Clinical Outcome In Esophageal Cancer Research Articles

Body Composition and Clinical Outcomes in Esophageal Cancer Patients Treated with Immune Checkpoint Inhibitors.

Obesity is associated with increased mortality in various cancers, but the relationship between obesity and clinical outcomes in unresectable or recurrent esophageal cancer who receive immune checkpoint inhibitors (ICIs) remains unknown. This study investigated the association between body composition and clinical outcomes in patients with unresectable or recurrent esophageal cancer who received ICIs. Utilizing an unbiased database of 111 unresectable or recurrent esophageal cancers, we evaluated the relationships between body composition (body mass index, waist circumference, psoas major muscle volume, and subcutaneous and visceral fat areas) at the initiation of ICI treatment and clinical outcomes including the disease control rate and progression-free survival (PFS). Waist circumference was significantly associated with the disease control rate at the first assessment (P = 0.0008). A high waist circumference was significantly associated with favorable PFS in patients treated with nivolumab. In an univariable model, for 5-cm increase of waist circumference in the outcome category of PFS, univariable hazard ratio (HR) was 0.73 (95% confidence interval [CI], 0.61-0.87; P = 0.0002). A multivariable model controlling for potential confounders yielded a similar finding (multivariable HR, 0.56; 95% CI, 0.33-0.94; P = 0.027). We observed the similar finding in esophageal cancer patients treated with pembrolizumab+CDDP+5-FU (P = 0.048). In addition, waist circumference was significantly associated with the prognostic nutritional index (P = 0.0073). A high waist circumference was associated with favorable clinical outcomes in ICI-treated patients with unresectable or recurrent esophageal cancer, providing a platform for further investigations on the relationships among body composition, nutrition, and the immune status.

PD-L1-expressing cancer-associated fibroblasts induce tumor immunosuppression and contribute to poor clinical outcome in esophageal cancer

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity.

Systemic Immune-Inflammatory Index, Tumor-Infiltrating Lymphocytes, and Clinical Outcomes in Esophageal Squamous Cell Carcinoma Receiving Concurrent Chemoradiotherapy.

Systemic inflammation may be involved in the entire cancer process as a promoter and is associated with antitumor immunity. The systemic immune-inflammation index (SII) has been shown to be a promising prognostic factor. However, the relationship between SII and tumor-infiltrating lymphocytes (TIL) have not been established in esophageal cancer (EC) patients receiving concurrent chemoradiotherapy (CCRT). Retrospective analysis of 160 patients with EC was performed, peripheral blood cell counts were collected, and TIL concentration was assessed in H&E-stained sections. Correlations of SII and clinical outcomes with TIL were analyzed. Cox proportional hazard model and Kaplan-Meier method were used to perform survival outcomes. Compared with high SII, low SII had longer overall survival (OS) (P = 0.036, hazard ratio (HR) = 0.59) and progression-free survival (PFS) (P = 0.041, HR = 0.60). Low TIL showed worse OS (P < 0.001, HR = 2.42) and PFS (P < 0.001, HR = 3.05). In addition, research have shown that the distribution of SII, platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio were negatively associated with the TIL state, while lymphocyte-to-monocyte ratio presented a positive correlation. Combination analysis observed that SIIlow + TILhigh had the best prognosis of all combinations, with a median OS and PFS of 36 and 22 months, respectively. The worst prognosis was identified as SIIhigh + TILlow, with a median OS and PFS of only 8 and 4 months. SII and TIL as independent predictors of clinical outcomes in EC receiving CCRT. Furthermore, the predictive power of the two combinations is much higher than a single variable.

Targeting endoplasmic reticulum associated degradation pathway combined with radiotherapy enhances the immunogenicity of esophageal cancer cells

ABSTRACT Immunogenic cell death (ICD) is essential for the activation of immune system against cancer. We aimed to investigate the efficacy of endoplasmic reticulum (ER)-associated protein degradation (ERAD) inhibitors (EerI and NMS-873) in enhancing radiation-induced ICD in esophageal cancer (EC). EC cells were administered with ERAD inhibitors, radiation therapy (RT), and the combination treatment. ICD hallmarks including calreticulin (CALR), adenosine triphosphate (ATP), and high mobility group protein B1 (HMGB1) were detected. The efficacy of ERAD inhibitors combined with RT in stimulating ICD was analyzed. Additionally, the role of ICD hallmarks in immune cell infiltration and patient survival was investigated. Inhibiting ERAD pathways was able to stimulate ICD component emission from dying EC cells in a dose-dependent pattern. Radiation-induced ICD was significantly increased after high doses RT (≥10 Gy). ERAD inhibitor combined with moderate dose RT (≥6 Gy) was capable of stimulating increased ICD in EC cells. Dual therapy could elicit the antitumor immune response by enhancing dendritic cells maturation and phagocytosis. Further investigation revealed a significant correlation between CALR and tumor-infiltrating immune cells. Low expression of ATP and HMGB1 and high expression of CALR were associated with favorable survival in patients with EC. The immunogenicityof EC can be enhanced by ERAD inhibitors combined with moderate doses of RT. ICD hallmark genes, especially CALR, are correlated to immune cell infiltration and clinical outcomes in EC. The present results demonstrated an important method to improve the immunogenicity of EC cells for enhanced antitumor immune response.

Pan-immune-inflammation Value and Prognosis in Patients With Esophageal Cancer.

The pan-immune-inflammation value was associated with clinical outcomes and tumor-infiltrating lymphocytes in 866 esophageal cancers. Systemic immune competence may influence patient prognosis through local immune response. To examine the relationship between the pan-immune-inflammation value (PIV), tumor immunity, and clinical outcomes in 866 patients with esophageal cancer. The PIV, calculated from all immune-inflammatory cells in the peripheral blood count, is a recently proposed marker for clinical outcomes in some types of cancers. Nonetheless, the prognostic significance of PIV in esophageal cancer remains unclear. In the derivation cohort (n = 433), we set the optimal cutoff value using a time-dependent receiver operating characteristic (ROC) curve. In the validation cohort (n = 433), the relationships between the PIV, tumor-infiltrating lymphocytes (TILs), CD8 expression by immunohistochemical staining, and patient prognosis were examined. The area under the ROC curve for the PIV at 5 years was 0.631 in the derivation cohort. The validation cohort, divided into PIV-low cases (n = 223) and PIV-high cases (n = 210), showed significantly worse overall survival (log-rank P = 0.0065; hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.12-1.98; P < 0.001; multivariate HR: 1.41; 95% CI: 1.05-1.90; P = 0.023). The prognostic effect of the PIV was not significantly modified by any clinical characteristics (P for interaction > 0.05). The PIV-high cases were significantly associated with a low TIL status (P < 0.001) and low CD8-positive cell counts (P = 0.011). The PIV was associated with clinical outcomes in esophageal cancer, supporting its role as a prognostic biomarker. Considering the relationship between the PIV and TILs, systemic immune competence may influence patient prognosis through a local immune response.

Prognostic significance of T-cell-inflamed gene expression profile and PD-L1 expression in patients with esophageal cancer.

PurposeThe ability of the T‐cell–inflamed gene expression profile (GEP) to predict clinical outcome in esophageal cancer (EC) is unknown. This retrospective observational study assessed the prognostic value of GEP and programmed death ligand 1 (PD‐L1) expression in patients with EC treated in routine clinical practice.MethodsTumor samples of 294 patients from three centers in Denmark, South Korea, and the United States, collected between 2005 and 2017, were included. T‐cell–inflamed GEP score was defined as non‐low or low using a cutoff of −1.54. A combined positive score (CPS) ≥10 was defined as PD‐L1 expression positivity. Associations between overall survival (OS) and GEP status and PD‐L1 expression were explored by Cox proportional hazards models adjusting for age, sex, histology, stage, and performance status.ResultsMedian age was 65 years; 63% of patients had adenocarcinoma (AC) and 37% had squamous cell carcinoma (SCC). Thirty‐six percent of tumors were GEP non‐low, with higher prevalence in AC (46%) than SCC (18%). Twenty‐one percent were PD‐L1–positive: 32% in South Korean samples versus 16% in non‐Asian samples and 26% in SCC versus 18% in AC. GEP scores and PD‐L1 CPS were weakly correlated (Spearman’s R = 0.363). OS was not significantly associated with GEP status (non‐low vs low; adjusted hazard ratio, 0.91 [95% CI, 0.69–1.19]) or PD‐L1 expression status.ConclusionNeither GEP nor PD‐L1 expression was a prognostic marker in Asian and non‐Asian patients with EC.

NOTCH3 limits the epithelial-mesenchymal transition and predicts a favorable clinical outcome in esophageal cancer.

BackgroundEsophageal squamous cell carcinoma (ESCC) is the deadliest of all human squamous cell carcinomas and is characterized by chemotherapy resistance and poor prognosis associated with the epithelial–mesenchymal transition (EMT). A subset of ESCC displays loss‐of‐function mutations in genes encoding Notch receptor family members, including NOTCH3. Although Notch signaling regulates EMT in ESCC cells, the role of NOTCH3 in EMT and chemotherapy resistance remains elusive. This study aimed to examine the role of NOTCH3 in EMT and chemotherapy resistance, and determine whether NOTCH3 expression can be used to predict the response to chemotherapy.MethodsIn vitro and in vivo assays were conducted to clarify the contribution of NOTCH3 to chemotherapy resistance. Using specimens from 120 ESCC patients treated with neoadjuvant chemotherapy, we compared the expression levels of NOTCH3 and genes involved in EMT according to the degree of chemotherapy sensitivity.ResultsIn ESCC cells, chemotherapy resistance was associated with NOTCH3 downregulation and concurrent activation of EMT. RNA interference to silence NOTCH3 resulted in induction of the EMT marker Vimentin (VIM), leading to chemotherapy resistance in ESCC cells. Conversely, ectopic expression of the activated form of NOTCH3 suppressed EMT and sensitized cells to chemotherapy. Results of chromatin immunoprecipitation assays suggested that NOTCH3 may repress transcription of the VIM.ConclusionsOur findings suggest that NOTCH3 may control chemotherapy sensitivity by regulating EMT. NOTCH3 may serve as a novel biomarker to predict better clinical outcomes in ESCC patients.

Nivolumab for the treatment of esophageal cancer

ABSTRACT Introduction: Esophageal cancer (EC) is the seventh most common cancer and the sixth leading cause of cancer death worldwide. The prognosis for advanced EC patients remains poor and there are few effective therapeutic agents available. Nivolumab is a fully human IgG4 monoclonal antibody that exerts antitumor activity by inhibiting the interaction of programmed cell death protein 1 on activated lymphocytes with its ligands. Nivolumab monotherapy showed significant benefit for overall survival of patients with advanced esophageal squamous cell carcinoma (ESCC) relative to taxane as a second-line treatment. Additionally, adjuvant nivolumab monotherapy showed significant disease-free survival benefit relative to placebo for resectable EC patients with residual pathologic disease who had received neoadjuvant chemoradiotherapy followed by surgery. Areas covered: Here, we provide an overview of checkpoint blockade with nivolumab and present the available clinical data related to its use in EC. Expert opinion: Nivolumab should be the standard second-line treatment for advanced ESCC patients and possibly adjuvant treatment of choice after neoadjuvant chemoradiotherapy followed by surgery. Trials assessing efficacy of a combination of cytotoxic agents and nivolumab as first-line treatment, nivolumab-containing chemoradiotherapy, and neoadjuvant chemotherapy are ongoing. These trials should result in improved protocols for better clinical outcomes in EC.

Prognostic Impact of PD-1 on Tumor-Infiltrating Lymphocytes in 433 Resected Esophageal Cancers

BackgroundImmune checkpoint inhibitors targeting the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have demonstrated antitumor effects in patients with various malignancies, including esophageal cancer. Thus, a better understanding of local immunity in esophageal cancer is crucial for improving treatment and clinical outcomes. MethodsWe evaluated PD-1 expression on tumor-infiltrating lymphocytes (TILs), as well as PD-L1 expression on cancer cells, by immunohistochemistry and immunofluorescence using a nonbiased database of 433 curatively resected esophageal cancers. With the idea of application as liquid biopsy, PD-1 expression status on peripheral lymphocytes was evaluated by flow cytometry. ResultsThe cutoff value of PD-1 expression was the median PD-1 count. Compared with cases of low PD-1 expression (n = 219), cases with high levels of PD-1 expression (n = 213) showed significantly worse overall survival (log-rank P = .0017). The prognostic effect of PD-1 differed according to the preoperative treatment status (P for interaction = .040); PD-1 expression was associated with high overall mortality among patients without preoperative therapy, while no such association was present among those with preoperative treatment. A stratification based on PD-1 and PD-L1 status was also significantly associated with overall survival (log-rank P = .0005). PD-1 expression on TILs was significantly associated with that on peripheral lymphocytes (P < .0001). ConclusionsPD-1 expression on TILs was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. The combination of PD-1 and PD-L1 expression enabled further classification of patients according to clinical outcome.

Lymphocyte-monocyte ratio as a predictive marker for pathological complete response to neoadjuvant therapy in esophageal squamous cell carcinoma.

BackgroundThe hematological markers of systemic inflammation has been proved to be significantly associated with clinical outcomes in esophageal cancer. This retrospectively study was to evaluate the value of the hematological markers in predicting pathological complete response (pCR) and overall survival (OS) in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) who received neoadjuvant chemoradiotherapy (nCRT).MethodsA total of 87 patients with newly diagnosed LA-ESCC were retrospectively analyzed. The pretreatment lymphocyte-monocyte ratio (LMR), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were selected as hematological markers.ResultsAfter nCRT, 26 (29.9%) patients achieved pCR and 61 (70.1%) patients had non-pCR. The LMR was significantly higher in patients who achieved pCR compared to that in patients who did not achieve pCR (4.35±1.68 vs. 3.33±1.13, P=0.002). Based on the receiver operating characteristic (ROC) curve, the optimal cut off value of LMR that predicted pCR was 3.73 [area under the curve: 0.712; 95% confidence interval (CI): 0.594–0.830; P=0.002], with a sensitivity of 65.4% and specificity of 77.0%. The pCR rate of patients with LMR ≥3.73 was 53.1%, while the pCR rate of patients with LMR <3.73 was only 16.4% (P<0.001). The univariate and multivariate logistic regression analysis confirmed that LMR was an independent predictor of pCR [odds ratio: 5.093; 95% CI: 1.658–15.646; P=0.004]. However, in the prediction of OS, a multivariate Cox proportional hazard model revealed that only clinical stage [hazard ratio (HR): 1.970; 95% CI: 1.144–3.391; P=0.014] and pCR (HR: 0.469; 95% CI: 0.237–0.928; P=0.030) were independent prognostic factors.ConclusionsPre-treatment LMR may predict pCR in LA-ESCC patients who were treated with nCRT. Having pCR is an independent prognostic factor for prolonged survival.

Mean cardiopulmonary dose and vertebral marrow dose differentially predict lineage-specific leukopenia kinetics during radiotherapy for esophageal cancer

Background and purposeLymphopenia is associated with poor outcomes in esophageal cancer (EC) patients undergoing chemoradiotherapy (CRT). We hypothesized that radiation dose to marrow (central) vs. circulating (peripheral) leukocytes (WBCs) may have unique effects on WBC counts and clinical outcomes in EC. Materials and methodsWeekly and 90-day post-CRT blood cell counts were evaluated for 46 patients with stage II-III EC treated with CRT. Thoracic vertebral volume spared (TVS) radiation was extracted from dose volume histograms (DVH). Mean cardiopulmonary dose (mCPD) was calculated as mean dose to the volumetric sum of heart, lungs, and great vessels as a surrogate for circulating blood pool. Linear and logistic regression identified associations between dosimetric variables and hematologic toxicities (HT). Repeated measures ANOVA tested associations between cell count trends and clinical predictors. ResultsWBCs and platelets reached nadir at week 6 of CRT. On multivariate analysis, mCPD was associated with lower WBC and neutrophil nadirs (p < 0.05). TVS5-40 Gy were associated with higher lymphocyte nadirs (all p < 0.05). Repeated measures ANOVA revealed an interaction effect of sex on absolute lymphocyte trend as well as age (<67 vs. >67) and diabetes on normalized lymphocyte trend (all p < 0.015). ConclusionsmCPD and volume of thoracic marrow spared radiation differentially predict lineage-specific leukopenias during CRT for EC. mCPD is significantly associated with lower total WBC and neutrophil nadirs. In contrast, greater thoracic marrow spared radiation is associated with mitigation of lymphopenia during CRT. Clinical factors such as sex, age, and diabetes may be associated with a more rapid decline in hematologic counts during treatment.

Clinical significance of preoperative serum concentrations of interleukin-6 as a prognostic marker in patients with esophageal cancer.

Although the clinical outcome of esophageal cancer has recently improved, the relapse rate remains high for all disease stages. At present, there is no diagnostic method to predict the long-term outcome for esophageal cancer. In this study, we evaluated serum preoperative proinflammatory cytokine levels and investigated the correlation between preoperative interleukin-6 (IL-6) and IL-8 levels and survival of patients with esophageal cancer. Between 2008 and 2015, we evaluated preoperative serum cytokine levels in 122 patients who underwent esophagectomy for esophageal cancer. Serum IL-6 and IL-8 levels were measured by enzyme-linked immunosorbent assays. We investigated the relationship between serum cytokine levels and the response to chemotherapy and survival. The preoperative IL-6 levels were significantly associated with shorter recurrence-free survival (RFS, p = 0.001) and overall survival (OS, p = 0.001) after esophagectomy. Higher IL-8 levels were significantly associated with RFS (p = 0.018). In the multivariate analysis, age, preoperative chemotherapy, lymph node metastasis, serum C-reactive protein (CRP) levels and serum IL-6 levels (hazard ratio (HR), 2.888; p = 0.049) were significantly independent prognostic factors of RFS. Additionally, age, pathological stage, and serum IL-6 levels (HR, 3.247; p = 0.027) were shown to be significantly independent prognostic factors of OS. Serum IL-6 levels were significantly higher in the non-responder group (pathological response pGrade0 and pGrade1) after neoadjuvant therapy. High preoperative serum IL-6 levels are associated with a poor response to chemotherapy or chemoradiotherapy and poor prognosis after esophagectomy. Preoperative serum IL-6 levels may be a useful independent prognostic marker for esophageal cancer patients.

IDO1 Expression Is Associated With Immune Tolerance and Poor Prognosis in Patients With Surgically Resected Esophageal Cancer.

To evaluate the relationship between indoleamine 2, 3-dioxygenase (IDO1) expression and tumoral immune status and clinical outcome in esophageal cancer. IDO1 is a primary enzyme that generates immunosuppressive metabolites such as tryptophan and kynurenine. Like the PD-1/PD-L1 pathway, IDO1 plays a major role in tumor immunology and is a potential immune-based therapeutic target. The expressions of IDO1, CD8 (a marker of cytotoxic T cells), FOXP3 [a marker of regulatory T cells (Treg)], and PD-L1 in 305 curatively resected esophageal cancers were evaluated by immunostaining. Overall survival was significantly better in the IDO1 negative cases (n = 234) than in the IDO1 positive cases (n = 71) [log-rank P = 0.0041; hazard ratio (HR): 1.75; 95% confidence interval (CI): 1.12-2.67; P = 0.015]. CD8 high expression was significantly positively correlated with overall survival (log-rank P = 0.025) and low IDO1 expression (P = 0.044). The inverse correlation between CD8 and IDO1 expressions was confirmed by double immunostaining for IDO1 and CD8. Stratification based on IDO1 and CD8 expressions was also significantly associated with overall survival (log-rank P = 0.0024). In addition, the IDO1-positive group was correlated with high counts of FOXP3-positive cells (P = 0.020), but not with PD-L1 expression status (P = 0.19). IDO1 expression was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. Combining the IDO1 and CD8 statuses enabled further classification of the clinical outcomes of patients.

Indoleamine 2, 3-dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer.

Indoleamine 2, 3‐dioxygenase 1 (IDO1) is a primary enzyme that generates immunosuppressive metabolites. It plays a major role in tumor immunology and is a potential immune‐based therapeutic target. We have reported that IDO1 protein expression was associated with an unfavorable clinical outcome in esophageal cancer. Recently, it has been reported that IDO1 expression is regulated by methylation of the IDO1 promoter. Thus, the aim of this study was to examine the relationship between IDO1 expression, IDO1 promoter methylation, and clinicopathological features in esophageal cancer. We first confirmed changes in IDO1 expression levels in vitro by treating cells with 5‐azacytidine. We then evaluated the relationship between IDO1 expression levels, IDO1 promoter methylation (bisulfite pyrosequencing), and clinicopathological features using 40 frozen samples and 242 formalin‐fixed, paraffin‐embedded samples resected from esophageal cancer patients. We treated cell lines with 5‐azacytidine, and the resulting hypomethylation induced significantly higher IDO1 expression (P < .001). In frozen samples, IDO1 expression levels correlated inversely with IDO1 promoter methylation levels (R = −0.47, P = .0019). Furthermore, patients in the IDO1 promoter hypomethylation group (n = 67) had a poor prognosis compared with those in the IDO1 promoter hypermethylation group (n = 175) (overall survival, P = .011). Our results showed that IDO1 promoter hypomethylation regulated IDO1 expression and was associated with a poor prognosis in esophageal cancer patients.

Enteral Access Potentially Endangers Esophageal Carcinoma Patients Under Multi-modality Therapy: A Population-based Study.

This study aimed to evaluate the clinical outcome of esophageal cancer (EC) patients with enteral access (EA) undergoing multimodality therapy. This retrospective study analyzed data between 1997 and 2012 in Taiwan using the National Health Insurance Research Database. Patients with newly-diagnosed EC undergoing multimodality therapy were identified and classified as either EA group or no-EA group. The mortality incidence of EC patients with EA was significantly higher than in no-EA patients. The Cox model revealed the EA group had a higher risk of mortality than the no-EA group. Patients with chronic obstructive pulmonary disease (COPD) were at significantly higher risk of mortality compared to patients without COPD. EA in EC patients undergoing multimodality therapy was associated with an increased risk of mortality.

PS02.202: CLINICAL SIGNIFICANCE OF MEASUREMENT OF SKELETAL MUSCLE VOLUME AND SERUM NUTRITIONAL MARKERS IN ESOPHAGEAL CANCER PATIENTS

Abstract Background Some studies reported the association of muscle mass or nutritional state with development of postoperative morbidity. However, it remains unknown whether body composition or nutritional state influences upon clinical outcome in esophageal cancer (EC) patients undergoing surgery following neoadjuvant chemotherapy (NAC). Methods A total of 100 EC patients who undergone NAC followed by curative surgical resection in our hospital from 2011 to 2013 was analyzed. The cross-sectional area of psoas was measured by computed tomography at third lumbar vertebra and the Psoas Muscle Index [PMI: total psoas area at L3/(height × height)] was calculated. Pre- and post-NAC PMI in addition to prognostic nutritional index (PNI), modified Glasgow prognostic scale (mGPS), and neutrophil/lymphocyte ratio (N/L) as an inflammation or nutrition marker were evaluated in terms of their association with development of NAC adverse event, postoperative complications and long-term survival. Results The PMI significantly decreased during chemotherapy from 705.5 to 682.7 cm2/m2 (P = 0.0008). Pre-NAC PMI (low vs high group, cutoff: 6.36cm2/m2 for male, 3.92cm2/m2 for female) was significantly associated with serum albumin (3.5 vs 3.8g/dl P = 0.0064) and body mass index (19.6 vs 22.2kg/m2P &lt; 0.001), and clinical response to NAC (response rate 66.7 vs 87.1% P = 0.02). Post-NAC PMI, meanwhile, correlated with development of postoperative pneumonia [Clavien-Dindo (C-D) classification grade &gt; II] (35.0 vs 8.3% P = 0.0009) and expectoration disorder of sputum (C-D classification grade &gt; III) (28.6 vs 10.5% P = 0.027) while neither pre- or post PMI were predictive of patient survival. Regarding serum nutritional markers, pre-NAC PNI and mGPS correlated with NAC-induced neutropenia [low vs high PNI (cutoff: 40): 100 vs 87% P = 0.019] and diarrhea (mGPS 0/1 vs 2: 27.4 vs 80.0% P = 0.017) while post-NAC mGPS (mGPS 0 vs 1/2) was predictive of development of postoperative pneumonia (11.5 vs 30.8%, P = 0.018) and expectoration disorder of sputum (10.7 vs 27.8%, P = 0.037), respectively. Notably, post-NAC mGPS (mGPS 0 vs 1/2: 76.4 vs 65.4%, P = 0.039) and N/L (N/L ≥ 2.5 vs &lt; 2.5: 43.5 vs 82.1% P = 0.006) showed the significant association with 2-year overall survival. Conclusion Pre- and post-NAC PMI in addition to serum inflammation/nutrition markers might be clinically useful in predicting outcome of multidisciplinary treatments for EC patients. Disclosure All authors have declared no conflicts of interest.

Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer

PurposeRelative radiation dose exposure to vital organs in the thorax could influence clinical outcomes in esophageal cancer (EC). We assessed whether the type of radiation therapy (RT) modality used was associated with postoperative outcomes after neoadjuvant chemoradiation (nCRT). Patients and methodsContemporary data from 580 EC patients treated with nCRT at 3 academic institutions from 2007 to 2013 were reviewed. 3D conformal RT (3D), intensity modulated RT (IMRT) and proton beam therapy (PBT) were used for 214 (37%), 255 (44%), and 111 (19%) patients, respectively. Postoperative outcomes included pulmonary, GI, cardiac, wound healing complications, length of in-hospital stay (LOS), and 90-day postoperative mortality. Cox model fits, and log-rank tests both with and without Inverse Probability of treatment Weighting (IPW) were used to correct for bias due to non-randomization. ResultsRT modality was significantly associated with the incidence of pulmonary, cardiac and wound complications, which also bore out on multivariate analysis. Mean LOS was also significantly associated with treatment modality (13.2days for 3D (95%CI 11.7–14.7), 11.6days for IMRT (95%CI 10.9–12.7), and 9.3days for PBT (95%CI 8.2–10.3) (p<0.0001)). The 90day postoperative mortality rates were 4.2%, 4.3%, and 0.9%, respectively, for 3D, IMRT and PBT (p=0.264). ConclusionsAdvanced RT technologies (IMRT and PBT) were associated with significantly reduced rate of postoperative complications and LOS compared to 3D, with PBT displaying the greatest benefit in a number of clinical endpoints. Ongoing prospective randomized trial will be needed to validate these results.

Prognostic significance of preoperative plasma fibrinogen and Albumin Score in esophageal cancer patients.

36 Background: The clinical outcome of esophageal cancer has recently improved. However, the relapse rate in any stages is still high. Prognostic classification in patients with esophageal cancer has not yet established. If the patients with poor prognosis could be extracted before surgery, we can add more intensive preoperative treatment, which might lead more favorable prognosis. We have previously reported clinical utility of fibrinogen (FNG) and Albumin (Alb) Score (FA score) in esophageal cancer. The purpose of this study was to analyze the utility of FA score comparing at each stage as a prognostic factor in esophageal cancer. Methods: Patient characteristics, clinicopathological factors, and preoperative biochemical markers (FNG, Alb, and CRP) were investigated in esophageal cancer patients who underwent transthoracic esophagectomy between January 2004 and November 2013. Correlation between preoperative FNG, CRP, Alb, clnicopathological factors and survival were investigated. We evaluated between recurrence-free survival (RFS), overall survival (OS) and FA score comparing at each stage. The cut-off value was defined according to previous reports; fibrinogen 350mg/dl, albumin 3.8mg/dl. Results: 252 patients were recorded. High FA score were correlated to worse OS and RFS (p &lt; 0.001). Especially in cStageI, high FA score showed remarkably worse 5-year RFS (score0/ score1/ score2, 5-year RFS 84%/ 64%/ 33%; p = 0.038). Conclusions: FA score was significantly associated with postoperative survival in esophageal cancer patients. If the patients with poor prognosis in cStageI could be extracted before surgery, we can add more intensive preoperative treatment, which might lead more favorable prognosis.

Prognostic gene expression profiling in esophageal cancer: a systematic review.

BackgroundIndividual variability in prognosis of esophageal cancer highlights the need for advances in personalized therapy. This systematic review aimed at elucidating the prognostic role of gene expression profiles and at identifying gene signatures to predict clinical outcome.MethodsA systematic search of the Medline, Embase and the Cochrane library databases (2000-2015) was performed. Articles associating gene expression profiles in patients with esophageal adenocarcinoma or squamous cell carcinoma to survival, response to chemo(radio)therapy and/or lymph node metastasis were identified. Differentially expressed genes and gene signatures were extracted from each study and combined to construct a list of prognostic genes per outcome and histological tumor type.ResultsThis review includes a total of 22 studies. Gene expression profiles were related to survival in 9 studies, to response to chemo(radio)therapy in 7 studies, and to lymph node metastasis in 9 studies. The studies proposed many differentially expressed genes. However, the findings were heterogeneous and only 12 (ALDH1A3, ATR, BIN1, CSPG2, DOK1, IFIT1, IFIT3, MAL, PCP4, PHB, SPP1) of the 1.112 reported genes were identified in more than 1 study. Overall, 16 studies reported a prognostic gene signature, which was externally validated in 10 studies.ConclusionThis systematic review shows heterogeneous findings in associating gene expression with clinical outcome in esophageal cancer. Larger validated studies employing RNA next-generation sequencing are required to establish gene expression profiles to predict clinical outcome and to select optimal personalized therapy.

Immune Profile-to-Lymphocyte Ratios During Chemoradiation are Predictors of Clinical Outcomes in Esophageal Cancer

Immune Profile-to-Lymphocyte Ratios During Chemoradiation are Predictors of Clinical Outcomes in Esophageal Cancer