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Esophageal cancer (EC) has a high incidence and poor prognosis. The two major histological types, squamous cell carcinoma and adenocarcinoma, differ in their epidemiology and treatment options. Patients with locally advanced EC benefit from multimodal therapy concepts including neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, and perioperative chemotherapy. Currently, immunotherapy for the solid tumor is a hot spot. Treatment with adjuvant immune checkpoint inhibitors (ICIs) is the first immunotherapy for resectable EC listed in the latest National Comprehensive Cancer Network Guidelines for the Esophageal and Esophagogastric Junction Cancers. Recent clinical trials have established ICIs for three treatment models of resectable EC. Their short-term results demonstrated ideal efficacy and tolerable toxicity, though some concerns remain. This review summarizes the novel data on the ICIs for resectable EC and lists the registered related clinical trials. Hopefully, this review can provide a reference for ongoing research on the treatment options for resectable EC.

Background For resectable adenocarcinoma of the esophagogastric junction (AEG), current treatment exploration primarily focuses on perioperative chemotherapy regimens combined with PD-1/PD-L1 inhibitors, but the long-term survival benefits of still require further investigation, and the use of upfront immunotherapy is typically restricted to patients with metastatic MSI-H (M1 MSI-H) disease due to their potential responsiveness to immunological agents. Adebrelimab, as a novel PD-L1 antibody, has not yet been proven for its efficacy and safety in adenocarcinoma of the esophagogastric junction. Methods The AEGIS study is a prospective, open-labeled, single-arm, phase II clinical trial. A total of 26 patients with AEG will be enrolled. The primary endpoint is the pathologic complete response (pCR) rate after perioperative neoadjuvant immunochemotherapy. Secondary outcomes of the study include the objective response rate (ORR), R0 resection rate, major pathological response (MPR) rate, and pCR rate in combined positive score(CPS) ≥ 5 and MSI-H populations, event-free survival (EFS), and overall survival (OS). The exploratory outcomes are the biomarkers related to therapeutic efficacy, such as PD-L1 expression, microsatellite instability (MSI), tumor mutational burden(TMB), Epstein-Barr virus(EBV) infection, and circulating tumor DNA(ctDNA). Discussion This trail aims to verify the efficacy and safety of the perioperative treatment regimen of anti-PD-L1 (Adebrelimab) combined with chemotherapy (capecitabine plus oxaliplatin, XELOX) for patients with resectable AEG. Considering the differences in chemotherapy regimen tolerance between Asian and Western populations, this study intends to evaluate the suitability of Adebrelimab combined with XELOX chemotherapy for the Asian population. Trial registration ClinicalTrials.gov: NCT06482788. The trial was prospectively registered on 22 May 2024, https://clinicaltrials.gov/study/NCT06482788 .

IntroductionCombining immunotherapy with neoadjuvant chemoradiotherapy (neoCRT) has been shown to be safe, achieving a pathological complete response (pCR) rate of 56% in patients with locally advanced oesophageal squamous cell carcinoma (ESCC) in the PALACE-1 trial. This high pCR rate encourages us to explore the feasibility of postponing surgery after immunotherapy combined with neoCRT under active surveillance. This study aims to assess the efficacy, safety and patient-reported quality of life (QOL) of camrelizumab combined with neoCRT and watch-and-wait strategy versus neoCRT followed by surgery in locally advanced resectable ESCC.Methods and analysisThe PALACE-3 trial is a multicentre, open-label, randomised non-inferiority trial expected to recruit 356 patients from six high-volume centres in China. The study is planned to start in May 2024 and end in December 2028. Eligible patients will be randomly assigned (1:1 ratio) to either camrelizumab combined with neoCRT and watch-and-wait strategy or neoCRT followed by surgery (standard surgery). In the active surveillance group, patients achieving a clinical complete response (cCR) to camrelizumab combined with neoCRT will undergo active surveillance, while those with residual disease or locoregional recurrence will undergo immediate surgery. Patients in the standard surgery group will proceed to surgery after neoCRT. The primary endpoint is the 3-year overall survival (OS) rate. The secondary endpoints include cCR rate, salvage surgery incidence, objective response rate, adverse events during the neoadjuvant therapy, pCR, tumour regression grade, R0 resection rate, lymph node ratio, perioperative complications, disease-free survival (DFS) and 3-year DFS rate, OS and health-related QOL.Ethics and disseminationThis study has been approved by the Ethics Committee of Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital (Shanghai, China), as well as the ethics committees of the following participating centres: National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China); Sichuan Cancer Hospital and Institute, Sichuan Cancer Centre, School of Medicine, University of Electronic Science and Technology of China (Chengdu, China); The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital (Zhengzhou, China); Fujian Medical University Union Hospital (Fuzhou, China). Complete information about the study status, relevant events and results will be regularly updated on the project’s webpage on ClinicalTrials.gov. Written informed consent (Supplemental Material) will be obtained from each participant. All research outputs will be published in peer-reviewed journals and presented at national or international conferences.Trial registration numberThe trial was meticulously registered in advance on 1 April 2024 and can be accessed through the following link: https://www.clinicaltrials.gov/study/NCT06339060. The current protocol version number is V.2.0, and the protocol date is 30 June 2024.

Background The ultrasonic scalpel is widely used during surgery. It is safe and effective to close the pulmonary artery branch vessels of 7 mm or below with an ultrasonic energy device as reported. However, there have been no multicenter randomized clinical trial to assess the safety and effectiveness of using ultrasonic scalpel to coagulate 5–7 mm blood vessels in thoracic surgery. Methods This is a prospective, multicenter, randomized, parallel controlled, non-inferiority clinical trial. A total of 144 eligible patients planning to undergo lung or esophageal surgery will be randomly allocated to the experimental group and the control group. The investigational product (Disposable Ultrasonic Shears manufactured by Reach Surgical, Inc.) and the control product (Harmonic Ace + 7, 5 mm Diameter Shears with Advanced Hemostasis) will be used in each group. The primary endpoint is the success rate of coagulating target blood vessels during surgery. Secondary endpoints include postoperative rebleeding, intraoperative bleeding volume, drainage volume, surgical duration, etc. Postoperative follow-up before and after discharge will be performed. Discussion This clinical trial aims to evaluate the safety and effectiveness of using the investigational product (Disposable Ultrasonic Shears manufactured by Reach Surgical, Inc.) and that of the control product (Harmonic Ace + 7, 5 mm Diameter Shears with Advanced Hemostasis) to coagulate 5–7 mm blood vessels in thoracic surgery. Trial registration ClinicalTrials.gov: NCT06002737. The trial was prospectively registered on 16 August 2023, https://www.clinicaltrials.gov/study/NCT06002737 .

Background We developed a novel concept, equivalent uniform length (EUL), to describe the relationship between the generalized equivalent uniform dose (EUD) and the geometric anatomy around a tumor target. By correlating EUL with EUD, we established two EUD–EUL knowledge-based (EEKB) prediction models for the bladder and rectum that predict initial EUD values for generating quality treatment plans. Methods EUL metrics for the rectum and bladder were extracted and collected from the intensity-modulated radiotherapy therapy (IMRT) plans of 60 patients with cervical cancer. The two EEKB prediction models were built using linear regression to establish the relationships between EUL r and EUD r (EUL and EUD of rectum) and EUL b , and EUD b (EUL and EUD of bladder), respectively. The EE plans were optimized by incorporating the predicted initial EUD parameters for the rectum and bladder with the conventional pinnacle auto-planning (PAP) initial dose parameters for other organs. The efficiency of the predicted initial EUD values were then evaluated by comparing the consistency and quality of the EE plans, PAP plans (based on default PAP initial parameters), and manual plans (designed manually by different dosimetrists) for a sample of 20 patients. Results Linear regression analyses showed a significant correlation between EUL and EUD (R 2  = 0.79 and 0.69 for EUD b and EUD r , respectively). In a sample of 20 patients, the average bladder V40 and V50 derived from the EE plans were significantly lower (V40: 30.00 ± 5.76, V50: 14.36 ± 4.00) than the V40 and V50 values derived from manual plans (V40: 36.03 ± 8.02, V50: 19.02 ± 5.42). Compared with the PAP plans, the EE plans produced significantly lower average V30 and Dmean values for the bladder (V30: 50.55 ± 6.33, Dmean: 31.48 ± 1.97 Gy). Conclusions Our EEKB prediction models predicted reasonable initial EUD values for the rectum and bladder based on patient-specific geometric EUL values, thereby improving optimization and planning efficiency.

Background The Halcyon is a new machine from the Varian company. The purpose of this study was to evaluate the dosimetry of the Halcyon in treatment of bilateral breast cancer with volumetric modulated arc therapy. Methods On CT images of 10 patients with bilateral breast cancer, four Halcyon plans with different setup fields were generated, and dosimetric comparisons using Bonferroni’s multiple comparisons test were conducted among the four plans. Whole and partial arc plans on the Trilogy and the Halcyon, referred to as T-4arc, T-8arc, H-4arc and H-8arc, were designed. The prescription dose was 50 Gy in 2-Gy fractions. All plans were designed with the Eclipse version 15.5 treatment planning system. The dosimetric differences between whole and partial arc plans in the same accelerator were compared using the Mann–Whitney U test. The better Halcyon plan was selected for the further dosimetric comparison of the plan quality and delivery efficiency between the Trilogy and the Halcyon. Results Halcyon plans with high‐quality megavoltage cone beam CT setup fields increased the D mean , D 2 and V 107 of the planning target volume (PTV) and the V 5 and D mean of the heart, left ventricle (LV) and lungs compared with other Halcyon setup plans. The mean dose and low dose volume of the heart, lungs and liver were significantly decreased in T-8arc plans compared to T-4arc plans. In terms of the V 5 , V 20 , V 30 , V 40 and D mean of the heart, the V 20 , V 30 , V 40 and D mean of the LV, the V 30 , V 40 , D max and D mean of the left anterior descending artery (LAD), and the V 5 and V 40 of lungs, H-8arc was significantly higher than H-4arc ( p  < 0.05). Compared with the Trilogy’s plans, the Halcyon’s plans reduced the high-dose volume of the heart and LV but increased the mean dose of the heart. For the dose of the LAD and the V 20 and V 30 of lungs, there was no significant difference between the two accelerators. Compared with the Trilogy, plans on the Halcyon significantly increased the skin dose but also significantly reduced the delivery time. Conclusion For the Halcyon, the whole-arc plans have more dosimetric advantages than partial-arc plans in bilateral breast cancer radiotherapy. Although the mean dose of the heart and the skin dose are increased, the doses of the cardiac substructure and other OARs are comparable to the Trilogy, and the delivery time is significantly reduced.

Background PI3K-Akt pathway activation and the expression of histone deacetylases (HDACs) are highly increased in esophageal cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy. Herein, we aimed to evaluate the anti-tumor effect of CUDC-907, a dual PI3K-HDAC inhibitor, in esophageal squamous cell carcinoma (ESCC). Methods The anti-tumor effects of CUDC-907 in ESCC were evaluated using cell counting kit-8, flow cytometry, and western blot. mRNA-sequencing was used to explore the mechanism underlying CUDC-907 anti-tumor effects. The relations of reactive oxygen species (ROS), lipocalin 2 (LCN2), and CUDC-907 were determined by flow cytometry, rescue experiments, and western blot. The activation of the IRE1α-JNK-CHOP signal cascade was confirmed by western blot. The in vivo inhibitory effects of CUDC-907 were examined by a subcutaneous xenograft model in nude mice. Results CUDC-907 displayed effective inhibition in the proliferation, migration, and invasion of ESCC cells. Through an mRNA-sequencing and functional enrichment analysis, autophagy was found to be associated with cancer cells death. CUDC-907 not only inhibited the PI3K-Akt-mTOR pathways to result in autophagy, but also induced ROS accumulation to activate IRE1α-JNK-CHOP-mediated cytotoxic autophagy by downregulating LCN2 expression. Consistently, the in vivo anti-tumor effects of CUDC-907 accompanied by the downregulated expression of p-mTOR and LCN2 and upregulated expression of p-IRE1α and LC3B-II were evaluated in a xenograft mouse model. Conclusion Our findings suggested the clinical development and administration of CUDC-907 might act as a novel treatment strategy for ESCC. A more in-depth understanding of the anti-tumor effect of CUDC-907 in ESCC will benefit the clinically targeted treatment of ESCC.

Background The aim of the study was to analyze the relationship between pretreatment inflammatory biomarkers (IBs) and survival outcomes for patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (neo‐CRT) and pembrolizumab. Methods Clinical variables and IBs (absolute monocyte count [AMC], absolute lymphocyte count [ALC], platelet count [PLT], neutrophil‐to‐lymphocyte ratio [NLR], platelet‐to‐lymphocyte ratio [PLR], lymphocyte‐to‐monocyte ratio [LMR], pan‐immune inflammation value [PIV], systemic immunoinflammatory index [SII], systemic immunoreactivity index [SIRI] and prognostic nutritional index [PNI]) were collected. Univariate and multivariate analysis were performed to identify the independent factors for outcomes of ESCC. Results A total of 51 patients were included. Of these, 35 patients achieved pathological complete response (pCR) after neo‐CRT and pembrolizumab (pCR: 68.6%). With a median follow‐up of 20 months, the two‐year PFS and OS of the cohort was 64% and 91%, respectively. Multivariate logistic regression analysis indicated that ALC (overall response [OR] 4.4, p = 0.051) and PLT (OR 6.7, p = 0.023) were two independent predictors for achieving pCR among ESCC treated with neo‐CRT and pembrolizumab. Multivariate Cox regression analysis showed that ALC (HR 0.27, p = 0.028) and SIRI (HR 3.13, p = 0.048) were two independent predictors associated with PFS. Kaplan Meier analysis demonstrated that the PFS of ESCC with high baseline ALC was significantly better than those with low ALC (2‐year PFS: 77% vs. 47%, p = 0.027), but not for overall survival (2‐year OS: 96% vs. 87%, p = 0.46). Conclusions This retrospective analysis based on a prospective cohort for the first time demonstrates that pretreatment ALC is an independent predictor for achieving pCR and favorable outcomes of ESCC treated with neo‐CRT and pembrolizumab. Baseline absolute lymphocyte count (ALC) is associated with PFS among ESCC treated with neo‐CRT and pembrolizumab.

Background Neoadjuvant chemoradiation followed by esophagectomy has been established as the first-line treatment for locally advanced esophageal cancer. Postoperative enteral nutrition has been widely used to improve perioperative outcomes. However, whether to implement preoperative nutritional intervention during neoadjuvant therapy is yet to be verified by prospective studies. Methods POINT trial is a multicenter, open-labeled, randomized controlled trial. A total of 244 patients with surgically resectable esophageal cancer are randomly assigned to nutritional therapy group (arm A) or control group (arm B) with a 2:1 ratio. Both groups receive neoadjuvant chemotherapy with concurrent radiotherapy based on the CROSS regimen followed by minimally invasive esophagectomy. The primary endpoint is the rate of nutrition and immune-related complications after surgery. Secondary endpoints include completion rate of neoadjuvant chemoradiation and related adverse events, rate of pathological complete response, perioperative outcomes, nutritional status, overall survival, progression-free survival and quality of life. Discussion This trial aims to verify whether immunonutrition during neoadjuvant chemoradiation can reduce the rate of complications and improve perioperative outcomes. Frequent communication and monitoring are essential for a multicenter investigator-initiated trial. Trial registration: ClinicalTrials.gov: NCT04513418. The trial was prospectively registered on 14 August 2020, https://www.clinicaltrials.gov/ct2/show/NCT04513418 .

Background The Preoperative Immunonutrition Therapy (POINT) trial compares immunonutrition supplements with a regular diet for surgically resectable esophageal patients during neoadjuvant chemoradiotherapy. The last patient is expected to be included by the end of 2025. The purpose of this update is to present all amendments to the POINT trial protocol as approved by the Ethics Committee of Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital. Design The initial protocol of the POINT trial has been previously published ( https://doi.org/10.1186/s12885-022-09721-y ). In this ongoing, multicenter, open-labeled, randomized controlled trial, patients are randomly assigned to nutrition therapy group or control group with a 2:1 ratio. Patients in the nutrition therapy group received immune-enhanced enteral nutritional emulsion during the neoadjuvant chemoradiotherapy. Both groups receive neoadjuvant chemoradiotherapy with concurrent radiotherapy followed by minimally invasive esophagectomy. The primary outcome is the rate of nutrition and immune-related complications after surgery. Update Amendments to the participants include the addition of exclusion criteria and the specification of written informed consent. Amendments to the intervention include an extended window period from neoadjuvant chemoradiotherapy to surgery. Amendments to the outcome include two additional exploratory endpoints, which are minimal residual disease and differences in the distribution of gut microbiota and metabolomics before and after neoadjuvant chemoradiotherapy. An independent assessment committee has been established to perform ongoing safety surveillance outcome evaluation. Conclusion These amendments do not affect the overall outcomes of the trial compared to the original protocol. The last patient is expected to be included by the end of 2025.