DDX18 Facilitates the Tumorigenesis of Lung Adenocarcinoma by Promoting Cell Cycle Progression through the Upregulation of CDK4.

Lung adenocarcinoma (LUAD) is the most prevalent and aggressive subtype of lung cancer, exhibiting a dismal prognosis with a five-year survival rate below 5%. DEAD-box RNA helicase 18 (DDX18, gene symbol DDX18), a crucial regulator of RNA metabolism, has been implicated in various cellular processes, including cell cycle control and tumorigenesis. However, its role in LUAD pathogenesis remains elusive. This study demonstrates the significant upregulation of DDX18 in LUAD tissues and its association with poor patient survival (from public databases). Functional in vivo and in vitro assays revealed that DDX18 knockdown potently suppresses LUAD progression. RNA sequencing and chromatin immunoprecipitation experiments identified cyclin-dependent kinase 4 (CDK4), a cell cycle regulator, as a direct transcriptional target of DDX18. Notably, DDX18 depletion induced G1 cell cycle arrest, while its overexpression promoted cell cycle progression even in normal lung cells. Interestingly, while the oncogenic protein c-Myc bound to the DDX18 promoter, it did not influence its expression. Collectively, these findings establish DDX18 as a potential oncogene in LUAD, functioning through the CDK4-mediated cell cycle pathway. DDX18 may represent a promising therapeutic target for LUAD intervention.

RNA modification-related genes illuminate prognostic signature and mechanism in esophageal squamous cell carcinoma.

Emerging studies have demonstrated the link between RNA modifications and various cancers, while the predictive value and functional mechanisms of RNA modification-related genes (RMGs) in esophageal squamous cell carcinoma (ESCC) remain unclear. Here we established a prognostic signature for ESCC based on five RMGs. The analysis of ESCC clinical samples further verified the prognostic power of the prognostic signature. Moreover, we found that the knockdown of NSUN6 promotes ESCC progression in vitro and in vivo, whereas the overexpression of NSUN6 inhibits the malignant phenotype of ESCC cells. Mechanically, NSUN6 mediated tRNA m5C modifications selectively enhance the translation efficiency of CDH1 mRNA in a codon dependent manner. Rescue assays revealed that E-cadherin is an essential downstream target that mediates NSUN6's function in the regulation of ESCC progression. These findings offer additional insights into the link between ESCC and RMGs, as well as provide potential strategies for ESCC management and therapy.

NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and gefitinib resistance in cancer.

Aberrant RNA modifications are frequently associated with cancers, while the underlying mechanisms and clinical significance remain poorly understood. Here, we find that the ac4C RNA acetyltransferase NAT10 is significantly upregulated in esophageal cancers (ESCAs) and associated with poor ESCA prognosis. In addition, using ESCA cell lines and mouse models, we confirm the critical functions of NAT10 in promoting ESCA tumorigenesis and progression in vitro and in vivo. Mechanistically, NAT10 depletion reduces the abundance of ac4C-modified tRNAs and decreases the translation efficiencies of mRNAs enriched for ac4C-modified tRNA-decoded codons. We further identify EGFR as a key downstream target that facilitates NAT10's oncogenic functions. In terms of clinical significance, we demonstrate that NAT10 depletion and gefitinib treatment synergistically inhibit ESCA progression in vitro and in vivo. Our data indicate the mechanisms underlying ESCA progression at the layer of mRNA translation control and provide molecular insights for the development of effective cancer therapeutic strategies.

Intratumoral microbiome impacts immune infiltrates in tumor microenvironment and predicts prognosis in esophageal squamous cell carcinoma patients.

Background: Different intratumoral microbiotaexist in different tumors and play a crucial function in carcinogenesis. However, whether they impact clinical outcomes in esophageal squamous cell carcinoma (ESCC) and their mechanism remain unclear. Methods: 16S rDNA amplicon sequencing was performed on surgically resected samples from 98 ESCC patients to analyze intratumoral microbiome abundance and composition. Multiplex fluorescent immunohistochemistry staining was used to profile the phenotypes of immune infiltrates in the tumor microenvironment (TME). Results: Patients with higher intratumoral Shannon index had significantly worse surgical outcomes. When patients were divided into short-term survivors and long-term survivors based on the median survival time, both intratumoral alpha-diversity and beta-diversity were found to be significantly inconsistent, and the relative abundance of Lactobacillus and Leptotrichia emerged as the two microorganisms that probably influenced the survival of ESCC patients. Only Lactobacillus in ESCC was validated to significantly worsen patients' prognoses and to be positively correlated with the Shannon index. Multivariate analysis revealed that the intratumoral Shannon index, the relative abundance of Lactobacillus, and the pathologic tumor-node-metastasis (pTNM) stage were independently associated with patients' overall survival. Furthermore, the relative abundance of both Lactobacillus and Shannon index was positively correlated with the proportions of PD-L1+ epithelial cells (ECs) and tumor-associated macrophages (TAMs). The Shannon index was negatively correlated with the proportions of natural killer (NK) cells in the TME. Conclusions: A high abundance of intratumoral Lactobacillus and bacterial alpha-diversity was associated with the formation of the immunosuppressive TME and predicted poor long-term survival in ESCC patients.

Efficiency of ectopic thymectomy by three surgical approaches in non-thymomatous myasthenia gravis.

BACKGROUND: To explore the efficiency of ectopic thymectomy by the three surgical approaches of trans-sternum, right unilateral thoracoscopy and thoracoscopic subxiphoid in patients with non-thymomatous myasthenia gravis. METHODS: 155 consecutive non-thymomatous myasthenia gravis patients who underwent extended thymectomy by 3 approaches including trans-sternum, right unilateral thoracoscopy and thoracoscopic subxiphoid in 1st affiliated hospital of Sun Yat-Sen University from January 2017 to October 2019 were reviewed. Differences of perioperative clinical characteristics in three surgical approaches were analyzed. RESULTS: Time to onset of myasthenia gravis (early or late) (p = 0.018), blood loss (p < 0.001), duration of operation (p = 0.031), duration and volume of thoracic drainage (p = 0.039 and p = 0.026), length of hospitalization (p = 0.039), the efficiency of ectopic thymectomy (p = 0.037), and the detection rate of ectopic thymus in the second quadrant (p = 0.018) were different among the three surgical approaches. In univariate logistic regression analysis, higher efficiency of ectopic thymectomy were associated with transsternal (OR 2.36, 95% CI 1.32-4.22, p = 0.011) and thoracoscopic subxiphoid approaches (OR 2.07, 95% CI 1.12-3.82, p = 0.033). In the multiple logistic regression analysis, the transsternal approach (OR 2.02, 95% CI 1.10-3.71, p = 0.024) was an independent protective factor for the efficiency of ectopic thymectomy. CONCLUSIONS: Both the right unilateral thoracoscopic and thoracoscopic subxiphoid approaches have advantages over the transsternal approach in short-term postoperative recovery. Transsternal approach is still the best choice for ectopic thymectomy while thoracoscopic subxiphoid approach show the potential as an alternative way.

The role of 18F-FDG PET/CT in predicting the pathological response to neoadjuvant PD-1 blockade in combination with chemotherapy for resectable esophageal squamous cell carcinoma.

PURPOSE: Accurate assessment of residual disease of tumor and lymph nodes after neoadjuvant immunochemotherapy is crucial in the active surveillance for patients with pathological complete response (pCR) and the optimal extent of lymphadenectomy for patients with non-pCR. This post hoc analysis aimed to evaluate the performance of 18F-FDG PET/CT to predict the pathological response to neoadjuvant immunochemotherapy for esophageal squamous cell carcinoma (ESCC). METHODS: Fifty-eight resectable ESCC patients received two cycles of camrelizumab in combination with chemotherapy and were enrolled in the final analysis. The 18F-FDG PET/CT scans were acquired at baseline (scan-1) and after immunochemotherapy but prior to surgery (scan-2). Maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), tumor-to-blood pool SUVmax ratio (SUVTBR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated for their association with the pathological response to immunochemotherapy. RESULTS: Nineteen patients (32.8%, 19/58) had pCR and thirty-nine patients (67.2%, 39/58) had non-pCR after two doses of camrelizumab and chemotherapy. At scan-2, the SUVmax, SUVmean, SUVTBR, TLG, and MTV were significantly lower in pCR than in non-pCR patients. Decrease in TLG and MTV between scan-2 and scan-1 of the same patient was significantly higher in the pCR than in the non-pCR group. In the receiver operating characteristic curve analysis, SUVmax, SUVmean, SUVTBR, TLG, and MTV in scan-2 showed excellent predictive value for the pCR of primary tumors. Furthermore, SUVmax in scan-2 were higher in positive lymph nodes than in negative ones, suggesting a high negative predictive ability (98.6%) with a cut-off value at 1.4. CONCLUSION: The parameters of 18F-FDG PET/CT have the excellent performance for predicting pCR after the combined neoadjuvant immunochemotherapy in resectable ESCC. TRIAL REGISTRATION: ChiCTR2000028900. Registered on January 6, 2020.

N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis.

Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.

Clinical significance and outcomes of bilateral and unilateral recurrent laryngeal nerve lymph node dissection in esophageal squamous cell carcinoma: A large-scale retrospective cohort study.

BACKGROUND: The survival benefits of recurrent laryngeal nerve lymph node dissection (RLNLD) in esophageal squamous cell carcinoma (ESCC) are still under debate, and the prognostic value of unilateral RLNLD has been rarely studied. Therefore, the aim of the present study was to investigate the clinical significance and outcomes of RLNLD in ESCC in a large-scale cohort study, to shed light on the outcomes of unilateral RLNLD, and to identify the factors that affect the prognostic outcome of RLNLD. METHODS: We retrospectively reviewed 1153 patients with thoracic ESCC who underwent right thoracotomy with lymphadenectomy. The impact of RLNLD on disease-free survival (DFS) and overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional hazard models. Inverse probability of treatment weighting (IPTW) was performed to adjust for differences in baseline variables in pairwise comparisons. Subgroup analysis of survival and postoperative complications was conducted for selective RLNLD. RESULTS: RLN lymph node (LN) metastasis was independently associated with tumor location and most other LN station metastases. RLNLD was an independent prognostic factor for DFS and OS. Both patients who underwent unilateral and bilateral RLNLD had significantly better DFS and OS than the non-RLNLD patients. Furthermore, pairwise comparisons with IPTW confirmed these results, and we found that patients who underwent bilateral RLNLD had better survival than those who underwent unilateral RLNLD. However, subgroup analysis showed that there was no survival benefit and higher morbidity after bilateral RLNLD for patients with cancer in the lower thoracic esophagus, and elderly and female patients. CONCLUSION: RLN LN metastasis is very frequent in ESCC, and both unilateral and bilateral RLNLD have considerable survival benefits. Selective RLNLD with better survival and lower morbidity was recommend for some defined subgroups.

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

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

METTL3-mediated m6A mRNA modification promotes esophageal cancer initiation and progression via Notch signaling pathway.

Esophageal cancer is a lethal malignancy with a high mortality rate, while the molecular mechanisms underlying esophageal cancer pathogenesis are still poorly understood. Here, we found that the N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) is significantly upregulated in esophageal squamous cell carcinoma (ESCC) and associated with poor patient prognosis. Depletion of METTL3 results in decreased ESCC growth and progression in vitro and in vivo. We further established ESCC initiation and progression models using Mettl3 conditional knockout mouse and revealed that 3METTL3-mediated m6A modification promotes ESCC initiation and progression in vivo. Moreover, using METTL3 overexpression ESCC cell model and Mettl3 conditional knockin mouse model, we demonstrated the critical function of METTL3 in promoting ESCC tumorigenesis in vitro and in vivo. Mechanistically, METTL3-catalyzed m6A modification promotes NOTCH1 expression and the activation of the Notch signaling pathway. Forced activation of Notch signaling pathway successfully rescues the growth, migration, and invasion capacities of METTL3-depleted ESCC cells. Our data uncovered important mechanistical insights underlying ESCC tumorigenesis and provided molecular basis for the development of novel strategies for ESCC diagnosis and treatment.

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

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

Phenotypic profiling and prognostic significance of immune infiltrates in esophageal squamous cell carcinoma.

The tumor microenvironment (TME) of esophageal squamous cell carcinoma (ESCC) impacts tumor progression but is poorly understood. We obtained tumor tissues from 279 patients after esophagectomy and characterized the TME in intraepithelial and stromal regions using multiplex fluorescent immunohistochemistry (mfIHC). A heterogeneous immune population infiltrating tumor and the uninvolved esophageal tissue were observed. The infiltration of intraepithelial programmed death ligand 1 (PD-L1)-positive tumor-associated macrophages (TAMs) and stromal granzyme B+ activated cytotoxic T cells (aCTLs) correlated with both prolonged overall survival (OS) and disease-free survival (DFS). The intraepithelial memory T cell infiltration predicted longer OS, while intraepithelial and stromal regulatory T cell (Treg) infiltration was associated with shortened OS and DFS, respectively. Multivariate models combining immune infiltrates and clinicopathological factors outperformed tumor-node-metastasis (TNM) stage in predicting OS and DFS at 3 and 5 years. The infiltration of Treg inversely correlated with that of the antitumor effectors including CTLs, aCTLs, and natural killer (NK) cells. Intraepithelial memory T cell infiltration also negatively correlated with PD-L1 expression. In spatial analysis, intraepithelial dendritic cell (DC)-memory T cell engagement increased in high PD-L1+ TAM infiltration group. The characterization of the TME revealed a complex interplay between immune populations and may be employed to stratify patient for prognosis prediction and immunotherapy.

A Novel Diagnosis Method Based on Methylation Analysis of SHOX2 and Serum Biomarker for Early Stage Lung Cancer.

OBJECTIVES: Lung cancer (LC) is often accompanied by significant methylation abnormalities. This study aimed to develop a decision tree (DT) accompanied the stature homeobox 2 gene (SHOX2) / prostaglandin E receptor 4 (PTGER4) gene DNA methylation with traditional tumor marker in the differential diagnosis of benign and malignant lung nodule. METHODS: We performed a study with 104 patients enrolled in the LC group and 36 patients in the benign lung diseases group. All the clinical data of these patients were collected through electronic medical record. Total Methylation (TM) status of both SHOX2 and PTGER4 was defined as methylation levels of SHOX2 plus methylation levels of PTGER4. One-way analysis was used to compare the concentrations of serum samples and t-test was used to compare pairwise mean values between groups. Receiver operating curve (ROC) was used to evaluate the diagnostic value. Furthermore, the strategy was validated in 19 LC patients and 11 patients with benign lung diseases. RESULTS: There were significant differences between the concentration of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA21 -1) and the methylation levels of SHOX2, PTGER4 and TM in lung benign diseases and cancer group. The AUCs of NSE, CEA, CYFRA21 -1, Methylation SHOX2, Methylation PTGER4 and TM were 0.721 (95% CI: 0.627-0.816), 0.753 (95% CI: 0.673-0.833) and 0.778(95% CI: 0.700-0.856), 0.851(0.786-0.916), 0.847(0.780-0.913) and 0.861(0.800-0.922) respectively. We developed a DT model with TM and CYFRA21 -1 used in this study, and the area under the curve (AUC) of DT was 0.921 and the sensitivity up to 0.856. In the validation cohort, the AUC of SHOX2, PTGER4 and TM was also much higher than traditional serum markers. CONCLUSIONS: Our results indicated that the DT model calculated from the TM and CYFRA21 -1 can accurately classify LC and benign diseases, which showed better diagnostic performance than traditional serum parameter.

Perioperative risk factors for occurrence of myasthenia gravis after thymectomy in patients with thymoma.

OBJECTIVES: The goal of this study was to identify the relationship between clinical characteristics and the occurrence of postoperative myasthenia gravis (PMG) in patients with thymomas and to further identify the relationship between PMG and prognosis. METHODS: Thymoma patients who had surgery at the First Affiliated Hospital of Sun Yat-sen University between July 2004 and July 2016 were reviewed and those who had no previous symptoms of myasthenia gravis were selected for further investigation. In total, 229 patients were included in the study; their clinical characteristics were gathered and analysed. RESULTS: Among the 229 patients, 19 (8.3%) had PMG. The time between the operation and the onset of myasthenia gravis was 134 days on average (range 2-730 days). Patients experiencing PMG showed a lower rate of complete thymoma resection (73.7% vs 91.4%; P = 0.014) and total thymectomy (63.2% vs 82.9%; P = 0.035) compared with those who did not. Univariable and multivariable logistic regression revealed that thymomectomy [odds ratio (OR) 2.81, 95% confidence interval (CI) 1.02-7.77; P = 0.047] and incomplete tumour resection (OR 3.79, 95% CI 1.20-11.98; P = 0.023) were associated with the occurrence of PMG. Multivariable Cox regression showed that the PMG was not related to overall survival (P = 0.087). CONCLUSIONS: This study revealed that incomplete tumour resection and thymomectomy were independent risk factors for PMG in thymoma patients with no previous history of myasthenia gravis.

Prophylactic thoracic duct ligation is associated with poor prognosis and regional lymph node relapse in esophageal squamous cell carcinoma.

OBJECTIVES: The ligation of thoracic duct interrupts the normal lymphatic circulation. Whether the ligation of thoracic duct would affect tumor recurrence and patient survival is unclear. METHODS: The correlations between prophylactic thoracic duct ligation (PLG) and prognosis were examined in patients with esophageal squamous cell carcinoma. Patients who received Ivor Lewis or McKeown esophagectomy with systemic lymph node dissection and R0 resection between 2003 and 2013 in Sun Yat-sen University Cancer Center were included in the study. RESULTS: A total number of 473 and 462 were included in the PLG group and non-prophylactic thoracic duct ligation (NPLG) group, respectively. The PLG group had a lower 5-year survival rate (48.2% vs 61.6%, P < .001). After a 1:1 propensity score matching, 874 cases (437 pairs) were included and the survival analysis showed that PLG was associated with worse 5-year cumulative survival of 48.6% vs 61.6% in those patients without ligation (P < .001). The multivariate analysis revealed that PLG was an independent factor for poor prognosis after esophagectomy (hazard ratio, HR = 1.56; 95% confidence interval, 95% CI, 1.26-1.93, P < .001). Additionally, PLG was associated with regional lymph node relapse (P = .015). CONCLUSIONS: PLG should not be performed routinely if no sign of thoracic duct rupture or tumor invasion were identified.

Preoperative weight loss is associated with poorer prognosis in operable esophageal cancer patients: A single-center retrospective analysis of a large cohort of Chinese patients.

Background: Preoperative weight loss has been shown to be a prognostic factor for many cancers. However, whether preoperative weight loss has clinical significance in patients with esophageal cancer is still controversial. Methods: A total of 2,174 Chinese patients underwent radical resection of esophageal cancer from 2000 to 2008 were included in our study. Patients were divided into two group: no weight loss (-) and weight loss (+), according to whether they had weight loss compared with their usual weight at diagnosis. The influence of preoperative weight loss on disease-free survival (DFS) and overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional hazard models. Results: weight loss (+) was significantly associated with age (P=0.001), alcoholism (P<0.001), tumor location (P=0.003), pT category (P=0.003), pN category (P=0.001). Patients of group weight loss (+) had significantly poorer DFS (Mean: 63.3 months (m) vs 76.8 m, P<0.001) and OS (67.4 m vs 83.3 m, P<0.001) than the no weight loss (-) group. In the final multivariate survival analysis with adjustment for covariates, we found that the weight loss (+) group had a 19% higher risk of death (HR=1.19, 95%CI: 1.07-1.33, P=0.002) and had a 13% higher risk of disease progression (HR=1.13, 95%CI: 1.01-1.25, P=0.027), respectively, than the no weight loss (-) group. Subgroup analysis indicated that the association with preoperative weight loss and better DFS or OS was observed in patients with esophageal squamous cell carcinoma (ESCC) and early pathological stage (I-II). Conclusion: Preoperative weight loss is associated with shorter OS and DFS, which means poor postoperative prognosis in esophageal cancer patients.

Prognostic Role of ABO Blood Type in Operable Esophageal Cancer: Analysis of 2179 Southern Chinese Patients.

BACKGROUND: The prognostic value of ABO blood types is not well clarified for esophageal carcinoma (EC). This study attempted to elucidate the associations between different ABO blood types and disease-free survival (DFS) and overall survival (OS) of EC. METHODS: This study was a retrospective review of the records of 2179 patients with EC who received surgery from December 2000 to December 2008. The prognostic impact of ABO blood group on DFS and OS were estimated using the Kaplan-Meier method and cox proportional hazard models. RESULTS: Univariate analyses found significant differences in DFS and OS among the four blood types. Multivariate analyses showed ABO blood type independently predicted DFS (P=0.001) and OS (P=0.002). Furthermore, patients with non-B blood types had a significantly shorter DFS (HR=1.22, 95%CI:1.07-1.38, P=0.002) and OS (HR=1.22, 95%CI:1.07-1.38, P=0.003) than patients with blood type B, and patients with non-O blood types had a significantly better DFS (HR=0.86, 95%CI:0.77-0.96, P=0.006) and OS (HR=0.86, 95%CI:0.77-0.96, P=0.007) than patients with blood type O. Subgroup analyses found that blood type B had a better DFS and OS than non-B in patients who were male, younger, early pathological stages and had squamous-cell carcinomas (ESCC). Blood type O had a worse DFS and OS than non-O in patients who were male, younger, and had ESCC (P<0.05). CONCLUSIONS: The results demonstrate that ABO blood group is an independent prognostic factor of survival, and that type B predicts a favorable prognosis, whereas type O predicts an unfavorable prognosis for survival in patients with EC, especially those with ESCC.

Hepatitis B Virus Infection is a Prognostic Biomarker for Better Survival in Operable Esophageal Cancer: Analysis of 2,004 Patients from an Endemic Area in China.

BACKGROUND: Hepatitis B Virus (HBV) infection has been proven to be associated with the survival of many cancers. However, the prevalence and prognostic value of HBV infection in esophageal cancer has not been investigated yet. METHODS: A total of 2,004 consecutive esophageal cancer patients who underwent esophagectomy between 2000 and 2008 were recruited in our study. ELISA was used to test serum HBV markers. Patients were divided into HBsAg-positive group (HBV infection) and HBsAg-negative group. The impact of HBV infection on disease-free survival (DFS) and overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: HBV infection was found in 12.6% (253/2,004) of patients. HBsAg-positive patients had significantly higher percentage of early pathologic T stage, lower frequency of liver metastasis, and extrahepatic metastasis than HBsAg-negative. HBsAg-positive patients had a favorable DFS [HR = 0.79; 95% confidence interval (CI): 0.66-0.94, P = 0.007) and OS (HR = 0.80; 95% CI: 0.65-0.95, P = 0.020] respectively, when compared with HBsAg-negative patients. Subgroup analysis showed that the association with HBV infection and better DFS and OS was observed in patients with esophageal squamous cell carcinoma and advanced pathologic stage (III-IV).Conclusion: HBV infection was an independent favorable prognostic factor for survival in operable esophageal cancer. IMPACT: Our large cohort study provided more definite and quantitative evidence that HBV infection is an independent favorable prognostic biomarker in patients with esophageal cancer, especially in patients with esophageal squamous cell carcinoma and advanced pathologic stage (III-IV).

Histone deacetylase 6 expression in metastatic lymph nodes is a valuable prognostic marker for resected node-positive esophageal squamous cell cancer.

BACKGROUND: Histone deacetylase 6 (HDAC6) exerts enzymatic deacetylation activity on histones and on non-histone substrates and plays a key role in microtubule dynamics and chaperone activities. In addition, previous studies have demonstrated its role in cancer progression. However, its clinical significance in esophageal squamous cell cancer (ESCC) has not been elucidated. We investigated the correlation of HDAC6 expression and clinical outcome in a group of T3N1-3M0 surgically resected ESCCs. METHODS: Tissue microarrays were conducted on 209 surgically resected T3N1-3M0 ESCC tumors, including 163 pairs of primary tumors (PTs) and their corresponding metastatic lymph nodes (MLNs). Immunohistochemistry was utilized to evaluate HDAC6 protein levels. The relationship between patient outcomes and HDAC6 expression was analyzed statistically. RESULTS: The level of HDAC6 expression in ESCC MLNs was found to be significantly lower than that in PTs (P<0.001). Patients with lower MLN HDAC6 expression demonstrated improved overall survival (P=0.011) and disease-free survival (P=0.012) than those with higher HDAC6 expression. HDAC6 expression levels in PTs revealed no prognostic significance. Multivariate analysis showed that the MLN HDAC6 expression level was an independent prognostic factor for both overall survival (HR 1.456, P=0.029) and disease-free survival (HR 1.432, P=0.033). CONCLUSION: High expression of HDAC6 in MLNs but not in PTs suggests a poor prognosis for patients with resected T3N1-3M0 ESCC. We should take into account the protein expression of MLNs when assessing prognosis in patients with lymph-node involvement.

miR-424 coordinates multilayered regulation of cell cycle progression to promote esophageal squamous cell carcinoma cell proliferation.

BACKGROUND: Dysregulation of the cell cycle has been implicated in esophageal squamous cell carcinoma (ESCC) progression. This study aimed to evaluate the role of miR-424 in cell cycle regulation and ESCC proliferation. METHODS: The role of miR-424 in cell proliferation was evaluated in vitro and in vivo. Transcriptional activation of miR-424 was determined using chromatin immunoprecipitation, and binding of miR-424 to targets was verified using miRNA ribonucleoprotein complex immunoprecipitation. FINDINGS: miR-424 was upregulated and correlated with poor survival in ESCC patients. Repression or overexpression of miR-424 respectively decreased or increased ESCC cell proliferation in vitro and in vivo. miR-424 expression is transcriptionally regulated by E2F1 and increased during G1/S transition. Knockdown or overexpression of miR-424 respectively inhibited or promoted both G1/S and G2/M cell cycle transitions in ESCC cells, and these effects were mediated by two newly identified miR-424 targets, PRKCD and WEE1, respectively. Consequently, elevation of PRKCD by miR-424 knockdown led to enhanced stability of the p21Cip1 protein via increased activation of PRKCD and downstream p38 MAPK and JNK signaling to block CDK2 activation and G1/S transition, while elevated WEE1 maintained CDC2 in an inactive state to block G2/M transition. However, circLARP4 could sponge the binding of miR-424 to PRKCD, thus compromising the regulation of G1/S progression by miR-424. INTERPRETATION: miR-424 coordinates a previously unknown, multilayered regulation of ESCC cell cycle progression to promote ESCC proliferation, and may be used as a novel prognostic marker and an effective therapeutic target for ESCCs. FUND: National Natural Science Foundation of China.