water evaporation on a local area of a membrane. The structure of the solar steam generation device was confirmed by the results of SEM and contact angle measurements, which insured the solar steam generation device self-floated on top of water, thereby providing a continuous water supply to the local area heated by the W18O49 mesocrystals from bulk water. Under one sun illumination, the evaporated water mass loss reached 1.13 kg m−2 for a membrane thickness of M/A = 9.83 g m−2 after 1 h irradiation, and the membrane showed a high efficiency of 80.7%. Limit of water evaporation rate for the W18O49@PDMS mesocrystal membrane was further calculated to be 1.15 kg m−2 after 1 h one-sun irradiation, with a limit of efficiency of 82.0%. The salinities of simulated seawater reduced to levels far below the World Health Organization's (WHO) standard after desalination. The rational design enhancing evaporation performance also provides enlightenment for further practical applications of solar steam generation technology.

Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have yielded unprecedented efficacy in B cell malignancies, most remarkably in anti-CD19 CAR-T cells for B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate. However, tumor antigen escape has emerged as a main challenge for the long-term disease control of this promising immunotherapy in B cell malignancies. In addition, this success has encountered significant hurdles in translation to solid tumors, and the safety of the on-target/off-tumor recognition of normal tissues is one of the main reasons. In this mini-review, we characterize some of the mechanisms for antigen loss relapse and new strategies to address this issue. In addition, we discuss some novel CAR designs that are being considered to enhance the safety of CAR-T cell therapy in solid tumors.

Introduction To further improve efficacy and duration of response of CAR-T therapy for Relapsed/Refractory Multiple Myeloma (R/R MM), we have designed a dual FasT CAR-T targeting both B cell maturation antigen (BCMA), a well-established MM target, and CD19, which is expressed on MM cells and their progenitors. Here we report early results from the first-in-human multicenter clinical study (NCT04236011; NCT04182581) to determine safety, pharmacokinetics (PK) and efficacy of BCMA-CD19-directed FasT CAR-T (GC012F) in patients with R/R MM. Methods The BCMA-CD19 dual CAR was constructed by linking BCMA and CD19 scFv, joined by a CD8 hinge, transmembrane domain, co-stimulatory domain and CD3z. Peripheral blood (PB) mononuclear cells were obtained by leukapheresis, T cells were isolated and CAR-T cells were manufactured (FasT CAR platform). From September 2019 to April 2020, we enrolled 16 heavily pretreated R/R MM patients (Age range 27-71), with a median of 5 prior lines of therapies (range 2-7), 93.8% (15/16) of these patients were high risk as defined by mSMART criteria, 5 had extramedullary disease. 4 out of 16 patients had received prior anti CD38 therapy, 93.8% (15/16) patients had received prior IMiD, all patients received at least 1 prior PI and corticosteroids with 3 patients being primary refractory to last therapy. Prior to CAR-T infusion patients received a conditioning regimen over 3 days of 30 mg/m2/d fludarabine and 300 mg/m2/d cyclophosphamide. CAR-T cells were administered in a single infusion at 3 dose levels 1x105/Kg (DL1) (1 patients), 2x105/Kg (DL2) (9 patients) and 3x105/Kg (DL3) (6 patients). Results As of July 17th 2020, all 16 patients were evaluable for response assessment, 15 out of 16 patients responded to treatment (ORR 93.8%) in all dose levels with the earliest response observed at day 28. Best response to date is MRD- CR/sCR in 9/16 patients (56.3%). In DL3 100% (6/6) of patients achieved sCR, 3 at data cut off had been confirmed by PET-CT. In all response evaluable patients, 78.6% (11/14) were MRD- by flow at month 1, and 100% at month 3 (11/11) and 6 (10/10) (sensitivity by flow cytometry measured at 10-4 in 7 patients, and at 10-6 in 9 patients tested by EuroFlow with at least 1.08x107 cells analyzed). At data cut off, the median follow up time was 7.3 months, the longest follow up was 10 months post infusion. CAR-T PK in PB was monitored by qPCR and flow cytometry. The CAR-T median proliferation peak was reached on Day10 (Day8-Day14), and the median peak copy number was 140,982 (16,011-374,346) copies /ug DNA. GC012F showed an acceptable safety profile with 14 out of 16 patients experiencing a cytokine release syndrome (CRS) grade 1-2 (n=14, 87.5%) and 2 grade 3 (n=2, 12.5%). The median duration of CRS was 4 days (1-8 days). No neurotoxicity of any grade was observed. One patient (DL2) presented with fever and died shortly after Day 78 of unknown cause during the COVID-19 Pandemic. Two patients had progression of extramedullary disease while achieving MRD negativity at month 1 and 3, respectively. At landmark analysis at 6 months, all patients in DL3 had achieved and maintained MRD- sCR including patients heavily pretreated including Daratumumab - among them 83.3% (5/6) patients in DL3 had high risk features according to mSMART criteria, and 5 out of 6 patients in DL3 were assessed by 10-6 Euroflow for MRD. The study is still enrolling patients and we will continue to be monitoring safety and efficacy including duration of response. Conclusion The data of BCMA-CD19 dual FasT CAR-T showed an early and high response rate with 93.8% ORR to date with a promising early high MRD-sCR rate in the highest dose level DL3 (100%) which was sustained with a median duration of follow up of 7.3 months at cut off. The data shows very promising activity of the BCMA-CD19 dual FasT CAR-T with a favorable safety profile in R/R MM patients. 93.8% (15/16) of the treated patients exhibited high risk features - a specifically difficult to treat patient population which remains a high unmet medical need in Multiple Myeloma. This data indicates that BCMA-CD19 dual FasT CAR-T (GC012F) may present an effective new treatment option for patients with R/R MM including those with high-risk features who failed multiple prior therapies including anti-CD38. The study is still ongoing and enrolling patients, we will update the results as they become available. Disclosures Zhao: Gracell Biotechnologies Ltd: Current Employment. Han:Gracell Biotechnologies Co., Ltd.: Current Employment. Chen:Gracell Biotechnologies Ltd: Current Employment. Xu:Gracell Biotechnologies Ltd: Current Employment. Zhang:Gracell Biotechnologies Ltd: Current Employment. He:Gracell Biotechnologies Co., Ltd.: Current Employment. Shi:Gracell Biotechnologies Ltd: Current Employment. Han:Gracell Biotechnologies Co., Ltd.: Current Employment. Ye:Gracell Biotechnologies Co., Ltd.: Current Employment. Wang:Gracell Biotechnologies Ltd: Current Employment. Liu:Gracell Biotechnologies Co., Ltd.: Current Employment. Shen:Gracell Biotechnologies Ltd: Current Employment. Cao:Gracell Biotechnologies Ltd: Current Employment. Sersch:Gracell Biotechnologies Co., Ltd.: Current Employment.

Introduction Multiple issues arise for a wider application of chimeric antigen receptor (CAR) T cell therapy including manufacturing time and antigen escape. Here we report data on an anti-CD19/CD22 dual CAR-T (GC022F) therapy based on a novel manufacturing platform, from a phase I clinical study (NCT04129099) in treating patients with B-cell acute lymphoblastic leukemia (B-ALL). Methods Peripheral blood (PB) mononuclear cells were obtained by leukapheresis. T-cells were separated and transduced with lentivirus that encodes a CD19/CD22 directed 4-1BB: ζ CAR. GC022F cells were manufactured using a novel FasTCARTM platform which takes 24 hours, while the conventional CD19/CD22 dual CAR-T (GC022C) cells used as parallel control in the preclinical study were manufactured by conventional process which typically takes 9-14 days. The phase I dose escalation study was initiated to explore the safety and efficacy of GC022F in patients with B-ALL. All patients received a conditioning regimen of IV fludarabine (25mg/m2/d) and cyclophosphamide (250mg/m2/d) for 3 days prior to GC022F infusion. Results When compared with the GC022C, GC022F cells showed 1) less exhaustion as indicated by lower percentage of PD-1+LAG3+ cells following co-culturing with tumor cells, 2) younger phenotypes as demonstrated by more abundant T central memory cells (Tcm; CCR7+CD45RA+ or CD45RO+CD62L+), 3) higher expansion fold at in vitro culture, and 4) high anti-leukemia efficacy in mice model (Fig.1). Comparing in vivo efficacy of GC022F with GC022C cells at lower doses, GC022F treatment were more potent and could reduce tumor burden earlier and faster, and led to significantly prolonged overall survival of the experimental animals. From Nov. 2019 to Jun. 2020, 9 children and 1 adult with B-ALL were enrolled and infused with GC022F, 2 in low-dose (6.0×104/kg), 7 in medium dose (1.0-1.5×105/kg), 1 in high-dose (2.25×105/kg). Patients' median observation time was 99 (14-210) days on the day of cut-off. Characteristics of enrolled patients are shown in Table 1. The median age was 10 (3-48) years, and the median bone marrow (BM) blasts were 21.0 (0.1-63.5) % at enrollment. Three patients had prior CD19 CAR-T cell therapy history and one of whom had prior allogeneic hematopoietic stem cell transplantation (allo-HSCT). After infusion, the median peak of circulating CAR-T cell copy number was 2.29 ×105 copies/µg genomic DNA (0.0014-5.66), which occurred around day 14 (day10 - day 28). Importantly, GC022F persisted well in PB with a median of 2.40×105 copies/µg genomic DNA (0.75-3.98) on day 28 in 5 of 9 patients with available 4 weeks of cellular kinetics data. GC022F exerted a superior safety profile with no observed grade ≥ 3 cytokine release syndrome (CRS) and neurotoxicity in all patients. Among those 6 patients with CRS, only 1 at high dose level had grade 2 CRS; only 1 developed grade 1 neurotoxicity. After GC022F infusion, 6/6 patients with BM blasts > 5% at enrollment achieved complete remission (CR) by day 28, 5/6 with minimal residual disease (MRD)-negative CR. For those 4 patients with MRD positive disease at enrollment, 3 became MRD-negative CR by day 28, 1 had persist MRD positive disease and withdrew from the study by 2 weeks. Five of 8 MRD-negative CR patients subsequently made a choice to pursue consolidation allo-HSCT with a median time interval of 57 (48-71) days post GC022F infusion and all have remained in MRD-negative CR except 1 died from graft-versus-host disease (GVHD) and infection 143 days post GC022F infusion. Of the other 3 patients without allo-HSCT, 2 relapsed with CD19+/CD22+ disease at 12-16 weeks follow-up, including the patient with prior history of CD19 CAR-T treatment and transplant. Conclusion This study demonstrated that anti-CD19/CD22 dual CAR T-cells could be successfully manufactured by FasTCARTM technology in 24 hours, with younger and less exhausted phenotypes. Moreover, the Dual FasTCAR-T cells showed more potent efficacy in xenograft mouse model compared to the conventional dual CAR-T cells. Our clinical data demonstrate that GC022F is safe and efficacious in treating patients with CD19+CD22+ B-ALL. More data on additional patients and longer observation time are needed to further evaluate CD19/CD22 dual FasTCAR-T cell product. Disclosures Cai: Gracell Biotechnologies Ltd: Current Employment. Wang:Gracell Biotechnologies Ltd: Current Employment. Chen:Gracell Biotechnologies Ltd: Current Employment. Ye:Gracell Biotechnologies Co., Ltd.: Current Employment. He:Gracell Biotechnologies Co., Ltd.: Current Employment. Cao:Gracell Biotechnologies Ltd: Current Employment. Sersch:Gracell Biotechnologies Co., Ltd.: Current Employment.

Objective: To evaluate the value of 2-dimensional (2D) and 3-dimensional (3D) computed tomography texture analysis (CTTA) models in distinguishing fat-poor angiomyolipoma (fpAML) from chromophobe renal cell carcinoma (chRCC). Methods: We retrospectively enrolled 32 fpAMLs and 24 chRCCs. Texture features were extracted from 2D and 3D regions of interest in triphasic CT images. The 2D and 3D CTTA models were constructed with the least absolute shrinkage and selection operator algorithm and texture scores were calculated. The diagnostic performance of the 2D and 3D CTTA models was evaluated with respect to calibration, discrimination, and clinical usefulness. Results: Of the 177 and 183 texture features extracted from 2D and 3D regions of interest, respectively, 5 2D features and 8 3D features were selected to build 2D and 3D CTTA models. The 2D CTTA model (area under the curve [AUC], 0.811; 95% confidence interval [CI], 0.695-0.927) and the 3D CTTA model (AUC, 0.915; 95% CI, 0.838-0.993) showed good discrimination and calibration ( P > .05). There was no significant difference in AUC between the 2 models ( P = .093). Decision curve analysis showed the 3D model outperformed the 2D model in terms of clinical usefulness. Conclusions: The CTTA models based on contrast-enhanced CT images had a high value in differentiating fpAML from chRCC.

Background Chimeric antigen receptor T (CAR-T) cell therapy simultaneously against CD19 and CD22 is an attractive strategy to address the antigen escape relapse after CD19-directed CAR-T cell therapies. However, the potential of optimizing the durability of remission by this approach in patients with B cell acute lymphoblastic leukemia (B-ALL) remains a critical unanswered question so far. Case presentation We treated an adult patient with relapsed and refractory B-ALL after haploidentical hematopoietic stem cell transplantation (HSCT) by administering haploidentical CAR-T cells targeting both CD19 and CD22 following preparative lymphodepleting chemotherapy. This patient has remained in minimal residual disease-negative remission for more than 14 months and has been tapered off graft versus host disease prophylaxis. Conclusions CAR simultaneously targeting CD19 and CD22 has the potential of inducing long-term remission in patients with B-ALL. Electronic supplementary material The online version of this article (10.1186/s13045-019-0741-6) contains supplementary material, which is available to authorized users.

Kimura's disease is a clinically rare, chronic, benign lymphoproliferative disorder of unknown etiology. A 36-year-old man presented with painless axillary swelling, which was suspected as lymphoma. PET/CT was performed for staging. The images showed multiple foci of increased activity in bilateral axillary and right inguinal lymph nodes. Laboratory tests revealed an increased eosinophil ratio and eosinophil count. Pathological examination from dissected axillary lymph nodes was consistent with Kimura's disease.

Desmoplastic small round cell tumors (DSRCTs) are rare and aggressive malignant tumors. The aim of the present study was to analyze computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET)/CT imaging features of intra-abdominal desmoplastic DSRCT, and investigate the association of these features with histopathological results. The present study was a retrospective investigation of 4 patients with DSRCT. All patients underwent CT and dynamic CT, and 1 additionally underwent FDG-PET/CT scanning. Following a tumor resection, routine hematoxylin and eosin staining, and immunostaining, were performed and evaluated. Multiple large abdominopelvic masses were identified in all 4 patients; however, no indications of their site of origin were demonstrated. CT revealed soft-tissue masses with patchy foci of hypodense lesions. Contrast-enhanced CT revealed slightly or moderately heterogeneous enhancement of the lesions. Other observations from these patients included calcification (n=2), peritoneal seeding (n=3), hepatic metastasis (n=3), retroperitoneal lymphadenopathy (n=3) and ascites (n=2). FDG-PET/CT revealed multiple nodular increased FDG uptake in the abdominopelvic masses, and in the liver and peritoneum in 1 case. Intra-abdominal DSRCT demonstrated significant diagnostic characteristics on plain and contrast-enhanced CT. Multiple, bulky soft-tissue masses inside the peritoneal cavity, particularly in male adolescents and young adults, should be considered as potential cases of DSRCT. FDG-PET/CT techniques may be utilized to aid the staging of tumors.

We explore two strategies to improve the performance of hybrid solar cells fabricated using poly(3-hexylthiophene) (P3HT) and colloidal PbSe nanocrystals, which have reached a 1 sun power conversion efficiency of 2.9%. Using an atomic passivation strategy towards inorganic ligand-capped nanocrystals, the electron mobilities of PbSe quantum dot films are improved from 1.95 × 10−6 cm2 V−1 s−1 to 1.15 × 10−5 cm2 V−1 s−1. Employing ultrasmall PbSe nanocrystals allows us to adjust their bandgaps towards the type II heterojunction with P3HT, thus achieving efficient charge separation and transfer between the polymer/inorganic constituents. The device performance dropped to half after 10 days' storage, and the P3HT/PbSe interface was found to play a primary role in this efficiency degradation.

In this study, the characteristics of the deformation and failure of the mine floor and the influence of the thickness of the mined seam on mine floor deformation are examined in the context of a mine with soft coal, soft mine floor, hard mine roof and varying thickness of the coal seam. The geological and mining conditions at the Working Face 23,301 of the Yungaishan No. 2 Coal Mine are taken into consideration when using the strain induction method to determine the depth of the failure zone which is found to be between 11.6 and 15.5 m based on strain measurements at different depths of the mine floor. The strain increments show that the distance before periodic weighting occurs is between 13.3 and 14.2 m, which is basically in agreement with the observed ground pressure from mining. On this basis, the geological profile of the working face is used in the development of a 3D numerical model. This numerical model is used to determine the depth of the failure zone which is at a depth of about 15 m, which is basically in agreement with the field measurements. It is found that the failure of the floor has obvious zonation. At the same time, the effect of different thicknesses of the mined coal seams on the degree of deformation of the mine floor is discussed with the other conditions unchanged. The results show that the thickness of the mined seam has little effect. That is also consistent with the results of multivariate regression equations and correlation analysis which show that the depth of the failure zone is less impact correlated with the thickness of the mined seam based on 65 sets of measurements of the depth of the failure zone. The research findings are an important practical reference source for preventing water inrush through the mine floor, and determining support strategies for mines.

Lymphovascular invasion (LVI) impairs surgical outcomes in lung adenocarcinoma (LAC) patients. Preoperative prediction of LVI is challenging by using traditional clinical and imaging factors. The purpose of this study was to evaluate the value of two-dimensional (2D) and three-dimensional (3D) CT texture analysis (CTTA) in predicting LVI in LAC.A total of 149 LAC patients (50 LVI-present LACs and 99 LVI-absent LACs) were retrospectively enrolled. Clinical data and CT findings were analyzed to select independent clinical predictors. Texture features were extracted from 2D and 3D regions of interest (ROI) in 1.25 mm slice CT images. The 2D and 3D CTTA signatures were constructed with the least absolute shrinkage and selection operator algorithm and texture scores were calculated. The optimized CTTA signature was selected by comparing the predicting efficacy and clinical usefulness of 2D and 3D CTTA signatures. A CTTA nomogram was developed by integrating the optimized CTTA signature and clinical predictors, and its calibration, discrimination and clinical usefulness were evaluated.Maximum diametre and spiculation were independent clinical predictors. 1125 texture features were extracted from 2D and 3D ROIs and reduced to 11 features to build 2D and 3D CTTA signatures. There was significant difference (P 0.001) in AUC (area under the curve) between 2D signature (AUC, 0.938) and 3D signature (AUC, 0.753) in the training set. There was no significant difference (P = 0.056) in AUC between 2D signature (AUC, 0.856) and 3D signature (AUC, 0.701) in the test set. Decision curve analysis showed the 2D signature outperformed the 3D signature in terms of clinical usefulness. The 2D CTTA nomogram (AUC, 0.938 and 0.861, in the training and test sets), which incorporated the 2D signature and clinical predictors, showed a similar discrimination capability (P = 1.000 and 0.430, in the training and test sets) and clinical usefulness as the 2D signature, and outperformed the clinical model (AUC, 0.678 and 0.776, in the training and test sets).2D CTTA signature performs better than 3D CTTA signature. The 2D CTTA nomogram with the 2D signature and clinical predictors incorporated provides the similar performance as the 2D signature for individual LVI prediction in LAC.

3038 Background: Our previous phase I study with MPTK-CAR-T (mesothelin-directed 28ζ CAR-T cells with PD-1 and TCR disruption by CRISPR-Cas9 system) demonstrated feasibility and safety of CRISPR-mediated PD-1 inactivation in CAR-T cells, and suggested the natural TCR is beneficial for the proliferation of CAR-T cells in solid tumors. Based on these observations, we initiated a pilot dose escalation study to investigate mesothelin-directed CAR-T cells with only PD-1 disruption by CRISPR (termed as GC008t) in patients with mesothelin-positive advanced solid tumors (NCT03747965). Methods: On the data cut-off date (Jan 20, 2020), nine patients (6 pancreatic cancers, 2 ovarian cancers, 1 colorectal cancer) were treated (5 received ≥12 numbers of therapy), three in cohort 1 (0.1-0.2×107/kg), four in cohort 2 (0.5-1.0×107/kg), two in cohort 3 (2.5-5×107/kg). Eight of the 9 patients received lymphodepletion regimen of cyclophosphamide and nab-paclitaxel with or without gemcitabine. Four of the 9 patients received repeat infusions of GC008t per protocol. Results: Comparable proliferation capacity was observed in vitro between the MPTK-CAR-T and the GC008t products. The mean PD-1 surface expression in cell products was 0.5% (range, 0.2%-0.9%). GC008t infusions were well tolerated with no observed on-target/off-tumor toxicity, autoimmune activity. Only two patients in cohort 3 developed grade 1 CRS with fever and rash. Circulating GC008t expanded with a peak at day 7-14 and became undetectable by qPCR beyond 1 month. The mean peak levels of circulating CAR-T cells between GC008t and MPTK-CAR-T at similar dose level were not statistically significant. Failure of GC008t engraftment after repeat infusion was observed in 2 out of 4 patients. The best response of the 7 evaluable patients was stable disease in 4 and partial response in 2 patients (dosed ≥ 1×107/kg) with PFS of 80 and 160 days. Conclusions: Phase I trial of GC008t further establishes that genetic inactivation of PD-1 in CAR-T cells by CRISPR is feasible and safe. The expansion and persistence of CAR-T cells with PD-1 disruption is not improved significantly even in the setting of natural TCR and lymphodepletion. Future endeavors are needed to improve the clinical efficacy of CAR-T therapy in the treatment of solid tumor. Clinical trial information: NCT03747965 .

The liver is an important reference organ for positron emission tomography/ computed tomography (PET-CT) examination using 18F-fluorodeoxyglucose (18F-FDG). However, 18F-FDG uptake by the liver is affected by many factors. We therefore investigated the effect of hepatic function on 18F-FDG uptake in the liver.A retrospective analysis of data on the hepatic function and the mean liver standardized up-take value (SUV) of 18F-FDG uptake in the liver during PET-CT examination of 500 (381 males, 119 females, aged 27-71) physical examinees.The mean liver SUV was 1.88 ± 0.20. The correlation coefficient and partial correlation coefficient for age, the levels of conjugated bilirubin, globulin, AST and the mean liver SUV were statistically significant (r' = 0.119, -0.197, -0.089 and 0.151, all p0.05). Multiple linear regression analysis showed that age and the levels of conjugated bilirubin, globulin and aspartate amino-transferase (AST) were independent factors that influenced changes in the mean liver SUV (β = 0.008, -0.025, -0.151 and 0.005, all p0.05). The globulin level had the biggest predictive ability (β' = -0.151, p0.05).The uptake of 18F-FDG in the liver was influenced by some liver function indexes. The levels of conjugated bilirubin, globulin and AST were independent factors for predicting changes in the uptake of 18F-FDG in the liver. Liver function test results should be combined with an evaluation of the metabolic activity of the liver.ZIEL:: Die Leber ist ein wichtiges Referenzorgan für die Positronen-Emissions-Tomographie/ Computertomographie (PET/CT) unter Einsatz vonRetrospektive Analyse von Daten zur Leberfunktion und zum standardisierten Aufnahmewert (SUV) derDer mittlere Leber-SUV lag bei 1,88 ± 0,20. Korrelationskoeffizient und partieller Korrelationskoeffizient für Alter, Serumspiegel von konjugiertem Bilirubin, Globulin, AST und mittleren Leber-SUV waren statistisch signifikant (r’ = 0,119, –0,197, –0,089 und 0,151, alle p0,05). Die multiple lineare Regressionsanalyse ergab, dass Alter und Serumspiegel von konjugiertem Bilirubin, Globulin und Aspartat-Aminotransferase (AST) als unabhängige Faktoren Veränderungen im mittleren Leber-SUV beeinflussten (β=0,008, –0,025, –0,151 und 0,005, alle p0,05). Der Globulin-Spiegel hatte dabei die größte prognostische Aussagekraft (β’ = –0,151, p0,05).Die 18F-FDG-Aufnahme in der Leber wurde durch einige Indikatoren der Leberfunktion beeinflusst. Die Serumspiegel von konjugiertem Bilirubin, Globulin und AST waren unabhängige Faktoren für die Vorhersage von Veränderungen der 18F-FDG-Aufnahme in der Leber. Die Leberwerte sollten daher mit einer Beurteilung der metabolischen Leistung der Leber kombiniert werden.

A cellulose paper is used impregnated with light-emitting CdTe nanocrystals and carbon dots, and filled with a polyurethane to fabricate uniform transparent composite films with bright photoluminescence of red (R), green (G), and blue (B) (RGB) colors. A building brick-like assembly method is introduced to realize RGB multicolor emission patterns from this composite material. By sectioning out individual pixels from monochrome-emissive composite sheets, the advantage of the self-healing properties of polyurethane is taken to arrange and weld them into a RGB patterned fabric by brief exposure to ethanol. This provides an approach to form single layer RGB light-emitting pixels, such as potentially required in the display applications, without the use of any lithographic or etching processing. The method can utilize a wide range of different solution-based kinds of light-emitting materials.

The aim of the study was to evaluate clinical value of contrast-enhanced ultrasonography (CEUS) and PET/CT for assessment of extramedullary lymphoma, using histopathology as reference standard.A total of 63 patients with histopathologically-confirmed extramedullary lymphoma who had underwent CEUS and PET/CT examinations of suspicious lymph nodes included in the study. CEUS patterns and parameters (arrival time, peak time and intensity, base intensity, area under the time-intensity curve, ascending and descending slopes) and PET/CT parameters including maximum standardized uptake value, mean standardized uptake value, and metabolic tumor volume (MTV) were evaluated. Patients were classified into Hodgkin lymphomas (HL), non-Hodgkin lymphomas (NHL), early (stage I and II) and advanced (stage III and IV) lymphoma, B cells and T cells lymphoma, and aggressive and indolent lymphoma. The differences between the two independent samples were compared using non-parametric rank and inspection, P 0.05 was considered statistically significant. The optimal cut-off value for parameters was used to predict the staging and pathology using Receiver Operating Characteristic (ROC) curve analysis.In the early and advanced group, the differences between △T and ascending slope (AS) were statistically significant (p = 0.010, 0.024 0.05). Hodgkin lymphomas (HL) or non-Hodgkin lymphomas (NHL) results were determined by optimal cut-off value of AT and TP (p = 0.001, 0.001 0.05). Aggressive or indolent lymphoma were determined by optimal cut-off values of Color Doppler flow resistance index (P = 0.001 0.05) and SUVmax (p = 0.001 0.05). There was no statistically significant difference between B and T cell lymphoma. And there was no statistically significant difference among the qualitative indexes. The optimal cutoff value for statistically significant indicators was calculated by ROC.The quantitative parameters of CEUS and SUVmax of PET/CT are proven useful in assessment of different clinical and pathologic patterns of extramedullary lymphoma.

Both chest radiography and MRI scan showed compression fracture of the T6 vertebral body in a 33-year-old man who presented with back pain. Because of the absence of predisposing factors for compression fracture, a pathologic fracture was considered. For this reason, an FDG PET/CT was performed. The images revealed not only the abnormal activity in the known T6 vertebral body but also an additional activity immediately anterosuperior to the urinary bladder in a partially calcified soft tissue nodule. A mucinous adenocarcinoma of urachus with solitary bone metastasis was confirmed histopathologically.

Introduction Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has demonstrated high success for B-cell acute lymphoblastic leukemia (B-ALL). Despite the initial high complete remission (CR) rate, about half of patients (pts) relapse at 1 year. CD19 antigen loss was observed in a significant number of relapsed patients. CD22 is another leukemic marker that often expressed on the surface of CD19- relapsed B-ALL blasts. We have developed a bispecific CAR construct targeting CD19 and CD22. Here we report results from a phase Ⅰ clinical trial of CD19/CD22 (GC022) dual CAR-T to evaluate the safety and feasibility of treating patients with relapsed/refractory B-ALL. Methods The CD19/CD22 dual CAR-T cells were manufactured in a cGMP facility. Patients' peripheral blood (PB) mononuclear cells were first collected, and CD3+ T cells were separated. The cells were then transfected by lentivirus encoded with CD19 CD22 bispecific scFv sequences. The CAR-T cells produced in this way contained a 4-1BB co-stimulatory signal domain. The CAR-T cells were then cultured for 8-14 days until sufficient cells were harvested for infusion. All pts received conditioning regimen of fludarabine and cyclophosphamide intravenously for 3 consecutive days with doses of 30 mg/m2/day and 250 mg/m2/day, respectively before a single infusion of CAR-T cells. The level of infused CAR-T cell proliferation in PB was analyzed by qPCR and flow cytometry. The primary end points were to evaluate feasibility and toxicity, and the secondary end points included disease response and engraftment/persistence of infused CD19/CD22 dual CAR-T cells. Results From Feb. 2019 to 23 July. 2019, 17 patients (pts) with relapsed/refractory B-ALL including 4 pts who previously treated with CD19 CAR-T cells were enrolled and pts were treated with CD19/CD22 dual CAR-T GC022 (US NIH Clinical#: NCT03825731). Four were adults, 13 pediatrics (age 1-45, Table 1). The median bone marrow (BM) blasts was 19.09 (0.36-87.82) %. Four patients received a low-dose (2.5-5×105/kg) dual CAR-T, 7 received a medium-dose (1-2.5×106/kg) and 5, a high-dose (3-5×106/kg). One patient withdrew immediately before CAR-T infusion due to his personal issue. Anti-leukemic efficacy was evaluated in 11/16 pts (5 pts have not yet reached D15). The 3/4 pts received low dose of GC022 had no response to treatment and 1 had MRD-positive CR. Seven patients who received medium dose achieved 100% CR on D15, highlighting the dose-dependent anti-leukemic activity. Six out of seven pts had MRD negative CR in this medium dose group. Five pts in high dose group have not reached the time for evaluation. No one relapsed with a median observation time of 60 (7-139) days. Cellular kinetic data was analyzed. Median peak of CAR-T copies was 1.09 (0.0022-4.98) x105 copy number/µg PB genomic DNA (Fig.1). The proliferation of medium or high dose groups was significantly better than the low dose group 3.47(0.43-4.98) x105 vs. 0.023(0.0022-0.81) x105(P=0.02) and 2.02(1.89-2.16) x105 vs. 0.023(0.0022-0.81) x105(P=0.004), (Fig.2). The peaks of IL-6, IFN-γ, IL-10, and CD25 were observed around day 7-10. Sixteen out of seventeen pts had grade 0-1 cytokine release syndrome (CRS) and only 1 patient experienced grade 2 CRS. None developed neurotoxicity. Conclusion Our study demonstrates safety and technical feasibility of CD19 and CD22 dual CAR-T in treating patients with CD19+CD22+ relapsed/refractory B-ALL. A low toxicity with dose-dependent high CR rate including pts who previously treated with CD19 CAR-T cells were observed. Longer observation time and more patients are needed to evaluate a beneficial advantage of the CD19/CD22 dual CAR-T over CD19 CAR-T product. Disclosures No relevant conflicts of interest to declare.

Introduction CD19-targeting chimeric antigen receptor (CAR) T cell therapy has demonstrated high success; however, its therapeutic potential can still be further improved. In addition, the high cost and lengthy process of CAR-T production limit its broad application. We have developed a new platform termed FasT (F) CAR-T with shortened manufacturing time to one day (plus 7 days of additional testing for regulatory requirements). Here we report results from a pre-clinical study of FasT (F) CAR-T (GC007F) and a phase Ⅰ clinical trial to assess the safety and feasibility of treating patients with CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Methods In this study, a second generation of CD19-directed CAR-T was manufactured using the FasT CAR-T platform. Peripheral blood (PB) mononuclear cells were obtained by leukapheresis either from healthy donors for the pre-clinical study or from patients undergoing the clinical trial. T cells were separated and used for CAR-T generation. A xenograft mouse model was used to determine the efficacy of GC007F in vivo. Conventional (C) CAR-T derived from the same healthy donor were also made and tested in parallel for comparison. Between Feb. 2019 and July 2019, 10 adolescent and adult patients with CD19+ relapsed/refractory B-ALL were enrolled in a feasibility trial for CD19 FasT CAR-T (www.clinicaltrials.gov, NCT03825718). FasT CAR-T cells for all patients were successfully manufactured. All patients received a conditioning regimen of IV fludarabine (30mg/m2/d) and cyclophosphamide (250mg/m2/d) for 3 days followed by a single infusion of CAR-T cells. Six patients received a low-dose 6.5 (5.86-7.04) x104/kg of FasT CAR-T, 2 received a medium-dose 1 (1-1.16) x105/kg, and 1, a high-dose 1.56x105/kg. The primary end points of the study were to evaluate feasibility and toxicity, and the secondary end points included disease response and engraftment/persistence of infused FasT CAR-T cells. Results This preclinical study has demonstrated several significant improvements of CD19-directed F CAR-T over C CAR-T: 1) 5-30 fold superior expansion capability (p For the phase Ⅰ clinical trial, the median observation period was 86 days (37-166 days). The median percentage of pre-treatment bone marrow (BM) blasts was 9.05% (0.19-32.5%). On day 15 after CAR-T cell infusion, 10/10 (100%) cases achieved complete remission (CR) or CR with incomplete count recovery (CRi) and 9/10 (90%) had minimal residual disease (MRD)-negative CR. Four of ten patients had a good blood count recovery on day 15. The number further increased to 6/10 on day 30. Patient F15 had rapidly growing disease in that his PB blasts increased from 1% on enrollment to 7% immediately before CAR-T cells infusion, and increased to 77% on day 7 post infusion. Notwithstanding the rapid disease progression, the patient achieved MRD-positive CR on day 15 with residual 0.06% BM blasts. Five of ten patients were bridged into allogeneic hematopoietic stem cell transplantation (allo-HSCT). All 10 patients have remained in CR thus far. After CAR-T infusion, the level of infused CD19 FasT CAR-T cells in PB was analyzed by qPCR and flow cytometry. Superior in vivo proliferation and persistence were detected regardless of the infused CAR-T doses. The median peak level was reached on day 7 (7-10) with 2.1(0.22-5.2) x105 copy/µg PB genomic DNA (Fig. 2) and the median CAR-T expression ratio was 44.5 (13.6-69.5) %. The peaks of IL6, IFNγ, IL10, and CD25 were observed around day 7. Despite the achievement of a very high CR rate, 9/10 had grade 1 cytokine release syndrome (CRS) and only 1 patient experienced grade 3 CRS. None developed neurotoxicity. Conclusion This study has demonstrated that FasT CAR-T cells with superior expansion capability and younger/less exhausted phenotypes can be generated rapidly. This first-in-human clinical study showed that FasT CAR-T is safe and highly effective for treating patients with B-ALL. Disclosures No relevant conflicts of interest to declare.

Andrey L. Rogach and co‐workers describe the enhanced emission of photoluminescent copper nanoclusters in solution and in powder state, in article 1600182. These blue‐ and orange‐emitting Cu nanoclusters are combined to create white light‐emitting devices.

Philadelphia chromosome-positive acute myeloid leukemia is controversial and difficult to distinguish from the blast phase of chronic myeloid leukemia. As a myeloid neoplasm, rare cases of this leukemia manifest multiple soft-tissue tumors or bone lytic lesions. In this paper, we describe a 49-year-old male patient who had an abrupt onset with sharp chest pain, fever, fatigue, emaciation, and splenomegaly. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) result showed diffuse and uneven hypermetabolic lesions in the bone marrow with peripheral bone marrow expansion, multiple soft tissue neoplasms with high 18F-FDG uptake, and lytic bone lesions. Bone marrow smear and biopsy detected aberrant blast cells expressing myeloid rather than lymphoid immunophenotype marker. For the existence of Philadelphia chromosome and BCR-ABL1 fusion gene together with complex chromosome abnormalities, a diagnosis of Philadelphia-positive acute myeloid leukemia was made, although the type (de novo or blast crisis) remained unclear.

Diffuse hepatic infiltration of lymphoma is extremely rare [1]. Conventional imaging techniques (CT, MR and ultrasound) usually fail to identify the abnormality. F-FDG PET is valuable in detecting diffuse hepatic diseases [2, 3]. A 58-year-old man was admitted to our hospital owing to fever of unknown origin for 2 weeks and jaundice for 10 days. Non-contrast CT images of chest, abdomen and pelvis showed a tender hepatomegaly, splenomegaly and ascites. A hepatic focal or diffuse lesion and enlargement of lymph nodes were not shown.Ultrasound identified hepatomegalywithout any definite hepatic lesions. Magnetic resonance cholangiopancreatography results (MRCP) were negative. Hematology-oncology consultation suggested a possible diffuse malignant infiltration process such as lymphoma or leukemia. Subsequently, a bone marrow biopsy andwhole-body F-FDGPET/CTscanwere performed. There was no evidence of malignancy on bone marrow biopsy. PET/CT images (a–d, Note: The artifact on b & d is because the patient could not lift his arms during the examination) demonstrated diffuse increased F-FDG uptake in the entire liver (“hepatic superscan”). PET/CT images strongly indicated the diagnosis of hepatic lymphoma. Liver biopsy showed a nongerminal center subtype of diffuse large B-cell lymphoma. Immunohistochemical stains (e–g) were positive for CD20 and MUM-1, and negative for CD10 and BCL-6. The patient died 2 days after liver biopsy due to rapid progression of the disease; an autopsy was not performed. This case highlights PET, rather than other imaging techniques, is of great value in detecting diffuse hepatic infiltration of lymphoma with characteristic appearance of Bhepatic superscan^.

A 57-year-old man presented with fever of unknown origin and pulmonary hypertension. An F-FDG PET/CT scan was performed to evaluate the source of fever, which showed diffuse, homogeneously increased FDG uptake in both lungs, which prompted the transbronchial lung biopsy. The pathological examination from biopsy specimen demonstrated intravascular large B-cell lymphoma.

PURPOSE: Based on practice guideline of "management of hepatocellular carcinoma (HCC): update" published by American Association for the Study of Liver Diseases (AASLD) and "Barcelona Clinic Liver Cancer staging system (BCLC)," this study investigated how to enroll the optimal VX2 liver tumor model for HCC researches by dynamically observing the biological progression of the tumor. MATERIALS: Thirty-two healthy New Zealand white rabbits were implanted VX2 liver tumor by cell suspension method (n=24) and tissue fragment method (n=8). All the rabbits underwent CT scans on day 7, 14, 21 and 28 after implantation to observe the size of the tumors, the time when metastases and ascites occurred and the survival time. Appropriate intervention times were estimated corresponding to different clinical HCC stages by using tumor diameter-time curve. RESULTS: The VX2 liver tumors grew rapidly within 28 days after implantation. And the tumors in the cell suspension group grew faster than those of the tissue fragment group. The appropriate intervention time corresponding to very early stage, early stage and intermediate stage were 16.9 days, respectively in the cell suspension group, and 25.5 days, respectively in the tissue fragment group. CONCLUSION: Preclinical animal research needs to improve on different levels to yield best predictions for human patients. Researchers should seek for an individualized proposal to select optimal VX2 liver tumor models for their experiments. This approach may lead to a more accurate determination of therapeutic outcomes.

The economic development of a country or a region is inseparable from human capital, while higher education is an important factor to ensure that the quantity and quality of human capital, in other words, higher education provides human indemnification for the economic development. Conversely speaking, the regional economic development will also increase investment in education, thus promoting the development of higher education. Therefore, interaction relationship between education and regional economic is very strong. The paper combed between the education and regional economic relationship firstly, then analyzes on the affect to each other, and put forward the both the directions and paths to get the coordinated development of them.

Most of the present‐day down‐conversion white light‐emitting devices (WLEDs) utilize rare‐earth elements, which are expensive and facing the problem of shortage in supply. WLEDs based on the combination of orange and blue emitting copper nanoclusters are introduced, which are easy to produce and low in cost. Orange emitting Cu nanoclusters (NCs) are synthesized using glutathione as both the reduction agent and stabilizer, followed by solvent induced aggregation leading to the emission enhancement. Photoluminescence quantum yields (PL QY) of 24% and 43% in solution and solid state are achieved, respectively. Blue emitting Cu nanoclusters are synthesized by reduction of polyvinylpyrrolidone supported Cu(II) ions using ascorbic acid, followed by surface treatment with sodium citrate which improves both the emission intensity and stability of the clusters, resulting in the PL QY of 14% both in solution and solid state. All‐copper nanocluster based down‐conversion WLEDs are fabricated by integrating powdered orange and blue emitting Cu NC samples on a commercial GaN LED chip providing 370 nm excitation. They show favorable white light characteristics with Commission Internationale de l'Eclairage color coordinates, color rendering index, and correlated color temperature of (0.36, 0.31), 92, and 4163 K, respectively.

Pulmonary chondromas are very rare benign tumors. We report a case of huge solitary pulmonary chondroma in a 53-year-old woman without specific symptom. The lesion was detected by CT and Tc-99m methylene diphosphonate bone scintigraphy. The primary diagnosis after radiologic examination was pulmonary hamartoma. Then, surgical excision was performed, and the pathology showed pulmonary chondroma.

e15556 Background: Variable uptake of 18FDG has been noticed in positron emission tomography (PET) studies of patients with esophageal squamous cell carcinoma (ESCC). The aim of the present study was to determine if 18F-FDG PET/CT standardized uptake value (SUV) could quantitatively reflect tumor proliferation, invasion and angiogenesis, and to reveal the relationship between SUV and pathological grading of ESCC. Methods: Preoperative PET scans were performed in 47 patients with histologically proven ESCC. 18FDG uptake was semiquantitatively measured by SUV.Tumour sections were HE stained to determine the pathological grading,and were stained by immunohistochemistry for proliferation marker (Ki67), invasion marker (MMP-2), and angiogenic marker (CD34). The correlations between FDG SUVmax and Ki67 expression, MMP-2 expression, corresponding MVD were statistically analysed respectively. Results: Among all the 47 cases,there were 13 well- differentiated squamous cell tumors, 16 moderately differentiated tumors and 18 poorly differentiated tumors,45 of 47 tumors revealed FDG. accumulation in primary tumor foci confirmed by subsequently histopathologically. The mean FDG SUVmax value was 12.504 ± 6.805. Average Ki-67 index was (7.837±29.798) %, average MMP-2 index was (71.551%±27.126) % and average MVD was (18.429±9.603) accordingly. The SUV and Ki-67 index, MMP-2 index were positively correlated (r=0.581,0.594), and it was not correlated with MVD(P>0.05). The mean SUV of well-differentiated, moderately differentiated and poorly differentiated tumors were 9.787±1.477, 12.313±0.479, 15.053±2.147 respectively, and a significant difference could be determined between them by statistical analysis(P=0.000). Conclusions: A significant positive correlation is demonstrated between FDG PET/CT SUV and Ki-67 index, MMP-2 index of the primary ESCC. SUV could reflect proliferation and invasion potential of tumor. However, there is no significant correlation between SUV and MVD, thus it could not reflect tumor angiogenesis in ESCC. To some extent, SUV could reflect pathologic grading of ESCC. No significant financial relationships to disclose.