Phosphorylation of LZTS2 by PLK1 activates the Wnt pathway.

Lung adenocarcinoma (LUAD), responsible for nearly half of lung cancer cases, is one of the most prevalent and lethal malignant tumors globally. There is increasing evidence suggesting that the oncoprotein PLK1 plays a role in the onset and advancement of different types of cancer, including LUAD. Nonetheless, the precise mechanism by which PLK1 promotes tumorigenesis remains unclear. In this study, we demonstrate the upregulation of PLK1 in LUAD samples, which leads to a poor prognosis for LUAD patients. Intriguingly, PLK1 enables to bind to LZTS2 and promote its phosphorylation without affecting LZTS2 degradation. Furthermore, we identify that Ser451 is a key phosphorylation site in LZTS2 protein. LZTS2 exerts an anti-tumor effect by restricting the translocation of the transcription factor ß-Catenin into the nucleus, thereby suppressing the Wnt pathway. PLK1 disrupts the interaction between LZTS2 and ß-Catenin, resulting in the nuclear accumulation of ß-Catenin and the activation of the Wnt pathway. Additionally, we reveal that LZTS2 inhibits the proliferation and migration of LUAD cells, which is rescued by PLK1. Finally, PLK1 inhibitors exhibit a dose-dependent suppression of LUAD cell proliferation and migration. Collectively, this study uncovers the pro-tumorigenic mechanism of PLK1, positioning it as a promising therapeutic target for Wnt-related LUAD.

Comprehensive analysis of lung adenocarcinoma: Unveiling differential gene expression, survival-linked genes, subtype stratification, and immune landscape implications.

This study offers a detailed exploration of lung adenocarcinoma (LUAD), addressing its heterogeneity and treatment challenges through a multi-faceted analysis that includes gene expression, genetic subtyping, pathway analysis, immune assessment, and drug sensitivity. It identifies 165 genes with significant expression differences and 46 genes associated with survival, revealing insights into oxidative stress and autophagy. LUAD samples were divided into three subtypes using consensus clustering on these 46 genes, with distinct survival outcomes. Gene Set Enrichment Analysis (GSEA) on HALLMARK gene sets indicated pathway variations with survival implications. The immune landscape, analyzed using the CIBERSORT algorithm, showed different immune cell distributions across subtypes, with the first subtype exhibiting a better immune environment and survival prospects. Advanced machine learning techniques developed a risk model from a set of four genes, effectively categorizing patients into high and low-risk groups, validated through external datasets and analyses. This model linked lower risk scores to better clinical stages, with a higher mutation rate and potential immunotherapy benefits observed in the high-risk group. Drug sensitivity assessments highlighted varied treatment responses between risk groups, suggesting avenues for personalized therapy. This comprehensive analysis enhances the understanding of LUAD's molecular and clinical nuances, offering valuable insights for tailored treatment approaches.

Amplifying "eat me signal" by immunogenic cell death for potentiating cancer immunotherapy.

Immunogenic cell death (ICD) is a unique mode of cell death, which can release immunogenic damage-associated molecular patterns (DAMPs) and tumor-associated antigens to trigger long-term protective antitumor immune responses. Thus, amplifying "eat me signal" during tumor ICD cascade is critical for cancer immunotherapy. Some therapies (radiotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), etc.) and inducers (chemotherapeutic agents, etc.) have enabled to initiate and/or facilitate ICD and activate antitumor immune responses. Recently, nanostructure-based drug delivery systems have been synthesized for inducing ICD through combining treatment of chemotherapeutic agents, photosensitizers for PDT, photothermal transformation agents for PTT, radiosensitizers for radiotherapy, etc., which can release loaded agents at an appropriate dosage in the designated place at the appropriate time, contributing to higher efficiency and lower toxicity. Also, immunotherapeutic agents in combination with nanostructure-based drug delivery systems can produce synergetic antitumor effects, thus potentiating immunotherapy. Overall, our review outlines the emerging ICD inducers, and nanostructure drug delivery systems loading diverse agents to evoke ICD through chemoradiotherapy, PDT, and PTT or combining immunotherapeutic agents. Moreover, we discuss the prospects and challenges of harnessing ICD induction-based immunotherapy, and highlight the significance of multidisciplinary and interprofessional collaboration to promote the optimal translation of this treatment strategy.

Two-year outcomes of clinical N2-3 esophageal squamous cell carcinoma after neoadjuvant chemotherapy and immunotherapy from the phase 2 NICE study.

OBJECTIVE: This study aims to report the 2-year outcomes of patients with clinical stage N2-3 esophageal squamous cell carcinoma who received neoadjuvant chemotherapy and immunotherapy followed by surgery from a phase 2 NICE trial. METHODS: Eligible patients with clinical stage N2-3 esophageal squamous cell carcinoma were screened and enrolled, then treated with regimen of nab-paclitaxel (100 mg/m2, days 1, 8, 15), carboplatin (area under the curve = 5, day 1), camrelizumab (200 mg, day 1) of two 21-day cycles and esophagectomy 4 to 6 weeks after the last chemotherapy. Oncologic outcomes, recurrence patterns, overall survival (OS), and recurrence-free survival (RFS) were explored. RESULTS: From November 20, 2019, to December 22, 2020, 60 patients were recruited. After a median follow-up of 27.4 months, disease recurrence was observed in 19 (37.3%) patients, with 5 (9.8%) locoregional recurrence, 9 (17.6%) distant metastasis, and 5 (9.8%) combined recurrence. Lung was the most commonly involved metastatic site. The median time to recurrence was 10.8 months (interquartile range, 7.5-12.7 months). The 2-year OS and RFS rates were 78.1% and 67.9%, respectively. Patients who achieved major pathologic response (MPR) had a significantly greater 2-year OS rate (91.4% vs 47.7%; P < .001) and RFS rate (77.1% vs 45.9%; P = .003). On multivariable analysis, MPR was indicated as an independent prognostic factor for disease recurrence (hazard ratio, 0.39; 95% confidence interval, 0.21-0.82; P = .029). CONCLUSIONS: In patients receiving neoadjuvant chemotherapy and immunotherapy, distant metastasis remains the predominant recurrence pattern. MPR is associated with lower recurrence and better survival. Long-term results derived from randomized controlled trials are further required. TRIAL REGISTRATION NUMBER: ChiCTR1900026240.

PET/CT-based deep learning grading signature to optimize surgical decisions for clinical stage I invasive lung adenocarcinoma and biologic basis under its prediction: a multicenter study.

PURPOSE: No consensus on a grading system for invasive lung adenocarcinoma had been built over a long period of time. Until October 2020, a novel grading system was proposed to quantify the whole landscape of histologic subtypes and proportions of pulmonary adenocarcinomas. This study aims to develop a deep learning grading signature (DLGS) based on positron emission tomography/computed tomography (PET/CT) to personalize surgical treatments for clinical stage I invasive lung adenocarcinoma and explore the biologic basis under its prediction. METHODS: A total of 2638 patients with clinical stage I invasive lung adenocarcinoma from 4 medical centers were retrospectively included to construct and validate the DLGS. The predictive performance of the DLGS was evaluated by the area under the receiver operating characteristic curve (AUC), its potential to optimize surgical treatments was investigated via survival analyses in risk groups defined by the DLGS, and its biological basis was explored by comparing histologic patterns, genotypic alternations, genetic pathways, and infiltration of immune cells in microenvironments between risk groups. RESULTS: The DLGS to predict grade 3 achieved AUCs of 0.862, 0.844, and 0.851 in the validation set (n = 497), external cohort (n = 382), and prospective cohort (n = 600), respectively, which were significantly better than 0.814, 0.810, and 0.806 of the PET model, 0.813, 0.795, and 0.824 of the CT model, and 0.762, 0.734, and 0.751 of the clinical model. Additionally, for DLGS-defined high-risk population, lobectomy yielded an improved prognosis compared to sublobectomy p = 0.085 for overall survival [OS] and p = 0.038 for recurrence-free survival [RFS]) and systematic nodal dissection conferred a superior prognosis to limited nodal dissection (p = 0.001 for OS and p = 0.041 for RFS). CONCLUSION: The DLGS harbors the potential to predict the histologic grade and personalize the surgical treatments for clinical stage I invasive lung adenocarcinoma. Its applicability to other territories should be further validated by a larger international study.

Aggregation-Induced Emission Photosensitizer-Engineered Anticancer Nanomedicine for Synergistic Chemo/Chemodynamic/Photodynamic Therapy.

Photodynamic therapy (PDT) with aggregation-induced emission (AIE) photosensitizers (PSs) is a promising therapeutic strategy to achieve better anticancer results. However, eradicating solid tumors completely by PDT alone can be difficult owing to the inherent drawbacks of this treatment, and the combination of PDT with other therapeutic modalities provides opportunities to achieve cooperative enhancement interactions among various treatments. Herein, this work presents the construction of a biocompatible nanocomposite, namely CaO2@DOX@ZIF@ASQ, featuring light-responsive reactive oxygen species (ROS) generation and tumor-targeting oxygen and hydrogen peroxide discharge, as well as controlled doxorubicin (DOX) and copper ion release, thus allowing the combined PDT/CT/CDT effect by AIE PS-enhanced PDT, DOX-based chemotherapy (CT), and copper-involved Fenton-like reaction-driven chemodynamic therapy (CDT). In vitro and in vivo studies verify that the generation of both ROS and O2 by this nanomedicine, stimulated by light, exhibits superior anticancer efficacy, alleviating tumor hypoxia and achieving synergistic PDT/CT/CDT therapeutic effect. This multifunctional nanomedicine remarkably suppresses the tumor growth with minimized systemic toxicity, providing a new strategy for constructing multimodal PDT/CT/CDT therapeutic systems to overcome hypoxia limitations, and potentially increase the antitumor efficacy at lower doses of PSs and chemotherapeutic drugs, thus minimizing potential toxicity to non-malignant tissues.

Retraction: ET-1 promotes the growth and metastasis of esophageal squamous cell carcinoma via activating PI3K/Akt pathway.

[This retracts the article DOI: 10.21037/tcr.2020.04.26.].

Single-center experience of transitioning from video-assisted laparoscopic to robotic Heller myotomy with Dor fundoplication for esophageal motility disorders.

BACKGROUND: Video-assisted laparoscopic Heller myotomy (LHM) has become the standard treatment option for achalasia. While robotic surgery offering some specific advantages such as better three-dimensional (3D) stereoscopic vision, hand-eye consistency, and flexibility and stability with the endowrist is expected to be shorter in learning curve than that of LHM for surgeons who are proficient in LHM. The aim of this study was to describe a single surgeon's experience related to the transition from video-assisted laparoscopic to robotic Heller myotomy with Dor fundoplication. METHODS: We conducted a retrospective observational study based on the recorded data of the first 66 Heller myotomy performed with laparoscopic Heller myotomy with Dor fundoplication (LHMD, 26 cases) and with the robotic Heller myotomy with Dor fundoplication (RHMD, 40 cases) by the same surgeon in Department of Thoracic Surgery of The First Affiliated Hospital of Nanchang University in China. The operation time and intraoperative blood loss were analyzed using the cumulative sum (CUSUM) method. Corresponding statistical tests were used to compare outcomes of both serials of cases. RESULTS: The median operation time was shorter in the RHMD group compared to the LHMD group (130 [IQR 123-141] minutes vs. 163 [IQR 153-169]) minutes, p < 0.001). In the RHMD group, one patient (2.5%) experienced mucosal perforation, whereas, in the LHMD group, the incidence of this complication was significantly higher at 19.2% (5 patients) (p = 0.031). Based on cumulative sum analyses, operation time decreased starting with case 20 in the LHMD group and with case 18 in the RHMD group. Intraoperative blood loss tended to decline starting with case 19 in the LHMD group and with case 16 in the RHMD group. CONCLUSIONS: Both RHMD and LHMD are effective surgical procedures for symptom relief of achalasia patients. RHMD demonstrates superior outcomes in terms of operation time and mucosal perforation during surgery compared to LHMD. Proficiency with RHMD can be achieved after approximately 16-18 cases, while that of LHMD can be obtained after around 19-20 cases.

PET/CT based cross-modal deep learning signature to predict occult nodal metastasis in lung cancer.

Occult nodal metastasis (ONM) plays a significant role in comprehensive treatments of non-small cell lung cancer (NSCLC). This study aims to develop a deep learning signature based on positron emission tomography/computed tomography to predict ONM of clinical stage N0 NSCLC. An internal cohort (n = 1911) is included to construct the deep learning nodal metastasis signature (DLNMS). Subsequently, an external cohort (n = 355) and a prospective cohort (n = 999) are utilized to fully validate the predictive performances of the DLNMS. Here, we show areas under the receiver operating characteristic curve of the DLNMS for occult N1 prediction are 0.958, 0.879 and 0.914 in the validation set, external cohort and prospective cohort, respectively, and for occult N2 prediction are 0.942, 0.875 and 0.919, respectively, which are significantly better than the single-modal deep learning models, clinical model and physicians. This study demonstrates that the DLNMS harbors the potential to predict ONM of clinical stage N0 NSCLC.

Impact of endoscopic thoracic R4 sympathicotomy combined with R3 ramicotomy for primary palmar hyperhidrosis.

Background: Endoscopic thoracoscopic sympathectomy (ETS) is the preferred method for treating primary palmar hyperhidrosis (PPH) that bears the risk of compensatory hyperhidrosis (CH) following surgery. The current study aims to evaluate the effectiveness and safety of an innovative surgical procedure of ETS. Methods: A survey of the clinical data of 109 patients with PPH who underwent ETS in our department from May 2018 to August 2021 was retrospectively conducted. The patients were organized into two groups. Group A underwent R4 sympathicotomy combined with R3 ramicotomy. Group B underwent R3 sympathicotomy. Patients were followed up to evaluate the safety, effectiveness and the incidence of postoperative CH of the modified surgical approach. Results: A total of 102 patients completed follow-up, and seven of the total enrolled patients were lost to follow-up, with a loss rate of 6% (7/109). Among these, Group A constitutes 54 cases, group B constitutes 48 cases, and the mean follow-up was 14 months (interquartile range 12-23 months). There was no statistically difference in surgical safety, postoperative efficacy, and postoperative quality of life (QoL) score between group A and group B (p > 0.05). The score of the psychological assessment was higher (p = 0.004) in group A (14.15 ± 2.06) compared to group B (13.30 ± 1.86). The incidence of CH in group A was lower than in group B (p = 0.019). Conclusion: R4 sympathicotomy combined with R3 ramicotomy is safe and effective for PPH treatment, along with a reduced incidence of postoperative CH rate and improved postoperative psychological satisfaction.

Effect of pleural invasion on survival of patients with small cell lung cancer: Propensity score analysis and nomogram establishment based on the SEER database.

Objectives: Pleural invasion (PI) is identified as an adverse prognostic factor for non-small cell lung cancer (NSCLC), but its value in small cell lung cancer (SCLC) remains unclear. We aimed to evaluate the survival effect of PI on overall survival (OS) in SCLC, meanwhile, we established a predictive nomogram based on related risk factors for OS in SCLC patients with PI. Methods: We extracted the data of patients diagnosed with primary SCLC between 2010 and 2018 from the Surveillance, Epidemiology, and End Results (SEER) database. The propensity score matching (PSM) method was used to minimize the baseline difference between the non-PI and PI groups. Kaplan-Meier curves and the log-rank test were used for survival analysis. Univariate and multivariate Cox regression analyses were applied to identify the independent prognostic factors. Randomly divided the patients with PI into training (70%) and validation (30%) cohorts. A prognostic nomogram was established based on the training cohort and was evaluated in the validation cohort. The C-index, receiver operating characteristic curves (ROC), calibration curves, and decision curve analysis (DCA) were applied to assess the performance of the nomogram. Results: A total of 1,770 primary SCLC patients were enrolled, including1321patients with non-PI and 449 patients with PI. After PSM, the 387 patients in the PI group matched the 387 patients in the non-PI group. By Kaplan-Meier survival analysis, we observed the exact beneficial effect of non-PI on OS in both original and matched cohorts. Multivariate Cox analysis showed similar results to demonstrate a statistically significant benefit for patients with non-PI in both original and matched cohorts. Age, N stage, M stage, surgery, radiotherapy, and chemotherapy were independent prognostic factors for SCLC patients with PI. The C-index of the nomogram in the training and validation cohort was 0.714 and 0.746, respectively. The ROC curves, calibration curves, and DCA curves also demonstrated good predictive performance in the training and validation cohorts of the prognostic nomogram. Conclusion: Our study shows that PI is an independent poor prognostic factor for SCLC patients. The nomogram is a useful and reliable tool to predict the OS in SCLC patients with PI. The nomogram can provide strong references to clinicians to facilitate clinic decisions.

TCR extracellular domain genetically linked to CD28, 2B4/41BB and DAP10/CD3ζ -engineered NK cells mediates antitumor effects.

NK cells, especially FDA-approved NK-92 cells, could be used for TCR engineering owing to their specialized cytotoxicity against tumors, safety profile and potential use as an off-the-shelf cellular therapy. The TCR complex requires assembly of TCR- α/ ß chains with CD3 molecules (CD3δ, CD3γ, CD3ε, CD3ζ) to be correctly expressed at the cell membrane, and yet NK cells lack expression of these CD3 subunits besides CD3ζ. Since transmembrane regions of TCR α and ß chains are involved in TCR complex assembly, transmembrane regions of TCR replaced by CD28 transmembrane domain could result in the expression of TCR independent of its companion CD3 subunits. However, since the absence of CD3 signaling components can influence the transmission of TCR signals to NK cells, it is necessary to add the signaling molecules of NK cells followed by CD28 transmembrane domain. Both CD3ζ and DAP10 play an important role in the activation and cytotoxicity of NK cells; moreover, 2B4 and 4-1BB are the main costimulatory molecules in NK cells. Therefore, we designed a chimeric TCR that consisted of the extracellular domains of the TCR α and ß chains specific for NYESO-1 fused to the CD28 transmembrane domain followed by the 41BB and CD3ζ signaling domains as well as the 2B4 and DAP10 signaling domain, respectively. The chimeric TCR genetically engineered NK-92 cells exhibit antigen-specific recognition and lysis of tumor cells both in vitro and in vivo. In addition, TCR-28-2B10/BBζ can be feasibly expressed in primary NK cells and exhibit antigen-reactive recognition and effect function. The overall encouraging data highlight the value of NK-92 cells and primary NK cells engineered to express therapeutic chimeric TCR for adoptive immunotherapies.

Expert consensus on indocyanine green fluorescence imaging for thoracoscopic lung resection (The Version 2022).

The use of the white-light thoracoscopy is hampered by the low contrast between oncologic margins and surrounding normal parenchyma. As a result, many patients with in situ or micro-infiltrating adenocarcinoma have to undergo lobectomy due to a lack of tactile and visual feedback in the resection of solitary pulmonary nodules. Near-infrared (NIR) guided indocyanine green (ICG) fluorescence imaging technique has been widely investigated due to its unique capability in addressing the current challenges; however, there is no special consensus on the evidence and recommendations for its preoperative and intraoperative applications. This manuscript will describe the development process of a consensus on ICG fluorescence-guided thoracoscopic resection of pulmonary lesions and make recommendations that can be applied in a greater number of centers. Specifically, an expert panel of thoracic surgeons and radiographers was formed. Based on the quality of evidence and strength of recommendations, the consensus was developed in conjunction with the Chinese Guidelines on Video-assisted Thoracoscopy, and the National Comprehensive Cancer Network (NCCN) guidelines on the management of pulmonary lesions. Each of the statements was discussed and agreed upon with a unanimous consensus amongst the panel. A total of 6 consensus statements were developed. Fluorescence-guided thoracoscopy has unique advantages in the visualization of pulmonary nodules, and recognition and resection of the anterior plane of the pulmonary segment. The expert panel agrees that fluorescence-guided thoracoscopic surgery has the potential to become a routine operation for the treatment of pulmonary lesions.

Deep learning for predicting major pathological response to neoadjuvant chemoimmunotherapy in non-small cell lung cancer: A multicentre study.

BACKGROUND: This study, based on multicentre cohorts, aims to utilize computed tomography (CT) images to construct a deep learning model for predicting major pathological response (MPR) to neoadjuvant chemoimmunotherapy in non-small cell lung cancer (NSCLC) and further explore the biological basis under its prediction. METHODS: 274 patients undergoing curative surgery after neoadjuvant chemoimmunotherapy for NSCLC at 4 centres from January 2019 to December 2021 were included and divided into a training cohort, an internal validation cohort, and an external validation cohort. ShuffleNetV2x05-based features of the primary tumour on the CT scans within the 2 weeks preceding neoadjuvant administration were employed to develop a deep learning score for distinguishing MPR and non-MPR. To reveal the underlying biological basis of the deep learning score, a genetic analysis was conducted based on 25 patients with RNA-sequencing data. FINDINGS: MPR was achieved in 54.0% (n = 148) patients. The area under the curve (AUC) of the deep learning score to predict MPR was 0.73 (95% confidence interval [CI]: 0.58-0.86) and 0.72 (95% CI: 0.58-0.85) in the internal validation and external validation cohorts, respectively. After integrating the clinical characteristic into the deep learning score, the combined model achieved satisfactory performance in the internal validation (AUC: 0.77, 95% CI: 0.64-0.89) and external validation cohorts (AUC: 0.75, 95% CI: 0.62-0.87). In the biological basis exploration for the deep learning score, a high deep learning score was associated with the downregulation of pathways mediating tumour proliferation and the promotion of antitumour immune cell infiltration in the microenvironment. INTERPRETATION: The proposed deep learning model could effectively predict MPR in NSCLC patients treated with neoadjuvant chemoimmunotherapy. FUNDING: This study was supported by National Key Research and Development Program of China, China (2017YFA0205200); National Natural Science Foundation of China, China (91959126, 82022036, 91959130, 81971776, 81771924, 6202790004, 81930053, 9195910169, 62176013, 8210071009); Beijing Natural Science Foundation, China (L182061); Strategic Priority Research Program of Chinese Academy of Sciences, China (XDB38040200); Chinese Academy of Sciences, China (GJJSTD20170004, QYZDJ-SSW-JSC005); Shanghai Hospital Development Center, China (SHDC2020CR3047B); and Science and Technology Commission of Shanghai Municipality, China (21YF1438200).

USP17L2-SIRT7 axis regulates DNA damage repair and chemoresistance in breast cancer cells.

PURPOSE: Sirtuin7 (SIRT7), as a member of the sirtuin and NAD+-dependent protein-modifying enzyme family, plays an important role in regulating cellular metabolism, stress responses, tumorigenesis, and aging. Ubiquitination and deubiquitination are reversible post-translational modifications that regulate protein stability, enzyme activity, protein-protein interactions, and cellular signaling transduction. However, whether SIRT7 is regulated by deubiquitination signaling is unclear. This study aims to elucidate the molecular mechanism of SIRT7 via deubiquitination signaling. METHODS: USP17L2 or SIRT7-targeting shRNAs were used to deplete USP17L2 or SIRT7. Western blot was applied to assess the effects of USP17L2 or SIRT7 depletion. A co-immunoprecipitation assay was used to detect the interaction relationship. Cell Counting Kit-8 assays were applied to assess the viability of breast cancer cells. An immunohistochemistry assay was employed to detect the protein level in samples from breast cancer patients, and the TCGA database was applied to analyze the survival rate of breast cancer patients. Statistical analyses were performed with the Student's t test (two-tailed unpaired) and χ2 test. RESULTS: We find that the deubiquitinase USP17L2 interacts with and deubiquitinates SIRT7, thereby increasing SIRT7 protein stability. In addition, USP17L2 regulates DNA damage repair through SIRT7. Furthermore, SIRT7 polyubiquitination is increased by knocking down of USP17L2, which leads to cancer cells sensitizing to chemotherapy. In breast cancer patient samples, high expression of USP17L2 is correlated with increased levels of SIRT7 protein. In conclusion, our study demonstrates that the USP17L2-SIRT7 axis is the new regulator in DNA damage response and chemo-response, suggesting that USP17L2 may be a prognostic factor and a potential therapeutic target in breast cancer. CONCLUSION: Our results highlighted that USP17L2 regulates the chemoresistance of breast cancer cells in a SIRT7-dependent manner. Moreover, the role of USP17L2 as a potential therapeutic target in breast cancer and a prognostic factor for patients was elucidated.

Preoperative pembrolizumab combined with chemoradiotherapy for esophageal squamous cell carcinoma: Trial design.

Objective: The safety and feasibility of preoperative pembrolizumab combined with chemoradiotherapy (PPCT) for resectable esophageal squamous cell carcinoma have been confirmed by the prior Preoperative Anti-PD-1 Antibody combined with Chemoradiotherapy for Locally Advanced Squmous Cell Carcinoma of Esophageus (PALACE)-1 trial. Potential therapeutic benefit was also observed with a pathologic complete response rate of 55.6% after PPCT. We will conduct the multicenter single-arm PALACE-2 study to investigate the efficacy and to further confirm the safety of PPCT (ClinicalTrials.gov ID: NCT04435197). Methods: A total of 143 patients with previously untreated, locally advanced, and surgically resectable esophageal squamous cell carcinoma (T2 through T4a, N0 through N+, M0) will be enrolled in PALACE-2. Main exclusion criteria are autoimmune disease, interstitial lung disease, ongoing immunosuppressive therapy, and having received chemotherapy, radiotherapy, target therapy, or immune therapy for this or any other malignancies. Positive programmed cell death ligand 1 expression is not mandatory for enrollment. Patients will receive PPCT, which includes concurrent pembrolizumab (200 mg on day 1 and day 22), carboplatin (area under the curve = 2, once a week for 5 weeks), nab-paclitaxel (50 mg/m2, once a week for 5 weeks), and radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week). Esophagectomy will be performed within 4 to 6 weeks after the completion of PPCT. Results: The primary end point is the rate of pathologic complete response. Secondary outcome measures are 3-year disease-free survival rate, 3-year overall survival rate, R0 resection rate, and adverse events during neoadjuvant and perioperative periods. Conclusions: PPCT was preliminarily demonstrated to be safe, feasible, and to provide potential therapeutic benefits by the PALACE-1 trial. The subsequent multicenter PALACE-2 study will investigate the efficacy and further confirm the safety of PPCT for locally advanced, resectable esophageal squamous cell carcinoma.

CircBCAR3 accelerates esophageal cancer tumorigenesis and metastasis via sponging miR-27a-3p.

RATIONALE: Circular RNAs (circRNAs) have been demonstrated to contribute to esophageal cancer progression. CircBCAR3 (hsa_circ_0007624) is predicted to be differentially expressed in esophageal cancer by bioinformatics analysis. We investigated the oncogenic roles and biogenesis of circBCAR3 in esophageal carcinogenesis. METHODS: Functions of circBCAR3 on cancer cell proliferation, migration, invasion, and ferroptosis were explored using the loss-of-function assays. A xenograft mouse model was used to reveal effects of circBCAR3 on xenograft growth and lung metastasis. The upstream and downstream mechanisms of circBCAR3 were investigated by bioinformatics analysis and confirmed by RNA immunoprecipitation and luciferase reporter assays. The dysregulated genes in hypoxia-induced esophageal cancer cells were identified using RNA-seq. RESULTS: CircBCAR3 was highly expressed in esophageal cancer tissues and cells and its expression was increased by hypoxia in vitro. Silencing of circBCAR3 repressed the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells in vitro, as well as inhibited the growth and metastasis of esophageal xenograft in mice in vivo. The hypoxia-induced promotive effects on esophageal cancer cell migration and ferroptosis were rescued by circBCAR3 knockdown. Mechanistically, circBCAR3 can interact with miR-27a-3p by the competitive endogenous RNA mechanism to upregulate transportin-1 (TNPO1). Furthermore, our investigation indicated that splicing factor quaking (QKI) is a positive regulator of circBCAR3 via targeting the introns flanking the hsa_circ_0007624-formed exons in BCAR3 pre-mRNA. Hypoxia upregulates E2F7 to transcriptionally activate QKI. CONCLUSION: Our research demonstrated that splicing factor QKI promotes circBCAR3 biogenesis, which accelerates esophageal cancer tumorigenesis via binding with miR-27a-3p to upregulate TNPO1. These data suggested circBCAR3 as a potential target in the treatment of esophageal cancer. Hypoxia induces the upregulation of E2F7, which transcriptionally activates QKI in esophageal cancer cells. QKI increases the formation of circBCAR3 by juxtaposing the circularized exons. CircBCAR3 binds with miR-27a-3p to promote TNPO1 expression. CircBCAR3 promoted the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells by miR-27a-3p.

Safety and efficacy of neoadjuvant treatment with immune checkpoint inhibitors in esophageal cancer: real-world multicenter retrospective study in China.

Immune checkpoint inhibitors (ICIs) have shown a powerful benefit in the neoadjuvant therapy for esophageal cancer, but evidence for its safety and efficacy is limited and may not reflect real-world practice. We retrospectively reviewed the database of treatment-naive patients from 15 esophageal cancer centers in China who received ICIs as neoadjuvant treatment for locally advanced esophageal cancer from May 2019 to December 2020. The primary endpoints were rate and severity of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs). Secondary endpoints included pathologically complete response (pCR) rate, R0 resection rate, mortality and morbidity. Among the 370 patients, 311 (84.1%) were male with a median age of 63 (range: 30-81) years and stage III or IVa disease accounted for 84.1% of these patients. A total of 299 (80.8%) patients were treated with ICIs and chemotherapy. TRAEs were observed in 199 (53.8%) patients with low severity (grade 1-2, 39.2%; grade 3-4, 13.2%; grade 5, 1.4%), and irAEs occurred in 24.3% of patients and were mostly of grade 1-2 severity (21.1%). A total of 341 (92.2%) patients had received surgery and R0 resection was achieved in 333 (97.7%) patients. The local pCR rate in primary tumor was 34.6%, including 25.8% of ypT0N0 and 8.8% of ypT0N+. The rate of postoperative complications was 41.4% and grade 3 or higher complications occurred in 35 (10.3%) patients. No death was observed within 30 days after surgery, and three patients (0.9%) died within 90 days postoperatively. This study shows acceptable toxicity of neoadjuvant immunotherapy for locally advanced esophageal cancer in real-world data. Long-term survival results are pending for further investigations.

Three-arm phase II trial comparing camrelizumab plus chemotherapy versus camrelizumab plus chemoradiation versus chemoradiation as preoperative treatment for locally advanced esophageal squamous cell carcinoma (NICE-2 Study).

BACKGROUND: Preoperative chemoradiotherapy (CRT) with CROSS regimen has been the recommended treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The addition of programmed cell death protein 1 (PD-1) inhibitor to preoperative CRT may further improve oncologic results. Preoperative camrelizumab plus chemotherapy has been demonstrated as a promising treatment modality based on results of the phase II NICE study (ChiCTR1900026240). METHODS: The NICE-2 study is designed as a three-arm, multicenter, prospective, randomized, phase II clinical trial, comparing camrelizumab plus chemotherapy (IO-CT) and camrelizumab plus CRT (IO-CRT) versus CRT as preoperative treatment for locally advanced ESCC. A total of 204 patients will be recruited from 8 Chinese institutions within 1.5 years. The primary endpoint is pathological complete response (pCR) rate and secondary endpoints include event-free survival (EFS), R0 resection rate, and adverse events. DISCUSSION: This is the first prospective randomized controlled trial to explore commonly used neoadjuvant treatments in clinical practice, which will provide high-level evidence of neoadjuvant treatment for patients with locally advanced ESCC. The purpose of this study is to establish the optimal modality of IO-CT, IO-CRT and CRT as preoperative treatment for locally advanced ESCC. The Institution Review Committee approved this study protocol in August 2021 and patient enrollment was started in September 2021. TRIAL REGISTRATION: ClinicalTrial.gov: NCT05043688 (August 29, 2021). The trial was prospectively registered.