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Background Although neoadjuvant chemotherapy and immunotherapy show promise in treating oesophageal squamous cell carcinoma (OSCC), long-term survival data are limited. This randomized, multicenter phase 2 study evaluated the efficacy of perioperative Nivolumab with chemotherapy, followed by surgery and adjuvant immunotherapy, in patients with locally advanced resectable OSCC, and explored the prognostic role of circulating tumor DNA (ctDNA) status. Methods In this trial, participants recruited from five centers were randomly assigned in a 2:1 ratio to receive either perioperative Nivolumab or a placebo in addition to chemotherapy (cisplatin and paclitaxel), followed by minimally invasive esophagectomy. For those who did not achieve a pathological complete response (pCR), adjuvant treatment with Nivolumab was administered. The main measure of success was the pCR rate, with secondary endpoints including the R0 resection rate, event-free survival, and overall survival. All outcomes and safety measures were assessed based on the intention-to-treat population. ctDNA levels were monitored as exploratory endpoints. Results Ninety patients were enrolled and randomized to Nivolumab or placebo plus chemotherapy. The pCR rate was slightly higher in the Nivolumab group (15%) compared to the control group (13.3%) (relative risk, 1.13; 95% CI, 0.38 to 3.36). No significant differences were observed in R0 resection rates (96.4% vs. 96.6%; P  > 0.05). The median follow-up duration was 24.9 months (interquartile range: 22.8 to 26.7 months). Two-year event-free survival rates were 63.11% in the Nivolumab group versus 60.47% in the chemo group (hazard ratio, 0.97; 95% CI, 0.49 to 1.92). Two-year overall survival rates were 83.32% and 79.4%, respectively (hazard ratio, 0.82; 95% CI, 0.29 to 2.31). All participants were ctDNA positive at baseline, but post-treatment, 89% of the Nivolumab group and 62.5% of the placebo group turned ctDNA negative ( P  = 0.01). Those negative for ctDNA at all testing points showed significantly better disease-free survival ( P  < 0.001). Conclusions Perioperative Nivolumab plus chemotherapy is a viable and safe option for systemically treating locally advanced resectable OSCC. Monitoring minimal residual disease through ctDNA could be potentially valuable for assessing the effectiveness of adjuvant therapy and for prognostic evaluation in a systemic manner. Trial registration ClinicalTrials.gov registration NCT05213312.

Purpose The aim of this study was to characterize trastuzumab population pharmacokinetics (PKs) in patients with human epidermal growth factor receptor 2-positive advanced gastric or gastroesophageal junction cancer and the relationship of trastuzumab PK with patient response. Methods A nonlinear mixed effects PK model was built using data from the ToGA study. Patients were randomized to intravenous trastuzumab plus chemotherapy or chemotherapy alone. The influence of demographic, laboratory, and disease characteristics on PK parameters was assessed. An exploratory exposure–response analysis compared various PK parameters at steady state with best overall tumor response and overall survival (OS). Results Trastuzumab PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. Total clearance (and half-life) of trastuzumab was concentration-dependent. Body weight, prior gastrectomy, and serum albumin had the greatest influence on trastuzumab PK; increasing weight and decreasing albumin levels were associated with increased clearance, while prior gastrectomy correlated with decreased clearance. Median values for AUC, C max , and C min were lower in patients with progressive disease (PD) than other response categories, although the 1.5 interquartile ranges overlapped. Patients with the lowest C min had the highest PD rate and a shorter OS. Conclusions In the advanced gastric cancer population, trastuzumab PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Predicted PK exposure was lower than previously reported for breast cancer. Patients with the lowest C min had a shorter OS and the highest PD rate, but a distinct correlation was not observed for tumor response.

Background Esophageal cancer (EC) is a highly lethal disease lacking early detection approaches. We previously identified that OTOP2 and KCNA3 were specifically hypermethylated in circulating cell-free DNA from patients with EC. We then developed a blood-based methylation assay targeting OTOP2 and KCNA3 (named “IEsohunter”) for esophageal cancer noninvasive detection. This double-blinded, multicenter, prospective study aimed to comprehensively evaluate its clinical diagnostic performance. Methods Participants with EC, high-grade intraepithelial neoplasia (HGIN), other malignancies, benign gastrointestinal lesions, or no abnormalities were prospectively enrolled from 5 tertiary referral centers across China. Peripheral blood samples were collected, followed by plasma cell-free DNA methylation analysis using the IEsohunter test based on multiplex quantitative polymerase chain reaction adopting an algorithm-free interpretation strategy. The primary outcome was the diagnostic accuracy of IEsohunter test for EC. Results We prospectively enrolled 1116 participants, including 334 patients with EC, 71 with HGIN, and 711 controls. The areas under the receiver operating characteristic curves of the IEsohunter test for detecting EC and HGIN were 0.903 (95% CI 0.880–0.927) and 0.727 (95% CI 0.653–0.801), respectively. IEsohunter test showed sensitivities of 78.5% (95% CI 69.1–85.6), 87.3% (95% CI 79.4–92.4), 92.5% (95% CI 85.9–96.2), and 96.9% (95% CI 84.3–99.8) for stage I-IV EC, respectively, with an overall sensitivity of 87.4% (95% CI 83.4–90.6) and specificity of 93.3% (95% CI 91.2–94.9) for EC detection. The IEsohunter test status turned negative (100.0%, 47/47) after surgical resection of EC. Conclusions The IEsohunter test showed high diagnostic accuracy for EC detection, indicating that it could potentially serve as a tool for noninvasive early detection and surveillance of EC.

Omega-3 (ω-3) fatty acids have potential positive effects during chemotherapy, such as body weight maintenance and muscle mass preservation. However, little is known about the effect this supplement might have on reducing chemotherapy-induced toxicities. The aim of this study was to determine the usefulness of ω-3 fatty acid supplementation in the reduction of chemotherapy-related toxicities. Sixty-one patients undergoing neoadjuvant chemotherapy for esophageal cancer randomly received ω-3–rich enteral nutrition (EN; n = 31) or ω-3–poor EN support (n = 30) for 15 d during chemotherapy. The daily dosage of ω-3 fatty acids was 900 mg in the ω-3–rich group and 250 mg in the ω-3–poor group. The primary endpoint was the frequency of grade 3/4 neutropenia, and secondary endpoints included other chemotherapy-related adverse events, body weight, and inflammatory markers. The total and dietary intake calories during chemotherapy were equal in both groups. There was no significant difference in the body weight change after chemotherapy between the two groups. There was no significant difference in the incidence of grade 3/4 leukopenia and neutropenia (P > 0.05). However, stomatitis was significantly less frequent in the ω-3–rich group, than in the ω-3–poor group (P = 0.018). Grade 3/4 diarrhea occurred relatively less frequently in the ω-3–rich group than in the ω-3–poor group; however, this difference was not significant (16.1% versus 36.7%, respectively, P = 0.068). Increases in the aspartate aminotransferase and alanine aminotransferase levels were seen significantly less frequently in the ω-3–rich group than in the ω-3–poor group (P = 0.012 and P = 0.015, respectively). ω-3–rich EN support decreased the frequency of chemotherapy-induced mucosal toxicities, such as stomatitis and diarrhea, and exhibited a hepatoprotective effect during chemotherapy, compared with the ω-3–poor EN support. •Little is known about the effect of ω-3 fatty acids on reducing chemotherapy-related toxicities.•A randomized study was conducted to compare ω-3–rich enteral nutrition (EN) with ω-3–poor EN in patients undergoing cisplatin-based chemotherapy.•ω-3–rich EN reduced the incidence of chemotherapy-related mucosal toxicities and had a hepatoprotective effect during chemotherapy.

Background Oesophagectomy is a major oncological surgical procedure. Previous studies have shown a wide range of bleeding during and after surgery, and it is unknown if perioperative bleeding associated with oesophagectomy is purely surgical in nature, or if it is exacerbated by impaired haemostasis. We aimed to perform a detailed investigation of the perioperative coagulation in patients undergoing oesophagectomy due to cancer. Methods The study was a prospective study including adult patients with adeno- or squamous cell carcinoma referred for intended curative oesophagectomy. Operative bleeding volume and blood transfusions were recorded. Blood samples were collected at three timepoints: before, at the end of surgery, and on postoperative day one. Dynamic global haemostasis was investigated employing thromboelastometry (ROTEM®). Platelet aggregation was analysed with a Multiplate Analyzer®, and routine coagulation parameters were analysed. Results We included 87 patients. Patients bled a median of 300 mL during surgery. One patient bled 1830 mL, while the remaining patients bled ≤1000 mL. Blood transfusions were administered to 14 (16%) patients. Median platelet aggregation was within the reference ranges at all time points. Platelet aggregation increased during surgery and normalised within 24 h. ROTEM® analyses showed no perioperative significantly decrease of clot formation or clot strength. Routine coagulation parameters were overall normal. Conclusions Severe perioperative bleeding was rare, and transfusions of blood products were used sparingly. Patients undergoing oesophagectomy due to cancer had an intact haemostasis with no sign of impaired haemostasis. Clinical trial registration The trial was registered prior to initiation at www.clinicaltrials.gov (identification number NCT05067153).

Purpose This study aims to investigate the influence of fast-track surgery (FTS) on insulin resistance indicators in a prospective randomized, controlled clinical trial in esophageal cancer patients. Methods Between November 2009 and March 2011, 34 patients underwent the FTS pathway, and 34 patients underwent the conventional pathway after esophagectomy in our department. The times to postoperative flatus and defecation, duration of postoperative hospital stay, hospitalization expenditures, and postoperative complications were recorded. Insulin resistance indicators were measured before operation as well as on the 1st, 3rd, and 7th postoperative days (PODs), including serum levels of fasting blood glucose (FBG), fasting insulin (FINS), interleukin-6 (IL-6), and C-reactive protein (CRP) in patients of both groups. The insulin resistance index (homeostasis model assessment of insulin resistance (HOMA-IR)) was calculated at each time point. Results We found a significantly shorter postoperative hospital stay and faster return of gastrointestinal function in patients who underwent FTS ( P  < 0.01). In addition, the total hospitalization expenditure was significantly lower in the FTS group ( P  < 0.01). The preoperative insulin resistance indicators showed no significant differences between the two groups. On PODs 1 and 3, the levels of log-HOMA-IR, FINS, IL-6, and CRP in the FTS group were significantly lower than those in the control group (all P  < 0.05). On POD 7, the CRP level in the FTS group was significantly lower than that in the control group ( P  < 0.05). Conclusions FTS promotes early recovery of gastrointestinal function and reduces stress reaction and postoperative insulin resistance after esophagectomy for esophageal cancer.

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.

To investigate the feasibility and safety of a 24-week exercise intervention, compared to control, in males with Barrett's oesophagus, and to estimate the effect of the intervention, compared to control, on risk factors associated with oesophageal adenocarcinoma development. A randomized controlled trial of an exercise intervention (60 minutes moderate-intensity aerobic and resistance exercise five days/week over 24 weeks; one supervised and four unsupervised sessions) versus attention control (45 minutes stretching five days/week over 24 weeks; one supervised and four unsupervised sessions) in inactive, overweight/obese (25.0-34.9 kg/m2) males with Barrett's oesophagus, aged 18-70 years. Primary outcomes were obesity-associated hormones relevant to oesophageal adenocarcinoma risk (circulating concentrations of leptin, adiponectin, interleukin-6, tumour necrosis factor-alpha, C-reactive protein, and insulin resistance [HOMA]). Secondary outcomes included waist circumference, body composition, fitness, strength and gastro-oesophageal reflux symptoms. Outcomes were measured at baseline and 24-weeks. Intervention effects were analysed using generalised linear models, adjusting for baseline value. Recruitment was difficult in this population with a total of 33 participants recruited (target sample size: n = 80); 97% retention at 24-weeks. Adherence to the exercise protocol was moderate. No serious adverse events were reported. A statistically significant intervention effect (exercise minus control) was observed for waist circumference (-4.5 [95% CI -7.5, -1.4] cm; p < 0.01). Effects on primary outcomes were not statistically significant. This small, exploratory trial provides important information to inform future trial development including recruitment rates and estimates of effect sizes on outcomes related to oesophageal adenocarcinoma risk. Future trials should investigate a combined dietary and exercise intervention to achieve greater weight loss in this population and relax inclusion criteria to maximize recruitment. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000401257.

Background Recent studies have demonstrated that long non-coding RNAs (lncRNAs) were present in the blood of cancer patients and have shown great potential as powerful and non-invasive tumor markers. However, little is known about the value of lncRNAs in the diagnosis of esophageal squamous cell carcinoma (ESCC). We hypothesized that ESCC-related lncRNAs might be released into the circulation during tumor initiation and could be utilized to detect and monitor ESCC. Methods Ten lncRNAs ( HOTAIR , AFAP1-AS1 , POU3F3 , HNF1A-AS1 , 91H , PlncRNA1 , SPRY4-IT1 , ENST00000435885.1 , XLOC_013104 and ENST00000547963.1 ) which previously found to be differently expressed in esophageal cancer were selected as candidate targets for subsequent circulating lncRNA assay. A four-stage exploratory study was conducted to test the hypothesis: (1) optimization of detected method to accurately and reproducibly measure ESCC-related lncRNAs in plasma and serum; (2) evaluation of the stability of circulating lncRNAs in human plasma or serum; (3) exploration the origin of ESCC-related lncRNAs in vitro and in vivo; (4) evaluation the diagnostic power of circulating lncRNAs for ESCC. Results ESCC-related lncRNAs were detectable and stable in plasma of cancer patients, and derived largely from ESCC tumor cells. Furthermore, plasma levels of POU3F3 , HNF1A-AS1 and SPRY4-IT1 were significantly higher in ESCC patients compared with normal controls. By receiver operating characteristic curve (ROC) analysis, among the three lncRNAs investigated, plasma POU3F3 provided the highest diagnostic performance for detection of ESCC (the area under the ROC curve (AUC), 0.842; p  < 0.001; sensitivity, 72.8%; specificity, 89.4%). Moreover, use of POU3F3 and SCCA in combination could provide a more effective diagnosis performance (AUC, 0.926, p  < 0.001, sensitivity, 85.7%; specificity, 81.4%). Most importantly, this combination was effective to detect ESCC at an early stage (80.8%). Conclusions Plasma POU3F3 could serve as a potential biomarker for diagnosis of ESCC, and the combination of POU3F3 and SCCA was more efficient for ESCC detection, in particular for early tumor screening.

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1 /2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort ( n  = 508). Furthermore, knockdown of BRCA1 /2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment. Esophageal squamous cell carcinoma (ESCC) is highly prevalent in China. Here, the authors carry out multi-region sampling of Chinese ESCC samples, and find recurrent ERBB4 mutations, BRCA1/2 variants, and amplification of CD274 ; together with high levels of genomic and T-cell receptor heterogeneity.