The predictors of lymphopenia and its effects on survival in locally advanced esophageal squamous cell carcinoma.

To investigate the impact of the effective radiation dose to immune cells (EDIC) and gross tumor volume (GTV) on lymphopenia and survival in patients with locally advanced esophageal squamous cell carcinoma (LAESCC). Between January 2013 and December 2020, 272 LAESCC patients were treated with definitive radiotherapy in two institutions. Based on radiation doses to the lungs, heart, and body region scanned, EDIC was calculated as an equal uniform dose to the total blood considering blood flow and fraction effect. The radiotherapy plan was used to calculate the GTVs. Lymphopenia was graded based on the lowest lymphocyte count during RT. The overall survival (OS), progress-free survival (PFS), and local recurrence-free survival (LRFS) were analyzed statistically. The lowest lymphocyte count was significantly correlated with EDIC (r= -0.389, p < .001) and GTV (r= -0.211, p < .001). Lymphopenia, EDIC, and GTV are risk factors for patients with ESCC. In a Kaplan-Meier analysis with EDIC and GTV as stratification factors, lymphopenia was not associated with OS in the EDIC>12.9 Gy group (p = .294)and EDIC ≤ 12.9 Gy group, and it was also not associated with OS in GTV>68.8 cm3 group (p = .242) and GTV ≤ 68.8 cm3 group(p = .165). GTV and EDIC had an impact on the relationship between lymphopenia and OS in patients with LAESCC undergoing definitive RT. Poorer OS, PFS, and LRFS are correlated with lymphopenia, higher EDIC, and larger GTV.

Correlation of PD-L1 expression with CD8+ T cells and oxidative stress-related molecules NRF2 and NQO1 in esophageal squamous cell carcinoma.

Oxidative stress and the immune microenvironment both contribute to the pathogenesis of esophageal squamous cell carcinoma (ESCC). However, their interrelationships remain poorly understood. We aimed to examine the status of key molecules involved in oxidative stress and the immune microenvironment, as well as their relationships with each other and with clinicopathological features and prognosis in ESCC. The expression of programmed death-ligand 1 (PD-L1), CD8, nuclear factor erythroid-2 related factor-2 (NRF2), and NAD(P)H quinone oxidoreductase 1 (NQO1) was detected using immunohistochemistry in tissue samples from 176 patients with ESCC. We employed both combined positive score (CPS) and tumor proportion score (TPS) to evaluate PD-L1 expression and found a positive correlation between CPS and TPS. Notably, PD-L1 expression, as assessed by either CPS or TPS, was positively correlated with both NRF2 nuclear score and NQO1 score in stage II-IV ESCC. We also observed a positive correlation between the density of CD8+ T cells and PD-L1 expression. Furthermore, high levels of PD-L1 CPS, but not TPS, were associated with advanced TNM stage and lymph node metastases. Moreover, both PD-L1 CPS and the nuclear expression of NRF2 were found to be predictive of shorter overall survival in stage II-IV ESCC. By using the Mandard-tumor regression grading (TRG) system to evaluate the pathological response of tumors to neoadjuvant chemotherapy (NACT), we found that the TRG-5 group had higher NRF2 nuclear score, PD-L1 CPS, and TPS in pre-NACT biopsy samples compared with the TRG-3 + 4 group. The NQO1 scores of post-NACT surgical specimens were significantly higher in the TRG-5 group than in the TRG 3 + 4 group. In conclusion, the expression of PD-L1 is associated with aberrant NRF2 signaling pathway, advanced TNM stage, lymph node metastases, and unfavorable prognosis. The dysregulation of PD-L1 and aberrant activation of the NRF2 signaling pathway are implicated in resistance to NACT. Our findings shed light on the complex interrelationships between oxidative stress and the immune microenvironment in ESCC, which may have implications for personalized therapies and improved patient outcomes.

Additional chemoradiotherapy for superficial esophageal squamous cell carcinoma after near-circumferential or full-circumferential noncurative endoscopic submucosal dissection: a retrospective study.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a potentially efficient therapeutic intervention for superficial esophageal cancer. Additional treatment such as chemoradiotherapy (CRT) or esophagectomy is recommended in cases of muscularis mucosa invasion with positive resection margins or lymphovascular invasion or submucosal layer invasion, which are considered noncurative ESD, due to an increased risk of lymph node metastasis. However, the adequacy of additional CRT after near-circumferential or full-circumferential noncurative ESD has not been fully discussed. In this study, we retrospectively evaluated the efficacy and toxicity of additional CRT for superficial esophageal squamous cell carcinoma (SCC) after near-circumferential or full-circumferential noncurative ESD, which was defined as a mucosal defect measuring ≥ 3/4 of the esophageal circumference. METHODS: We retrospectively evaluated 24 patients who received additional CRT for superficial esophageal SCC after near-circumferential or full-circumferential noncurative ESD between 2012 and 2018. Elective nodal irradiation (ENI) was performed in all patients and boost irradiation (BI) was performed after ENI in 4 patients with positive resection margins. The prescription doses of ENI and BI were 41.4 Gy in 23 fractions and 9 Gy in 5 fractions, respectively. Concurrent chemotherapy (a combination of cisplatin or nedaplatin and 5-fluorouracil) was administered to all patients. RESULTS: The 3-year and 5-year overall survival rates were 92% and 78%, respectively, while the 3-year and 5-year progression-free survival rates were 83% and 70%, respectively. Grade 2 esophageal stenosis occurred in 8 (33%) patients. There was no case of Grade 3 or worse esophageal stenosis. Among them, 4 (17%) patients developed stenosis before additional CRT, which persisted after the completion of additional CRT. The remaining 4 (17%) patients developed de novo stenosis within 5 months following the completion of additional CRT. One patient (4%) still requires regular bougie dilation. Grade 3 and Grade 4 acute toxicity, including anemia, neutropenia, thrombocytopenia, and esophagitis occurred in 1 (4%) and 0 (0%), 6 (25%) and 1 (4%), 1 (4%) and 0 (0%), and 1 (4%) and 0 (0%) patients, respectively. One (4%) patient who underwent salvage CRT for the out-of-field lymph node recurrence died with acute myeloid leukemia. CONCLUSIONS: Additional CRT is a viable treatment option even in patients who have undergone near-circumferential or full-circumferential noncurative ESD. Esophageal stenosis after additional CRT following near-circumferential or full-circumferential noncurative ESD is manageable and acceptable.

Definitive chemoradiotherapy with paclitaxel for locally advanced esophageal squamous cell carcinoma in older patients (PARADISE-1): a phase I trial.

BACKGROUND: In older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients. METHODS: Enrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m2 or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT). RESULTS: We enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m2 groups, respectively. All adverse events, except death in the 60 mg/m2 group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores. CONCLUSIONS: The recommended PTX dose with concomitant radiation was determined to be 50 mg/m2 weekly. Phase II trials at this dose are underway.

Prognostic relevance of prognostic nutritional indices in gastric or gastro-esophageal junction cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: The Prognostic Nutritional Index (PNI) has become an important predictive tool for assessing patients' nutritional status and immune competence. It is widely used in prognostic evaluations for various cancer patients. However, the prognostic relevance of the Prognostic Nutritional Index (PNI) in gastric or gastro-esophageal junction cancer patients (GC/GEJC) undergoing immune checkpoint inhibitors (ICIs) treatment remains unclear. This meta-analysis aimed to determine the prognostic impact of PNI in this specific patient cohort. Methods: We conducted a thorough literature search, covering prominent databases such as PubMed, Embase, Web of Science, SpringerLink, and the Cochrane Library. The search spanned from the inception of these databases up to December 5, 2023. Employing the 95% confidence interval and Hazard Ratio (HR), the study systematically evaluated the relationship between PNI and key prognostic indicators, including the objective remission rate (ORR), disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) in GC/GEJC patients undergoing ICI treatment. Results: Eight studies comprising 813 eligible patients were selected. With 7 studies consistently demonstrating superior Overall Survival (OS) in the high-Prognostic Nutritional Index (PNI) group compared to their low-PNI counterparts (HR 0.58, 95% CI: 0.47-0.71, P<0.001). Furthermore, the results derived from 6 studies pointed out that the significant correlation between he low-PNI and poorer progression-free survival (PFS) (HR 0.58, 95% CI: 0.47-0.71, P<0.001). Subgroup analyses were performed to validate the robustness of the results. In addition, we conducted a meta-analysis of three studies examining the correlation between PNI and objective response rate/disease control rate (ORR/DCR) and found that the ORR/DCR was significantly superior in the high PNI group (ORR: RR: 1.24, P=0.002; DCR: RR: 1.43, P=0.008). Conclusion: This meta-analysis indicates that the low-PNI in GC/GEJC patients undergoing ICI treatment is significantly linked to worse OS and PFS. Therefore, PNI can serve as a prognostic indicator of post-treatment outcomes in patients with GC receiving ICIs. Further prospective studies are required to assess the reliability of these findings. Systematic review registration: https://inplasy.com/, identifier INPLASY202450133.

Association of the Scottish inflammatory prognostic score with treatment-related adverse events and prognosis in esophageal cancer receiving neoadjuvant immunochemotherapy.

Background: To investigate the relationship between the Scottish inflammatory prognostic score (SIPS), treatment-related adverse events (TRAEs), and prognostication in patients with neoadjuvant immunochemotherapy (NICT) for esophageal squamous cell carcinoma (ESCC). Methods: A retrospective investigation was carried out on 208 ESCC patients treated with NICT. The relationships between the SIPS, TRAEs, and prognosis [disease-free survival (DFS) and overall survival (OS)] were analyzed. Results: The patients, comprising 62 (29.8%) cases of SIPS0, 103 (49.5%) cases of SIPS1, and 43 (20.7%) cases of SIPS2, were categorized into three groups based on SIPS. Among patients with SIPS2, the oldest age (P=0.006), lowest BMI (P=0.001), longest tumor length (P=0.001), most advanced ypT stage (P=0.014), and ypN stage (P<0.001) were identified. Pathological complete response (PCR) rates showed statistically significant variations between the three groups (SIPS0: 45.2%, SIPS1: 27.2%, SIPS2: 16.3%, P=0.004). All TRAEs were found in 63.9% (133 cases) of the cases, with serious TRAEs (grade 3-4) accounting for 13.9% (29 cases). TRAEs themselves were not linked with SIPS (P=0.668), while serious TRAEs had a significant correlation with SIPS (P=0.002). Multivariate logistic analysis showed that SIPS2 seemed to confer serious TRAEs [odds radio (OR)=4.044; 95% CI: 1.395-11.722; P=0.010]. For patients classified as SIPS0, 1, or 2, the 3-year DFS was 83.9%, 58.3%, and 39.5% (P<0.001). The 3-year OS for those with SIPS0, 1, or 2 was 88.7%, 72.8%, and 53.5%, respectively (P<0.001). SIPS was substantially correlated with DFS (but not with OS) and could be utilized as an independent predictor [SIPS2: hazard ratio (HR)=3.743, 95% CI: 1.770-7.914, P=0.001; SIPS1: HR=2.303, 95% CI: 1.149-4.616, P=0.019]. Conclusion: The SIPS is associated with serious TRAEs and can be used as a predictor of serious TRAEs in ESCC receiving NICT. SIPS may be employed for pretreatment assessment since it was found to be substantially correlated with DFS.

A propensity score-matched comparison of neoadjuvant chemoradiotherapy with cisplatin-5FU and carboplatin-paclitaxel in locally advanced esophageal squamous cell carcinoma: A Turkish oncology group study.

BACKGROUND: Neoadjuvant treatment is the standard treatment in locally advanced ESCC. However, the optimal chemotherapy regimen is not known. METHOD: This is a retrospective observational cohort study conducted with propensity score matching. Patients with resectable ESCC from 13 tertiary centers from Türkiye were screened between January 2011 and December 2021. We compared the efficacy and safety of neoadjuvant chemoradiotherapy with the CF and the CROSS regimens in patients with ESCC. RESULTS: Three hundred and sixty-two patients were screened. Patients who received induction chemotherapy (n = 72) and CROSS-ineligible (n = 31) were excluded. Two hundred and fifty nine patients received neoadjuvant chemoradiotherapy. After propensity score matching (n = 97 in both groups), the mPFS was 18.4 months (95% CI, 9.3-27.4) and 25.7 months (95% CI, 15.6-35.7; p = 0.974), and the mOS was 35.2 months (95% CI, 18.9-51.5) and 39.6 months (95% CI 20.1-59.2; p = 0.534), in the CF and the CROSS groups, respectively. There was no difference between subgroups regarding PFS and OS. Compared with the CF group, the CROSS group had a higher incidence of neutropenia (34.0% vs. 62.9%, p < 0.001) and anemia (54.6% vs. 75.3%, p = 0.003) in all grades. On the other hand, there was no significant difference in grade 3-4 anemia, grade 3-4 neutropenia, and febrile neutropenia between groups. There were more dose reductions and dose delays in the CROSS group than in the CF group (11.3% vs. 3.1%, p = 0.026 and 34.0% vs. 17.5%, p = 0.009, respectively). The resection rate was 52.6% in the CF-RT and 35.1% in the CROSS groups (p = 0.014). CONCLUSION: Favorable PFS and pCR rates and a comparable OS were obtained with the CROSS regimen over the CF regimen as neoadjuvant chemoradiotherapy in patients with ESCC.

Small cell carcinoma esophagus-A tertiary cancer center experience of a rare variant.

BACKGROUND: Esophageal cancer is quite prevalent worldwide and usually carries a poor prognosis. Histologically, although squamous cell carcinoma and adenocarcinoma predominate, small cell carcinoma (SmCC) cases have been reported. Overall, there is a paucity of literature regarding this variant. In this article, we aim to highlight this uncommon entity of carcinoma esophagus and share our experience of SmCC patients seen over a decade at our institute. METHOD: Records of patients with SmCC histology from 2010 to 2020 were assessed. Patients' demographic characteristics, clinical characteristics, treatment received, and outcomes were taken into consideration. Results were analyzed statistically using SPSS version 22. RESULTS: Fourteen patients (nine males and five females) with a median age of 57 years (range: 35 - 72 years) were analyzed. The majority of the patients 10/14 (71.4%) received palliative radiotherapy of either 30Gy/10 fractions or 35Gy/15 fractions. Only 1/14 (7.14%) patients received neoadjuvant chemotherapy and concurrent chemoradiation (CCRT). Overall, partial response was noted in all 11 patients (78.6%) who received treatment. The average median survival was 5 months (range: 1-11 months). CONCLUSION: Although the small sample size of the study prevents us from drawing a firm conclusion, we propose national and international collaborative prospective studies for framing definitive oncologic management strategies for this rare histological variant of esophageal cancer.

Radiotherapy for patients with locally advanced esophageal squamous cell carcinoma receiving neoadjuvant immunotherapy combined with chemotherapy.

With the success of immunotherapy in advanced esophageal cancer, neoadjuvant chemo-immunotherapy (CIT) is being increasingly used for local staged esophageal cancer, especially in the context of clinical trials, which brings similar pCR with neoadjuvant chemoradiotherapy and shows promising results. However, there is still a part of potentially operable patients can't undergo surgery after neoadjuvant chemo-immunotherapy. The follow-up treatment and prognosis of this population remain unclear. Patients pathologically diagnosed with ESCC, clinical stage T1-3N+M0 or T3-4aNanyM0 (AJCC 8th), PS 0-1 were retrospectively enrolled from 1/2020 to 6/2021 in Zhejiang Cancer Hospital. All patients firstly received PD-1 inhibitors plus chemotherapy (albumin paclitaxel, 260 mg/m2 on day 1 plus carboplatin AUC = 5 on day 1) every 3 weeks for 2-4 cycles. For those patients who did not receive surgery, definitive radiotherapy with 50.4 Gy/28F or 50 Gy/25F was adopted using VMAT, concurrent with chemotherapy or alone. The concurrent chemotherapy regimens included weekly TC (paclitaxel 50 mg/m2, d1, carboplatin AUC = 2, d1) or S1 (60 mg bid d1-14, 29-42). The survival outcomes and treatment toxicity were recorded and analyzed. A total of 56 eligible patients were finally identified from 558 patients who were treated in department of thoracic surgery, among all the patients, 25 (44.6%) received radiotherapy alone, and 31 (55.4%) received chemoradiotherapy after neoadjuvant CIT. The median follow-up was 20.4 months (interquartile range [IQR] 8.7-27 months). The median PFS and OS were 17.9 months (95% confidence interval [CI] 11.0-21.9 months) and 20.5 months (95% CI 11.8-27.9 months), respectively. In the subgroup analysis, the median OS was 26.3 months (95% CI 15.33-NA) for patients exhibiting partial response (PR) to CIT, compared to 17 months (95% CI 8.77-26.4) for those with stable disease (SD) or progressive disease (PD), yielding a hazard ratio (HR) of 0.54 (95% CI 0.27-1.06, P = 0.07). No significant difference was observed for patients received radiotherapy alone or chemoradiotherapy with HR = 0.73 (95% CI 0.72-2.6, P = 0.33). The most common Adverse events (AEs) observed during this study were anemia (98.2%), leukopenia (83.9%), thrombocytopenia (53.6%). AEs of grade ≥ 3 radiation-induced pneumonitis and esophagitis were 12.5% and 32.1%, especially, 6 patients (10.7%) died from esophageal fistula and 2 patients (3.6%) died from grade 5 pneumonitis. For local advanced ESCC patients after neoadjuvant CIT who did not receive surgery, definitive radiotherapy was an optional treatment strategy. However, those patients with no response to CIT also showed poor response to radiotherapy, and particular attention should be paid to treatment related toxicity, especially esophageal fistula.

Prognostic value of sarcopenia and inflammatory indices synergy in patients with esophageal squamous cell carcinoma undergoing chemoradiotherapy.

BACKGROUND AND PURPOSE: Sarcopenia has been demonstrated to be adversely correlated with the prognosis of various cancers. Our study aimed to estimate the prognostic value of sarcopenia in conjunction with inflammatory indices [neutrophil-to-lymphocyte ratio (NLR)] for evaluating the prognosis of patients with esophageal squamous cell carcinoma (ESCC) undergoing chemoradiotherapy. MATERIALS AND METHODS: This study retrospectively analyzed 255 patients with ESCC who received chemoradiotherapy from January 2012 to December 2018. Multivariate Cox regression analysis was employed to identify prognostic values of assessed factors following a novel prognostic scoring system (SMI-NLR), covering sarcopenia and NLR during different treatment courses. RESULTS: Kaplan-Meier analysis revealed significantly greater overall survival (OS) rates in the nonsarcopenia group than in the sarcopenia group (P = 0.011). The low NLR group (< 4.84) demonstrated significantly higher OS rates than the high NLR group (≥ 4.84) (P < 0.001). The SMI-NLR prognostic model was established through multivariate analysis, revealing that Karnofsky performance status [hazard ratio (HR) = 0.285; 95% confidence interval (CI) = 0.117-0.699; P = 0.006], clinical staging (HR = 5.223; 95% CI = 1.879-14.514; P = 0.002), and preSMI-NLR (HR = 0.544; 95% CI = 0.330-0.898; P = 0.017) were independent factors affecting the prognosis of patients with ESCC. Nomograms were constructed based on these data providing more accurate 1-, 3-, and 5-year survival rates for patients with ESCC. CONCLUSION: Our study indicates the effectiveness of the combined sarcopenia and NLR prognostic model for the prognostic evaluation of patients with ESCC having undergone chemoradiotherapy.

Diffuse-Type Histology Is Prognostic for All Siewert Types of Gastroesophageal Adenocarcinoma.

PURPOSE: The optimal treatment for gastroesophageal junction adenocarcinoma (GEJA) remains controversial. We evaluated the treatment patterns and outcomes of patients with locally advanced GEJA according to the histological type. MATERIALS AND METHODS: We conducted a single-institution retrospective cohort study of patients with locally advanced GEJA who underwent curative-intent surgical resection between 2010 and 2020. Perioperative therapies as well as clinicopathologic, surgical, and survival data were collected. The results of endoscopy and histopathological examinations were assessed for Siewert and Lauren classifications. RESULTS: Among the 58 patients included in this study, 44 (76%) were clinical stage III, and all received neoadjuvant therapy (72% chemoradiation, 41% chemotherapy, 14% both chemoradiation and chemotherapy). Tumor locations were evenly distributed by Siewert Classification (33% Siewert-I, 40% Siewert-II, and 28% Siewert-III). Esophagogastrectomy (EG) was performed for 47 (81%) patients and total gastrectomy (TG) for 11 (19%) patients. All TG patients received D2 lymphadenectomy compared to 10 (21%) EG patients. Histopathological examination showed the presence of 64% intestinal-type and 36% diffuse-type histology. The frequencies of diffuse-type histology were similar among Siewert groups (37% Siewert-I, 36% Siewert-II, and 33% Siewert-III). Regardless of Siewert type and compared to intestinal-type, diffuse histology was associated with increased intraabdominal recurrence rates (P=0.03) and decreased overall survival (hazard ratio, 2.33; P=0.02). With a median follow-up of 31.2 months, 29 (50%) patients had a recurrence, and the median overall survival was 50.5 months. CONCLUSIONS: Present in equal proportions among Siewert types of esophageal and gastric cancer, a diffuse-type histology was associated with high intraabdominal recurrence rates and poor survival. Histopathological evaluation should be considered in addition to anatomic location in the determination of multimodal GEJA treatment strategies.

The prognostic value of preoperative laboratory data indicators in patients with esophageal carcinoma: An observational study.

Preoperative laboratory data indicators significantly affect the prognosis of a variety of tumors. Nevertheless, the combined effect of systemic immune-inflammation index (SII) and prognostic nutritional index (PNI) on overall survival (OS) in patients with esophageal carcinoma remains unclear. Thus, we examined these associations among patients with postoperative staged T3N0M0 esophageal carcinoma. The data of 246 patients with postoperative staged T3N0M0 esophageal carcinoma from January 1, 2010, to December 31, 2022, were retrospectively analyzed. OS was measured from the date of pathological diagnosis until either death or the last follow-up. The Kaplan-Meier method and multivariate Cox regression model were used to analyze the relationship between neutrophil-to-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR), Platelet-to-lymphocyte ratio (LMR), SII, PNI, and OS. The predictive value of SII and PNI as a combined index was analyzed by the receiver operating characteristic curve (ROC). A total of 246 patients aged 65.5 ±â€…7.4 years were included in this study and 181 (73.6%) were male. The univariate analysis revealed that differentiation, vessel involvement, postoperative treatment, NLR, SII, PLR, LMR, PNI were predictors of OS (P < .05). After adjusted for potential confounds, multivariate Cox regression analysis showed that the differentiation, SII, PNI, and postoperative treatment were independent prognostic factors correlated with OS in patients with postoperative staged T3N0M0 esophageal carcinoma (P < .05). SII and PNI, as a combined indicator, have a higher predictive value for OS. The NLR, SII, PLR, LMR, and PNI could all be used as independent predictors of OS in patients with postoperative staged T3N0M0 esophageal carcinoma. The combination of SII and PNI can significantly improve the accuracy of prediction.

Kinetics of plasma cell-free DNA as a prospective biomarker to predict the prognosis and radiotherapy effect of esophageal cancer.

PURPOSE: The lack of reliable biomarkers for the prognosis and radiotherapy efficacy in esophageal cancer (EC) necessitates further research. The aim of our study was to investigate the predictive utility of plasma cell-free DNA (cfDNA) kinetics in patients with EC. MATERIALS AND METHODS: We retrospectively analyzed the clinical data and cfDNA levels (pre-radiotherapy [pre-RT] and post-radiotherapy [post-RT]) and the cfDNA kinetics (cfDNA ratio: post-RT cfDNA/pre-RT cfDNA) of 88 patients. We employed Kaplan-Meier curves to examine the relationship between cfDNA and overall survival (OS) as well as progression-free survival (PFS). Univariate and multivariate Cox regression analyses were executed to ascertain the independent risk factors in EC. RESULTS: The pre-RT cfDNA levels were positively correlated with clinical stage (P=0.001). The pre-RT cfDNA levels (cutoff value=16.915ng/mL), but not the post-RT cfDNA levels, were linked to a diminished OS (P<0.001) and PFS (P=0.0137). CfDNA kinetics (cutoff value=0.883) were positively associated with OS (P=0.0326) and PFS (P=0.0020). Notably, we identified independent risk factors for OS in EC treated with RT, including cfDNA ratio (high/low) (HR=0.447 [0.221-0.914] P=0.025), ECOG (0/1/2) (HR=0.501 [0.285-0.880] p=0.016), and histological type (esophagal squamous cell carcinoma [ESCC]/non-ESCC) (HR=3.973 [1.074-14.692] P=0.039). CONCLUSION: Plasma cfDNA kinetics is associated with prognosis and radiotherapy effect in EC undergoing RT, suggesting potential clinical application of a cheap and simple blood-based test.

A novel mitochondrial metabolism-related gene signature for predicting the prognosis of oesophageal squamous cell carcinoma.

Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide. Due to the important role of mitochondrial metabolism in cancer progression, a clinical prognostic model based on mitochondrial metabolism and clinical features was constructed in this study to predict the prognosis of ESCC. Firstly, the mitochondrial metabolism scores (MMs) were calculated based on 152 mitochondrial metabolism-related genes (MMRGs) by single sample gene set enrichment analysis (ssGSEA). Subsequently, univariate Cox regression and LASSO algorithm were used to identify prognosis-associated MMRG and risk-stratify patients. Functional enrichment, interaction network and immune-related analyses were performed to explore the features differences in patients at different risks. Finally, a prognostic nomogram incorporating clinical factors was constructed to assess the prognosis of ESCC. Our results found there were differences in clinical features between the MMs-high group and the MMs-low group in the TCGA-ESCC dataset (P<0.05). Afterwards, we identified 6 MMRGs (COX10, ACADVL, IDH3B, AKR1A1, LIAS, and NDUFB8) signature that could accurately distinguish high-risk and low-risk ESCC patients. A predictive nomogram that combined the 6 MMRGs with sex and N stage to predict the prognosis of ESCC was constructed, and the areas under the receiver operating characteristic (ROC) curve at 1, 2 and 3 years were 0.948, 0.927 and 0.848, respectively. Finally, we found that COX10, one of 6 MMRGs, could inhibit the malignant progression of ESCC in vitro. In summary, we constructed a clinical prognosis model based on 6 MMRGs and clinical features which can accurately predict the prognosis of ESCC patients.

A nomogram based on pretreatment radiomics and dosiomics features for predicting overall survival associated with esophageal squamous cell cancer.

OBJECTIVES: To propose a nomogram-based survival prediction model for esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy using pretreatment computed tomography (CT), positron emission tomography (PET) radiomics and dosiomics features, and common clinical factors. METHODS: Radiomics and dosiomics features were extracted from CT and PET images and dose distribution from 2 institutions. The least absolute shrinkage and selection operator (LASSO) with logistic regression was used to select radiomics and dosiomics features by calculating the radiomics and dosiomics scores (Rad-score and Dos-score), respectively, in the training model. The model was trained in 81 patients and validated in 35 patients at Center 1 using 10-fold cross validation. The model was externally tested in 26 patients at Center 2. The predictive clinical factors, Rad-score, and Dos-score were identified to develop a nomogram model. RESULTS: Using LASSO Cox regression, 13, 11, and 19 CT, PET-based radiomics, and dosiomics features, respectively, were selected. The clinical factors T-stage, N-stage, and clinical stage were selected as significant prognostic factors by univariate Cox regression. In the external validation cohort, the C-index of the combined model of CT-based radiomics, PET-based radiomics, and dosiomics features with clinical factors were 0.74, 0.82, and 0.92, respectively. Significant differences in overall survival (OS) in the combined model of CT-based radiomics, PET-based radiomics, and dosiomics features with clinical factors were observed between the high- and low-risk groups (P = 0.019, 0.038, and 0.014, respectively). CONCLUSION: The dosiomics features have a better predicter for OS than CT- and PET-based radiomics features in ESCC treated with radiotherapy. CLINICAL RELEVANCE STATEMENT: The current study predicted the overall survival for esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy. The dosiomics features have a better predicter for overall survival than CT- and PET-based radiomics features.

Practice pattern and risk of not receiving planned surgery after neoadjuvant chemoradiotherapy for locally advanced oesophageal squamous cell carcinoma.

OBJECTIVES: Unlike the initial plan, some patients with oesophageal squamous cell carcinoma cannot or do not receive surgery after neoadjuvant chemoradiotherapy (nCRT). This study aimed to report the epidemiology of patients not receiving surgery after nCRT and to evaluate the potential risk of refusing surgery. METHODS: We analysed patients with clinical stage T3-T4aN0M0 or T1-T4aN1-N3M0 oesophageal squamous cell carcinoma who underwent nCRT as an initial treatment intent between January 2005 and March 2020. Patients not receiving surgery were categorized using predefined criteria. To evaluate the risk of refusing surgery, a propensity-matched comparison with those who received surgery was performed. Recurrence-free (RFS) and overall survival (OS) was compared between groups, according to clinical response to nCRT. RESULTS: Among the study population (n = 715), 105 patients (14.7%) eventually failed to reach surgery. There were three major patterns of not receiving surgery: disease progression before surgery (n = 25), functional deterioration at reassessment (n = 47), and patient's refusal without contraindications (n = 33). After propensity-score matching, the RFS curves of the surgery group and the refusal group were significantly different (P < 0.001), while OS curves were not significantly different (P = 0.069). In patients who achieved clinical complete response on re-evaluation, no significant difference in the RFS curves (P = 0.382) and in the OS curves (P = 0.290) was observed between the surgery group and the refusal group. However, among patients who showed partial response or stable disease on re-evaluation, the RFS and OS curves of the refusal group were overall significantly inferior compared to those of the surgery group (both P < 0.001). The 5-year RFS rates were 10.3% for the refusal group and 48.2% for the surgery group, and the 5-year OS rates were 8.2% for the refusal group and 46.1% for the surgery group. CONCLUSIONS: Patient's refusal remains one of the major obstacles in completing the trimodality therapy for oesophageal squamous cell carcinoma. Refusing surgery when offered may jeopardize oncological outcome, particularly in those with residual disease on re-evaluation after nCRT. These results provide significant implications for consulting patients who are reluctant to oesophagectomy after nCRT.

Clinical value of measuring plasma D-dimer levels in patients with esophageal cancer.

BACKGROUND: Esophageal cancer represents a significant public health concern; however, reliable diagnostic and prognostic markers have not been established. This study aimed to investigate the clinical value of plasma D-dimer levels in patients with esophageal cancer. METHODS: Overall, 120 patients with esophageal cancer who underwent radical surgical resection at our department between January 2019 and 2020 were included (esophageal cancer group). Plasma D-dimer levels were measured preoperatively and on postoperative days 1 and 14. Additionally, 60 healthy participants (control group) with measured plasma D-dimer levels were included. The preoperative D-dimer levels and positive D-dimer test rates were compared between the groups. The 3-year survival rate in patients with esophageal cancer was calculated using the Kaplan-Meier method. RESULTS: Preoperative D-dimer concentration in the esophageal cancer group was (0.65 ± 0.859 µg/mL) significantly higher than that in the control group (0.32 ± 0.369 µg/mL). The positivity rate in the esophageal cancer group (35.0%, 42/120) was significantly higher than that in the control group (15%, 9/60). D-dimer concentrations were significantly higher 1 day postoperatively than preoperatively. Conversely, D-dimer concentrations were significantly lower 14 days postoperatively than preoperatively. Patients in the esophageal cancer group with plasma D-dimer concentrations ≤ 0.5 µg/mL had significantly higher 3-year survival rates than those with higher concentrations. In the logistic multivariate analysis, tumor pathological stage and preoperative plasma D-dimer levels were independent prognostic factors of 3-year survival rates in patients with esophageal cancer. CONCLUSION: Plasma D-dimer concentrations are clinically valuable in esophageal cancer diagnosis, postoperative recurrence monitoring, and prognosis prediction.

Prognostic and clinicopathological value of Ki-67 in patients with oesophageal squamous cell carcinoma: a systematic review and meta-analysis.

OBJECTIVES: The relationship between Ki-67 expression and the prognosis of patients with oesophageal squamous cell carcinoma (ESCC) has been extensively studied. However, their findings were inconsistent. Consequently, the present meta-analysis was performed to identify the precise value of Ki-67 in predicting the prognosis of ESCC. DESIGN: The current meta-analysis was carried out in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. DATA SOURCES: Electronic databases of PubMed, Embase, Web of Science and Cochrane Library were systematically searched until 26 September 2023. STATISTICAL METHODS: Pooled HRs and corresponding 95% CIs were calculated to estimate the role of Ki-67 in predicting overall survival (OS) and disease-free survival (DFS) in ESCC. Between-study heterogeneity was evaluated using Cochrane's Q test and I2 statistics. Specifically, significant heterogeneities were identified based on p<0.10 on the Q statistic test or I2>50% so the random-effects model should be used; otherwise, the fixed-effects model should be used. The relationship between Ki-67 and clinicopathological characteristics of ESCC was evaluated by combining ORs with their corresponding 95% CIs. RESULTS: 11 articles with 1124 patients were included in the present meta-analysis. Based on our analysis, increased Ki-67 expression was markedly associated with poor OS (HR 1.62, 95% CI 1.15 to 2.28, p=0.006) and DFS (HR 1.72, 95% CI 1.22 to 2.43, p=0.002) in ESCC. Moreover, subgroup analysis revealed that Ki-67 upregulation significantly predicted OS and DFS when a Ki-67 threshold of >30% was used. Nonetheless, Ki-67 was not significantly associated with sex, T stage, N stage, TNM stage, tumour differentiation or tumour location. CONCLUSIONS: In the present meta-analysis, high Ki-67 expression significantly predicted OS and DFS in patients with ESCC, especially when Ki-67>30% was used as the threshold. These results suggest that Ki-67 could serve as an effective and reliable prognostic indicator for ESCC.

Surgical and Perioperative Treatments for Esophagogastric Junction Cancer.

Esophagogastric junction cancer (EGJC) is a rare malignant disease that occurs in the gastroesophageal transition zone. In recent years, its incidence has been rapidly increasing not only in Western countries but also in East Asia, and it has been attracting the attention of both clinicians and researchers. EGJC has a worse prognosis than gastric cancer (GC) and is characterized by complex lymphatic drainage pathways in the mediastinal and abdominal regions. EGJC was previously treated in the same way as GC or esophageal cancer, but, in recent years, it has been treated as an independent malignant disease, and treatment focusing only on EGJC has been developed. A recent multicenter prospective study revealed the frequency of lymph node metastasis by station and established the optimal extent of lymph node dissection. In perioperative treatment, the combination of multi-drug chemotherapy, radiation therapy, molecular targeted therapy, and immunotherapy is expected to improve the prognosis. In this review, we summarize previous clinical trials and their important evidence on surgical and perioperative treatments for EGJC.

Dynamic volume-outcome association for esophagectomies: Do current volume thresholds still apply?

BACKGROUND: It is unknown if the current minimum case volume recommendation of 20 cases per year per hospital is applicable to contemporary practice. METHODS: Patients undergoing esophageal resection between 2005 and 2015 were identified in the National Cancer Database. High, medium, and low-volume hospital strata were defined by quartiles. Adjusted odds ratios and adjusted 30-day mortality between low-, medium-, and high-volume hospitals were calculated using logistic regression analyses and trended over time. RESULTS: Only 1.1% of hospitals had ≥20 annual cases. The unadjusted 30-day mortality for esophagectomy was 3.8% overall. Unadjusted and adjusted 30-day mortality trended down for all three strata between 2005 and 2015, with disproportionate decreases for low-volume and medium-volume versus high-volume hospitals. By 2015, adjusted 30-day mortality was similar in medium- and high-volume hospitals (odds ratio 1.35, 95% confidence interval 0.96-1.91). For hospitals with 20 or more annual cases the adjusted 30-day mortality was 2.7% overall. To achieve this same 30-day mortality the minimum volume threshold had lowered to 7 annual cases by 2015. CONCLUSION: Only 1.1% of hospitals meet current volume recommendations for esophagectomy. Differential improvements in postoperative mortality at low- and medium- versus high-volume hospitals have led to 7 cases in 2015 achieving the same adjusted 30-day mortality as 20 cases in the overall cohort. Lowering volume thresholds for esophagectomy in contemporary practice would potentially increase the proportion of hospitals able to meet volume standards and increase access to quality care without sacrificing quality.