Operable Esophageal Squamous Cell Carcinoma Research Articles

Single-cell sequencing reveals immune features of treatment response to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma

Neoadjuvant immunochemotherapy (nICT) has dramatically changed the treatment landscape of operable esophageal squamous cell carcinoma (ESCC), but factors influencing tumor response to nICT are not well understood. Here, using single-cell RNA sequencing paired with T cell receptor sequencing, we profile tissues from ESCC patients accepting nICT treatment and characterize the tumor microenvironment context. CXCL13+CD8+ Tex cells, a subset of exhausted CD8+ T cells, are revealed to highly infiltrate in pre-treatment tumors and show prominent progenitor exhaustion phenotype in post-treatment samples from responders. We validate CXCL13+CD8+ Tex cells as a predictor of improved response to nICT and reveal CXCL13 to potentiate anti-PD-1 efficacy in vivo. Post-treatment tumors from non-responders are enriched for CXCL13+CD8+ Tex cells with notably remarkable exhaustion phenotype and TNFRSF4+CD4+ Tregs with activated immunosuppressive function and a significant clone expansion. Several critical markers for therapeutic resistance are also identified, including LRRC15+ fibroblasts and SPP1+ macrophages, which may recruit Tregs to form an immunosuppressive landscape. Overall, our findings unravel immune features of distinct therapeutic response to nICT treatment, providing a rationale for optimizing individualized neoadjuvant strategy in ESCC.

Comparison of pathologic response and survival outcomes between neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant immunochemotherapy (nICT) in patients with locally advanced esophageal squamous cell carcinoma: a propensity score-matched analysis

BackgroundIn locally advanced, operable esophageal squamous cell carcinoma (ESCC), neoadjuvant immunochemotherapy (nICT) has shown results that are somewhat comparable to those of standard neoadjuvant chemoradiotherapy (nCRT). The impact of these neoadjuvant treatments on survival outcomes, however, has yet to be elucidated.MethodsThis study included 489 patients with locally advanced ESCC who underwent surgery at Sichuan Cancer Hospital after receiving neoadjuvant treatment between June 2017 and September 2023. Patients were categorized into nCRT and nICT groups based on whether they received neoadjuvant treatment. To mitigate potential biases and balance covariates between the two cohorts, 1:2 propensity score matching (PSM) was conducted using a caliper width of 0.05.ResultsAfter PSM, the baseline characteristics of the 360 patients remained balanced between the two groups. The findings indicated a superior pathological response in the nCRT group, as evidenced by significantly greater rates of complete response (32.87% vs 14.58%, P < 0.001) and favorable tumor regression grade (TRG), as well as reduced ypT stages and less perineural and angioinvasion, despite comparable ypN stages. Despite the improvement in complete pathological response (pCR) in the nCRT group, the 3-year disease-free survival (DFS) and overall survival (OS) rates did not significantly differ between the groups (DFS: 58.32% vs 56.16%, P = 0.67; OS: 69.96% vs 71.99%, P = 0.99). Crucially, The nICT group showed a lower incidence of grade 3 and 4 adverse events in Leukopenia (2.8% vs 29%; P < 0.001) and Neutropenia (2.8% vs 24%; P < 0.001) during neoadjuvant treatment, comparing with nCRT group.ConclusionsOur preliminary findings suggest that nICT followed by surgery offers comparable survival rates to nCRT, despite being less effective in pathologic outcomes. Nonetheless, nICT is a safe and feasible strategy for locally advanced ESCC, warranting further exploration to understand its impact on long-term survival.

Impact of positive tumor-informed margin and TP53 mutations on surgical outcomes in esophageal squamous cell carcinoma.

e16024 Background: The complete removal of esophageal squamous cell carcinoma (ESCC) with clear margins (R0 resection) is pivotal for patient prognosis. However, it is limited by the potential inaccuracies of conventional histopathology. Next-generation sequencing (NGS) for minimal residual disease (MRD) detection might improve the prediction of postoperative outcomes. Methods: The study cohort included a total of 48 operable ESCC patients, from whom resected esophageal tumors, resection margins, and normal tissues were collected and profiled by a 425-gene panel. Comparisons of mutational features were conducted across various tissue types, and their associations with disease-free survival (DFS) were explored. Results: Mutations were detected in 81.8% (27/33) of normal tissues, 95.8% (46/48) of tumors, and 50.0% (24/48) of resection margins. In general, genetic alterations in resection margins closely resembled those in tumor tissues, but were distinct from normal tissues. Both tumor and margin samples showed higher variant allele frequencies (VAFs) and fewer mutations per patient than normal samples ( p &lt; 0.0001). Moreover, eight patients exhibited identical mutations in paired margin and tumor samples. Notably, one patient out of eight with the same TP53 p.T175H mutation across all sample types exhibited the shortest DFS of only two months. Mutations in TP53 and NOTCH1 were the most common, displaying unique mutational patterns among different sample types. While NOTCH1 mutations were detected more frequently in normal tissues ( p = 0.001), TP53 mutations were enriched in tumors ( p = 0.04). Furthermore, normal tissues exhibited a distinct pattern of mutation sites for TP53 and NOTCH1 compared to those observed in tumor or margin tissues. We characterized tumor-informed margin (TiM) by the presence of identical mutations in both tumor and adjacent margins. The positive TiM status was associated with a shorter DFS, particularly when considering TP53 mutations alone ( p = 0.022) or excluding NOTCH1 mutations ( p = 0.031). Conclusions: A positive TiM status with TP53 mutations is a promising biomarker indicating poor surgical outcomes in ESCC. Mutations within NOTCH1 are common but showed no association with DFS. These findings provide novel insights into the feasibility of genetic profiling of resection margins to facilitate optimizing postoperative therapeutic regimens for ESCC.

Surgical quality determines the long-term survival superiority of right over left thoracic esophagectomy for localized esophageal squamous cell carcinoma patients: a real-world multicenter study.

The objective was to compare the long-term overall survival (OS) of right versus left thoracic esophagectomy, and to evaluate whether surgical quality impacts comparison result. Controversy regarding the optimal thoracic esophagectomy approach persists for esophageal squamous cell carcinoma (ESCC). No study has assessed the effect of surgical quality in comparison between right and left approaches. The authors consecutively recruited 5556 operable ESCC patients from two high-volume centers in China, of whom 2220 and 3336 received right and left thoracic esophagectomy, respectively. Cumulative sum was used to evaluate the learning curve for operation time of right approach, as the indicator of surgical proficiency. With a median follow-up of 83.1 months, right approach, harvesting more lymph nodes, tended to have a better OS than left approach (Mean: 23.8 vs. 16.7 nodes; adjusted hazard ratio (HR)=0.93, 95% CI: 0.85-1.02). Subset analysis by the extent of lymphadenectomy demonstrated that right approach with adequate lymphadenectomy (≥15 nodes) resulted in statistically significant OS benefit compared with left approach (adjusted HR=0.86, 95% CI: 0.77-0.95), but not with limited lymphadenectomy. Subset analysis by surgical proficiency showed that proficient right approach conferred a better OS than left approach (adjusted HR=0.75, 95% CI: 0.64-0.88), but improficient right approach did not have such survival advantage. Surgical quality plays a crucial role in survival comparison between surgical procedures. Right thoracic esophagectomy performed with adequate lymphadenectomy and surgical proficiency, conferring more favorable survival than left approach, should be recommended as the preferred surgical procedure for localized ESCC.

Progenitor-like exhausted SPRY1+CD8+ T cells potentiate responsiveness to neoadjuvant PD-1 blockade in esophageal squamous cell carcinoma

Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here, we perform single-cell RNA-sequencing of tumors from patients with ESCC undergoing neoadjuvant ICB, revealing a subset of exhausted CD8+ Tcells expressing SPRY1 (CD8+ Tex-SPRY1) that displays a progenitor exhausted Tcell (Tpex) phenotype and correlates with complete response to ICB. We validate CD8+ Tex-SPRY1 cells as an ICB-specific predictor of improved response and survival using independent ICB-/non-ICB cohorts and demonstrate that expression of SPRY1 in CD8+ Tcells enforces Tpex phenotype and enhances ICB efficacy. Additionally, CD8+ Tex-SPRY1 cells contribute to proinflammatory phenotype of macrophages and functional state of B cells, which thereby promotes antitumor immunity by enhancing CD8+ Tcell effector functions. Overall, our findings unravel progenitor-like CD8+ Tex-SPRY1 cells' role in effective responses to ICB for ESCC and inform mechanistic biomarkers for future individualized immunotherapy.

204. CORRELATION OF CIRCULATING T LYMPHOCYTES WITH RESPONSE TO NEOADJUVANT CHEMOIMMUNOTHERAPY IN OPERABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background There is growing evidence indicating that neoadjuvant chemotherapy combined immune-oncology therapy (neoCTIO) with anti-PD-1 antibodies is effective in esophageal squamous cell carcinoma (ESCC). However, the precise benefits remain unclear. This study aimed to explore whether the subsets and production of effector cytokines in circulating T lymphocytes were correlated with response to neoCTIO with toripalimab in operable ESCC. Methods ESCC patients staged cT2N1–2 M0 or cT3–4aN0-2 M0, with ECOG PS 0–1 status randomly received two cycles of different sequences of toripalimab plus chemotherapy (paclitaxel and carboplatin) on day 1 to 2 of each 21-day cycle. Minimally invasive esophagectomy (MIE) was performed 4–8 weeks after neoCTIO. Peripheral blood was collected before and after neoCTIO. Flow cytometry was used to detect the effector cytokines and subsets of CD8+ and CD4+ T lymphocytes. The primary endpoints were the advanced change of subsets, effector cytokines in T lymphocytes, and pathological complete response (pCR). The secondary endpoints included major pathological response (MPR) (NCT05044728). Results 96.7% (32/33) patients received MIE with R0 resection. 18.8% (6/32) patients achieved pCR and 31.3% (10/32) patients achieved MPR. In the responders, CD8+ T lymphocytes showed higher IFNγ and TNFα coexpression compared to non-responders before neoCTIO (P = 0.010). The responders had higher frequency of effector subsets (P = 0.029) and lower naive subsets (P = 0.006) of CD8+ T lymphocytes than the non-responders before neoCTIO. No difference was found in the cell frequency of CD4+ T lymphocyte subsets between the responders and non-responders. There was no correlation between the change of subsets, effector cytokines in T lymphocytes and the sequence of neoCTIO. Conclusion NeoCTIO with toripalimab is effective in the treatment of ESCC. The baseline frequency of effector subsets and coexpression of IFNγ and TNFα in circulating CD8+ T lymphocytes have positive predictive value while the baseline frequency of Naive subsets is a negative biomarker. CD4+ T cell subsets have no correlation with the treatment response. The change of circulating CD8+ T lymphocytes is not affected by the sequence of neoCTIO.

Family history of cancer is a prognostic factor for better survival in operable esophageal squamous cell carcinoma: A propensity score matching analysis.

Patients with a family history of cancer, especially digestive tract cancer and esophageal cancer, a family history of cancer in the first degree, and more than one relative affected by cancer were associated with favorable survival when compared to those without a family history of cancer. A family history of cancer is a favorable independent prognostic factor in ESCC. Patients with a family history of cancer, especially digestive tract cancer and esophageal cancer, a family history of cancer in the first degree, and more than one relative affected by cancer were associated with favorable survival when compared to those without a family history of cancer. A family history of cancer (FH) is closely associated with the risk and survival of many cancers. However, the effect of FH on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains unclear. We performed a large cohort study in the Chinese population to obtain insight into the prognostic value of FH in patients with operable ESCC. A total of 1,322 consecutive patients with thoracic ESCC who had undergone esophagectomy between January 1997 and December 2013 were included. The FH group included patients with any degree of FH, while the non-FH group included patients without any degree of FH. In total, 215 patients with FH and 215 without FH were matched using the propensity score matching analysis method to adjust for differences in baseline variables between the two groups. The impact of FH on disease-free survival (DFS) and overall survival (OS) was estimated using the Kaplan-Meier method and Cox's proportional hazards models. Before matching, 280 (21.2%) patients were included in the FH group and 1,042 (78.8%) in the non-FH group. FH was associated with early pathological T stage (p = 0.001), lymph node-negative status (p = 0.022), and early pathological stage (p = 0.006). After matching, FH was an independent prognostic factor for DFS and OS in ESCC patients. Patients with FH had 35% lower risk of disease progression (hazard ratio [HR] = 0.65, 95% CI: 0.51-0.84, p = 0.001) and 34% lower risk of death (HR = 0.66, 95% CI: 0.51-0.86, p = 0.002) than those without FH. Patients with a family history of digestive tract cancer (FH-DC), a family history of esophageal cancer (FH-EC), FH in first-degree relatives (FH-FD), and more than one relative affected by cancer were associated with favorable DFS and OS as compared to those without FH. FH is a favorable independent prognostic factor in ESCC. Patients with FH, especially those with FH-DC, FH-EC, FH-FD, and more than one relative affected by cancer, had improved survival.

Elevated Preoperative NMPR Predicts an Unfavorable Chance of Survival in Resectable Esophageal Squamous Cell Carcinoma.

Background and objectives: Combined peripheral neutrophil−platelet indexes reflecting the systemic inflammatory status have been reported to predict the clinical outcome in patients with various types of cancer. However, the prognostic value of combined neutrophil−platelet indexes in operable esophageal squamous cell carcinoma (ESCC) remains unclear. The study introduced a novel combined neutrophil−meanplateletvolume−platelet ratio (NMPR) index and investigated its clinical and prognostic value in patients with operable ESCC receiving curative surgery. Materials and Methods: A retrospective analysis of the clinicopathologic data of 277 consecutive ESCC patients who received curative resection at Zhejiang Cancer Hospital in China between January 2007 and December 2010 was conducted (the training cohort). In addition, the clinicopathologic data of 101 resectable ESCC patients at Renmin Hospital of Hubei University of Medicine between December 2018 and June 2021 were collected (the external validation cohort). The optimal cutoff value of NMPR concerning overall survival (OS) in the training cohort was determined by X-tile software. Univariate and multivariate Cox regression analyses were used to evaluate the prognostic value of NMPR along with other variables in the training cohort, which was further validated with the same cutoff value in the external validation cohort. Significant predictors of OS were used to construct the nomogram, of which the discrimination and calibration was evaluated by concordance index (C-index) and calibration plots. Results: With a cutoff value of 16.62, the results from both the training and external validation cohorts supported the association of high NMPR (>16.62) with increased tumor length and advanced T stage but not with other variables. In the training cohort, a significant association between shorter OS and high NMPR (p = 0.04) as well as high CRP (p < 0.001), poor tumor differentiation (p = 0.008), advanced T stage (p = 0.006), advanced N stage (p < 0.001) and high CEA (p = 0.007) was revealed. Additionally, the high NMPR was verified to independently predict unfavorable OS (p = 0.049) in the external validation cohort. The C-index of the OS nomogram cooperating significant predictors in the training cohort was 0.71 and the calibration plots of the OS nomogram fitted well. Conclusions: The present study demonstrates that high NMPR is an independent predictor of unfavorable OS in resectable ESCC patients without neoadjuvant therapy.

Signaling pathways and their potential therapeutic utility in esophageal squamous cell carcinoma.

Esophageal cancer is a complex gastrointestinal malignancy with an extremely poor outcome. Approximately 80% of cases of this malignancy in Asian countries including India are of squamous cell origin, termed Esophageal Squamous Cell Carcinoma (ESCC).The five-year survival rate in ESCC patients is less than 20%.Neo-adjuvant chemo-radiotherapy (NACRT) followed by surgical resection remains the major therapeutic strategy for patients with operable ESCC. However, resistance to NACRT and local recurrence after initial treatment are the leading cause of dismal outcomes in these patients. Therefore, an alternative strategy to promote response to the therapy and reduce the post-operative disease recurrence is highly needed. At the molecular level, wide variations have been observed in tumor characteristics among different populations, nevertheless, several common molecular features have been identified which orchestrate disease progression and clinical outcome in the malignancy. Therefore, determination of candidate molecular pathways for targeted therapy remains the mainstream idea of focus in ESCC research. In this review, we have discussed the key signaling pathways associated with ESCC, i.e., Notch, Wnt, and Nrf2 pathways, and their crosstalk during disease progression. We further discuss the recent developments of novel agents to target these pathways in the context of targetedcancer therapy. In-depth research of the signaling pathways, gene signatures, and a combinatorial approach may help in discovering targeted therapy for ESCC.

Pretreatment BAN Score Based on Body-mass-index, Albumin and Neutrophil-lymphocyte Ratio Could Predict Long-term Survival for Patients with Operable Esophageal Squamous Cell Carcinoma.

Background: The present study was designed to examine the prognostic value of a systemic inflammation marker-BAN score, which was established based on body-mass-index (BMI), albumin (ALB) and neutrophil-lymphocyte ratio (NLR) in resectable esophageal squamous cell carcinoma (ESCC) patients.Methods: A total of 420 newly diagnosed ESCC patients in our hospital between January 2008 and December 2013 were included. Their baseline characteristics were retrospectively reviewed and collected. BAN score was calculated as (BMI × ALB/ NLR). The optimal cutoff value for BAN score was defined as 28.0 in terms of survival. Patients were then allocated to high BAN (≥ 28.0) and low BAN (< 28.0) score groups.Results: Pretreatment BAN score was significantly associated with tumor length, white blood cell count, BMI, ALB and NLR levels. However, no significant difference was observed in patients' age, gender, tumor location, degree of differentiation, depth of invasion, lymph node involvement, tumor-node-metastasis (TNM) stage or other variables between groups. Moreover, those with high pretreatment BAN scores (≥ 28.0) tended to have favorable disease free survival (DFS) [hazard ratio (HR), 0.650; 95% confidence interval (CI), 0.481-0.877; P = 0.005] and overall survival (OS) (HR, 0.608; 95% CI, 0.445-0.829; P = 0.002) by univariate analysis. Furthermore, multivariate Cox regression analysis suggested that high BAN score (≥ 28.0) could serve as an independent predictor for both DFS (HR, 0.726; 95% CI, 0.532-0.993; P = 0.045) and OS (HR, 0.670; 95% CI, 0.485-0.927; P = 0.016).Conclusions: Pretreatment BAN score could independently predict long-term survival for resectable ESCC patients.

Role of Esophagectomy after Chemoradiation Therapy in Patients with Locally Advanced Squamous Cell Carcinoma: A Comparative Analysis Stratified by Clinical Response to Chemoradiation Therapy.

PurposeThis study aimed to evaluate the long-term effect of esophagectomy in patients with esophageal squamous cell carcinoma (ESCC) by comparing the chemoradiotherapy (CRT)-only group and the trimodality treatment (TMT) group who received concurrent CRT followed by surgery.Materials and MethodsWe included 412 operable ESCC patients treated with TMT or CRT between January 2005 and December 2015. The oncological outcomes of the two groups were compared using a weighted Cox proportional-hazards model with inverse probability of treatment weighting (IPTW).ResultsThe median survival time was 64 and 32 months in the TMT (n=270) and CRT (n=142) groups, respectively (p < 0.001). After IPTW, the median overall survival (OS) remained significantly higher in the TMT group than in the CRT group (61 months vs. 32 months, p=0.016). Moreover, the TMT group showed a better local recurrence–free rate (LRFR; p < 0.001) and distant metastasis–free rate (p=0.007). In the subgroup of patients with clinical complete response (cCR), the OS was not significantly different between the two groups, both before and after IPTW adjustment (p=0.35 and p=0.93). However, among non-cCR patients, the OS was significantly higher in the TMT group (64% vs. 45%, p < 0.001).ConclusionIn patients with locally advanced ESCC, TMT was superior to CRT in terms of OS and LRFR. Such difference was more prominent in the non-cCR subgroup. In patients who achieved cCR, esophagectomy was effective in improving LRFR but not OS, suggesting that esophagectomy may be omitted in complete responders.

The characteristics and prognostic significance of esophageal squamous cell carcinoma with synchronous multiple lesions: over 10-year experience.

Esophageal squamous cell carcinoma (ESCC) is occasionally observed with synchronous multiple tumor lesions. Our study is aiming to define the clinical and prognostic features of this pathological subtype. This study included a large cohort of 1126 ESCC patients received esophagectomy with systemic lymph-node dissection between 2003 and 2013 in Sun Yat-sen University Cancer Center. The characteristics and prognostic significance of ESCC with multiple lesions were analyzed. The propensity score matching was performed to balance the baseline clinical characteristics. A total of 103 patients (9.1%) with 216 synchronous multiple lesions were identified from postoperative gross samples. Among them, 94 patients had two lesions, and 8 patients had three lesions, while only one patient had four lesions. The consistency of pT stages and histological grade among tumor lesions from the same gross sample were 19.4% (20/103) and 37.9% (39/103), respectively. Additionally, the tumor sites, sizes, and even the pathological subtypes can be variant in one patient. The preoperative upper gastrointestinal endoscopy could only identified 80.1% of the multiple tumor lesions. The male gender (P = 0.012), positive personal cancer history (P < 0.001), and higher pN stages (P < 0.001) were independent risk factors for synchronous multiple lesions. Patients with multiple lesions showed significantly lower survival rate (P = 0.002), and the multiple-lesion was an independently adverse prognostic factor in operable ESCC (P = 0.002). ESCC with multiple lesions had unique clinical features and should not be simply treated as the one-lesion ESCC. Due to its worse prognostic impact, advanced multidisciplinary therapies should be considered for patients with multiple esophageal tumor lesions.

Molecular characterization of amplification of 11q13 region in patients with operable esophageal squamous cell carcinoma.

e16053 Background: The efficacy of programmed cell death 1 (PD-1) targeted therapy had showed effective treatment in patients (pts) with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). Meanwhile some studies have shown that PD-1 as neoadjuvant therapy showed promising anti-tumor activity with acceptable tolerance for locally advanced ESCC. Previous studies have shown genomic amplification of 11q13 region may serve as a negative predictive marker for ESCC patients receiving anti-PD-1 based immunotherapy. However, related molecular characterization study of amplification of 11q13 region in patients with operable ESCC is rare reported. Methods: The study recruited pts with operable ESCC whose tissues were send to perform target-capture deep sequencing with the pan-cancer panel and immunohistochemistry of PD-L1 with 22C3 assay. Pair-wise comparison of TMB and PD-L1 was analyzed in pts with 11q13 amplification and pts without 11q13 amplification. Results: 58 operable ESCC pts (cT1-T3N0) were enrolled, median age at diagnosis was 63 years(yrs) (45-73). Copy number analysis identified 30 out of 58 (52%) patients with amplifications of four genes located in chromosome 11q13 region, including CCND1(Cyclin D1) and fibroblast growth factor family members ( FGF3/4/19). Among the 11q13 amplification cohort, four genes amplified together were occurred in 27(90%) pts, 1(3%) patient had amplification of three genes ( CCND1 and FGF3/4), 2 (7%) pts had amplification of one gene that are FGF3 and CCND1 respectively. The prevalence rate of 11q13 amplification was not significantly different between older age (≥ 63 yrs) and young age ( &lt; 63 yrs). Among 58 pts with TMB evaluated, median TMB was 5.76 muts/Mb (range: 0 - 20.16 muts/Mb). The prevalence of TMB-H and microsatellite instability was 12% (7/58) and 0% (0/58). TMB and expression of PD-L1 showed no significantly difference between 11q13 amplification cohort and 11q13 wild cohort. The most frequently mutated genes were TP53 (96.7%, 29/30 pts), NOTCH1 (33.3%, 10/30 pts), CDKN2A (23.3%, 7/30 pts) and MLL2 (20%, 6/30 pts) in 11q13 amplification cohort, while TP53 (89.3%, 25/28), NOTCH1 (39.3%,11/28), MLL2 (28.6%, 8/28), FAT1 (25%,7/28) were the most frequently mutated genes in 11q13 wild cohort. Conclusions: Amplification of 11q13 region was a high prevalence event in operable ESCC and there was show no age bias. Molecular characterization of amplification of 11q13 region in patients receiving PD-1 as neoadjuvant therapy before surgery may be meaningful.

Prognostic Value of Combined Detection of Preoperative Albumin-to-Fibrinogen Ratio and Neutrophil-to-Lymphocyte Ratio in Operable Esophageal Squamous Cell Carcinoma Patients without Neoadjuvant Therapy.

BackgroundWe retrospectively analyzed the prognostic value of the albumin-to-fibrinogen ratio (AFR)–neutrophil-to-lymphocyte ratio (NLR) score, comprising preoperative AFR and NLR, in esophageal squamous cell carcinoma (ESCC) patients after radical resection.Patients and MethodsOverall, 215 patients were included. The optimal cutoff value was determined using the receiver operating characteristic (ROC) curve. Based on a low AFR (<12.06) and high NLR (≥1.78), the AFR–NLR score was classified as 2 (both hematological abnormalities present), 1 (one abnormality present), or 0 (both abnormalities absent). Kaplan–Meier curves, Cox regression, and predicted nomogram were used to evaluate the prognostic value of the score.ResultsThe prognostic value of the AFR–NLR score was better than that of AFR or NLR alone (P <0.05). Multivariate analysis showed that a high AFR–NLR score was an independent predictor of poor prognosis for overall survival (P <0.001). Additionally, in the nomogram including the AFR–NLR score, the net reclassification improvement index increased by 35.5% (P <0.001), and the integrated discrimination improvement index increased by 9.0% (P <0.001). The predictive accuracy of the established nomogram model was proved using Harrell’s concordance index (0.811, 95% confidence interval: 0.765–0.856) and calibration curve. Notably, the decision analysis curve showed that the nomogram had a higher net benefit within most of the threshold probability range, indicating better clinical applicability.ConclusionThe AFR–NLR score is a useful predictor of the prognosis of ESCC patients after radical resection, and the nomogram established on the basis of this score has a good prognostic value.

High level of preoperative serum fibrinogen is a predictor of poor prognosis in patients with esophageal squamous cell carcinoma

Abstract Objective This study aimed to elucidate the association between the level of preoperative serum fibrinogen (PSF) and the prognosis of patients with esophageal squamous cell carcinoma (ESCC). Methods From January 2010 to December 2016, all patients diagnosed with ESCC who underwent surgery in Qingdao Municipal Hospital were analyzed retrospectively. Moreover, the fibrinogen levels of all patients were assessed before surgery, and hyperfibrinogenemia was diagnosed when the fibrinogen level was ≥4.0 g/L. The impact of PSF on disease-free survival (DFS) and overall survival (OS) was analyzed using the log-rank method and Cox proportional hazards regression model. P value less than 0.05 was considered statistically significant. Results A total of 336 patients were finally analyzed, and approximately 102 patients (30.36%) were diagnosed with hyperfibrinogenemia before surgery. Hyperfibrinogenemia was associated with older age (≥ 70 years) (P = 0.012), advanced pathological T stage (P = 0.003), and lymph node involvement (P = 0.024). Univariate analysis showed that patients with hyperfibrinogenemia had shorter DFS (1.96 years vs. 3.64 years, P = 0.001) and OS (2.27 years vs. 4.15 years, P &lt; 0.001) than patients without hyperfibrinogenemia. Multivariate analysis confirmed that PSF was an independent factor affecting DFS (risk ratio [RR]: 1.35, 95% confidence interval [CI]: 1.02-1.79, P = 0.038) and OS (RR: 1.37, 95% CI: 1.03-1.83, P = 0.034) in patients with ESCC. Conclusion For patients with operable ESCC, hyperfibrinogenemia had poor prognosis. Moreover, PSF is an independent prognostic factor for operable ESCC.

Serum Fibrinogen Is An Independent Prognostic Factor In Operable Esophageal Squamous Carcinoma: A Real-World Study.

PurposeTo fully elucidate the relationship of serum fibrinogen and the prognosis of esophageal squamous cell carcinoma.MethodsThe concentrations of serum fibrinogen were measured by the Clauss method in a total of 1331 operable esophageal squamous cell carcinoma (ESCC) patients from the past 3 years. The correlation of serum fibrinogen concentration and patient outcome and clinical pathological factors was tested.ResultsHyperfibrinogenemia was significantly correlated with advanced pathological T stage and TNM stage. Serum fibrinogen was determined as a worse independent survival predictor in ESCC by survival analysis. The hazard ratio was 1.672 (95% confidence interval [CI] 1.043–2.681). A subgroup analysis further elucidated a significant correlation between hyperfibrinogenemia and younger age (P=0.011), being female (P=0.002), not having a history of smoking (p<0.001) or alcohol consumption (p<0.001), pathological N0 stage (P=0.002), and early pathological TNM stage (I-II) (P=0.004).ConclusionThis research showed that preoperative serum fibrinogen is an independent prognostic factor for survival in ESCC, especially for the early pathological TNM stage (I-II) and N0 patients.

Abstract 4896: A novel approach identifies the potential biomarkers of targeted drug sensitivity in esophageal squamous cell carcinoma

Abstract Purpose: Esophageal squamous cell carcinoma (ESCC) has a high mortality with no effective targeted therapies. Previous studies from Cancer Cell Line Encyclopedia (CCLE) project adopted a commercial human pan-cancer cell line model incorporating genomic landscape to systematically identify drug sensitivity biomarkers. However, the biomarker of drug sensitivity in ESCC is still lack of widely exploring. Here, we established a novel approach combined patient-derived models, targeted deep sequencing and a drug sensitivity evaluation system to investigate potential biomarkers of targeted drug sensitivity in ESCC. Materials and Methods: Deep sequencing of 365 tumor drug-related genes was performed in tumor tissues and matched blood from an ESCC cohort (n = 161). In order to explore the potential biomarkers of drug sensitivity, we systematically established patient-derived cell lines (PDCs) from an independent cohort including 123 operable ESCC patients. Targeted deep sequencing, RNA sequencing and high-through drug sensitivity were integrated to identify the potential biomarkers of targeted drug sensitivity in ESCC PDCs. Molecular characterization methods and animal models were used to validate the potential biomarker in vitro and in vivo. In addition, patient-derived xenograft (PDX) was further confirmed the results. Results: The mutational profile of tumor drug-related genes indicated a mean of 9 non-silent somatic mutations (mutation allele frequency &amp;gt;= 0.05) per patient and a high recurrence rate of copy number variation (CNV) were discovered. To explore potential biomarkers of targeted drug sensitivity, we established eight PDCs derived from 123 ESCC patients were successfully established and used for molecular characterization and drug screening. Drug sensitivity evaluation and pharmacogenomics analyses of the eight PDCs revealed prevalent CDKN2A or CDKN2B loss as potentially sensitive biomarkers of the CDK4/6 inhibitors palbociclib and ribociclib, which was neither found in the previous study from CCLE models nor in the present study using commercial ESCC cell lines. Importantly, patient-derived models integrated with DNA and RNA sequencing validated this result in vitro. Moreover, ESCC patient-derived cell line xenografts (PDCX) models with CDKN2A/2B loss are more sensitive to the CDK4/6 inhibitor palbociclib than that in PDCX models with wild-type CDKN2A/2B. Furthermore, mouse model with PDX further confirmed CDKN2A/2B loss as a biomarker of the CDK4/6 inhibitor sensitivity. Conclusions: These results suggested that patient-derived models combined with deep sequencing and a drug sensitivity evaluation system, incorporating in vitro and in vivo validation platform, could be used as a novel and effective approach for exploring biomarkers of drug sensitivity in ESCC. Citation Format: Dan Su, Dadong Zhang, Jiaoyue Jin, Lisha Ying, Miao Han, Kaiyan Chen, Bin Li, Junzhou Wu, Zhenghua Xie, Fanrong Zhang, Yihui Lin, Guoping Cheng, Jinchao Wang, Minran Huang, Jing-Yu Li, Jianjun Zhang, Fugen Li, Lei Xiong, Andrew Futreal, Weimin Mao. A novel approach identifies the potential biomarkers of targeted drug sensitivity in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4896.

Neoadjuvant chemoradiotherapy combined with surgery in the treatment of potentially operable thoracic squamous cell carcinoma of the esophagus(ChiCTR-OIC-17011648): A phase II single center clinical study.

e15543 Background: To investigate the efficacy and safety of neoadjuvant radiotherapy and chemotherapy combined with surgery in the treatment of potentially operable thoracic esophageal squamous cell carcinoma. Methods: Nineteen patients with advanced thoracic esophageal squamous cell carcinoma hospitalized in our hospital from July 2016 to June 2018 were prospectively studied. All patients received neoadjuvant concurrent radiotherapy and chemotherapy: intensity modulated conformal radiotherapy (40 ∽ 44Gy/20 ∽22f, 2 Gy/f), chemotherapy (paclitaxel 150 ∽ 175 mg/m2 d1, 22+lobaplatin 25-30 mg/m2 d2, 23, 2 cycles). After radiotherapy and chemotherapy, the efficacy and safety of the operation were observed. Results: Two case (10.5%) was completely remitted after neoadjuvant radiotherapy and chemotherapy, 17 cases (89.5%) were partially remitted, and the objective effective rate was 100%. All patients underwent radical surgery successfully, the R0 resection rate was 100% and the pCR rate was 52.6%. The main adverse reactions of neoadjuvant radiotherapy and chemotherapy were granulocytopenia and grade III-IV granulocytopenia. The rate of survival was 16.7%, and anastomotic leakage occurred in 1 patients after operation. Conclusions: Neoadjuvant chemoradiotherapy for thoracic esophageal squamous cell carcinoma can effectively reduce the volume of the tumor, significantly reduce the pathological grade, improve the resection rate, and have less adverse reactions, which is worthy of clinical application. Clinical trial information: ChiCTR-OIC-17011648.

Effect of Adjuvant Radiation Therapy on Survival in Resected Thoracic Esophageal Squamous Cell Carcinoma According to the 8th AJCC Stage System: Pooled Analysis of Two Cancer Centers in China

The objective of this study was to investigate the impact of postoperative radiotherapy on the overall survival (OS) after radical esophagectomy according to the eighth edition of AJCC esophageal cancer staging, using two large hospital-based datasets from two big cancer hospitals in the northern and southern China, individually. A total of 3,811 cases were enrolled in the analysis. The patients who received R0 esophagectomy pathologically were diagnosed with squamous cell carcinoma and with or without postoperative radiotherapy (PORT) were selected. The tumor stage T1b-4aN1-3M0 was determined according to the newly published AJCC 8th staging in all the analysis. The OS was analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox regression analysis was used to identify covariates associated with OS. PSM analysis was performed on gender, age, vascular thrombosis, pathological differentiation, and AJCC 8th staging to balance the treatment bias between the surgery group and the postoperative radiotherapy group. The median duration of follow-up was 65.7 months (95% CI: 63.8-67.5 months) using reverse Kaplan–Meier method. The 5-year survival rates of 2725 cases in no PORT group were 83.5%, 66.9%, 57.3%, 50.6%, 29.5%, and 11.3% in IB, IIA, IIB, IIIA, IIIB, and IVA (p < 0.001). Before PSM, PORT did not improve the OS. Further subgroup analysis found that PORT in patients with stage IIB, IIIB, IVA based on the AJCC 8th staging can significantly improve OS. After PSM, 990 patients were included in PORT and no PORT group. PORT could improve the OS significantly (median survival, 52.3 months and 31.0 months, respectively; HR 0.716, 95% CI 0.638-0.804, P<0.001). The subgroup analysis was consistent with that before PSM. PORT in stages IIB, IIIB, and IVA could improve the OS after PSM. Multivariate analysis showed that gender, differentiation, vascular cancer thrombosis, TNM stage and postoperative radiotherapy were independent prognostic factors for both before and after PSM. The prognosis of operable esophageal squamous cell carcinoma cancer can be predicted perfectly by using the AJCC 8th staging. Postoperative radiotherapy after R0 esophagectomy potentially improved the OS for patients with stage IIB, IIIB, and IVA, further prospective studies are needed to confirm these results.

A nomogram-based immunoprofile predicts overall survival for previously untreated patients with esophageal squamous cell carcinoma after esophagectomy

BackgroundImmunoscore, as a prognostic tool defined to quantify in situ immune cell infiltrates, appears to be superior to the TNM staging system. In esophageal squamous cell carcinoma (ESCC), no immunoscore has been established; however, in situ tumor immunology is recognized as highly important. Our study aimed to construct a comprehensive immunoprofile for ESCC.MethodsThe infiltration of four immune cell types (CD8+/CD4+/Foxp3+/CD33+ cells), the expression of both inhibitory (PD-1/PD-L1/Tim-3/LAG-3) and stimulatory checkpoints (OX-40/ICOS), and IDO1 were evaluated by IHC staining and multi-color immunofluorescence in two independent cohorts (95 patients in the primary cohort and 55 patients in the validation cohort). The association with patients’ overall survival was analyzed by the Kaplan-Meier method and the Cox model. Nomogram-based immunoprofile was established using the independent prognostic variables. To determine its predictive accuracy and discriminatory capacity, the C-index and calibration curve were calculated.ResultsSignificant correlation of PD-L1 expression in tumor cells with PD-1+ T cell infiltration was found (P = 0.035), indicating the activation of the inhibitory PD-1/PD-L1 pathway in ESCC cases. More PD-L1+ ICs, Tim-3+ ICs and LAG-3+ ICs were found in the CD8-rich tumor microenvironment, which is in accordance with the feedback nature of immune system. After adjustment by TNM stage, four immune variables including the infiltration of CD8+/Foxp3+/CD33+ cells and the PD-L1 expression by tumor cells were selected to construct a prognostic nomogram. The calibration curves showed good accuracy of the nomogram for survival prediction. To overcome the complexity of applying a nomogram in a clinical setting, a simple immunoprofile was then established according to the points of each factor from the nomogram. Our immunoprofile model could separate same-stage patients into different risk subgroups, and showed superior accuracy for survival prediction than the TNM staging system based on the C-index calculation and ROC analysis.ConclusionsOur nomogram-based immunoprofile can provide more accurate prognosis prediction and is an important complement to the TNM staging system for operable ESCC patients.