Lymph node metastases in middle and upper mediastinum of Siewert type II adenocarcinoma: A real-world retrospective study.

OBJECTIVE: To explore whether the upper and/or middle mediastinal nodes (UMMN) should be dissected in Siewert type II adenocarcinoma (AC) according to the incidence of lymph node metastasis. Additionally, to investigate the association between the length of esophageal involvement (LEI) and the UMMN metastases. METHODS: A cohort with Siewert type II AC who were operated on by a surgical team that routinely treated esophagogastric junction (EGJ) tumors with esophagectomy and extended lymphadenectomy were assessed retrospectively. The primary endpoint of the research was the metastasis rate of UMMN. RESULTS: A total of 94 patients with EGJ tumor from July 2018 to September 2022 were enrolled. Station 106recR (6.4%, 6/94) was the only station among upper mediastinal nodes (UMN) that presented positive nodes. Middle mediastinal nodes (MMN) metastases of station 107, 109 and station 108 were 2.1% (2/94) and 5.0% (4/80), respectively. Among the 11 patients with MMN or UMN metastases, 63.6% (7/11) had lesser than seven metastatic nodes, and 54.5% (6/11) had a pathological N stage ≤2. LEI >3 cm (p = 0.042) showed a higher risk for MMN metastases in univariable logistic analysis. However, no independent risk factor for mediastinal node metastases was detected. CONCLUSION: This study demonstrated that the incidence of positive MMN and UMN is relatively low in resectable Siewert type II AC, which indicated that it is not necessary to perform a routine dissection upon these stations. LEI >3 cm might be associated with higher risk for mediastinal node metastasis. Certain patients could benefit from extended lymphadenectomy since most of the patients with positive MMN or UMN have a limited number of metastatic nodes.

Comparison of neoadjuvant nab-paclitaxel plus immunotherapy versus paclitaxel plus immunotherapy for esophageal squamous cell carcinoma.

BACKGROUND: This study aimed to compare the feasibility of nab-paclitaxel plus platinum-based chemotherapy (nabTP) versus paclitaxel plus platinum-based chemotherapy (TP) with immune checkpoint inhibitors (ICIs) as a neoadjuvant modality for locally resectable esophageal squamous cell carcinoma (ESCC). METHODS: Between April 2019 and March 2022, we identified ESCC patients who received neoadjuvant immunotherapy with both nabTP (n = 213) and TP (n = 98) at our institution and Henan Cancer Hospital. The patients in the ICIs-nabTP and ICIs-TP groups were pair-matched (1:1) for tumor location, sex, smoking, drinking, clinical T and N stage. The primary endpoint was the hazard of 30-day major postoperative complications. Second, logistic models were applied to estimate the risk factors for pathological complete response (pCR) rate. RESULTS: All patients underwent esophagectomy with R0 resection. A statistically significant increase in the risk of developing major pulmonary (odds ratio [OR], 1.182; 95% confidence interval [CI]: 0.530-2.635; p = 0.683), anastomotic (OR, 1.881; 95% CI: 0.607-5.830; p = 0.267), cardiac (OR, 1.000; 95% CI: 0.426-2.349; p = 1.000) complications after neoadjuvant immunotherapy plus nabTP was not observed. The median interval to surgery was 39 days in the ICIs-nabTP group versus 44 days in the ICIs-TP group (p = 0.119). There was no 30-day mortality in each group. However, there was a slight difference in the 30-day readmission rate (p = 0.043) and the incidence of hydropneumothorax (p = 0.027) between the two groups. The pCR rates of the ICIs-nabTP and ICIs-TP group were 36.7 and 21.4%, respectively (p = 0.018). CONCLUSIONS: It appears to be feasible to add immunotherapy to nabTP regimen for locally advanced ESCC. Compared with TP, nabTP plus ICIs can achieve a better pCR rate in ESCC.

Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer: final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial.

EMERGING-CTONG 1103 showed improved progression-free survival (PFS) with neoadjuvant erlotinib vs. chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer (NSCLC) (NCT01407822). Herein, we report the final results. Recruited patients were randomly allocated 1:1 to the erlotinib group (150 mg/day orally; neoadjuvant phase for 42 days and adjuvant phase to 12 months) or to the GC group (gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously; 2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase). Objective response rate (ORR), complete pathologic response (pCR), PFS, and overall survival (OS) were assessed along with safety. Post hoc analysis was performed for subsequent treatments after disease recurrence. Among investigated 72 patients (erlotinib, n = 37; GC, n = 35), the median follow-up was 62.5 months. The median OS was 42.2 months (erlotinib) and 36.9 months (GC) (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.47-1.47; p = 0.513). The 3- and 5-year OS rates were 58.6% and 40.8% with erlotinib and 55.9% and 27.6% with GC (p3-y = 0.819, p5-y = 0.252). Subsequent treatment was administered in 71.9% and 81.8% of patients receiving erlotinib and GC, respectively; targeted therapy contributed mostly to OS (HR, 0.35; 95% CI, 0.18-0.70). After disease progression, the ORR was 53.3%, and the median PFS was 10.9 months during the EGFR-TKI rechallenge. During postoperative therapy, grade 3 or 4 adverse events (AEs) were 13.5% in the erlotinib group and 29.4% in the GC group. No serious adverse events were observed. Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.

Pathologic responses and surgical outcomes after neoadjuvant immunochemotherapy versus neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.

Background: Currently, the role of immunotherapy in neoadjuvant setting for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is gradually attracting attention. Few studies compared the efficacy of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT). Our study aimed to compare treatment response and postoperative complications after NICT followed by surgery with that after conventional NCRT in patients with locally advanced ESCC. Methods: Of 468 patients with locally advanced ESCC, 154 received conventional NCRT, whereas 314 received NICT. Treatment response, postoperative complications and mortality between two groups were compared. Pathological response of primary tumor was evaluated using the Mandard tumor regression grade (TRG) scoring system. Pathological complete response (pCR) of metastatic lymph nodes (LNs) was defined as no viable tumor cell within all resected metastatic LNs. According to regression directionality, tumor regression pattern was summarized into four categories: type I, regression toward the lumen; type II, regression toward the invasive front; type III, concentric regression; and type IV, scattered regression. Inverse probability propensity score weighting was performed to minimize the influence of confounding factors. Results: After adjusting for baseline characteristics, the R0 resection rates (90.9% vs. 89.0%, P=0.302) and pCR (ypT0N0) rates (29.8% vs. 34.0%, P=0.167) were comparable between two groups. Patients receiving NCRT showed lower TRG score (P<0.001) and higher major pathological response (MPR) rate (64.7% vs. 53.6%, P=0.001) compared to those receiving NICT. However, NICT brought a higher pCR rate of metastatic LNs than conventional NCRT (53.9% vs. 37.1%, P<0.001). The rates of type I/II/III/IV regression patterns were 44.6%, 6.8%, 11.4% and 37.1% in the NICT group, 16.9%, 8.2%, 18.3% and 56.6% in the NCRT group, indicating a significant difference (P<0.001). Moreover, there were no significant differences in the incidence of total postoperative complications (35.8% vs. 39.9%, P=0.189) and 30-d mortality (0.0% vs. 1.1%, P=0.062). Conclusion: For patients with locally advanced ESCC, NICT showed a R0 resection rate and pCR (ypT0N0) rate comparable to conventional NCRT, without increased incidence of postoperative complications and mortality. Notablely, NICT followed by surgery might bring a promising treatment response of metastatic LNs.

The risk and prognostic factors for liver metastases in esophageal cancer patients: A large-cohort based study.

BACKGROUND: This retrospective study aimed to explore risk factors for liver metastases (LiM) in patients with esophageal cancer (EC) and to identify prognostic factors in patients initially diagnosed with LiM. METHODS: A total of 28 654 EC patients were retrieved from the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2018. A multivariate logistic regression model was utilized to identify risk factors for LiM. A Cox regression model was used to identify prognostic factors for patients with LiM. RESULTS: Of 28 654 EC patients, 4062 (14.2%) had LiM at diagnosis. The median overall survival (OS) for patients with and without LiM was 6.00 (95% CI: 5.70-6.30) months and 15.00 (95% CI: 14.64-15.36) months, respectively. Variables significantly associated with LiM included gender, age, tumor site, histology, tumor grade, tumor size, clinical T stage, clinical N stage, bone metastases (BoM), brain metastases (BrM) and lung metastases (LuM). Variables independently predicting survival for EC patients with LiM were age, histology, tumor grade, BoM, BrM, LuM, and chemotherapy. A risk prediction model and two survival prediction models were then constructed revealing satisfactory predictive accuracy. CONCLUSIONS: Based on the largest known cohort of EC, independent predictors of LiM and prognostic indicators of survival for patients with LiM were identified. Two models for predicting survival as well as a risk prediction model were developed with robust predictive accuracy.

Neoadjuvant Chemoradiotherapy and Surgery for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed: The Study Protocol for the Randomized Controlled NEEDS Trial.

Background: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC. Methods: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04460352.

Pembrolizumab Combined With Neoadjuvant Chemotherapy Versus Neoadjuvant Chemoradiotherapy Followed by Surgery for Locally Advanced Oesophageal Squamous Cell Carcinoma: Protocol for a Multicentre, Prospective, Randomized-Controlled, Phase III Clinical Study (Keystone-002).

Background: To compare the efficacy and safety of pembrolizumab combined with neoadjuvant chemotherapy (neoCT) versus neoadjuvant chemoradiotherapy (neoCRT) followed by surgery for locally advanced resectable oesophageal squamous cell carcinoma (ESCC). Methods: This study is a multicentre, prospective, randomized-controlled, phase III clinical study. Eligible ESCC (staging: cT1N2M0 or cT2-3N0-2M0 (stage II/III, high-risk lesions in T2N0M0)) patients will be randomly assigned to either the experimental group (pembrolizumab with neoCT, n = 228) or the control group (neoCRT, n = 114) at a ratio of 2:1. Within 4-6 weeks after preoperative therapy, the McKeown procedure will be performed. Patients in the experimental group will also receive pembrolizumab alone as adjuvant therapy after surgery until 1 year or until the radiographically confirmed PD or other condition indicated for premature termination is observed. The primary endpoint is event-free survival (EFS). The secondary endpoints are 1-, 3-, and 5-year overall survival (OS) and disease-free survival (DFS), short-term outcomes, and quality of life. Discussion: This is the first prospectively randomized controlled trial designed to compare pembrolizumab plus chemotherapy and chemoradiotherapy as neoadjuvant therapy for resectable ESCC. According to our hypothesis, preoperative pembrolizumab combined with chemotherapy will result in a better tumour response and prolong the survival of patients, with acceptable toxicity. This study started in December 2021, and the enrolment time is estimated to be 2 years. Trial Registration: This prospective study has been registered at ClinicalTrials.gov (NCT04807673), March 2021.

Comparative genomic analysis of esophageal squamous cell carcinoma among different geographic regions.

Introduction: Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence, survival, and risk factors. Although the genomic characteristics of ESCC have been extensively characterized, the genomic differences between different geographic regions remain unclear. Methods: In this study, we sequenced 111 patients with ESCC from northern (NC) and southern (SC) China, combined their data with those of 1081 cases from previous reports, and performed a comparative analysis among different regions. In total, 644 ESCC cases were collected from six geographic regions (NC, SC, Xinjiang, China [XJC], Japan [JP], Vietnam [VN], and Europe & America [EA]) as the discovery cohort. Validation cohort 1 included 437 patients with ESCC from the NC region. Validation cohort 2 included 54 and 57 patients from the NC and SC regions, respectively. Results: Patients with ESCC in different regions had different genomic characteristics, including DNA signatures, tumor mutation burdens, significantly mutated genes (SMGs), altered signaling pathways, and genes associated with clinical features. Based on both the DNA mutation signature and the mutation profile of the most common genes, the NC and SC groups were clustered close together, followed by the JP, XJC, EA, and VN groups. Compared to patients with ESCC from SC, SMGs, including KMT2D, FAT1, and NOTCH1 were more frequently identified in patients with ESCC from NC. Furthermore, some genes (TDG and DNAH8) correlated with overall survival in completely opposite ways in patients with ESCC from different geographical regions. Conclusions: Our study provides insights into genomic differences in ESCC among different regions. These differences may be related to differences in environmental carcinogens, incidence, and survival.

A randomized controlled trial of oral nutritional supplementation versus standard diet following McKeown minimally invasive esophagectomy in patients with esophageal malignancy: a pilot study.

BACKGROUND: Body weight loss (BWL) following esophagectomy is a common complication in esophageal cancer (EC) which represents a deterioration in quality of life (QoL) and poor long-term prognosis. A pilot randomized controlled study was initiated to evaluate the feasibility, safety, and efficacy of a short-term oral nutritional supplementation (ONS) on postoperative BWL and QoL in patients undergoing esophagectomy. METHODS: Patients enrolled in this study were randomly divided into two different groups: the intervention group which received oral nutritional intervention (300 mL/day for 4 weeks) and the control group which received standard diet alone. Participants were assessed at discharge and 1, 3, and 6 months following discharge for BWL and QoL. At the same time, the data of clinical baseline characteristics, nutrition-related complications, and feasibility were prospectively collected and analyzed. RESULTS: A total of 77 patients were enrolled in this study. However, owing to severe postoperative complications and discontinuation of the program, 33 participants in the ONS group and 31 participants in the control group were eligible for final analysis of body weight change and QoL. Significant differences in percentage of BWL (%BWL) between the two groups were discovered at 3 and 6 months follow-up: participants in the ONS group had lower %BWL than those in the control group (P=0.024; P=0.025, respectively). There were significant differences in body mass index (BMI) loss between the two groups. At 1 month, QoL was significantly improved in the ONS group (P=0.031); however, no differences of QoL were noticed at 3 and 6 months. Compared with the control group, ONS improved the physical function and role function and eased the symptom of fatigue (P=0.014, P=0.030, and P=0.008, respectively). It was also noted that ONS increased the nutrition-related complications compared to the standard diet (50% vs. 42.9%), although the difference was not statistically significant (P=0.647). CONCLUSIONS: This pilot study indicated that addition of ONS was feasible, safe, and might prevent the loss of body weight and BMI and have a positive impact on the QoL in esophagectomy patients. The effectiveness of ONS requires further confirmation in an appropriately powered study. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100045303.

Efficacy of transcutaneous electrical acupoint stimulation combined with general anesthesia for sedation and postoperative analgesia in minimally invasive lung cancer surgery: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Multimodal opioid-sparing analgesia is a key component of an enhanced recovery pathway after surgery that aims to improve postoperative recovery. Transcutaneous electrical acupoint stimulation (TEAS) is assumed to alleviate pain and anxiety and to modify the autonomic nervous system. This study aimed to determine the efficacy of TEAS for sedation and postoperative analgesia in lung cancer patients undergoing thoracoscopic pulmonary resection. METHODS: A total of 80 patients were randomized into two groups: the TEAS group and the sham TEAS combined with general anesthesia group. Postoperative pain levels at six, 24, 48 hours, and one month after surgery were measured using the visual analogue scale (VAS). Bispectral index (BIS) score during the TEAS prior to anesthetic induction, Observer's Assessment of Alertness/Sedation (OAAS) score, sufentanil consumption during postoperative patient-controlled intravenous analgesia (PCIA), number of total and effective attempts of PCIA pump use, and incidence of postoperative nausea and vomiting were recorded and analyzed statistically. RESULTS: Patients in the TEAS group had significantly lower VAS scores at six, 24, and 48 hours after surgery (P < 0.01); lower BIS scores at 10, 20, and 30 minutes before induction (P < 0.01); lower levels of postoperative sufentanil consumption; lower number of PCIA attempts and effective rates (P < 0.01); lower incidences of nausea at 0, six, 24, and 48 hours; and lower incidence of vomiting at 24 hours after surgery (P < 0.05). The postoperative OAAS scores were similar between the groups. CONCLUSIONS: TEAS could be a feasible approach for sedation and postoperative analgesia in thoracoscopic pulmonary resection.

Multiple Pulmonary Resections for Synchronous and Metachronous Lung Cancer at Two Chinese Centers.

BACKGROUND: To determine oncologic and surgical outcomes after multiple pulmonary resections (MPR) for synchronous or metachronous lung cancer with multiple pulmonary sites of involvement and to identify prognostic factors for these patients. METHODS: We retrospectively analyzed data from two Chinese high-volume institutions. Eligible patients underwent MPR for synchronous or metachronous lung cancer with multiple pulmonary sites of involvement. Overall survival and disease-free survival after MPR were analyzed, and prognostic factors were explored using multivariable Cox analysis. Postoperative mortality and major morbidities within 30 days were evaluated. RESULTS: In total, 142 patients were included: 36 (25%) underwent MPR for the metachronous disease, and 106 (75%) underwent MPR for the synchronous disease. Five-year disease-free survival was 85.4% for the metachronous group and 69.1% for the synchronous group; 5-year overall survival was 86.1% and 84.8%, respectively. Five-year accumulated local and distant recurrence rates were 11.9% and 3.0% for the metachronous group and 26.6% and 5.9% for the synchronous group, respectively. In the synchronous MPR group, a larger sum of tumor size (hazard ratio [HR] 1.04; 95% confidence interval [CI], 1.00 to 1.08) and regional nodal involvement (HR 6.17; 95% CI, 1.42 to 35.46) were both independently associated with worse overall survival. In the metachronous MPR group, the longer disease-free interval was independently associated with favorable overall survival (HR 0.94; 95% CI, 0.88 to 0.98) and disease-free survival (HR 0.96; 95% CI, 0.93 to 0.99). There was no 30-day mortality. The overall rate of major morbidities was 12%. CONCLUSIONS: Multiple pulmonary resection is valid for patients with synchronous and metachronous lung cancer with multiple pulmonary sites of involvement.

Clinical outcomes following an initial experience with a novel powered vascular stapler in video-assisted thoracoscopic lobectomies: results of a Chinese multi-center study.

BACKGROUND: The development of minimally invasive surgical approaches has revolutionized surgical care and greatly improved surgical outcomes. This study aimed to evaluate the clinical effectiveness of a powered vascular stapler (PVS) during video-assisted thoracoscopic surgery (VATS) lobectomy. METHODS: This prospective, multi-center, post-market clinical study in China enrolled 50 patients with either a suspected or formal diagnosis of clinical stage IA to IIB non-small cell lung cancer (NSCLC) scheduled for VATS lobectomy. The clinical effectiveness of the PVS for successful pulmonary artery (PA)/pulmonary vein (PV) transection was evaluated. In addition, the surgeon's stress, device usability, and surgeon satisfaction were measured using multiple questionnaires. RESULTS: A total of 167 PAs/PVs were transected with 3 (1.8%) requiring intra-operative intervention. Fourteen of the 50 patients (28.0%) experienced at least one adverse event (AE), among whom 5 (10.0%) suffered from serious AEs. There were no postoperative hemorrhagic complications related to transection of the PA/PV with PVS. Surgeon satisfaction was surveyed by questionnaire after each of the 50 procedures resulting in a 96% reported satisfaction with device usability, specifically related to a low stress load and an increase in work efficiency. CONCLUSIONS: For VATS lobectomy, the PVS demonstrated a positive surgical effectiveness and value in cognitive and physical distress reduction. Complications following VATS lobectomy to treat NSCLC were generally low and as expected. Intraoperative complications were few and there were no postoperative complications related to the transection of the PA and PV during VATS lobectomy. Favorable results were reported on the surgeon satisfaction questionnaire regarding usability and surgeon stress.

Genome-scale CRISPR activation screening identifies a role of ELAVL2-CDKN1A axis in paclitaxel resistance in esophageal squamous cell carcinoma.

Neoadjuvant chemotherapy (NAC) may provide survival benefits for patients with advanced esophageal squamous cell carcinoma. However, tumor cells can display primary or secondary resistance to paclitaxel (PTX), a primary component of induction chemotherapy regimen. To identify genes capable of conveying PTX resistance, we performed a genome-wide CRISPR transcriptional activation library in human KYSE-180 cells. High throughput next generation sequencing was further applied to establish the phenotype-to-genotype relationship. Our highest-ranking hits are CDKN1A, TSPAN4, ELAVL2, JUNB and PAAF1. We generated evidence that esophageal tumors with high CDKN1A, ELAVL2 and TSPAN4 levels, quantified using qRT-PCR and Western blot assays, showed poorer chemotherapy response. Higher expression levels of TSPAN4 and ELAVL2 protein are independent risk factors for poor chemotherapy response in ESCC patients. We then found that overexpression of CDKN1A, ELAVL2 or TSPAN4 in ESCC cell lines significantly promoted the resistance to PTX by inhibiting cell apoptosis. Interestingly, ESCC cells overexpressed CDKN1A, ELAVL2 or TSPAN4 also acquired resistance to cisplatin (DDP). This phenomenon may be explained by cross-resistance of chemotherapy. We additionally found an association between ELAVL2 and CDKN1A, which may be regarded as the upstream and downstream factors that synergistically involved in the regulation of chemo-resistance in ESCC. Therefore, our study demonstrated that the genome-wide CRISPR activation library is a powerful strategy for the discovery of chemo-resistant genes critical for ESCC and we reported the first evidence that the ELAVL2-CDKN1A axis may be an important mechanism involved in chemo-resistance in ESCC.

Survival After Induction Chemotherapy and Esophagectomy Is Not Improved by Adjuvant Chemotherapy.

BACKGROUND: It remains unclear whether postoperative chemotherapy improves survival among patients with esophageal squamous cell carcinoma who have undergone preoperative chemotherapy and radical resection. METHODS: Patients treated between January 2000 and December 2016 were reviewed. Eligible patients were divided into two groups: perioperative chemotherapy (preoperative and postoperative chemotherapy) and neoadjuvant chemotherapy only. The primary endpoint was disease-free survival; the secondary endpoints were overall survival and toxicities attributable to postoperative chemotherapy. To minimize the effect of patient heterogeneity between the two groups, we used propensity score matching. The survival analysis was performed using univariate analysis and a multivariable Cox regression model. RESULTS: In total, 252 patients were included in the study. Most were men (208 of 252; 82.5%); median age was 59 years. The follow-up rate was 93.3%. Age, performance status, minimally invasive surgery, and Clavien-Dindo classification were statistically different between the groups (P <.05). After propensity score matching, each group had 59 patients. Five-year disease-free survival (52.4% vs 43.6%, P = .372) and overall survival (68.6% vs 62.4%, P = .359) were not statistically different between the neoadjuvant chemotherapy group and the perioperative chemotherapy group. Cox regression identified both pathologic nodal stage and tumor regression grade are independent prognostic factors for disease-free survival and overall survival (P < .05); adjuvant chemotherapy did not influence disease-free survival (hazard ratio 1.049, 95% confidence interval, 0.587 to 1.876, P = .872) or overall survival (hazard ratio 1.297; 95% confidence interval, 0.606 to 2.775, P = .504). In the perioperative chemotherapy group, 8.5% of patients (5 of 59) had grade 3 or greater toxicity. CONCLUSIONS: Adjuvant chemotherapy is not indicated for patients with locally advanced esophageal squamous cell carcinoma after neoadjuvant platinum-based chemotherapy and surgery.

Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study.

PURPOSE: To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced EGFR mutation-positive non-small-cell lung cancer. PATIENTS AND METHODS: This was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non-small-cell lung cancer with EGFR mutations in exon 19 or 21 (EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postsurgery. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS: Of 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84; P = .092). No pathologic complete response was identified in either arm. Three (9.7%) of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms, respectively, had a major pathologic response. Median PFS was significantly longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard ratio, 0.39; 95% CI, 0.23 to 0.67; P < .001). Observed adverse events reflected those most commonly seen with the two treatments. CONCLUSION: The primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.

Preemptive one lung ventilation enhances lung collapse during thoracoscopic surgery: A randomized controlled trial.

In routine practice, one lung ventilation (OLV) is initiated upon pleural opening. We conducted a randomized controlled trial to compare lung collapse after preemptive OLV versus conventional OLV in thoracoscopic surgery. A total of 67 patients were enrolled (34 with conventional OLV; 33 with preemptive OLV). Preemptive OLV was conducted by closing the DLT lumen to the non-ventilated lung immediately upon assuming the lateral position with the distal port closed to the atmosphere until pleural opening (>6 minutes in all cases). Lung collapse was assessed at 1, 5, 10, 20, 30 and 40 minutes after pleural opening using a 10-point rating scale (10: complete collapse). The primary end point was the duration from pleural opening to satisfactory lung collapse (score of 8). Secondary end points included PaO2 and hypoxemia. The duration from pleural opening to satisfactory lung collapse was shorter in the preemptive OLV group (9.1 ± 1.2 vs. 14.1 ± 4.7 minutes, P < 0.01). PaO2 was comparable between the two groups prior to anesthetic induction (T0), and 20 (T2), 40 minutes (T3) after pleural incision, but was lower in the preemptive OLV group at zero minutes after pleural incision (T1) (457.5 ± 19.0 vs. 483.1 ± 18.1 mmHg, P < 0.01). No patients in either group developed hypoxemia. In summary, preemptive OLV expedites lung collapse during thoracoscopic surgery with minimal safety concern.

Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus.

Mutations in the genes encoding nuclear factor (erythroid-derived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found to cause esophageal hyperproliferation and hyperkeratosis in mice. However, the underlying mechanism is unclear. In this study, we aimed to understand the molecular mechanisms of esophageal hyperproliferation in mice due to hyperactive Nrf2. Esophageal tissues were obtained from genetically modified mice that differed in the status of the Nrf2 gene and genes in the same pathway (Nrf2-/-, Keap1-/-, K5Cre;Pkm2fl/fl;Keap1-/-, and WT) and analyzed for metabolomic profiles, Nrf2 ChIP-seq, and gene expression. We found that hyperactive Nrf2 causes metabolic reprogramming and up-regulation of metabolic genes in the mouse esophagus. One of the glycolysis genes encoding pyruvate kinase M2 (Pkm2) was not only differentially up-regulated, but also glycosylated and oligomerized, resulting in increased ATP biosynthesis. However, constitutive knockout of Pkm2 failed to inhibit this esophageal phenotype in vivo, and this failure may have been due to compensation by Pkm1 up-regulation. Transient inhibition of NRF2 or glycolysis inhibited the growth of human ESCC cells in which NRF2 is hyperactive in vitro In summary, hyperactive Nrf2 causes metabolic reprogramming in the mouse esophagus through its transcriptional regulation of metabolic genes. Blocking glycolysis transiently inhibits cell proliferation and may therefore have therapeutically beneficial effects on NRF2high ESCC in humans.

Multiregion Sequencing Reveals the Genetic Heterogeneity and Evolutionary History of Osteosarcoma and Matched Pulmonary Metastases.

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K-Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis. SIGNIFICANCE: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.

The identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma.

Inducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival. Therefore, ATM or ATR inhibition is considered as a promising strategy for sensitizing cancer cells to chemotherapy. This study is aimed to explore the effect of ATR inhibitor on sensitizing ESCC (esophageal squamous cell carcinoma) cells to cisplatin, and whether ATM deficiency could impact the sensitization. We found that 21.5% of ESCC cases had ATM deficiency and that patients with ATR activation after neoadjuvant chemotherapy had worse chemotherapy response and poorer overall survival than that without ATR activation (32 mons vs. >140mons). Then, it was shown that VE-822 inhibited ATR-CHK1 pathway activation, leading to the accumulation of cisplatin-modified DNA. And it inhibited cell proliferation, induced cell cycle arrest in G1 phase and enhanced cell apoptosis. Moreover, VE-822 significantly sensitized ESCC cells to cisplatin, and these two drugs had synergistic effects, especially in ATM-deficient cells, in vitro and in vivo. Our results suggest that ATR inhibition combining with cisplatin is a new strategy for managing patients with ESCC, especially those with ATM-deficiency. However, this is an idea that requires further validation.

Efficacy of repeated surgery is superior to that of non-surgery for recurrent/second primary lung cancer after initial operation for primary lung cancer.

BACKGROUND: The current study aimed to determine the oncological efficacy and surgical safety of multiple pulmonary resections (MPRs) after prior curative surgery for local regional recurrent or second primary lung cancers. METHODS: All cases of lung cancer included in our prospective database between January 2000 and July 2015 were retrospectively reviewed. The oncological efficacy endpoints for synchronous and metachronous MPR were five-year overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) rates after the second surgery. The surgical safety endpoints were postoperative mortality and complications (Clavien-Dindo classification) within 30 days. RESULTS: In total, 67 MPR cases were identified. There were no significant differences in the five-year OS and DFS between the synchronous MPR group (n = 50) and the propensity score-matched solitary major pulmonary resection group (n = 250) (5-year OS 84.5% vs. 69.0%, log rank P = 0.112; DFS 64.4% vs. 58.0%, log rank P = 0.278). The five-year OS and PFS of the metachronous MPR group (n = 17) were significantly better than those in the non-surgical control group (n = 19) (5-year OS 94.1% vs. 50.7%, log rank P = 0.005; 5-year PFS 53.9% vs. 10.5%, log rank P = 0.020). No postoperative mortality or severe complications occurred in the MPR group. CONCLUSION: The oncological efficacy of MPR is superior to the non-surgical approach for the management of local regional recurrent or second primary lung cancer, with comparable postoperative mortality and complications.