Impact of Skeletal Muscle Loss and Sarcopenia on Outcomes of Locally Advanced Esophageal Cancer during Neoadjuvant Chemoradiation.

BACKGROUND: The impact of changes in skeletal muscle and sarcopenia on outcomes during neoadjuvant chemoradiotherapy (NACR) for patients with esophageal cancer remains controversial. PATIENTS AND METHODS: We retrospectively analyzed the data of patients with locally advanced esophageal squamous cell cancer who received NACR followed by esophagectomy between June 2013 and December 2021. The images at third lumbar vertebra were analyzed to measure the cross-sectional area and calculate skeletal muscle index (SMI) before and after NACR. SMI less than 52.4 cm2/m2 for men and less than 38.5 cm2/m2 for women were defined as sarcopenia. The nonlinearity of the effect of percent changes in SMI (ΔSMI%) to survival outcomes was assessed by restricted cubic splines. RESULTS: Overall, data of 367 patients were analyzed. The survival outcomes between sarcopenia and non-sarcopenia groups had no significant differences before NACR. However, patients in post-NACR sarcopenia group showed poor overall survival (OS) benefit (P = 0.016) and poor disease-free survival (DFS) (P = 0.043). Severe postoperative complication rates were 11.9% in post-NACR sarcopenia group and 5.0% in post-NACR non-sarcopenia group (P = 0.019). There was a significant non-linear relationship between ΔSMI% and survival outcomes (P < 0.05 for non-linear). On the multivariable analysis of OS, ΔSMI% > 12% was the independent prognostic factor (HR 1.76, 95% CI 1.03-2.99, P = 0.039) and significant difference was also found on DFS analysis (P = 0.025). CONCLUSIONS: Patients with post-neoadjuvant chemoradiotherapy sarcopenia have worse survival and adverse short-term outcomes. Moreover, greater loss in SMI is associated with increased risks of death and disease progression during neoadjuvant chemoradiotherapy, with maximum impact noted with SMI loss greater than 12%.

MTHFD1L confers a poor prognosis and malignant phenotype in esophageal squamous cell carcinoma by activating the ERK5 signaling pathway.

MTHFD1L, a key enzyme of folate metabolism, is seldom reported in cancer. In this study, we investigate the role of MTHFD1L in the tumorigenicity of esophageal squamous cell carcinoma (ESCC). ESCC tissue microarrays (TMAs) containing 177 samples from 109 patients were utilized to evaluate whether MTHFD1L expression, determined using immunohistochemical analysis, is a prognostic indicator for ESCC patients. The function of MTHFD1L in the migration and invasion of ESCC cells was studied with wound healing, Transwell, and three-dimensional spheroid invasion assays in vitro and a lung metastasis mouse model in vivo. The mRNA microarrays and Ingenuity pathway analysis (IPA) were used to explore the downstream of MTHFD1L. Elevated expression of MTHFD1L in ESCC tissues was significantly associated with poor differentiation and prognosis. These phenotypic assays revealed that MTHFD1L significantly promote the viability and metastasis of ESCC cell in vivo and in vitro. Further detailed analyses of the molecular mechanism demonstrated that the ESCC progression driven by MTHFD1L was through up-regulation ERK5 signaling pathways. These findings reveal that MTHFD1L is positively associated with the aggressive phenotype of ESCC by activating ERK5 signaling pathways, suggesting that MTHFD1L is a new biomarker and a potential molecular therapeutic target for ESCC.

The development and progress of nanomedicine for esophageal cancer diagnosis and treatment.

Esophageal cancer (EC) is a common gastrointestinal malignancy with poor prognosis and high mortality. Although combined therapeutic strategies have been developed, the 5-year survival rate of patients with EC remains relatively poor. Conventional anti-cancer drug delivery techniques have some shortcomings, such as nontargeted delivery and nonspecific toxicity. Nanoparticles (NPs) provide a promising platform for delivering drugs in various therapeutic modalities for EC, which possess several remarkable advantages in cancer therapy, such as reduced side effects, prolonged circulation time, and preferential accumulation at the tumor site. In this review, we summarized various types of NPs applied in the treatment of EC, including polymers, micelles, liposomes, inorganic NPs and organic NPs. Meanwhile, we discussed the efficacy and safety of newly designed nanomedicine in various treatments of EC, including chemotherapy, radiotherapy, gene therapy, photodynamic therapy (PDT), photothermal therapy (PTT), and their synergetic therapy. In addition, nanomedicine applied in tumor imaging and diagnoses were also reviewed. Current studies have suggested the potential advantages of nanoformulations over conventional formulations. More researches to promote clinical translation of nanomedicine for EC are anticipated in the future.

The Prognostic Value of Nodal Skip Metastasis in Patients with Esophageal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Esophageal cancer (EC) is the sixth leading cause of cancer deaths worldwide. Nodal skip metastasis (NSM), a common form of lymphatic spread in EC, can be defined as the metastatic involvement of distant lymph nodes (LNs) without prior involvement of adjacent LNs. The results of the previous studies investigating the association between NSM and survival outcomes in patients with EC were inconsistent and even contradictory. The aim of this systematic review and meta-analysis is to investigate the prognostic value of NSM and to summarize the NSM definitions of EC in previous studies. METHODS: Four databases were used in this meta-analysis. The association between NSM and overall survival (OS) was evaluated by using pooled HRs and their 95% confidence interval (CI). The sensitivity analysis and funnel plot were used to assess the publication bias. RESULTS: Nine studies were included in this meta-analysis. The pooled results of meta-analysis indicated that there was no significant association between NSM and OS (HR = 0.99, 95% CI: 0.75-1.31; P = 0.951). Meanwhile, according to the results of sub-group analysis on the basis of histological feature, method of lymphadenectomy, node staging system, and NSM definitions, no significant association was found between NSM and OS. CONCLUSIONS: On the basis of available evidences, NSM could not be used as a prognostic factor for patients with EC. For future studies investigating the prognostic value of NSM, only three-field lymphadenectomy with adequate harvested LNs can be performed. NSM definitions based on lymph node station and anatomical compartment could both be feasible classification for EC.

Overexpressed COL3A1 has prognostic value in human esophageal squamous cell carcinoma and promotes the aggressiveness of esophageal squamous cell carcinoma by activating the NF-κB pathway.

Alpha-1 Type Ⅲ Collagen (COL3A1) encodes the Collagen alpha-1(Ⅲ) chain, which is a fibrillar collagen that exists in extensile connective tissues. Few studies have reported its role in tumorigenicity. In the present study, we identified that COL3A1 protein and mRNA expression levels were considerably up-regulated in esophageal squamous cell carcinoma (ESCC) cells in comparison with normal esophageal squamous epithelial cells (P < 0.05). Immunohistochemical (IHC) analysis of 114 paraffin-embedded archived ESCC tissues demonstrated that COL3A1 expression was positively correlated with the postoperative T stage. Univariate and multivariable analysis demonstrated that COL3A1 expression was an independent poor prognostic factor for overall survival in the whole cohort. Silencing COL3A1 inhibited, while overexpressing COL3A1 promoted, the proliferation, migration, and invasion of ESCC cells. Furthermore, down-regulation of COL3A1 expression also suppressed the growth of ESCC in subcutaneous xenograft mouse models and inhibited ESCC metastasis in lung metastasis mouse models. In addition, we proved that the tumor-promoting effect of COL3A1 on ESCC cells was related to the activation of NF-κB signaling pathway. These findings indicate that COL3A1 confers a poor prognosis and malignant phenotype by activating the NF-κB pathway in ESCC, potentially representing a novel biomarker and/or providing a new curative target for ESCC.

Acid-Responsive Aggregated Gold Nanoparticles for Radiosensitization and Synergistic Chemoradiotherapy in the Treatment of Esophageal Cancer.

Radiotherapy and chemotherapy are limited by insufficient therapeutic efficacy of low-dose radiation and nonspecific drug biodistribution. Herein, an acid-responsive aggregated nanosystem (AuNPs-D-P-DA) loaded with doxorubicin (DOX) is designed for radiosensitization and synergistic chemoradiotherapy. In response to the acid microenvironment of esophageal cancer (EC), small-sized AuNPs-D-P-DA forms large-sized gold nanoparticle (AuNPs) aggregates in tumor tissues to hinder the backflow of AuNPs to the circulation, resulting in enhanced tumor accumulation and retention. Simultaneously, the AuNPs-based radiosensitization is significantly improved because of the high concentration and large size of intratumoral AuNPs, while DOX are delivered and released specifically into tumor cells triggered by the acid microenvironment for chemo-radio synergistic therapy. Acid-responsive AuNPs exacerbate radiation-induced DNA damage, cell apoptosis, cell cycle arrest, and low colony formation ability in vitro and enhance anti-tumor efficacy in vivo compared to un-responsive control. When combined with acid-responsive DOX, the therapeutic efficacy of the formulation is further improved by their synergistic effect. After the treatment of acid-responsive AuNPs plus radiotherapy, fatty acid metabolism is reprogrammed in xenograft models, which provides potential targets for further improvement of radiosensitization. In summary, the acid-responsive AuNPs-D-P-DA nanosystem leverages the radio- and chemotherapeutic synergies of AuNPs-sensitized X-ray irradiation and acid-responsive DOX in the treatment of EC.

The emerging role of long noncoding RNAs in esophageal carcinoma: from underlying mechanisms to clinical implications.

Long noncoding RNAs (lncRNAs), a type of transcriptional product more than 200 nucleotides in length, have emerged as crucial regulators in human cancers. Accumulating data have recently indicated relationships between lncRNAs and esophageal carcinoma (EC). Of note, lncRNAs act as decoys/sponges, scaffolds, guides, and signals to regulate the expression of oncogenes or tumor suppressors at epigenetic, post-transcriptional, and protein levels, through which they exert their unique EC-driving or EC-suppressive functions. Moreover, the features of EC-related lncRNAs have been gradually exploited for developing novel diagnostic and therapeutic strategies in clinical scenarios. LncRNAs have the potential to be used as diagnostic and prognostic indicators individually or in combination with other clinical variables. Beyond these, although the time is not yet ripe, therapeutically targeting EC-related lncRNAs via gene editing, antisense oligonucleotides, RNA interference, and small molecules is likely one of the most promising therapeutic strategies for the next generation of cancer treatment. Herein, we focus on summarizing EC-driving/suppressive lncRNAs, as well as discussing their different features regarding expression profiles, modes of action, and oncological effects. Moreover, we further discuss current challenges and future developing possibilities of capitalizing on lncRNAs for EC early diagnosis and treatment.

The Efficacy of Neoadjuvant Versus Adjuvant Therapy for Resectable Esophageal Cancer Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: Inconclusive results are available as to whether chemo/radiotherapy should be administered to resectable esophageal cancer patients before surgery (neoadjuvant therapy) or after surgery (adjuvant therapy). The paper, via a meta-analysis of effects of treatment modalities when administering chemo/radiotherapy, aims to systematically evaluate the effect of timing of chemo/radiotherapy and surgery. METHODS: We performed a systematic literature search for clinical trials of neoadjuvant and adjuvant therapy for patients with esophageal cancer. Using meta-analysis, we conducted direct and adjusted indirect comparisons of overall survival, complete resection rate (R0 resection), perioperative mortality, leakage rate and local recurrence in patients with resectable esophageal cancer. RESULTS: A total of 32 studies involving 7985 patients with esophageal cancer were included in the meta-analysis. Twenty-five randomized controlled studies indirectly compared neoadjuvant/adjuvant therapy with surgery alone, while five non-randomized controlled studies and two randomized controlled studies directly compared neoadjuvant with adjuvant therapy. Neoadjuvant therapy followed by surgery, compared with surgery along with adjuvant therapy, showed a significant overall survival advantage in our pooled analysis (HR 0.88; 95% CI 0.79-0.98). Directly compared with adjuvant therapy, neoadjuvant therapy demonstrated a lower local recurrence rate (OR 0.56; 95% CI 0.43-0.74) with low heterogeneity (I2 = 1%). Neoadjuvant therapy, comparing to surgery with or without adjuvant therapy, showed a significantly higher R0 resection rate (OR 2.86; 95% CI 2.02-4.04) with moderate heterogeneity (I2 = 38%) and no significant differences in postoperative anastomotic leakage (P = 0.50). However, neoadjuvant therapy, compared with surgery adjuvant therapy, significantly increased perioperative mortality in both direct and indirect comparisons (P < 0.01). CONCLUSIONS: We found that neoadjuvant therapy was associated with higher overall survival and R0 resection rate without increasing postoperative anastomotic leakage for patients with resectable esophageal cancer, whereas neoadjuvant therapy was associated with higher perioperative mortality after esophagectomy.

Value of reduced glomerular filtration rate assessment with cardiometabolic index: insights from a population-based Chinese cohort.

BACKGROUND: Recent studies have suggested that cardiometabolic index (CMI), a novel estimate of visceral adipose tissue, could be of use in the evaluation of cardiovascular risk factors. However, the potential utility and clinical significance of CMI in the detection of reduced estimated glomerular filtration rate (eGFR) remains uncertain. The purpose of this study was to investigate the usefulness of CMI in assessing reduced eGFR in the general Chinese population. METHODS: This cross-sectional analysis included 11,578 participants (mean age: 53.8 years, 53.7% females) from Northeast China Rural Cardiovascular Health Study (NCRCHS) of general Chinese population (data collected from January 2013 to August 2013). CMI was calculated by triglyceride to high density lipoprotein cholesterol ratio multiply waist-to-height ratio. Reduced eGFR was defined as eGFR< 60 ml/min per 1.73m2. Multivariate regressions were performed to determine CMI's association with eGFR value and eGFR reduction, ROC analyses were employed to investigate CMI's discriminating ability for decreased eGFR. RESULTS: The prevalence of reduced eGFR was 1.7% in males and 2.5% in females. CMI was notably more adverse in reduced eGFR groups, regardless of genders. In fully adjusted multivariate linear models, each 1 SD increment of CMI caused 3.150 ml/min per 1.73m2 and 2.411 ml/min per 1.73m2 loss of eGFR before CMI reached 1.210 and 1.520 in males and females, respectively. In logistic regression analyses, per 1 SD increase of CMI brought 51.6% additional risk of reduced eGFR in males while caused 1.347 times of risk in females. After divided into quartiles, people in the top quartile of CMI had higher adjusted ORs of having reduced eGFR, with ORs of 4.227 (1.681, 10.627) and 3.442 (1.685-7.031) for males and females respectively. AUC of CMI was revealed to be 0.633 (0.620-0.646) in males and 0.684 (0.672-0.695) in females. CONCLUSIONS: Higher CMI was independently associated with greater burden of reduced eGFR, highlighting VAT distribution and dysfunction as a potential mechanism underlying the association of obesity with kidney damage and adverse cardiovascular outcomes. The findings from this study provided important insights regarding the potential usefulness and clinical relevance of CMI in the detection of reduced eGFR among general Chinese population.

Impact of change in the Naples prognostic score after neoadjuvant chemoradiotherapy on survival in esophageal squamous cell carcinoma patients.

OBJECTIVES: To assess the clinical relevance and prognostic value of changes in the Naples prognostic score (NPS) after neoadjuvant chemoradiotherapy (NACR) among esophageal squamous cell carcinoma (ESCC) patients. METHODS: We studied 232 locally advanced ESCC patients who received NACR before undergoing esophagectomy retrospectively. Categorizing individuals into the elevated NPS group and the non-elevated NPS group based on the change in NPS after NACR (ΔNPS > 0 or ∆NPS ≤ 0), we examined and compared the clinicopathological characteristics, survival rates, and postoperative complications between these 2 groups (∆NPS = post-NACR NPS - pre-NACR NPS). RESULTS: Results: Out of the 232 patients enrolled, 105 exhibited elevated NPS levels, while 127 showed non-elevated NPS levels. Survival analyses indicated inferior overall survival (OS) (p=0.024) and recurrence-free survival (RFS) (p=0.047) in the elevated NPS cohort compared to the non-elevated NPS cohort. Subsequent cox regression analyses identified the post-NACR change in NPS as an independent prognostic indicator for RFS (p=0.029) and OS (p=0.036). CONCLUSION: Elevated NPS post-NACR emerged as a significant indicator of worse prognosis for locally advanced ESCC patients who underwent NACR. This finding has great potential to be useful for recognizing high-risk ESCC patients who received NACR before undergoing esophagectomy and making individualized subsequent therapeutic decisions in clinical practice.

Association between plasma circulating tumor DNA and the prognosis of esophageal cancer patients: a meta-analysis.

BACKGROUND: The application of liquid biopsy analysis utilizing circulating tumor DNA (ctDNA) has gained prominence as a biomarker in specific cancer types. Nevertheless, the correlation between ctDNA and the prognostic outcomes of patients with esophageal cancer (EC) remains a subject of controversy. This meta-analysis aims to assess the correlation between ctDNA and the prognosis of EC patients. METHODS: We systematically explored Embase, PubMed, and the Cochrane Database to identify studies reporting on the prognostic value of ctDNA in EC patients before November 2023. The primary outcome involved the determine of associations between ctDNA with overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS), as well asprogression-free survival (PFS) among EC patients. Secondary outcomes encompassed a detailed subgroup analysis in the setting of EC, including parameters such as detection time, histological subtypes, treatment modalities, regions, anatomic locations, and detection methods. Publication bias was assessed utilizing Begg's test, Egger's test, and funnel plots. A sensitivity analysis was conducted by systematically excluding individual studies to evaluate the stability of the results. RESULTS: A total of 1203 studies were initially screened, from which 13 studies underwent further analysis, encompassing 604 patients diagnosed with EC. The comprehensive pooled analysis indicated a significant association between the detection of ctDNA and poor OS (HR: 3.65; 95% CI: 1.97-6.75, P<0.001), DFS/RFS (HR: 6.08; 95% CI: 1.21-30.50, P<0.001), and PFS (HR: 2.84; 95% CI: 1.94-4.16, P<0.001). Subgroup analysis showed that ctDNA remained a consistent negative predictor of OS when stratified by different detection time, histological subtypes, regions, anatomic locations, and detection methods. Furthermore, subgroup analysis stratified by regions and study types demonstrated an association between ctDNA detection and poor PFS in EC patients. CONCLUSION: Our results indicate plasma ctDNA may serve as robust prognostic markers for OS, DFS/RFS, and PFS among EC patients. This finding suggests that plasma ctDNA could offer a highly effective approach for risk stratification and personalized medicine.

A novel tumor staging system incorporating cN status for stratifying early stage esophageal squamous cell carcinoma patients after trimodal therapy.

BACKGROUNDS: The aim of this study is to investigate the prognostic value of cN status for early stage esophageal squamous cell carcinoma (ESCC) patients after neoadjuvant chemoradiotherapy (nCRT) and construct a new staging model for individual survival prediction. METHODS: Patients with ESCC who underwent nCRT and esophagectomy were included in this study. Both the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC) were meticulously ascertained to assess the cogency of each oncological staging system. A discernible abatement in the values of AIC and BIC signifies a model endowed with enhanced predictive prowess and exemplary veracity. RESULTS: A new staging model was established based on ypTNM stage and cN status by precisely stratifying ypI ESCC patients. The novel ypTNM-cN staging demonstrated superior overall survival trend alignment over the AJCC 8th ypTNM staging, with a notably lower AIC of 3143.014 versus 3149.950. This superiority was supported by a BIC of 3146.605 against 3153.541. In the context of disease-free survival outcomes, the emergent ypTNM-cN staging, with an AIC value registering at 3196.057 and a BIC value at 3199.648, distinctively eclipsed the AJCC 8th ypTNM staging, which documented values of 3203.853 and 3207.444, respectively. CONCLUSION: We constructed a new staging system based on ypTNM stage and cN status to precisely stratify the patients with ypI stage. Our new ypTNM-cN staging system provides new insights for classifying stage ypI ESCC and shows reliable classification efficacy for all ESCC patients after nCRT and surgery.

Self-Assembled Acid-Responsive Nanosystem for Synergistic Anti-Angiogenic/Photothermal/Ferroptosis Therapy against Esophageal Cancer.

Esophageal cancer (EC) treatment via anti-angiogenic therapy faces challenges due to non-cytotoxicity and non-specific biodistribution of the anti-angiogenic agents. Hence, the quest for a synergistic treatment modality and a targeted delivery approach to effectively address EC has become imperative. In this study, an acid-responsive release nanosystem (Bev-IR820@FeIII TA) that involves the conjugation of bevacizumab, an anti-angiogenic monoclonal antibody, with TA and Fe3+ to form a metal-phenolic network, followed by loading with the near-infrared photothermal agent (IR820) to achieve combinational therapy, is designed. The construction of Bev-IR820@FeIII TA can be realized through a facile self-assembly process. The Bev-IR820@FeIII TA exhibits tumor-targeting capabilities and synergistic therapeutic effects, encompassing anti-angiogenic therapy, photothermal therapy (PTT), and ferroptosis therapy (FT). Bev-IR820@FeIII TA exhibits remarkable proficiency in delivering drugs to EC tissue through its pH-responsive release properties. Consequently, bevacizumab exerts its therapeutic effects by obstructing tumor angiogenesis, thereby impeding tumor growth. Meanwhile, PTT facilitates localized thermal ablation at the tumor site, directly eradicating EC cells. FT synergistically collaborates with PTT, giving rise to the formation of a reactive oxygen species (ROS) storm, subsequently culminating in the demise of EC cells. In summary, this amalgamated treatment modality carries substantial promise for synergistically impeding EC progression and showcases auspicious prospects for future EC treatment.

Substitute or coexistence? mediastinoscopy-assisted versus thoracoscope-assisted esophagectomy in esophageal cancer - a meta-analysis of perioperative outcomes and long-term survival.

BACKGROUND: Currently, mediastinoscopy-assisted esophagectomy (MAE) and thoracoscope-assisted esophagectomy (TAE) represent two prevalent forms of minimally invasive esophagectomy extensively employed in the management of esophageal cancer (EC). The aim of this meta-analysis is to assess and compare these two surgical approaches concerning perioperative outcomes and long-term survival, offering valuable insights for refining surgical strategies and enhancing patient outcomes in this field. METHODS: Adhering to PRISMA guidelines, we systematically searched PubMed, Web of Science, Cochrane Library, Embase, and CNKI databases until March 1, 2024, for studies comparing MAE and TAE. Outcomes of interest included perioperative outcomes (intraoperative outcomes, postoperative recovery, postoperative complications) and survival rates. Statistical analyses were performed using RevMan 5.4, with heterogeneity dictating the use of fixed or random-effects models. RESULTS: Totally 21 relevant studies were finally included. MAE was associated with significantly shorter operation times ((MD=-59.58 min, 95% CI: -82.90, -36.26) and less intraoperative blood loss (MD=-68.34 mL, 95% CI: -130.45, -6.23). However, MAE resulted in fewer lymph nodes being dissected (MD=-3.50, 95% CI: -6.23, -0.78). Postoperative recovery was enhanced following MAE, as evidenced by reduced hospital stays and tube times. MAE significantly reduced pulmonary complications (OR=0.59, 95% CI: 0.44, 0.81) but increased the incidence of recurrent laryngeal nerve injury (OR=1.84, 95% CI: 1.30, 2.60). No significant differences were observed in anastomotic leakage, chylothorax, cardiac complications, wound infections, and gastric retention between MAE and TAE. The long-term survival outcomes showed no statistical difference (HR=1.05, 95% CI: 0.71-1.54). CONCLUSIONS: MAE offers advantages in reducing operation time, blood loss, and specific postoperative complications, particularly pulmonary complications, with a shorter recovery period compared to TAE. However, it poses a higher risk of recurrent laryngeal nerve injury and results in fewer lymph nodes being dissected. No difference in long-term survival was observed, indicating that both techniques have distinct benefits and limitations. These findings underscore the need for personalized surgical approaches in EC treatment, considering individual patient characteristics and tumor specifics.

Clinical efficacy of different therapeutic strategies in patients with spontaneous rupture of the esophagus: a multicenter retrospective cohort study.

BACKGROUND: The therapeutic strategy for patients with spontaneous rupture of the esophagus includes surgical repair, endoscopic therapy, supportive care, and others. However, no evidence exists to direct clinical decision-making regarding the choice of operative and nonoperative management. The aim of this study was to determine the clinical efficacy of different therapeutic strategies in both general and stratified patients. METHODS: This study retrospectively analyzed a consecutive cohort of 101 patients at nine tertiary referral hospital centers in China. Patients were divided into operative and nonoperative groups based on the initial treatment. Short-term outcomes, including 90-day mortality, length of hospital stay, and postoperative leakage were compared. Subgroup analysis was performed based on treatment timing and Pittsburgh perforation severity score (PSS). RESULTS: Of 101 patients, 60 (58.4%) underwent operative management. A significant difference of 90-day mortality between operative and nonoperative groups was observed (15.0% vs. 34.1%, P=0.031). Operative management tend to yield similar therapeutic benefits in timely (OR, 0.250; 95% CI, 0.05-1.14, P=0.073) and delayed (OR, 0.42; 95% CI, 0.12-1.47, P=0.175) treatment groups. Based on PSS stratification, operative management significantly decreased the risk of 90-day mortality (OR, 0.211; 95% CI, 0.064-0.701; P=0.011) for patients in low- and moderate-risk groups but may be detrimental for patients in high-risk group (OR, 1.333; 95% CI, 0.233-7.626; P=0.746). CONCLUSIONS: Operative management might be superior to nonoperative management for low- and moderate-risk patients with spontaneous rupture of the esophagus. However, for patients at high risks, operative management might not provide additional benefits compared with nonoperative management. Further research involving larger sample sizes is required for accurate patient stratification and conclusive evidence-based guideline.

Unraveling the Complexity of Regulated Cell Death in Esophageal Cancer: from Underlying Mechanisms to Targeted Therapeutics.

Esophageal cancer (EC) is the sixth most common and the seventh most deadly malignancy of the digestive tract, representing a major global health challenge. Despite the availability of multimodal therapeutic strategies, the existing EC treatments continue to yield unsatisfactory results due to their limited efficacy and severe side effects. Recently, knowledge of the subroutines and molecular mechanisms of regulated cell death (RCD) has progressed rapidly, enhancing the understanding of key pathways related to the occurrence, progression, and treatment of many types of tumors, including EC. In this context, the use of small-molecule compounds to target such RCD subroutines has emerged as a promising therapeutic strategy for patients with EC. Thus, in this review, we firstly discussed the risk factors and prevention of EC. We then outlined the established treatment regimens for patients with EC. Furthermore, we not only briefly summarized the mechanisms of five best studied subroutines of RCD related to EC, including apoptosis, ferroptosis, pyroptosis, necroptosis and autophagy, but also outlined the recent advances in the development of small-molecule compounds and long non-coding RNA (lncRNA) targeting the abovementioned RCD subroutines, which may serve as a new therapeutic strategy for patients with EC in the future.

The prognostic value of sarcopenia in oesophageal cancer: A systematic review and meta-analysis.

The loss of skeletal muscle mass and function is defined as sarcopenia, which might develop in elderly patients with cancers. It has been indicated as a potential negative factor in the survival of patients with malignant tumours. The aim of this systematic review and meta-analysis was to evaluate the associations between sarcopenia and survival outcomes or postoperative complications in patients with oesophageal cancer (EC). Web of Science, Embase, Medline, and Cochrane Library databases were searched until 10 May 2022, using keywords: sarcopenia, oesophageal cancer, and prognosis. Studies investigating the prognostic value of sarcopenia on EC survival were included. Forest plots and summary effect models were used to show the result of this meta-analysis. The quality of included studies was evaluated with the Newcastle-Ottawa Scale (NOS). A total of 1436 studies were identified from the initial search of four databases, and 41 studies were included for the final quantitative analysis. This meta-analysis revealed a significant association between sarcopenia and overall survival (OS) [hazard ratios (HR):1.68, 95% confidence interval (CI):1.54-1.83, P = 0.004, I2  = 41.7%] or disease-free survival (DFS) 1.97 (HR: 1.97, 95% CI: 1.44-2.69, P = 0.007, I2  = 61.9%) of EC patients. Subgroup analysis showed that sarcopenia remained a consistent negative predictor of survival when stratified by different treatment methods, populations, or sarcopenia measurements. Sarcopenia was also a risk factor for postoperative complications with a pooled odds ratio of 1.47 (95% CI: 1.21-1.77, P = 0.094, I2  = 32.7%). The NOS scores of all included studies were ≥6, and the quality of the evidence was relatively high. The results from the study suggested that sarcopenia was significantly associated with both survival outcomes and postoperative complications in EC patients. Sarcopenia should be appropriately diagnosed and treated for improving short-term and long-term outcomes of patients with EC.

Lymphovascular and Perineural Invasion After Neoadjuvant Therapy in Esophageal Squamous Carcinoma.

BACKGROUND: Lymphovascular invasion and perineural invasion are unfavorable prognostic factors in patients with esophageal squamous cell carcinoma. However, the prevalence and prognostic importance of lymphovascular invasion and perineural invasion after neoadjuvant chemoradiotherapy in these patients remains unclear. METHODS: We retrospectively reviewed specimens of 321 patients with pathologically diagnosed esophageal squamous cell carcinoma who underwent neoadjuvant chemoradiotherapy in our institution from 2017 to 2020. Lymphovascular invasion and perineural invasion were assessed by hematoxylin and eosin staining. Survival was analyzed using the log-rank test and multivariable Cox regression analysis. RESULTS: Lymphovascular invasion and perineural invasion were present in 12.5% (n = 40) and 17.8% (n = 57) of resection specimens, respectively. Lymphovascular invasion and perineural invasion were significantly more common in patients with advanced cancer (both P < .05). In the univariate analyses, lymphovascular invasion and perineural invasion were associated with shorter overall survival and disease-free survival. Multivariable analysis revealed that lymphovascular invasion after neoadjuvant therapy was an independent adverse prognostic factor for overall survival and disease-free survival. Subgroup analyses showed that lymphovascular invasion could identify cases with worse overall survival or disease-free survival among node-negative patients, indicating the role of lymphovascular invasion in the precise staging of pN0 patients. CONCLUSIONS: Lymphovascular invasion and perineural invasion were significantly negatively correlated with overall survival and disease-free survival. Lymphovascular invasion was an independent prognostic predictor in esophageal squamous cell carcinoma patients after neoadjuvant chemoradiotherapy. Lymphovascular invasion and perineural invasion should be considered in the histopathology workup for esophageal squamous cell carcinoma patients after neoadjuvant chemoradiotherapy.

DASES: a database of alternative splicing for esophageal squamous cell carcinoma.

Esophageal carcinoma ranks as the sixth leading cause of cancer-related mortality globally, with esophageal squamous cell carcinoma (ESCC) being particularly prevalent among Asian populations. Alternative splicing (AS) plays a pivotal role in ESCC development and progression by generating diverse transcript isoforms. However, the current landscape lacks a specialized database focusing on alternative splicing events (ASEs) derived from a large number of ESCC cases. Additionally, most existing AS databases overlook the contribution of long non-coding RNAs (lncRNAs) in ESCC molecular mechanisms, predominantly focusing on mRNA-based ASE identification. To address these limitations, we deployed DASES (http://www.hxdsjzx.cn/DASES). Employing a combination of publicly available and in-house ESCC RNA-seq datasets, our extensive analysis of 346 samples, with 93% being paired tumor and adjacent non-tumor tissues, led to the identification of 257 novel lncRNAs in esophageal squamous cell carcinoma. Leveraging a paired comparison of tumor and adjacent normal tissues, DASES identified 59,094 ASEs that may be associated with ESCC. DASES fills a critical gap by providing comprehensive insights into ASEs in ESCC, encompassing lncRNAs and mRNA, thus facilitating a deeper understanding of ESCC molecular mechanisms and serving as a valuable resource for ESCC research communities.