Citations

Background and Aims: A better understanding of the underlying mechanism of acetaminophen (APAP)‐induced liver injury (AILI) remains an important endeavor to develop therapeutic approaches. Eosinophils have been detected in liver biopsies of patients with APAP overdose. We recently demonstrated a profound protective role of eosinophils against AILI; however, the molecular mechanism had not been elucidated. Approach and Results: In agreement with our previous data from experiments using genetic deletion of eosinophils, we found that depletion of eosinophils in wild‐type (WT) mice by an anti‐IL‐15 antibody resulted in exacerbated AILI. Moreover, adoptive transfer of eosinophils significantly reduced liver injury and mortality rate in WT mice. Mechanistic studies using eosinophil‐specific IL‐4/IL‐13 knockout mice demonstrated that these cytokines, through inhibiting interferon‐γ, mediated the hepatoprotective function of eosinophils. Reverse phase protein array analyses and in vitro experiments using various inhibitors demonstrated that IL‐33 stimulation of eosinophils activated p38 mitogen‐activated protein kinase (MAPK), and in turn, cyclooxygenases (COX), which triggered NF‐κB–mediated IL‐4/IL‐13 production. In vivo adoptive transfer experiments showed that in contrast to naive eosinophils, those pretreated with COX inhibitors failed to attenuate AILI. Conclusions: The current study revealed that eosinophil‐derived IL‐4/IL‐13 accounted for the hepatoprotective effect of eosinophils during AILI. The data demonstrated that the p38 MAPK/COX/NF‐κB signaling cascade played a critical role in inducing IL‐4/IL‐13 production by eosinophils in response to IL‐33.

Background: Patients with advanced emphysema experience breathlessness due to impaired respiratory mechanics and diaphragm dysfunction. Bronchoscopic lung volume reduction (BLVR) is a minimally invasive bronchoscopic procedure done to reduce hyperinflation and air trapping, promoting atelectasis in the targeted lobe and allowing improved respiratory mechanics. Real-world data on safety and complications outside of clinical trials of BLVR are limited. Methods: We queried the US Food and Drug Administrations (FDA) Manufacturers and User Device Experience database from May 2019 to June 2020 for reports involving BLVR with endobronchial valve (EBV) placement. Events were reviewed for data analysis. Results: We identified 124 cases of complications during BLVR with EBV implantation. The most-reported complication was pneumothorax (110/124, 89%), all of which required chest tube placement. A total of 54 of these cases (54/110, 49%) were complicated by persistent air leak requiring additional interventions. Repeat bronchoscopy was needed to remove the valves in 28 patients, 12 were discharged with a Heimlich valve, and 10 had an additional pleural catheter placed. The other complications of BLVR with EBV placement included respiratory failure (6/124, 5%), pneumonia (4/124, 3%), hemoptysis (2/124, 1.6%), valve migration (1/124, 1%), and pleural effusion (1/124, 1%). A total of 14 deaths were reported during that year. Conclusion: Pneumothorax is the most-reported complication for BLVR with EBV placement, and in 65% of cases, pneumothorax is managed without removing valves. Importantly, 14 deaths were reported during that timeframe. Further studies are needed to estimate the true magnitude of the complications associated with BLVR.

8028 Background: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies, led to early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study (NCT03548207) in heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM). At ̃1-year (y) median follow-up (MFU), overall response rate (ORR) was 97%; 67% of pts achieved stringent complete response (sCR). 1-y progression-free survival (PFS) and overall survival (OS) rates were 77% and 89%, respectively (Berdeja 2021). Updated results 2-y post last patient in (LPI) will be presented (̃30-month total MFU). Here, we report CARTITUDE-1 results at 21.7-month MFU. Methods: Eligible pts with RRMM received ≥3 prior lines of therapy (LOT) or were refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and had received a PI, IMiD, and anti-CD38 antibody. Bridging therapy was permitted after apheresis. Pts received a single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) 5–7 days after lymphodepletion. Primary objectives were to evaluate cilta-cel safety and efficacy. Response was assessed per International Myeloma Working Group criteria by independent review committee and minimal residual disease (MRD) negativity at 10-5 by next-generation sequencing. Results: As of July 22, 2021, 97 pts (59% male; median age 61 y) received cilta-cel. Pts had a median of 6 (range 3–18) prior LOT; 84% were penta-drug exposed, 88% were triple-class refractory, 42% were penta-drug refractory, and 99% were refractory to last LOT. ORR was 97.9% (95% CI 92.7–99.7), 94.9% achieved very good partial response, and 82.5% achieved sCR. Median times to first response, best response, and ≥CR were 1.0, 2.6, and 2.9 months (m), respectively; median duration of response was not reached (NR). Of 61 pts evaluable for MRD, 92% were MRD negative (10-5), sustained for ≥6 m in 44% (27/61) and ≥12 m in 18% (11/61). 2-y PFS was 60.5% (95% CI 48.5–70.4). Median PFS and OS were NR. 2-y PFS rates in pts with sustained MRD negativity for ≥6 m and ≥12 m were 91% and 100%, respectively. There were no new safety signals or new events of CAR-T cell neurotoxicity, movement and neurocognitive treatment-emergent adverse events, or treatment-related deaths since 1-y MFU. 15 second primary malignancies were reported in 11 pts over ̃2-y MFU. Conclusions: At ̃2-y MFU, a single cilta-cel infusion led to deepening and durable responses in heavily pretreated pts with RRMM with a manageable safety profile. Follow-up is ongoing, and landmark 2-y post LPI data (̃8 m additional follow-up; ̃30 m total MFU) will be presented. Further investigations of cilta-cel are ongoing in earlier LOT and outpatient settings across the CARTITUDE program (NCT04133636, NCT04181827, NCT04923893). Clinical trial information: NCT03548207.

e16550 Background: Improved computational power and modern algorithms have generated significant interest in radiomics for cancer diagnosis and staging. Here we assess the performance of deep learning (DL) models as a means for feature extraction in combination with supervised machine learning (ML) algorithms for accurate staging and chemotherapy response assessment of bladder cancer. Methods: Deidentified grayscale CT images from bladder cancer patients scheduled to undergo radical cystectomy were included in this retrospective study. These images were manually annotated with two regional masks (normal region and cancer region). Five DL models- namely, AlexNet, GoogleNet, InceptionV3, ResNet-50, and XceptionNet pre-trained on the ImageNet dataset, a public dataset, were then fine-tuned on our bladder CT scan data to extract features. Through feature selection process, the subset of the features was used to build ML classifiers for classification. The classification was performed using five different ML classifiers, namely k-Nearest Neighbor (KNN), Naïve-Bayes (NB), Support Vector Machine (SVM), Linear Discriminant Analysis (LDA), and Decision Tree (DT). The classification task was performed with 10-fold cross-validation, and each of the experiments contained a different but not mutually exclusive subset of samples. The evaluation metrics include accuracy, sensitivity, specificity, precision, and F1-score. Results: A total of 200 deidentified grayscale CT images of 100 patients with histologically proven bladder cancer, were included in this study. For experiment (1) normal vs. cancer, the LDA classifier on XceptionNet based features provides the best performance with an accuracy of 86.07%, sensitivity of 96.75%, specificity of 69.65%, precision of 83.07%, and F1-score of 89.39%. For experiment (2) non-muscle invasive Cancer (NMIBC) vs. muscle invasive bladder cancer (MIBC), the LDA classifier on XceptionNet based features provided the best performance with an accuracy of 79.72%, sensitivity of 66.62%, specificity of 87.39%, precision of 75.58%, and F1-score of 70.81%. For experiment (3) T0 lesion vs. MIBC, the LDA classifier on XceptionNet based features provides the best performance with an accuracy of 74.96%, sensitivity of 80.51%, specificity of 70.22%, precision of 69.78%, and F1-score of 74.73%. Conclusions: Our proposed model has shown good results in differentiating normal vs cancer and promising performance in differentiating T0 vs MIBC after chemotherapy treatment. We are expanding our dataset to further improve the performance in differentiating T0 vs MIBC. In addition, we will investigate the applicability of GAN for data augmentation to address data limit. We believe the hybrid DL and ML framework may facilitates radiologists' decisions and clinical decision-making in patients with bladder cancer.

PURPOSE CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups. METHODS Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee. RESULTS At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel–related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report. CONCLUSION At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.

Pain is the most frequently encountered symptom by patients with fibromyalgia (FM). Dietary supplements (DSs) in particular have a proven impact as a possible adjunctive therapy for symptom management in FM. However, there is currently no conclusive review outlining the evidence for DSs in pain management in FM. This study aims to assess currently available studies evaluating the use of DSs for pain relief in FM. Randomized controlled trials regarding the use of DSs on adult FM patients were included for evidence synthesis. Study results indicated that DSs significantly relieved pain in FM (SMD 1.23; 95% CI 0.02–2.43, P = 0.046) but did not improve quality of life (QoL) (SMD 0.73; 95% CI −0.07–1.53, P = 0.075) in the data. Adverse events of DSs varied from mild to severe, with the most common being gastrointestinal symptoms and androgenic side effects in 5.7% and 3.9% of patients, respectively. More well-designed RCTs are required in the future. The protocol for this review has been published on PROSPERO (CRD42020149941).