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Cheng Zhou,1,* Zhang-Fu Yang,1,* Bao-Ye Sun,1,* Yong Yi,1 Zheng Wang,1 Jian Zhou,1 Jia Fan,1 Wei Gan,1 Ning Ren,1,2 Shuang-Jian Qiu1 1Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Institute of Fudan Minhang Academic Health System & Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuang-Jian Qiu, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200030, People’s Republic of China, Tel +86 13916625289, Email qiu.shuangjian@zs-hospital.sh.cnPurpose: Immunogenic cell death (ICD) is a cell death modality that plays a vital role in anticancer therapy. In this study, we investigated whether lenvatinib induces ICD in hepatocellular carcinoma and how it affects cancer cell behavior.Patients and Methods: Hepatoma cells were treated with 0.5 μM lenvatinib for two weeks, and damage-associated molecular patterns were assessed using the expression of calreticulin, high mobility group box 1, and ATP secretion. Transcriptome sequencing was performed to investigate the effects of lenvatinib on hepatocellular carcinoma. Additionally, CU CPT 4A and TAK-242 were used to inhibit TLR3 and TLR4 expressions, respectively. Flow cytometry was used to assess PD-L1 expression. Kaplan–Meier and Cox regression models were applied for prognosis assessment.Results: After treatment with lenvatinib, there was a significant increase in ICD-associated damage-associated molecular patterns, such as calreticulin on the cell membrane, extracellular ATP, and high mobility group box 1, in hepatoma cells. Following treatment with lenvatinib, there was a significant increase in the downstream immunogenic cell death receptors, including TLR3 and TLR4. Furthermore, lenvatinib increased the expression of PD-L1, which was later inhibited by TLR4. Interestingly, inhibiting TLR3 in MHCC-97H and Huh7 cells strengthened their proliferative capacity. Moreover, TLR3 inhibition was identified as an independent risk factor for overall survival and recurrence-free survival in patients with hepatocellular carcinoma.Conclusion: Our study revealed that lenvatinib induced ICD in hepatocellular carcinoma and upregulated PD-L1 expression through TLR4 while promoting cell apoptosis through TLR3. Antibodies against PD-1/PD-L1 can enhance the efficacy of lenvatinib in the management of hepatocellular carcinoma.Graphical Abstract: Keywords: hepatocellular carcinoma, immunogenic cell death, lenvatinib, toll-like receptor

Background In this study we explored whether one pleural catheter plus single chest tube drainage could achieve a noninferior drainage effect when compared with the traditional two chest tubes in uniportal video-assisted thoracoscopic surgery (VATS) for an upper pulmonary lobectomy. Methods Patients that underwent an upper pulmonary lobectomy from January to November 2020 were enrolled in this single-center, randomized, open-label, noninferiority trial. Prior to closure, patients were randomized to an intervention group who received an improved drainage strategy involving one pleural catheter with one chest tube (24 Fr), while traditional double chest tube drainage was applied for the control group. Results A total of 390 patients entered the study, although 190 were excluded for changing nonuniportal surgical approaches or opting for nonlobectomy resections. Finally, 200 patients were randomized (100 in the intervention group and 100 in the control group). The baseline demographic and clinical characteristics were comparable between the groups. The incidence of pneumothorax in the intervention and control groups was similar on postoperative Day 1 (noninferiority, 10% vs. 13%, p = 0.658). In addition, there were no significant differences in secondary outcomes such as incidence of pneumothorax by Day 30, postoperative chest tube/pleural catheter removal time, amount of drainage on Day 1, total amount of drainage after operation, or postoperative hospitalization. A significantly lower pain score was observed in the intervention group (3.33 ± 0.68 vs. 3.68 ± 0.94, p = 0.003). Conclusions The new strategy is noninferior to double chest tube drainage after an upper pulmonary lobectomy offers superior pain control, and is recommended for an upper lobectomy by uniportal VATS.