Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer:A systematic review and meta-analysis

BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overex-pressed in many cancers.The prognostic significance of HSPs and their regulatory factors,such as heat shock factor 1(HSF1)and CHIP,are poorly understood.AIM To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer.METHODS A systematic review was conducted in accordance with PRISMA recommend-ations(PROSPERO:CRD42022370653),on Embase,PubMed,Cochrane,and LILACS.Cohort,case-control,and cross-sectional studies of patients with eso-phagus or esophagogastric cancer were included.HSP-positive patients were compared with HSP-negative,and the endpoints analyzed were lymph node metastasis,tumor depth,distant metastasis,and overall survival(OS).HSPs were stratified according to the HSP family,and the summary risk difference(RD)was calculated using a random-effect model.RESULTS The final selection comprised 27 studies,including esophageal squamous cell carcinoma(21),esophagogastric adenocarcinoma(5),and mixed neoplasms(1).The pooled sample size was 3465 patients.HSP40 and 60 were associated with a higher 3-year OS[HSP40:RD=0.22;95%confidence interval(CI):0.09-0.35;HSP60:RD=0.33;95%CI:0.17-0.50],while HSF1 was associated with a poor 3-year OS(RD=-0.22;95%CI:-0.32 to-0.12).The other HSP families were not associated with long-term survival.HSF1 was associated with a higher probability of lymph node metastasis(RD=-0.16;95%CI:-0.29 to-0.04).HSP40 was associated with a lower probability of lymph node dissemination(RD=0.18;95%CI:0.03-0.33).The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis.CONCLUSION The expression levels of certain families of HSP,such as HSP40 and 60 and HSF1,are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.

Sporadic gastrinoma with refractory benign esophageal stricture:A case report

BACKGROUND Gastrinoma is characterized by an excessive release of gastrin,leading to hypersecretion of gastric acid,subsequently resulting in recurrent peptic ulcers,chronic diarrhea,and even esophageal strictures.This case report aims to improve awareness and facilitate early diagnosis and treatment of gastrinoma by presenting a rare case of gastrinoma with refractory benign esophageal stricture(RBES).Additionally,it highlights the persistent challenges that gastroenterologists encounter in managing RBES.CASE SUMMARY This case demonstrates a patient with gastrinoma who developed RBES and complete esophageal obstruction despite management with maximal acid suppressive therapy,multiple endoscopic bougie dilations and endoscopic incisional therapy(EIT).CONCLUSION It is essential to diagnose gastrinoma as early as possible,as inadequately controlled acid secretion over an extended period increases the risk of developing severe esophageal strictures.In patients with esophageal strictures causing complete luminal obstruction,blind reopening EIT presents challenges and carries a high risk of perforation.

Endoscopic submucosal dissection for superficial esophageal neoplasms

Endoscopic submucosal dissection(ESD) is currently accepted as the major treatment modality for superficial neoplasms in the gastrointestinal tract including the esophagus.An important advantage of ESD is its effectiveness in resecting lesions regardless of their size and severity of fibrosis.Based on excellent outcomes for esophageal neoplasms with a small likelihood of lymph node metastasis,the number of ESD candidates has increased.On the other hand,ESD still requires highly skilled endoscopists due to technical difficulties.To avoid unnecessary complications including perforation and postoperative stricture,the indications for ESD require careful consideration and a full understanding of this modality.This article,in the highlight topic series,provides detailed information on the indication,procedure,outcome,complications and their prevention in ESD of superficial esophageal neoplasms.

Endoscopic submucosal tunnel dissection for largesuperficial esophageal squamous cell neoplasms

Endoscopic submucosal dissection(ESD)is a wellestablished treatment for superficial esophageal squamous cell neoplasms(SESCNs)with no risk of lymphatic metastasis.However,for large SESCNs,especially when exceeding two-thirds of the esophageal circumference,conventional ESD is time-consuming and has an increased risk of adverse events.Based on the submucosal tunnel conception,endoscopic submucosal tunnel dissection(ESTD)was first introduced by us to remove large SESCNs,with excellent results.Studies from different centers also reported favorable results.Compared with conventional ESD,ESTD has a more rapid dissection speed and R0 resection rate.Currently in China,ESTD for large SESCNs is an important part of the digestive endoscopic tunnel technique,as is peroral endoscopic myotomy for achalasia and submucosal tunnel endoscopic resection for submucosal tumors of the muscularis propria.However,not all patients with SESCNs are candidates for ESTD,and postoperative esophageal strictures should also be taken into consideration,especially for lesions with a circumference greater than three-quarters.In this article,we describe our experience,review the literature of ESTD,and provide detailed information on indications,standard procedures,outcomes,and complications of ESTD.

Short term results of endoscopic submucosal dissection in superficial esophageal squamous cell neoplasms

AIM: To evaluate the efficacy of endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms. METHODS: Between July 2007 and March 2009, 27 consecutive superficial esophageal squamous cell neoplasms in 25 enrolled patients were treated by endoscopic submucosal dissection. The therapeutic efficacy, complications, and follow-up results were assessed. RESULTS: The mean size of the lesions was 21 ± 13 mm (range 2-55 mm); the mean size of the resection specimens was 32 ± 12 mm (range 10-70 mm). The enblock resection rate was 100% (27/27), and en block resection with tumor-free lateral/basal margins was 88.9% (24/27). Perforation occurred in 1 patient who was managed by conservative medical treatments. None of the patients developed local recurrence or distant metastasis in the follow-up period. CONCLUSION: Endoscopic submucosal dissection is applicable to superficial esophageal squamous cell neoplasms with promising results.

Endoscopic submucosal dissection for early esophageal neoplasms using the stag beetle knife

AIM To determine short-and long-term outcomes of endoscopic submucosal dissection(ESD) using the stag beetle(SB) knife, a scissor-shaped device.METHODS Seventy consecutive patients with 96 early esophageal neoplasms, who underwent ESD using a SB knife at Kure Medical Center and Chugoku Cancer Center, Japan, between April 2010 and August 2016, were retrospectively evaluated. Clinicopathological characteristics of lesions and procedural adverse events were assessed. Therapeutic success was evaluated on the basis of en bloc, histologically complete, and curative or non-curative resection rates. Overall and tumor-specific survival, local or distant recurrence, and 3-and 5-year cumulative overall metachronous cancer rates were also assessed.RESULTS Eligible patients had dysplasia/intraepithelial neoplasia(22%) or early cancers(squamous cell carcinoma, 78%). The median procedural time was 60 min and on average, the lesions measured 24 mm in diameter, yielding 33-mm tissue defects. The en bloc resection rate was 100%, with 95% and 81% of dissections deemed histologically complete and curative, respectively. All procedures were completed without accidental incisions/perforations or delayed bleeding. During follow-up(mean, 35 ± 23 mo), no local recurrences or metastases were observed. The 3-and 5-year survival rates were 83% and 70%, respectively, with corresponding rates of 85% and 75% for curative resections and 74% and 49% for noncurative resections. The 3-and 5-year cumulative rates of metachronous cancer in the patients with curative resections were 14% and 26%, respectively.CONCLUSION ESD procedures using the SB knife are feasible, safe, and effective for treating early esophageal neoplasms, yielding favorable short-and long-term outcomes.

Risk factors for Mallory-Weiss Tear during endoscopic submucosal dissection of superficial esophageal neoplasms

BACKGROUND Adverse events during endoscopic submucosal dissection(ESD)of superficial esophageal neoplasms,such as perforation and bleeding,have been welldocumented.However,the Mallory-Weiss Tear(MWT)during esophageal ESD remains under investigation.AIM To investigate the incidence and risk factors of the MWT during esophageal ESD.METHODS From June 2014 to July 2017,patients with superficial esophageal neoplasms who received ESD in our institution were retrospectively analyzed.The clinicopathological characteristics of the patients were collected.Patients were divided into an MWT group and non-MWT group based on whether MWT occurred during ESD.The incidence of MWTs was determined,and the risk factors for MWT were then further explored.RESULTS A total of 337 patients with 373 lesions treated by ESD were analyzed.Twenty patients developed MWTs during ESD(5.4%).Multivariate analysis identified that female sex(OR=5.36,95%CI:1.47-19.50,P=0.011)and procedure time longer than 88.5 min(OR=3.953,95%CI:1.497-10.417,P=0.005)were independent risk factors for an MWT during ESD.The cutoff value of the procedure time for an MWT was 88.5 min(sensitivity,65.0%;specificity,70.8%).Seven of the MWT patients received endoscopic hemostasis.All patients recovered satisfactorily without surgery for the laceration.CONCLUSION The incidence of MWTs during esophageal ESD was much higher than expected.Although most cases have a benign course,fatal conditions may occur.We recommend inspection of the stomach during and after the ESD procedure for timely management in cases of bleeding MWTs or even perforation outside of the procedure region.

Combination of concurrent endoscopic submucosal dissection and modified peroral endoscopic myotomy for an achalasia patient with synchronous early esophageal neoplasms

Achalasia is generally accepted as a condition associated with an increased risk for developing esophageal squamous cell carcinoma. In our paper, we introduced an achalasia patient combined with synchronous early esophageal neoplasms. We performed a combination of concurrent endoscopic submucosal dissection(ESD) and peroral endoscopic myotomy(POEM). No complications other than postoperative pain that needed morphine treatment for two days had occurred. Dysphagia was significantly improved. Neither reflux nor cough occurred. The short-term efficacy and safety of our case is favorable and suggests that concurrent ESD and POEM could be a treatment option to such patients.

Epidemiology of esophageal cancer

Esophageal cancer(EsC)is one of the least studied and deadliest cancers worldwide because of its extremely aggressive nature and poor survival rate.It ranks sixth among all cancers in mortality.In retrospective studies of EsC,smoking,hot tea drinking,red meat consumption,poor oral health,low intake of fresh fruit and vegetables,and low socioeconomic status have been associated with a higher risk of esophageal squamous cell carcinoma.Barrett’s esophagus is clearly recognized as a risk factor for EsC,and dysplasia remains the only factor useful for identifying patients at increased risk,for the development of esophageal adenocarcinoma in clinical practice.Here,we investigated the epidemiologic patterns and causes of EsC.Using population based cancer data from the Surveillance,Epidemiology and End Results Program of the United States;we generated the most up-to-date stage distribution and 5-year relative survival by stage at diagnosis for 1998-2009.Special note should be given to the fact that esophageal cancer,mainly adenocarcinoma,is one of the very few cancers that is contributing to increasing death rates(20%)among males in the United States.To further explore the mechanism of development of EsC will hopefully decrease the incidence of EsC and improve outcomes.

Long-term outcomes and prognostic factors for patients with esophageal cancer following radiotherapy

AIM:To evaluate long-term outcomes and prognostic factors for esophageal squamous cell carcinoma(SCC) treated with three dimensional conformal radiotherapy(3D-CRT).METHODS:Between January 2005 and December 2006,153 patients(120 males,33 females) with pathologically confirmed esophageal SCC and treated with 3D-CRT in Cancer Hospital of Shantou University were included in this retrospective analysis.Median age was 60 years(range:37-84 years).The proportion of tumor location was as follows:upper thorax(including the cervical region),73(48%);middle thorax,73(48%);lower thorax,7(5%),respectively.The median radiation dose was 64 Gy(range:50-74 Gy).Fifty four cases(35%) received cisplatin-based concurrent chemotherapy.Univariate and multivariate analysis were performed to determine the association between the correlative factors and prognosis.RESULTS:The five-year overall survival rate was 26.3%,with a median follow-up of 49 mo(range:3-66 mo) for patients who were still alive.On univariate analysis,lesion location,lesion length by barium esophagogram,computed tomography imaging characteristics including Y diameter(anterior-posterior,AP,extent of tumor),gross tumor volume of primary lesion(GTV-E),volume of positive lymph nodes(GTV-LN),and the total target volume(GTV-T = GTV-E + GTVLN) were prognostic for overall survival.By multivariate analysis,only the Y diameter [hazard ratio(HR) 2.219,95%CI 1.141-4.316,P = 0.019] and the GTV-T(HR 1.372,95%CI 1.044-1.803,P = 0.023) were independent prognostic factors for survival.CONCLUSION:The overall survival of esophageal carcinoma patients undergoing 3D-CRT was promising.The best predictors for survival were GTV-T and Y diameter.

A preliminary study on ras protein expression in human esophageal cancer and precancerous lesions

INTRODUCTIONThe esophageal carcinoma is a common malignanttumor in Linzhou City (Linxian) of Henan Provincein northern China.Although the etiology andnatural history of csophageal carcinoma are notclear,a substantial amount of evidence has beenprovided to suggest that the development of humanesophageal squamous cell carcinomas (SCC) is amultistage progressive process.An

Annual cost of illness of stomach and esophageal cancer patientsin urban and rural areas in China： A multi-center study

Objective: Stomach and esophageal cancer are imposing huge threats to the health of Chinese people whereas there were few studies on the financial burden of the two cancers.Methods: Costs per hospitalization of all patients with stomach or esophageal cancer discharged between September 2015 and August 2016 in seven cities/counties in China were collected, together with their demographic information and clinical details. Former patients in the same hospitals were sampled to collect information on annual direct non-medical cost, indirect costs and annual number of hospitalization. Annual direct medical cost was obtained by multiplying cost per hospitalization by annual number of hospitalization. Annual cost of illness(ACI)was obtained by adding the average value of annual direct medical cost, direct non-medical cost and indirect cost,stratified by sex, age, clinical stage, therapy and pathologic type in urban and rural areas. Costs per hospitalization were itemized into eight parts to calculate the proportion of each part. All costs were converted to 2016 US dollars(1 USD=6.6423 RMB).Results: Totally 19,986 cases were included, predominately male. Mean ages of stomach cancer and urban patients were lower than that of esophageal cancer and rural patients. ACI of stomach and esophageal cancer patients were $10,449 and $13,029 in urban areas, and $2,927 and $3,504 in rural areas, respectively. Greater ACI was associated with male, non-elderly patients as well as those who were in stage I and underwent surgeries.Western medicine fee took the largest proportion of cost per hospitalization.Conclusions: The ACI of stomach and esophageal cancer was tremendous and varied substantially among the population in China. Preferential policies of medical insurance should be designed to tackle with this burden and further reduce the health care inequalities.

Changes of p53 and Waf1p21 and cell proliferation in esophageal carcinogenesis

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Radiobiological characteristics of cancer stem cells from esophageal cancer cell lines

AIM:To study the cancer stem cell population in esophageal cancer cell lines KYSE-150 and TE-1 and identify whether the resulting stem-like spheroid cells display cancer stem cells and radiation resistance characteristics.METHODS:A serum-free medium(SFM)suspension was used to culture esophageal cancer stem cell lines and enrich the esophageal stem-like spheres.A reverse transcription polymerase chain reaction assay was used to detect stem cell gene expression in the spheroid cells.Radiosensitivity of stem-like spheres and parental cells were evaluated by clonogenic assays.Furthermore,different cells after different doses of irradiation were tested to evaluate the change in sphere formation,cell cycle and CD44+CD271+expression of tumor stem-like spheroid cells using flow cytometry beforeand after irradiation.RESULTS:The cells were observed to generate an increased number of spheres in SFM with increasing cell passage.Radiation increased the rate of generation of stem-like spheres in both types of cells.The average survival fraction(SF2)of the cultured KYSE-150compared with TE-1 stem-like spheres after 2 Gy of radiation was 0.81±0.03 vs 0.87±0.01(P<0.05),while the average SF2 of KYSE-150 compared with TE-1 parental cells was 0.69±0.04 vs 0.80±0.03,P<0.05.In the esophageal parental cells,irradiation dose-dependently induced G2 arrest.Stem-like esophageal spheres were resistant to irradiation-induced G2arrest without significant changes in the percentage population of irradiated stem-like cells.Under irradiation at 0,4,and 8 Gy,the CD44+CD271+cell percentage for KYSE150 parental cells was 1.08%±0.03%vs1.29%±0.07%vs 1.11%±0.09%,respectively;the CD44+CD271+cell percentage for TE1 parental cells was 1.16%±0.11%vs 0.97%±0.08%vs 1.45%±0.35%,respectively.The differences were not statistically significant.Under irradiation at 0,4,and 8 Gy,the CD44+CD271+cell percentage for KYSE-150 stemlike spheres was 35.83%±1.23%vs 44.9%±1.67%vs 57.77%±1.88%,respectively;the CD44+CD271+cell percentage for TE1 stem-like spheres was 16.07%±0.91%vs 22.67%±1.12%,16.07%±0.91%vs33.27%±1.07%,respectively.The 4 and 8 Gy irradiated KYSE-150 and TE-1 stem-like spheres were compared with the 0 Gy irradiated group,and the differences were statistically significant(P<0.05).CONCLUSION:The KYSE-150 and TE-1 stem-like spheres are more radioresistant than their parental cells which may suggest that cancer stem cells are related to radioresistance.

Experimental and clinic-opathologic study on the relationship between transcription factor Egr-1 and esophageal carcinoma

AIM To observe the growth suppression effect of exogenous introduction of early growth response gene-1 (Egr-1 gene) on esophageal carcinoma tissue as well as on esophageal carcinoma cell line Eca109 and to explore the potential application of Egr-1 gene in gene therapy of tumor.METHODS Eukaryotic expression vector of PCMV-Egr-1 plasmid was introduced into Eca109 cell line which expressed no Egr-1 protein originally with lipofectamine transfection method. The introduction and expression of PCMV-Egr-1 plasmid into Eca109 cell line was confirmed by G418 selection culture, PCR amplification of neogene contained in the vector, Western blot analysis and immunocytochemical analysis. The cell growth curve,soft agar colony formation rate and tumorigenicity in SClD mice were examined to demonstrate the growth suppression effect of exogenous Egr-1 gene on Eca109 cell line. The Egr-1 mRNA and Egr-1 protein were also detected in 50 surgical specimens of esophageal carcinoma by in situ hybridization and immunohistochemistry.RESULTS Exogenous Egr-1 gene was introduced successfully into Eca109 cell line and expressed Egr-1 protein stably. The transfected Eca109 cell line grew more slowly than control Eca109 as shown by cell growth curves, the soft agar colony formation rate (4.0% vs 6.9%, P＜0.01) and the average growth rate of tumor in SCID mice (35.5 ± 7.6 vs 65.8 ± 7.6, P＜0.05). The expression level of Egr-1 mRNA and protein significantly increased in dysplastic epithelia adjacent to cancer rather than in cancer tissues (65.8% vs 20.0% by ISH and 57.9% vs 14.0% by IHC, P＜0.01).CONCLUSION Exogenous Egr-1 gene shows the strong effect of growth inhibition in Eca109 cell line. Egr-1 in the cancer tissue shows down-regulated expression that supports the inhibited function of Egr-1 in cancer growth and suggests Egr-1 may have an important role in gene therapy of esophageal carcinoma.

Medical expenditure for esophageal cancer in China:a 10-year multicenter retrospective survey(2002-2011)

Background: Esophageal cancer is associated with substantial disease burden in China, and data on the economic burden are fundamental for setting priorities in cancer interventions. The medical expenditure for the diagnosis and treatment of esophageal cancer in China has not been fully quantified. This study aimed to examine the medical expenditure of Chinese patients with esophageal cancer and the associated trends.Methods: From 2012 to 2014, a hospital-based multicenter retrospective survey was conducted in 37 hospitals in 13 provinces/municipalities across China as a part of the Cancer Screening Program of Urban China. For each esophageal cancer patient diagnosed between 2002 and 2011, clinical information and expense data were extracted by using structured questionnaires. All expense data were reported in Chinese Yuan(CNY; 1 CNY = 0.155 USD) based on the2011 value and inflated using the year-specific health care consumer price index for China.Results: A total of 14,967 esophageal cancer patients were included in the analysis. It was estimated that the overall average expenditure per patient was 38,666 CNY, and an average annual increase of 6.27% was observed from 2002(25,111 CNY) to 2011(46,124 CNY). The average expenditures were 34,460 CNY for stage Ⅰ,39,302 CNY for stage Ⅱ,40,353 CNY for stage Ⅲ, and 37,432 CNY for stage IV diseases(P < 0.01). The expenditure also differed by the therapy type, which was 38,492 CNY for surgery, 27,933 CNY for radiotherapy, and 27,805 CNY for chemotherapy(P < 0.05).Drugs contributed to 45.02% of the overall expenditure.Conclusions: These conservative estimates suggested that medical expenditures for esophageal cancer in China substantially increased in the last 10 years, treatment for early-stage esophageal cancer costs less than that for advanced cases, and spending on drugs continued to account for a considerable proportion of the overall expenditure.

Programmed death ligand-1 expression and its prognostic role in esophageal squamous cell carcinoma

AIM To investigate the expression and prognostic role of programmed death ligand-1(PD-L1) in locally advanced esophageal squamous cell carcinoma(ESCC).METHODS A total of 200 patients with ESCC who underwent radical esophagectomy with standard lymphadenectomy as the initial definitive treatment in Seoul National University Hospital from December 2000 to April 2013 were eligible for this analysis. Tissue microarrays were constructed by collecting tissue cores from surgical specimens, and immunostained with antibodies directed against PD-L1, p16, and c-Met. Medical records were reviewed retrospectively to assess clinical outcomes. Patients were divided into two groups by PD-L1 status, and significant differences in clinicopathologic characteristics between the two groups were assessed. RESULTS Tumor tissues from 67 ESCC patients(33.5%) were PDL1-positive. Positive p16 expression was observed in 21 specimens(10.5%). The H-score for c-Met expression was ≥ 50 in 42 specimens(21.0%). Although PDL1-positivity was not significantly correlated with any clinical characteristics including age, sex, smoking/alcoholic history, stage, or differentiation, H-scores for c-Met expression were significantly associated with PDL1-positivity(OR = 2.34, 95%CI: 1.16-4.72, P = 0.017). PD-L1 expression was not significantly associated with a change in overall survival(P = 0.656). In contrast, the locoregional relapse rate tended to increase(P = 0.134), and the distant metastasis rate was significantly increased(HR = 1.72, 95%CI: 1.01-2.79, P = 0.028) in patients with PD-L1-positive ESCC compared to those with PD-L1-negative ESCC.CONCLUSION PD-L1 expression is positively correlated with c-Met expression in ESCC. PD-L1 may play a critical role in distant failure and progression of ESCC.

Intensify standardized therapy for esophageal and stomach cancer in tumor hospitals

INTRODUCTIONCancer treatment situation in tumor hospitals inChina has its own unique characteristics which arenot found in other parts of the world. Because ofthe huge population and high incidence rates ofesophageal and stomach cancer[1-5], the number ofcancer patients waiting for admission isinconceivably large.

Oesophageal surgery

INTRODUCTIONThe origins of oesophageal surgery ,like most surgical treatments ,are based in the treatment of traumatic injury .The Smith Surgical Papyrus describes the examination, diagnosis and treatment of 'a gaping wound of throat, penetrating the gullet' [1].

Human papillomavirus 16 E6 is associated with the nuclear matrix of esophageal carcinoma cells

AIM: To explore the etiologic role of HPV infection in esophageal carcinoma, and the association of HPV-16 E6with the nuclear metrix of carcinoma cells.METHODS: Two esophageal carcinoma cell lines, EC/CUHK1 and EC/CUHK2, were tested for HPV-16 E6subgenetic fragment by polymerase chain reaction amplification of virus DNA associated nuclear matrix. RT-PCR and immunocytochemistry were also used to visualizethe expression of E6 subgene in the cells.RESULTS: The HPV-16 E6 subgenetic fragment wes found to be present in nuclear metrix-associeted DNA, E6oncoprotein localized in the nucleus where it is tightly associated with nuclear matrix after sequential extraction in EC/CUHK2 cells. It was not detected, however, in EC/CUHK1 cells.CONCLUSION: The interaction between HPV-16 E6 and nuclear matrix may contribute to the virus induced carcinogenesis in esophageal carcinoma.