Explore the vast range of titles available.

Adjuvant chemotherapy has not improved disease-free survival among patients with resected esophageal or gastroesophageal junction cancer. In this trial, after neoadjuvant chemoradiotherapy and resection, patients with residual disease were randomly assigned to receive nivolumab or placebo. Nivolumab doubled the median disease-free survival from 11.0 to 22.4 months.

Background Anti-programmed cell death-1 (PD-1) immunotherapy and platinum-based chemotherapy are key components of first-line treatment for advanced Gastric or Gastroesophageal Junction (G/GEJ) cancer. However, the role of immune cells infiltrating the tumor microenvironment (TME) in predicting both therapy responses is still unclear. Methods ORIENT-16 is a randomized, double-blind, placebo-controlled, phase 3 clinical trial, and enrolled 650 patients with unresectable locally advanced or metastatic G/GEJ cancer between January 3, 2019, and August 5, 2020. For patients enrolled from the First Affiliated Hospital of Zhejiang University School of Medicine, we analyzed progression-free survival(PFS) and overall survival (OS) based on PD-L1 expression and landmark analysis, and developed a multiplexed immunofluorescence (mIF) assay for CD4, CD8, PD-L1, CD68 and FoxP3 coupled with digital image analysis and machine learning to assess prognostic survival associations of immune cells. Results A total of 54 eligible patients were enrolled in this study, 35 received sintilimab plus platinum-based chemotherapy and 19 received placebo plus platinum-based chemotherapy. For patients with PD-L1 combined positive score (CPS) < 10, survival disparities between anti-PD-1 immunotherapy and chemotherapy emerged 300 days post-treatment. High PD-L1 expression correlated with longer survival in anti-PD-1 therapy but less benefit in platinum-based chemotherapy. The mIF analysis also demonstrated significantly higher stromal PD-L1 density in immunotherapy responders, but tended to be lower in chemotherapy responders. Besides, high tumor stromal CD8 expression could be used as a positive biomarker in anti-PD-1 immunotherapy, and high tumor stromal CD4 expression was found associated with worse prognosis in platinum-based chemotherapy. Conclusions Increased PD-L1 expression was associated with an increased effect on anti-PD-1 immunotherapy and reduced benefit from chemotherapy. The signature of TME immune cells has the potential to predict the response of anti-PD-1 immunotherapy and chemotherapy in G/GEJ cancer. Trial registration ClinicalTrials.gov Identifier: NCT03745170.

Background Esophagogastric adenocarcinoma (EGA) currently represents a main cause of cancer related death. Despite an intensified treatment for locally advanced or metastatic EGA with a doublet chemotherapy consisting of a platinum compound and a fluoropyrimidine in combination with trastuzumab for HER2-positive disease or in selected cases with docetaxel, survival remains poor. Recently, immune-oncology based strategies relevantly improved the treatment of different solid tumors and showed some promise in late or later stage trials in EGA. Notably, the combination of immunotherapy with trastuzumab to enhance anti-tumor immunity through activation of innate and adaptive immunity was beneficial in preclinical studies or clinical studies in breast cancer. Methods The INTEGA study is an open-label, randomized, multicenter, exploratory phase II trial designed to assess clinical performance, safety and tolerability of ipilimumab or 5-FU/folinic acid and oxaliplatin (FOLFOX) in combination with nivolumab and trastuzumab in patients with previously untreated HER2-positive, locally advanced or metastatic EGA. The primary objective is to determine the clinical performance of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in terms of overall survival. Secondary objectives are safety and tolerability, efficacy in terms of progression-free survival and objective response rate and blood-based signatures (e.g. immune response or suppression of anti-HER2 resistance) that may correlate with treatment response. Discussion Recent evidence from the phase II NCT02954536 study (oxaliplatin, capecitabine, trastuzumab and pembrolizumab) suggests the clinical feasibility of combining chemotherapy, trastuzumab and checkpoint inhibition in EGA. However, evidence for a chemotherapy-free regimen is also mounting in HER2-positive disease (NCT02689284) i.e. margetuximab and Pembrolizumab. Both studies excelled with high overall response rates and manageable toxicities. The INTEGA study aims to comparatively assess these results and select a promising new 1st line regimen which then needs to be confirmed in a randomized phase III trial. Further, the translational part of the study might help to better stratify patients and tailor treatment of either arm. Trial registration NCT03409848 24.01.2018.

BackgroundS-588410, a cancer peptide vaccine (CPV), comprises five HLA-A*24:02-restricted peptides from five cancer-testis antigens. In a phase 2 study, S-588410 was well-tolerated and exhibited antitumor efficacy in patients with urothelial cancer. Therefore, we aimed to evaluate the efficacy, immune response, and safety of S-588410 in patients with completely resected esophageal squamous cell carcinoma (ESCC).MethodsThis phase 3 study involved patients with HLA-A*24:02-positive and lymph node metastasis-positive ESCC who received neoadjuvant therapy followed by curative resection. After randomization, patients were administered S-588410 and placebo (both emulsified with Montanide™ ISA 51VG) subcutaneously. The primary endpoint was relapse-free survival (RFS). The secondary endpoints were overall survival (OS), cytotoxic T-lymphocyte (CTL) induction, and safety. Statistical significance was tested using the one-sided weighted log-rank test with the Fleming–Harrington class of weights.ResultsA total of 276 patients were randomized (N = 138/group). The median RFS was 84.3 and 84.1 weeks in the S-588410 and placebo groups, respectively (P = 0.8156), whereas the median OS was 236.3 weeks and not reached, respectively (P = 0.6533). CTL induction was observed in 132/134 (98.5%) patients who received S-588410 within 12 weeks. Injection site reactions (137/140 patients [97.9%]) were the most frequent treatment-emergent adverse events in the S-588410 group. Prolonged survival was observed in S-588410-treated patients with upper thoracic ESCC, grade 3 injection-site reactions, or high CTL intensity.ConclusionsS-588410 induced immune response and had acceptable safety but failed to reach the primary endpoint. A high CTL induction rate and intensity may be critical for prolonging survival during future CPV development.

Signaling pathway between human leukocyte antigen (HLA)-G and immune inhibitory receptors immunoglobulin-like transcript (ILT)-2/4 has been acknowledged as one of immune checkpoints, and as a potential target for cancer immunotherapy. Like other immune checkpoints, inter- and even intratumor heterogeneity of HLA-G could render a rather complexity for HLA-G-target immunotherapy. However, little information for intratumor heterogeneity of HLA-G is available. In this study, HLA-G expression in a serial section of colorectal cancer (CRC) lesions from three CRC patients (each sample with serial section of 50 slides, 10 randomized slides for each antibody), three different locations within a same sample (five CRC), and three case-matched blocks that each includes 36 esophageal cancer samples, were evaluated with immunohistochemistry using anti-HLA-G antibodies (mAbs 4H84, MEM-G/1 and MEM-G/2 probing for all denatured HLA-G isoforms, 5A6G7, and 2A12 probing for denatured HLA-G5 and HLA-G6 isoforms). Our results revealed that, in addition to the frequently observed inter-tumor heterogeneity, intratumor heterogeneous expression of HLA-G is common in different areas within a tumor in CRC and esophageal cancer samples included in this study. Moreover, percentage of HLA-G expression probed with different anti-HLA-G antibodies also varies dramatically within a tumor. Given HLA-G has been considered as an important immune checkpoint, intratumor heterogeneity of HLA-G expression, and different specificity of anti-HLA-G antibodies being used among studies, interpretation and clinical significance of HLA-G expression in cancers should be with caution.

Background Our aim was to investigate the influence of FTS on human cellular and humoral immunity using a randomized controlled clinical study in esophageal cancer patients. Methods Between October 2013 and December 2014, 276 patients with esophageal cancer in our department were enrolled in the study. The patients were randomized into two groups: FTS pathway group and conventional pathway group. The postoperative hospital stay, hospitalization expenditure, and postoperative complications were recorded. The markers of inflammatory and immune function were measured before operation as well as on the 1st, 3rd, and 7th postoperative days (POD), including serum level of interleukin-6 (IL-6), C-reactive protein (CRP), serum globulin, immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA) and lymphocyte subpopulations (CD3 lymphocytes, CD4 lymphocytes, CD8 lymphocytes and the CD4/CD8 ratio) in the patients between the two groups. Results In all, 260 patients completed the study: 128 in the FTS group and 132 in the conventional group. We found implementation of FTS pathway decreases postoperative length of stay and hospital charges ( P  < 0.05). In addition, inflammatory reactions, based on IL-6 and CRP levels, were less intense following FTS pathway compared to conventional pathway on POD1 and POD3 ( P  < 0.05). On POD1 and POD3, the levels of IgG, IgA, CD3 lymphocytes, CD4 lymphocytes and the CD4/CD8 ratio in FTS group were significantly higher than those in control group (All P  < 0.05). However, there were no differences in the level of IgM and CD8 lymphocytes between the two groups. Conclusions FTS improves postoperative clinical recovery and effectively inhibited release of inflammatory factors via the immune system after esophagectomy for esophageal cancer. Trial registration ChiCTR-TRC-13003562 , the date of registration: August 29, 2013.

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.

BackgroundPrevious studies have reported that the amplification of some genes, such as Murine Double Minute 2 or 4 and Epidermal Growth Factor Receptor (EGFR), may be related to hyperprogressive disease (HPD). Exploring somatic gene alterations might be an effective method to predict HPD. Herein we characterize the somatic alterations in a patient with esophageal squamous cell carcinoma (ESCC) who developed HPD to investigate the potential origins of HPD.Case presentationA man in his mid-40s was diagnosed with ESCC. After the failure of first-line treatment with cisplatin and docetaxel, the patient participated in a phase III randomized, open, multicenter clinical trial (CTR20170307) and subsequently received camrelizumab. After 4 weeks of immunotherapy, the tumor size increased by 79% compared with baseline imaging; the progressive pace was 2.5-fold higher than preimmunotherapy, and a new liver metastasis appeared. A rare EGFR exon 2–28 duplication was discovered in both preimmunotherapy and postimmunotherapy tumor tissues.ConclusionThis is the first report on a patient with ESCC harboring rare EGFR kinase domain duplication in exons 2–28 and developing HPD in the process of camrelizumab treatment. This case suggested that EGFR kinase domain duplication might be associated with HPD. Administration of immune checkpoint inhibitor monotherapy in this subgroup of patients harboring EGFR kinase domain duplication should be performed with caution. These results need to be further confirmed in a larger cohort of patients.

Background This study was performed as a substudy analysis of a randomized trial comparing conventional open esophagectomy [open surgical technique (OE)] by thoracotomy and laparotomy with minimally invasive esophagectomy [minimally invasive procedure (MIE)] by thoracoscopy and laparoscopy. This additional analysis focuses on the immunological changes and surgical stress response in these two randomized groups of a single center. Methods Patients with a resectable esophageal cancer were randomized to OE ( n  = 13) or MIE ( n  = 14). All patients received neoadjuvant chemoradiotherapy. The immunological response was measured by means of leukocyte counts, HLA-DR expression on monocytes, the acute-phase response by means of C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-8 (IL-8), and the stress response was measured by cortisol, growth hormone, and prolactin. All parameters were determined at baseline (preoperatively) and 24, 72, 96, and 168 h postoperatively. Results Significant differences between the two groups were seen in favor of the MIE group with regard to leukocyte counts, IL-8, and prolactin at 168 h (1 week) postoperatively. For HLA-DR expression, IL-6, and CRP levels, there were no significant differences between the two groups, although there was a clear rise in levels upon operation in both groups. Conclusion In this substudy of a randomized trial comparing minimally invasive and conventional open esophagectomies for cancer, significantly better preserved leukocyte counts and IL-8 levels were observed in the MIE group compared to the open group. Both findings can be related to fewer respiratory infections found postoperatively in the MIE group. Moreover, significant differences in the prolactin levels at 168 h after surgery imply that the stress response is better preserved in the MIE group. These findings indicate that less surgical trauma could lead to better preserved acute-phase and stress responses and fewer clinical manifestations of respiratory infections.

Background. Monocytic human leukocyte antigen D related (mHLA-DR) is essential for antigen-presentation. Downregulation of mHLA-DR emerged as a general biomarker of impaired immunity seen in patients with sepsis and pneumonia and after major surgery. Influencing factors of mHLA-DR such as age, overweight, diabetes, smoking, and gender remain unclear. Methods. We analyzed 20 patients after esophageal or pancreatic resection of a prospective, randomized, placebo-controlled, double-blind trial (placebo group). mHLA-DR was determined from day of surgery (od) until postoperative day (pod) 5. Statistical analyses were performed using multivariate generalized estimating equation analyses (GEE), nonparametric multivariate analysis of longitudinal data, and univariate post hoc nonparametric Mann–Whitney tests. Results. In GEE, smoking and gender were confirmed as significant influencing factors over time. Univariate analyses of mHLA-DR between smokers and nonsmokers showed lower preoperative levels (p=0.010) and a trend towards lower levels on pod5 (p=0.056) in smokers. Lower mHLA-DR was seen in men on pod3 (p=0.038) and on pod5 (p=0.026). Overweight patients (BMI > 25 kg/m2) had lower levels of mHLA-DR on pod3 (p=0.039) and pod4 (p=0.047). Conclusion. Smoking is an important influencing factor on pre- and postoperative immune function while postoperative immune function was influenced by gender and overweight. Clinical trial registered with ISRCTN27114642.