Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by minimally invasive esophagectomy for locally advanced esophageal squamous cell carcinoma: a prospective multicenter randomized clinical trial.

BACKGROUND: Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) versus neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1 : 1) to the nCRT or nCT group stratified by age, cN stage, and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy was added for the nCRT group; then MIE was carried out. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov (NCT03001596). RESULTS: A total of 264 patients were eligible for the intention-to-treat analysis. By 30 November 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range 36.6-49.3 months). The overall survival in the intention-to-treat population was comparable between the nCRT and nCT strategies [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.58-1.18; P = 0.28], with a 3-year survival rate of 64.1% (95% CI 56.4% to 72.9%) versus 54.9% (95% CI 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR 0.83, 95% CI 0.59-1.16; P = 0.27) and recurrence-free survival (HR 1.07, 95% CI 0.71-1.60; P = 0.75), although the pathological complete response in the nCRT group (31/112, 27.7%) was significantly higher than that in the nCT group (3/104, 2.9%; P < 0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802). CONCLUSIONS: NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC.

Analysis of a registry database for esophageal cancer from high-volume centers in China.

Esophageal cancer has a high incidence among malignancies in China, but a comprehensive picture of the status of its surgical management in China has hitherto not been available. A nationwide database has recently been established to address this issue. METHOD: A National Database was setup through a network platform, and data was collected from 70 high-volume centers (>100 esophagectomies/per year) across China. Data was entered between January 2009 and December 2014, and was analyzed in June 2015 after a minimal follow-up of 6 months for all patients. 8181 patients with complete data who received surgery for primary esophageal cancer on the Database were included in the analysis. RESULT: In this series, there were 6052 males and 2129 females, with a mean age of 60.5 years (range: 22-90 years). The pathology in 95.5% of patients was squamous cell carcinoma. The pathological stage distribution was 1.2% in stage 0, 2.5% in Ia, 11.5% in Ib, 14.8% in IIa, 36.1% in IIb, 19.3% in IIIa, 8.3% in IIIb, 6.2% in IIIc. 1800 patients (22.0%) with locally advanced disease received preoperative neoadjuvant therapy and 3592 patients (43.9%) underwent postoperative adjuvant chemotherapy and/or radiotherapy. The esophagectomies were performed through left thoracotomy approach in 5870 cases (72.6%), through right chest approach in 2215 cases (27.4%) including right thoracotomy (21.3%) and VATS (6.1%). The 30-day postoperative mortality rate was 0.6% (43 patients), and the overall postoperative complication rate was 11.6% (951 patients). The 1-, 3-, and 5-year overall survival rates were 82.6%, 61.6%, and 52.9%, respectively. CONCLUSION: This National Registry Database from high-volume centers provides a comprehensive picture of surgical management for esophageal cancer in China for the first time. Squamous cell carcinoma predominates, but there is heterogeneity with respect to the surgical approach and perioperative oncologic management. Overall, surgical mortality and morbidity rates are low, and good survival rates have been achieved due to improvement of surgical treatment technology in recent years.

[Epidemiological characteristic and current status of surgical treatment for esophageal cancer by analysis of national registry database].

Objective: To investigate the epidemiological characteristics and current status of surgical management for esophageal cancer in China. Methods: A national database was setup through a network platform. The clinical data of esophageal cancer treated by surgery was collected from 70 major hospitals in China between January 2009 and December 2014. Results: Complete data of 8 181 cases of esophageal cancer patients who underwent surgery were recorded in the database and recruited in the analysis. Among them, 6 052 cases were male and 2 129 were female, the average age was 60.5 years.The epidemiological investigation results showed that 148 cases (1.8%) had history of psychological trauma, 7 527 cases (92.0%) were lower social economic status, 5 072 cases (62.0%) were short of fresh vegetables and fruits, 6 544 cases (80.0%) ate rough food frequently, 3 722 cases (45.5%) drank untreated water directly from lake or river or shallow well, 3 436 cases (42.0%) had a unhealthy eating habit, including habits of eating food fast (507 cases, 6.2%), eating hot food or drinking hot tea/soup (998 cases, 12.2%), eating fried food (1 939 cases, 23.7%), 4 410 cases (53.9%) had the habits of smoking cigarettes and 2 822 cases (34.5%) drank white wine frequently.The pathological results showed that 7 813 cases (95.5%) were squamous cell carcinoma, 267 cases were adenocarcinoma (3.3%), 25 cases were adenosquamous cell carcinoma (0.3%) and 50 cases were small cell carcinoma (0.6%). A total of 1 800 cases (22.0%) received preoperative neoadjuvant therapy due to locally advanced disease or difficulty of resection. The esophagectomies were performed through left thoracotomy approach in 5 870 cases (71.8%), through right chest approach in 2 215 cases (27.1%), and the remain 96 cases (1.2%) received surgery though other approaches.A total of 8 001 cases (97.8%) underwent radical resection, the other 180 cases (2.2%) received palliative resection. The 30-day postoperative mortality rate was 0.5%, the overall ≥ grade Ⅱ postoperative complication rate was 11.6% (951 cases). The 1-yr, 3-yr, and 5-yr overall actual survival rates were 82.6%, 61.6%, and 52.9%, respectively. Conclusions: The data analysis of the national database for esophageal cancer shows that bad eating habits or eating rough food without enough nutrients, lower social and economic status, drinking white wine and smoking cigarettes frequently may be correlated with tumorigenesis of esophageal cancer. However, strong evidences produced by prospective observation studies are needed. Overall, the long-term survival of esophageal cancer patients has been improved gradually due to the application of advanced surgical techniques and reasonable multimodality treatment.

[Analysis of relationship between (18)F-FDG PET/CT SUVmax of esophageal squamous cell carcinoma before treatment and postoperative survival].

Objective: To evaluate the value of (18)F-FDG PET/CT in predicting long-term survival of esophageal squamous cell carcinoma(ESCC) before initial treatment. Methods: A total of 167 ESCC patients were retrospectively analyzed who underwent surgery between January 2010 and December 2014 in prospective database of Peking University Cancer Hospital Thoracic Surgery Department One, all cases were included according to inclusion and exclusion criteria.The relationship between SUVmax of the primary tumor and patients' age, gender, tumor location, tumor differentiation, tumor regression grade as well as long term survival were compared. Results: The median follow-up time of the 167 cases was 46.9 months(ranging from 30.5 to 86.2 months), with 1 year and 3 years postoperatively being 95.1% and 68.4%, respectively.The SUVmax of the tumor was positively correlated with cT(P<0.01), cN(P=0.033), cTNM(P=0.002) and pTNM(P=0.003)of the tumor.Patients with SUVmax ≤6 obtained a survival significantly better compared with patients with SUVmax>6, the 3 years OS were 83.4 % vs 65.6% (P=0.02) , and DFS were 82.4% vs 55.4%(P=0.006), respectively.The multivariate regression analysis demonstrated that the SUVmax>6 before treatment was the independent prognostic factor for OS (HR=3, 95%CI 1.050-8.568) and DFS (HR=3.971, 95% CI 1.408-11.200) of the ESCC patients. Conclusions: The higher the (18)F-FDG PET/CT SUVmax of the ESCC primary tumor, the poorer survival of the patients. Therefore, SUVmax could be used as an indicator to predict long term survival of the ESCC patients before treatment.

[A retrospective comparative study of continuous pumping for home enteral nutrition after esophagectomy].

Objective: To discuss the effect and safety of continuous pumping for home enteral nutrition after esophagectomy. Methods: The current study retrospectively analyzed the esophageal cancer patients who underwent transthoracic esophagectomy between January 2017 and November 2017 at First Department of Thoracic Surgery, Peking University Cancer Hospital and Institute. There were totally 108 cases, including 88 males and 20 females, with an average age of 62 years. The patients were divided into pump feeding group (n=56) and traditional tube feeding group (n=52). The postoperative short-term safety, weight maintenance, enteral nutrition tolerance and nutritional support complete rate of the 2 groups were compared by χ(2) test, Fisher exact test and t test, respectively. Results: Compared with traditional tube feeding group, the patient safety in pumping feeding group was significantly better, with complications within 2 months after discharge were 11/52 and 4/56 respectively (χ(2)=2.393, P=0.035); the weight maintenance was significantly better, the weight loss within 4 weeks after discharge were 3.90 kg and 0.13 kg, respectively (t=7.720, P=0.000); the general enteral complications were significantly lower (26/52 vs. 5/56, χ(2)=22.225, P=0.000), the nutritional support complete rate was significantly higher (23/52 vs. 55/56, χ(2)=39.167, P=0.000). Conclusions: Continuous pump feeding enteral nutrition support after discharge postoperatively could help improve patient safety after discharge, which is better for weight maintenance of the patients. Pump feeding could also enhance tolerability of tube feeding and ensure the effective accomplishment of nutritional support.

Worldwide Esophageal Cancer Collaboration: clinical staging data.

To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5-25 mg/kg2 , 47%), little weight loss (2.4 ± 7.8 kg), 0-1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cN0 (44%), cM0 (95%), and cG2-G3 (89%); most involved the distal esophagus (73%). Non-risk-adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cN0 versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre-treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection.

Worldwide Esophageal Cancer Collaboration: neoadjuvant pathologic staging data.

To address uncertainty of whether pathologic stage groupings after neoadjuvant therapy (ypTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for pathologically staged cancers after neoadjuvant therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 7,773 pathologically staged neoadjuvant patients, 2,045 had squamous cell carcinoma, 5,686 adenocarcinoma, 31 adenosquamous carcinoma, and 11 undifferentiated carcinoma. Patients were older (61 years) men (83%) with normal (40%) or overweight (35%) body mass index, 0-1 Eastern Cooperative Oncology Group performance status (96%), and a history of smoking (69%). Cancers were ypT0 (20%), ypT1 (13%), ypT2 (18%), ypT3 (44%), ypN0 (55%), ypM0 (94%), and G2-G3 (72%); most involved the distal esophagus (80%). Non-risk-adjusted survival for yp categories was unequally depressed, more for earlier categories than later, compared with equivalent categories from prior WECC data for esophagectomy-alone patients. Thus, survival of patients with ypT0-2N0M0 cancers was intermediate and similar regardless of ypT; survival for ypN+ cancers was poor. Because prognoses for ypTNM and pTNM categories are dissimilar, prognostication should be based on separate ypTNM categories and groupings. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics and should direct 9th edition data collection.

Advantages of positron emission tomography-computed tomography imaging in esophageal squamous cell carcinoma.

To explore the value of positron emission tomography-computed tomography (PET-CT) scan in esophageal squamous cell carcinoma (ESCC), we retrospectively summarize the results of PET-CT scan from 118 patients, with ESCC who underwent PET-CT scan in the different courses during treatment. Then, the results of PET-CT scan plus other conventional methods were analyzed to identify the value of PET-CT scan in diagnosis, staging, response evaluation, monitoring recurrence, and metastasis following treatment. It is suggested that PET-CT scan possess high value in diagnosis and gives more favorable indication in N and M staging. PET-CT scan should be translated into routine surveillance for postoperation follow up and is one of more helpful evaluators of response to chemoradiotherapy or chemotherapy.

Neoadjuvant nivolumab plus chemotherapy versus chemotherapy for resectable NSCLC: subpopulation analysis of Chinese patients in CheckMate 816.

BACKGROUND: Neoadjuvant nivolumab plus chemotherapy significantly improved event-free survival (EFS) and pathologic complete response (pCR) versus chemotherapy alone in patients with resectable non-small-cell lung cancer (NSCLC) in the global phase III CheckMate 816 study. Here, we report post hoc exploratory efficacy, safety, and surgical outcomes in the Chinese subpopulation of this study. METHODS: Adults with stage IB-IIIA resectable NSCLC were randomized to receive nivolumab 360 mg plus chemotherapy or chemotherapy alone every 3 weeks for three cycles followed by surgery. Primary endpoints included EFS and pCR (both per blinded independent review). EFS and pCR results were from 14 October 2022, and 16 September 2020, database locks, respectively. RESULTS: The Chinese subpopulation comprised 97 patients (nivolumab plus chemotherapy, 44; chemotherapy, 53). At 38.2 months of minimum follow-up, median EFS was not reached [95% confidence interval (CI) 23.4 months-not reached] in the nivolumab plus chemotherapy arm and 13.9 months (95% CI 8.3-34.3 months) in the chemotherapy arm (hazard ratio 0.47, 95% CI 0.25-0.88). pCR rates were 25.0% (95% CI 13.2% to 40.3%) and 1.9% (95% CI 0.0% to 10.1%), respectively (odds ratio 11.05; 95% CI 1.41-86.49). Of 97 Chinese patients, 36 (82%) in the nivolumab plus chemotherapy arm and 41 (77%) in the chemotherapy arm underwent definitive surgery. Grade 3-4 treatment-related adverse events occurred in 18/43 patients (42%) treated with nivolumab plus chemotherapy and 22/53 patients (42%) treated with chemotherapy. CONCLUSIONS: Consistent with findings in the global study population of CheckMate 816, neoadjuvant nivolumab plus chemotherapy improved EFS and pCR versus chemotherapy in the Chinese subpopulation without impacting treatment tolerability or the feasibility of surgery. These findings support the use of nivolumab plus chemotherapy as a standard neoadjuvant treatment option for Chinese patients with resectable NSCLC.

Diffusion of co-sputtered metals as bonding materials for 3D interconnects during thermal treatments.

Diffusion behaviors of co-sputtered metals during thermal treatments were investigated, where these co-sputtered metals can be used as bonding materials for 3D Interconnects. In this paper, we report the diffusion behaviors and discuss the diffusion mechanisms of co-sputtered metals before and after annealing. Atom and vacancy volume, vacancy formation energy, and activation energy are proposed to explain the diffusion direction and diffusion rate among different co-sputtered metals. Based on the excellent bonding performance of this method, Cu/metal co-sputtering bonding is considered as a potential candidate for advanced bonding technology.

[Preliminary measurement and analysis of the condylar movement envelope surface parameters in healthy adults].

Objective: To measure and analyze parameters of the three-dimensional (3D) model of the condylar movement envelope surface (ES) and provide a reference for the design of the temporomandibular prosthesis. Methods: Thirty-four healthy adults aged (25.4±2.8) years were recruited from the Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology as subjects. There were 9 males and 25 females, most of them were university students and others outside the university have received undergraduate education or above. Condylar movement ES were obtained using the previous method on the 3D trajectory of condyle. The simulations of condylar movement were projected according to opening movements, protrusion movements, and lateral movements respectively. The total area of the ES and the area proportions of models formed by above different mandibular movements were measured and calculated. The adults' head and maxillofacial 3D models reconstructed by cone beam CT were registered with ES in Geomagic Studio. The inner and outer poles of the condyle, the corrective sagittal axis of the ES, and the median sagittal plane (MSP) were calibrated in registration models using Geomagic Studio, and the parameters were measured as follows: the anteroposterior and medialateral diameters of the condyle, the anteroposterior diameters and the transverse diameters (anterior, middle and posterior parts) of the ES, the angles between the corrective sagittal axis of the ES and MSP (ES-MSP). Pearson correlation analysis was performed by SPSS 24.0. Results: The total area of the ES was (760±133) mm2, the opening movement part accounted for (63.3±15.2)%, the protrusion movement part accounted for (14.9±9.6)%, the lateral movement part accounted for (21.8±13.3)%. Parameter measurements were as follows: mediolateral diameters of condyle was (19.8±2.3) mm; anteroposterior diameter of the ES was (21.2±3.1) mm, the transverse diameters (anterior, middle and posterior parts) of the ES were (20.6±2.4), (20.4±2.4), (22.0±2.6) mm, respectively; the transverse diameters of the ES were about 2 mm larger than that of the condyle. The angle between the corrective sagittal axis of ES and the MSP was 6.8°±6.2°. The coefficient of variation (CV) in these parameters showed: CV of the transverse diameters (anterior, middle and posterior parts) of the ES and mediolateral diameter of the condyle were 0.98, 0.99, 0.93, respectively (P<0.001). CV of aera of ES and mediolateral diameter of the condyle was 0.64 (P=0.002). CV of aera of ES and anteroposterior diameter of ES was 0.62 (P=0.004). Conclusions: The 3D envelope surface model formed by mandibular opening movements accounted for the largest proportion of the ES. The corrective sagittal axis of the ES was at an angle to the MSP, the transverse diameters (anterior, middle and posterior parts) of the ES were approximately 2 mm larger than the mediolateral diameter of the condyle, the transverse diameters (anterior, middle and posterior parts) of the ES were highly positively correlated with the mediolateral diameter of the condyle.

Coherent magnetic plasmon modes in a contacting gold nano-sphere chain on a gold slab.

A coupled magnetic resonator waveguide, composed of a contacting gold nanosphere chain on a gold slab, is proposed and investigated. A broadband coherent magnetic plasmon mode can be excited in this one dimensional nanostructure. By employing the Lagrangian formalism and the Fourier transform method, the dispersion properties of the wave vector and group velocity of the magnetic plasmon mode are investigated. Small group velocity can be obtained from this system which can be applied as subwavelength slow wave waveguides.

Fabrication of nano-scale Cu bond pads with seal design in 3D integration applications.

A method to fabricate nano-scale Cu bond pads for improving bonding quality in 3D integration applications is reported. The effect of Cu bonding quality on inter-level via structural reliability for 3D integration applications is investigated. We developed a Cu nano-scale-height bond pad structure and fabrication process for improved bonding quality by recessing oxides using a combination of SiO2 CMP process and dilute HF wet etching. In addition, in order to achieve improved wafer-level bonding, we introduced a seal design concept that prevents corrosion and provides extra mechanical support. Demonstrations of these concepts and processes provide the feasibility of reliable nano-scale 3D integration applications.

Bonding temperature optimization and property evolution of SU-8 material in metal/adhesive hybrid wafer bonding.

Bonding temperature optimization of SU-8 material for metal/adhesive hybrid bonding was investigated. The good bond quality of SU-8 adhesive can be achieved with the bonding temperature between 150 degrees C and 250 degrees C, while bond failures of SU-8 wafers are observed starting from 275 degrees C. IR transmittance spectra measurements indicate the crosslinks inside SU-8 break and further bond failure is observed due to the large decomposition of epoxy rings and phenyl in plane bending above 275 degrees C. This research provides guidelines of material selection and bonding parameters for heterogeneous integration, 3DIC and MEMS applications using metal/adhesive hybrid bonding.

Electrical performances and structural designs of copper bonding in wafer-level three-dimensional integration.

The integrity of bonded Cu interconnects in wafer-level three-dimensional integration has been investigated as the function of pattern size and density, as well as bonding process parameter. The desired pattern density coupled with the application of bonding process profile we developed gives optimal yield and alignment accuracy, and provides excellent electrical connectivity and contact resistance through the entire wafer. This result is a key milestone in establishing the manufacturability of Cu-based interconnections for 3D integration technology.

Wafer-level self-aligned nano tubular structures and templates for device applications.

A method to fabricate self-aligned nano-scale tubular structures is introduced and investigated. These tubular structures, can be fabricated on wafer-level using common CMOS technologies, are robust and cannot be removed through standard etching or resist strip techniques. This method has shown the potential to be used in different nano device applications since the size of nano-scale tubular structures is adjustable. In addition, these structures can be fabricated as nano-scale templates in advanced device applications.

Microbiological and chemical properties of kefir manufactured by entrapped microorganisms isolated from kefir grains.

In this study, various yeasts (Kluyveromyces marxianus, Saccharomyces turicensis, Pichia fermentans) and lactic acid bacteria (Lactobacillus kefiranofaciens, Lactobacillus kefiri, Leuconostoc mesenteroides) were entrapped in 2 different microspheres using an entrapment ratio for the strains that was based on the distribution ratio of these organisms in kefir grains. The purpose of this study was to develop a new technique to produce kefir using immobilized starter cultures isolated from kefir grains. An increase in cell counts with fermentation cycles was observed for both the lactic acid bacteria (LAB) and yeasts, whereas the cell counts of kefir grains were very stable during cultivation. Scanning electron microscopy showed that the short-chain lactobacilli and lactococci occupied the surface of the LAB microspheres, whereas the long-chain lactobacilli were inside the microspheres. When the yeasts were analyzed, cells at a high density were entrapped in cracks on the surface and within the microspheres, where they were surrounded by the short-chain lactobacilli. The distribution of the LAB and yeast species in kefir produced from grains and microspheres showed that there was no significant difference between the kefirs produced by the 2 methods; moreover, Leu. mesenteroides and K. marxianus were the predominating microflora in both types of kefir. There was no significant difference in the ethanol and exopolysaccharide contents between the 2 kefirs, although the acidity was different.