T4 Esophageal Squamous Cell Carcinoma Research Articles

Expression of SOX4 Significantly Predicts the Risk of Lymph Node Metastasis for Patients With Early-Stage Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma stands as a notably aggressive malignancy within the digestive system. In cases of early esophageal cancer without lymph node metastasis, endoscopic surgical resection offers a viable alternative, often resulting in improved patient quality of life. However, the paucity of methods to preoperatively ascertain lymph node involvement complicates surgical planning. SOX4 gene was previously found to be highly associated with invasive metastasis in our work through single-cell RNA sequencing on 5 paired tumor/peritumor tissues. This research included the collection of 124 tissue samples from 106 patients (106 tumor and 18 lymph node specimens). Samples were methodically arranged into a tissue microarray and treated with immunohistochemical staining. Statistical analysis was conducted to assess the relationship between them. In the univariate analysis, 3 factors were identified as statistically significant in relation to lymph node metastasis: T category (P = .014), vascular invasion (P < .001), and SOX4 intensity (P = .001). Additionally, when evaluating SOX4 intensity alongside other clinical indicators, SOX4 was shown to independently influence lymph node metastasis. Further, the multivariate analysis revealed that vascular invasion (P < .001) and SOX4 intensity (P = .003) were significantly associated with lymph node metastasis, exhibiting hazard ratios of 10.174 and 7.142, respectively. The results of our study indicate that both SOX4 expression and vascular invasion serve as predictors of lymph node metastasis in patients diagnosed with category T1 esophageal squamous cell carcinoma, underscoring the potential utility of SOX4 in prognostic evaluations.

Prediction of lymph node status in stage T1 esophageal squamous cell carcinoma.

263 Background: With the development of endoscopic therapy and the introduction of immunotherapies, it is more important for preserving the esophagus and uninvaded lymph nodes to avoid the damages involving the long-term quality of life and normal immune function caused by esophagectomy with radical lymphadenectomy. Methods: We collected patients with T1 ESCC who underwent endoscopic resection or esophagectomy from 2014 to 2021 in three cancer centers. The primary end point was presence of lymph node metastasis (LNM) in surgical resection specimens or detection of metastases during follow-up. Univariate and multivariate logistic regression were used to screen the clinicopathological features related to LNM. Using the function 'lrm' constructed the prediction model. The area under the curve (AUC) of receiver operating characteristic and calibration graphs were used to assess the performance of the model. An external validation was conducted to evaluate the generalization of the model. We then prospectively collected 28 surgically resected tissue samples of T1 ESCC to further supplement the model from the cellular and molecular level, and used 6 markers (CK, CD34, D2-40, CD4, CD8, FOXP3) and DAPI dye to process multiple immunofluorescence (mIF) staining. Afterwards, we analyzed the density, spatial distribution of microvessels, lymphatic capillaries and tumor-associated immune cells and the interaction between them and malignant cells in the tumor microenvironment of T1 ESCC to explore the relationship between tumor microenvironment and risk of LNM. Results: 1109 patients with T1 ESCC were included. 653 patients from two centers constituted the training cohort, and 456 patients from the third center served as the validation cohort. Multivariate logistic regression based on the training cohort showed that tumor invasion into the submucosa, poor histological grade, and lymphovascular invasion were risk factors for LNM in T1 ESCC. Subsequently, we constructed a model based on three variables to predict the risk of LNM in T1 ESCC. The model demonstrated good discriminative ability (AUC 0.858, 95%CI 0.826-0.890). After mIF staining of 28 prospectively collected T1 ESCC tissue samples, we observed that microvessels and lymphatic capillaries were abundant in the mucosa in lymph node-positive samples but not in lymph node-negative samples. In addition, the average density of FOXP3+ T cells in samples with and without metastasis was 253/mm2 and 26/mm2 (P &lt; 0.001), and the average density of CD8+ T cells was 112/mm2 and 432/mm2 (P &lt; 0.001) in quantitative analysis, respectively. Conclusions: This study (RENMIN-237) developed a well-performing LNM risk stratification model of T1 ESCC to reduce both overtreatment and undertreatment, and we found that FOXP3+ T cells in the tumor microenvironment are a risk factor for LNM, while CD8+ T cells can serve as a protective factor against LNM.

Identification and Prognostic Effect of Extramural Venous Invasion in Locally Advanced Esophageal Squamous Cell Carcinoma.

The role of extramural venous invasion (EMVI) in esophageal cancer is still unclear. This study aimed to identify EMVI and assess its impact on survival and recurrences in esophageal squamous cell carcinoma (ESCC). Retrospectively, we reviewed resection specimens of 147 locally advanced ESCC (pT3-T4aN0-3M0) patients who had a curative intended surgery alone at the Cancer Hospital of Shantou University from March 2009 to December 2013. After confirming pT≥3 in hematoxylin-eosin tumor slides, EMVI was evaluated by Verhoeff and Caldesmon staining. The impact of EMVI with other clinicopathological characteristics and survival were analyzed using the χ 2 test, Cox regression, and Kaplan-Meier method. EMVI was present in 30.6% (45/147) of the P ≥T3 ESCCs and associated with lymph-vascular invasion and poor differentiation grade ( P <0.05). Disease-free survival and overall survival in patients with EMVI-absent tumors were about 2.0 times longer than in those with EMVI-present tumors. In pN0 patients, EMVI-presence was associated with poor overall survival (HR 4.829, 95% CI 1.434-16.26, P =0.003) and Disease-free Survival (HR 4.026, 95% CI 0.685-23.32, P =0.018). In pN1-3 patients, EMVI had no additional effect on survival. Conclusions EMVI has an independent adverse prognostic effect on survival in ESCC patients after surgery alone. EMVI should be included in pathology reports as it might contribute to identify high-risk patients for potential additional treatment.

Lymph node metastasis is not associated with survival in patients with clinical stage T4 esophageal squamous cell carcinoma undergoing definitive radiotherapy or chemoradiotherapy.

BackgroundClinical T4 stage (cT4) esophageal tumors are difficult to be surgically resected, and definitive radiotherapy (RT) or chemoradiotherapy (dCRT) remains the main treatment. The study aims to analyze the association between the status of lymph node (LN) metastasis and survival outcomes in the cT4 stage esophageal squamous cell carcinoma (ESCC) patients that underwent treatment with dCRT or RT.MethodsThis retrospective study analyzed the clinical data of 555 ESCC patients treated with dCRT or RT at the Shandong Cancer Hospital and the Liaocheng People’s Hospital from 2010 to 2017. Kaplan–Meier and Cox regression analyses was performed to determine the relationship between LN metastasis and survival outcomes of cT4 and non-cT4 ESCC patients. The chi-square test was used to evaluate the differences in the local and distal recurrence patterns in the ESCC patients belonging to various clinical T stages.ResultsThe 3-year survival rates for patients with non-cT4 ESCC and cT4 ESCC were 47.9% and 30.8%, respectively. The overall survival (OS) and progression-free survival (PFS) rates were strongly associated with the status of LN metastasis in the entire cohort (all P < 0.001) and the non-cT4 group (all P < 0.001) but not in the cT4 group. The local recurrence rates were 60.7% for the cT4 ESCC patients and 45.1% for the non-cT4 ESCC patients (P < 0.001). Multivariate analysis showed that clinical N stage (P = 0.002), LN size (P = 0.007), and abdominal LN involvement (P = 0.011) were independent predictors of favorable OS in the non-cT4 group. However, clinical N stage (P = 0.824), LN size (P = 0.383), and abdominal LN involvement (P = 0.337) did not show any significant correlation with OS in the cT4 ESCC patients.ConclusionsOur data demonstrated that the status of LN metastasis did not correlate with OS in the cT4 ESCC patients that received dCRT or RT. Furthermore, the prevalence of local recurrence was higher in the cT4 ESCC patients.

A retrospective study comparing definitive chemoradiotherapy vs. chemoradiotherapy followed by surgery in T4 esophageal squamous cell carcinoma patients who were downstaged after neochemoradiotherapy

BackgroundThe outcome of patients with T4 esophageal squamous cell carcinoma (ESCC) is extremely poor. Two distinct therapeutic options are currently available for T4 esophageal cancers: neochemoradiotherapy followed by surgery (CRT-S) and definitive chemoradiotherapy (D-CRT). This study aimed to investigate the clinicopathologic characteristics of T4 ESCC in Chinese patients and compare the survival between the two therapeutic options.MethodsWe retrospectively analyzed 125 patients with clinically unresectable T4 ESCC in Tianjin Medical University Cancer Institute and Hospital from January 2010 to December 2020. Overall survival (OS), progression-free survival (PFS) and associated factors were analyzed.ResultsA total of 106 of 125 T4 ESCC patients were downstaged of the tumor by neoadjuvant CRT. Among 106 patients, 32 patients underwent CRT-S, and 74 patients underwent D-CRT. Patients in the CRT-S group had a higher OS (20.4 months vs. un-reached median OS, p = 0.037) and PFS (8.6 months vs. 21.0 months, p = 0.008) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor of PFS. After propensity score matching (PSM), 50 patients (CRT-S = 25; D-CRT = 25) were matched. Among these 50 patients, patients in the CRT-S group had a higher OS (15.6 months vs. un-reached median OS, p = 0.025) and PFS (7.2 months vs. 18.8 months, p = 0.026) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor for PFS.ConclusionWe demonstrated that CRT-S was superior to D-CRT for T4 ESCC patients who were downstaged by neo-CRT with respect to longer OS and PFS. Randomized controlled trials involving large population samples are needed to define the standard treatment for T4 ESCC.

Lymphatic Drainage System and Lymphatic Metastasis of Cancer Cells in the Mouse Esophagus.

Lymphatic metastasis is commonly seen in patients with esophageal squamous cell carcinoma (ESCC). Both lymphatic metastasis and the number of involved nodes are prognostic for post-operative survival. To better understand lymphatic metastasis of ESCC, there is a need to develop proper animal models. This study is aimed to characterize the morphology and function of the lymphatic drainage system in the mouse esophagus. Immunostaining and fluorescence imaging were used to visualize the lymphatic drainage system in the mouse esophagus. Tracers and cancer cells were orthotopically inoculated into the submucosa of the mouse esophagus to mimic lymphatic metastasis of T1 ESCC. Using immunostaining of a lymphatic vessel marker (LYVE1), we found that lymphatic vessels were located in the submucosa and muscularis propria of the mouse esophagus, similar to the human esophagus. In the esophagus of ProxTom mice expressing tdTomato in the lymphatic vessels, we discovered a microscopic meshwork of lymphatic vessels. Functionally, orthotopically inoculated tracers (Indian ink and FITC-dextran) were drained from the submucosa into peri-esophageal lymph nodes via lymphatic vessels. Orthotopically inoculated mouse cancer cells (LLC-eGFP, MOC2) metastasized from the submucosa to lymphatic vessels, peri-esophageal lymph nodes, and distant organs (liver and lung) in immunocompetent mice. Similarly, in immunodeficient mice, orthotopically inoculated human ESCC cells (KYSE450-eGFP-Luc) metastasized via the same route. We have characterized the morphology and function of the lymphatic drainage system of the mouse esophagus. These observations lay a foundation for mechanistic and therapeutic studies on lymphatic metastasis of T1 ESCC.

Development and validation of a nomogram for preoperative prediction of lymph node metastasis in pathological T1 esophageal squamous cell carcinoma.

Endoscopic resection is increasingly used to treat patients with pathological T1 (pT1) esophageal squamous cell carcinoma (ESCC) because of its small surgical trauma. However, reports of the risk factors for lymph node metastasis (LNM) have been controversial. Therefore, we aim to build a nomogram to individually predict the risk of LNM in pT1 ESCC patients, to make an optimal balance between surgical trauma and surgical income.One hundred seventy patients with pT1 esophageal cancer in our hospital were analyzed retrospectively. Logistic proportional hazards models were conducted to find out the risk factor associated with LNM independently, and those were imported into R library “RMS” for analysis. A nomogram is generated based on the contribution weights of variables. Finally, decision analysis and clinical impact curve were used to determine the optimal decision point.Twenty-five (14.7%) of the 170 patients with pT1 ESCC exhibited LNM. Multivariable logistic regression analysis showed that smoking, carcinoembryonic antigen, vascular tumor thromboembolus, and tumor differentiation degree were independent risk factors for LNM. The nomogram had relatively high accuracy (C index of 0.869, 95% confidence interval: 0.794–0.914, P < .0001). The decision curve analysis provided the most significant clinical benefit for the entire included population, with scores falling just above the total score of 85 in the nomogram.Smoking, carcinoembryonic antigen, vascular tumor thromboembolus, and tumor differentiation degree may predict the risk of LNM in tumor 1 ESCC. The risk of LNM can be predicted by the nomogram.

Effect of chemoradiation on the development of second primary cancers after endoscopic resection of T1 esophageal squamous cell carcinoma.

Patients with early esophageal squamous cell carcinoma (ESCC) may develop multiple second primary ESCC and cancers in other organs even after curative endoscopic resection (ER). We investigated whether administration of chemoradiotherapy (CRT) after ER decreases the incidence of second primary cancers. We conducted a post hoc analysis of the prospective study. Among the registered 170 patients with clinical submucosal ESCC, 74 underwent ER alone, and 96 underwent ER followed by CRT (ER + CRT) because of pathological results of submucosal or lympho-vascular invasion. We compared the incidence of second primary cancers in esophagus and in other organs between two treatment groups. A univariate analysis was performed to investigate the related risk factors. All patients were followed up with esophagogastroduodenoscopy and CT every 4months for the first 3years and every 6months thereafter. Sixty-one ESCC were detected in 32 patients, and the 3-year cumulative incidence of multiple ESCCs was not different between ER + CRT and ER alone (10.4% vs. 13.5%). Sixty-three second primary cancers in other organs were detected in 45 patients, and there was no difference in the cumulative incidence between two groups. The risk factors for multiple ESCCs were high alcohol consumption and grade C multiple Lugol-voiding lesions. Heavy drinker or patients with grade C multiple Lugol-voiding lesion rather than CRT were at risk for second primary ESCC. CRT after ER did not decrease the cumulative incidence of second primary ESCC nor cancers in other organs comparing with ER alone.

Development and Validation of the Optimal Circumferential Resection Margin in Pathological T3 Esophageal Cancer: A Multicenter, Retrospective Study.

The clinical significance of circumferential resection margin (CRM) in esophageal squamous cell carcinoma (ESCC) remains unclear. Optimal CRM for predicting the recurrence of pathological T3 ESCC was investigated. Seventy-three patients were retrospectively investigated in the development cohort. Patients were divided into CRM-negative and CRM-positive groups, and clinicopathological factors and survival outcomes were compared between the groups. The cutoff value was validated in another validation cohort (n = 99). Receiver operating characteristic analysis in the development cohort showed the cutoff value of CRM was 600 μm. In the validation cohort, patients in the CRM-positive group showed a significantly higher rate of locoregional recurrence (p = 0.006) and worse recurrence-free survival (RFS) (p < 0.001) than those in the CRM-negative group. Multivariate analysis identified positive CRM as an independent predictive factor for poor RFS (hazard ratio, 2.695; 95% confidence interval, 1.492-4.867; p = 0.001). The predictive value of our criteria of positive CRM for RFS was higher than that of the Royal College of Pathologists (RCP) and the College of American Pathologists (CAP) criteria. Stratified analysis in the neoadjuvant chemotherapy groups also revealed that the rate of locoregional recurrence was higher in the CRM-positive group than in the CRM-negative group both in the pathological N0 and N1-3 subgroups. CRM of 600 μm can be the optimal cutoff value rather than the RCP and CAP criteria for predicting locoregional recurrence after esophagectomy. These results may support the impact of perioperative locoregional control of locally advanced ESCC.

Endoscopic submucosal dissection versus esophagectomy for t1 esophageal squamous cell carcinoma: a propensity score-matched analysis.

Endoscopic submucosal dissection (ESD) has been a preferred treatment option for superficial esophageal squamous cell carcinoma (SESCC). To compare the outcomes of ESD and esophagectomy in the treatment of SESCC, especially for lesions invading muscularis mucosa or submucosa (pT1a-MM/T1b). We retrospectively analyzed data from patients with SESCC who underwent ESD or esophagectomy between 2015 and 2021. After propensity score matching, overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), and treatment-related events were compared between the ESD and esophagectomy groups. Furthermore, we performed a Cox regression analysis to identify factors associated with survival. OS and DSS were significantly higher in the ESD group (n = 508) than that in the esophagectomy group (n = 466). After matching, 404 patients (202 per group) were included in the study. No significant differences were found between the ESD and esophagectomy groups in OS (p = 0.566), RFS (p = 0.586), and DSS (p = 0.912). The ESD group showed less blood loss, shorter procedure duration and hospital stay, lower hospital cost, and fewer adverse events. However, a lower R0 resection rate was observed in the ESD group compared to the esophagectomy group. Subgroup analysis showed comparable survival outcomes between the two groups. In Cox regression analysis, age was the independent factor associated with OS. In the treatment of SESCC, ESD showed sufficient safety and advantages. Even for pT1a-MM/pT1b SESCC, ESD may be an alternative treatment to esophagectomy.

Assessment of the Diagnostic Performance of Endoscopic Ultrasonography After Conventional Endoscopy for the Evaluation of Esophageal Squamous Cell Carcinoma Invasion Depth

Distinguishing between mucosal and submucosal cancers is important for selecting the optimal treatment for patients with esophageal squamous cell carcinoma (ESCC); however, standard procedures for diagnosing cancer invasion depth have not yet been determined. To evaluate the diagnostic performance of endoscopic ultrasonography (EUS) after conventional endoscopy for the evaluation of ESCC invasion depth. This prospective single-arm confirmatory diagnostic study comprising 372 patients with T1 esophageal cancer was conducted at 41 secondary or tertiary hospitals in Japan. Enrollment began on July 20, 2017; patients were enrolled in 2 steps, with the first registration occurring from August 4, 2017, to December 11, 2019, and the second from August 9, 2017, to December 11, 2019. After the completion of all first and second registration examinations, patients received treatment and were followed up for 30 days, with follow-up ending on February 14, 2020. Patients were eligible for inclusion if they had pathologically or endoscopically diagnosed esophageal cancer with T1 clinical depth of invasion. In the first registration, nonmagnifying endoscopy (non-ME) and magnifying endoscopy (ME) were used to diagnose cancer invasion depth. In the second registration, patients from the first registration who had cancers invading the muscularis mucosa or submucosa were enrolled and received EUS. After completion of the protocol examinations, patients received treatment with endoscopic resection or esophagectomy. The pathological results of the resected specimens were used as the reference standard for evaluating cancer invasion depth. The primary end point was the proportion of overdiagnosis of submucosal cancer (defined as invasion depth >200 μm) after receipt of non-ME and ME, with or without the addition of EUS. The secondary end points were underdiagnosis, sensitivity, and specificity. Among 372 patients enrolled in the first registration, 371 received non-ME and ME. Of those, 300 patients were enrolled in the second registration, and 293 patients received EUS. A total of 269 patients (217 men [80.7%]; median age, 69 years; interquartile range, 62-75 years) were included in the final analysis. The addition of EUS was associated with a 6.6% increase in the proportion of overdiagnosis (from 16 of 74 patients [21.6%; 95% CI, 12.9%-32.7%] after non-ME and ME to 29 of 103 patients [28.2%; 95% CI, 19.7%-37.9%] after the addition of EUS; 1-sided P = .93). All subgroup analyses found similar increases in overdiagnosis of submucosal cancer. The addition of EUS was associated with a 4.5% reduction in the proportion of underdiagnosis (from 57 of 195 patients [29.2%; 95% CI, 23.0%-36.2%] after non-ME and ME to 41 of 166 patients [24.7%; 95% CI, 18.3%-32.0%] after the addition of EUS). After non-ME and ME, diagnostic sensitivity was 50.4% (95% CI, 41.0%-59.9%), specificity was 89.6% (95% CI, 83.7%-93.9%), and accuracy was 72.9% (95% CI, 67.1%-78.1%). After the addition of EUS, diagnostic sensitivity was 64.3% (95% CI, 54.9%-73.1%), specificity was 81.2% (95% CI, 74.1%-87.0%), and accuracy was 74.0% (95% CI, 68.3%-79.1%). This study found that the addition of EUS was not associated with improvements in the diagnostic accuracy of cancer invasion depth. These findings do not support the routine use of EUS after conventional endoscopy for evaluating the invasion depth among patients with T1 ESCC.

Development and validation of a nomogram to predict overall survival of T1 esophageal squamous cell carcinoma patients with lymph node metastasis

PurposeTo develop a nomogram for predicting the prognosis of T1 esophageal squamous cell carcinoma (ESCC) patients with positive lymph node. MethodsT1 ESCC patients with lymph node metastasis diagnosed between 2010 and 2015 were selected from the Surveillance, Epidemiology, and Final Results (SEER) database. The entire cohort was randomly divided in the ratio of 7:3 into a training group (n=457) and validation group (n=192), respectively. Prognostic factors were identified by univariate and multivariate Cox regression models. Harrell's concordance index (C-index), receiver operating characteristic (ROC) curve, and calibration curve were used to evaluate the discrimination and calibration of the nomogram. The accuracy and clinical net benefit of the nomogram compared with the 7th AJCC staging system were evaluated using net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA). ResultsThe nomogram consisted of eight factors: insurance, T stage, summary stage, primary site, radiation code, chemotherapy, surgery, and radiation sequence with surgery. In the training and validation cohorts, the AUCs exceeded 0.700, and the C-index scores were 0.749 and 0.751, respectively, indicating that the nomogram had good discrimination. The consistency between the survival probability predicted by the nomogram and the actual observed probability was indicated by the calibration curve in the training and validation cohorts. For NRI>0 and IDI>0, the predictive power of the nomogram was more accurate than that of the 7th AJCC staging system. Furthermore, the DCA curve indicated that the nomogram achieved better clinical utility than the traditional system. ConclusionsUnlike the 7th AJCC staging system, the developed and validated nomogram can help clinical staff to more accurately, personally and comprehensively predict the 1-year and 3-year OS probability of T1 ESCC patients with lymph node metastasis.

Ability of artificial intelligence to detect T1 esophageal squamous cell carcinoma from endoscopic videos and the effects of real-time assistance

Diagnosis using artificial intelligence (AI) with deep learning could be useful in endoscopic examinations. We investigated the ability of AI to detect superficial esophageal squamous cell carcinoma (ESCC) from esophagogastroduodenoscopy (EGD) videos. We retrospectively collected 8428 EGD images of esophageal cancer to develop a convolutional neural network through deep learning. We evaluated the detection accuracy of the AI diagnosing system compared with that of 18 endoscopists. We used 144 EGD videos for the two validation sets. First, we used 64 EGD observation videos of ESCCs using both white light imaging (WLI) and narrow-band imaging (NBI). We then evaluated the system using 80 EGD videos from 40 patients (20 with superficial ESCC and 20 with non-ESCC). In the first set, the AI system correctly diagnosed 100% ESCCs. In the second set, it correctly detected 85% (17/20) ESCCs. Of these, 75% (15/20) and 55% (11/22) were detected by WLI and NBI, respectively, and the positive predictive value was 36.7%. The endoscopists correctly detected 45% (25–70%) ESCCs. With AI real-time assistance, the sensitivities of the endoscopists were significantly improved without AI assistance (p < 0.05). AI can detect superficial ESCCs from EGD videos with high sensitivity and the sensitivity of the endoscopist was improved with AI real-time support.

Prediction of the tumor response and survival based on computed tomography in esophageal squamous cell carcinoma after trimodality therapy.

Predicting the response to neoadjuvant chemoradiotherapy (NCRT) and the prognosis of esophageal squamous cell carcinoma (ESCC) is challenging. This study evaluated the potential of a preoperative computed tomography (CT) analysis for predicting the pathological response and survival of patients with ESCC who received trimodality therapy. A total of 119 patients with cT3 or T4 ESCC who underwent surgery following NCRT between 2007 and 2019 were assessed. The CT-based parameters were measured with enhanced CT preoperatively, prior to and during treatment. Associations between these parameters and the pathologic response, as well as the prognosis, were examined. Pretreatment maximum CT value (p = 0.009), pretreatment mean CT value (p = 0.022), preoperative whole tumor volume (WTV, p = 0.003), preoperative largest cross section (LCS, p = 0.002), ΔLCS (pretreatment to preoperative, p = 0.004), ΔWTV (pretreatment to preoperative, p = 0.012), and Δmean CT value (pretreatment to preoperative, p = 0.012) of the primary lesion were significantly associated with a good pathological response. A Cox-regression analysis of recurrence-free survival (RFS) and overall survival (OS) showed that preoperative LCS was an independent CT-based predictor. RFS and OS were significantly higher at the optimal cut-off value of the preoperative LCS (p = 0.036 and p = 0.016, respectively). CT-based parameters are thus considered to be valuable predictors of the tumor response and survival after trimodality therapy for ESCC.

Comparison of Aggressive Planned Salvage Surgery Versus Neoadjuvant Chemoradiotherapy Plus Surgery for Borderline Resectable T4 Squamous Cell Carcinoma

We compare planned salvage surgery after definitive chemoradiotherapy (SALV) versus neoadjuvant chemoradiotherapy plus surgery (NCRS) for borderline resectable T4 esophageal squamous cell carcinoma. A total of 37 patients underwent planned SALV, and 20 underwent NCRS from 2004 to 2017. The short-term outcome measures were the R0 resection rate, complications, and treatment-related mortality. The long-term outcome measures were the 5-year overall survival rate and causes of death. R0 resection rate was similar between the SALV and NCRS groups (81% versus 85%). The incidence of postoperative pneumonia (35% versus 18%) and treatment-related mortality rate (9% versus 0%) tended to be higher in the SALV. ypT grade 2-3 (65% versus 30%, p = 0.012) and Clavien-Dindo grade ≥ IIIb complications (32% versus 0%, p = 0.008) were significantly more frequent in the SALV group. The groups had similar 5-year overall survival (26% versus 27%). The causes of death in the SALV and NCRS groups were primary esophageal cancer in 35% and 55% of patients, respectively, and pulmonary-related mortality in 24% and 5%, respectively. Multivariable Cox regression analysis revealed the following significant poor prognostic factors: stable disease as the clinical response, preoperative body mass index (BMI) of < 18.5 kg/m2, ypN stage 1-3, and R1-2 resection. SALV was associated with a higher incidence of late pulmonary-related mortality but had a stronger antitumor effect than NCRS. Consequently, the survival rate was similar between the groups. Surgery is recommended for patients with a partial response and preoperative BMI of ≥ 18.5 kg/m2.

Risk factors for lymph node metastasis in T1 esophageal squamous cell carcinoma: A systematic review and meta-analysis.

BACKGROUNDLymph node metastasis (LNM) affects the application and outcomes of endoscopic resection in T1 esophageal squamous cell carcinoma (ESCC). However, reports of the risk factors for LNM have been controversial.AIMTo evaluate risk factors for LNM in T1 ESCC. METHODSWe searched Embase, PubMed and Cochrane Library to select studies related to LNM in patients with T1 ESCC. Included studies were divided into LNM and non-LNM groups. We performed a meta-analysis to examine the relationship between LNM and clinicopathologic features. Odds ratio (OR), mean differences and 95% confidence interval (CI) were assessed using a fixed-effects or random-effects model.RESULTSSeventeen studies involving a total of 3775 patients with T1 ESCC met the inclusion criteria. After excluding studies with heterogeneity based on influence analysis, tumor size (OR = 1.93, 95%CI = 1.49-2.50, P < 0.001), tumor location (OR = 1.46, 95%CI = 1.17-1.82, P < 0.001), macroscopic type (OR = 3.17, 95%CI = 2.33-4.31, P < 0.001), T1 substage (OR = 6.28, 95%CI = 4.93-8.00, P < 0.001), differentiation (OR = 2.11, 95%CI = 1.64-2.72, P < 0.001) and lymphovascular invasion (OR = 5.86, 95%CI = 4.60-7.48, P < 0.001) were found to be significantly associated with LNM. Conversely, sex, age and infiltrative growth pattern were not identified as risk factors for LNM.CONCLUSIONA tumor size > 2 cm, lower location, nonflat macroscopic type, T1b stage, poor differentiation and lymphovascular invasion were associated with LNM in patients with T1 ESCC.

Clinical significance of HDAC1, -2 and -3 expression levels in esophageal squamous cell carcinoma.

The present study analyzed the expression of the histone deacetylase (HDAC) 1, 2 and 3 in primary esophageal squamous cell carcinoma (ESCC) samples and how their levels correlate with clinicopathological parameters. ESCC patients (n=88) in the present study had received no previous treatment before undergoing surgical excision. The mRNA expression of HDAC1, -2 and -3 were detected by semi-quantified PCR in ESCC samples and distal normal samples. The relationship of HDAC1, -2 and -3 expression with clinicopathological parameters was analyzed by χ2 test. The correlation among these HDACs was analyzed by Pearson's correlation test. Compared with distal normal tissues, ESCC samples had higher expression of HDAC1, but not HDAC2 or HDAC3 (P<0.05). The expression of HDACs was different between Kazak and Han ethnicities. The expression of HDAC2 was correlated with invasion depth (P<0.05), but not with sex, age, metastasis, or the degree of tumor differentiation (P>0.05). There was no association between HDAC1 or HDAC3 and clinicopathological parameters (P>0.05). For the Kazak and Han ethnicities, HDAC1 expression was present in male patients, patients with well/moderate differentiated ESCC and T3 and T4 ESCC (P<0.01). HDAC1 in patients aged <60 was associated with ethnicity (P<0.05). HDAC2 expression was different in positive LN metastasis, well/moderate differentiation and T3 and T4 ESCC (P<0.01). HDAC3 expression in male patients, patients with negative LN metastasis and well/moderate differentiation ESCC was associated with ethnicity (P<0.05). Additionally, the expression levels of HDAC1, -2 and -3 did not correlate with each other. Thus, HDAC1 expression may be used as a risk factor for ESCC and HDAC2 levels may be used to predict invasion depth. The expression of HDAC1, -2 and -3 has ethnic differences.

Appropriate Candidates for Salvage Esophagectomy of Initially Unresectable Locally Advanced T4 Esophageal Squamous Cell Carcinoma.

Standard treatment for unresectable locally advanced esophageal cancer is definitive chemoradiotherapy (dCRT). Although salvage esophagectomy is the only curative treatment available following dCRT failure, the appropriate candidates for salvage esophagectomy remain unclear. Three hundred seventeen patients who underwent dCRT from April 2004 to December 2016 were stratified into three study groups-a complete response (CR) group, chemotherapy or best supportive care (BSC) group, and salvage esophagectomy group-and compared. We also investigated the clinical outcomes and prognostic factors of salvage esophagectomy. Seventy-one patients (22.4%) achieved CR after dCRT, 18 patients (5.7%) underwent salvage esophagectomy, and 228 patients (71.9%) underwent palliative chemotherapy or BSC. The 5-year overall survival (OS) rates of the CR group, salvage esophagectomy group, and chemotherapy or BSC group were 83.0%, 51.6%, and 1.3%, respectively. Salvage esophagectomy recipients had a worse OS rate than CR patients (p < 0.001) but a better OS rate than those in the chemotherapy or BSC group (p < 0.001). Incomplete resection was the only significant variable associated with poor OS on univariate Cox proportional-hazards analysis (hazard ratio: 7.633, 95% confidence interval: 1.692-34.482; p = 0.008). Patients with tumors in the upper thoracic esophagus were more likely to undergo incomplete resection (p = 0.011). Patients who achieve R0 resection are good candidates for salvage esophagectomy regardless of their response to dCRT. Those with upper thoracic esophageal tumors are at risk of incomplete resection; careful attention is required when considering these patients for salvage esophagectomy.

ASO Author Reflections: Appropriate Candidates for Salvage Esophagectomy of Initially Unresectable Locally Advanced T4 Esophageal Squamous Cell Carcinoma.

ASO Author Reflections: Appropriate Candidates for Salvage Esophagectomy of Initially Unresectable Locally Advanced T4 Esophageal Squamous Cell Carcinoma.

Tumor infiltrative growth pattern correlates with the immune microenvironment and is an independent factor for lymph node metastasis and prognosis in stage T1 esophageal squamous cell carcinoma.

In this retrospective study, we analyzed the association between the tumor infiltrative growth pattern (INF) and tumor immune environment and its predictive value for lymph node metastasis and overall survival (OS) in stage T1 esophageal squamous cell carcinoma (ESCC). In total, 593 patients with a diagnosis of stage T1 ESCC who underwent esophagectomy and regional lymphadenectomy between 2009 and 2018 were included. The INF type and elements of the tumor immune microenvironment, including tumor infiltrative lymphocytes (TILs) and tertiary lymphoid structures (TLSs), were microscopically evaluated within the tumor invasive margin with hematoxylin and eosin (HE)-stained slices. The infiltrative-type INF (INFc) was associated with low-grade TILs and the absence of TLSs, deep tumor invasion, poorly differentiated phenotype. Multivariate logistic regression identified INFc as one of the independent risk factors for lymph node metastasis. INFc and low-grade TILs were independent inferior predictive factors for OS. A novel histologic risk stratification model was classified as INFa/b and high-grade TILs, INFa/b and low-grade TILs, INFc and high-grade TILs, and INFc and low-grade TILs. The Kaplan-Meier curves showed that INFa/b and high-grade TILs were associated with the best prognosis, and INFc and low-grade TILs were associated with the worst prognosis, and there was significant difference between groups. In conclusion, INFc is an independent risk factor for lymph node metastasis and an independent inferior prognostic factor for stage T1 ESCC. Furthermore, INFc is associated with immunosuppression, and the combination of the INF and TILs is useful for the risk stratification of prognosis.